INTRODUCTION:

The oral route is considered as the most promising and popular route of drug delivery because the low cost of the therapy and ease of administration lead to high levels of patient compliance. More than 50% of the drug delivery systems available in the market are oral drug delivery systems including conventional or modified drug delivery system^[1]. Conventional drug delivery system achieves as well as maintains the drug concentration within the therapeutically effective range needed for treatment, only when taken several times a day, if the drug has short biological half-life. There may be chance for dosing errors leads to lower or higher levels of the drug in blood needed to treatment. Development of prolonged release systems like controlled/ sustained release preparations using alternative routes have been formulated but the oral route still remains preferable^[2].

Over the last three decades, various attempts have been done to enhance the residence time there by retain the dosage form in the stomach as a way of increasing retention time^[3]. Gastro retentive system can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of the drug in the GIT thereby improves the rate of absorption followed by enhancement of bioavailability, reducing drug waste and enhance the solubility of drugs that are less soluble in high pH environment.

The present research is focused to develop Nicorandil gastro retentive tablets by melt granulation technique using combination of hydrophilic plus retarding plus swellable natural gum like almond gum (hereinafter called as AG) and hydrophobic plus retarding polymer like cetosteryl alcohol (hereinafter called as CSA) selected to develop floating tablets because the drug is highly water soluble^[4]. Nicorandil is common choice of drug in cardiovascular diseases like hypertension and angina pectoris, which require constant monitoring. Nicorandil has a short elimination half-life of 1.33 hr ^[5] and the immediate-release (IR) tablets of the drug has to be given frequently at three times a day. To reduce the frequency of administration and to improve patient compliance, a once-daily controlled release formulation of Nicorandil is desirable. Here, Nicorandil gastro retentive tablets are prepared by melt granulation technique. The prepared tablets are evaluated for in vitro drug release study followed by drug release mechanism using Korsmeyer-Peppas model. Further, the resulting values are compared with theoretical percentage of drug released in order to determine the percentage deviation from an ideal release profile.

MATERIALS AND METHODS:

Materials:

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.

Methods:

Calculation of Theoretical Release Profile of Nicorandil from Controlled Release Formulations^[6,7]:

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

Where, X_o = Conventional daily dose (20 mg), K_e = First order elimination rate constant (0.521 hr^-1)^[5], (Toe) = Dosing interval (24 hr), T_p = Time to reach peak plasma concentration (0.448 hr) ^[8]. By substituting the kinetic values of Nicorandil in the above equations the results as follows, DI = 1.599 mg, 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 (approximately) 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 CSA as retarding polymer. The composition of various formulations of effervescent tablets with their codes is listed in Table 1. All the ingredients except wax were passed through sieve 60 (#). The wax/oil were melted in large china dish on hot plate and drug is added to it. Then to this mixture, other sieved ingredients except talc are added and stirred well to mix. The resultant mixture is allowed to solidify at room temperature and then passed through sieve 44 (#) to form granules. The granules are 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

Ingredients	Quantity per tablet (mg)
Ingredients	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

(NCRD = Nicorandil, AG = Almond gum, CSA = Cetosteryl alcohol, NaHCO₃ = Sodium bicarbonate, CA = Citric acid, SA = Stearic acid).

In vitro Release Studies of Prepared Tablets^[9]:

The release rate of Nicorandil from prepared floating matrix tablets was determined using USP dissolution testing apparatus II (Paddle type). The dissolution test was performed using 900 ml of 0.1N HCL, at 37 ± 0.5°C and 50 rpm. A sample (5ml) of the specimen was withdrawn from the dissolution apparatus periodically, and the samples were replaced with fresh dissolution medium. 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:

Drug release from Nicorandil floating tablets evaluated at 0.1N HCl (pH 1.2) influenced by polymer concentration. Release rate usually depends upon the presence of drug closer to the surface which decreases with increasing hydrophobic polymer concentration and decreases the amount of uncoated drug^[10]. All the formulation showed maximum amount of drug release for prolonged period of time about 24 hr. From Table 2 it can be observed that, the drug release for the formulations MCS1, MCS2, MCS3, MCS4, MCS5, and MCS6 is found to be 99.686 %, 99.174 %, 98.786 %, 97.264 %, 94.042 % and 91.528 %, respectively at the end of 24 hours (Table 2). 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. The 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.

Table 2: In vitro drug release profiles of Nicorandil from floating tablets.

Time (hr)	MCS 1	MCS2	MCS3	MCS4	MCS5	MCS6	MCS7	MCS8	MCS9	MCS 10	MCS 11	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

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. Drug release kinetics for formulation MCS4 was showed the highest linearity for R² and explained by zero order kinetics (0.9994 and 0.9993 respectively) than first order kinetics (0.7563 and 0.7292, respectively) calculated by Microsoft Office Excel-2007. It was notable that R²and values were closed to one for zero order, indicating the drug release followed nearly independent of initial drug concentration in the matrix. The fitting of drug release data by appropriate mathematical models that supports the interpretation and comprehension of Higuchi’s mechanism (drug release by diffusion) as dominant mechanism in which the plots showed the highest linearity for R² and (0.9224 and 0.9146, respectively) than Hixson-Crowell (drug release by dissolution) equation (0.9162 and 0.9078, respectively). As these values were highest for Higuchi’s plot indicating the data fits the Higuchi’s model well and the drug release was found to be predominantly controlled by diffusion process. Furthermore, these models might fail whenever there was a need for taking drug release into account specific physicochemical processes. In order to evaluate the modeling of drug release from swellable polymeric systems, the drug release data was fitted into Korsmeyer-Peppas equation and the model showed higher R² and (0.9974 and 0.9971, respectively) with the diffusional exponent value (n) of 0.87. Analogously, Case-II transport was defined by an initial linear time dependence of the functional release with n=0.89±0.02 (0.87 to 0.91). Therefore, the value of diffusional exponent (n) form the selected formulation (MCS4) characterize an Case-II transport.

Mathematical Method for Quantitative Expression of Deviation from Korsmeyer-Peppas Equation:

Theoretical Consideration:

The first step was to calculate the theoretical prospective for cumulative percentage of drug released for 24 hr at predetermined time intervals using Korsmeyer-Peppas equation (hereinafter called as Peppas equation). The straight line of theoretical cumulative percentage (or fraction) of drug released versus (time in hr)^0.87 is considered as a reference line (Figure 1).

From the graph (Figure 1), the dissolution of drug from dosage forms that do not disaggregate and release the drug followed Korsmeyer-Peppas equation at time 't' can be predicted by the following equation,

Figure 1: Area under the curve for an ideal release profile form Korsmeyer-Peppas equation.

The value of n (0.87) is incorporated in the above equation to get a new equation of,

And at time (t-a), the above equation can be predicted by,

Where, M_t= absolute cumulative amount of drug released at time , M_∞= absolute cumulative amount of drug release after infinite time (which should be equal to the absolute amount of drug incorporated within the system at time t= 0), M_t/M∞ = fraction of drug released at time 't', k_KP= release rate constant at the elapsed time (time^-n) incorporating structural and geometric characteristics of the release device, which was dependent of the system, i.e. polymer, solvent, drug loading, excipients, etc., n= the time exponent or diffusional exponent characteristic of the release mechanism of the system and this value was used to characterize different release for cylindrical shaped matrices, and a = difference between two successive sampling time points.

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 Peppas release profile, the shaded area (time period from 't' to 't- a' ) of Figure 1, with zero percent deviation can be calculated by the following equations,

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

For example, an ideal 24 hr Peppas model 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^0.87' to '(t-a)^0.87' ) of Figure 1, with 'α' percent deviation from Peppas model can be predicted by the following equations,

Consider the example, for +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 9.

Equation 9 denotes that AADA was a linear (y=mx, where m was slope) function of 'α' with slope of ' ' and the intercept was zero.

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	3.149	3.306	3.464	3.621	3.779	3.936	4.094
2	7.370	7.738	8.107	8.475	8.844	9.212	9.581
3	10.780	11.319	11.858	12.398	12.937	13.476	14.015
4	13.837	14.529	15.221	15.913	16.605	17.296	17.988
5	16.670	17.503	18.337	19.170	20.004	20.837	21.671
6	19.341	20.308	21.275	22.242	23.209	24.176	25.143
9	72.917	76.563	80.209	83.854	87.500	91.146	94.792
12	93.592	98.271	102.951	107.631	112.310	116.990	121.669
15	112.750	118.388	124.025	129.663	135.300	140.938	146.575
18	130.818	137.358	143.899	150.440	156.981	163.522	170.063
24	312.630	328.261	343.893	359.524	375.156	390.787	406.419
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	3.149	2.992	2.834	2.677	2.519	2.362	2.204
2	7.370	7.001	6.633	6.264	5.896	5.527	5.159
3	10.780	10.241	9.702	9.163	8.624	8.085	7.546
4	13.837	13.145	12.453	11.762	11.070	10.378	9.686
5	16.670	15.836	15.003	14.169	13.336	12.502	11.669
6	19.341	18.374	17.407	16.440	15.473	14.506	13.539
9	72.917	69.271	65.625	61.979	58.333	54.688	51.042
12	93.592	88.912	84.233	79.553	74.873	70.194	65.514
15	112.750	107.113	101.475	95.838	90.200	84.563	78.925
18	130.818	124.277	117.736	111.195	104.654	98.113	91.572
24	312.630	296.998	281.367	265.735	250.104	234.472	218.841

Table 4: Theoretical prospective of average absolute difference of AUCs (AADA) at different percentage deviations from ideal Peppas model.

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	0.157	0.315	0.472	0.630	0.787	0.945
2	0.368	0.737	1.105	1.474	1.842	2.211
3	0.539	1.078	1.617	2.156	2.695	3.234
4	0.692	1.384	2.076	2.767	3.459	4.151
5	0.833	1.667	2.500	3.334	4.167	5.001
6	0.967	1.934	2.901	3.868	4.835	5.802
9	3.646	7.292	10.938	14.583	18.229	21.875
12	4.680	9.359	14.039	18.718	23.398	28.078
15	5.638	11.275	16.913	22.550	28.188	33.825
18	6.541	13.082	19.623	26.164	32.704	39.245
24	15.631	31.263	46.894	62.526	78.157	93.789

DISCUSSION:

The drug release data of selected formulation MCS4 was fitted into Korsmeyer-Peppas equation to evaluate the modeling of drug release from swellable polymeric systems. The experimental data obtained from the formulation MCS4 showed a good fit for Korsmeyer-Peppas models with the values of R² and more than 0.99 (0.9974 and 0.9971, respectively) and the diffusional exponent value (n) found to be 0.87. These highest values of R² and confirms that good fit for drug release from Korsmeyer-Peppas equation. The n value was below 0.89 indicates the drug to follow non-Fickian or anomalous release mechanism from floating tablet. The results of this fitting were presented in Table 6.

An ideal 24 hr Peppas model profile are back-calculated by plotting a graph between (time)^0.87 versus cumulative percentage of drug release and treated as reference line (Figure 1). The comparative dissolution profiles of the ideal 24 hr Peppas model and test product was presented in Figure 2. For a 24 hr controlled release formulation, ideally the percentage drug released at 24 hours should be 100, where as for test formulation the percentage drug released at 24 hours was found to be 97.264. 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 (Table 5) 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 were slightly lower than ideal 24 hr Peppas model drug release profile. The values of slope and intercept obtained from the nonlinear equation of the Peppas model for ideal release found to be 6.339 and -3.559, respectively, whereas for test formulation found to be 6.064 and -2.049, respectively. The percentage deviation (α ) of test formulation from ideal Peppas model was low at initial time (7.839 % at first hour), reached to a maximum of 15.458 % at 6^th hour and finally decreased gradually to a minimum of 4.244 % at 24^th hr. Low percentage deviation (α ) for test formulation (MCS4) was observer indicates that the drug release from test formulation ideally follows Peppas model. The lowest values of SSR (28.862) and F-value (2.886) also indicates that the test product follows Peppas model for release kinetics.

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	3.149	5.812	2.906	0.243	7.839
2	8.334	7.370	9.718	6.427	0.943	12.997
3	12.501	10.780	13.628	9.024	1.756	16.550
4	16.668	13.837	17.721	11.593	2.244	16.473
5	20.835	16.670	21.612	14.075	2.594	15.809
6	25.002	19.341	25.426	16.398	2.943	15.458
9	37.503	72.917	36.817	62.571	10.346	14.413
12	50.004	93.592	49.621	83.134	10.458	11.350
15	62.505	112.750	60.147	102.159	10.592	9.543
18	75.006	130.818	73.158	120.857	9.960	7.734
24	100.008	312.630	97.264	299.568	13.061	4.244
Slope	6.339		6.064
Intercept	-3.559		-2.049

Table 6: Model fitting of test formulation and ideal release.

Formulation	R²		SSR	F	Slope	Intercept
Test	0.9974	0.9971	28.862	2.552	6.064	-2.049
Ideal	0996	0.9965	34.731	3.473	6.339	-3.559

Figure 2: Comparative dissolution profiles of the ideal Peppas model and test product.

CONCLUSION:

The present study used to develop Nicorandil floating tablets using combination of hydrophilic and hydrophobic polymers at different concentration. In vitro drug release is calculated for all the formulations and the best formulation (MCS4) is selected which contain the identical drug as that of theoretical profile. The drug release data was fitted into Korsmeyer-Peppas equation and showed higher R² and (0.9974 and 0.9971, respectively) with the diffusional exponent value (n) of 0.87. A quantitative mathematical model is developed for quantitative expression of the deviation from Peppas model is calculated for test formulation and confirmed that the test formulation showed very slight deviation from an ideal release. Finally it is concluded that, the test formulation is confirmed to follow Korsmeyer-Peppas model mechanism.

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Received on 31.05.2016 Accepted on 30.06.2015

Asian J. Pharm. Tech. 2016; 6 (3): 189-196.

DOI: 10.5958/2231-5713.2016.00027.1