Development and Optimization of Floating Tablets Containing Rebamipide

 

Jigar Vyas*, Jai Mehta, Neha Pal, Kapil Daxini

 

ABSTRACT:

The objective of the present study is to develop floating sustained release tablet of Rebamipide for the treatment of drug induced gastric ulcer using the force of buoyancy to remain in stomach and/or Upper part of GIT for prolonged period of time for getting local action. The floating sustained release tablets of Rebamipide were prepared by direct compression method using various polymers like HPMC K100M, PEO WSR- 301, sodium bicarbonate, citric acid, PVP K30, dibasic calcium phosphate and talc. Sodium bicarbonate was used as a floating effervescent agent. After preliminary screening, the floating sustained release tablets were prepared using 3² full factorial design taking HPMC K100M and PEO WSR- 301 as two independent variables, and the formulation batches were evaluated for all pre-compression and post-compression parameters. The study is focused on swelling index, floating lag time, total floating Time and % CDR. From batches suggested by the design, formulation batch F8 was selected and studied extensively for release kinetic, mechanism and stability studies.

 

 

 

INTRODUCTION:

Oral route is considered to be the safest and convenient route of drug delivery. 90% of the drug available is designed to be given through the oral route due to patient acceptance. In conventional oral drug delivery, the drug resides for a shorter period time in absorption window, so bioavailability is less. Oral controlled drug delivery systems represent the most popular form of controlled drug delivery. This type of drug delivery systems releases the drug with constant or variable release rates to meet the drug regime^1-3.

 

The most preferable approach of oral controlled drug delivery is Gastro-Retentive Drug Delivery Systems (GRDDS), in which the dosage form retains in stomach for prolonged period increasing the Gastric Residence Time (GRT). GRDDS can be defined as a system which retains in the stomach for a sufficient period of time and releasing the active moiety in a controlled manner⁴. Over the last two decades, numbers of GRDDS have been designed to prolong GRT. The main aim of preparing GRDDS is to minimize the problem associated with existing oral sustained release dosage form and to develop patient benefited drug delivery^5-7.

 

So the present work is designed with antiulcer drug used in the treatment of drug induced ulcer treatment, Rebamipide with different type of controlled release and polymers with different concentration to optimize a formulation which will help to overcome the above problem.

 

Rebamipide is an amino acid analog of 2(1H)- quinolinone. It is being introduced and used since 1980 for the treatment of peptic ulcer. Its therapeutic use in recurrent aphthous ulcer was not known. It acts by the decrease in oxygen radicals, increase in blood flow and production of protective prostaglandins in ulcer mucosa, which accelerates the process of healing⁸.

 

MATERIAL AND METHODS:

The Rebamipide is obtained from Macleods Pharmaceuticals Pvt. Ltd. Mumbai, India with the certification of purity. Apart from the drug remaining polymers like HPMC K100M, PEO WSR 301, PVP K-30 and other reaming excipients like, Sodium Bicarbonate, Citric Acid, Dibasic Calcium Phosphate and Talc were obtained from Chemdyes Corporation, Vadodara. All the excipients and reagents used were of laboratory grade. Distilled water was used in all experiments.

 

Pre-compression evaluations like angle of repose, bulk density, tapped density, carr’s index and hausner’s ratio were evaluated to determine the flow property of the prepared powder mixture. The standard curves for Rebamipide was established in 0.1 N HCl and from the slope of the straight line the solubility of Rebamipide was calculated. The studies were repeated in triplicate (n=3), and mean was calculated. Drug-excipient compatibility was checked by FTIR spectroscopy.

 

The prepared Rebamipide Floating tablets were studied for weight variation, hardness, thickness, friability and drug content.

 

In-vitro Buoyancy studies:

The in vitro buoyancy was determined by floating lag time and total floating time. The tablets were placed in a 100ml beaker containing 0.1N HCL. The time required for the tablet to rise to the surface and float was determined as floating lag time (FLT) and duration of time the tablet constantly floats on the dissolution medium was noted as Total Floating Time respectively (TFT).

 

Swelling index study:

For each formulation batch, one tablet was weighed and placed in a beaker containing 200 ml of buffer media. After each interval the tablet was removed from beaker and weighed again up to 12 h. The swelling index was calculated using following formula.

 

Swelling index (S.I) = {(W_t-W_o) /W_O} ×100

Where, S.I. = Swelling index, W_t = Weight of tablet at time t, W_O = Weight of tablet before placing in the Beaker.

 

In-vitro release studies:^9-10

The drug release rate from Floating tablets was studied using the USP type II dissolution test apparatus. The dissolution medium was 900 ml of 0.1N HCl at 50 rpm at a temperature of 37 ± 0.5 °C. Samples of 5 mL were collected at different time intervals up to 12 hrs and analyzed after appropriate dilution by using UV Spectrophotometer at 230nm.

 

Kinetic analysis of dissolution data:^11-17

Various kinetic models were used to analyze the in vitro release data

1.       Zero – order kinetic model – Cumulative % drug released versus time.

2.       First – order kinetic model – Log cumulative percent drug remaining versus time.

3.       Higuchi’s model – Cumulative percent drug released versus square root of time.

4.       Korsmeyer equation / Peppa’s model – Log cumulative % drug released versus log time.

 

A 32full factorial design was used in the present study to obtain optimized formulation. In this design, 2 factors were evaluated, each at 3 levels and experimental trials were performed at all 9 possible combinations. The amount of Polymer 1- HPMC K100M (X1) and Polymer 2- PEO WSR-301 (X2) were selected as independent variables. Buoyancy Lag Time (Y1) and % In-vitro drug release study at 3h (Y2) and % In vitro drug release study at 9hr (Y3) were selected as dependent variables (responses). The responses were recorded and analysis of the data was carried out using ANOVA in DESIGN EXPERT 11 demo version software (STAT-EASE). The polynomial equation generated by this experimental design is as follows:

 

Y= B₀+ B₁X1+ B₂X2+ B₁₂X1X2+ B₁₁X12+ B₂₂X2+ E

Where, B0 = Intercept, B1 and B2 = Co-efficient of X1 and X2 variable, B12 = Co-efficient of interaction, B11 and B22 = Co-efficient of quadratic terms X1 and X2 Variables, E = Error

 

Table 1. Coded and actual values of independent variables

Independent Variables
X1			X2
Coded Values
Concentration of Polymer (HPMC K100M)			Concentration of Polymer (PEO WSR-301)
-1	0	+1	-1	0		+1
Actual Values
Concentration of Polymer (HPMC K100M)			Concentration of Polymer (PEO WSR-301)
50	75	100	50	75		100
Dependent Variables
Buoyancy Lag Time			In-Vitro Drug Release Study
Y1			Y2		Y3
			3 Hours		9 Hours

 

Table 2. Formulation table for nine factorial batches

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Rebamipide	100	100	100	100	100	100	100	100	100
HPMC K100M	50	50	50	75	75	75	100	100	100
PEO WSR-301	50	75	100	50	75	100	50	75	100
PVP K30	20	20	20	20	20	22.5	22.5	22.5	22.5
Sod. Bicarbonate	48	48	48	48	48	54	54	54	54
Citric Acid	32	32	32	32	32	36	36	36	36
DCP	96	71	46	71	46	58	83	58	33
Talc	4	4	4	4	4	4.5	4.5	4.5	4.5
Total Weight (mg)	400	400	400	400	400	450	450	450	450

 

RESULT AND DICSUSSION:

Drug - Excipient Compatibility Studies:

Compatibility studies of pure drug Rebamipide with polymers were carried out prior to the preparation of tablets and it was observed that all the characteristic peaks of Rebamipide drug were present in spectra thus indicating compatibility between drugs and the polymers used in the formulation.

 

Table 3. Post-compression parameters of factorial formulations

Batches	Buoyancy Lag Time (sec.)	Total Floating Time		Drug Content (%)
		Hrs.	Min.
F1	110	4	05	98.57
F2	95	7	30	98.56
F3	92	7	55	99.32
F4	84	8	00	98.94
F5	79	10	15	99.89
F6	74	10	55	99.74
F7	63	12	00	99.65
F8	56	12	00	99.82
F9	58	12	00	99.57

 

Post compression evaluation tests:

Formulations F1-F9 has hardness in range of 4.7 to 5.2 Kg/cm. Friability was found to be less than 1%. Drug content of all batches complied IP standard. Average weight variation of all formulations was found to be close to 400 and 450 mg which complied with the IP standards.

 

Results of Buoyancy lag time, floating lag time and Drug content were recorded in Table 3 and results of swelling study were presented in Figure 1 below.

 

 

Figure 1. Swelling Index (%) of Factorial batches

Data of In-vitro drug release in % CDR was recorded in Table 4 and compared with USP Standard Criteria for 12 Hrs.¹⁸

 

 

Design outcome:

The response was recorded and analysis of the data was carried out using ANOVA in DESIGN-EXPERT 11.0. demo version software (STATE-EASE). The individual parameters were evaluated using F test.

 

Table 4. In vitro drug release profile of factorial formulations

Time (Hr.)	F1	F2	F3	F4	F5	F6	F7	F8	F9	USP Standard Criteria
	% cumulative drug release
0	0	0	0	0	0	0	0	0	0
0.5	10.24	7.95	7.04	6.91	5.53	4.15	3.92	2.89	1.73
1	19.21	18.06	16.88	12.99	10.66	8.43	5.8	7.05	3.9
2	29.87	32.75	35.39	25.25	17.51	19.78	10.66	14.45	9.6
3	51.74	49.68	41.49	34.14	29.14	28.23	17.55	15.64	15.19	Between 10% and 25%
4	65.71	60.88	52.18	46.86	38.45	35.17	20.78	26.44	20.15
5	79.52	73.74	60.12	59.41	47.13	44.43	28.83	33.41	31.98
6	92.88	85.94	73.12	67.75	55.63	52.19	34.74	40.37	40.31
7	99.56	95.58	89.98	79.00	64.54	60.98	40.76	49.62	45.27
8	-	101.30	97.6	91.39	77.23	73.56	49.79	58.13	52.74
9	-	-	100.25	99.87	87.45	80.46	66.09	64.32	60.62	Between 45% and 85%
10	-	-	-	-	94.01	90.31	70.62	79.66	68.94
11	-	-	-	-	100.01	96.68	76.69	89.53	73.14
12	-	-	-	-	-	99.23	86.57	98.54	79.84

 

 

 

Table 5. 3² formulation table with Response

Std	Run	Factor 1 A: HPMC K100M (mg)	Factor 2 B: PEO WSR-301 (mg)	Response 1 Buoyancy Lag Time (Seconds)	Response 2 % In-Vitro Drug Release @ 3 hrs ((%)	Response 3 % In-Vitro Drug Release @ 9 hrs (%)
1	1	50	50	110	51.74	100
9	2	100	100	58	15.19	60.62
7	3	50	100	92	41.49	100
2	4	75	50	84	34.14	100
6	5	100	75	45	19.64	69.57
5	6	75	75	79	29.14	87.45
4	7	50	75	95	49.68	100
3	8	100	50	65	12.55	55.09
8	9	75	100	74	26.23	80.46

 

Table 6. ANOVA for Response 1 (Buoyancy Lag Time)

Source	Sum of Squares	df	Mean Square	F- value	p- value
Model	2977.67	2	1488.83	36.86	0.0004	Significant
A-HPMC K100M	2773.50	1	2773.50	68.67	0.0002
B-PEO WSR-301	204.17	1	204.17	5.06	0.0656
Residual	242.33	6	40.39
Cor Total	3220.00	8

 

 

Figure 2. Dissolution profile of Factorial Formulations F1-F9

 

 

Figure 3. Response surface plot (3D) showing the effect of HPMCK100M and PEO WSR-301 on Buoyancy Lag Time

 

The Model F-value of 60.29 implies the model is significant. There is only a 0.01% chance that an F-value this large could occur due to noise.

 

Figure 4. Response surface plot (3D) showing the effect of HPMC K100M and PEO WSR-301 on % In-Vitro Drug Release Study at 3 Hours

 

 

Figure 5.  Response surface plot (3D) showing the effect of HPMC K100M and PEO WSR-301 on % In-Vitro Drug Release Study at 9 Hours

 

Table 7. ANOVA for Response 2: % In-Vitro Drug Release Study at 3 Hours

Source	Sum of Squares	df	Mean Square	F- value	p-value
Model	1551.46	2	775.73	60.29	0.0001	Significant
A-HPMC K100M	1521.00	1	1521.00	118.22	< 0.0001
B-PEO WSR- 301	30.47	1	30.47	2.37	0.1748
Residual	77.20	6	12.87
Cor Total	1628.66	8

Table 8. ANOVA for Response 3 % In-Vitro Drug Release Study at 9 Hours

Source	Sum of Squares	df	Mean Square	F- value	p- value
Model	2226.16	2	1113.08	16.21	0.0038	Significant
A-HPMC K100M	2193.45	1	2193.45	31.94	0.0013
B-PEO WSR- 301	32.71	1	32.71	0.4764	0.5159
Residual	412.03	6	68.67
Cor Total	2638.19	8

 

Table 9. Selected batches from the solutions given by design

 

Table 10. Comparison between observed and predicted result of check point batch

 

Table 11. Release Pattern of optimized batch

 

 

Figure 6. Overlay plot of HPMC K100M and PEO WSR-301

 

Solutions Given by Design:-

After data fitting in design, it provided 100 solutions to fulfill the limits of both of response, but for the ease of study, total eight batches were taken for study from design solutions and compared in Table 9.

 

From the eight batches chosen from the solution batches, two batches were selected as check point batches, i.e. CP1 and CP2 and compared in Table 10 as shown below.

 

From the above two check point batches, considering low polymer concentration and % CDR, check point batch 2 (CP2) containing HPMC K100M (100mg) and PEO WSR-301 (75mg) was chosen and further studied for kinetic models like zero order, first order, Higuchi model and Korsemeyer-Peppas as reported in Table 11.

 

Final selected batch was kept in stability chamber for three months for evaluation of stability and reported in Table 12.

 

Table 12. Stability study of optimized formulation (F8)

Parameters	Initially	After 3 month
Hardness (Kg/cm2)	5.0	4.8
Friability (%)	0.54	0.57
Drug content (%)	99.82	99.45
Buoyancy lag time	56	55
% In-Vitro Drug Release @ 12 hrs.	98.54	98.27

 

CONCLUSION:

Controlled release floating gastro retentive tablet dosage form of Rebamipide was successfully developed using 3² full factorial design. The formulation was optimized for amount of swellable matrix polymers and the optimized formulation was tested for kinetic model for drug release pattern and stability (3 months).  From the factorial design results, it was concluded that the optimized formulation F8 containing HPMC K100M and PEO WSR-301 in 100mg and 75mg respectively, shows better swelling properties with desired drug release kinetics, specially follows zero order release and floating behavior.

 

ACKNOWLEDGEMENT:

The authors acknowledge Macleods Pharmaceuticals Pvt. Ltd, Mumbai for providing gratis sample of Rebamipide.

 

CONFLICT OF INTEREST:

The author disclose on conflict of interest.

 

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Received on 05.02.2020         Modified on 14.02.2020

Accepted on 20.02.2020       ©A&V Publications All right reserved