INTRODUCTION:

Oral drug delivery has been known for decades as the most widely utilized route of administration among all routes that have been explored for systemic delivery of drugs in case of different dosage forms¹.

Matrix tablet is one of the most convenient approaches for the preparation of the sustained/controlled release dosage forms. Among the different strategies to prolong the drug action, formulation of the matrix tablet has gained immense popularity now a day because it has the advantage of simple processing and a low cost of fabrication. Sustained release matrix tablet can be prepared in two ways, one is direct compression of the powder blend containing the drug, polymer and other additives, and another one involves granulation prior to compression.

Selection of the proper method depends on the properties of the drug, polymer and other ingredients. There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Any or all of these mechanism may occur in the given release system².

Now day matrix diffusion controlled drug delivery system employing release controlling polymers is extensively exploited as sustained/controlled release system, in which homogeneous dispersion of drug particles in either lipophilic or hydrophilic polymer matrix results in the drug reservoir. Amongst various types of matrices, hydrophilic polymer matrices are widely used in oral controlled drug delivery systems as they provide flexibility to obtain a desirable drug release profile, have ability to release and regulate drug in an aqueous medium by controlled-swelling and cross linking³.

Repaglinide is a non-sulfonylurea oral hypoglycaemic agent of the meglitinide class, is mainly used in the management of type II diabetes mellitus. Chemically it is (S)-2-ethoxy-4-{2-[3-methyl-1-[2-(1-piperidinyl) phenyl] butyl] amino]-2-oxoethyl} benzoic acid. It has short biological half-life of less than one hour and rapidly eliminated from body. Repaglinide is a BCS class II compound and the bioavailability of Repaglinide following oral administration is low (60%), BCS class II compounds are poorly soluble but highly permeable, and they exhibit bioavailability that is limited by dissolution rate. The dissolution rate of BCS class II drug substances may be accelerated by improvement of the wetting characteristics of the bulk powder. The poor solubility and slow dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability especially for class-II substances according to BCS. Repaglinide is well absorbed following oral administration and shows low oral bioavailability due to extensive first pass metabolism^4-6.

Hence, in the present work sustain release matrix tablets of Repaglinide will be prepared by using different polymers to overcome bioavailability related problems with increase in bioavailability, to overcome poor biological half life and drug instability in GIT.

MATERIALS AND METHODS:

Repaglinide was obtained as gift sample from Torrent Pharmaceuticals Limited, Ahmadabad, Gujarat, India. Eudragit RS-100 was procured from Yarrow Chemicals, Mumbai. Microcrystalline cellulose was procured form Ozone International, Mumbai. Hydroxy propyl methyl cellulose, Talc, Magnesium stearate, Polyvinyl pyrrolidone K-30 and Iso propyl alcohol were procured form Loba Chemicals Pvt. Ltd.

Method of preparation of matrix tablets:

Wet granulation method has been employed to prepare matrix tablet of Repaglinide using hydroxy propyl methyl cellulose and Micro crystalline cellulose, Eudragit Rs100 as polymers.

Preparation⁷:

Matrix tablets each containing 1mg of Repaglinide was prepared by wet granulation method (using isopropyl alcohol). All the ingredients except lubricants were mixed in the order of ascending weights and blended for 10 min in an inflated polyethylene pouch and then Repaglinide was added in this mixture then mixed for 2 min for uniform mixing. Granulation was done with binder solution of PVP which was previously dissolved in isopropyl alcohol, this damp mass passed through sieve #10. The granules were dried at 40ºC for 30 min. And then passed through sieve #22-44 and lubricants such as magnesium stearate and talc were mixed and then compressed it with 10‐station rotary compression machine into 100mg tablet, to a hardness of 5‐7kg/cm² using 6 mm punch. Composition of the prepared sustained release matrix tablet formulations of Repaglinide were given in Table No.1.

Evaluation of pre-compressed matrix tablet⁸:

The formed granules were evaluated for bulk and tapped density, angle of repose, Hausner’s ratio and Carr’s index. Results shown in Table No. 2.

Evaluation of matrix tablets:

All prepared matrix tablets were evaluated for weight variation, friability, hardness and drug content. Results shown in Table No. 3.

Weight variation⁹:

To study weight variation, 20 tablets of each formulation were weighed using an electronic balance and the test was performed according to the official method.

Hardness¹⁰:

Tablet hardness (tablet crushing strength), the force required for breaking a tablet in a diametric compression of five tablets was measured using a Pfizer hardness tester.

Friability¹¹:

Friability of the tablets was determined using Electrolab Friabilator. This device subjects the tablets to the combined effect of abrasion and shock in a plastic chamber revolving at 25rpm and dropping the tablets at a height of 6 inches in each revolution. Pre weighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were de dusted using a soft muslin cloth and re weighed. The friability (f) is given by the formula:

Friability (f) = 100 (W₀ -W) / W₀

Where W₀ is weight of the tablets before the test and W is the weight of the tablet after the test.

Drug content uniformity¹²:

Ten tablets were weighed and powdered. An amount of the powder equivalent to 10mg of Repaglinide was dissolved in 100ml of pH 7.4 buffers, filtered, diluted suitably and analyzed for drug content at 243nm using UV-Visible spectrophotometer.

In-vitro drug release study¹³:

In-vitro drug release study was carried out using a USP-23 rotating dissolution tester. The dissolution was measured at 37.0±0.5 ºC and 100rpm speed. Drug release from the tablets was studied in 900ml acidic medium (pH 1.2) for 2 hours, in alkaline medium (pH 7.4 phosphate buffer) for remaining hours end of the study. At predetermined time intervals, 5ml aliquots were withdrawn and replaced with the same volume of fresh solution. The amount of drug released was analyzed using UV-visible spectrophotometer at a λmax of 243nm. Results shown in Table No. 4.

The results of in vitro release profiles were fitted into four models of data treatment as follows:

1. Cumulative percent drug released versus time (zero order kinetic model).

2. Log cumulative percent drug remaining versus time (first- order kinetic model).

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

4. Log cumulative percent drug released versus log time (Korsmeyer-Peppas equation).

Scanning electron microscopy¹⁴:

The surface morphology of the matrix tablets was analyzed with a scanning electron microscope (JEOL-JSM-6360, Kyoto, Japan).

Fourier transforms infrared spectroscopy¹⁵:

Fourier transform infrared spectroscopy studies were carried out using Shimadzu Fourier transform infrared spectroscopy 8400S. The pellets were prepared with KBr using pure drug, polymers and crushed tablet formulations, and the spectra recorded in the range of 400 – 4000 cm-1.

Differential scanning calorimetric analysis¹⁵:

The test was performed on 2 - 4mg samples of drug, polymer and mixture of drug and polymer in the temperature range of 0 – 300ºC. The samples were sealed in a perforated aluminium pan, under nitrogen atmosphere and at a heating rate of 10 ºC/min.

RESULTS:

All the granules were evaluated for Bulk density, Tap density, Carr’s index (%), Hausner ratio, and Angle of repose. Carr’s index varied from 6.71 to 16.75% and Hausner ratio varied from 1.08 to 1.25 which indicates the good packing ability of the granules. The angle of repose was varied from 21.85 to 30.94ºC which indicates the flow property of granules (Table No. 2).

All the formulations were evaluated for weight variation, hardness, friability and % drug content. The weight of the formulation varied from 100 to 104mg. Hardness of the tablets varied from 4.6 to 5.6kg/cm². Friability of the tablets varied from 0.66 to 0.990% and drug content was found to be 93.26 to 98.55 (Table No. 3).

All formulation showed uniform hardness. The average percentage deviation of all parameters was found within the limit. The friability for all formulations was found below 1% indicating good abrasion resistance characteristics of tablets.

The percentage drug release of all the formulations in acidic medium (pH 1.2) for 2 h, and in alkaline medium (pH 7.4) for remaining 10 h. The release was found to be 84.91 to 99.92 %. Formulation F8 and F12 showed prolonged release over a period of 12 h and % drug release found to be 84.91 %.

Optimized formulations F8 and F12 were subjected to Differential scanning calorimetric analysis and Scanning electron microscopy analysis to study the surface morphology of the formulation. And the photographs were shown in the fig 1, 2, 6, 7. Fourier transform infrared spectroscopy was used to determine the drug polymers compatibility (fig 3, 4, 5) which shows the Infrared spectra of pure Drug, Hydroxypropyl-methylcellulose and Drug + Hydroxypropyl-methylcellulo

Table No. 1 Formulation for Preparation of Matrix Tablet Repaglinide

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Repaglinide	1	1	1	1	1	1	1	1	1	1	1	1
Eudragit RS100	-	-	-	-	30	40	50	60	15	20	25	30
Hydroxypropyl-methylcellulose	30	40	50	60	-	-	-	-	15	20	25	30
Microcrystalline cellulose	66	56	46	36	66	56	46	36	66	56	46	36
Magnesium stearate	1	1	1	1	1	1	1	1	1	1	1	1
Talc	2	2	2	2	2	2	2	2	2	2	2	2

Table No. 2: Pre Compression Evaluation of Granules of Repaglinide Matrix Tablets

Formulation code	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Bulk density (gm/cc)	0.190	0.195	0.177	0.145	0.135	0.142	0.164	0.199	0.134	0.165	0.145	0.170
Tap density (gm/cc)	0.206	0.219	0.192	0.154	0.174	0.150	0.192	0.230	0.234	0.151	0.219	0.220
Carr’s index	7.71	6.71	13.52	13.46	14.25	9.25	16.75	14.92	13.25	12.25	11.52	10.33
Hausner ratio	1.09	1.08	1.15	1.14	1.24	1.12	1.25	1.10	1.20	1.18	1.16	1.15
Angle of repose	30.61	25.63	21.85	23.74	24.77	25.75	26.52	25.74	22.56	25.46	23.74	30.94

Table No. 3: Evaluation of Repaglinide Matrix Tablet

Formulation code	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Weight variation (mg)	100	101	103	101	100	104	100	101	100	101	100	100
Hardness (kg/cm²)	5.6	5.6	5.6	5.6	6.7	6.7	6.7	6.7	4.6	4.6	4.6	4.6
Friability (%)	0.891	0.866	0.921	0.891	0.901	0.745	0.665	0.990	0.930	0.980	0.865	0.891
Drug content (%)	97.32	95.14	96.00	93.26	98.55	96.45	96.15	94.22	95.55	98.22	97.66	96.42

Table No 4: Kinetic Values of Repaglinide Matrix Tablets

Formulation code	Regression coefficient values of				Slope value (n)
Formulation code	Zero order	First order	Peppas	Higuchi	Peppas	Higuchi
F1	0.889	0.984	0.659	0.963	0.996	33.90
F2	0.863	0.986	0.656	0.960	0.995	30.82
F3	0.911	0.980	0.740	0.955	1.077	31.70
F4	0.888	0.983	0.618	0.977	0.923	28.11
F5	0.946	0.887	0.720	0.972	1.064	34.60
F6	0.888	0.986	0.665	0.969	0.997	31.43
F7	0.946	0.979	0.735	0.957	1.065	31.70
F8	0.892	0.987	0.641	0.979	0.942	27.95
F9	0.925	0.990	0.638	0.960	0.974	33.57
F10	0.901	0.993	0.691	0.965	1.035	31.73
F11	0.884	0.966	0.737	0.956	1.079	31.77
F12	0.887	0.986	0.630	0.978	0.931	27.76

Fig 3: Scanning electron microscopic studies (SEM) of formulation F8 and F12

Fig 4: Cumulative percent drug released Vs time plots of formulations F1, F2, F3, F4, F5 and F6

Fig 5: Cumulative percent drug released Vs time plots of formulations F7, F8 F9, F10, F11 and F12

DISCUSSION:

The main goal of this work was to develop new sustain release matrix tablet of Repaglinide which is a used in type 2 diabetic patients with various forms of origins. The tablets were prepared by wet granulation method using various polymers like Hydroxypropyl-methylcellulose, Microcrystalline cellulose, Eudragit Rs100, in different ratios. According to work plan, all the tablets were evaluated for their appearance, hardness, friability, weight variation, drug content, and in-vitro release and drug excipient interaction.

All batches tablets show the hardness, friability, weight variation and drug content uniformity were found within recommended pharmacopoeia limits.

The in-vitro dissolution profiles data of all the designed formulation are shown in table no. 4 and dissolution profiles depicted in fig 4 and 5. From the dissolution data it is evident that the formulation containing Eudragit RS100 (60mg) and formulation containing Eudragit RS100 (30mg) + Hydroxy propyl methyl cellulose (30 mg) had sustained dissolution rate as compared to other formulations. Based on the results of evaluation data of all the 12 formulations F8 and F12 were optimized because of their good drug content uniformity and sustained release data. Further they over ruled the drug- polymer interaction by Infrared spectroscopy and Differential scanning calorimetric analysis.

The Differential scanning calorimetric analysis thermo gram analysis of drug and polymer combinations. The drug loaded tablets showed and enothermic peak at 101 ºC to 280ºC due to the melting of the drug was dispersed uniformly throughout the formulation a drug undergone physical completion with polymer. The Scanning electron microscopy analysis to study the surface morphology. And the photographs clearly show that a smooth and uniform surface of the prepared formulation.

CONCLUSION:

Matrix tablet of Repaglinide was prepared by the wet granulation method using Hydroxy propyl methyl cellulose, Microcrystalline cellulose and Eudragit Rs100 polymers in different ratios. The prepared tablets were evaluated for drug content, Fourier transform infrared spectroscopy, Differential scanning calorimeter, in-vitro drug release, Scanning electron microscopy.

All the prepared tablets were found to be good without any capping and chipping. In all the tablet formulation, 10% PVP-K30 solution in Iso propyl alcohol was used as binder which showed acceptable hardness of prepared tablets. Infrared spectra studies and Differential scanning calorimetric data was studied and indicated that there are no drug excipient interactions.

Formulations of F8 and F12 are optimized because of their good drug content uniformity and ability to prolong the release of the drug from the matrix over the 12h period.

ACKNOWLEDGEMENT:

The authors are thankful to Torrent Pharmaceuticals Limited, Ahmadabad for providing gift sample of Repaglinide. Authors thank full to B.L.D.E.A.’s college of pharmacy for providing all facilities for research work.

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Received on 26.06.2020 Modified on 07.08.2020

Research J. Pharm. and Tech. 2021; 14(8):4429-4434.

DOI: 10.52711/0974-360X.2021.00769