INTRODUCTION:

Metformin hydrochloride is a biguanide derivative of highly water soluble oral antihyperglycaemic agent used in the treatment of type II non-insulin dependent diabetic mellitus^1,2. It is slowely and incompletely absorb from the gastrointestinal track due to its relatively low 50-60% bioavailability together with its short biological half life 1.5-4.5 hrs^3,4,5,6. Metformin is not metabolized initially; its main sites of concentration are the intestinal mucosa. The plasma concentration of drug at steady-state ranges about 1 to 2 mcg/ml90and relatively narrow absorption window⁷.Administration of sustained release Metformin Hydrochloride form could reduce the dosing frequency and improve patient compliance. Inspite of the clinical response and lack of significant drawback ,chronic therapy with Metformin Hydrochloride suffers problems of which high dose (1-3g/day) and enhancing the incidence of metallic taste, gastrointestinal tract i.e., lactic acidosis, to improve the pharmaceutical formulation of Metformin hydrochloride^8,9. In order to achieve an optimal therapy, the effort mainly focus on formulation of a sustained release matrix tablet of Metformin hydrochloride dosage forms.

The primary benefit of a sustained release dosage form, compared to a conventional dosage form, is the uniform drug plasma concentration and therefore uniform therapeutic effect^10-12.

Matrix devices were used due to their chemical inertness, drug embedding ability and drug release character, have gained steady popularity for sustaining the release of a drug. Preparation of sustain release formulation by matrix technique is commonly employed method because of ease of preparation, flexibility and cost efficiency^{11, 12, 13, 14}.

The objective of this study was to prepare sustained release matrix Metformin HCl tablets using Hydrophilic HPMC K100 M and hydrophobic ethylcellulose (EC), to study the effect of HPMC and EC on the in vitro release characteristics and to predict and correlate the release behavior of metformin HCl from the matrix.

MATERIALS AND METHODS:

Materials:

Metformin hydrochloride was obtained as gift sample from BlueCross Pharmaceuticals Ltd, Nashik. HPMCK100 was obtained as gift sample from Colorcon, Mumbai. Ethylcellulse (7cps) was obtained as gift Sample from Glenmark Pharmaceuticals Ltd, Nashik.

Preparation of matrix tablet:

Matrix tablets containing 500mg of Metformin HCl along with various amount of polymers such as HPMC K100M, EC and other inactive ingredients were mixed and tablet were prepared by direct compression technique. In the first step, active and inactive ingredients (except magnesium Stearate) weighed accurately and were screened through a 40-mesh sieve. Required materials except lubricant were then combined and passed through 40-mesh sieve. In, the screened powder following the addition of given amount of lubricant powder was again mixed. Before compression, the surfaces of the die and punch were lubricated with magnesium stearate, and then desired amount of blend was compressed into tablets using rotary tablet compression machine (Rimek tablet machine, Minipress) equipped with 13 mm flat circular punch. All the preparations were stored in airtight containers at room temperature for further study.

EVALUATION OF TABLETS: ^{14- 16}

The compressed matrix tablets were evaluated for thickness, weight variation, hardness and drug content.

Thickness:

The thickness of tablet was determined using Vernier Calliper (Kayco, India). Six tablets from each batch of formulation were used and mean thickness value and SD was calculated for each formulation.

Hardness:

For each formulation, the hardness of six tablets was measured using the Pfizer hardness tester (Cadmach, Ahemadabad, India) and mean value and SD was calculated.

Weight variation:

To study the weight variation, 20 tablets of each formulation were weighed using an electronic digital balance. The average weight of each tablet was calculated and from that the percentage deviation in weight was calculated.

Friability:

For each formulation the friability of 6 tablets was determined using Roche Friabilator. (Remi Equipments).

Drug content:

Five tablets were weighed and powdered. Weigh accurately a quantity of the powder equivalent to 0.1 g of Metformin HCl shake with 50 ml of 6.8 pH phosphate buffer for 10 minutes, and add sufficient buffer to produce 100.0 ml and filter. After suitable dilution with solvent measure the absorbance of the resulting solution at the maximum at about 233 nm. Calculate the content of C4H11N5, HCl, at the maximum at about 233 nm.

In vitro drug release study: ^17-20

In vitro drug release studies of the prepared matrix tablets were conducted for a period of 12 hours by using an USP 24 Dissolution Apparatus type II (2000) (Labindia, Mumbai, India) at 37± 0.5° C. The agitation speed was 100 rpm. The Dissolution study was carried out in 900 ml 0.1N HCl at 37±0.5 ºC for first 2 hours and then in 900 ml of phosphate buffer (pH 6.8).5ml of the sample was withdrawn at regular intervals and the same volume of fresh dissolution medium was replaced to maintain the volume constant. The samples withdrawn were filtered through a 0.45 μ membrane filter and the drug content in each sample was analyzed after suitable dilution with a Shimadzu 2501PC UV/VIS spectrophotometer at 233 nm. The amount of drug present in the samples was calculated with the help of calibration curve constructed.

RESULT AND DISCUSSION:

Evaluation of Tablets:

The thickness of all the formulations were varies within ranges from 4.43-4.66 mm. All the formulation showed uniform thickness. The weight variation test was carried out as per official method and it was found that all formulation to be within the limit (as per pharmacopoeial standard). The content uniformity test was also carried out as per official method and it was found that different batches shown good content uniformity. It was found that all batches shown percent drug content more than 98 %. The tablet hardness of all the formulations was determined and it was found sufficient in the range 7.2-7.9 kg/cm2. Another measure of tablet hardness was the friability. A compressed tablet that loses less than 1 % of their weight is generally considered acceptable. For all formulation tried here the weight loss was less than 1 % hence acceptable.

In vitro release study:

The in vitro drug release characteristics were studied in 900 ml 0.1N HCl for a period of 2 hours and 6.8 pH phosphate buffer for Remaining 10 hrs using USP XXIII dissolution apparatus 2. According to the USP release pattern, the conventional formulation release not less than 70% in 45 minute. Various formulations were tried here and out of that F3 was the best formulation of the study.

Fig 1: Dissolution profile of matrix tablets

Table 1: Table shows Formulation of Matrix Tablet

Ingredients	F1	F2	F3	F4	F5	F6
Metformin HCl	500	500	500	500	500	500
HPMC K 100	200	160	200	160	200	160
Ethylcellulose	-	-	40	40	80	80
Avicel PH 102	80	120	40	80	-	40
PVP-K-30	10	10	10	10	10	10
Talc	5	5	5	5	5	5
Magnesium Stearate	5	5	5	5	5	5
Total	800	800	800	800	800	800

Table 2: Table shows Evaluation of Tablets

Formulation code	Thickness (mm) (mean ±S.D)	Hardness (Kg/cm²) (mean ±S.D)	Weight Variation (%)	Friability (%) (mean ±S.D)	Drug Content
F1	4.56± 0.033	7.9± 0.11	1.762	0.48± 0.069	101.10
F2	4.66± 0.020	7.5± 0.25	2.722	0.35± 0.077	100.08
F3	4.53± 0.041	7.8± 0.32	2.570	0.20± 0.007	99.12
F4	4.50± 0.030	7.3± 0.10	2.286	0.29± 0.056	99.67
F5	4.43± 0.029	7.8± 0.27	3.046	0.45± 0.021	99.02
F6	4.53± 0.020	7.2± 0.11	2.634	0.30± 0.028	99.80

Table 3: Table Shows Drug Release Profile of Matrix Tablets

Time (Hrs)	% cumulative drug release
	Formulation code
	F1	F2	F3	F4	F5	F6
1	38.80±0.73	39.92±0.96	33.18±1.24	40.21±0.80	32.74±1.28	34.65±0.51
2	47.95±0.46	50.35±1.12	41.70±0.42	51.13±1.06	40.90±1.56	42.02±1.25
3	60.95±0.29	67.18±0.22	53.17±0.80	63.32±1.49	51.12±0.78	57.28±0.46
4	72.45±0.95	76.36±0.49	66.55±1.57	71.45±0.77	57.35±0.39	65.47±2.51
6	87.86±1.31	90.41±1.18	80.36±1.49	81.66±0.93	66.69±2.65	76.19±1.22
8	-	-	89.01±0.47	88.12±1.25	74.92±0.85	89.62±0.58
10	-	-	94.17±1.98	95.39±0.29	85.31±4.53	99.94±1.62
12	-	-	97.11±0.65	-	95.95±1.07	-

Table 4: Table shows Data Treatments of Matrix Tablets

Formulation code	Coefficient of determination (r²)				Korsmeyer plot n (release exponent)
Formulation code	Zero order	First order	Higuchi	Korsmeyer plot	Korsmeyer plot n (release exponent)
F1	0.9617	0.9771	0.9886	0.9812	0.46
F2	0.9689	0.9855	0.9881	0.9846	0.47
F3	0.9131	0.9945	0.9715	0.9745	0.16
F4	0.9454	0.9830	0.9843	0.9982	0.30
F5	0.9837	0.8946	0.9943	0.9934	0.31
F6	0.9736	0.7170	0.9928	0.9867	0.45

Data treatment:

Different kinetic treatments (zero order, first order, Higuchi’s square root equation and (Korsmeyer treatment) were applied to interpret the release of Metformin HCl from different matrices. The data was given in (Table 4). The Korsmeyer Peppas kinetic treatment gave consistently higher values (0.9745 to 0.9982) for all formulations. First order kinetic treatment also gave higher values (0.7170 to 0.9945). Zero order kinetic treatment gives higher values (0.9131 to 9837). In order to determine the release mechanism of drug from different matrices different kinetic models was applied. The release profile was fitted into Higuchi model. This model was used to analyze the release from pharmaceutical dosage forms, where the release mechanism was well known or more than one phenomenon could be involved. The values of release exponent (n) and coefficient of determination (R2) were shown in table 4. The value of release exponent (n) was used to characterize the release mechanism from dosage form.

Influence of quantity of HPMC K100M and addition of Ethylcellulose on in vitro release rate of Metformin HCl from Matrix Tablets:

To study the effect of HPMCK 100M on release of Metformin Hydrochloride, batches F1 to F6 were formulated using various proportions of HPMCK 100M as per the formulas given in Tables 1. Figs 1 reveal the effect of quantity of HPMC K 100M on release of Metformin Hydrochloride from the tablet matrix. As expected the release rate was slower with higher quantities and higher viscosities of HPMC. The tablet compositions containing 25 and 20 % of HPMC K100M with respect to anhydrous drug provided sustained release for 12 hrs as shown in Fig¹. Formulations having low concentrations of HPMC K100M i.e. 20% (F2) and high concentration 25% HPMC K 100 M (F1) have shown initial fast drug release 39.92% and 38.80% respectively after 1 hour (Table 2). After 2 hours F2 and F1 have shown 50.35% and 47.95% drug release respectively and complete drug release within 8 hrs. HPMC formulations containing plastic polymers such as Ethylcellulose (E.C.) have shown slower and constant release and controlled burst effect at initial 2 hours which signifies that HPMC and EC were used as sustained release agents in the core tablet. In the matrix drug delivery systems the characteristics of the matrix forming agent play an important role in the mechanisms of the drug. Among the hydrophilic polymers, HPMC was one of the carriers most commonly used for the preparation of oral controlled drug delivery systems because of the ability to swell upon gellification once in contact with water. The gel becomes a viscous layer acting as a protective barrier to both the influx of water and efflux of the drug in solution. On the other hand EC was an inert matrix with no physiological action, stable at different pH and moisture levels. That controls the diffusion of the drug toward the surface prior to release. High HPMC K 100M content results in a greater amount of gel being formed this gel increases the diffusion path length of the drug as a result reduction in drug release obtained. Formulations containing lower levels of HPMC and 5% ethyl cellulose viz. F3 and F4 have showed 33.18 % & 40.21% after 1 hour and 41.70 % & 51.13 % after 2 hours respectively. Formulations containing higher concentration of E.C 10% Viz. F5 & F6 have shown significant slower release 32.74 % & 34.65% in 1 hour and 40.90% & 42.02 % of the drug after 2 hours. The effect on the release rates of formulations of ethyl cellulose was shown in (fig.1) observed that combination of HPMC K 100M and hydrophobic EC have better retarding property which was observed from dissolution profile.

CONCLUSION:

In the matrix drug delivery systems the characteristics of the matrix forming agent play an important role in the mechanisms of the drug. The swelling and gel able properties of hydrophilic polymer matrix like HPMC which form protective barrier to influx of water and efflux of drug solution along with ethylcellulose has no inert matrix with no physiological action controls diffusion of drug towords surface of matrices. Due to these properties the combination of hydrophilic HPMC K 100M and hydrophobic EC in matrix have better retarding property to give desire dissolution profile.

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Received on 21.11.2009 Modified on 23.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 522-525