Design, Fabrication and in Vitro Evaluation of Metformin HCl Matrix Tablets for Treatment of Diabetes Mellitus

Diabetes mellitus is a growing problem in today’s world. The aim of the present study was to design and develop matrix tablets of metformin HCl (MTH) with hydroxy propyl methyl cellulose K15M (HPMCK15M) and ethyl cellulose (EC) in different ratios. The prepared tablets were evaluated in terms of hardness, friability, drug content and in vitro drug release profiles. It was observed that formulation with HPMC and EC in a ratio of 2:1 gave reproducible results in all aspects and showed sustained drug release profile for 12h.


Introduction
Diabetes mellitus is rapidly beco ming a serious threat to human health . Acco rd ing to World Health Organ izat ion estimates, nu mber of peop le with diabetes worldwide, in 2000, was 171 million, which is likely to increase at least 366 million by 2030 [1]. This increase will be most noticeable in develop ing countries, where th e nu mber o f peop le with diabetes is expected to increase fro m 84 million to 228 million. Accord ing to the WHO, Southeast Asia and the Western Pacific region are at the forefront of the cu rrent diabetes epidemic, with India and China facing the greatest challenges. In these countries, the incidence and prevalence of type 2 diabetes among children are also increasing at an alarming rate, with potentially devastating consequences [2]. Metformin HCl (MTH) is an ant i-d iabet ic d rug wh ich is prescribed fo r t he t reat ment o f non -insu lin dep end ent diabetes mellitus [3]. In addition, it has a favourable action on cardiovascular risk factors, wh ich are often present in these individuals. It helps in maintaining d iet-induced weight loss and lowers fasting plasma insulin concentrations, total and lo w density lipoprotein-cho lestero l, and free fatty acids. These effects make MTH a first-line agent for the prevention of type 2 diabetes [4]. The average MTH elimination half-life in plas ma is 6.2h and its peak plasma concentration (C max ) is ach iev ed with in 4 to 8 ho u rs with exten ded -release formulat ions. In spite of its favourable clin ical response and lack of significant drawbacks, ch ronic therapy with MTH suffers fro m certain specific problems of which, the most prominent being the high dose (1.5-2.0 g/day), low bioavailability (60%), high incidence of gastrointestinal (GI) tract side effects (30% cases) and decreased absorption of the drug with food that delays time to reach maximu m drug concentration in blood (t max ) by half-an-hour [5,6]. Thus there exists a potential for MTH to be used in the sustained release formu lation tablets. The primary benefit of sustained release preparations of MTH compared to an immediate release formulat ion is that a more uniform maintenance of blood plasma active concentration can be achieved, potentially avoiding undesirable peaks and troughs associated with mult iple immediate release preparation applications.
Hydro xy propyl methyl cellulose (HPMC) is the most commonly and successfully used hydrophilic poly mer for the preparation of oral controlled drug delivery systems [7]. Upon contact with the gastrointestinal fluid, HPM C swells, gels, and finally dissolves slowly [8]. The gel becomes a viscous layer acting as a protective barrier to both the influ x of water and the efflu x o f the drug insolation. Vo lu me proportion of the polymer in the fo rmulat ion increases, the gel formed is more likely to diminish the diffusion of the drug and delay the erosion of the matrix. The dissolution can be either disentanglement or diffusion controlled depending on the molecular weight and thickness of the coating layer. The rates of polymer swelling, dissolution and drug release are found to increase with both increasing levels of drug loading or with use of lower viscosity grades of HPMC. Additionally, use of hydrophobic polymers significantly slows the drug release. So in the present investigation, an attempt has been made to formu late the extended -release matrix tablets of MTH using hydrophilic matrix material HPM C K15 M in comb ination with hydrophobic ethyl cellu lose.
The present study focuses at the development and optimization of an extended release formulat ion (matrix tablet) of MTH HCl for the treat ment of diabetes mellitus.

Materials and Methods
Metformin HCl was obtained as a gift sample fro m Ranbaxy Laboratories Limited, India. Hydro xy propyl methyl cellu lose K15M was obtained as a gift sample fro m Colorcon Asia Pvt Ltd. Ethyl cellu lose, Micro crystalline cellu lose, Magnesium stearate and talc were purchased from S.D. Fine Chemicals.

Preparati on of the Matrix Tablet
Matrix tablets were prepared by non-aqueous wet granulation method. The co mposition of various formulat ions is given in Table 1. MTH HCL, HPM C K15M, EC, M CC were weighed accurately and individually passed through a 60 mesh and the mixture was passed through sieve mesh No. 40. The powdered ingredients were comp ressed into tablets on a 10-station mini rotary tableting machine with 12-mm round punches at a constant rotational speed of 72 rp m.

Drug content
To determine drug content, 6 tablets of each formulat ion were weighed and crushed to powder with mortar and pestle. 300 mg of powder was taken and dissolved with appropriate amount of methanol with the aid of sonicator. After which the solution was filtered through filter paper. The total amount of the drug in the tablet was analysed after appropriate dilution of test solution by using UV spectrophotometer (UV-VIS Spectrophotometer, Sh imadzu, Japan) at 233 n m against the reference solution with suitable dilution.

In Vitro Drug Release Study
In vitro drug release study of each formulation was determined using the USP Type II Dissolution apparatus (Labindia Instruments, India) where 900 ml o f phosphate buffer saline (pH 6.8) were used as dissolution media and maintained at 37±0.50 ℃ at 50 rp m. The release rate experiments were conducted in 0.1 N HCl for 2 h and thereafter in phosphate buffer saline of pH 7.4 for 12 h. Aliquots of 1 ml were withdrawn at fixed intervals and replaced with fresh media. Then samples were analysed in the same spectrophotometer at 233 n m, keep ing the dissolution med ia as reference sample.
In order to determine the release model which best describes the pattern of drug release, the in vitro release data were fitted to zero order, first order and diffusion controlled release mechanis ms according to the simplified Higuchi model [11]. The selection of a preferred mechanism was based on the correlation coefficient (r) for the parameters studied, where the highest correlation coefficient is preferred for the selection of mechanis m of release. Data analysis was carried out using the following Korsmeyer and Peppas [12] Mt/M∞=K·t n (1) where Mt/M ∞ is the fract ion released by the drug at time t, K is a constant incorporating structural and geometric characteristic and n is the release exponent characteristic for the drug transport mechanism. When n = 0.5 fickian diffusion is observed and the release rate in dependent on t, while 0.5 < n < 1.0 indicate ano malous (non-fickian) transport and when n = 1 and the release model is ze ro order.

3.Results and discussion
Tablets of different formu lations were subjected to various evaluation tests, such as weight variation, drug content, hardness, friability, and in vitro dissolution study. The average weight variation of 20 tablets of each formu lation M etformin HCl M atrix Tablets for Treatment of Diabetes M ellitus was less than ± 5%. Drug content was found to be uniform among different batches of the tablets and ranged from 98.00±0.34 to 99.77±0.53 %. The hardness and percentage friability of the tablets of all batches ranged from 4.50 ±0.51 to 5.50 ± 0.72 kg/cm 2 and 0.62% to 0.70%, respectively ( Table 2). Tablets of all formulat ions showed uniform thickness. In a weight variation test, the pharmacopoeial limit for the percentage deviation for tablets of more than 250 mg is ± 5 %. The average percentage deviation of all tablet formulat ions was found to be within the above limit, and hence all formu lat ions passed the test for uniformity of weight as per official requirements [10].
Conventionally, the co mpressed tablets that lose less than 1% of their weight are generally considered acceptable. In the present study, the percentage friability for all the formulat ions was below 1%, indicating that the friability is within the prescribed limits. All the tablet formu lations showed acceptable pharmacopoeial properties and co mplied with the prescribed specificat ions for weight variat ion, drug content, hardness, and friability. Table 2 contains a summary of the above parameters measured for five different formu lations F1-F5 (corresponding compositions -see Table 1)  Figure 1 shows the in vitro drug release profiles indicating that formu lation F2 reaches maximu m release rate in shorter time and has longest time of stable release with respect to other formulat ions. Tablets F1 released 100% of the drug in 6 h; F2 released 40% of the drug in 1 h and then release rate was stable for 12 h; F3 released 29% of the drug in 1h and then showed stable release for 12 h; F4 and F5 released 9% and 5% of the drug respectively in 1h and released 100% and 71% in 12 h. Values of r 2 of different release kinetic models are displayed in Table 3. The formu lations with a co mb ination of HPM CK15 and EC with rat ion of 2:1 were found to be more effect ive. HPM CK15 as a hydrophilic material takes up aqueous med iu m and swells up. On the other hand EC as a hydrophobic material which reduces the penetration of water into the matrix. Thus the polymer matrix beco mes mo re rig id. The mechanis m of drug release is both dissolution and diffusion controlled. The drug release fro m the matrix tablet formulat ions F1, F2, F4, F5 fo llo ws Korsmeyer Peppas release kinetics. No burst release is observed. Un iform release is essential to maintain constant drug plasma concentration. It was observed that F3 formu lation follows Higuchi release kinetics [11].
In swellable systems, factors affecting the release kinetics are liquid d iffusion rate and polymeric chain relaxation rate. When the liquid diffusion is slower than the relaxation rate of the polymeric chains, the diffusion is Fickian [12], whereas when the relaxation process is very slow co mpared with the diffusion rate, the case II transport occurs [12]. When liquid d iffusion rate and poly mer relaxation rate are of the same order of magnitude, anomalous or non-fickian diffusion is observed [12].
The values of n (equation 1) as estimated by linear regression of log Mt/M ∞ vs log t of different formu lations are shown in Table 3 [13], the obtained values of n ranges between 0.3455 and 0.8280 for MTH HCl release for all the prepared tablets which indicates drug release mechanisms involving a co mb ination of both diffusion and chain relaxation mechanis ms. Therefore, the release of MTH fro m the prepared tablets is controlled by the swelling of the polymer fo llowed by drug diffusion through the swelled polymer and slow erosion of the tablet.
Specifically, the hydration rate o f HPM C increases with an increase in the hydroxypropyl content. The solubility of HPM C is pH independent. In the present study, HPM C K15 was used because it forms a strong viscous gel on contact with aqueous med ia, wh ich may be useful in controlled delivery of h ighly water-soluble drugs.

4.Conclusions
Fro m the above study it can be inferred that matrix tab let prepared with HPM C and EC in a ratio of 2:1 showed desirable results in terms of hardness, friability, drug content and in vitro drug release profiles.