Introduction

Aceclofenac, a phenylacetic acid derivative, is a non-steroidal anti-inflammatory drug (NSAID) related to diclofenac. It is used in the management of osteoarthritis, rheumatoid arthritis and alkylosing spondylitis (1). Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions. Aceclofenac is well tolerated, with most adverse effects being minor and reversible, affecting mainly gastrointestinal system (2). It is well absorbed from gastrointestinal tract and peak plasma concentrations (C_max) are reached 1-3 h after oral dose. The short biological half life (approximately 4.3 h) ^{and the need for long duration favour development of a sustained release formulation. Sustained release tablets can offer advantages like limiting fluctuation within the therapeutic range, decreasing dosage frequency and improving patient compliance.}

The simplest way to retard drug release is to disperse it in a solid matrix. The matrix system is commonly used for manufacturing sustained release dosage forms especially tablets because it makes such manufacturing easy. Hydrophilic matrices are an interesting option when formulating an oral sustained release (SR) of a drug. The dosage release properties of matrix devices may be dependent upon the solubility of the drug in the polymer matrix or, in case of porous matrices, the solubility in the sink solution within the particle’s pore network (3). Hydroxypropyl methylcellulose (HPMC) is the dominant hydrophilic vehicle used for the preparation of oral controlled drug delivery systems (4). Numerous studies have been reported in literature investigating the HPMC matrices to control the release of a variety of drugs from matrices and trying to predict drug release kinetic models (5-9). According to most of these models, diffusion is thought to occur in release of drugs and anomalous release due to effect of excipients in matrices. One of the common complaints of oral NSAID including aceclofenac is gastric irritation associated with their use. Therefore enteric coated aceclofenac tablets are interesting option to circumvent this problem of GI irritation.

The objective of the study was to prepare enteric coated sustained release aceclofenac tablets using HPMC matrix, to examine the in vitro release characteristics, to predict the release behavior of aceclofenac from the matrix and to elucidate shelf life of the fabricated formulation. In order to elucidate release kinetics it is necessary to fit drug release data into a suitable model. The commonly adopted models for understanding the release of drugs from hydrophilic matrices are first-order equation (log cumulative percentage of drug remaining versus time), Higuchi equation (10) (cumulative percentage of release versus square root of time) and Korsmeyer-Peppas simple exponential equation (11, 12) (log cumulative percentage of drug released versus log time) models. These simple exponential equation models have been used to elucidate the mode of release.

Experimental

Materials

Aceclofenac was obtained from New Drug and Chemical Company, Mumbai. HPMC K100M, a grade of hydroxypropyl methylcellulose was procured from Colorcon Asia Pvt. Ltd., Mumbai. Microcrystalline cellulose (MCC, Avicel pH 101), PVP K90 (Polyvinyl pyrrolidone K-90) and lactose monohydrate (spray dried) were purchased from Coveral and Company, Chennai. Aqueous coat, a ready mix sodium alginate was purchased from Corel Pharma Chem. Ltd. Magnesium stearate and talc were purchased from SD Fine Chemicals Ltd., Mumbai. Materials and excipients used in preparing tablets were Indian Pharmacopoeial grades. All other ingredients used throughout the study were of analytical grades and were used as received.

Figure 1

Table 1: Formulae of aceclofenac uncoated matrix tablets

Methods

Calculation of Theoretical Release Profile of Aceclofenac from Sustained Release Tablets

The total dose of aceclofenac for a once daily sustained release formulation was calculated by following four equations (13) using available pharmacokinetic data (2) from a design of one compartment model with simultaneous release of loading dose and a zero order release maintenance dose, as described by Robison and Eriksen (14).

Figure 2

Where, k₀= zero order drug release; D_i= initial dose, D_m= maintenance dose; T= time for sustained action; D_l= loading dose; T_p= time to reach peak plasma concentration; D_t= total dose of drug.

Therefore the total dose of the drug is calculated using the equations.

Figure 3

The formulation behaves a delayed release tablet. Hence the matrix tablet should contain a total dose of 200 mg, no drug should release in first 2 h, and it should release 25.82+8.06 = 33.88 mg in 3rd hour like conventional dosage, and 8.06 mg per hour up to 24 h thereafter.

Preparation of Matrix Tablets

Matrix tablets, each containing 200 mg aceclofenac, were prepared by wet granulation technique. The drug polymer ratio was developed to adjust drug release as per theoretical release profile (Table 3) and to keep total weight of tablet constant for all the fabricated batches under experimental conditions of preparations. The total weight of the matrix tablets were 470 mg with different drug polymer (HPMC) ratio. A batch of 5000 tablets was prepared in each formula. The composition of tablets is shown in Table 3. MCC was incorporated as filler excipient to maintain tablet weight constant. This water insoluble filler was incorporated also to counter balance the faster solubility of the drug in presence of hydrophilic polymer and to provide a stable monolithic matrix. The ingredients were passed through sieve no. 40 and thoroughly mixed for 8-10 min in a polythene bag. Granulation was done manually with a solution of calculated quantity of PVP K90 in sufficient isopropyl alcohol. The wet masses were passed through sieve no. 20 and the wet granules produced were first air dried for 10 min and finally at 45-55° C in tray drier for 2 h. The dried granules were sized by sieve no.22 and mixed with 10% (200-220 g/batch) of fines (granules that passed through sieve no. 22). Talc and magnesium stearate were added as glidant and lubricant and blended with remaining HMPC for 10 min in a twin-shell blender. Granules thus obtained were compressed into tablets on 16-station rotary Cadmach machine (Cadmach, Ahmedabad) at a constant compression force using 13/32 mm deep concave punches.

Film Coating of Aceclofenac Matrix Tablets

The coating solution was prepared by dissolving 100 g aqueous coat ready mix powder in 650 ml water in a homogenizer. The coating (viscous) solution was sprayed continuously at 10 g/min rate over the tablet bed (pre-warmed to 40° C) loaded in 9.4 inches diameter coating pan using 1 mm fluid nozzle spray gun. The rpm of the coating pan, the atomizer’s air pressure and the drying temperature were maintained at 30, 50 psi and 40 to 45° C respectively. The tablets were coated to weight gain of 6 ± 1% by weight of uncoated tablets and to get uniform thickness of coating

Evaluation of Tablets

The prepared matrix core tablets were evaluated for hardness, weight variation, thickness, friability and drug content. Hardness of the tablets was tested using a Strong-Cobb hardness tester (Tab-machine, Mumbai). Friability of the tablets was determined in a Roche friabilator (Campbell Electronics, Mumbai). The thickness of the tablets was measured by vernier caliper. Weight variation test was performed according to IP method (15) Drug content for aceclofenac was carried out by measuring the absorbance of samples at 275 nm using Shimadzu 1201 UV/Vis spectrophotometer and comparing the content from a calibration curve, prepared with standard aceclofenac in same medium.

Figure 4

Table 2: Properties of compressed aceclofenac matrix tablets

In Vitro Drug Release Studies

The in vitro dissolution studies were carried out using USP 24 dissolution apparatus type II (16) (paddle method) at 50 rpm. Dissolution test was carried out for a total period of 24 h using 0.1N HCl (pH 1.2) solution (750 ml) as dissolution medium at 37 ± 0.5° C for first 2 h and pH 6.8 phosphate buffer solution (1000 ml) for the rest of the period. Five milliliters of the sample was withdrawn at regular intervals and replaced with the same volume pre-warmed (37 ± 0.5° C) fresh dissolution medium. The samples withdrawn were filtered through 0.45  membrane filter and drug content in each sample was analyzed after suitable dilution by above mentioned spectrophotometer at 275 nm. The actual content in samples was read from a calibration curve, prepared with standard aceclofenac. The dissolution test was repeated thrice. The standard deviation of all data was less than 2.5%, hence only mean value was considered.

Kinetic Analysis of Dissolution Data

The release data obtained, for selected batch(s), were treated according to first-order, Higuchi and Korsmeyer-Peppas equation models to determine the release rate and mechanism of drug release from matrices.

Stability Studies

One selected fabricated tablet batch (formulation-V) was strip packaged and divided into three lots and kept in incubators at 30° C, 40° C and 50° C with humidity in the working area (40-55% relative humidity) in order to accelerate the degradation. Samples were withdrawn at 0.5, 1 and 1.5 months for evaluation of appearance, drug content and in vitro drug release. Ten tablets were used per lot and the method repeated thrice. Assuming zero order degradation, K₀ was calculated at different temperatures (Table 3). The rate of degradation (K₀) at 25° C was obtained by extrapolation of line from Arrhenius plot (log K₀versus 1/T10⁴). The expiration date was calculated by the equation:

Figure 5

Where, A₀is 200 mg (i.e. initial amount) and A₉₀is 180 mg (i.e. 90% of 200 mg).

Results And Discussion

The results of hardness and friability of the prepared matrix tablets ranged from 5.2 ± 0.35 to 5.9 ± 0.37 and 0.03 to 0.06 respectively (Table 1). The tablet formulations in all the prepared batches contained aceclofenac within 100 ± 5% of labeled content. As such all the batches of the fabricated tablets were of good quality with regard to hardness, friability and drug content. All tablets complied with Indian pharmacopoeial specifications for weight variation. Aceclofenac release from tablets was extended from 16 to 24 h from formulated batches. The results of dissolution studies of formulations F-I, F-II, F-III, F-IV and F-V are shown in Figure 1. Drug release rate from the tablets was found to decrease with increase in drug polymer ratio. Formulation F-II, composed of drug polymer ratio of 1:0.375, failed to sustained release beyond 10 h. On the contrary formulation F-I, composed of drug polymer ratio of 1:0.625, released only 60.89% at the end of 20 h. However all the formulations but one (F-V) failed to show drug release close to theoretical release profile.

The release of drug depends not only on the nature of matrix but it also depends upon the drug polymer ratio. As the percentage of polymer increased, the kinetics of release decreased. This may be due to structural reorganization of hydrophilic HPMC polymer. As concentration of HPMC increases that may result in increase in the tortuosity or gel strength of the polymer. When HPMC polymer is exposed to aqueous medium, it undergoes rapid hydration and chain relaxation to form viscose gelatinous layer (gel layer). Failure to generate a uniform and coherent gel may cause a rapid drug release (17).

The release of drug depends not only on the nature of matrix but it also depends upon the drug polymer ratio. As the percentage of polymer increased, the kinetics of release decreased. This may be due to structural reorganization of hydrophilic HPMC polymer. As concentration of HPMC increases that may result in increase in the tortuosity or gel strength of the polymer. When HPMC polymer is exposed to aqueous medium, it undergoes rapid hydration and chain relaxation to form viscose gelatinous layer (gel layer). Failure to generate a uniform and coherent gel may cause a rapid drug release [17].

Figure 6

Table 3: Zero order rate constant (k) at various temperatures

It may be concluded from the present study that slow, controlled and complete release of aceclofenac over a period of 24 h was obtained from matrix tablets (F-V) formulated employing drug polymer ratio of 1:0.470. It is also evident from the results that formulation F-V is a good system for once daily SR of aceclofenac. The formulation exhibited diffusion mechanism of drug release. The resulting fabricated formulation of matrix tablet utilizing HPMC K 100M produced robust tablets with optimum hardness, consistent weight uniformity and low tablet friability. The study demonstrated that fabrication procedure employed provides reliable shelf life for the tablet.

Acknowledgement