Design and Evaluation of Diclofenac Sodium Megaloporous Matrix System Aimed for Colonic Drug Delivery

1. Introduction

     Diclofenac sodium (DS) is a well-known representative of non-steroidal anti-inflammatory drugs (NSAIDs), widely used to control pain and inflammation of rheumatic and non-rheumatic origin [1]. The conventional DS tablets make the drug immediately available for absorption in upper gastrointestinal (GI) tract resulting local GI toxicity varying from minor gastric discomfort to ulceration and bleeding of the mucosa [2]. It is well documented that the GI toxicity is not only caused by the inhibition of the prostaglandin synthesis, but is probably also due to direct contact of the drug with the mucosa [3]. In addition, due to the rapid systemic clearance of this drug, repeated daily dosing of 3 to 4 times a day is required in maintenance therapy that influences patient compliance. Colon targeted controlled release formulations are thus warranted to promote patient compliance and to reduce upper GI toxicity to some extent. DS is well adsorbed in the colon [4] and thus colon-specific release can be used for the treatment of widespread inflammatory bowel diseases.

     The colon-specific drug delivery may be designed based on one of the following mechanisms viz., prodrugs [5], pH-sensitive polymer [6], time-controlled dissolution [7], and microflora-activated drug release [8]. Geometric shape controlled matrix systems [9], inert matrix systems [10], megaloporous matrix systems [11, 12], lipid matrix systems [13] and hydrogel matrix systems [14] are the various options available to achieve controlled drug release in matrix systems.

      Principally, the megaloporous matrix system comprises two kinds of granules, namely restraining-phase matrix granule (RMG) and the soluble housing-phase matrix granule (HMG), which operate together to release the drug from the dosage form with a constant rate over an extended period of time. Usually, the RMG structure comprises the drug and rate controlling material and the other structure, HMG comprises the drug and a penetration rate controlling material. Previous studies on megaloporous matrix systems [11,12], reveals the use of substances such as carnauba wax, carbopol 934, Eudragit L, stearyl and cetyl alcohol, calcium hydrogen phosphate, talc and Encompress for RMG while polyethylene glycol 6000, lactose, magnesium stearate, calcium hydrogen phosphate and Encompress for HMG.

      In the present  work, megaloporous DS controlled release matrix system has been developed using carnauba wax polymer in RMG and Eudragit L100 polymer in HMG.

Figure 1: The effect of carnauba wax content and tablet hardness on the release profile of diclofenac sodium in simulated gastric fluid (pH 1.2) for the first 2 hours and in phosphate buffer (pH 7.2) for the next 10 hours. Values are given in mean±SD, (n=6).

2. Materials and methods

2.1. Materials

     Diclofenac sodium was obtained from HATTI drugs, Maharashtra. Eudragit L100 was procured from Rohm GmbH, Germany. Carnauba wax was purchased from Koster Keunen Inc. USA. Microcrystalline cellulose (Avicel^® PH 101) was purchased from, FMC Corp., Philadelphia. Lactose I.P was obtained from Genuine Chemicals, Mumbai. Polyvinylpyrrolidone (PVP K30 with approximate molecular weight 50 000) was purchased from Merck, Germany. The commercially available DS sustained release tablets (Voveran^® SR-75 mg) were procured from Novartis, Mumbai. All other reagents used were of analytical or pharmaceutical grade.

2.2. Preparation and characterization of matrix tablets

     The megaloporous matrix tablets were prepared from HMG and RMG as shown in Table 1. The HMG were prepared by wet mixing of DS, Eudragit L100 and Avicel^® PH 101 in 101-capacity rapid mixer-granulator (Rotamix HSMG 10, Kevin Engineers, India) for 5 min. using isopropyl alcohol as granulating fluid. At semi-dried condition the granules were screened through sieve #14 and then dried at 40 °C in a tray drier (Bombay Engineering Works, India) until loss on drying became 2.0% in IR balance (Advanced Ltd. Mumbai, India). The dried granules were screened through sieve #14 and then sieve #80. The RMG were prepared by similar method as HMG employing DS, carnauba wax and lactose using 10% w/v PVP K30 and isopropyl alcohol as granulating agent. Finally, required portions of HMG and RMG were mixed, lubricated with magnesium stearate and compressed on a single punch tablet machine (Korsh, Germany) using 9.0 mm flat punches. The tablets were evaluated for their physical characters [15] like, weight variation, thickness and hardness. The drug content of each formulation was determined spectro-metrically at 276 nm, in a Shimadzu UV-160A spectrophotometer. Friability [16] was measured on a Roche friabilator (Hoffman la Roche, Basel).

Figure 2: Comparison of release profiles of an ideal formulation containing diclofenac sodium (F), reference product (Voveran ® SR) and theoretical release. Values are given in mean±SD, (n=6).

2.3. Plotting of theoretical release profile

     The theoretical release profile was designed from the pharmacokinetic parameters of the drug [17, 18] according to Krüger-Thiemer and Eriksen [19] and Robinson and Eriksen [20]. The theoretical release profile was proposed purposely designed for obtaining a controlled release profile characterized by an initial phase (2 h) of lag-time followed by a controlled release phase (12 h), according to zero order kinetics. The theoretical release profile was composed of initial and sustaining doses and the drug was considered to be released from both the portions simultaneously [21]. In order to select an ideal formulation among various formulations studied, the respective dissolution profiles were compared with the theoretical release profile for similarity.

2.4. In vitro release studies

     The in vitro release of DS from the formulated tablets was carried out in USP 25 dissolution test apparatus II [15] using 900 ml of dissolution medium maintained at 37.0±0.5°C and a stirring rate of 50 rpm. Six tablets from each formulation were tested individually in simulated gastric fluid (pH1.2) for the first 2 h and in phosphate buffer (pH 7.2) for the following 10 h. At every 1 h interval, samples of 5 ml were withdrawn from the dissolution medium and replaced with fresh medium to maintain the volume constant. After filtration and appropriate dilution, the amount of DS present in each sample was determined spectrophotometrical-ly at 276 nm.

2.5. Independent-model method (data analysis)

     In order to compare the dissolution profiles, two model-independent methods were used: Area under dissolution curve (AUC), obtained by trapezoidal rule [22] and Lin Ju and Liaw's [23] difference factor (ƒ₁) and similarity factor (ƒ₂).

In the present study, AUC was considered instead of mean dissolution time (MDT), because this parameter can probably provide a better indication of in vivo performance [24]. In order to assess the statistical significance between AUC values, a single factor analysis of variance (ANOVA) followed by Duncan's multiple range test (DMRT) [25] was carried out, at a 5% significance level.

The ƒ₁  and ƒ₂  factors provide a simple measure of similarity between pairs of dissolution profiles. The difference factor (ƒ1) is the percentage difference between two dissolution profiles at each time interval:

ƒ₁ = {[Σ | R_t - T_t |] / Σ R_t} × 100 (1)

where, R_t indicates the released amount of drug of reference formulation; and T_t, the released amount of drug of test formulation. If the dissolution profiles are superimposed, ƒ₁ reaches a value of 0, whereas the factor value increases when the differences between dissolution profiles also increase. From a practical point of view, values of ƒ₁ between 0 and 15 can be considered as superimposed dissolution profiles. The similarity factor (ƒ₂) can be calculated using the following expression:

ƒ₂ = 50 × log {[1 / (1 + (Σ (R_t - T_t) ²) / N)]^1/2 × 100} (2)

where, N indicates the number of experimental data. Values of ƒ₂ between 50 and 100 can be considered as superimposed dissolution profiles.

Table 1.Formulation and characteristics of megaloporous tablets containing diclofenac sodium (Batch size-5000 tablets).

F₁ to F₄-fabricated formulations, HMG-housing matrix granules, RMG-restraining matrix granules.

2.6. Dependent-model method (data analysis)

In order to describe the DS release kinetics from individual tablet formulations, the corresponding dissolution data were fitted in various kinetic dissolution models [26]: Zero order, first order, and Higuchi [27], respectively.

matrix and K₁ the first order kinetic constant.

mechanism of drug release from matrices, dissolution data were analyzed using the equation proposed by Harland et al. [28].

Q _(t-l) /Q_α = K_K.(t-l)ⁿ (6)

where, Q_t corresponds to the amount of drug released in time t, l is the lag time (l = 2 h), Q_α is the total amount of drug that must be released at infinite time, K_K a constant comprising the structural and geometric char-acteristics of the tablet, and ‘n’ is the release exponent indicating the type of drug release mechanism. To determine the exponent ‘n’, only the points in the release curves where Q_(t-l)/Q_α>0.6 were used. If ‘n’ approaches to 0.5, the release mechanism can be Fickian. If ‘n’ approaches to 1, the release mechanism can be zero order and on the other hand if 0.52). Further, the selected "best model" was confirmed by evaluating the statistical differences between R² values of various kinetic models, using one way ANOVA followed by DMRT analysis. The values were considered statistically significant if the p < 0.05.