(W1130-01-02) Study of Etamsylate Release Kinetics from Controlled Release Matrix Tablets Using the Buffer Transition In Vitro Dissolution Method

Purpose: The primary objective of this investigation was to prepare etamsylate controlled release matrix tablets with different rates of release, fast (CR_fast), medium (CR_medium), and slow (CR_slow), and to study etamsylate release kinetics from these tablets using the buffer transition in vitro dissolution method.

Methods: Pre-formulation studies were performed to prepare four different formulations which contain 500 mg etamsylate. Lactose and magnesium stearate were used in all formulations as diluent and lubricant, respectively. For the preparation of immediate release (IR) tablets, Na CMC was used as disintegrant and PVP K30 was used as binder. HPMC K15M (15000 cps) and Carbopol^® were used in the CR tablets in different quantities as drug release modifier. The effect of pH on etamsylate dissolution rate from the IR tablets was investigated in vitro by the paddle method using USP Dissolution Testing Apparatus II, at pH 1.2, 4.5, 6.8 and 7.4. While the in-vitro buffer transition method, using the same apparatus, was used to study the in vitro dissolution of the CR matrix tablets to mimic the physiological pH of the different GIT segments. The buffer transition method consisted of three phases. The dissolution medium of the first phase was 900 ml of phosphate buffer (0.02 M potassium phosphate adjusted to pH 1.2 with phosphoric acid) for two hours. While the dissolution medium for the second phase was adjusted to pH 6.8 with 10 N NaOH and continued for another three hours. For the third phase, the pH of the dissolution medium was adjusted to pH 7.4 with 10 N NaOH and the dissolution was continued for additional 7 hours. The pH was adjusted without interruption or withdrawal of the tested tablets and the dissolution was continued for 12 hours. Samples were withdrawn periodically and etamsylate dissolved was determined. The dissolution profiles were used to calculate the dissolution parameters. To investigate the kinetics and mechanism of etamsylate release from the tested formulations, the in-vitro dissolution profiles were fitted to the equations for the Zero-order, First order, Higuchi, Korsmeyer-peppas and Hixson-Crowell models. The best model that can describe the different dissolution profiles was determined. A pilot in vivo pharmacokinetic study was performed in 4 normal male volunteers who received the three CR matrix tablets in three-way crossover experimental design. Serial plasma samples were obtained for 24 hr following administration. Samples were analyzed for etamsylate using HPLC method. Etamsylate pharmacokinetic parameters after administration of the three CR tablets were calculated using noncompartmental data analysis approach.

Results: The dissolution profiles of IR tablets were best fitted to first order model in all pHs. The dissolution was complete within 1 hour in all pHs. However, the dissolution at pH 7.4 was significantly slower than those at pH 1.2, 4.5, and 6.8. This pH-dependent etamsylate dissolution of the IR tablets was the reason for using the pH transition dissolution method to study the dissolution of the CR tablets. The in vitro release profiles of etamsylate CR matrix tablets are shown in Figure 1. The dissolution patterns of the three CR matrix tablets were significantly different, as indicated by the values of mean dissolution time (MDT), mean residence time in the dosage form (MRT_in-vitro), time required for 50% drug release (T_50%), and time required for 80% drug release (T_80%). The calculated MDT was 2.02±0.005, 2.71±0.1, and 4.82±0.2 hr, while MRT_in-vitro was 0.89±0.03, 2.23±0.005, and 3.70±0.04 hr for CR_fast, CR_medium, and CR_slow, respectively. Whereas T_50% was1.35±0.02, 2.48±0.01, and 5.12±0.02 hr, whilst T_80% was 3.45±0.2, 6.36±0.09, and 13.1±1.01 hr for CR_fast, CR_medium, and CR_slow, respectively. The Higuchi model described the dissolution profile of the CR matrix tablets well as shown in figure 2, with Higuchi release rate constant of 43.0, 31.7, and 25.1 mg.hr^−1/2, for CR_fast, CR_medium, and CR_slow, respectively. The mean plasma concentration-time profiles of etamsylate following oral administration of CR_fast, CR_medium, and CR_slow in normal volunteers are shown in Figure 3. After oral administration of the matrix tablets, the Cp_max was 5.72±1.3, 3.93±0.96 and 3.13±0.27 ug/ml, while t_max was 6 (5-8), 8 (8-10), and 10 (8-10) hr, whereas the in vivo mean resident time was 7.68±2.03, 9.55±0.25, and 10.52±1.70 hr for CR_fast, CR_medium, and CR_slow, respectively. This was consistent and in the same order of the in vitro dissolution results obtained using the buffer transition method.

Conclusion: The use of the buffer transition in vitro dissolution method was appropriate to accurately characterize the release of etamsylate from the CR matrix tablets and predict the in vivo performance of the CR tablets. The results of the pilot in vivo pharmacokinetic study demonstrated that the rate of absorption after administration of CR_fast, CR_medium, and CR_slow tablets was consistent with the observed in vitro dissolution results, and the buffer transition method was suitable to characterize the dissolution of the prepared CR tablets.

Fig. 1: In vitro release profiles of CR matrix tablets (CRfast, CRmedium, CRslow) using buffer transition method. Data are presented as n=3, mean±SE.



Fig. 2: Fitting of the Higuchi model to the in vitro dissolution data for the CRfast (R2 = 0.978), CRmedium (R2 = 0.972), and CRslow (R2 = 0.9823) using the buffer transition method.



Fig. 3: The average plasma concentration versus time profiles of etamsylate following oral administration of CR matrix tablets (Mean ± SE; n=4).