A new design for a chronological release profile of etodolac from coated bilayer tablets: In-vitro and in-vivo assessment

Abstract

Repeated dose medication usually maximizes adverse effects, while sustained release systems did not offer a fast onset of action. Etodolac was formulated to enable pulsatile and sustained drug release, which was chronologically more suitable as an anti-inflammatory drug. Eudragit® RSPO, Eudragit® RLPO, and HPMC K15M were added in the sustained release layer and tried in different ratios. Croscarmellose sodium or sodium starch glycolate were used as superdisintegrants for the fast release layer offering the loading dose for rapid onset of drug action. Bilayer tablets were successively coated with Opadry®II, HPMC K4M and E5 (1:40), and Surelease®. All formulations complied with the Pharmacopeial standards for post-compression parameters. In-vitro release profile illustrated a lag-time of 4 h followed by a rapid loading dose release for 2 h. A prolonged steady state release with a t_1/2 of 11 h lastly occurred. The coated bilayer tablet showed pulsatile and sustained release effects in rats. The licking time and swelling degree were tested and results demonstrated significant difference (P < 0.05) between the sustained anti-inflammatory action of formulation C1 compared to other groups. Therefore the new chronological design could provide a consistent drug release over 24 h with good protection against associated symptoms of gastric release.

Keywords: Bilayer tablet; Etodolac; Opadry; Pulsatile release; Surelease; Sustained release.

Graphical abstract

Fig. 1

In-vitro release profiles of ETD from different fast release formulations containing different types of disintegrants in simulated gastric fluid (pH 1.2).

Fig. 2

In-vitro release profiles of ETD from different sustained release formulations containing Eudragit® RSPO, Eudragit® RLPO and/or HPMC in simulated gastric fluid (pH 1.2) for 2 h then in simulated intestinal fluid (pH 6.8).

Fig. 3

Disintegration levels of the fast release layer of the bilayer tablet in simulated gastric fluid (pH 1.2) after (a) 5 mins, (b) 10 mins and (c) 15 mins.

Fig. 4

In-vitro release profiles of ETD from bilayer tablet before and after coating in simulated gastric fluid (pH 1.2) for 2 h then in simulated intestinal fluid (pH 6.8).

Fig. 5A

FT-IR spectra of (a) ETD, (b) PEG 6000, (c) Eudragit® RSPO, (d) Eudragit® RLPO, (e) HPMC, (f) Avicel PH-101, (g) SSG, (h) CCNa, (i) Magnesium stearate and (j) powder mixture.

Fig. 5B

DSC curves of (a) ETD, (b) HPMC, (c) PEG 6000, (d) Eudragit® RSPO, (e) Eudragit® RLPO, and (f) Mixture of the optimized formulation.

Fig. 5C

SEM photomicrographs of (a) bilayer tablet, (b) fast release layer, (c) and (d) sustained release layer.

Fig. 6

Swelling degrees in rats groups after inflammation induction.