Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Tranilast with Enhanced Solubility in Gastric Fluid and Improved Oral Bioavailability

Abstract

In the present study, amorphous solid dispersion (ASD) formulations of tranilast (TL) with 8 hydrophilic polymers were prepared by a solvent evaporation method with the aim of improving dissolution behavior in gastric fluid and thereby enhancing oral bioavailability. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, drug-polymer interaction, and stability. Of all TL formulations, ASD formulation with Eudragit EPO exhibited the highest improvement in dissolution behavior with a 3,000-fold increase in the first-order dissolution rate under acidic conditions (pH 1.2). Spectroscopic studies using infrared and near-infrared analyses revealed the drug-polymer interaction in the Eudragit EPO-based ASD formulation. On the basis of dissolution, crystallinity, and stability data, the maximum allowable drug load in the Eudragit EPO-based ASD formulation was deduced to be ca. 50%. Pharmacokinetic profiling of orally dosed TL formulations in rats was also carried out using UPLC/ESI-MS. After oral administration of the Eudragit EPO-based ASD formulation in rats, enhanced TL exposure was observed with an increase of oral bioavailability by 19-fold, and the variation of AUC was ca. 4 times lower than that with crystalline TL. With these data, the ASD approach could be a viable formulation strategy for enhancing the wettability and oral bioavailability of TL, resulting in improved therapeutic potential of TL for the treatment of inflammatory diseases.

Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology

“…19) FT-IR spectroscopic analysis was performed in order to investigate the possible interaction between DP and polymer in SD-Eud/DP/TA (Fig. 6).…”

In vitro/in vivo characterization of nanocrystalline formulation of tranilast with improved dissolution and hepatoprotective properties

“…To prepare a physical mixture of crystalline TL and polymer (PM/TL), crystalline TL (100 mg) and HPC-SL (400 mg) were added into a polyethylene tube and blended with a Turbula Ò Shaker-Mixer (Willy A. Bachofen AG Maschinenfabrik, Switzerland) at 30 rpm for 15 min. The amount of TL in the obtained formulation was determined by a Waters Acquity UPLC system (Waters, Milford, MA) as reported previously [2].…”

“…Ltd., Mumbai, India). Samples after storage were subjected to the UPLC/ESI-MS [2], PXRD and DLS experiments.…”

“…There are over 100 million people with hepatic fibrosis globally, and progressive fibrosis ultimately leads to increased mortality and morbidity from portal hypertension, end-stage liver failure and ultimately cirrhosis. Tranilast [TL: N- (3,4-dimethoxycinnamoyl) anthranilic acid] has been clinically used as an anti-inflammatory and anti-fibrotic drug since it can attenuate the production or release of inflammatory cytokines or prostanoids from mast cells and monocytes [2]. TL has also been shown to inhibit collagen synthesis and the activation of transforming growth factor b1; therefore, considerable attention has been drawn to the therapeutic potential of TL for various fibrotic diseases, including hepatic fibrosis and pulmonary fibrosis.…”

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization

“…Conversely, when utilising EPO as a matrix carrier, 624 competition between EPO and the coformer isonicotinamide to form hydrogen 625 bonds with ibuprofen would further impact upon cocrystal yield. There have 626 been many reports of interactions between carboxylic acids and EPO [66][67][68] . 627…”