Formulation Approaches for Improving the Dissolution Behavior and Bioavailability of Tolvaptan Using SMEDDS

• Main Authors: Jong-Hwa Lee (Author), Gye-Won Lee (Author)
• Format: Book
• Published: MDPI AG, 2022-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Tolvaptan, a selective vasopressin receptor antagonist, is a Class IV agent of Biopharmaceutical Classification System (BCS). To improve bioavailability after oral administration, the new tolvaptan-loaded self-microemulsifying drug delivery system (SMEDDS) was further optimized using a "design of the experiment (DoE)" including components of D-optional mixture design. Based on a solubility study of tolvaptan in various oils, surfactants, and cosurfactants, Capryol^® 90, Tween 20, and Transcutol^® HP [or polyethylene glycol 200 (PEG 200)] were finally selected for optimization of tolvaptan-loaded SMEDDS formulations. The fitting models of, and poly-nominal equations for, all response variables were acceptable, as revealed by analysis of variance (ANOVA, <i>R</i>² > 0.900, <i>p</i> < 0.0001). The optimized formulations A-1 (Capryol^® 90/Tween 20/Transcutol^® HP = 10%/70%/20% <i>w</i>/<i>w</i>) and B-1 (Capryol^® 90/Tween 20/PEG 200 = 10%/70%/20% <i>w</i>/<i>w</i>) with desirabilities of 0.905 and 1.000, respectively, showed low droplet size and the dissolution rate exceeded 95% at 15 and 60 min. The tolvaptan-loaded SMEDDS remained stable for 3 months under accelerated conditions, thus with no change in any of content, color, particle size, or dissolution rate. In a rat pharmacokinetic study, the bioavailability of formulations A-1 (16.6%) and B-1 (11.5%) were 23-33-fold higher than that of raw tolvaptan powder (0.5%). Thus, the use of "quality by design (QbD)" during development of tolvaptan-loaded SMEDDS improved the dissolution rate and oral drug bioavailability.

Item Description

10.3390/pharmaceutics14020415
1999-4923