Diacerein solid dispersion loaded tablets for minimization of drug adverse effects: statistical design, formulation, in vitro, and in vivo evaluation.

Diacerein is a BCS class II drug employed in osteoarthritis management. The acid/base hydrolysis of the unabsorbed diacerein in the colon is responsible for its laxative effect. Therefore, this work aimed to enhance the solubility, dissolution, and oral bioavailability of diacerein. Such enhancement means lower doses and fewer gastrointestinal adverse effects. A 41.31.21 full factorial design was adopted to prepare 24 solid dispersion formulae. Solid-state characterization showed the dissolution of diacerein crystals as metastable amorphous or microcrystalline forms in a matrix system that enhanced the drug dissolution. Desirability factor suggested compounding an optimized formula (F1) of Pluronic®F68 with 1:3 drug:carrier ratio using rotavap that showed higher drug solubility (187.61 µg/mL) than drug powder (22.5 µg/mL). It achieved higher dissolution efficiency (4.04-fold) and rate (6.6-fold) as well as 100% release in 2 min. F1 was compressed into tablets recording greater dissolution efficiency (1.24-fold) and rate (12.5-fold) than the marketed product. The prepared tablet accomplished a 2.66-fold enhancement in diacerein bioavailability compared to the marketed product. In conclusion, the formulation of diacerein as solid dispersion loaded tablets could be of added value for the treatment of osteoarthritis in terms of enhanced patient compliance. Solid dispersion is an easy and scalable technique.

Solid Form of Lipid-Based Self-Nanoemulsifying Drug Delivery Systems for Minimization of Diacerein Adverse Effects: Development and Bioequivalence Evaluation in Albino Rabbits.

This work aimed to enhance the oral bioavailability of diacerein. The drug was incorporated in self-nanoemulsifying drug delivery system. Ternary phase diagrams were constructed using Capryol™90, Miglyol®812 and isopropyl myristate as oils, Tween®80 and Tween®20 as surfactants and PEG 200 and PEG 300 as co-surfactants. Among a total of 432 formulae, 17 formulae were clear. They were assessed for mean droplet size, polydispersity index (PDI), saturation solubility and transmission electron microscopy. Solid granules were obtained by adsorption on Aeroperl®300. Results for DSC, PXRD, and SEM of prepared granules revealed that diacerein was molecularly dispersed within the formula. Desirability factor was adopted to find the granules with maximum solubility, maximum dissolution efficiency, maximum dissolution rate and percentage of drug dissolved at 5 min and minimum dissolution time and Carr's index. The optimized formula consisted of 10% Miglyol®812, 70% Tween®80 and 20% PEG 200 adsorbed to Aeroperl® 300 with a ratio of 2:1 preconcentrate:carrier. It recorded a 3.77-fold increase in bioavailability, compared to the marketed product. Such enhancement means lower doses and less gastrointestinal side effects.