Development and Pharmacokinetic Evaluation of Binary Carrier-Based Solid Dispersion of Desidustat, a New Drug for Chronic Kidney Disease-Associated Anemia
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Abstract
Purpose
Desidustat is a new oral hypoxia-inducible factor prolyl hydroxylase inhibitor indicated for the management of chronic kidney disease-related renal anemia. Poor aqueous solubility of desidustat restricts its dissolution and leads to poor oral bioavailability.
Methods
A simple melt quenching method has been developed for solid dispersions (SD) of desidustat using PVP K30 and poloxamer 188 as a binary carrier system. Polymer selection was done based on the miscibility study with the drug.
Results
The aqueous solubility of desidustat was increased up to 8 times in SD with a drug: carrier (PVPK30-poloxamer 188) ratio of 1:3 (w/w). Thermal analysis by DSC indicated conversion of crystalline desidustat to amorphous in solid dispersion. Hydrogen bonding between the drug and polymer was noticed by infrared (IR) spectroscopy. Powdered X-ray diffraction revealed the loss of crystalline drug peaks in SD, confirming its conversion from crystalline to partially amorphous. An in vitro drug release study showed 96.8% release from desidustat SD in 6 hours in a basic medium (pH 6.8). The enhancement of dissolution was dependent on the drug: carrier ratio. The increased solubility by the hydrophilic carrier system and the loss of crystallinity are two main reasons for enhanced dissolution. An in vivo pharmacokinetic study showed 1.6 times enhancement in oral bioavailability from desidustat solid dispersion compared to the raw drug.
Conclusion
The solid dispersion approach can improve desidustat oral bioavailability. PVP K30 and poloxamer 188 can serve as an effective binary carrier system for the dispersion.
期刊介绍:
The Journal of Pharmaceutical Innovation (JPI), is an international, multidisciplinary peer-reviewed scientific journal dedicated to publishing high quality papers emphasizing innovative research and applied technologies within the pharmaceutical and biotechnology industries. JPI''s goal is to be the premier communication vehicle for the critical body of knowledge that is needed for scientific evolution and technical innovation, from R&D to market. Topics will fall under the following categories:
Materials science,
Product design,
Process design, optimization, automation and control,
Facilities; Information management,
Regulatory policy and strategy,
Supply chain developments ,
Education and professional development,
Journal of Pharmaceutical Innovation publishes four issues a year.