New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium

Abstract

Candesartan cilexetil (CC) is a poorly soluble antihypertensive drug with in vivo absorption limited by its low aqueous solubility. Aiming to generate CC supersaturation as strategy to improve its absorption and bioavailability, amorphous solid dispersions (ASDs) of CC with hydroxypropylmethylcellulose acetate succinate type M (HPMCAS M) were developed and evaluated by in vitro and in vivo techniques. The ASDs were characterized by several solid-state techniques and evaluated regarding the supersaturation generation and maintenance under non-sink conditions in biorelevant medium. Stability studies at different storage conditions and in vivo pharmacodynamics studies were performed for the best formulation. The ASD developed presented appropriate drug amorphization, confirmed by solid state characterization, and CC apparent solubility increases around 85 times when compared to the pure crystalline drug. Supersaturation was maintained for up to 24 h in biorelevant medium. The in vivo pharmacodynamics studies revealed that ASD of CC with the polymer HPMCAS M presented an onset of action about four times faster when compared to the pure crystalline drug. The CC-HPMCAS ASD were successfully developed and demonstrated good physical stability under different storage conditions as well as promising results that indicated the ASD potential for improvement of CC biopharmaceutical properties.

Keywords:

• Candesartan cilexetil
• HPMCAS
• supersaturating drug delivery systems
• biorelevant media
• in vitro supersaturation
• in vivo evaluation

Acknowledgements

The authors gratefully acknowledge Dr. Marcos José Machado (UFSC) for the availability of PLM, Dr. Adailton Bortolluzi and FINEP for XRDP analyses, LCME (UFSC) for the availability of SEM, and Univille for the opportunity of using the mechanical ball mill. We also gratefully acknowledge Ashland for providing the HPMCAS M polymer.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors gratefully acknowledge the Brazilian Governmental Agencies CAPES and CNPq for the financial support.