Three dimensional macroporous hydroxyapatite/chitosan foam-supported polymer micelles for enhanced oral delivery of poorly soluble drugs

In the current study, a novel three-dimensional macroporous hydroxyapatite/ chitosan foam (HA/CS)-supported polymer micelle (PM/HA/CS) was developed, and its potential as an oral drug delivery system to enhance the solubility and oral bioavailability of poorly soluble compounds was systemically studied. Candesartan cilexetil (CC) was selected as a poorly soluble model drug. Firstly, HA/CS foam was synthesized using a wet chemical coprecipitation approach and poly-(methyl methacrylate) colloidal crystals as a macropore template. Subsequently, the CC-loaded polymer micelles were efficiently encapsulated into the macropores of the HA/CS foam and freeze-dried to produce powdery CC-loaded PM/HA/CS composites (CC-PM/HA/CS). The resulting CC-PM/HA/CS particles were then characterized in terms of porous structure, morphology, angle of repose, crystallinity, drug loading, dissolution profiles, and physical stability. Differential scanning calorimetry (DSC) analysis confirmed that CC-PM/HA/CS was present in an amorphous form and has an excellent physical stability. Under both simulated gastric and intestinal conditions, the aqueous solubility and dissolution rate of the PM/ HA/CS-based CC formulation were significantly increased compared with the pure drug powder. In addition, PM/HA/CS is almost completely non-cytotoxic. The PM/HA/CS-based CC formulation produced approximately 1.9-fold increased bioavailability when compared to the marketed tablets (Blopress) administered to fasted Sprague-Dawley rats. On the whole, PM/HA/CS benefits from the advantages of three dimensional macroporous HA/CS foam and polymer micelles, and exhibits great potential as a drug delivery system for increasing the solubility and oral bioavailability of a poorly soluble compound, like CC.