Nanocrystalline Suspensions of Irbesartan Enhance Oral Bioavailability by Improving Drug Solubility and Leading Endocytosis Uptake into the Intestine

We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.

The thermodynamic study of p-methoxycinnamic acid inclusion complex formation, using β-cyclodextrin and hydroxypropyl-β-cyclodextrin

Objectives Cyclodextrin’s ability to form an inclusion complex with a guest molecule is a function of two factors. The first is steric and depends on the relative size of cyclodextrin cavity to the guest molecule, while the second is the thermodynamic interaction between the different system components. This study therefore aims to determine the effect of β-cyclodextrin and hydroxypropyl-β-cyclodextrin as complex formers, on thermodynamic parameter values (ΔH, ΔG, and ΔS) in the formation of inclusion complex with p-methoxycinnamic acid (pMCA). Methods The pMCA complex formation with β-cyclodextrin or hydroxypropyl-β-cyclodextrin was determined in 0.02 pH 4.0 M acetate buffer and 0.02 M pH 7.0 phosphate buffer, with a 0.2 µ value at 32, 37, and 42 ± 0.5 °C. This experiment was carried out in a waterbath shaker until a saturated solution was obtained. Subsequently, pMCA concentration was determined using UV spectrophotometer at the maximum pMCA wavelength, at each pH. Results The result showed pMCA formed inclusion complex with β-cyclodextrin or hydroxypropyl-β-cyclodextrin and exhibited increased solubility with increase in β-cyclodextrin or hydroxypropyl-β-cyclodextrin concentration. This temperature rise led to a decrease in the complex’s constant stability (K). Furthermore, the interaction showed a negative enthalpy (∆H<0) and is a spontaneous processes (∆G<0). At pH 4.0, an increase in the system’s entropy occurred (∆S>0), however, at pH 7.0, the system’s entropy decreased (∆S<0). Conclusions The rise in pMCA solubility with increase in cyclodextrin solution concentration indicates an inclusion complex has been formed, and is supported by thermodynamic data.

A detailed computational study on binding of kinase inhibitors into β-cyclodextrin: inclusion complex formation

It is well known that the limited aqueous solubility of some drugs often reduces their bioavailability to targets.