Hydroxypropyl-β-cyclodextrin functionalized calcium carbonate microparticles as a potential carrier for enhancing oral delivery of water-insoluble drugs

Abstract

The objective of the present study was to demonstrate that a novel hydroxypropyl-β-cyclodextrin functionalized calcium carbonate (HP-β-CD/CC) based amorphous solid dispersion (ASD) can be used to increase the solubility and oral bioavailability of water-insoluble drugs. Irbesartan (IRB) was selected as a model compound and loaded into the nanoporous HP-β-CD/CC matrix using an immersion method. The IRB-loaded HP-β-CD/CC formulation was characterized by various analytical techniques, such as specific surface area analysis, scanning electron microscopy (SEM), dynamic light scattering (DLS), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Analyses with PXRD and DSC confirmed that IRB was fully converted into the amorphous form in the nanopores of HP-β-CD/CC. From the solubility and dissolution tests, it was observed that the aqueous solubility and dissolution rate of IRB-loaded HP-β-CD/CC were increased significantly compared with those of pure IRB and IRB-loaded mesoporous silica. Likewise, the IRB-loaded HP-β-CD/CC formulation exhibited better absorption compared with that of the commercially available IRB capsules in beagle dogs. The mean peak plasma concentration (C max) and the area under the mean plasma concentration-time curve (AUC[0→48]) of IRB-loaded HP-β-CD/CC were 1.56- and 1.52-fold higher than that of the commercial product, respectively. Furthermore, the IRB-loaded HP-β-CD/CC formulation exhibited excellent stability against re-crystallization. These results clearly demonstrate that HP-β-CD/CC based porous ASD is a promising formulation approach to improve the aqueous solubility and the in vivo absorption performance of a water-insoluble compound like IRB.

Keywords: bioavailability; dissolution rate; nanopore; solid dispersion; solubility.

Figure 1

SEM photographs of (A) and (B) HP-β-CD/CC, (C) crude IRB, and (D) IRB-HP-β-CD/CC. Notes: (B inset) primary particles of HP-β-CD/CC, and (D inset) high-magnification of IRB-HP-β-CD/CC. Abbreviations: HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; IRB-HP-β-CD/CC, irbesartan loaded-HP-β-CD/CC; SEM, scan ning electron microscopy.

Figure 2

TEM photographs of (A) HP-β-CD/CC and (C) SBA-16; SEM photographs of (B) SBA-16 and (D) IRB-SBA-16. Note: (A inset) primary particles of HP-β-CD/CC. Abbreviations: HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; SBA-16, Santa Barbara amorphous materials-16; IRB-SBA-16, irbesartan loaded-SBA-16; TEM, transmission electron microscopy.

Figure 3

PXRD patterns of (A) crude IRB, (B) HP-β-CD/CC, (C) PM, (D) IRB-HP-β-CD/CC, (E) IRB-SBA-16, and (F) IRB-HP-β-CD/CC after 6 months of storage. Abbreviations: HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; IRB-HP-β-CD/CC, irbesartan loaded-HP-β-CD/CC; SBA-16, Santa Barbara amorphous materials-16; IRB-SBA-16, irbesartan loaded-SBA-16; PXRD, powder X-ray diffraction; PM, physical mixture.

Figure 4

DSC thermograms of (A) HP-β-CD/CC, (B) crude IRB, (C) PM, (D) IRB-HP-β-CD/CC and (E) HP-β-CD/CC after 6 months of storage. Abbreviations: HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; IRB-HP-β-CD/CC, irbesartan loaded-HP-β-CD/CC; PM, physical mixture; DSC, differential scanning calorimetry.

Figure 5

Dissolution of IRB from different formulations in (A) SGF and (B) SIF. Notes: (a) crude IRB, (b) PM, (c) IRB-HP-β-CD/CC, (d) IRB-HP-β-CD/CC after 6 months of storage, and (e) IRB-SBA-16. Each data point represents the mean ± SD (n=3). Abbreviations: IRB, irbesartan; SGF, simulated gastric fluid; SIF, simulated intestinal fluid; SBA-16, Santa Barbara amorphous materials-16; IRB-SBA-16, irbesartan loaded-SBA-16; HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; IRB-HP-β-CD/CC, irbesartan loaded-HP-β-CC; PM, physical mixture; SD, standard deviation.

Figure 6

Effect of HP-β-CD/CC and SBA-16 on HT-29 cell viability at various concentrations (n=6). Abbreviations: HP-β-CD/CC, hydroxypropyl-β-cyclodextrin functionalized calcium carbonate; SBA-16, Santa Barbara amorphous materials-16.

Figure 7

Plasma concentration–time profiles of the IRB formulations tested. Note: Each data point represents the mean ± SD (n=6). Abbreviations: IRB, Irbesartan; HP-β-CD/CC, hydroxypropyl-β-cyclodextrin fun-ctionalized calcium carbonate; IRB-HP-β-CD/CC, irbesartan loaded-HP-β-CC; SD, standard deviation.