Inhomogeneous Phase Significantly Reduces Oral Bioavailability of Felodipine/PVPVA Amorphous Solid Dispersion

Abstract

Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous "30 wt % ASD" prepared by spray drying, as well as inhomogeneous "30 wt % PM" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug−polymer interaction mechanism and "apparent" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single T g in 30 wt % ASD confirmed its homogeneous phase. 1 H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous "30 wt % ASD" has more numbers of interacting drug−polymer pairs, and thus exhibits stronger "apparent" interaction strength comparing with that of inhomogeneous "30 wt % PM". Unexpectedly,in the in vitro dissolution studies, inhomogeneous "30 wt % PM" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous "30 wt % ASD". However, drug precipitate recrystallized much slower in homogeneous "30 wt % ASD", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous "30 wt % ASD" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (C max ) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous "30 wt % PM". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug−polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.

Characterization and Dissolution Mechanism of Low-Molecular-Weight Organic Acids or Inorganic Mesoporous Particle-Based Piperine Amorphous Solid Dispersions

“…It indicated that PIP and MSN performed hydrogen bonds. Similar hydrogen-bonded complexion was commonly mentioned in the literature …”

“…Similar hydrogen-bonded complexion was commonly mentioned in the literature. 36 In Vitro Dissolution Behavior of PIP-ASDs. The dissolution profiles of PIP, PMs, and PIP-ASDs in different dissolution media are presented in Figure 6.…”

Preparation of astaxanthin‐loaded composite micelles with coaxial electrospray technology for enhanced oral bioavailability and improved antioxidation capability

“…Physical status of the AST in the composite micelles Differential scanning calorimetry and XRD tests 5,20 were performed to determine the physical status of the AST in the composite micelles. The DSC thermograms are shown in Fig.…”

“…3 Amorphous solid dispersion (ASD) refers to a single homogeneous dispersion system formed when drugs are highly dispersed in solid carriers in an amorphous form. 4,5 Amorphous drugs have higher apparent solubility than crystalline drugs. 6,7 The dispersion of solid carriers could increase the dissolution surface area of drugs by improving the dissolution rate of waterinsoluble drugs as well as their bioavailability, and this has good prospects for commercial development.…”

“…So far, the strategies commonly used to improve the solubility of water‐insoluble drugs include the use of cyclodextrin, self‐emulsification systems, solid lipid nanoparticles, solid dispersions, liposomes, co‐crystallization, and microenvironmental pH regulation 3 . Amorphous solid dispersion (ASD) refers to a single homogeneous dispersion system formed when drugs are highly dispersed in solid carriers in an amorphous form 4,5 . Amorphous drugs have higher apparent solubility than crystalline drugs 6,7 .…”