mp0c00471_si_001.pdf (1.63 MB)
Novel High-Drug-Loaded Amorphous Dispersion Tablets of Posaconazole; In Vivo and In Vitro Assessment
journal contribution
posted on 2020-09-04, 09:29 authored by Deanna M. Mudie, Aaron M. Stewart, Nishant Biswas, Timothy J. Brodeur, Kimberly B. Shepard, Adam Smith, Michael M. Morgen, John M. Baumann, David T. VodakAmorphous solid dispersions (ASDs)
can increase the bioavailability
of drugs with poor aqueous solubility. However, concentration-sustaining
dispersion polymers (CSPs) incorporated in ASDs can result in low
drug loading and, therefore, a large dosage-form size or multiple
units to meet dose requirements, potentially decreasing patient compliance.
To address this challenge, a high-loaded dosage-form (HLDF) architecture
for ASDs was developed, in which a drug is first spray-dried with
a high glass-transition temperature (Tg) dispersion polymer to facilitate high drug loading while maintaining
physical stability. The ASD is then granulated with a CSP designed
to extend supersaturation in solution. The HLDF differs from traditional
ASD architectures in which the dispersion polymer inside the ASD acts
as the CSP. By strategically combining two different polymers, one
“inside” and one “outside” the ASD, solubilization
performance, physical stability, and overall drug loading are maximized.
This study demonstrates in vivo performance of the
HLDF architecture using posaconazole as a model drug. Two sizes of
HLDF tablets were tested in beagle dogs, along with traditional ASD
architecture (benchmark) tablets, ASD tablets without a CSP, and a
commercial crystalline oral suspension (Noxafil OS). HLDF tablets
performed equivalently to the benchmark tablets, the smaller HLDF
tablet being 40% smaller (by mass) than the benchmark tablet. The
HLDF tablets doubled the blood plasma AUC relative to Noxafil OS.
In line with the in vivo outcome, in vitro results in a multicompartment dissolution apparatus demonstrated
similar area under the curve (AUC) values in the intestinal compartment
for ASD tablets. However, the in vitro data underpredicted
the relative in vivo AUC of Noxafil OS compared to
the ASD tablets. This study demonstrated that the HLDF approach can
increase drug loadings while achieving good performance for ASD drug
products.