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Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane

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Abstract

Purpose

The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature.

Method

Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations.

Results

Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5–3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature.

Conclusions

It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.

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Abbreviations

A:

Area (cm2)

ABL:

Aqueous boundary layer;

ACN:

Acetonitrile;

API:

Active pharmaceutical ingredient;

ASB:

Acceptor sink buffer;

ASD:

Amorphous solid dispersion;

C:

Concentration (μg/mL), subscripts D or R refer to donor or receiver;

Daq :

Aqueous diffusion coefficient (cm2 s−1);

Deff :

Effective diffusion coefficient (cm2 s−1);

DLS:

Dynamic light scattering;

DMSO:

Dimethyl sulfoxide;

DSC:

Differential scanning calorimetry;

FaSSGF:

Fasted state simulated gastric fluid;

FaSSIF:

Fasted state simulated intestinal fluid;

FeSSIF:

Fed state simulated intestinal fluid;

GIT:

Gastrointestinal;

hABL :

Thickness of aqueous boundary layer;

HCl:

Hydrochloric acid;

HME:

Hot melt extrusion;

HPC-L:

Hydroxypropylcellulose;

HPβCD:

Hydroxypropyl-β-cyclodextrin;

HPMC:

Hydroxypropyl methylcellulose;

ITZ:

Itraconazole, a studied compound;

J:

Flux (μg min−1 cm−2)

LLD:

Laser light diffraction;

OH-ITZ:

Hydroxy-itraconazole;

PABL :

ABL permeability (cm s−1);

Pe :

Effective permeability (cm s−1);

Pm :

Membrane permeability (cm s−1);

PAMPA:

Parallel artificial membrane permeability assay;

PK:

Pharmacokinetic;

PVDF:

Polyvinylidenfluoride;

SEM:

Scanning electron microscopy;

TFA:

Trifluoroacetic acid;

UPLC:

Ultra performance liquid chromatography;

V:

Volume (mL);

v/v/v:

Volume/volume/volume;

w/w:

Weight/weight;

XRPD:

X-ray powder diffraction;

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors would like to thank Dr. Karl Box (Sirius Analytical - a Pion Company) for providing supporting experimental data for pKa measurements of Itraconazole.

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Authors and Affiliations

  1. Pion Inc., 10 Cook St, Billerica, Massachusetts, 01821, USA

    Konstantin Tsinman, Oksana Tsinman & Ram Lingamaneni

  2. Technical R&D Shangai Novartis Trading Ltd., Novartis Pharma AG, Shangai, China

    Saijie Zhu

  3. Technical R&D, Novartis Pharma AG, Basel, Switzerland

    Bernd Riebesehl, Arnaud Grandeury, Michael Juhnke & Bernard Van Eerdenbrugh

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  1. Konstantin Tsinman
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  2. Oksana Tsinman
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Correspondence to Konstantin Tsinman.

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Tsinman, K., Tsinman, O., Lingamaneni, R. et al. Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane. Pharm Res 35, 161 (2018). https://doi.org/10.1007/s11095-018-2440-3

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  • DOI: https://doi.org/10.1007/s11095-018-2440-3

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