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Pharmaceutical Research

, 35:161 | Cite as

Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane

  • Konstantin Tsinman
  • Oksana Tsinman
  • Ram Lingamaneni
  • Saijie Zhu
  • Bernd Riebesehl
  • Arnaud Grandeury
  • Michael Juhnke
  • Bernard Van Eerdenbrugh
Research Paper

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.

KEY WORDS

Flux dissolution-permeation itraconazole solid dispersion nanosuspension 

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;

Notes

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Konstantin Tsinman
    • 1
  • Oksana Tsinman
    • 1
  • Ram Lingamaneni
    • 1
  • Saijie Zhu
    • 2
  • Bernd Riebesehl
    • 3
  • Arnaud Grandeury
    • 3
  • Michael Juhnke
    • 3
  • Bernard Van Eerdenbrugh
    • 3
  1. 1.Pion Inc.BillericaUSA
  2. 2.Technical R&D Shangai Novartis Trading Ltd.Novartis Pharma AGShangaiChina
  3. 3.Technical R&DNovartis Pharma AGBaselSwitzerland

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