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In Vivo-Relevant Transwell Dish-Based Dissolution Testing for Orally Inhaled Corticosteroid Products

  • Masahiro SakagamiEmail author
  • Hua Li
  • Jügen Venitz
Research Paper
  • 69 Downloads

Abstract

Purpose

To establish an in vivo-relevant Transwell dish-based dissolution test system for the “respirable” aerosols of inhaled corticosteroids (ICSs) using marketed inhaler products.

Methods

“Respirable” ≤ 5.8 or 6.5 μm aerosols of 7 ICSs from 11 inhaler products were collected onto the filter membranes under the modified assembly of the cascade impactor. Their dissolution in 10 ml of the simulated lung lining fluid (sLLF) was determined over time in the Transwell dish at 37°C and ~100% relative humidity in the presence of subsequent diffusive permeation across the Transwell’s supporting membrane.

Results

While three ICSs with high-to-intermediate solubility enabled the first-order “sink” and complete dissolution in 6 h, 4 ICSs with poor solubility including fluticasone propionate (FP) resulted in the pseudo-zero-order “non-sink”, slow and limited dissolution. The aerosol dissolution rate constants (kdiss) were derived, well-correlated with the solubility. For FP, but not for highly-soluble flunisolide (FN), dissolution was kinetically aerosol mass-dependent. However, for a given ICS, dissolution profiles were indistinguishable between the formulations and products upon comparable aerosol mass collection.

Conclusions

The in vivo-relevant Transwell dish-based “respirable” aerosol dissolution test system was developed, kinetically discriminative in accordance with the ICS solubility, but indistinguishable for a given ICS between the marketed products.

KEY WORDS

bioequivalence cascade impactor dissolution inhaled corticosteroid transwell 

Abbreviations

ACI

Andersen cascade impactor

BD

Budesonide

BDP

Beclomethasone dipropionate

BE

Bioequivalence

CFC

Chlorofluorocarbon

CIC

Ciclesonide

DPI

Dry powder inhaler

DPPC

Dipalmitoyl phosphatidylcholine

FDA

Food and Drug Administration

FN

Flunisolide

FP

Fluticasone propionate

HFA

Hydrofluoroalkane

HPLC-UV

High performance liquid chromatography method with ultraviolet detection

ICS

Inhaled corticosteroid

IVIVC

In vitro and in vivo correlation

kdiss

Rate constant for dissolution

kobs

Observed rate constant for dissolution and permeation

kperm

Rate constant for permeation

LLF

Lung lining fluid

MDI

Metered dose inhaler

MF

Mometasone furoate

NC

Nitrocellulose

OIDP

Orally inhaled drug product

PC

Polycarbonate

PK

Pharmacokinetics

SD

Standard deviation

sLLF

Simulated lung lining fluid

TA

Triamcinolone acetonide

TPGS

d-α-tocopheryl polyethylene glycol 1000 succinate

USP

United States Pharmacopeia

Notes

Supplementary material

11095_2019_2635_MOESM1_ESM.docx (45 kb)
ESM 1 (DOCX 45 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutics, School of PharmacyVirginia Commonwealth University (VCU)RichmondUSA

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