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

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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.

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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

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University (VCU), 410 N 12th Street, P.O. Box 980533, Richmond, Virginia, 23298-0533, USA

    Masahiro Sakagami, Hua Li & Jügen Venitz

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  1. Masahiro Sakagami
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  2. Hua Li
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  3. Jügen Venitz
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Correspondence to Masahiro Sakagami.

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Sakagami, M., Li, H. & Venitz, J. In Vivo-Relevant Transwell Dish-Based Dissolution Testing for Orally Inhaled Corticosteroid Products. Pharm Res 36, 95 (2019). https://doi.org/10.1007/s11095-019-2635-2

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