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In Vitro Aqueous Fluid-Capacity-Limited Dissolution Testing of Respirable Aerosol Drug Particles Generated from Inhaler Products

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Abstract

Purpose

To develop a unique in vitro aqueous fluid-capacity-limited dissolution system for the kinetic assessment of respirable aerosol drug particles from inhaler products.

Methods

Aerosol particles of 5 inhaled corticosteroids (ICSs) from 7 inhaler products were collected in the aerodynamic 2.1–3.3 or 4.7–5.8 μm on the filter membranes using the Andersen cascade impactor. Each filter membrane was then placed onto the donor compartment of the Transwell® system, where addition of 0.04ml aqueous fluid initiated aerosol ICS dissolution and permeation across its supporting membrane at 37°C and ∼100% humidity.

Results

The % profiles of dissolution and permeation were apparent first-order or pseudo-zero-order, reaching varying 1.9–95.0% by 5 h. Their kinetics overall conformed to the ICS aqueous solubility. With increasing aerosol mass, however, the profiles decelerated, attributed to undissolved ICSs left by the limited dissolution fluid capacity. The profiles could be also product-specific, as beclomethasone dipropionate aerosols from QVAR® dissolved faster than those from VANCERIL®, whereas fluticasone propionate aerosols from two different inhaler products exhibited comparable profiles. The 2.1–3.3 μm aerosols dissolved faster than the 4.7–5.8 μm aerosols.

Conclusions

Aerosol ICS dissolution into the limited aqueous fluid volume differed kinetically due to ICS solubility and aerosol mass, size, formulation and/or generation.

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Abbreviations

ACI:

Andersen non-viable Cascade Impactor

ANOVA:

analysis of variance

APCI:

atmospheric pressure chemical ionization

API:

active pharmaceutical ingredient

BD:

budesonide

BDP:

beclomethasone dipropionate

CFC:

chlorofluorocarbon

DDW:

distilled deionized water

DPI:

dry powder inhaler

ESI:

electrospray ionization

FN:

flunisolide

FP:

fluticasone propionate

HFA:

hydrofluoroalkane

HPLC:

high performance liquid chromatography

ICS:

inhaled corticosteroid

LOQ:

limit of quantification

MS:

mass spectrometry

PBS:

phosphate-buffered saline

pMDI:

pressurized metered dose inhaler

PVDF:

polyvinylidene difluoride

SD:

standard deviation

TA:

triamcinolone acetonide

US:

United States

USP:

United States Pharmacopeia

UV:

ultraviolet

VCU:

Virginia Commonwealth University

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Acknowledgments

The authors are grateful to H. Thomas Karnes, Ph.D. (VCU School of Pharmacy, VCU-SOP) for allowing the use of HPLC-MS/MS for FP and BDP assays. This research was funded by the Medical College of Virginia Foundation and VCU-SOP. D.A. acknowledges financial supports from the International Foundation of Ethical Research and VCU-SOP during her graduate study.

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Correspondence to Masahiro Sakagami.

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Arora, D., Shah, K.A., Halquist, M.S. et al. In Vitro Aqueous Fluid-Capacity-Limited Dissolution Testing of Respirable Aerosol Drug Particles Generated from Inhaler Products. Pharm Res 27, 786–795 (2010). https://doi.org/10.1007/s11095-010-0070-5

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  • DOI: https://doi.org/10.1007/s11095-010-0070-5

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