Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products

Robert Price,Nikoletta Fotaki,Sau Lee,Gonçalo Farias,Bhawana Saluja,William Ganley,Renishkumar Delvadia,Denise S. Conti,Mohammad Absar,Jagdeep Shur

doi:10.1208/s12248-020-0422-y

Robert Price, Nikoletta Fotaki + Show 8 more

Open Access

https://doi.org/10.1208/s12248-020-0422-y

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Abstract

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.

Highlights

For a locally acting inhaled drug product to elicit a pharmacological effect, the therapeutic dose must first reach the mucosal surface, lining the respiratory tract
The system was used to study the relationship between mean absorption time and dissolution kinetics of a series of low solubility inhaled corticosteroids
To validate the collection efficiency of the aerosol dose collection (ADC) system, the impactor stage mass (ISM) collected onto the glass fiber filter within the ADC, from a commercial 250 μg fluticasone propionate (FP) dry powder inhaler (DPI), was compared with standard in vitro Next Generation Impactor (NGI) recovery at a flow rate of 60 L/min

Summary

Introduction

For a locally acting inhaled drug product to elicit a pharmacological effect, the therapeutic dose must first reach the mucosal surface, lining the respiratory tract. The US Food and Drug Administration (FDA) currently recommend the aggregated weight of evidence approach to establish bioequivalence between test and reference OIDPs [2] This relies on comparative in vitro studies (for equivalence in product performance) and comparative in vivo studies [pharmacokinetic (PK) for equivalence in systemic exposure and pharmacodynamic (PD) or clinical endpoint (CE) for equivalence in drug delivery at the sites of action] in addition to formulation sameness (Q1 and Q2, i.e., the same inactive ingredients and at the same concentration ± 5% as the reference product) and device similarity.

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