Ranking in Vitro Dissolution of Inhaled Micronized Drug Powders including a Candidate Drug with Two Different Particle Sizes

Abstract

Pulmonary dissolution of poorly soluble drug substances (DSs) may limit the drug absorption rate and consequently influence clinical performance. Dissolution rate is thus an important quality attribute, and its influence on in vivo drug release must be characterized, understood, and controlled early in the development process. The aim of this study is to establish an in vitro dissolution method with the capability to capture therapeutically relevant differences in the dissolution rate between drug batches and drug compounds. A method was developed by which a biorelevant aerosol fraction was captured on a filter using a sedimentation technique in a modified Andersen cascade impactor to avoid particle agglomeration. Subsequently, the filters were transferred to a commercial Transwell system where dissolution in 3 mL of phosphate buffer at pH 6.8 with 0.5% sodium dodecyl sulfate (SDS) occurred at sink conditions. Dissolved DS was quantified over time using UPLC-UV. Dissolution data was obtained on a series of micronized and aerosolized lipophilic DSs, budesonide, fluticasone furoate (FF), fluticasone propionate (FP), and AZD5423. The latter is a lipophilic AstraZeneca development compound available in two different mass median diameters (MMD), 1.3 (AZD54231.3) and 3.1 μm (AZD54233.1). Dissolution data were evaluated using a Weibull fit and expressed as t 63, the time to dissolution of 63% of the initial dose. The following rank-order of t 63 was obtained (mean t 63 and MMD in brackets), budesonide (10 min, 2.1 μm) = AZD54231.3 (10 min, 1.3 μm) < AZD54233.1 (19 min, 3.1 μm) < FP (38 min, 2.4 μm) < FF (63 min, 2.5 μm). The method could differentiate between different drug compounds with different solubility but similar particle size distribution, as well as between the same drug compound with different particle size distributions. Furthermore, a relation between the in vitro dissolution rate (t 63) and mean pulmonary absorption time in man (literature data) was observed, indicating clinical relevance. It is thus concluded, that the method may be useful for the characterization and ranking of DSs and drug products in early development, as well as being a potential tool for the control of dissolution as a potential quality attribute.

Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

“…The phenomena of a high drug amount being delivered to a dissolution setup, hindering the in vitro dissolution rate of OIDPs, has been reported for almost all dissolution methods developed for OIDPs [ 8 , 13 , 37 , 38 ]. Different approaches have been explored to counter this mass effect.…”

“…Published approaches have utilized a range of dose collection and dissolution methodologies [ 5 , 6 ]. Suggested dissolution systems ranged from conventional USP dissolution apparatuses (e.g., USP II or V [ 7 , 8 ], and IV [ 9 , 10 ]), to fluid-limited diffusion-based approaches (e.g., Franz cell [ 11 ] and Transwell ® [ 12 , 13 , 14 ]), and Dissolv It [ 15 , 16 ], with a range of particle collection methods used for sample preparation [ 17 , 18 , 19 , 20 ].…”

A Pathway From Porous Particle Technology Toward Tailoring Aerogels for Pulmonary Drug Administration

“…The dissolution rate-limiting process in pulmonary absorption of poorly water-soluble substances could reduce the therapeutic outcomes or cause acute toxicity to the lungs by drug accumulation ( Kumar et al, 2017 ; Franek et al, 2018 ; Eriksson et al, 2019 ). Two main classes of drugs with limited dissolution rates in pulmonary drug delivery are distinguished: (i) “potent inhaled corticosteroids with a nominal dose less than 1 mg,” and (ii) “high-dose antiinfectives with a nominal dose >1 mg” ( Hastedt et al, 2016 ).…”

Hyaluronic Acid Hydrogels for Controlled Pulmonary Drug Delivery—A Particle Engineering Approach

“…The charging behavior of the microparticles was analyzed using a Malvern Zetasizer Nano-ZS (Malvern Instruments, Worcester-shire, UK) in NaCl electrolyte (10 mM) at a temperature of 25 • C. The electrophoretic mobility was used for the calculation of the ζ potential using Smoluchowski's equation [31]:…”