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Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
AstraZeneca, Pharmaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
AstraZeneca, Pharmaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.
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2019 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 7, p. 3053-3064Article in journal (Refereed) Published
Abstract [en]

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Place, publisher, year, edition, pages
2019. Vol. 16, no 7, p. 3053-3064
Keywords [en]
inhalation, lung dissolution, isolated perfused lung model, pulmonary drug delivery, pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-390996DOI: 10.1021/acs.molpharmaceut.9b00289ISI: 000474475400020PubMedID: 31136181OAI: oai:DiVA.org:uu-390996DiVA, id: diva2:1343804
Funder
AstraZenecaAvailable from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved

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Eriksson, JohannaSjögren, ErikLennernäs, Hans

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