| 1. |
- Ganguly, Koustav, et al.
(författare)
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Computational modeling of lung deposition of inhaled particles in chronic obstructive pulmonary disease (COPD) patients : identification of gaps in knowledge and data
- 2019
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Ingår i: Critical reviews in toxicology. - : TAYLOR & FRANCIS LTD. - 1040-8444 .- 1547-6898. ; 49:2, s. 160-173
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Forskningsöversikt (refereegranskat)abstract
- Computational modeling together with experimental data are essential to assess the risk for particulate matter mediated lung toxicity and to predict the efficacy, safety and fate of aerosolized drug molecules used in inhalation therapy. In silico models are widely used to understand the deposition, distribution, and clearance of inhaled particles and aerosols in the human lung. Exacerbations of chronic obstructive pulmonary disease (COPD) have been reported due to increased particulate matter related air pollution episodes. Considering the profound functional, anatomical and structural changes occurring in COPD lungs, the relevance of the existing in silico models for mimicking diseased lungs warrants reevaluation. Currently available computational modeling tools were developed for the healthy adult (male) lung. Here, we analyze the major alterations occurring in the airway structure, anatomy and pulmonary function in the COPD lung, as compared to the healthy lung. We also scrutinize the various physiological and particle characteristics that influence particle deposition, distribution and clearance in the lung. The aim of this review is to evaluate the availability of the fundamental knowledge and data required for modeling particle deposition in a COPD lung departing from the existing healthy lung models. The extent to which COPD pathophysiology may affect aerosol deposition depends on the relative contribution of several factors such as altered lung structure and function, bronchoconstriction, emphysema, loss of elastic recoil, altered breathing pattern and altered liquid volumes that warrant consideration while developing physiologically relevant in silico models.
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| 2. |
- Frenning, Göran, et al.
(författare)
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Model for the Analysis of Membrane-Type Dissolution Tests for Inhaled Drugs
- 2020
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Ingår i: Molecular Pharmaceutics. - : AMER CHEMICAL SOC. - 1543-8384 .- 1543-8392. ; 17:7, s. 2426-2434
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Tidskriftsartikel (refereegranskat)abstract
- Impactor-type dose deposition is a common prerequisite for dissolution testing of inhaled medicines, and drug release typically takes place through a membrane. The purpose of this work is to develop a mechanistic model for such combined dissolution and release processes, focusing on a drug that initially is present in solid form. Our starting points are the Noyes-Whitney (or Nernst-Brunner) equation and Fick's law. A detailed mechanistic analysis of the drug release process is provided, and approximate closed-form expressions for the amount of the drug that remains in solid form and the amount of the drug that has been released are derived. Comparisons with numerical data demonstrated the accuracy of the approximate expressions. Comparisons with experimental release data from literature demonstrated that the model can be used to establish rate-controlling release mechanisms. In conclusion, the model constitutes a valuable tool for the analysis of in vitro dissolution data for inhaled drugs.
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| 3. |
- Nikjoo, Dariush, 1977-, et al.
(författare)
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Hyaluronic Acid Hydrogels for Controlled Pulmonary Drug Delivery—A Particle Engineering Approach
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- Hydrogels warrant attention as a potential material for use in sustained pulmonary drug delivery due to their swelling and mucoadhesive features. Herein, hyaluronic acid (HA) is considered a promising material due to its therapeutic potential, the effect on lung inflammation, and possible utility as an excipient or drug carrier. In this study, the feasibility of using HA hydrogels (without a model drug) to engineer inhalation powders for controlled pulmonary drug delivery was assessed. A combination of chemical crosslinking and spray-drying was proposed as a novel methodology for the preparation of inhalation powders. Different crosslinkers (urea; UR and glutaraldehyde; GA) were exploited in the hydrogel formulation and the obtained powders were subjected to extensive characterization. Compositional analysis of the powders indicated a crosslinked structure of the hydrogels with sufficient thermal stability to withstand spray drying. The obtained microparticles presented a spherical shape with mean diameter particle sizes from 2.3 ± 1.1 to 3.2 ± 2.9 μm. Microparticles formed from HA crosslinked with GA exhibited a reasonable aerosolization performance (fine particle fraction estimated as 28 ± 2%), whereas lower values were obtained for the UR-based formulation. Likewise, swelling and stability in water were larger for GA than for UR, for which the results were very similar to those obtained for native (not crosslinked) HA. In conclusion, microparticles could successfully be produced from crosslinked HA, and the ones crosslinked by GA exhibited superior performance in terms of aerosolization and swelling.
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| 4. |
- Tehler, Ulrika, et al.
(författare)
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Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:6, s. 2690-2694
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Tidskriftsartikel (refereegranskat)abstract
- Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.
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| 5. |
- van der Zwaan, Irès, et al.
(författare)
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Characterization of Membrane-Type Dissolution Profiles of Clinically Available Orally Inhaled Products Using a Weibull Fit and a Mechanistic Model
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:9, s. 3114-3124
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Tidskriftsartikel (refereegranskat)abstract
- Dissolution rate impacts the absorption rate of poorly soluble inhaled drugs. In vitro dissolution tests that can capture the impact of changes in critical quality attributes of the drug product on in vivo dissolution are important for the development of products containing poorly soluble drugs, as well as modified release formulations. In this study, an extended mathematical model allowing for dissolution of polydisperse powders and subsequent diffusion of dissolved drug across a membrane is described. In vitro dissolution profiles of budesonide, fluticasone propionate, and beclomethasone dipropionate delivered from three commercial drug products were determined using a membrane-type Transwell dissolution test, which consists of a donor and an acceptor compartment separated by a membrane. Subsequently, the profiles were analyzed using the developed mechanistic model and a semi-empirical model based on the Weibull distribution. The two mathematical models provided the same rank order of the performance of the three drug products in terms of dissolution rates, but the rates were significantly different. The faster rate extracted from the mechanistic model is expected to reflect the true dissolution rate of the drug; the Weibull model provides an effective and slower rate that represents not only drug dissolution but also diffusion across the Transwell membrane. In conclusion, the developed extended model provides superior understanding of the dissolution mechanisms in membrane-type (Transwell) dissolution tests.
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