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Advanced Drug Delivery Reviews (v.64, #4)
In silico models of aerosol delivery to the respiratory tract — Development and applications
by P. Worth Longest; Landon T. Holbrook (pp. 296-311).
This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract.Display Omitted
Keywords: Respiratory drug delivery; Pharmaceutical aerosols; Aerosol deposition; Lung models; 1-D models; CFD models; Spray momentum; Targeted aerosol delivery; Validation of deposition simulations; Stochastic individual path (SIP) model
The use of computational approaches in inhaler development
by William Wong; David F. Fletcher; Daniela Traini; Hak-Kim Chan; Paul M. Young (pp. 312-322).
Computational Fluid Dynamics (CFD) and Discrete Element Modelling (DEM) studies relevant to inhaled drug delivery are reviewed. CFD is widely used in device design to determine airflow patterns and turbulence levels. CFD is also used to simulate particles and droplets, which are subjected to various forces, turbulence and wall interactions. These studies can now be performed routinely because of the availability of commercial software containing high quality turbulence and particle models.DEM allows for the modelling of agglomerate break-up upon interaction with a wall or due to shear in the flow. However, the computational cost is high and the number of particles that can be simulated is minimal compared with the number present in typical inhaled formulations. Therefore DEM is currently limited to fundamental studies of break-up mechanisms.With decreasing computational limitations, simulations combining CFD and DEM that can address outstanding issues in agglomerate break-up and dispersion will be possible.Display Omitted
Keywords: Abbreviations; AFM; Atomic force microscopy; API; Active pharmaceutical ingredient; CAG; Capillary aerosol generation; CFC; Chlorofluorocarbon; CFD; Computational Fluid Dynamics; DDPM; Dense Discrete Particle Modelling; DEM; Discrete Element Modelling; DNA; Deoxyribonucleic acid; DPI; Dry powder inhaler; DPM; Discrete Particle Modelling; FEA; Finite Element Analysis; FPF; Fine particle fraction; HFA; Hydrofluoroalkane; MT; Realistic mouth–throat geometry; PIV; Particle image velocimetry; pMDI; Pressurized metered dose inhalers; RMM; Rapid mixing model; SMI; Soft Mist Inhaler; SST; Shear Stress Transport; USP-IP; United States pharmacopeia-induction portComputational Fluid Dynamics (CFD); Discrete Element Modelling (DEM); Particle behaviour; Deagglomeration; Dry powder inhaler (DPI); Pressurised metered dose inhaler (pMDI); Nebulizer
Structural modelling and dynamics of proteins for insights into drug interactions
by Tim Werner; Michael B. Morris; Siavoush Dastmalchi; W. Bret Church (pp. 323-343).
Proteins are the workhorses of biomolecules and their function is affected by their structure and their structural rearrangements during ligand entry, ligand binding and protein–protein interactions. Hence, the knowledge of protein structure and, importantly, the dynamic behaviour of the structure are critical for understanding how the protein performs its function. The predictions of the structure and the dynamic behaviour can be performed by combinations of structure modelling and molecular dynamics simulations. The simulations also need to be sensitive to the constraints of the environment in which the protein resides. Standard computational methods now exist in this field to support the experimental effort of solving protein structures. This review presents a comprehensive overview of the basis of the calculations and the well-established computational methods used to generate and understand protein structure and function and the study of their dynamic behaviour with the reference to lung-related targets.Display Omitted
Keywords: Molecular dynamics; Protein structure; Computational biology; Structural biology; Drug targets; Drug–target interactions
Advances in microscopy and complementary imaging techniques to assess the fate of drugs ex vivo in respiratory drug delivery
by Chun-Woong Park; Yun-Seok Rhee; Frederick G. Vogt; Don Hayes Jr.; Joseph B. Zwischenberger; Patrick P. DeLuca; Heidi M. Mansour (pp. 344-356).
The technical advances in microscopy imaging techniques have been applied to assess the fate of drugs for researching respiratory drug delivery in ex vivo and in vivo experiments. Recent developments in optical imaging (confocal microscopy, multi-photon microscopy, fluorescence imaging (FLI) and bioluminescence imaging (BLI)), and in non-optical imaging (magnetic resonance imaging (MRI), computing tomography (CT), positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT)) are presented with their derivative medical devices. Novel microscopy have been utilized to address many biological questions in basic research and are becoming powerful clinical tools for non-invasive objective diagnosis, guided treatment, and monitoring therapies. The goal of this paper is to present recent advances in microscopy imaging techniques and to discuss their novel applications in respiratory drug delivery imaging.Display Omitted
Keywords: Multimodal/multifunctional imaging; Targeted pulmonary delivery; Ex vivo; In vivo; Optical imaging; Non-optical imaging; Confocal Raman microspectroscopy; Chemical imaging
Lung imaging — Two dimensional gamma scintigraphy, SPECT, CT and PET
by Joy Conway (pp. 357-368).
This review will cover the principles of imaging the deposition of inhaled drugs and some of the state-of-the art imaging techniques being used today. Aerosol deposition can be imaged and quantified by the addition of a radiolabel to the aerosol formulation. The subsequent imaging of the inhaled deposition pattern can be acquired by different imaging techniques. Specifically, this review will focus on the use of two-dimensional planar, gamma scintigraphy, SPECT, CT and PET.This review will look at how these imaging techniques are used to investigate the mechanisms of drug delivery in the lung and how the lung anatomy and physiology have the potential to alter therapeutic outcomes.Display Omitted
Keywords: Abbreviations; SPECT; single photon emission computed tomography; CT; computed tomography; HRCT; high resolution computed tomography; PET; positron emission tomography; PK; pharmacokinetics; MMAD; mass median aerodynamic diameter; GSD; geometric standard deviation; MDI; metered dose inhaler; DPI; dry powder inhaler; 99m; Tc; technetium; 81m; Kr; krypton; 133; Xe; Xenon; 57; Co; Cobalt; 111; In; Indium; 123; I; Iodine; 13; N; 2; Nitrogen; MCC; mucociliary clearance; CF; cystic fibrosis; COPD; chronic obstructive pulmonary disease; PCD; primary ciliary dyskinesia; V/Q; ventilation/perfusion; HU; Hounsfield Unit; HFA; hydrofluoroalkane; ITU; intensive therapy unit; TLC; total lung capacity; EBUS; endobronchial ultrasound; OCT; optical coherence tomographyGamma scintigraphy; SPECT; CT; HRCT; PET; Lung imaging; Drug deposition; Lung anatomy
Advanced microscopy techniques to assess solid-state properties of inhalation medicines
by Jagdeep Shur; Robert Price (pp. 369-382).
Efficient control and characterisation of the physico-chemical properties of active pharmaceutical ingredients (APIs) and excipients for orally inhaled drug products (OIDPs) are critical to successful product development. Control and reduction of risk require the introduction of a material science based approach to product development and the use of advanced analytical tools in understanding how the solid-state properties of the input materials influence structure and product functionality. The key issues to be addressed, at a microscopic scale, are understanding how the critical quality attributes of input materials influence surface, interfacial and particulate interactions within OIDPs. This review offers an in-depth discussion on the use of advanced microscopy techniques in characterising of the solid-state properties of particulate materials for OIDPs. The review covers the fundamental principles of the techniques, instrumentation types, data interpretation and specific applications in relation to the product development of OIDPs.Display Omitted
Keywords: Raman chemical imaging; Dry powder inhalers; Metered dose inhalers; Atomic force microscopy; Microscopy; Chemical imaging; Tomography; Interferometry
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