CFD Assessment of Respiratory Drug Delivery Efficiency in Adults and Improvements Using Controlled Condensational Growth

Pharmaceutical aerosols provide a number of advantages for treating respiratory diseases that include targeting high doses directly to the lungs and reducing exposure of other organs to the medication, which improve effectiveness and minimize side effects. However, difficulties associated with aerosolized drug delivery to the lungs include drug losses in delivery devices and in the extrathoracic region of human upper airways. Intersubject variability of extrathoracic and thoracic drug deposition is a key issue as well and should be minimized. Improvements to respiratory drug delivery efficiency have been recently proposed by Dr. P. Worth Longest and Dr. Michael Hindle through the use controlled condensational growth methods, which include enhanced condensational growth (ECG) and excipient enhanced growth (EEG). These methods reduce inhaled drug loss through the introduction of an aerosol with an initial submicrometer aerodynamic diameter, which then experiences condensational growth to increase droplet size and enhance thoracic deposition. Tracheobronchial and nasal human airway computational models were developed for this study to assess drug delivery using conventional and EEG methods. Computational versions of these models are used to assess drug delivery and variability with computational fluid dynamics (CFD) simulations, which are validated with experimental data where possible. Using CFD, steady state delivery of albuterol sulfate (AS) during high flow therapy (HFT) through a nasal cannula was characterized with four nasal models developed for this study, with results indicating an increase in average delivered dose from 24.0% with a conventional method to 82.2% with the EEG technique and an initially sized 0.9 µm aerosol, with a corresponding decrease in the coefficient of variation from 15% to 3%. Transient CFD simulations of nebulized AS administration through a mask during noninvasive positive pressure ventilation (NPPV) were performed and validated with experimental data, which resulted in 40.5% delivered dose with the EEG method as compared with 19.5% for a conventional method and a common inhalation profile. Using two newly created face-nose-mouth-throat models, dry powder delivery of ciprofloxacin during NPPV was assessed for the first time with steady state CFD predictions, which showed an increase in average delivered lung dose through a new mask design of 78.2% for the EEG method as compared with 36.2% for conventional delivery, while corresponding differences in delivered dose between the two models were reduced from 45.4% to 12.8% with EEG. In conclusion, results of this study demonstrate (i) the use of highly realistic in silico and in vitro models to predict the lung delivery of inhaled pharmaceutical aerosols, (ii) indicate that the EEG approach can reduce variability in nose-to-lung aerosol delivery through a nasal cannula by a factor of five, and (iii) introduce new high efficiency methods for administering aerosols during NPPV, which represents an area of current clinical need

Effect of an upstream grid on the fluidization of pharmaceutical carrier powders

The influence of grid generated mixing on the fluidization of pharmaceutical carrier powders 15 is studied in a channel-flow experiment using direct high-speed imaging and particle image 16 velocimetry (PIV). Four different lactose powders with mass median diameters that range 17 between 61μm to 121μm are used. The degree of powder mixing in the flow as a function of 18 grid position relative to the powder bed and grid area blockage ratios (ranging from ~25% to 19 ~40%) is studied for a range of flow-rates. The study presents comprehensive mappings of how 20 pharmaceutical powders are fluidised under the influence of mixing, by examining powder bed 21 morphology, powder emptying rate, and the local flow-field surrounding the pocket. The use 22 of a grid results in higher evacuation percentages (void fraction) and a faster evacuation rate 23 but is associated with randomized evacuation behaviour as observed from the powder bed 24 morphology. Use of a grid can enable evacuation of powder at lower overall flow-rates, which 25 may have important implications on respiratory drug delivery. PIV results show the trend of 26 mean velocities with the mass median powder diameter and demonstrates how a grid with 27 lower blockage ratio can increase the degree of mixing of the evacuating powder and make the 28 evacuation process more rapid. This study contributes towards a better understanding of 29 fluidization processes as relevant to dry powder inhaler devices and sheds light on how simple 30 design alterations, such as adding an upstream grid, can be incorporated to optimise device 31 effectiveness

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report

Abstract For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost‐prohibitive. Mechanistic modeling approaches, such as physiologically‐based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model‐integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products

Regulatory utility of mechanistic modeling to support alternative bioequivalence approaches: A workshop overview

Abstract On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report

Abstract In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established