In Vitro Tests for Aerosol Deposition. VI: Realistic Testing with Different Mouth-Throat Models and In Vitro-In Vivo Correlations for a Dry Powder Inhaler, Metered Dose Inhaler, and Soft Mist Inhaler.

Background:In vitro-in vivo correlations (IVIVC) for lung deposition may be established by testing inhalers in vitro with realistic mouth-throat (MT) models and inhalation profiles (IP). This study was designed to compare the currently available MT models and their ability to predict in vivo lung deposition. Methods: Budelin® Novolizer®, Ventolin® Evohaler®, and Respimat® fenoterol were chosen to represent a dry powder inhaler (DPI), metered dose inhaler (MDI), and soft mist inhaler (SMI) in tests using eight MT models: small, medium, and large Virginia Commonwealth University (VCU) models; small, medium, and large oropharyngeal consortium (OPC) models, the medium adult Alberta Idealized Throat (AIT), and the United States Pharmacopeia (USP) Induction Port, with IPs that simulated those used by volunteers in lung scintigraphy studies. Drug deposition in MT was compared across the models, and IVIVCs evaluated by comparing values for total lung dose in vitro (TLDin vitro) to those reported in the clinic. Results: MT deposition was dependent on both the flow condition and MT geometry for all the inhalers, while the deposition rank order was independent of both factors. The overall ranking was USP

In Vitro Tests for Aerosol Deposition. V: Using Realistic Testing to Estimate Variations in Aerosol Properties at the Trachea.

BACKGROUND: The dose and aerodynamic particle size distribution (APSD) of drug aerosols' exiting models of the mouth and throat (MT) during a realistic inhalation profile (IP) may be estimated in vitro and designated Total Lung Dose, TLDin vitro, and APSDTLDin vitro, respectively. These aerosol characteristics likely define the drug's regional distribution in the lung. METHODS: A general method was evaluated to enable the simultaneous determination of TLDin vitro and APSDTLDin vitro for budesonide aerosols' exiting small, medium and large VCU-MT models. Following calibration of the modified next generation pharmaceutical impactor (NGI) at 140 L/min, variations in aerosol dose and size exiting MT were determined from Budelin® Novolizer® across the IPs reported by Newman et al., who assessed drug deposition from this inhaler by scintigraphy. RESULTS: Values for TLDin vitro from the test inhaler determined by the general method were found to be statistically comparable to those using a filter capture method. Using new stage cutoffs determined by calibration of the modified NGI at 140 L/min, APSDTLDin vitro profiles and mass median aerodynamic diameters at the MT exit (MMADTLDin vitro) were determined as functions of MT geometric size across Newman's IPs. The range of mean values (n ≥ 5) for TLDin vitro and MMADTLDin vitro for this inhaler extended from 6.2 to 103.0 µg (3.1%-51.5% of label claim) and from 1.7 to 3.6 µm, respectively. CONCLUSIONS: The method enables reliable determination of TLDin vitro and APSDTLDin vitro for aerosols likely to enter the trachea of test subjects in the clinic. By simulating realistic IPs and testing in different MT models, the effects of major variables on TLDin vitro and APSDTLDin vitro may be studied using the general method described in this study.

In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing.

BACKGROUND: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLDin vitro. This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training. METHODS: In a drug-free clinical trial, inhaler-naïve, nonsmoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance. RESULTS: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%), and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates (PIFR) were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, TPIFR, and the total inhaled volume (V) were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of TPIFR and V. CONCLUSIONS: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device.

In vitro tests for aerosol deposition. I: Scaling a physical model of the upper airways to predict drug deposition variation in normal humans.

BACKGROUND: In vitro-in vivo correlations (IVIVCs) are needed to relate in vitro test results for deposition to mean data from clinical trials, as well as the extremes in a population. Because drug deposition variations are related to differences in airway dimensions and inhalation profiles, this article describes the development and validation of models and methods to predict in vivo results. METHODS: Three physical models of the upper airways were designed as small, medium, and large versions to represent 95% of the normal adult human population. The physical dimensions were validated by reference to anatomy literature. The models were constructed by rapid prototyping, housed in an artificial thorax, and used for in vitro testing of drug deposition from 200 µg Budelin Novolizers using a breath simulator to mimic the inhalation profiles used in the clinic. In vitro results were compared to those reported in vivo. RESULTS: The "average" model was scaled to produce "small" and "large" versions by multiplying linear dimensions by 0.748 or 1.165, respectively, based on reports of the mean and standard deviation of airway volume across a normal adult population. In vitro deposition variation under fixed test conditions was small. Testing in the model triplet however, using air flow rate versus time profiles based on the mean and the extremes reported in the clinic, produced results for total lung deposition (TLD) in vitro consistent with the complete range of drug deposition results reported in vivo. The effects of variables such as flow rate in vitro were also predictive of in vivo deposition. CONCLUSIONS: A new in vitro test method is described to predict the median and range of aerosol drug deposition seen in vivo. The method produced an IVIVC that was consistent with 1:1 predictions of total lung deposition from a marketed powder inhaler in trained normal adults.