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

Abstract

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.

Keywords: airflow resistance; dry powder inhaler; in vitro–in vivo correlations; inhalation profiles; patient training; peak inhalation flow rate; realistic inhaler testing.

FIG. 1.

Experimental setup for realistic in vitro testing. A passive powder inhaler with known airflow resistance (R) is primed and inserted into small, medium, or large mouth-throat (MT) model(s) that span 95% of the volumetric range seen in human adults. Internal surfaces of MT are coated to retain powder particles. A breath simulator with sufficient capacity is programmed to withdraw a volume V through a low resistance filter using a range of simulated IPs, as described in the text. The mass of drug that reaches the filter, TLD_{in vitro}, depends on the product, and the MT-IP combination.^{(1–4,14–17)}

FIG. 2.

The inhalation flow cell (IFC) with top views of two “Resistance Tubes” with identical external, but different internal, dimensions. Six IFC resistances were chosen for IP recordings in the clinic: 0.0179, 0.0200, 0.0241, 0.0344, 0.0432, and 0.0462 kPa^0.5L⁻¹ min. These values were determined experimentally from the slope of plots measured pressure drop^0.5 (flowmeter inlet to mouthpiece) vs. the volumetric airflow rate exiting the mouthpiece (ASL 5000-XL, Ingmar Medical, Pittsburgh, PA). In the clinic, flow rates entering IFC were recorded every 50 msec using a calibrated digital flow meter (EM1, Sensirion Inc., CA). All flow rates in this article are expressed as the volumetric flow rate exiting the mouthpiece and are identical to those used to program the breath simulator (Fig. 1).

FIG. 3.

Written instructions for inhalation. Instruction A (Artwork adapted from patient information leaflets).

FIG. 4.

Idealized IP or flow rate (FR) versus time curve and the primary variables: AUC, area under the curve; PIFR, peak inspiratory flow rate; T_PIFR, the time at which PIFR occurs; V, inhaled volume. Total inhalation time (T) is a secondary variable, dependent on PIFR and V.

FIG. 5.

Individual flow profiles (gray) or volumetric flow rates exiting the mouthpiece of IFC vs. time from 20 volunteers (10 M, 10 F; 20 gray profiles per panel) after reading written instruction A (Fig. 3). IFC airflow resistance (R) is shown in each panel. Red profiles show the 10, 50, and 90 percentile IP in each case.

FIG. 6.

Individual flow profiles (gray) or volumetric flow rates exiting the mouthpiece of IFC vs. time from 20 volunteers (10 M, 10 F) after Instruction B (40 gray profiles, from B1 and B2, per panel). IFC airflow resistance (R) is shown in each panel. Red profiles show the 10, 50, and 90 percentile IP in each case.

FIG. 7.

PIFR versus I/R from pooled data collected after (a) Instruction A (reading only) and (b) Instruction B (training by professional; r² > 0.995). 10, 50, and 90 percentile values can be predicted based on a pre-selected value for R in the range 0.018–0.046 kPa^0.5 L⁻¹ min.

FIG. 8.

Simulated inhalation profiles (black curves) generated using Equations 7–10 for resistances shown in each panel and the algorithm described in the text. PIFR was calculated from Equations 4–6 (Instruction B); T_PIFR = T_PIFR50% = 0.49 s for all black curves, while values for V_10%, V_50%, and V_90% were 1.4, 2.7, and 4.6 L. Gray (non-smooth) profiles shown for comparison are the 10, 50, and 90 percentile IPs from Figure 6.

FIG. 9.

Distribution of values for T_PIFR (seconds) across genders after Instruction B. The 10, 50, and 90 percentile values were 0.28, 0.49, and 0.88 seconds, respectively. Instruction A yielded a similar distribution with 10, 50, and 90 percentile values of 0.43, 0.66, and 1.68 seconds, respectively. Selection of the values for T_PIFR and PIFR permits the study of device behavior at different flow accelerations according to Equation 7.