New generation pulmonary drug delivery systems

The advances in pulmonary drug delivery can be leveraged further by adopting the technologies already in development

In the past decade, a number of companies have developed technology platforms for delivering drugs into the systemic circulation via the lungs. While some of these technologies have yet to advance beyond early-stage development, others have been able to progress into clinical trials and beyond.

At Aradigm, with the AERx system in phase III, that question is being answered in the form of a new platform called AERx Essence. In much the same way that the electronics industry creates follow-on products that are smaller, simpler, and often less expensive, Aradigm is developing AERx Essence. to have many, but not all, of the features in AERx in a smaller and less expensive package. Encouraging results have been achieved in recently completed in vitro and user-preference studies using fully functional, handheld AERx Essence. prototypes.

Overview

Table 1 shows part of the landscape of first-generation technologies under development for systemic delivery of drugs via the lungs. In addition to the companies shown in Table 1, companies such as Alexza Molecular Delivery and Chrysalis Technologies are developing delivery systems using condensation aerosols, and companies such as MicroDose are developing delivery systems using electronically driven dry-powder inhalers. With the Nektar and Aradigm products in phase III clinical trials or beyond, next-generation offerings are beginning to emerge.

The AERx technology

The AERx system has been described in previous publications and has been shown to be effective in a number of clinical trials. AERx consists of a single-use, disposable drug container (the AERx Strip) and a device that aerosolizes the drug formulation into the patient’s inhalation air stream through a nozzle in the strip. The AERx system has electronic components in the device in order to operate features related to dose titration, breath actuation and coordination, inhaled air temperature control, and electronic storage of dosing information.

To broaden Aradigm’s product offerings, an all-mechanical AERx system (AERx Essence) has been developed as an option for drugs and therapies that may not require as many features. The AERx Essence system offers a level of performance (efficiency and reproducibility) close to the existing AERx system, but in a smaller and lower-cost package that does not have the dose titration, air temperature control, or dosing history features. In order to maintain a high level of performance and a similar level of breath coordination, a number of technological advances were required. The outcome of these efforts, a prototype AERx Essence device, is shown in Figure 1.

In vitro performance of AERx Essence

The in vitro performance of the AERx Essence system was characterised using several devices identical to the one shown in Figure 1. The objective of the in vitro characterisation was to establish the emitted dose efficiency (ED), expressed as a percentage of the nominal loaded dose, and the particle size distribution (PSD), represented by a median particle size and a fine particle fraction.

In vitro study: Design and methods

Cromolyn sodium was used as a model compound for in vitro testing. The strips used in the study were filled with 50 mL of a 30 mg/mL aqueous solution. ED was measured by simulating an inhalation at 30 L/min (the target nominal inhalation flow rate) and collecting the aerosolized drug on a filter downstream of the device mouthpiece.

Filters were subsequently assayed for drug content. PSD was characterised using the HELOS laser diffraction system (Sympatec GmbH), with the primary metrics being the volume-median diameter (VMD) and the volume fraction of particles smaller than five mm (fine particle fraction, or FPF). Two devices were tested over the course of two days, with 12 ED and four PSD measurements taken per device each day.

User-preference study & results

In addition to the in-vitro studies, a non-dosing user study was conducted. The study had two objectives: to qualitatively evaluate the level of acceptability among study subjects, including ease of inhalation and overall ease of use; and to quantitatively evaluate the ability of the subjects to perform the intended inhalation manoeuver with a minimum amount of training.

User study design and methods

A total of 30 healthy subjects were enrolled in the study, which included a preliminary in-office visit to screen for pulmonary function and seven in-office visits to answer questionnaires and perform inhalation manoeuvers. All of the subjects successfully completed all of the in-office visits.

A total of three AERx Essence devices were used in the study. Two were used for the qualitative evaluation, and these devices were used with saline-filled strips to simulate the handling and loading of actual strips. The third device was outfitted with instrumentation to measure inhalation flow rate and inspiratory effort as a function of time, and to record the time at which the device was actuated. These devices were used with empty strips to ensure that no aerosol was inhaled, and also with Pulmogard filters to avoid inter-subject contamination.

The seven study visits were conducted over three weeks, with device-handling sessions and qualitative questionnaires in the first visits of the first and third weeks. Additionally, in each of the seven visits, each subject performed three inhalation manoeuvers, and data were recorded for each manoeuver. Subjects were given a minimum of training at the start of the first visit. They were provided with a set of instructions; they were shown each of the individual steps (loading, dosing, unloading) once slowly; and then were shown a full dosing manoeuver once at a normal pace. No further training or feedback on inhalation techniques was provided.

User study results: Qualitative responses

The questionnaires given to the subjects asked them to rate various attributes of the device on a one to five scale, with one being the lowest rating, three being neutral, and five being the highest rating.

More than 90 per cent of subjects responded favourably (positive or neutral) to the intuitiveness and usability of the AERx Essence device, providing a preliminary validation of the feature set of the system and the overall design.

User study results: Quantitative data

The AERx Essence system is designed to have low enough resistance to easily get above the target minimum flow rate of 20 L/min, and a proprietary flow-regulation valve is designed to keep the inhalation flow rate below the target maximum of 40 L/min. The aim of the quantitative arm of the user study was to determine how well subjects could comply with the intended breathing manoeuver.

Throughout the course of the study, a total of 630 inhalations were recorded (30 subjects x7 visits x3 inhalations per visit). With a post-study validation rate of 96 per cent, a total of 604 inhalation profiles were available for subsequent analysis. Figure 5 shows the median time-averaged flow rate reached by each subject, averaged in 0.5-second intervals.

It is evident that the majority of inhalation manoeuvers easily and quickly reached the target flow rate of 20 L/min and remained above that flow rate for more than the target duration. Analogous to the qualitative results, these data provide a preliminary validation of the breath coordination features of the AERx Essence system.

Summary

The in vitro and user-preference results to date indicate that the all-mechanical AERx Essence system can be a viable platform for pulmonary delivery of locally or systemically acting drugs, following the path of the existing electronic AERx system. The data show that AERx Essence is able to maintain the standard of performance set by the existing AERx system, although without electronics and with slightly fewer features. This outcome demonstrates that additional advances can be made in pulmonary drug delivery by leveraging the technologies already in development.

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