Conference Proceedings
December 2002 / Volume 47 / Number 12 / Page 1392
New Liquid Aerosol Generation Devices: Systems That Force Pressurized Liquids Through Nozzles
IntroductionOver the past few decades, aerosol delivery devices have been relatively inefficient, wasteful, and difficult for patients to use. These drawbacks have been tolerated because the drugs available for inhalation have wide therapeutic margins and steep dose-response curves at low doses. Recently several forces have converged to drive innovation in the aerosol device industry: the ban on chlorofluorocarbon propellants in metered-dose inhalers, the need for more user-friendly devices, and the invention of expensive inhalable therapies for topical and systemic lung delivery. Numerous devices are in development to improve the efficiency, ease of use, and reproducibility of aerosol delivery to the lung, including systems that force liquid through a nozzle to form the aerosol cloud. The Respimat is a novel, compact, propellant-free, multi-dose inhaler that employs a spring to push drug solution through a nozzle, which generates a slow-moving aerosol. Deposition studies show that the Respimat can deliver 39-44% of a dose to the lungs. Clinical asthma and chronic obstructive pulmonary disease trials with bronchodilators show that the Respimat is 2-8 times as effective as a metered-dose inhaler. Respimat has been tested with bronchodilators and inhaled corticosteroids. The AERx device uses sophisticated electronics to deliver aerosol from a single-dose blister, using an integral, disposable nozzle array. The electronics control dose expression and titration, timing of aerosol generation with the breath, and provide feedback for proper inhalation technique. Lung deposition ranges from 50 to 80% of the loaded dose, with remarkable reproducibility. AERx has been tested with a variety of drugs, for both topical and systemic delivery, including rhDNase (dornase alfa), insulin, and opioids. These novel devices face competition from other technologies as well as financial and regulatory hurdles, but they both offer a marked improvement in the efficiency of pulmonary drug delivery.
New Liquid Aerosol Generators
Devices That Create an Aerosol by Forcing Liquids Through Nozzles
The Respimat
Respimat Deposition Studies
Respimat Clinical Studies
Challenges for Respimat
The AERx System
AERx Deposition Studies
AERx Clinical Trials: Systemic Drugs
AERx Clinical Trials: Pulmonary Delivery for Lung Disease
Challenges for the AERx System
Summary
Introduction
For the past half century the devices available for the delivery of aerosolized drugs to the lung have included pressurized metered-dose inhalers (pMDIs), jet and ultrasonic nebulizers, and dry powder inhalers (DPIs). Each of these systems has benefits and drawbacks with respect to the type of drug used and the target patient population. The well-recognized inefficiencies of these devices have not been of concern until recently, since most of the aerosolized drugs for topical lung delivery (ie, bronchodilators and anti-inflammatory agents) are inexpensive and have wide therapeutic margins. However, over the past decade there have been many driving forces for the innovation of new inhalable drug formulations and devices to deliver them.
First, the ban on chlorofluorocarbon (CFC) (to preserve the upper atmosphere's ozone layer) has required pharmaceutical companies to seek alternative propellants. The pMDI has for decades been one of the most commonly prescribed delivery methods for asthma and chronic obstructive pulmonary disease (COPD) drugs, so the ban on CFC is a major driving force for change in the industry. The basic design of the pMDI is almost 50 years old, with few modifications until recently. The pMDI was a landmark innovation that has had tremendous impact on inhaled drug delivery, though the problems with its use are well known. The pMDI is relatively difficult to teach and to use and requires synchronization of actuation and inhalation to achieve successful lung deposition. Pressurized MDIs produce high-velocity particles that impact in the oropharynx and cause adverse effects. Drug delivery to the lung with CFC pMDIs is only 5-20% of the label dose, even with good technique. Children under a few years old are incapable of mastering the pMDI technique. To overcome these difficulties, several companies designed spacers and valved holding chambers to reduce oropharyngeal deposition and improve coordination. The competition between the companies that manufacture spacers led to a huge body of literature arguing the merits of the various devices, leading to confusion among clinicians and patients.
Alternatives to the CFC pMDI include other propellants, such as hydrofluoroalkane (HFA), new DPIs, and the recently developed propellant-free liquid systems. The HFA pMDIs have been redesigned to solve some of the problems with the CFC devices. The plume has a slower velocity, there is no "cold freon" effect, and the last few doses in the canister are delivered more consistently. Some of the inhaled corticosteroids are soluble in the HFA propellant/excipient mixture and have been engineered to deliver small-particle aerosols (average droplet size of only 1 micron), which improves lung deposition and decreases throat deposition. Other HFA formulations have particle size characteristics similar to their inefficient CFC counterparts. Like CFC pMDIs, HFA pMDIs require synchronization of the actuation and the inspiratory effort, so holding chambers may be necessary for some patients. DPIs are also available for many medications and come in single-dose and multiple-dose formats. DPIs are breath-actuated and rely on the patient's inspiratory effort to deaggregate the powder into fine particles that can be deposited in the lung. DPI deposition efficiency is in the range of approximately 12-37%, depending on the device, the formulation, and the patient. Since a stronger inspiratory effort is required with current DPIs, there is substantial oropharyngeal deposition. The difficulties with pMDIs and DPIs are partly responsible for the development of propellant-free liquid aerosol systems.
Another force driving innovation of new aerosol technology is the recognition that existing devices are either inefficient, difficult to use, or have poor precision (high intra-subject and inter-subject variability). In addition to the above-described problems with pMDIs and DPIs, jet and ultrasonic nebulizers waste drug by having large dead volumes (ie, medication remaining in the nebulizer after nebulization has ceased), by nebulizing during exhalation, and by forming polydisperse aerosols that have a high percentage of droplets too large to reach the lung. With most of the available systems the patient is not guided or prompted to breathe in an appropriate or consistent fashion, which increases variability of lung deposition. Drugs with large therapeutic windows, such as anti-inflammatories, beta 2 agonists, and anticholinergics, can be clinically effective even when delivered by inefficient devices, but more recent medications and novel therapies in development, including gene therapies, are too expensive to tolerate substantial waste.
Nebulizers are the most time-consuming method of aerosol delivery. Patients with cystic fibrosis (CF) and other chronic lung diseases may have numerous aerosol medications to use, which may take up to 2 hours daily. New user-friendly devices that reduce treatment time may improve patient compliance with therapy and thus improve outcomes and quality of life.
Finally, the need for novel device development has been fueled by the invention of innovative liquid formulations and modifications of older formulations designed to use the large absorptive surface of the peripheral lung as a portal for systemic drug delivery. These therapies include peptides, proteins, small molecules, hormones, and liposome/drug suspensions. Many of these agents have a very narrow therapeutic index and require a marked improvement in efficiency and precision of dosing to the distal lung. DPIs with drugs reformulated into easily dispersible powders with improved aerodynamic properties have been used for systemic drug delivery via inhalation (eg, by Inhale Therapeutics). However, for most novel drugs, liquid formulations are used as a starting point for development. Many formulations have already been used as parenteral solutions or suspensions, with known storage and stability variables. The aerosol characteristics of an aqueous compound are mostly controlled by the device design, not by the inhalation pattern. Feasibility studies to demonstrate the usefulness of inhaling a compound can proceed more quickly with liquid formulations. The new devices must optimize aerosol delivery to the peripheral lung, which maximizes the absorption of drug into the bloodstream and minimizes drug loss by mucociliary transport. Also, the intra-subject and inter-subject variability of pharmacokinetic variables should be comparable to those of conventional methods.
The new aerosol systems developed for systemic drug delivery are so efficient that many have been modified for use with topical airway drugs as well. Improved design features of the new devices include smaller device size to improve portability, a flow sensor to match bolus drug delivery to the breathing pattern, and features that guide the patient to inhale at the proper flow rate. These improvements should improve dosing reliability and patient acceptance.