Variable breathing patterns are a complication for pulmonary drug delivery. Dr Gerhard Scheuch and Axel Fischer of Activaero discuss new methods of controlling inhalation
Inhaled medications are commonly used in the treatment of respiratory diseases,1 while the lung has also recently been considered as the portal of entry for a number of aerosolised drugs designed to act systemically (e.g. insulin, growth hormone, interferons and calcitonin).2
Over the past two decades, huge efforts have been made to develop safe methods for the delivery of small molecules, proteins and peptides via the lungs, allowing fast uptake into blood circulation for treatment of pulmonary and also of systemic diseases. Although inhaled insulin recently failed to meet reimbursement criteria, pulmonary drug delivery is nevertheless on the rise since lung diseases such as asthma and COPD are increasing in prevalence.
Historically, effective delivery through the lungs presented severe restrictions, mainly due to the limited consideration of one critical factor: the patient and their behaviour.
The structure of the lung in effect presents a succession of physiological filters aimed at preventing environmental aerosol pollutants from damaging the lungs, which in turn means that inhaled therapeutic aerosols have a poor chance of bringing the drug into the lung. Add to this the wide variety of breathing patterns seen, particularly in patients who have damaged lungs, and it becomes apparent that the dosing level in the patient is almost impossible to predict or maintain in a consistent manner, using traditional low-tech nebuliser and inhaler technologies.
Despite this, the pulmonary system should present a potentially ideal means for topical and systemic therapeutic agents. If the physiological filters and inter-patient variability of breathing patterns could be overcome, the lung would present a safer and more versatile organ for drug delivery than oral or intravenous delivery. The lung has a surface area (80m2 - 120m2), good vascularisation, low thickness of the alveolar epithelium (0.1µm - 0.2µm) and a capacity for solute exchange.
There are a number of biophysical and physiological parameters to be considered when designing technologies for the delivery of inhaled aerosols. These include both physical properties of the drug formulation (particle diameter, particle density, hygroscopicity, electrical charge, chemical properties of the substance) and factors relating to the patient themselves (age, pulmonary diseases and breathing patterns).
Variations in any of these parameters can result in a substantial change of particle deposition in the lung. For example, large particles (>10µm) are not able to penetrate into the lung, because they are deposited by impaction in the upper respiratory tract. On the other hand, small particles (0.1 - 1.0µm) are inspired into the alveoli but also expired without being deposited significantly. Particles of diameters 2 - 5µm show the ideal pulmonary deposition behaviour and are able to transport a substantial mass of pharmaceuticals into the lung.
The patient's own style of breathing can have great importance. The physical properties of the drug composition can be optimised to maximise uptake, and have been by the major pharmaceutical companies for many years. However, variability in breathing patterns, which can be exacerbated by both age and illness, is much harder to accommodate when designing an optimal pulmonary delivery system.
Breathing patterns are important in inhaled particle deposition since the location of deposition can dictate the percentage of the compound that is absorbed with obvious implications for dosing and drug effectiveness.
One study found that patients with pulmonary disease using a standard inhalation device varied between 20% and 95% in total respiratory tract deposition (figure 3).3 Such variability can mean some patients are not receiving doses adequate for a therapeutic response, while others are taking doses in excess of the therapeutic window (see Figure 2).
With such significant variability, inhalation schedules often require the patient to inhale for long periods to ensure adequate dosing. Such long treatment schedules have obvious implications for treatment compliance and may not lend themselves to treatments such as corticosteroids that have toxicity problems at higher doses over sustained periods. It becomes apparent then that for adequate and efficient dosing that is simple, safe and quick to complete, breathing patterns have to be controlled in some way .
Research in recent years has sought to develop technologies to control the breathing patterns of patients and ensure consistent and optimal dosing. The first commercially available device to meet these objectives was the AKITA technology, including the AKITA JET system. These devices allow individualised, controlled inhalations in combination with proven SPRINT and APIXNEB nebulisers from Pari4 (see figure 1). The incorporation of innovative membrane type nebulisers allows the device to be lighter and more efficient in drug usage, due to reduced residual volume in the nebuliser.
Using the AKITA systems, patients do not have to concentrate on the correct breathing technique, because the device induces the optimum breathing pattern for them. In effect, the device takes over control of the inhalation and gives the patient status information on a display.
This breathing control is achieved by using a patient- and drug-specific smart card so that the inhalation flow rate and inhaled volume can be predetermined based specifically on the patient's respiratory condition.
The AKITA systems also make possible very precise targeting of different lung regions appropriate to different treatment strategies. The device allows for pulsing of the aerosol at any period of the inspiration: for example, either permitting the inspiration phase to be terminated with an aerosol-free interval so as to avoid useless drug deposition in the dead space of the lung or introducing the aerosol in a small bolus in the middle of inspiration to target the larger airways.
The smart card contains the optimised delivery parameters for a drug and is inserted into the AKITA device before the first inhalation. The predetermined breathing flow rate of the aerosol to the lung is then delivered with each inhalation by a compressor unit through the nebuliser in the AKITA device.
When the patient initiates a breath, the device takes over control of the inhalation, ventilating the lung with gentle positive pressure at a constant rate. The patient can view the progress of the inhalation and the number of inhalations still to go on a small screen. The smart card also records the progress of each inhalation session, providing valuable compliance data on each treatment. This information is valuable in a clinical trial setting, particularly when patients inhale at home.
Because the breathing is controlled to induce optimal aerosol drug delivery, overall treatment times with AKITA can be very much shorter than traditional methods. In the clinical setting with cystic fibrosis patients, it has been observed that the device is well accepted due to the reliable dosing,5 which leads to greater compliance.6
This technology has been validated in the clinical setting in multiple indications such as hereditary lung emphysema,4 cystic fibrosis7,8 and asthma.9 Potential further indications under investigation include COPD, lung metastases, Idiopathic Pulmonary Fibrosis (IPF) and Pulmonary Hypertension (PAH).
In the clinical development of pulmonary drugs, the decision about the device to be used is an important one. In large indications such as asthma, the target formulation of a drug may favour the use of a dry powder inhaler (DPI). However, such a decision involves tremendous formulation effort that would have cost and time implications. It is also crucial to demonstrate clinical feasibility as soon as possible. It is usually best to conduct early clinical trials using a liquid formulation.
The risk for selecting a 'wrong' or highly variable device can endanger the success for the entire drug and lead to a premature 'no go' decision. The AKITA systems are a good starting point in the first trials for pulmonary drug delivery, because only the precise knowledge of lung dose and risk/benefit ratio of the drug can lead to the best commercial formulation strategy. Table 1 compares the risks/benefits of different formulation and device strategies.
This technology has proven to be effective in delivering precise doses of aerosols into different regions of the lungs. Having control over important delivery parameters provides the current gold standard for best transparency on the performance of an investigated drug. Besides the clinical aspect, for certain indications such as cystic fibrosis, severe asthma and COPD, this technology has also strong potential for home treatment.