Dr. Anne de Boer
Senior Technologist Inhalation
For the treatment of pulmonary diseases inhalation therapy offers several advantages compared to therapies via other routes of administration:
- targeted drug delivery to the lungs reduces the risk of (systemic) adverse effects;
- it allows for higher drug concentrations to be reached at the site of action;
- and intestinal as well as hepatic metabolism will be circumvented.
However, for successful transportation of pharmaceutically active particles (powders or droplets) into the lower respiratory tract, these particles have to be in the aerodynamic size range of approximately 1-5 µm and preferably 1-3 µm. Larger particles will deposit in the upper respiratory tract due to inertial impaction, while smaller particles are likely to be exhaled. Such small powder particles (approximately 2-8 million would make up a single sugar crystal) are generally very cohesive and therefore raise two important challenges, namely:
- accurate and reproducible dose metering (especially in the usual dose range of 50-200 µg or half a sugar crystal)
- and effective dispersion of agglomerates into primary particles upon inhalation.
These are the challenges that form the basis of the research projects at the pulmonary drug delivery division of Pharmaceutical Technology and Biopharmacy. We design and develop new dry powder inhalers that are more effectively dispersing agglomerates within inhaler formulations into respirable particles. In addition we perform research aimed at elucidating the mechanisms of interaction between particles in inhalation formulations and developing new formulations suitable for dispersion with our own inhalers. Furthermore we are actively involved in developing and improving aerosol characterisation techniques. Our group has several ongoing cooperations with hospitals in The Netherlands as well as pharmaceutical companies and other universities which greatly extends our research capabilities.
Inhaler design and development
Our knowledge of dry powder inhalers obtained through many years of inhaler testing has been implemented and applied in the design and development of the Novolizer®. The Novolizer® is a unique dry powder inhaler with a dispersion principle based on air classifier technology. Air classifiers are used in many industries but have never been implemented in dry powder inhalers before. Within the classifier of the Novolizer® particle agglomerates are broken up very effectively into respirable particles due to inertial impaction with the classifier wall. The Novolizer® was first marketed in 2000 by MEDA Pharma and is currently available with budesonide, salbutamol and formoterol formulations for the treatment of asthma and COPD. In 2010 the development of the Novolizer® was awarded with the Wubbo Ockels award.
The same air classifier technology as applied in the Novolizer® has been used to develop a small and disposable inhaler specifically for the treatment of cystic fibrosis patients with the antibiotic colistin sulphomethate. Because two classifiers are incorporated in this small inhaler, called the Twincer™, it is capable of dispersing very high drug loads of up to 60 mg. Despite several successful small scale clinical trials in both healthy volunteers and cystic fibrosis patients, the Twincer™ is not available on the market yet. Continued research is focused at optimising the Twincer™ for use with other formulations and, the other way around, optimising other formulations (tobramycin, kanamycin, adhesive mixtures) for use in the Twincer™. Therefore we anticipate the Twincer™ to be suitable for the treatment of a wide range of pulmonary diseases from asthma and COPD to infectious diseases like cystic fibrosis and tuberculoses in the near future.
Antibiotics in the Twincer™
Tuberculosis (TB) is an infectious disease caused by bacteria from the Mycobacterium Tuberculosis-complex. TB is difficult to cure and current therapy consists of multiple orally or intravenously administered antibiotics for at least 6 months, but this can last up to several years. TB most frequently (75-80%) expresses as pulmonary tuberculosis, so we strongly believe that pulmonary application of antibiotics will be a valuable addition to current anti-TB therapy.
Cystic fibrosis (CF) is a hereditary disease affecting multiple organs, including the lungs. CF patients often suffer from chronic pulmonary infections with bacteria, especially Pseudomonas aeruginosa, which induce inflammation and fibrosis of the lungs, resulting in deterioration of lung capacity. Maintenance treatment with nebulised antibiotics, like tobramycin and colistin sulphomethate, is common practice in patients with CF. These antibiotics have shown to be effective in interfering with and slowing down of pulmonary deterioration.
Because the Twincer™ is capable of dispersing drug loads up to 60 mg this dry powder inhaler can compete with pulmonary administration via nebulisation. The use of dry powder inhalers has several advantages over the use of nebulisers. Nebulisation takes 10-20 minutes (2 to 3 times daily), where a single dry powder inhalation takes less than a minute. Dry powder inhalers are portable where nebulizers are not and nebulizers need regular cleaning and adequate disinfection to prevent contamination with microorganisms. Because the Twincer™ is a disposable device the latter problem is completely resolved. An even greater drawback of nebulizers is their low efficiency. Because of this we believe that our dry powder inhalers are more favourable than nebulisers.
Although the Twincer™ is capable of dispersing many inhalation powder formulations very effectively, most antibiotic powder formulations have to be optimised even for this device to reduce inhaler losses and improve the fine (respirable) particle fraction. However, there is little room for excipients in antibiotic dry powder formulations, because antibiotic doses need to be extremely high to kill the microorganisms. Excipients would make the formulations too bulky and would reduce the maximum dose to be dispersed by the Twincer™. Therefore the ideal dry powder formulation is pure micronised powder, but micronised powders exhibit poor flowability and an extreme agglomeration and adhesion tendency, so pure micronised powders often show poor dispersion efficiency. Most of the antibiotics we focus on are very hygroscopic and water uptake makes these powders ‘sticky’, which also is disastrous to their dispersion efficiency.
We try to improve dispersion efficiency from the Twincer™ by applying particle preparation techniques like spray-drying and pelletisation or addition of small amounts of excipients like dry lubricants and/or sweeper crystals (lactose crystals that keep the inner walls of the air classifier chambers free from adhering drug particles). Another tool available at our department is a climate box which enables us to control the relative humidity (to < 3% RH) during handling of the formulations to prevent water uptake by the drug.
Bronchial provocation tests from the Twincer™
Bronchial hyperresponsiveness is an important characteristic of the pathology of asthma. Measurements of bronchial hyperresponsiveness are performed for the diagnosis and monitoring of asthma in epidemiological studies, but also in clinical trials for the development of new anti-asthma treatment. The stimuli used in these tests can either have a direct or indirect effect. Direct stimuli are pharmacological agents that cause bronchoconstriction, resulting in a reduction of the airflow, by a direct stimulation of the smooth muscle cells of the bronchial tree. Indirect stimuli have the same result, i.e. a reduced airflow, but act on other cells like inflammatory or nerve cells. Indirect stimuli can be both pharmacological and physical (e.g. dry air, exercise).
In our department we focus on the pharmacological challenge tests with both direct and indirect stimuli. Up until now, most of these tests are performed by nebulisation of a solution of the stimulating agent. The patient (or healthy volunteer) breathes normally through the nebuliser for a fixed period of time during which the dose is given gradually. This tidal breathing is quite shallow and the ventilation (hence accessibility) of the lower regions of the lungs is not optimal. We aim to improve these challenge tests by replacing nebulisation by dry formulations of various agents in the Twincer™. Not only does powder inhalation enhance the deposition of the agent, it also gives the opportunity to target different regions of the lungs by altering the particle size of the agent. Moreover, the disposable character of the Twincer™ makes it a very suitable device for diagnostics.
Adhesive mixtures for inhalation
To improve the flow properties and enhance dose metering of the very fine drug particles for inhalation they are often mixed with coarse ‘carrier particles’ which are roughly 60-250 µm in diameter and consist mostly of lactose. The fine drug particles adhere to the carrier particles to form an adhesive mixture that is homogeneous and exhibits a flowability that allows for reproducible and accurate dose metering. However, the carrier-drug agglomerates are too large for inhalation into the lower respiratory tract and have to be deagglomerated and dispersed by the inhaler at the moment of inhalation. Our research into adhesive mixtures is aimed at understanding the underlying mechanisms that are involved in the interaction between particles within these mixtures as well as finding the relevant parameters that influence the interaction forces. Hopefully this will provide us with the knowledge and the tools to, based on the properties of the drug and carrier while also taking into account the dispersion principle applied, optimise the delicate balance of forces involved to form a stable mixture that at the same time can be readily dispersed.
The result of what we call ‘carrier residue measurements’ (i.e. measurements in which we collect the carrier from the classifier of a test inhaler after an inhalation experiment and analyse the residual amount of drug left on the carrier surface) are a measure for the interaction forces between drug and carrier. These measurements are used to investigate the effect of parameters like for example mixing time, drug load and carrier size as well as the effect of added ternary components on the interparticulate forces. Other important tools for this research subject that are at our disposal are laser diffraction and scanning electron microscopy.
An important aspect of testing and developing inhalers and inhalation formulations is the evaluation of the aerosols they produce. Several methods can be used for aerosol characterisation, of which cascade impaction and laser diffraction are the most widely used, also at our department. Together with Sympatec GmbH we developed a special modular adaptor that allows the rapid and reproducible testing with laser diffraction of practically all inhalation devices available. For cascade impaction measurements we use the Next Generation Impactor (NGI) and the Multi Stage Liquid Impinger. Currently one of our research projects, which is a cooperation with the University of Sidney, involves the measurement of electrostatic charge in powder aerosols with a specially adapted NGI.
Together with the Haga Pharmacy of the Haga Hospitals in The Hague we performed small scale clinical trials with healthy volunteers as well as cystic fibrosis patients with colistin from the Twincer™. More recently the Twincer™ was used to treat a child, suffering from diabetes combined with subcutaneous insulin resistance, with an insulin dry powder formulation called Exubera. We were able to demonstrate increased dispersion efficiency and a higher reproducibility compared to the Exubera inhaler. This was a collaboration with the University Medical Center Groningen, with which we are currently also planning to perform clinical trials in patients with antibiotics from the Twincer™.
Besides the research activities mentioned we are actively sharing our knowledge with health care professionals by giving lectures and participating in advisory committees.
PhD students currently enrolled
· Marcel Hoppentocht: working on antibiotics from the Twincer™.
· Anne Lexmond: working on bronchial provocation tests from the Twincer™.
· Floris Grasmeijer: working on adhesive mixtures for inhalation.
Research projects for students
Students who are interested in performing their master research in the area of pulmonary drug delivery, who are analytical, critical and patient and are not afraid of performing labour intensive measurements are always welcome to drop by and discuss the options for an interesting and challenging research project.
For more information please contact Anne de Boer, room 232 building 3213, MWF-complex (tel. +31 50 363 3286).
|11 oktober 2012 10:47