|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ARTICLE |
|---|
TOP
Article
REFERENCES
|
|---|
Although there are potential health benefits in targeting drug delivery to the lungs, attempts to deliver aerosol medication to specific regions of the bronchial tree have been limited. However, there is now greater understanding of the various factors influencing particle size, behavior, and deposition. This article reviews these issues and the limited clinical studies that have been tried to assess the benefits of regional drug deposition and our ability to achieve it.
Modern asthma therapy has promoted the benefits of aerosol drug delivery to the lung (1, 2). However, little consideration has been given to the advantage of targeting specific regions of the airway anatomy. By increasing the precision of drug deposition it may be possible to target specific disease or receptor locations, decrease drug exposure of normal airways, and decrease side effects, thereby increasing the efficiency and effectiveness of health care delivery. In this context, the small airways have an increased surface area relative to the larger airways and are subject to a variety of disease processes; unfortunately they remain difficult to quantify and to treat.
Why Target Drug Delivery to Small Airways?
Small-airway disease is a significant component of obstructive airway pathology. Emphysema classically involves the terminal bronchioles, but increasingly there is recognition that asthma, and in particular chronic persistent asthma, also involves the small airways (3). A variety of other lung diseases, including bronchiectasis, extrinsic allergic alveolitis, and sarcoidosis also involve the small airways. Current metered-dose inhalers (MDIs), pressurized inhalers, or dry-power inhalers (DPIs) are not very efficient at specifically depositing medication in the more peripheral airways of the lung. In many patients it is more effective to use oral medication.
Mechanisms of Particle Deposition in the Airways
There are three main ways in which particles become deposited in the lung: inertial impaction, sedimentation, and diffusion. Inertial impaction tends to occur in the upper airways when the velocity and mass of the particles cause them to impact the airway surface. For this reason, inertial impaction can be influenced to some degree by hyperventilation. In contrast, sedimentation occurs in more peripheral airways, is gravitational in character, and tends to be influenced by breath-holding, which allows more time for gravity to have an effect. Diffusion is based on Brownian motion and is relevant to particles < 1 µm in diameter (3, 4).
Determinants of Effective and Specific Aerosol Drug Delivery
To deliver a specific drug to a particular part of the airway as efficiently as possible, we must consider three broad areas: respiratory tract morphology, ventilatory parameters, and aerosol characteristics.
Respiratory tract morphology. The upper airway (nose, mouth, and throat) has a very high filtering capacity and removes between 70 and 90% of pressurized MDI (pMDI) particles. In the laboratory it is possible to create surrogate airway systems that replicate the human airway anatomy, including the 23 divisions with bifurcation angles of approximately 70°. These can then be used to study the effect that alterations in the airway anatomy have on drug delivery.
Ventilatory parameters. Among individuals and from breath to breath there is considerable variation in tidal volume, flow rates, and respiratory rate. All of these will affect drug deposition; breath-holding is of particular significance. However, it is important to realize that once a drug is packaged, ventilatory parameters become the only variables that can be changed.
Aerosol characteristics. There are many aerosol variables that will influence airway deposition. These include the size (diameter), shape (e.g., fibers), electrical charge (in particles < 1 µm in diameter), hygroscopic characteristics, density, and mass of the particles being generated (3, 5, 6). In addition, particle deposition varies depending upon whether its source is a suspension or a solution. Specific properties also influence deposition of particles if they are suspended in a cloud, as cigarette smoke is (7).
Hygroscopic properties of aerosol particles have been subject to much scientific investigation, particularly since it has become apparent that particles can grow up to six times their original size as they travel down the airway. The extent to which this happens depends upon the airway tonicity and water content; both are related to the airway's temperature and humidity. Hygroscopic effects appear to be more pertinent in the normal than the asthmatic airway. Hygroscopic effects are also more obvious in the peripheral airways, where the temperature is approximately 37° C and the humidity is 44 µg/cm3 (6).
Modeling
In order to develop aerosols with specific deposition properties and understand how aerosols behave while traveling down the airways, a variety of modeling approaches have been pursued.
At a theoretical level, mathematical models have been developed based upon the physics of fluids moving in simple tubes, with additional variables being added to the equations to allow for specific airway or particle variables (4, 8). Interestingly, the equations that have been developed appear to predict the deposition outcomes in clinical studies reasonably well (4, 9).
In vitro studies are vital for developing new aerosols. The most commonly used in vitro model is the Anderson Cascade Impactor, which allows particles of diminishing size to be captured on a series of plates, with each plate having successively smaller exit holes (Figure 1). Other in vitro approaches involve using spectral analyses of the particles being emitted from a given delivery device (10). However, these approaches do not allow assessment of the airway anatomy's effect on aerosolized particles. As mentioned earlier, morphologic models have been developed with varying degrees of sophistication. Some models have artificial diaphragms, chest walls, and appropriate ventilatory volumes and flow rates to mimic human tidal breathing (Figure 2). With these models, radiolabeled or unlabeled particles can be inhaled and deposition patterns noted.
|
|
In vivo and animal models, such as the rabbit, provide more realistic outcomes. Studying human lung deposition is the ultimate model, but that method brings with it issues of safety and limitations of drug labeling and detection.
Assessing Particle Deposition: The Generation and Labeling of Particles
Choice of particle. When studying particle deposition in airways it is possible to use either inert particles, which physically mimic the drug in question, or use the native drug. The advantages of using inert particles are that they are nontoxic, biologically inert, insoluble, and readily labeled. All of these properties help by reducing the number of variables that need to be accounted for when assessing the results. Examples of inert particles include Teflon, clay, polystyrene, albumin, and iron. Using the drug itself has the advantage of representing the product as it will be used by patients. However, the drug particles need to be labeled, which can be quite difficult; in some cases, the labeling itself can alter the physical properties of the drug particle (11). It is also possible to study a mixture of drug and inert particles.
Generation of particles (size, charge, shape, and uniformity). A variety of devices can be used to generate the test particles. Ideally, the particles should be uniform in size (monodisperse), have no charge, and be spherical. The extent to which this occurs is influenced by the system used to generate test particles (Table 1). Of these devices, the spinning disc method (12) or the vibrating orifice (11) appear to be the best for generating aerosol particles, particularly since both can generate a variety of particle sizes with a high degree of precision and uniformity.
|
Methods of measurement. Once a method for generating particles has been chosen, it is equally important to consider labeling techniques and subsequent methods of detection. Either the particles are labeled or one measures the native material, usually the drug itself (13, 14). Alternatively, one can measure a clinical outcome, such as FEV1, as an index of effective drug deposition, although this may give little information as to where in the airway the particles have been deposited.
Labeling particles
radiolabeling. Gamma radiation is preferred because it has a short half-life and is therefore safer for staff and volunteers alike. The most popular label is Technetium (15). It is important to be aware that any label can dissociate (leach) from the test particles and then, because of its
different aerodynamic properties, have a different deposition
pattern than the test material (15). Good studies will assess
the level of leaching before and after testing. A simple method
of labeling is to mix the test material and the radiolabel together in a nebulizer and let both be aerosolized (and fragmented) together. Most solid/liquid particles can be labeled
equally well after particle generation. In contrast, labeling of a
dry-power formulation is not so simple; it currently involves
crushing the labeled material to the correct particle size and
then mixing it with the dry powder in the inhaler (11).
Detection of radiolabel or drug. The degree of lung deposition can either be determined by radiation from a radiolabel or by quantifying the drug in question by means of chemical assays and pharmacokinetic analysis (13).
Radiation detection. There has been considerable debate over developing algorithms to assess signal attenuation due to body tissue; at this stage, not all investigators are making such corrections. There is an increasing preference for single photon emission computed tomography, which provides three-dimensional images, rather than a single detection head gamma camera. The former provides greater information about the degree of drug distribution, rather than simply providing data on its quantity. Nevertheless, partitioning deposition into central and peripheral compartments is becoming increasingly complex, with mathematical modeling and computer algorithms being used to calculate the location of the central and peripheral airways within each lobe, segment, and secondary lobule.
Drug assay. Drug assays have the advantage that the test drug itself is being measured, and there are no safety issues about radiation or concerns over labeling, leaching, or detection systems. However, this approach cannot provide specific comparison of peripheral and central deposition. It also relies on adequately blocking oral absorption (usually with charcoal) and making prestudy measures of drug clearance in the individual using blood and urine measurements (14).
Clinical studies. The number of clinical studies assessing small airway deposition and/or response is relatively small. Some have looked at labeled drug deposition, some at drug levels, some at physiologic responses, and some at a combination of these. Very few have directly compared delivery devices, and it becomes more difficult to do so if the drug differs along with the device. Studies using monodisperse particles are likely to provide more meaningful data if questions relating to particle size or delivery device efficiency are being investigated. It is these studies that are emphasized below.
Small airway deposition. In the study by Melchor and colleagues (16), peripheral airway deposition of salbutamol appeared to be greater for the pMDI plus spacer than either pMDI alone or a DPI device (Table 2). However, the degree of bronchodilatation did not differ for the three devices, and the total lung deposition appeared to be less than reported in other studies using DPI devices (17). In a previous study using labeled Teflon particles, peripheral deposition was shown to be 16%, 13%, and 24% for pMDI, DPI, and nebulizer respectively, but on this occasion bronchodilator effects favored the pMDI (18). These results and those of others (19, 20) highlight the variability than can occur using different assessment methods.
|
In an interesting study from Zanen and colleagues (21), patients with chronic obstructive airway disease were treated on different study days with salbutamol (20 µg) or ipratropium (8 µg). The drug was delivered as a monodisperse aerosol with the particle size being 1.5, 2.8, or 5 µm in diameter; patients' lung functions were also assessed. The maximum improvement in lung function occurred with the 2.8-µm particle aerosol; therefore, a particle size of approximately 3 µm seems ideal for a bronchodilator. Data from previous studies by the same authors (22, 23) had suggested that a particle size of 1.5 µm may be effective in small airways, but this effect was not demonstrated in this particular patient cohort. An additional bonus of using monodisperse particles, which have a more uniform size, appears to be an associated increase in airway deposition, allowing lower drug dosages in this study, lower by a factor of 10). Monodisperse aerosols are a promising area for future therapeutic aerosol development.
However, the few other studies (24) assessing optimum particle size do not necessarily agree. In a similar study of patients with chronic, stable, severe asthma (24), Technetium-labeled salbutamol produced a similar deposition pattern and similar bronchodilator effect for both 1.4- and 5.5-µm particles. Clay and colleagues (25), however, have demonstrated that nebulized 1.8-µm terbutaline is superior to both 4.6- and 10.3-µm nebulized terbutaline.
Comparative studiesdifferent drugs, different devices. The
lung deposition of most inhaled respiratory medications (ipratropium, salbutamol, terbutaline, cromoglycate, and budesonide),
most delivery devices (pMDI, DPI, nebulizers, and spacers)
and different inhalation techniques has been investigated (27,
28). However, comparative studies are hard to interpret and a
large number of permutations of drug and delivery device exist,
making the task that much more difficult. As a consequence,
studies using inhaled 
agonists, anticholinergics, and inhaled
steroids continue to give contradictory results. One of the
many of these studies is documented in Table 3 (29).
|
How reliable are deposition studies? Intra- and inter-individual variation in pMDI and Turbuhaler. Very little attention has been given to this important area. In a study by Beckman and colleagues (30) using terbutaline, the results in Table 4 were obtained.
|
Although these data suggest that in the laboratory the pMDI is less variable in its performance than the DPI and in clinical practice the converse is true, the study needs to be repeated or redesigned. The degree of in vivo drug deposition was quite different for each device. Therefore, the denominator for calculating the coefficient of variation for the pMDI was very small, making it likely that any measurable variation in deposition would result in a high coefficient of variation. One previous study (29) had assessed interindividual variation for pMDI and DPI using terbutaline in normal volunteers and concluded variation was less with the Turbuhaler (Pulmicort).
Conclusion
These studies raise a variety of issues and show that our knowledge of drug delivery to the small airways is still relatively limited. Data from recent studies of a CFC-free beclomethasone formulation have shown that the reformulation of beclomethasone enhances drug delivery to the small airways (30). However, until techniques are refined to allow an accurate appraisal of the differential delivery of drugs to the large and small airways, it will be difficult to clearly define the importance of such targeting. In addition, there is little understanding of the circulatory absorption and tissue delivery of drugs from the small airways, or indeed, of their metabolism at the site. There is much work yet to be done in this area.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Professor Philip J. Thompson, Asthma and Allergy Research Unit, University Department of Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia 6009.
| |
References |
|---|
|
TOP
Article
REFERENCES
|
|---|
1. Newhouse, M. T. 1990. Managing reversible airflow obstruction: role of MDI accessory devices, powder inhalers and nebulisers. Respirology June:1-15.
2.
Lipworth, B. J..
1995.
New perspectives on inhaled drug delivery and systemic bioactivity.
Thorax
50:
105-110
3.
Ariyananda, P. L.,
S. W. Clarke, and
J. E. Agnew.
1996.
Aerosol delivery
systems for bronchial asthma.
Postgrad. Med. J
72:
151-156
4. Mortonen, T., and Y. Yang. 1996. Deposition mechanics of pharmaceutical particles in human airways. In A. J. Hickey, editor. Inhalational Aerosols: Physical and Biological Basis for Therapy. Marcel Dekker, New York. 1-21.
5. Vincent, J. H.. 1985. On the practical significance of electrostatic lung deposition of isometric fibrous aerosols. J. Aerosol Med 16: 511-519 .
6. Ferron, G. A.. 1994. Aerosol properties and lung deposition. Eur. Respir. J 7: 1392-1394 [Medline].
7. Martonen, T. B.. 1992. The behavior of cigarette smoke in human airways. Am. Ind. Hyg. Assoc. J 53: 6-15 [Medline].
8. Rudolph, G., R. Kobrich, and W. Stahlhofen. 1990. Modelling and algebraic formulation of regional aerosol deposition in man. J. Aerosol. Med. 21(Suppl. 1):S306-S406.
9. James, A. C., G. Rudolf, and W. Stahlhofen. 1991. The respiratory tract deposition model proposed by the ICRP task group. Rad. Prot. Dos 38: 159-165 .
10. Clark, A. R.. 1995. The use of laser defraction for the evaluation of the aerosol clouds generated by medical nebulisers. Int. J. Pharm 115: 69-78 .
11. Newman, S. P. 1984. Production of radioaerosols. In S. W. Clarke and D. Pavia, editors. Aerosols and the Lung. Butterworth and Co., London. 71-89.
12.
Cheah, P. K. P., and
C. N. Davies.
1984.
The spinning top aerosol generatorimproving the performance.
J. Aerosol Med
15:
741-751
.
13. Newman, S. P.. 1993. Scintigraphic assessment of therapeutic aerosols. Crit. Rev. Ther. Drug Carrier Syst 10: 65-109 [Medline].
14. Borgstrom, L., and M. Nilsson. 1990. A method for determination of the absolute pulmonary bioavailability of inhaled drugs: terbutaline. Pharm. Res 7: 1068-1070 [Medline].
15. Few, J. D., M. D. Short, and M. L. Thomson. 1970. Preparation of 99mTc labelled particles for aerosol studies. Radiochem. Radioanal. Lett 5: 275-277 .
16.
Melchor, R.,
M. F. Biddiscombe,
V. H. F. Mak,
M. D. Short, and
S. G. Spiro.
1993.
Lung deposition patterns of directly labelled salbutamol
in normal subjects and in patients with reversible airflow obstruction.
Thorax
48:
506-511
17. Thorsson, L., S. Edsbacker, and T. B. Conradsson. 1994. Lung deposition of budesonide from Turbuhaler is twice that from a pressurised metered dose inhaler. Eur. Respir. J 7: 1839-1844 [Abstract].
18.
Zainudin, B. N. Z.,
M. Biddiscombe,
S. E. J. Tolfree,
M. Short, and
S. G. Spiro.
1993.
Comparison of bronchodilator response and deposition
patterns of salbutamol inhaled from a pressurised aerosol metered
dose inhaler, as a dry powder and as a nebulised solution.
Thorax
45:
469-473
19. Short, M. D., C. A. Singh, J. D. Few, P. R. Studdy, P. J. D. Heaf, and S. G. Spiro. 1981. The labelling and monitoring of lung deposition of an inhaled synthetic anticholinergic bronchodilating agent. Chest 80(Suppl.): 918S-921S .
20.
Newman, S. P.,
A. W. B. Weisz,
N. Talaee, and
S. W. Clark.
1991.
Improvement of drug delivery with a breath actuated pressurised aerosol
for patients with poor inhaler technique.
Thorax
46:
712-716
21.
Zanen, P.,
T. L. Go, and
J. W. J. Lammers.
1996.
Optimal particle size
for beta 2 agonist and anticholinergic aerosols in patients with severe
airflow obstruction.
Thorax
51:
977-980
22. Zanen, P., T. L. Go, and J. W. J. Lammers. 1995. The optimal particle size for parasymathicolytic aerosols in mild asthmatics. Int. J. Pharm 114: 111-115 .
23. Zanen, P., T. L. Go, and J. W. J. Lammers. 1994. The optimal particle size for Beta adrenergic aerosols in mild asthmatics. Int. J. Pharm 107: 211-217 .
24. Mitchell, D. M., M. A. Solomon, S. E. J. Tolfree, M. Short, and S. G. Spiro. 1993. The effect of particle size of bronchodilator aerosols on lung function in patients with chronic asthma. Thorax 48: 506-511 .
25.
Clay, M. M.,
D. Pavia, and
S. W. Clarke.
1986.
Effect of aerosol particle
size on bronchodilatation with nebulised terbutaline in asthmatic subjects.
Thorax
41:
364-368
26.
Johnson, M. A.,
S. P. Newman, and
R. Bloom.
1989.
Delivery of albuterol and ipratropium bromide from two nebulizer systems in
chronic stable asthma: efficacy and pulmonary deposition.
Chest
96:
6-10
27.
Selroos, O.,
A. Pietinalho, and
H. Riska.
1986.
Delivery devices for inhaled asthma medicationclinical implications of differences in effectiveness.
Clin. Immunotherapy
6:
273-299
.
28. Borgstrom, O., and S. P. Newman. 1993. Total and regional lung deposition of terbutaline sulphate inhaled via a pressurised MDI or via a turbuhaler. Int. J. Pharm 97: 47-53 .
29. Borgstrom, L., E. Bondesson, F. Moren, E. Trofast, and S. P. Newman. 1994. Lung deposition of budesonide inhaled via turbuhaler: a comparison with terbutaline sulphate in normal subjects. Eur. Respir. J 7: 69-73 [Abstract].
30. Beckman, O., E. Bondesson, L. Asking, A. Kallen, and L. Borgstrom. 1995. Intra- and inter-individual variation in pulmonary deposition via turbuhaler and pMDI. In Drug Delivery to the Lungs VI. London. 138-141.
31. Leach, C. 1996. Enhanced drug delivery through reformulating MDIs with HFA propellants: drug deposition and its effect on preclinical and clinical programs. In R. N. Dalby, P. R. Byron, and S. J. Farr, editors. Respiratory Drug Delivery V Proceedings. Interpharm Press, Buffalo Grove, IL. 133-144.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |