Review
Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges Christian A Ruge, Julian Kirch, Claus-Michael Lehr
Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Introduction Inhalation of pharmacologically active compounds—ie, the pulmonary route of drug administration—has been used to treat various diseases for millennia. With the development of modern aerosol medicines in the past century, inhalation of active pharmaceutical ingredients was indicated mainly for diseases of the lungs themselves, such as asthma or chronic obstructive pulmonary disease. Lung diseases benefit most from air-to-lung delivery, by which high local concentrations of active pharmaceutical ingredients can be delivered, with a lower burden for the rest of the body.1 Clinically, inhalation as a method of drug delivery is widely accepted, particularly because there is no risk of needle injuries, health-care staff are not needed, and patients are able to use this method at home provided that they are appropriately trained. However, pulmonary drug delivery provides more opportunities than just inhalation of β2-adrenergic agonists or corticosteroid drugs. Other than local treatment of lung diseases, the respiratory tract is a recognised point of entry for systemic therapies. The surface area and the epithelial layer of the peripheral lung is large (100 m²) and very thin (0·2–0·7 μm), making it an ideal site for high blood perfusion with perfect sink conditions.2,3 These properties allow a rapid onset of action of inhaled drugs—provided that the active pharmaceutical ingredients can permeate through the respective biological barriers. Furthermore, the pulmonary tissue seems to be the best non-invasive absorption route for specific molecules. For example, pulmonary tissue has notably high levels of systemic bioavailability for macromolecules such as peptides or proteins, although their enzymatic activity is low.4 For this reason, air-to-blood delivery of these compounds via the lung is a good alternative whenever transdermal or oral delivery is not possible. The best example of this is peptide delivery of insulin via the lungs. An inhalation product containing insulin was briefly marketed under the trade
Key messages [panel] •
Pulmonary drug delivery is a complex challenge. Since the first inhala on drugs came to the market, scien fic efforts have focused mainly on aerosol technologies to enable efficient and reproducible par cle deposi on deep in the lungs.
•
Although impressive progress has been made in the aerosol component, our understanding of, and the possibili es to control, the processes a er aerosol deposi on at the air–blood barrier are s ll rather scarce.
•
To close this gap in knowledge and technology, advanced in-vitro models, preferably based on human cells and ssues, and innova ve aerosolisable nano-par culate carrier systems, are needed.
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
Published Online June 4, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70072-9 Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany (C A Ruge PhD, J Kirch PhD, C-M Lehr PhD); HelmholtzInstitute for Pharmaceutical Research Saarland (HIPS), Saarland University, Saarbrücken, Germany (C-M Lehr); and Institut Galien Paris-Sud, CNRS UMR 8612, LabEx, LERMIT, University Paris-Sud, Paris, France (C A Ruge) Correspondence to: Prof Claus-Michael Lehr, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, Campus A4 1,D-66123 Saarbrücken, Germany [email protected]
1
Review
name Exubera (Pfizer, New York, NY, USA). Although this product was withdrawn from the market shortly after its launch in 2007 (mostly for business reasons), pulmonary drug delivery continues to be a topic of intensive research, perhaps even more so than before. New particle technologies and inhaler devices are still being marketed today with more in the pipeline. The development of pharmaceutical aerosol products is still a complex technical problem. However, technologies enabling inhaled drugs to reach the deep lungs are actually widely available. The deposition mechanisms of aerosol particles or droplets—impaction, sedimentation, diffusion, and combinations thereof—in the respiratory tract have been extensively studied.5,6 Efficient and reproducible pulmonary deposition of aerosol medicines is now possible with current technology. However, the processes that take place after an aerosol particle has landed on the pulmonary epithelial surfaces are still unclear.1 Little is known about what happens between deposition and first appearance of the drug in the blood circulation. The mechanism of action of particles after pulmonary deposition is a highly complex topic, and particle–lung interactions are still being researched. Therefore, the old concept of pulmonary drug delivery, which states that “efficient aerosol generation and particle deposition in the lung are the main and only challenges for effective inhalation therapy,”1 is no longer valid. Thus, a rational optimisation of active pharmaceutical ingredients and formulations for pulmonary delivery is still hindered by the lack of knowledge about the processes that occur after the deposition of drug particles in the respiratory tract.7
Shifting of the focus from generation of aerosols to overcoming biological barriers What happens after the drug is delivered into the lung, and how do inhaled particles interact with the air–blood barrier? Unfortunately, these questions cannot be answered accurately because there is evidence only for a few basic principles, mostly regarding the association between basic physicochemical properties of the active pharmaceutical ingredients and its absorption kinetics. The simplest mechanism of action is probably the pulmonary administration of highly soluble and permeable active pharmaceutical ingredients; here, the active pharmaceutical ingredient, or carrier particle, shows an immediate dissolution on contact with the pulmonary surfaces, allowing the active ingredients to be absorbed very rapidly into the bloodstream. This absorption can happen in seconds to minutes for small hydrophobic molecules (eg, nicotine).4,8 Rapid absorption probably applies to, or is at least intended for, all inhalation products on the market.1 However, there are several medical indications for which rapid absorption from the deposition site is actually disadvantageous; when the lung is the target organ, prolonged sustainability of the aerosol particle would be desirable. Retention of a particle that contains the active pharmaceutical ingredient 2
with sustained release properties could lead to positive therapeutic benefits due to altered pharmacokinetic profiles (eg, longer duration of local effects) and reduced dosing frequencies, resulting in better patient compliance because fewer inhalations per day are required. Drug formulations are mostly assessed by in-vivo administration and subsequent monitoring of the pharmacological endpoint. The actual mechanism of action of the particles after their deposition, however, is rarely investigated, particularly on a nanometric or molecular level. On first contact with the biological environment of the lungs, deposited particles are immediately exposed to a highly complex interplay between non-cellular and cellular elements of the air–blood barrier. Unfortunately, little is known about these processes. Hence, a new framework for pulmonary drug delivery is needed that focuses on the question: what happens to particles after their deposition in the lungs? The answer to this question could pave the way to more efficient and safer carrier systems. There are three main post-deposition challenges for pulmonary drug delivery to overcome biological barriers: (1) modulation of solubility in the lining fluids and permeability across the epithelial barrier to improve pulmonary bioavailability of the active pharmaceutical ingredients; (2) control of clearance processes to prolong the action of the active pharmaceutical ingredients; and (3) specific targeting within the lungs (ie, specific regions, tissues, and cells) to intensify the local or spatial effect of the active pharmaceutical ingredients. In this Review, we focus mainly on the challenges that might arise from a new framework for pulmonary drug delivery, and how improved drug delivery to (ie, air-tolung) and via the lungs (ie, air-to-blood) could have important advantages compared with existing treatments. We will also discuss biopharmaceutical approaches and clinically relevant formulations that might lead to improvements in pulmonary drug delivery.
Medical challenges to improve pulmonary drug delivery Conditions and modalities for improved drug absorption Several disorders—not only respiratory disorders—could benefit from improved delivery of active pharmaceutical ingredients via the lungs and resulting fast onset of the pharmacological effect. For instance, most active pharmaceutical ingredients to treat CNS disorders have notable and rapid metabolic inactivation when passing through the liver after oral drug delivery, which could be avoided by pulmonary drug delivery. Because CNS-active drugs are usually expensive compounds, lung-to-brain delivery can result in higher bioavailability, thus substantially reducing the dose and the costs of drugs necessary to obtain a therapeutic effect. Hence, there is a reasonable number of CNS-active drugs that are in phase 2 clinical testing for pulmonary delivery for disorders such as anxiety (alprazolam), Parkinson’s
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
Review
disease (apomorphine), analgesia (morphine, fentanyl), and migraine (loxapine, prochlorperazine), and a new drug application is being filed for inhaled dihydroergotamine (Levadex, MAP Pharmaceuticals, Mountain View, CA, USA) for migraine.9 Furthermore, in December, 2012, the inhaled dibenzodiazepine loxapine (Adasuve, Alexza Pharmaceuticals, Mountain View, CA, USA) was approved in the USA by the US Federal Drugs Administration for treatment of agitation associated with schizophrenia or bipolar I disorder in adults.10 Treatment of nicotine addiction could be optimised with pulmonary administration, since products for smoking cessation currently available on the market deliver nicotine or substitutes (such as bupropion or varenicline) very slowly, and do not have the ultra-rapid onset obtained through inhalation of cigarette smoke.11 Another very promising class of compounds that are ideally suited for pulmonary delivery are biopharmaceuticals, particularly peptides and proteins. Macromolecules have notably high bioavailability across the lung epithelium, which can be up to 200 times higher than via any other non-invasive route into the body.3 Thus, the lungs have been investigated for decades to systemically deliver therapeutic proteins. The best known example showing the feasibility of this approach is pulmonary delivery of insulin for treatment of diabetes, for which a product was briefly commercially available (Exubera). Other companies are working on second-
API properties • Molecular weight • Charge • Solubility • Lipophilicity
generation insulins for inhalation, but Technosphere insulin (fumaryl diketopiperazine-based porous micronsized carrier particles with recombinant human insulin; MannKind Corporation, Valencia, CA, USA) is the only product that is still in clinical development, and for which a decision by regulatory authorities is awaited in the near future.12 Other than insulin, the pulmonary route is being assessed in clinical or preclinical trials for various other peptides and proteins, such as heparin (anticoagulation),13 calcitonin and parathyroid hormone (osteoporosis), human growth hormone (growth hormone deficiency), and erythropoietin (anaemia).14 As long as a disease does not affect the lung itself, systemic administration via this organ makes good sense, and there are some promising candidates in clinical trials. However, there has been little progress in air-to-blood delivery, mostly as a result of post-deposition issues of the active pharmaceutical ingredients and its formulation affecting dissolution and absorption (figure 1). Not every molecule species can be delivered via the lungs. First, the rate and extent of pulmonary absorption depends on intrinsic properties of the active pharmaceutical ingredients, particularly solubility and permeability. The pharmacokinetic profile of a pulmonary-administered active pharmaceutical ingredient is also strongly dependent on its formulation, which can modify the maximum therapeutic blood concentration (Cmax), the time at which this maximum is
Formulation properties • Desintegration • Dissolution • Particle size • Wettability
Aerosol particle
Central lung
Peripheral lung
3 Mucociliary clearance Surfactant Mucus
Alveolar macrophage
1 3 Macrophage clearance
Surfactant
Bronchial epithelium
Alveolar epithelium
1
Endothelium Blood
Endothelium 2
2
Blood
Systemic circulation
Figure 1: What happens to an aerosol drug after deposition in the lungs? (1) First contact with the lung lining fluids: release of the active pharmaceutical ingredient (API) from the deposited aerosol particle comprises different processes, governed by the amount and composition of the locally available lining fluid and by intrinsic properties of the API and the carrier particle. (2) Absorption of the API across the pulmonary epithelium: this process is mainly controlled by its physicochemical properties. (3) Clearance of the undissolved particle.
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
3
Review
observed (Tmax), and the elimination half-life time.15 An aerosol particle must dissolve after its deposition in the lungs before the active pharmaceutical ingredient can be absorbed.3 In the case of highly soluble active pharmaceutical ingredients (such as salbutamol, or peptides and proteins), there are no notable barriers to this process because these drugs rapidly dissolve after making contact with the lung lining fluid. However, with active pharmaceutical ingredients with low solubility, dissolution can affect the absorption rate of the drug by the pulmonary mucosa. Unfortunately, low dissolution affects some important active pharmaceutical ingredients relevant to pulmonary drug delivery—eg, CNS-active drugs or inhaled corticosteroids. The amount of liquid available for dissolution is also an important factor. Estimation of the total volume of the lung lining fluid in human lungs is 15–70 mL.16 However, the proportion of this total fluid volume that an aerosol particle is finally exposed to after deposition is difficult to predict.1 Moreover, the thickness of the lining layer, and consequently the volume of the lung lining fluid, differs between the central to the peripheral lungs. An aerosol particle deposited in the upper airways might dissolve faster as a result of a larger solid–liquid interface than in the alveoli.7 Furthermore, components of the pulmonary surfactant layer can also affect dissolution processes. For example, phospholipids—the main constituent of the pulmonary surfactant—can increase the solubility of active pharmaceutical ingredients.17,18 However, therapeutic peptides or proteins can be aggregated or inactivated as a result of interaction with surfactant components.3 The rate and extent of the dissolution process is therefore the first challenge to improve absorption. Fast dissolution and absorption of therapeutic peptides and proteins is important since they can be rapidly degraded by ubiquitous peptidases, or opsonised by endogenous proteins leading to increased phagocytosis— ie, premature elimination of the drug.3 Moreover, undissolved (carrier) particles are exposed to clearance mechanisms resulting in fast removal of the active pharmaceutical ingredients from the body. Taken together, the processes that occur after deposition are mainly a function of the physical state and dissolution properties of the carrier or drug particle.
Conditions and modalities for prolonged drug action Severe lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, and cystic fibrosis are among the leading causes of morbidity and mortality worldwide. In patients with these disorders, a reduction of frequency and duration of aerosol treatment are important for both physicians and patients to increase adherence to and compliance with therapies. The main challenge in achieving such a reduction is the improvement of relevant formulations in terms of prolonged sustainability at the site of action, which is 4
antagonised by the various clearance mechanisms of the lungs (figure 1). These clearance mechanisms pose particular challenges for medical management by pulmonary specialists, since persistence of the drug at the site of deposition is notably reduced by mucociliary and macrophage clearance. Moreover, the tenacious mucus barrier in the upper lungs is a further barrier to advanced pulmonary drug delivery. Overcoming these obstacles by controlling the clearance mechanisms of the lungs is important in disorders such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension, for which frequent and long-lasting treatment is necessary for sustainability of the drug at the site of action. Other diseases that can benefit from prolonged sustainability of the drug at the site of action, while attaining maximum exposure to specific lung targets, are cystic fibrosis and associated secondary infections or other inflammatory pathological disorders. For these diseases, formulations might need to be more sophisticated, typically including expensive and fragile active pharmaceutical ingredients such as antibiotics, prostacyclins, peptides, proteins, or nucleotides. Apart from coughing, the lungs have developed two main clearance mechanisms: mucociliary clearance and macrophage clearance. These two different, yet overlapping, mechanisms show the unique adaptation of the human body to various airborne and inhaled threats of organic and inorganic nature. Both clearance mechanisms are highly dependent on the properties of the noncellular pulmonary barrier, which are the mucus blanket in the upper and central lungs and the pulmonary surfactant film predominantly in the peripheral lungs. In the upper lungs, mucociliary clearance is the dominant mechanism and there is a complex interplay between non-cellular (the mucus blanket) and cellular elements (ciliated epithelial cells, secretory cells).19-21 Pulmonary mucus is a thick viscoelastic hydrogel layer (up to 30 μm),22 and is mainly composed of water and glycoproteins (mucins).23 Complex and coordinated beating patterns (3–12 Hz) of the cilia under the mucus blanket accelerate this layer and cause ascending transport of the mucus (about 3 mm per min),24,25 along with material deposited on, and trapped in, the mucus. Subsequently, mucus is swallowed and thus delivered into the gastrointestinal tract. This fast and unspecific clearance mechanism is highly efficient, with 80–90% of inhaled material being excreted from the upper and central lung within 24 h.26,27 Effective cilia function is highly dependent on hydration status and rheological properties of the mucus layer. Therefore, the way in which altered properties of the mucus blanket and thus impaired mucociliary clearance cause exacerbations in diseases such as cystic fibrosis is being studied.28 Although it is dominant in the peripheral lungs, the second clearance mechanism (ie, clearance by alveolar macrophages) is strongly associated with mucociliary clearance. Alveolar macrophages are present in the lungs
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
Review
and phagocytose inhaled organic and inorganic particulate matter. After phagocytosis, alveolar macrophages travel along the so-called mucociliary escalator. By contrast with mucociliary clearance, alveolar macrophages show size-dependent uptake, which is most effective for particles with a geometric diameter of 0·5–5 μm.29 A second non-cellular barrier—the pulmonary surfactant layer—is also important. This ultrathin layer (0·09–0·89 μm) spreads over the pulmonary surfaces,30 and is the main non-cellular barrier in the peripheral lung where mucus is not present in the healthy state. Pulmonary surfactant mainly consists of lipids (about 90%) but also contains various proteins (about 10%).31 Several studies on particle–surfactant interactions have assessed the displacement of particles into the surfactant layer,32 and the effect such particles exert on the biophysical functionality of the surfactant film.33 However, little is known about the interactions between surfactant components and inhaled particles on a molecular level. Furthermore, the surface properties of particles affect the occurrence and intensity of interactions with pulmonary surfactant components (eg, opsonisation), and biomolecule adsorption to inhaled material can largely affect subsequent cellular reactions, particularly macrophage clearance.34,35 For example, adsorption of surfactant proteins (SP), predominantly SP-A and SP-D, can increase the uptake of particles by alveolar macrophages, whereas the interaction with surfactant lipids controls the overall uptake of particulate matter, and can balance protein-mediated effects.36 In summary, both clearance processes notably affect residence time of inhaled drug carriers in the lung and thus have to be overcome to increase bioavailability. Clearance processes are less relevant for highly soluble active pharmaceutical ingredients given in droplet aerosol form or as rapidly dissolving particulate carriers, for which the limiting factors are diffusion properties. The key to solving the challenge of sustainability of inhaled drug carriers lies in smart carrier design that Second order: site of disease
aims to overcome or specifically reduce mucociliary clearance or clearance of alveolar macrophages.
Conditions and modalities for targeted delivery The other main post-deposition challenge in pulmonary drug delivery is specification of the location where the active pharmaceutical ingredient needs to be effectively available—ie, targeted delivery to the lungs. Targeted delivery is important in disorders with a confined localisation of the disease, such as lung malignancies and respiratory infections associated with cystic fibrosis or tuberculosis. In patients with such diseases, delivery of the active pharmaceutical ingredients to a defined region only within the respiratory tract is desirable (figure 2). The first level of targeting is delivery to the central or peripheral, right or left lung. In a second level of targeting, the drug should be delivered ideally to the site of disease—eg, to a tumour or tuberculosis granuloma. The third level of targeted delivery would be to target distinct cell types, such as mutated or degenerated barrier cells (ie, epithelial cells in cystic fibrosis or lung cancer), infected alveolar macrophages, or cells of the lung associated lymphatic tissue (eg, for antigen delivery). Lung cancer is the most common form of cancer worldwide and has poor survival rate, which is usually a result of late diagnosis.37 Treatment of lung cancer is with surgery, radiotherapy, or chemotherapy, either applied alone or in combination with other methods. Most chemotherapeutic options for lung cancer are given by intravenous injection, with the exception of a few active pharmaceutical ingredients that can be given orally.38 Unfortunately, the concentration of the drugs at the site of action (ie, the tumour in the lung) by systemic application are low compared with the applied dose, and systemic adverse effects are consequently more pronounced. Furthermore, active pharmaceutical ingredients for treatment of lung cancer are typically aggressive and expensive. A local and specific delivery of anticancer drugs
First order: lung regions
Third order: specific cells
Epithelial cells
Central lung Local infections
Fibroblasts
Tumour tissue
Tumour cells
Right lung
Peripheral lung
Left lung Immune cells
Figure 2: Different levels of targeting within the respiratory tract in pulmonary drug delivery
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
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Review
via the pulmonary route could therefore have a real therapeutic benefit in efficiency of the drug and endurability of the drug by patients.38 There are several studies assessing inhalation formulations for lung cancer treatment in cell culture and animal models, and phase 1 and 2 clinical studies. So far, however, clinical trials of inhaled chemotherapy have been restricted to patients with advanced lung cancer; patients with early stage A
(i)
(ii)
(vi)
(iii)
(v)
cancer are treated otherwise, mainly because of the intrinsic pulmonary toxicity of the respective formulations. Moreover, inhalation of anticancer drugs was applied as adjuvant therapy in combination with other methods, mainly intravenously administered chemotherapeutic drugs, in patients with advanced stage disease.39 In patients with diseases associated with respiratory infections, such as cystic fibrosis and tuberculosis, one of the main challenges in treatment via inhalation is the poor accessibility of the respective pathogen. A comparable scenario is given in early infections with Mycobacterium tuberculosis, which is able to invade alveolar macrophages and survive intracellularly while being protected from antituberculosis drugs.40
Biopharmaceutical approaches and possible therapeutic benefits
(iv)
Improving pulmonary deposition and absorption
B 1 µm PRINT cylinders
Jet milled powder
10 µm
2 µm
C 1·0
Respirable fraction (
Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges Christian A Ruge, Julian Kirch, Claus-Michael Lehr
Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Introduction Inhalation of pharmacologically active compounds—ie, the pulmonary route of drug administration—has been used to treat various diseases for millennia. With the development of modern aerosol medicines in the past century, inhalation of active pharmaceutical ingredients was indicated mainly for diseases of the lungs themselves, such as asthma or chronic obstructive pulmonary disease. Lung diseases benefit most from air-to-lung delivery, by which high local concentrations of active pharmaceutical ingredients can be delivered, with a lower burden for the rest of the body.1 Clinically, inhalation as a method of drug delivery is widely accepted, particularly because there is no risk of needle injuries, health-care staff are not needed, and patients are able to use this method at home provided that they are appropriately trained. However, pulmonary drug delivery provides more opportunities than just inhalation of β2-adrenergic agonists or corticosteroid drugs. Other than local treatment of lung diseases, the respiratory tract is a recognised point of entry for systemic therapies. The surface area and the epithelial layer of the peripheral lung is large (100 m²) and very thin (0·2–0·7 μm), making it an ideal site for high blood perfusion with perfect sink conditions.2,3 These properties allow a rapid onset of action of inhaled drugs—provided that the active pharmaceutical ingredients can permeate through the respective biological barriers. Furthermore, the pulmonary tissue seems to be the best non-invasive absorption route for specific molecules. For example, pulmonary tissue has notably high levels of systemic bioavailability for macromolecules such as peptides or proteins, although their enzymatic activity is low.4 For this reason, air-to-blood delivery of these compounds via the lung is a good alternative whenever transdermal or oral delivery is not possible. The best example of this is peptide delivery of insulin via the lungs. An inhalation product containing insulin was briefly marketed under the trade
Key messages [panel] •
Pulmonary drug delivery is a complex challenge. Since the first inhala on drugs came to the market, scien fic efforts have focused mainly on aerosol technologies to enable efficient and reproducible par cle deposi on deep in the lungs.
•
Although impressive progress has been made in the aerosol component, our understanding of, and the possibili es to control, the processes a er aerosol deposi on at the air–blood barrier are s ll rather scarce.
•
To close this gap in knowledge and technology, advanced in-vitro models, preferably based on human cells and ssues, and innova ve aerosolisable nano-par culate carrier systems, are needed.
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
Published Online June 4, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70072-9 Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany (C A Ruge PhD, J Kirch PhD, C-M Lehr PhD); HelmholtzInstitute for Pharmaceutical Research Saarland (HIPS), Saarland University, Saarbrücken, Germany (C-M Lehr); and Institut Galien Paris-Sud, CNRS UMR 8612, LabEx, LERMIT, University Paris-Sud, Paris, France (C A Ruge) Correspondence to: Prof Claus-Michael Lehr, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, Campus A4 1,D-66123 Saarbrücken, Germany [email protected]
1
Review
name Exubera (Pfizer, New York, NY, USA). Although this product was withdrawn from the market shortly after its launch in 2007 (mostly for business reasons), pulmonary drug delivery continues to be a topic of intensive research, perhaps even more so than before. New particle technologies and inhaler devices are still being marketed today with more in the pipeline. The development of pharmaceutical aerosol products is still a complex technical problem. However, technologies enabling inhaled drugs to reach the deep lungs are actually widely available. The deposition mechanisms of aerosol particles or droplets—impaction, sedimentation, diffusion, and combinations thereof—in the respiratory tract have been extensively studied.5,6 Efficient and reproducible pulmonary deposition of aerosol medicines is now possible with current technology. However, the processes that take place after an aerosol particle has landed on the pulmonary epithelial surfaces are still unclear.1 Little is known about what happens between deposition and first appearance of the drug in the blood circulation. The mechanism of action of particles after pulmonary deposition is a highly complex topic, and particle–lung interactions are still being researched. Therefore, the old concept of pulmonary drug delivery, which states that “efficient aerosol generation and particle deposition in the lung are the main and only challenges for effective inhalation therapy,”1 is no longer valid. Thus, a rational optimisation of active pharmaceutical ingredients and formulations for pulmonary delivery is still hindered by the lack of knowledge about the processes that occur after the deposition of drug particles in the respiratory tract.7
Shifting of the focus from generation of aerosols to overcoming biological barriers What happens after the drug is delivered into the lung, and how do inhaled particles interact with the air–blood barrier? Unfortunately, these questions cannot be answered accurately because there is evidence only for a few basic principles, mostly regarding the association between basic physicochemical properties of the active pharmaceutical ingredients and its absorption kinetics. The simplest mechanism of action is probably the pulmonary administration of highly soluble and permeable active pharmaceutical ingredients; here, the active pharmaceutical ingredient, or carrier particle, shows an immediate dissolution on contact with the pulmonary surfaces, allowing the active ingredients to be absorbed very rapidly into the bloodstream. This absorption can happen in seconds to minutes for small hydrophobic molecules (eg, nicotine).4,8 Rapid absorption probably applies to, or is at least intended for, all inhalation products on the market.1 However, there are several medical indications for which rapid absorption from the deposition site is actually disadvantageous; when the lung is the target organ, prolonged sustainability of the aerosol particle would be desirable. Retention of a particle that contains the active pharmaceutical ingredient 2
with sustained release properties could lead to positive therapeutic benefits due to altered pharmacokinetic profiles (eg, longer duration of local effects) and reduced dosing frequencies, resulting in better patient compliance because fewer inhalations per day are required. Drug formulations are mostly assessed by in-vivo administration and subsequent monitoring of the pharmacological endpoint. The actual mechanism of action of the particles after their deposition, however, is rarely investigated, particularly on a nanometric or molecular level. On first contact with the biological environment of the lungs, deposited particles are immediately exposed to a highly complex interplay between non-cellular and cellular elements of the air–blood barrier. Unfortunately, little is known about these processes. Hence, a new framework for pulmonary drug delivery is needed that focuses on the question: what happens to particles after their deposition in the lungs? The answer to this question could pave the way to more efficient and safer carrier systems. There are three main post-deposition challenges for pulmonary drug delivery to overcome biological barriers: (1) modulation of solubility in the lining fluids and permeability across the epithelial barrier to improve pulmonary bioavailability of the active pharmaceutical ingredients; (2) control of clearance processes to prolong the action of the active pharmaceutical ingredients; and (3) specific targeting within the lungs (ie, specific regions, tissues, and cells) to intensify the local or spatial effect of the active pharmaceutical ingredients. In this Review, we focus mainly on the challenges that might arise from a new framework for pulmonary drug delivery, and how improved drug delivery to (ie, air-tolung) and via the lungs (ie, air-to-blood) could have important advantages compared with existing treatments. We will also discuss biopharmaceutical approaches and clinically relevant formulations that might lead to improvements in pulmonary drug delivery.
Medical challenges to improve pulmonary drug delivery Conditions and modalities for improved drug absorption Several disorders—not only respiratory disorders—could benefit from improved delivery of active pharmaceutical ingredients via the lungs and resulting fast onset of the pharmacological effect. For instance, most active pharmaceutical ingredients to treat CNS disorders have notable and rapid metabolic inactivation when passing through the liver after oral drug delivery, which could be avoided by pulmonary drug delivery. Because CNS-active drugs are usually expensive compounds, lung-to-brain delivery can result in higher bioavailability, thus substantially reducing the dose and the costs of drugs necessary to obtain a therapeutic effect. Hence, there is a reasonable number of CNS-active drugs that are in phase 2 clinical testing for pulmonary delivery for disorders such as anxiety (alprazolam), Parkinson’s
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
Review
disease (apomorphine), analgesia (morphine, fentanyl), and migraine (loxapine, prochlorperazine), and a new drug application is being filed for inhaled dihydroergotamine (Levadex, MAP Pharmaceuticals, Mountain View, CA, USA) for migraine.9 Furthermore, in December, 2012, the inhaled dibenzodiazepine loxapine (Adasuve, Alexza Pharmaceuticals, Mountain View, CA, USA) was approved in the USA by the US Federal Drugs Administration for treatment of agitation associated with schizophrenia or bipolar I disorder in adults.10 Treatment of nicotine addiction could be optimised with pulmonary administration, since products for smoking cessation currently available on the market deliver nicotine or substitutes (such as bupropion or varenicline) very slowly, and do not have the ultra-rapid onset obtained through inhalation of cigarette smoke.11 Another very promising class of compounds that are ideally suited for pulmonary delivery are biopharmaceuticals, particularly peptides and proteins. Macromolecules have notably high bioavailability across the lung epithelium, which can be up to 200 times higher than via any other non-invasive route into the body.3 Thus, the lungs have been investigated for decades to systemically deliver therapeutic proteins. The best known example showing the feasibility of this approach is pulmonary delivery of insulin for treatment of diabetes, for which a product was briefly commercially available (Exubera). Other companies are working on second-
API properties • Molecular weight • Charge • Solubility • Lipophilicity
generation insulins for inhalation, but Technosphere insulin (fumaryl diketopiperazine-based porous micronsized carrier particles with recombinant human insulin; MannKind Corporation, Valencia, CA, USA) is the only product that is still in clinical development, and for which a decision by regulatory authorities is awaited in the near future.12 Other than insulin, the pulmonary route is being assessed in clinical or preclinical trials for various other peptides and proteins, such as heparin (anticoagulation),13 calcitonin and parathyroid hormone (osteoporosis), human growth hormone (growth hormone deficiency), and erythropoietin (anaemia).14 As long as a disease does not affect the lung itself, systemic administration via this organ makes good sense, and there are some promising candidates in clinical trials. However, there has been little progress in air-to-blood delivery, mostly as a result of post-deposition issues of the active pharmaceutical ingredients and its formulation affecting dissolution and absorption (figure 1). Not every molecule species can be delivered via the lungs. First, the rate and extent of pulmonary absorption depends on intrinsic properties of the active pharmaceutical ingredients, particularly solubility and permeability. The pharmacokinetic profile of a pulmonary-administered active pharmaceutical ingredient is also strongly dependent on its formulation, which can modify the maximum therapeutic blood concentration (Cmax), the time at which this maximum is
Formulation properties • Desintegration • Dissolution • Particle size • Wettability
Aerosol particle
Central lung
Peripheral lung
3 Mucociliary clearance Surfactant Mucus
Alveolar macrophage
1 3 Macrophage clearance
Surfactant
Bronchial epithelium
Alveolar epithelium
1
Endothelium Blood
Endothelium 2
2
Blood
Systemic circulation
Figure 1: What happens to an aerosol drug after deposition in the lungs? (1) First contact with the lung lining fluids: release of the active pharmaceutical ingredient (API) from the deposited aerosol particle comprises different processes, governed by the amount and composition of the locally available lining fluid and by intrinsic properties of the API and the carrier particle. (2) Absorption of the API across the pulmonary epithelium: this process is mainly controlled by its physicochemical properties. (3) Clearance of the undissolved particle.
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
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observed (Tmax), and the elimination half-life time.15 An aerosol particle must dissolve after its deposition in the lungs before the active pharmaceutical ingredient can be absorbed.3 In the case of highly soluble active pharmaceutical ingredients (such as salbutamol, or peptides and proteins), there are no notable barriers to this process because these drugs rapidly dissolve after making contact with the lung lining fluid. However, with active pharmaceutical ingredients with low solubility, dissolution can affect the absorption rate of the drug by the pulmonary mucosa. Unfortunately, low dissolution affects some important active pharmaceutical ingredients relevant to pulmonary drug delivery—eg, CNS-active drugs or inhaled corticosteroids. The amount of liquid available for dissolution is also an important factor. Estimation of the total volume of the lung lining fluid in human lungs is 15–70 mL.16 However, the proportion of this total fluid volume that an aerosol particle is finally exposed to after deposition is difficult to predict.1 Moreover, the thickness of the lining layer, and consequently the volume of the lung lining fluid, differs between the central to the peripheral lungs. An aerosol particle deposited in the upper airways might dissolve faster as a result of a larger solid–liquid interface than in the alveoli.7 Furthermore, components of the pulmonary surfactant layer can also affect dissolution processes. For example, phospholipids—the main constituent of the pulmonary surfactant—can increase the solubility of active pharmaceutical ingredients.17,18 However, therapeutic peptides or proteins can be aggregated or inactivated as a result of interaction with surfactant components.3 The rate and extent of the dissolution process is therefore the first challenge to improve absorption. Fast dissolution and absorption of therapeutic peptides and proteins is important since they can be rapidly degraded by ubiquitous peptidases, or opsonised by endogenous proteins leading to increased phagocytosis— ie, premature elimination of the drug.3 Moreover, undissolved (carrier) particles are exposed to clearance mechanisms resulting in fast removal of the active pharmaceutical ingredients from the body. Taken together, the processes that occur after deposition are mainly a function of the physical state and dissolution properties of the carrier or drug particle.
Conditions and modalities for prolonged drug action Severe lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, and cystic fibrosis are among the leading causes of morbidity and mortality worldwide. In patients with these disorders, a reduction of frequency and duration of aerosol treatment are important for both physicians and patients to increase adherence to and compliance with therapies. The main challenge in achieving such a reduction is the improvement of relevant formulations in terms of prolonged sustainability at the site of action, which is 4
antagonised by the various clearance mechanisms of the lungs (figure 1). These clearance mechanisms pose particular challenges for medical management by pulmonary specialists, since persistence of the drug at the site of deposition is notably reduced by mucociliary and macrophage clearance. Moreover, the tenacious mucus barrier in the upper lungs is a further barrier to advanced pulmonary drug delivery. Overcoming these obstacles by controlling the clearance mechanisms of the lungs is important in disorders such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension, for which frequent and long-lasting treatment is necessary for sustainability of the drug at the site of action. Other diseases that can benefit from prolonged sustainability of the drug at the site of action, while attaining maximum exposure to specific lung targets, are cystic fibrosis and associated secondary infections or other inflammatory pathological disorders. For these diseases, formulations might need to be more sophisticated, typically including expensive and fragile active pharmaceutical ingredients such as antibiotics, prostacyclins, peptides, proteins, or nucleotides. Apart from coughing, the lungs have developed two main clearance mechanisms: mucociliary clearance and macrophage clearance. These two different, yet overlapping, mechanisms show the unique adaptation of the human body to various airborne and inhaled threats of organic and inorganic nature. Both clearance mechanisms are highly dependent on the properties of the noncellular pulmonary barrier, which are the mucus blanket in the upper and central lungs and the pulmonary surfactant film predominantly in the peripheral lungs. In the upper lungs, mucociliary clearance is the dominant mechanism and there is a complex interplay between non-cellular (the mucus blanket) and cellular elements (ciliated epithelial cells, secretory cells).19-21 Pulmonary mucus is a thick viscoelastic hydrogel layer (up to 30 μm),22 and is mainly composed of water and glycoproteins (mucins).23 Complex and coordinated beating patterns (3–12 Hz) of the cilia under the mucus blanket accelerate this layer and cause ascending transport of the mucus (about 3 mm per min),24,25 along with material deposited on, and trapped in, the mucus. Subsequently, mucus is swallowed and thus delivered into the gastrointestinal tract. This fast and unspecific clearance mechanism is highly efficient, with 80–90% of inhaled material being excreted from the upper and central lung within 24 h.26,27 Effective cilia function is highly dependent on hydration status and rheological properties of the mucus layer. Therefore, the way in which altered properties of the mucus blanket and thus impaired mucociliary clearance cause exacerbations in diseases such as cystic fibrosis is being studied.28 Although it is dominant in the peripheral lungs, the second clearance mechanism (ie, clearance by alveolar macrophages) is strongly associated with mucociliary clearance. Alveolar macrophages are present in the lungs
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
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and phagocytose inhaled organic and inorganic particulate matter. After phagocytosis, alveolar macrophages travel along the so-called mucociliary escalator. By contrast with mucociliary clearance, alveolar macrophages show size-dependent uptake, which is most effective for particles with a geometric diameter of 0·5–5 μm.29 A second non-cellular barrier—the pulmonary surfactant layer—is also important. This ultrathin layer (0·09–0·89 μm) spreads over the pulmonary surfaces,30 and is the main non-cellular barrier in the peripheral lung where mucus is not present in the healthy state. Pulmonary surfactant mainly consists of lipids (about 90%) but also contains various proteins (about 10%).31 Several studies on particle–surfactant interactions have assessed the displacement of particles into the surfactant layer,32 and the effect such particles exert on the biophysical functionality of the surfactant film.33 However, little is known about the interactions between surfactant components and inhaled particles on a molecular level. Furthermore, the surface properties of particles affect the occurrence and intensity of interactions with pulmonary surfactant components (eg, opsonisation), and biomolecule adsorption to inhaled material can largely affect subsequent cellular reactions, particularly macrophage clearance.34,35 For example, adsorption of surfactant proteins (SP), predominantly SP-A and SP-D, can increase the uptake of particles by alveolar macrophages, whereas the interaction with surfactant lipids controls the overall uptake of particulate matter, and can balance protein-mediated effects.36 In summary, both clearance processes notably affect residence time of inhaled drug carriers in the lung and thus have to be overcome to increase bioavailability. Clearance processes are less relevant for highly soluble active pharmaceutical ingredients given in droplet aerosol form or as rapidly dissolving particulate carriers, for which the limiting factors are diffusion properties. The key to solving the challenge of sustainability of inhaled drug carriers lies in smart carrier design that Second order: site of disease
aims to overcome or specifically reduce mucociliary clearance or clearance of alveolar macrophages.
Conditions and modalities for targeted delivery The other main post-deposition challenge in pulmonary drug delivery is specification of the location where the active pharmaceutical ingredient needs to be effectively available—ie, targeted delivery to the lungs. Targeted delivery is important in disorders with a confined localisation of the disease, such as lung malignancies and respiratory infections associated with cystic fibrosis or tuberculosis. In patients with such diseases, delivery of the active pharmaceutical ingredients to a defined region only within the respiratory tract is desirable (figure 2). The first level of targeting is delivery to the central or peripheral, right or left lung. In a second level of targeting, the drug should be delivered ideally to the site of disease—eg, to a tumour or tuberculosis granuloma. The third level of targeted delivery would be to target distinct cell types, such as mutated or degenerated barrier cells (ie, epithelial cells in cystic fibrosis or lung cancer), infected alveolar macrophages, or cells of the lung associated lymphatic tissue (eg, for antigen delivery). Lung cancer is the most common form of cancer worldwide and has poor survival rate, which is usually a result of late diagnosis.37 Treatment of lung cancer is with surgery, radiotherapy, or chemotherapy, either applied alone or in combination with other methods. Most chemotherapeutic options for lung cancer are given by intravenous injection, with the exception of a few active pharmaceutical ingredients that can be given orally.38 Unfortunately, the concentration of the drugs at the site of action (ie, the tumour in the lung) by systemic application are low compared with the applied dose, and systemic adverse effects are consequently more pronounced. Furthermore, active pharmaceutical ingredients for treatment of lung cancer are typically aggressive and expensive. A local and specific delivery of anticancer drugs
First order: lung regions
Third order: specific cells
Epithelial cells
Central lung Local infections
Fibroblasts
Tumour tissue
Tumour cells
Right lung
Peripheral lung
Left lung Immune cells
Figure 2: Different levels of targeting within the respiratory tract in pulmonary drug delivery
www.thelancet.com/respiratory Published online June 4, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70072-9
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via the pulmonary route could therefore have a real therapeutic benefit in efficiency of the drug and endurability of the drug by patients.38 There are several studies assessing inhalation formulations for lung cancer treatment in cell culture and animal models, and phase 1 and 2 clinical studies. So far, however, clinical trials of inhaled chemotherapy have been restricted to patients with advanced lung cancer; patients with early stage A
(i)
(ii)
(vi)
(iii)
(v)
cancer are treated otherwise, mainly because of the intrinsic pulmonary toxicity of the respective formulations. Moreover, inhalation of anticancer drugs was applied as adjuvant therapy in combination with other methods, mainly intravenously administered chemotherapeutic drugs, in patients with advanced stage disease.39 In patients with diseases associated with respiratory infections, such as cystic fibrosis and tuberculosis, one of the main challenges in treatment via inhalation is the poor accessibility of the respective pathogen. A comparable scenario is given in early infections with Mycobacterium tuberculosis, which is able to invade alveolar macrophages and survive intracellularly while being protected from antituberculosis drugs.40
Biopharmaceutical approaches and possible therapeutic benefits
(iv)
Improving pulmonary deposition and absorption
B 1 µm PRINT cylinders
Jet milled powder
10 µm
2 µm
C 1·0
Respirable fraction (
