ARTICLE IN PRESS
G Model IJP 13757 1–17
International Journal of Pharmaceutics xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Review
1
The impact of pulmonary diseases on the fate of inhaled medicines—A review
2
3
4 5 6
Q1
Yi-Bo Wang a , Alan B. Watts a , Jay I. Peters b , Robert O. Williams III a,∗ a b
College of Pharmacy, The University of Texas at Austin, Austin, TX, USA Department of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, University of Texas Health Science Center at San Antonio, TX, USA
7
8
a r t i c l e
i n f o
a b s t r a c t
9 10 11 12 13 14
Article history: Received 4 October 2013 Received in revised form 20 November 2013 Accepted 20 November 2013 Available online xxx
15
22
Keywords: Inhaled medicines Lung diseases Modeling Aerosol deposition Absorption Lung clearance
23
Contents
16 17 18 19 20 21
24 25 26
1. 2. 3.
27 28 29 30
4. 5.
31 32 33 34 35 36
6. 7.
The portfolio of compounds approved for inhalation therapy has expanded rapidly for treatment of lung diseases. To assess the efficacy and safety of inhaled medicines, a better understanding of their fate in the lungs is essential; especially in diseased lungs where a change in anatomical structure, ventilation parameters and breathing pattern may occur. In this article, the impact of lung pathophysiology factors on the fate of inhaled medicines is reviewed, and discussed in the context of aerosol deposition, dissolution, absorption and clearance. Special emphasis is given to computational modeling of aerosol deposition and clearance taking disease factors into consideration. In silico modeling can be used as a valuable tool to characterize the biopharmaceutics and pharmacodynamics of inhaled medicines, or assess risks associated with inhaled environmental pollutants for patients with pulmonary diseases. The deposition pattern of aerosol particles is greatly altered by different lung diseases based on both experimental data and model simulation. The fate of inhaled medicines after deposition primarily depends on the site of aerosol deposition. Therefore, when developing inhalation products for treatment of lung diseases, the dosing regimen, safety and pharmacokinetic studies should be conducted on patients with lung diseases, in addition to healthy subjects. © 2013 Published by Elsevier B.V.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lung physiology and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug deposition altered by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Present state of art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Modeling of aerosol deposition and associated lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug absorption affected by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary clearance influenced by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Mucociliary clearance and impact of lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Alveolar macrophage uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Clearance modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00
37
38
39 40 41
1. Introduction Treatment of lung diseases by drug inhalation has a long history beginning in the early 1950s when the first inhaled drug for asthma therapy emerged. Over thepast 60 years, significant inhalation
∗ Corresponding author at: 2409 University Avenue, Mail stop 1920A, Austin, TX 78712, USA. Tel.: +1 512 471 4681; fax: +1 512 471 7474. E-mail address: [email protected] (R.O. Williams III).
products have been developed not only for the treatment of asthma, but also for other pulmonary diseases, such as chronic obstruction pulmonary diseases (COPD), cystic fibrosis, pneumonia, to name a few. The rationale for such treatments includes more localized and targeted delivery with minimum systemic exposure. More recently, systemic delivery of drugs administered by inhalation has gained attention due to advantages including: (1) enormous surface area of the lungs; (2) good epithelial permeability; (3) extensive vascularization; (4) faster onset of action compared to the oral route; (5) avoidance of first pass metabolism (Patton and Byron,
0378-5173/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
Please cite this article in press as: Wang, Y.-B., et al., The impact of pulmonary diseases on the fate of inhaled medicines—A review. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
42 43 44 45 46 47 48 49 50 51
ARTICLE IN PRESS
G Model IJP 13757 1–17
Y.-B. Wang et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx
2
Table 1a Current inhaled pharmaceuticals for treatment of lung diseases on the market or undergoing clinical studies. Therapeutic usage
Drug classifications
Drugs
Inhalation device
Current development status
COPD and asthma
Short-acting beta-2 agonist (SABAs)
Salbutamol (albuterol) Fenoterol Pirbuterol Terbutaline Levalbuterol Salmeterol Formeterol Arformoterol Indacaterol Ipratropium bromide Tiotropium bromide Aclidinium bromide Oxitropium bromide Glycopyrronium bromide Beclomethasone dipropionate Budesonide Fluticasone propionate Mometasone furoate Ciclesonide Fenoterol/Ipratropium Salbuterol/Ipratropium Formeterol/Budesonide Formeterol/Mometasone Salmeterol/Fluticasone Glycopyrronium/formoterol Mannitol AIR-645 PXSTPI-1100 ATL-1102 QAX-935 (IMO-2134) Excellair
Nebulizer, pMDI, DPI pMDI Nebulizer, pMDI DPI pMDI pMDI, DPI pMDI, DPI Nebulizer DPI Nebulizer, pMDI pMDI, DPI DPI pMDI DPI Nebulizer, pMDI, DPI Nebulizer, DPI pMDI, DPI pMDI, DPI pMDI pMDI pMDI pMDI, DPI DPI pMDI, DPI pMDI DPI Nebulizer Nebulizer Nebulizer Nebulizer Nebulizer
Marketed Marketed outside of US Discontinued by Dec.2013 Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Outside of US Outside of US Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Phase II Marketed Phase II Preclinical Preclinical Phaes I Phase II
Antiproteases MRSA lung infections
Tobramycin Aztreonam Colistimethate sodium Liposomal ciprofloxacin Liposomal amikacin Levofloxacin PUR118 Dornase alfa Lancovutide Hypertonic saline Mannitol Alpha1 -antitrypsin Vancomycin
Nebulizer, DPI Nebulizer Nebulizer Nebulizer Nebulizer Nebulizer DPI Nebulizer Nebulizer Nebulizer DPI Nebulizer DPI
Marketed Marketed Pilot trials Phase II Phase III Phase III Phase I Outside of US Phase II Marketed Phase III Phase II Phase II
Pulmonary surfactant Antiviral
Phospholipids/surfactant proteins MDT-637
Endo-tracheal tube Novel inhaler
Marketed Phase II
Long-acting beta-2 agonist (LABAs)
Anticholinergic agents
Inhaled corticosteroids (ICS)
Combination therapy
Sugar alcohol Antisense Oligonucleotides CpG oligonucleotides siRNA Cystic fibrosis
Antibiotics
Mucous mobilizers Restore Airway Surface Liquid
Respiratory distress syndrome Respiratory Syncytial Virus
There are more than 70 pipeline medicines in development for asthma and more than 50 pipeline medicines in development for COPD. For more information, please refer to Medicines in Development Asthma 2012 report and Medicines in Development COPD 2012 report presented by Pharmaceutical Research and Manufacturers of America (available on PhRMA’s web site).
Table 1b Current inhaled pharmaceuticals for systemic application on the market or undergoing clinical studies. Therapeutic usage
Drug classifications
Drugs
Inhalation device
Current development status
Analgesia
Opioids
Fentanyl Liposomal fentanyl
Novel inhaler Nebulizer
Phase II Phase II
Migrane
Triptan
Sumatriptan
Intranasal powder
Phase III
Diabetes
Peptides
Insulin Glucagon-like peptide
DPI DPI
Phase III Phase I
Nerve gas poisoning Parkinson’s disease Schizophrenia
Nerve agent antidote Psychoactive drug Antipsychotic medication
Atropine Levodopa Loxapine
Novel inhaler DPI DPI
Phase I Phase II Outside of US
DPI, dry powder inhaler; pMDI, pressurized Metered Dose Inhaler. Adapted with permission from Ungaro et al. J Pharm Pharmacol 64, 1217–1235 (2012). Other sources are from Global Initiative for Chronic Obstructive Lung Disease (GOLD) web site, Global Initiative for Asthma (GINA) web site and http://clinicaltrials.gov/.
52 53 54 55
2007). Therefore, a variety of inhalation products are under development for treatment of systemic diseases. Table 1 briefly summarizes the current inhalation products on the market or undergoing clinical studies, their drug
classification and therapeutic usage (GINA, 2012; GOLD, 2012; Ungaro et al., 2012). As listed in this table, majority of the inhalation products available on the market are locally acting drugs for treatment of lung diseases. These drugs are delivered to the lungs to
Please cite this article in press as: Wang, Y.-B., et al., The impact of pulmonary diseases on the fate of inhaled medicines—A review. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
56 57 58 59
G Model IJP 13757 1–17
ARTICLE IN PRESS Y.-B. Wang et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx
60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88
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90 91 92 93
either relieve the airway constriction or reduce inflammation and infection, which are mainly bronchodilators, corticosteroids and antibiotics. Most of the inhaled products designed to exert a systemic effect are still in clinical development, including fast-onset analgesics, peptides and proteins. Despite the rapid development of inhaled drugs for systemic delivery, the inhalation market is still dominated by products for treatment of lung diseases. Understanding the fate of inhaled drugs in the lungs is essential for determining the therapeutic efficacy of inhaled pharmaceuticals for treatment of lung diseases. Recently published reviews have categorized the fate of inhaled medicines in healthy lungs into four processes, including deposition, dissolution, absorption and clearance.(Forbes et al., 2011; Niven, 2011; Olsson et al., 2011; Todoroff and Vanbever, 2011; Yang et al., 2008b; Zhang et al., 2011). However, none of these reviews have considered the impact of diseased lung pathophysiology on each of these processes in the respiratory tract. A series of questions were posed by Patton et al. (2010) regarding how lung diseases affect the biopharmaceutics and pharmacodynamics of inhaled medicines. Still remarkably little is known in this field. If such questions are addressed, the pace of development of therapeutics for treating lung diseases may be accelerated. This review focuses on the fate of inhaled drugs in the lungs and the impact of lung pathophysiology on their fate. Aerosol drug deposition, dissolution, absorption and clearance are discussed in terms of how each process is influenced by pulmonary diseases. Computational modeling of aerosol deposition and clearance is discussed in detail as a powerful tool to predict the therapeutic efficacy of inhaled pharmacological drugs and risks associated with inhaled environmental aerosols. 2. Lung physiology and pathophysiology The lungs are composed of a series of branching airways, which can be classified into two parts: the conducting zone and the respiratory zone, as described by Weibel’s airway model (Fig. 1) (Weibel, 1963). The conducting zone (generations 0–16) comprises of the
Fig. 1. Model of airways described by Weibel. Reprinted with permission from Lee et al. AAPS J 11, 414–423 (2009).
3
trachea, bronchi, bronchioles and terminal bronchioles, which are responsible for conducting air to the respiratory regions of the lung (Weibel, 1963). There are no alveoli in the conducting zone and the walls are too thick for diffusion; accordingly, no gas exchange occurs in this region (West, 2007). The total volume of the conducting zone is about 150 mL for a healthy human, and is also referred as the anatomic dead space (West, 2007). The terminal bronchioles branch into respiratory bronchioles, which have alveoli occasionally embedded within their walls. The respiratory bronchioles continuously branch into alveolar ducts and alveolar sacs, which are completely covered by alveoli. The respiratory bronchioles, alveolar ducts and alveolar sacs constitute the respiratory zone (generations 17–23), which facilitates gas exchange between airspaces and blood capillaries (Weibel, 1963). The length of the respiratory zone is only a few millimeters, but it composes most of the lung with a total volume of 2.5–3 L (West, 2007). Different types of epithelium line in different regions of the lung (Fig. 2). In human bronchi, epithelia are composed of columnar basal, ciliated, brush and goblet cells (about 60 m in height) (Patton and Byron, 2007). There is a surface gel-aqueous layer lined on top of the cells. This layer is composed of a luminal mucus layer (consisting of 95% water, 2% mucin, polymer, salts, proteins, and lipids), and a periciliary layer underlying the mucus layer with low viscosity to facilitate the cilia beating (Yang et al., 2008b). The coordinate beating of the cilia and the expiratory airflow transport the mucus toward the mouth to clear dust, microorganisms and insoluble particles out of the lungs, and this is referred as mucociliary clearance (Todoroff and Vanbever, 2011). The movement speed of mucus varies in different regions of the airways. It can go up to 20 mm/min in trachea and as slow as 1 mm/min in small peripheral airways (Olsson et al., 2011). When reaching the bronchioles and terminal bronchioles, the same types of cells are present on the epithelium but they are relatively small (around 10 m in height). The complex gel-aqueous layer lines the entire conducting airways and becomes progressively thinner from the trachea (up to 100 m) to the bronchi (around 8 m), and then to terminal bronchioles (about 3 m) (Patton and Byron, 2007; Ungaro et al., 2012). In the alveolar region, the gel-aqueous layer is replaced by a thin liquid layer (
G Model IJP 13757 1–17
International Journal of Pharmaceutics xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Review
1
The impact of pulmonary diseases on the fate of inhaled medicines—A review
2
3
4 5 6
Q1
Yi-Bo Wang a , Alan B. Watts a , Jay I. Peters b , Robert O. Williams III a,∗ a b
College of Pharmacy, The University of Texas at Austin, Austin, TX, USA Department of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, University of Texas Health Science Center at San Antonio, TX, USA
7
8
a r t i c l e
i n f o
a b s t r a c t
9 10 11 12 13 14
Article history: Received 4 October 2013 Received in revised form 20 November 2013 Accepted 20 November 2013 Available online xxx
15
22
Keywords: Inhaled medicines Lung diseases Modeling Aerosol deposition Absorption Lung clearance
23
Contents
16 17 18 19 20 21
24 25 26
1. 2. 3.
27 28 29 30
4. 5.
31 32 33 34 35 36
6. 7.
The portfolio of compounds approved for inhalation therapy has expanded rapidly for treatment of lung diseases. To assess the efficacy and safety of inhaled medicines, a better understanding of their fate in the lungs is essential; especially in diseased lungs where a change in anatomical structure, ventilation parameters and breathing pattern may occur. In this article, the impact of lung pathophysiology factors on the fate of inhaled medicines is reviewed, and discussed in the context of aerosol deposition, dissolution, absorption and clearance. Special emphasis is given to computational modeling of aerosol deposition and clearance taking disease factors into consideration. In silico modeling can be used as a valuable tool to characterize the biopharmaceutics and pharmacodynamics of inhaled medicines, or assess risks associated with inhaled environmental pollutants for patients with pulmonary diseases. The deposition pattern of aerosol particles is greatly altered by different lung diseases based on both experimental data and model simulation. The fate of inhaled medicines after deposition primarily depends on the site of aerosol deposition. Therefore, when developing inhalation products for treatment of lung diseases, the dosing regimen, safety and pharmacokinetic studies should be conducted on patients with lung diseases, in addition to healthy subjects. © 2013 Published by Elsevier B.V.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lung physiology and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug deposition altered by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Present state of art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Modeling of aerosol deposition and associated lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug absorption affected by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary clearance influenced by lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Mucociliary clearance and impact of lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Alveolar macrophage uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Clearance modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00
37
38
39 40 41
1. Introduction Treatment of lung diseases by drug inhalation has a long history beginning in the early 1950s when the first inhaled drug for asthma therapy emerged. Over thepast 60 years, significant inhalation
∗ Corresponding author at: 2409 University Avenue, Mail stop 1920A, Austin, TX 78712, USA. Tel.: +1 512 471 4681; fax: +1 512 471 7474. E-mail address: [email protected] (R.O. Williams III).
products have been developed not only for the treatment of asthma, but also for other pulmonary diseases, such as chronic obstruction pulmonary diseases (COPD), cystic fibrosis, pneumonia, to name a few. The rationale for such treatments includes more localized and targeted delivery with minimum systemic exposure. More recently, systemic delivery of drugs administered by inhalation has gained attention due to advantages including: (1) enormous surface area of the lungs; (2) good epithelial permeability; (3) extensive vascularization; (4) faster onset of action compared to the oral route; (5) avoidance of first pass metabolism (Patton and Byron,
0378-5173/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
Please cite this article in press as: Wang, Y.-B., et al., The impact of pulmonary diseases on the fate of inhaled medicines—A review. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
42 43 44 45 46 47 48 49 50 51
ARTICLE IN PRESS
G Model IJP 13757 1–17
Y.-B. Wang et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx
2
Table 1a Current inhaled pharmaceuticals for treatment of lung diseases on the market or undergoing clinical studies. Therapeutic usage
Drug classifications
Drugs
Inhalation device
Current development status
COPD and asthma
Short-acting beta-2 agonist (SABAs)
Salbutamol (albuterol) Fenoterol Pirbuterol Terbutaline Levalbuterol Salmeterol Formeterol Arformoterol Indacaterol Ipratropium bromide Tiotropium bromide Aclidinium bromide Oxitropium bromide Glycopyrronium bromide Beclomethasone dipropionate Budesonide Fluticasone propionate Mometasone furoate Ciclesonide Fenoterol/Ipratropium Salbuterol/Ipratropium Formeterol/Budesonide Formeterol/Mometasone Salmeterol/Fluticasone Glycopyrronium/formoterol Mannitol AIR-645 PXSTPI-1100 ATL-1102 QAX-935 (IMO-2134) Excellair
Nebulizer, pMDI, DPI pMDI Nebulizer, pMDI DPI pMDI pMDI, DPI pMDI, DPI Nebulizer DPI Nebulizer, pMDI pMDI, DPI DPI pMDI DPI Nebulizer, pMDI, DPI Nebulizer, DPI pMDI, DPI pMDI, DPI pMDI pMDI pMDI pMDI, DPI DPI pMDI, DPI pMDI DPI Nebulizer Nebulizer Nebulizer Nebulizer Nebulizer
Marketed Marketed outside of US Discontinued by Dec.2013 Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Outside of US Outside of US Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Marketed Phase II Marketed Phase II Preclinical Preclinical Phaes I Phase II
Antiproteases MRSA lung infections
Tobramycin Aztreonam Colistimethate sodium Liposomal ciprofloxacin Liposomal amikacin Levofloxacin PUR118 Dornase alfa Lancovutide Hypertonic saline Mannitol Alpha1 -antitrypsin Vancomycin
Nebulizer, DPI Nebulizer Nebulizer Nebulizer Nebulizer Nebulizer DPI Nebulizer Nebulizer Nebulizer DPI Nebulizer DPI
Marketed Marketed Pilot trials Phase II Phase III Phase III Phase I Outside of US Phase II Marketed Phase III Phase II Phase II
Pulmonary surfactant Antiviral
Phospholipids/surfactant proteins MDT-637
Endo-tracheal tube Novel inhaler
Marketed Phase II
Long-acting beta-2 agonist (LABAs)
Anticholinergic agents
Inhaled corticosteroids (ICS)
Combination therapy
Sugar alcohol Antisense Oligonucleotides CpG oligonucleotides siRNA Cystic fibrosis
Antibiotics
Mucous mobilizers Restore Airway Surface Liquid
Respiratory distress syndrome Respiratory Syncytial Virus
There are more than 70 pipeline medicines in development for asthma and more than 50 pipeline medicines in development for COPD. For more information, please refer to Medicines in Development Asthma 2012 report and Medicines in Development COPD 2012 report presented by Pharmaceutical Research and Manufacturers of America (available on PhRMA’s web site).
Table 1b Current inhaled pharmaceuticals for systemic application on the market or undergoing clinical studies. Therapeutic usage
Drug classifications
Drugs
Inhalation device
Current development status
Analgesia
Opioids
Fentanyl Liposomal fentanyl
Novel inhaler Nebulizer
Phase II Phase II
Migrane
Triptan
Sumatriptan
Intranasal powder
Phase III
Diabetes
Peptides
Insulin Glucagon-like peptide
DPI DPI
Phase III Phase I
Nerve gas poisoning Parkinson’s disease Schizophrenia
Nerve agent antidote Psychoactive drug Antipsychotic medication
Atropine Levodopa Loxapine
Novel inhaler DPI DPI
Phase I Phase II Outside of US
DPI, dry powder inhaler; pMDI, pressurized Metered Dose Inhaler. Adapted with permission from Ungaro et al. J Pharm Pharmacol 64, 1217–1235 (2012). Other sources are from Global Initiative for Chronic Obstructive Lung Disease (GOLD) web site, Global Initiative for Asthma (GINA) web site and http://clinicaltrials.gov/.
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2007). Therefore, a variety of inhalation products are under development for treatment of systemic diseases. Table 1 briefly summarizes the current inhalation products on the market or undergoing clinical studies, their drug
classification and therapeutic usage (GINA, 2012; GOLD, 2012; Ungaro et al., 2012). As listed in this table, majority of the inhalation products available on the market are locally acting drugs for treatment of lung diseases. These drugs are delivered to the lungs to
Please cite this article in press as: Wang, Y.-B., et al., The impact of pulmonary diseases on the fate of inhaled medicines—A review. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.11.042
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either relieve the airway constriction or reduce inflammation and infection, which are mainly bronchodilators, corticosteroids and antibiotics. Most of the inhaled products designed to exert a systemic effect are still in clinical development, including fast-onset analgesics, peptides and proteins. Despite the rapid development of inhaled drugs for systemic delivery, the inhalation market is still dominated by products for treatment of lung diseases. Understanding the fate of inhaled drugs in the lungs is essential for determining the therapeutic efficacy of inhaled pharmaceuticals for treatment of lung diseases. Recently published reviews have categorized the fate of inhaled medicines in healthy lungs into four processes, including deposition, dissolution, absorption and clearance.(Forbes et al., 2011; Niven, 2011; Olsson et al., 2011; Todoroff and Vanbever, 2011; Yang et al., 2008b; Zhang et al., 2011). However, none of these reviews have considered the impact of diseased lung pathophysiology on each of these processes in the respiratory tract. A series of questions were posed by Patton et al. (2010) regarding how lung diseases affect the biopharmaceutics and pharmacodynamics of inhaled medicines. Still remarkably little is known in this field. If such questions are addressed, the pace of development of therapeutics for treating lung diseases may be accelerated. This review focuses on the fate of inhaled drugs in the lungs and the impact of lung pathophysiology on their fate. Aerosol drug deposition, dissolution, absorption and clearance are discussed in terms of how each process is influenced by pulmonary diseases. Computational modeling of aerosol deposition and clearance is discussed in detail as a powerful tool to predict the therapeutic efficacy of inhaled pharmacological drugs and risks associated with inhaled environmental aerosols. 2. Lung physiology and pathophysiology The lungs are composed of a series of branching airways, which can be classified into two parts: the conducting zone and the respiratory zone, as described by Weibel’s airway model (Fig. 1) (Weibel, 1963). The conducting zone (generations 0–16) comprises of the
Fig. 1. Model of airways described by Weibel. Reprinted with permission from Lee et al. AAPS J 11, 414–423 (2009).
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trachea, bronchi, bronchioles and terminal bronchioles, which are responsible for conducting air to the respiratory regions of the lung (Weibel, 1963). There are no alveoli in the conducting zone and the walls are too thick for diffusion; accordingly, no gas exchange occurs in this region (West, 2007). The total volume of the conducting zone is about 150 mL for a healthy human, and is also referred as the anatomic dead space (West, 2007). The terminal bronchioles branch into respiratory bronchioles, which have alveoli occasionally embedded within their walls. The respiratory bronchioles continuously branch into alveolar ducts and alveolar sacs, which are completely covered by alveoli. The respiratory bronchioles, alveolar ducts and alveolar sacs constitute the respiratory zone (generations 17–23), which facilitates gas exchange between airspaces and blood capillaries (Weibel, 1963). The length of the respiratory zone is only a few millimeters, but it composes most of the lung with a total volume of 2.5–3 L (West, 2007). Different types of epithelium line in different regions of the lung (Fig. 2). In human bronchi, epithelia are composed of columnar basal, ciliated, brush and goblet cells (about 60 m in height) (Patton and Byron, 2007). There is a surface gel-aqueous layer lined on top of the cells. This layer is composed of a luminal mucus layer (consisting of 95% water, 2% mucin, polymer, salts, proteins, and lipids), and a periciliary layer underlying the mucus layer with low viscosity to facilitate the cilia beating (Yang et al., 2008b). The coordinate beating of the cilia and the expiratory airflow transport the mucus toward the mouth to clear dust, microorganisms and insoluble particles out of the lungs, and this is referred as mucociliary clearance (Todoroff and Vanbever, 2011). The movement speed of mucus varies in different regions of the airways. It can go up to 20 mm/min in trachea and as slow as 1 mm/min in small peripheral airways (Olsson et al., 2011). When reaching the bronchioles and terminal bronchioles, the same types of cells are present on the epithelium but they are relatively small (around 10 m in height). The complex gel-aqueous layer lines the entire conducting airways and becomes progressively thinner from the trachea (up to 100 m) to the bronchi (around 8 m), and then to terminal bronchioles (about 3 m) (Patton and Byron, 2007; Ungaro et al., 2012). In the alveolar region, the gel-aqueous layer is replaced by a thin liquid layer (
