Special Issue "Advances in Pulmonary Drug Delivery"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editors

Prof. Dr. Carsten Ehrhardt
E-Mail Website
Guest Editor
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
Interests: inhalation biopharmaceutics; lung drug disposition; pulmonary epithelial transport and molecular origins of airways disease
Special Issues, Collections and Topics in MDPI journals
Dr. Ayca Yildiz-Pekoz
E-Mail Website
Co-Guest Editor
Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Beyazıt, Istanbul 34116, Turkey
Interests: pulmonary drug targeting; COPD; micro/nano-particles; polymers; cell culture
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug delivery to the lungs by oral inhalation represents an attractive non-invasive administration route for therapeutics. In addition to locally acting drugs, molecules  that are intended to produce a systemic effect can be delivered via the pulmonary route. Pulmonary delivery requires the patient to inhale an aerosol of the therapeutics agent. For the successful delivery via oral inhalation, formulation into an appropriate inhalable dosage form with a sufficient stability is critical. It is also essential that the formulation is paired with a device, which generates an aerosol of the appropriate particle/droplet size to ensure deposition into the desired regions of the respiratory tract.

This Special Issue attempts to highlight current research activities in the areas of inhaler device development; formulation development approaches for inhaled drugs; in vitro and in silico models of pulmonary drug deposition and drug disposition; and advanced delivery options for complex drugs, such as vaccines, antibiotics, nucleic acids, or peptides, to or via the lungs.

Prof. Dr. Carsten Ehrhardt
Guest Editor

Manuscript Submission Information

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Keywords

  • aerosol
  • inhalation
  • pulmonary drug delivery
  • inhaler
  • mucosal vaccination
  • antibiotics
  • peptide drugs
  • nucleic acid delivery
  • in vitro models
  • PBPK models

Published Papers (25 papers)

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Editorial

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Editorial
Advances in Pulmonary Drug Delivery
Pharmaceutics 2020, 12(10), 911; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12100911 - 23 Sep 2020
Cited by 7 | Viewed by 1136
Abstract
Pulmonary drug delivery represents an attractive, non-invasive administration option. In addition to locally acting drugs, molecules that are intended to produce systemic effects can be delivered via the pulmonary route. Several factors need to be considered in the context of delivering drugs to [...] Read more.
Pulmonary drug delivery represents an attractive, non-invasive administration option. In addition to locally acting drugs, molecules that are intended to produce systemic effects can be delivered via the pulmonary route. Several factors need to be considered in the context of delivering drugs to or via the lungs—in addition to the drug itself, its formulation into an appropriate inhalable dosage form of sufficient stability is critical. It is also essential that this formulation is paired with a suitable inhaler device, which generates an aerosol of a particle/droplet size that ensures deposition in the desired region of the respiratory tract. Lastly, the patient’s (patho-) physiology and inhalation manoeuvre are of importance. This Special Issue brings together recent advances in the areas of inhalation device testing, aerosol formulation development, use of in vitro and in silico models in pulmonary drug deposition and drug disposition studies, and pulmonary delivery of complex drugs, such as vaccines, antibiotics and peptides, to or via the lungs. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)

Research

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Article
Development of an Innovative, Carrier-Based Dry Powder Inhalation Formulation Containing Spray-Dried Meloxicam Potassium to Improve the In Vitro and In Silico Aerodynamic Properties
Pharmaceutics 2020, 12(6), 535; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12060535 - 10 Jun 2020
Cited by 7 | Viewed by 1322
Abstract
Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, [...] Read more.
Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, which is an interactive physical blend of a surface-modified carrier and a spray-dried drug with suitable shape and size for pulmonary application. Meloxicam potassium, a nonsteroidal anti-inflammatory drug (NSAID), was used as an active ingredient due to its local anti-inflammatory effect and ability to decrease the progression of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The results of the in vitro and in silico investigations showed high lung deposition in the case of this new formulation, confirming that the interparticle interactions were changed favorably. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs
Pharmaceutics 2020, 12(5), 408; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12050408 - 29 Apr 2020
Cited by 3 | Viewed by 1432
Abstract
Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, [...] Read more.
Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
In Silico Optimization of Fiber-Shaped Aerosols in Inhalation Therapy for Augmented Targeting and Deposition across the Respiratory Tract
Pharmaceutics 2020, 12(3), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12030230 - 05 Mar 2020
Cited by 5 | Viewed by 947
Abstract
Motivated by a desire to uncover new opportunities for designing the size and shape of fiber-shaped aerosols towards improved pulmonary drug delivery deposition outcomes, we explore the transport and deposition characteristics of fibers under physiologically inspired inhalation conditions in silico, mimicking a dry [...] Read more.
Motivated by a desire to uncover new opportunities for designing the size and shape of fiber-shaped aerosols towards improved pulmonary drug delivery deposition outcomes, we explore the transport and deposition characteristics of fibers under physiologically inspired inhalation conditions in silico, mimicking a dry powder inhaler (DPI) maneuver in adult lung models. Here, using computational fluid dynamics (CFD) simulations, we resolve the transient translational and rotational motion of inhaled micron-sized ellipsoid particles under the influence of aerodynamic (i.e., drag, lift) and gravitational forces in a respiratory tract model spanning the first seven bifurcating generations (i.e., from the mouth to upper airways), coupled to a more distal airway model representing nine generations of the mid-bronchial tree. Aerosol deposition efficiencies are quantified as a function of the equivalent diameter (dp) and geometrical aspect ratio (AR), and these are compared to outcomes with traditional spherical particles of equivalent mass. Our results help elucidate how deposition patterns are intimately coupled to dp and AR, whereby high AR fibers in the narrow range of dp = 6–7 µm yield the highest deposition efficiency for targeting the upper- and mid-bronchi, whereas fibers in the range of dp= 4–6 µm are anticipated to cross through the conducting regions and reach the deeper lung regions. Our efforts underscore previously uncovered opportunities to design the shape and size of fiber-like aerosols towards targeted pulmonary drug delivery with increased deposition efficiencies, in particular by leveraging their large payloads for deep lung deposition. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Systematic Development and Optimization of Inhalable Pirfenidone Liposomes for Non-Small Cell Lung Cancer Treatment
Pharmaceutics 2020, 12(3), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12030206 - 28 Feb 2020
Cited by 20 | Viewed by 2492
Abstract
Non-small cell lung cancer (NSCLC) is a global disorder, treatment options for which remain limited with resistance development by cancer cells and off-target events being major roadblocks for current therapies. The discovery of new drug molecules remains time-consuming, expensive, and prone to failure [...] Read more.
Non-small cell lung cancer (NSCLC) is a global disorder, treatment options for which remain limited with resistance development by cancer cells and off-target events being major roadblocks for current therapies. The discovery of new drug molecules remains time-consuming, expensive, and prone to failure in safety/efficacy studies. Drug repurposing (i.e., investigating FDA-approved drug molecules for use against new indications) provides an opportunity to shorten the drug development cycle. In this project, we propose to repurpose pirfenidone (PFD), an anti-fibrotic drug, for NSCLC treatment by encapsulation in a cationic liposomal carrier. Liposomal formulations were optimized and evaluated for their physicochemical properties, in-vitro aerosol deposition behavior, cellular internalization capability, and therapeutic potential against NSCLC cell lines in-vitro and ex-vivo. Anti-cancer activity of PFD-loaded liposomes and molecular mechanistic efficacy was determined through colony formation (1.5- to 2-fold reduction in colony growth compared to PFD treatment in H4006, A549 cell lines, respectively), cell migration, apoptosis and angiogenesis assays. Ex-vivo studies using 3D tumor spheroid models revealed superior efficacy of PFD-loaded liposomes against NSCLC, as compared to plain PFD. Hence, the potential of inhalable liposome-loaded pirfenidone in NSCLC treatment has been established in-vitro and ex-vivo, where further studies are required to determine their efficacy through in vivo preclinical studies followed by clinical studies. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine
Pharmaceutics 2020, 12(1), 24; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12010024 - 25 Dec 2019
Cited by 14 | Viewed by 1634
Abstract
Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid [...] Read more.
Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine w/w. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops® dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
An Inhalable Theranostic System for Local Tuberculosis Treatment Containing an Isoniazid Loaded Metal Organic Framework Fe-MIL-101-NH2—From Raw MOF to Drug Delivery System
Pharmaceutics 2019, 11(12), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11120687 - 17 Dec 2019
Cited by 21 | Viewed by 1948
Abstract
The theranostic approach to local tuberculosis treatment allows drug delivery and imaging of the lungs for a better control and personalization of antibiotic therapy. Metal-organic framework (MOF) Fe-MIL-101-NH2 nanoparticles were loaded with isoniazid. To optimize their functionality a 23 factorial design of [...] Read more.
The theranostic approach to local tuberculosis treatment allows drug delivery and imaging of the lungs for a better control and personalization of antibiotic therapy. Metal-organic framework (MOF) Fe-MIL-101-NH2 nanoparticles were loaded with isoniazid. To optimize their functionality a 23 factorial design of spray-drying with poly(lactide-co-glycolide) and leucine was employed. Powder aerodynamic properties were assessed using a twin stage impinger based on the dose emitted and the fine particle fraction. Magnetic resonance imaging (MRI) contrast capabilities were tested on porous lung tissue phantom and ex vivo rat lungs. Cell viability and uptake studies were conducted on murine macrophages RAW 246.9. The final product showed good aerodynamic properties, modified drug release, easier uptake by macrophages in relation to raw isoniazid-MOF, and MRI contrast capabilities. Starting from raw MOF, a fully functional inhalable theranostic system with a potential application in personalized tuberculosis pulmonary therapy was developed. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Pharmaceutical Benefits of Fluticasone Propionate Association to Delivery Systems: In Vitro and In Vivo Evaluation
Pharmaceutics 2019, 11(10), 521; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11100521 - 10 Oct 2019
Cited by 5 | Viewed by 1279
Abstract
The objective of the present work was to characterize the ability of liposomes and cyclodextrin (CyD) complexes to modulate the in vivo profile of fluticasone (FTZ). In vitro cell compatibility tests were performed, exposing A549 cells to FTZ in the free form and [...] Read more.
The objective of the present work was to characterize the ability of liposomes and cyclodextrin (CyD) complexes to modulate the in vivo profile of fluticasone (FTZ). In vitro cell compatibility tests were performed, exposing A549 cells to FTZ in the free form and FTZ associated to liposomes and complexed with CyD. The in vivo fate of a selected FTZ liposomal formulation and of several FTZ CyD complexes was achieved following intranasal instillation or pulmonary administration in BALB/c mice, respectively. For pulmonary administration, an inhalation chamber was constructed to enable the simultaneously pulmonary administration to six mice. Thirty minutes and 3 h after administration, mice were sacrificed, their blood, lungs, livers, and spleens were removed, and FTZ level was determined by HPLC using an extraction procedure. The in vitro tests revealed no toxic effects of FTZ formulations, as cellular viability was always superior to 90% for FTZ concentrations ranging from 5 to 60 µM 72 h after incubation. The in vivo biodistribution results showed that FTZ incorporated in liposomes resulted in 20 and 30 times higher accumulation in the lungs in comparison with free FTZ, at 0.5 and 3 h after i.n. administration, respectively. FTZ associated to Hydroxypropyl-γ-cyclodextrin (HP-CyD) was the complex that permitted the higher accumulation of FTZ in the lungs in comparison with the respective free form. The results also suggest that the inhalation chamber apparatus can effectively facilitate the evaluation of in vivo inhalation. The establishment of an animal model of asthma allows us to further study the therapeutic efficacy of the developed FTZ formulations. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies
Pharmaceutics 2019, 11(10), 502; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11100502 - 01 Oct 2019
Cited by 7 | Viewed by 1518
Abstract
Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels and cardiac arrhythmias (prolongation of [...] Read more.
Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels and cardiac arrhythmias (prolongation of QT-interval). This study aimed to develop inhalable dry powder particles of bedaquiline with high aerosolization efficiency to reduce the side-effects of oral bedaquiline. Bedaquiline (with or without l-leucine) powders were prepared using a Buchi Mini Spray-dryer. The powders were characterized for physicochemical properties and for their in vitro aerosolization efficiency using a next-generation impactor (NGI). The formulation with maximum aerosolization efficiency was investigated for physicochemical and aerosolization stability after one-month storage at 20 ± 2 °C/30 ± 2% relative humidity (RH) and 25 ± 2 °C/75% RH in an open Petri dish. The cytotoxicity of the powders on A549 and Calu-3 cell-lines was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The powders were also evaluated for antimicrobial activity against Mycobacterium tuberculosis. The aerodynamic diameter of the l-leucine-containing powder was 2.4 µm, and the powder was amorphous in nature. The aerosolization efficiency (fine-particle fraction) of l-leucine-containing powder (fine-particle fraction (FPF): 74.4%) was higher than the bedaquiline-only powder (FPF: 31.3%). l-leucine containing powder particles were plate-shaped with rough surfaces, but the bedaquiline-only powder was spherical and smooth. The optimized powder was stable at both storage conditions during one-month storage and non-toxic (up to 50 µg/mL) to the respiratory cell-lines. Bedaquiline powders were effective against Mycobacterium tuberculosis and had a minimal inhibitory concentration (MIC) value of 0.1 µg/mL. Improved aerosolization may help to combat pulmonary tuberculosis by potentially reducing the side-effects of oral bedaquiline. Further research is required to understand the safety of the optimized inhalable powder in animal models. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Aerosolization Performance of Jet Nebulizers and Biopharmaceutical Aspects
Pharmaceutics 2019, 11(8), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11080406 - 11 Aug 2019
Cited by 8 | Viewed by 1589
Abstract
In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the [...] Read more.
In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the aerosol output, aerosol output rate, mass median aerodynamic diameter, and fine particle fraction, were determined according to the European Standard EN 13544-1, using sodium fluoride as a reference formulation. A comparison between the aerosol output nebulization time and the fine particle fraction displayed a correlation between the aerosol quality and the nebulization rate. Indeed, the quality of the nebulization significantly increased when the rate of aerosol emission was reduced. Moreover, the performance of the nebulizers was analyzed in terms of respirable delivered dose and respirable dose delivery rate, which characterize nebulization as the rate and amount of respirable product that could be deposited into the lungs. Depending on which of these two latter parameters was used, the nebulizers showed different performances. The differences, in terms of the rate and amount of delivered aerosol, could provide relevant information for the appropriate choice of nebulizer as a function of drug product, therapy, and patient characteristics. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
OCTN2-Mediated Acetyl-l-Carnitine Transport in Human Pulmonary Epithelial Cells In Vitro
Pharmaceutics 2019, 11(8), 396; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11080396 - 07 Aug 2019
Cited by 7 | Viewed by 1554
Abstract
The carnitine transporter OCTN2 is associated with asthma and other inflammatory diseases. The aims of this work were (i) to determine carnitine uptake into freshly isolated human alveolar type I (ATI)-like epithelial cells in primary culture, (ii) to compare the kinetics of carnitine [...] Read more.
The carnitine transporter OCTN2 is associated with asthma and other inflammatory diseases. The aims of this work were (i) to determine carnitine uptake into freshly isolated human alveolar type I (ATI)-like epithelial cells in primary culture, (ii) to compare the kinetics of carnitine uptake between respiratory epithelial in vitro cell models, and (iii) to establish whether any cell line was a suitable model for studies of carnitine transport at the air-blood barrier. Levels of time-dependent [3H]-acetyl-l-carnitine uptake were similar in ATI-like, NCl-H441, and Calu-3 epithelial cells, whereas uptake into A549 cells was ~5 times higher. Uptake inhibition was more pronounced by OCTN2 modulators, such as l-Carnitine and verapamil, in ATI-like primary epithelial cells compared to NCl-H441 and Calu-3 epithelial cells. Our findings suggest that OCTN2 is involved in the cellular uptake of acetyl-l-carnitine at the alveolar epithelium and that none of the tested cell lines are optimal surrogates for primary cells. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis
Pharmaceutics 2019, 11(7), 345; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11070345 - 17 Jul 2019
Cited by 5 | Viewed by 1537
Abstract
‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol [...] Read more.
‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol administration would produce phospholipidosis-induced FAM that could be characterized and used in comparative inhalation toxicology. Han-Wistar rats were given amiodarone via (1) intranasal administration (6.25 mg/kg) on two days, (2) aerosol administration (3 mg/kg) on two days, (3) aerosol administration (10 mg/kg) followed by three days of 30 mg/kg or (4) oral administration (100 mg/kg) for 7 days. Alveolar macrophages in bronchoalveolar lavage were evaluated by differential cell counting and high content fluorescence imaging. Histopathology and mass-spectrometry imaging (MSI) were performed on lung slices. The higher dose aerosolised amiodarone caused transient pulmonary inflammation (p < 0.05), but only oral amiodarone resulted in FAM (p < 0.001). MSI of the lungs of orally treated rats revealed a homogenous distribution of amiodarone and a putative phospholipidosis marker, di-22:6 bis-monoacylglycerol, throughout lung tissue whereas aerosol administration resulted in localization of both compounds around the airway lumen. Thus, unlike oral administration, aerosolised amiodarone failed to produce the expected FAM responses. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Impact of Gas Flow and Humidity on Trans-Nasal Aerosol Deposition via Nasal Cannula in Adults: A Randomized Cross-Over Study
Pharmaceutics 2019, 11(7), 320; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11070320 - 07 Jul 2019
Cited by 13 | Viewed by 1677
Abstract
Background: Trans-nasal pulmonary aerosol delivery using high flow nasal cannula (HFNC) devices is described with the administration of high gas flows exceeding patient inspiratory flow (HF) and with lower flows (LF). The aim of this pilot clinical trial was to compare deposition and [...] Read more.
Background: Trans-nasal pulmonary aerosol delivery using high flow nasal cannula (HFNC) devices is described with the administration of high gas flows exceeding patient inspiratory flow (HF) and with lower flows (LF). The aim of this pilot clinical trial was to compare deposition and distribution of radiolabeled aerosol via nasal cannula in healthy adults across three rates of gas flow delivered with active heated humidification, and to further identify the impact of aerosol administration without heated humidity. Methods: Twenty-three (23) healthy adults (16F) were randomized to receive aerosol with active heated humidification or unheated oxygen at gas flows of 10 L/min (n = 8), 30 L/min (n = 7), or 50 L/min (n = 8). Diethylenetriaminepentaacetic acid labeled with 1 millicurie (37 MBq) of Technetium-99m (DTPA-Tc99m) was mixed with NaCl to a fill volume of 1 mL, and administered via mesh nebulizer placed at the inlet of the humidifier. Radioactivity counts were performed using a gamma camera and the regions of interest (ROIs) were delimited with counts from the lungs, upper airways, stomach, nebulizer, circuit, and expiratory filter. A mass balance was calculated and each compartment was expressed as a percentage of the total. Results: Lung deposition (mean ± SD) with heated humidified gas was greater at 10 L/min than 30 L/min or 50 L/min (17.2 ± 6.8%, 5.71 ± 2.04%, and 3.46 ± 1.24%, respectively; p = 0.0001). Using unheated carrier gas, a lung dose of aerosol was similar to the active heated humidification condition at 10 L/min, but greater at 30 and 50 L/min (p = 0.011). Administered gas flow and lung deposition were negatively correlated (r = −0.880, p < 0.001). Conclusions: Both flow and active heated humidity inversely impact aerosol delivery through HFNC. Nevertheless, aerosol administration across the range of commonly used flows can provide measurable levels of lung deposition in healthy adult subjects (NCT 02519465). Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Epoprostenol Delivered via High Flow Nasal Cannula for ICU Subjects with Severe Hypoxemia Comorbid with Pulmonary Hypertension or Right Heart Dysfunction
Pharmaceutics 2019, 11(6), 281; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11060281 - 14 Jun 2019
Cited by 14 | Viewed by 6256
Abstract
Inhaled epoprostenol (iEPO) has been utilized to improve oxygenation in mechanically ventilated subjects with severe hypoxemia, but the evidence for iEPO via high-flow nasal cannula (HFNC) is rare. Following approval by the institutional review board, this retrospective cohort study evaluated subjects who received [...] Read more.
Inhaled epoprostenol (iEPO) has been utilized to improve oxygenation in mechanically ventilated subjects with severe hypoxemia, but the evidence for iEPO via high-flow nasal cannula (HFNC) is rare. Following approval by the institutional review board, this retrospective cohort study evaluated subjects who received iEPO via HFNC for more than 30 min to treat severe hypoxemia comorbid with pulmonary hypertension or right heart dysfunction between July 2015 and April 2018. A total of 11 subjects were enrolled in the study of whom 4 were male (36.4%), age 57.5 ± 22.1 years, and APACHE II score at ICU admission was 18.5 ± 5.7. Ten subjects had more than three chronic heart or lung comorbidities; seven of them used home oxygen. After inhaling epoprostenol, subjects’ SpO2/FIO2 ratio improved from 107.5 ± 26.3 to 125.5 ± 31.6 (p = 0.026) within 30–60 min. Five subjects (45.5%) had SpO2/FIO2 improvement >20%, which was considered as a positive response. Heart rate, blood pressure, and respiratory rate were not significantly different. Seven subjects did not require intubation, and seven subjects were discharged home. This retrospective study demonstrated the feasibility of iEPO via HFNC in improving oxygenation. Careful titration of flow while evaluating subjects’ response may help identify responders and avoid delaying other interventions. This study supports the need for a larger prospective randomized control trial to further evaluate the efficacy of iEPO via HFNC in improving outcomes. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Investigation of Fugitive Aerosols Released into the Environment during High-Flow Therapy
Pharmaceutics 2019, 11(6), 254; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11060254 - 01 Jun 2019
Cited by 21 | Viewed by 3205
Abstract
Background: Nebulised medical aerosols are designed to deliver drugs to the lungs to aid in the treatment of respiratory diseases. However, an unintended consequence is the potential for fugitive emissions during patient treatment, which may pose a risk factor in both clinical and [...] Read more.
Background: Nebulised medical aerosols are designed to deliver drugs to the lungs to aid in the treatment of respiratory diseases. However, an unintended consequence is the potential for fugitive emissions during patient treatment, which may pose a risk factor in both clinical and homecare settings. Methods: The current study examined the potential for fugitive emissions, using albuterol sulphate as a tracer aerosol during high-flow therapy. A nasal cannula was connected to a head model or alternatively, a interface was connected to a tracheostomy tube in combination with a simulated adult and paediatric breathing profile. Two aerodynamic particle sizers (APS) recorded time-series aerosol concentrations and size distributions at two different distances relative to the simulated patient. Results: The results showed that the quantity and characteristics of the fugitive emissions were influenced by the interface type, patient type and supplemental gas-flow rate. There was a trend in the adult scenarios; as the flow rate increased, the fugitive emissions and the mass median aerodynamic diameter (MMAD) of the aerosol both decreased. The fugitive emissions were comparable when using the adult breathing profiles for the nasal cannula and tracheostomy interfaces; however, there was a noticeable distinction between the two interfaces when compared for the paediatric breathing profiles. The highest recorded aerosol concentration was 0.370 ± 0.046 mg m−3 from the tracheostomy interface during simulated paediatric breathing with a gas-flow rate of 20 L/min. The averaged MMAD across all combinations ranged from 1.248 to 1.793 µm by the APS at a distance of 0.8 m away from the patient interface. Conclusions: Overall, the results highlight the potential for secondary inhalation of fugitive emissions released during simulated aerosol treatment with concurrent high-flow therapy. The findings will help in developing policy and best practice for risk mitigation from fugitive emissions. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis
Pharmaceutics 2019, 11(5), 239; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11050239 - 17 May 2019
Cited by 6 | Viewed by 1505
Abstract
Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung [...] Read more.
Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery. Methods: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation. Droplet size distribution was determined by laser diffraction and cascade impaction. Delivery to a model lung was determined in models of spontaneously-breathing and mechanically-ventilated patients. Results: The physical characteristics and antimicrobial activities were unchanged after nebulisation. Mean droplet size diameters were below 5 μm in both determinations, with the fine particle fraction approximately 67% for both peptides. Approximately 25% of the nominal dose was delivered in the spontaneously-breathing model for both peptides, with higher deliveries observed in the mechanically-ventilated model. Delivery times were approximately 170 s per mL for both peptides and the residual volume in the nebuliser was below 10% in nearly all cases. Conclusions: These results demonstrate that the delivery of (pro-)AMPs to the lung using a VMN is feasible and that the prodrug modification is not detrimental. They support the further development of pro-AMPs as therapeutics in CF. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Characterization and Formulation of Isoniazid for High-Dose Dry Powder Inhalation
Pharmaceutics 2019, 11(5), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11050233 - 13 May 2019
Cited by 9 | Viewed by 1721
Abstract
Tuberculosis is a major health problem and remains one of the main causes of mortality. In recent years, there has been an increased interest in the pulmonary delivery of antibiotics to treat tuberculosis. Isoniazid is one of these antibiotics. In this study, we [...] Read more.
Tuberculosis is a major health problem and remains one of the main causes of mortality. In recent years, there has been an increased interest in the pulmonary delivery of antibiotics to treat tuberculosis. Isoniazid is one of these antibiotics. In this study, we aimed to characterize isoniazid and formulate it into a dry powder for pulmonary administration with little or no excipient, and for use in the disposable Twincer® inhaler. Isoniazid was jet milled and spray dried with and without the excipient l-leucine. Physiochemical characterization showed that isoniazid has a low Tg of −3.99 ± 0.18 °C and starts to sublimate around 80 °C. Milling isoniazid with and without excipients did not result in a suitable formulation, as it resulted in a low and highly variable fine particle fraction. Spray drying pure isoniazid resulted in particles too large for pulmonary administration. The addition of 5% l-leucine resulted in a fraction <5 µm = 89.61% ± 1.77% from spray drying, which dispersed well from the Twincer®. However, storage stability was poor at higher relative humidity, which likely results from dissolution-crystallization. Therefore, follow up research is needed to further optimize this spray dried formulation. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
The Ratio of Nasal Cannula Gas Flow to Patient Inspiratory Flow on Trans-nasal Pulmonary Aerosol Delivery for Adults: An in Vitro Study
Pharmaceutics 2019, 11(5), 225; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11050225 - 10 May 2019
Cited by 12 | Viewed by 1980
Abstract
Trans-nasal aerosol deposition during distressed breathing is higher than quiet breathing, and decreases as administered gas flow increases. We hypothesize that inhaled dose is related to the ratio of gas flow to patient inspiratory flow (GF:IF). An adult manikin (Laerdal) with a collecting [...] Read more.
Trans-nasal aerosol deposition during distressed breathing is higher than quiet breathing, and decreases as administered gas flow increases. We hypothesize that inhaled dose is related to the ratio of gas flow to patient inspiratory flow (GF:IF). An adult manikin (Laerdal) with a collecting filter placed at trachea was connected to a dual-chamber model lung, which was driven by a ventilator to simulate quiet and distressed breathing with different inspiratory flows. Gas flow was set at 5, 10, 20, 40 and 60 L/min. Albuterol (2.5mg in 1 mL) was nebulized by vibrating mesh nebulizer at the inlet of humidifier at 37 °C for each condition (n = 3). Drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). GF:IF was the primary predictor of inhaled dose (p < 0.001). When the ratio was < 1.0, the inhaled dose was higher than ratio > 1.0 (21.8 ± 3.8% vs. 9.0 ± 3.7%, p < 0.001), and the inhaled dose was similar between quiet and distressed breathing (22.3 ± 5.0% vs. 21.3 ± 2.7%, p = 0.379). During trans-nasal aerosol delivery, GF:IF primarily affected the inhaled dose. Compared to the ratio above 1.0, the ratio below 1.0 produced a higher and more-consistent inhaled dose. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Excipient Interactions in Glucagon Dry Powder Inhaler Formulation for Pulmonary Delivery
Pharmaceutics 2019, 11(5), 207; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11050207 - 01 May 2019
Cited by 6 | Viewed by 1532
Abstract
Purpose: This study describes the development and characterization of glucagon dry powder inhaler (DPI) formulation for pulmonary delivery. Lactose monohydrate, as a carrier, and L-leucine and magnesium stearate (MgSt) were used as dispersibility enhancers for this formulation. Methods: Using Fourier-transform infrared (FTIR) spectroscopy, [...] Read more.
Purpose: This study describes the development and characterization of glucagon dry powder inhaler (DPI) formulation for pulmonary delivery. Lactose monohydrate, as a carrier, and L-leucine and magnesium stearate (MgSt) were used as dispersibility enhancers for this formulation. Methods: Using Fourier-transform infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), and Raman confocal microscopy, the interactions between glucagon and all excipients were characterized. The fine particle fractions (FPFs) of glucagon in different formulations were determined by a twin stage impinger (TSI) using a 2.5% glucagon mixture, and the glucagon concentration was measured by a validated LC-MS/MS method. Results: The FPF of the glucagon was 6.4%, which increased six-fold from the formulations with excipients. The highest FPF (36%) was observed for the formulation containing MgSt and large carrier lactose. The FTIR, Raman, and DSC data showed remarkable physical interactions of glucagon with leucine and a minor interaction with lactose; however, there were no interactions with MgSt alone or mixed with lactose. Conclusion: Due to the interaction between L-leucine and glucagon, leucine was not a suitable excipient for glucagon formulation. In contrast, the use of lactose and MgSt could be considered to prepare an efficient DPI formulation for the pulmonary delivery of glucagon. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Sodium Hyaluronate Nanocomposite Respirable Microparticles to Tackle Antibiotic Resistance with Potential Application in Treatment of Mycobacterial Pulmonary Infections
Pharmaceutics 2019, 11(5), 203; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11050203 - 01 May 2019
Cited by 11 | Viewed by 1879
Abstract
Tuberculosis resistant cases have been estimated to grow every year. Besides Mycobacterium tuberculosis, other mycobacterial species are responsible for an increasing number of difficult-to-treat infections. To increase efficacy of pulmonary treatment of mycobacterial infections an inhalable antibiotic powder targeting infected alveolar macrophages [...] Read more.
Tuberculosis resistant cases have been estimated to grow every year. Besides Mycobacterium tuberculosis, other mycobacterial species are responsible for an increasing number of difficult-to-treat infections. To increase efficacy of pulmonary treatment of mycobacterial infections an inhalable antibiotic powder targeting infected alveolar macrophages (AMs) and including an efflux pump inhibitor was developed. Low molecular weight sodium hyaluronate sub-micron particles were efficiently loaded with rifampicin, isoniazid and verapamil, and transformed in highly respirable microparticles (mean volume diameter: 1 μm) by spray drying. These particles were able to regenerate their original size upon contact with aqueous environment with mechanical stirring or sonication. The in vitro drugs release profile from the powder was characterized by a slow release rate, favorable to maintain a high drug level inside AMs. In vitro antimicrobial activity and ex vivo macrophage infection assays employing susceptible and drug resistant strains were carried out. No significant differences were observed when the powder, which did not compromise the AMs viability after a five-day exposure, was compared to the same formulation without verapamil. However, both preparations achieved more than 80% reduction in bacterial viability irrespective of the drug resistance profile. This approach can be considered appropriate to treat mycobacterial respiratory infections, regardless the level of drug resistance. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Simulation of Airway Deposition of an Aerosol Drug in COPD Patients
Pharmaceutics 2019, 11(4), 153; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11040153 - 01 Apr 2019
Cited by 7 | Viewed by 1945
Abstract
Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled [...] Read more.
Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled drugs is sensitive to the breathing pattern of the patients which is also connected with the patient’s disease severity. The objective of this work was to measure the realistic inhalation profiles of mild, moderate, and severe COPD patients, simulate the deposition patterns of Symbicort® Turbuhaler® dry powder drug and compare them to similar patterns of healthy control subjects. For this purpose, a stochastic airway deposition model has been applied. Our results revealed that the amount of drug depositing within the lungs correlated with the degree of disease severity. While drug deposition fraction in the lungs of mild COPD patients compared with that of healthy subjects (28% versus 31%), lung deposition fraction characteristic of severe COPD patients was lower by a factor of almost two (about 17%). Deposition fraction of moderate COPD patients was in-between (23%). This implies that for the same inhaler dosage severe COPD patients receive a significantly lower lung dose, although, they would need more. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Article
Investigation of the Quantity of Exhaled Aerosols Released into the Environment during Nebulisation
Pharmaceutics 2019, 11(2), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11020075 - 12 Feb 2019
Cited by 25 | Viewed by 2563
Abstract
Background: Secondary inhalation of medical aerosols is a significant occupational hazard in both clinical and homecare settings. Exposure to fugitive emissions generated during aerosol therapy increases the risk of the unnecessary inhalation of medication, as well as toxic side effects. Methods: This study [...] Read more.
Background: Secondary inhalation of medical aerosols is a significant occupational hazard in both clinical and homecare settings. Exposure to fugitive emissions generated during aerosol therapy increases the risk of the unnecessary inhalation of medication, as well as toxic side effects. Methods: This study examines fugitively-emitted aerosol emissions when nebulising albuterol sulphate, as a tracer aerosol, using two commercially available nebulisers in combination with an open or valved facemask or using a mouthpiece with and without a filter on the exhalation port. Each combination was connected to a breathing simulator during simulated adult breathing. The inhaled dose and residual mass were quantified using UV spectrophotometry. Time-varying fugitively-emitted aerosol concentrations and size distributions during nebulisation were recorded using aerodynamic particle sizers at two distances relative to the simulated patient. Different aerosol concentrations and size distributions were observed depending on the interface. Results: Within each nebuliser, the facemask combination had the highest time-averaged fugitively-emitted aerosol concentration, and values up to 0.072 ± 0.001 mg m−3 were recorded. The placement of a filter on the exhalation port of the mouthpiece yielded the lowest recorded concentrations. The mass median aerodynamic diameter of the fugitively-emitted aerosol was recorded as 0.890 ± 0.044 µm, lower the initially generated medical aerosol in the range of 2–5 µm. Conclusions: The results highlight the potential secondary inhalation of exhaled aerosols from commercially available nebuliser facemask/mouthpiece combinations. The results will aid in developing approaches to inform policy and best practices for risk mitigation from fugitive emissions. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Review

Jump to: Editorial, Research

Review
Influence of Composition and Spray-Drying Process Parameters on Carrier-Free DPI Properties and Behaviors in the Lung: A review
Pharmaceutics 2020, 12(1), 55; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12010055 - 09 Jan 2020
Cited by 26 | Viewed by 1867
Abstract
Although dry powder inhalers (DPIs) have attracted great interest compared to nebulizers and metered-dose inhalers (MDIs), drug deposition in the deep lung is still insufficient to enhance therapeutic activity. Indeed, it is estimated that only 10–15% of the drug reaches the deep lung [...] Read more.
Although dry powder inhalers (DPIs) have attracted great interest compared to nebulizers and metered-dose inhalers (MDIs), drug deposition in the deep lung is still insufficient to enhance therapeutic activity. Indeed, it is estimated that only 10–15% of the drug reaches the deep lung while 20% of the drug is lost in the oropharyngeal sphere and 65% is not released from the carrier. The potentiality of the powders to disperse in the air during the patient’s inhalation, the aerosolization, should be optimized. To do so, new strategies, in addition to classical lactose-carrier, have emerged. The lung deposition of carrier-free particles, mainly produced by spray drying, is higher due to non-interparticulate forces between the carrier and drug, as well as better powder uniformity and aerosolization. Moreover, the association of two or three active ingredients within the same powder seems easier. This review is focused on a new type of carrier-free particles which are characterized by a sugar-based core encompassed by a corrugated shell layer produced by spray drying. All excipients used to produce such particles are dissected and their physico-chemical properties (Péclet number, glass transition temperature) are put in relation with the lung deposition ability of powders. The importance of spray-drying parameters on powders’ properties and behaviors is also evaluated. Special attention is given to the relation between the morphology (characterized by a corrugated surface) and lung deposition performance. The understanding of the closed relation between particle material composition and spray-drying process parameters, impacting the final powder properties, could help in the development of promising DPI systems suitable for local or systemic drug delivery. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Review
Mucosal Vaccination via the Respiratory Tract
Pharmaceutics 2019, 11(8), 375; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11080375 - 01 Aug 2019
Cited by 24 | Viewed by 2676
Abstract
Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the mucosal immune system, which is the largest lymphoid tissue in the human body. The [...] Read more.
Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the mucosal immune system, which is the largest lymphoid tissue in the human body. The mucosal immune response involves systemic, antigen-specific humoral and cellular immune response in addition to a local response which is characterised by a predominantly cytotoxic T cell response in combination with secreted IgA. This antibody facilitates pathogen recognition and deletion prior to entrance into the body. Hence, administration via the respiratory mucosa can be favoured for all pathogens which use the respiratory tract as entry to the body, such as influenza and for all diseases directly affecting the respiratory tract such as pneumonia. Additionally, the different mucosal tissues of the human body are interconnected via the so-called “common mucosal immune system”, which allows induction of an antigen-specific immune response in distant mucosal sites. Finally, mucosal administration is also interesting in the area of therapeutic vaccination, in which a predominant cellular immune response is required, as this can efficiently be induced by this route of delivery. The review gives an introduction to respiratory vaccination, formulation approaches and application strategies. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Review
Inhaled Antibiotics for Mycobacterial Lung Disease
Pharmaceutics 2019, 11(7), 352; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics11070352 - 19 Jul 2019
Cited by 13 | Viewed by 2873
Abstract
Mycobacterial lung diseases are an increasing global health concern. Tuberculosis and nontuberculous mycobacteria differ in disease severity, epidemiology, and treatment strategies, but there are also a number of similarities. Pathophysiology and disease progression appear to be relatively similar between these two clinical diagnoses, [...] Read more.
Mycobacterial lung diseases are an increasing global health concern. Tuberculosis and nontuberculous mycobacteria differ in disease severity, epidemiology, and treatment strategies, but there are also a number of similarities. Pathophysiology and disease progression appear to be relatively similar between these two clinical diagnoses, and as a result these difficult to treat pulmonary infections often require similarly extensive treatment durations of multiple systemic drugs. In an effort to improve treatment outcomes for all mycobacterial lung diseases, a significant body of research has investigated the use of inhaled antibiotics. This review discusses previous research into inhaled development programs, as well as ongoing research of inhaled therapies for both nontuberculous mycobacterial lung disease, and tuberculosis. Due to the similarities between the causative agents, this review will also discuss the potential cross-fertilization of development programs between these similar-yet-different diseases. Finally, we will discuss some of the perceived difficulties in developing a clinically utilized inhaled antibiotic for mycobacterial diseases, and potential arguments in favor of the approach. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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