Advances in Pulmonary Drug Delivery, Volume II

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 July 2022) | Viewed by 28050

Special Issue Editors

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
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 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
Dr. Ayca Yildiz-Pekoz
Guest Editors

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 (10 papers)

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Research

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15 pages, 2674 KiB  
Article
Pulmonary Delivery of Favipiravir in Rats Reaches High Local Concentrations without Causing Oxidative Lung Injury or Systemic Side Effects
by Ozlem Akbal-Dagistan, Mustafa Sevim, Leyla Semiha Sen, Nur Sena Basarir, Meltem Culha, Aybige Erturk, Hanan Fael, Engin Kaptan, Serap Sancar, Lutfiye Mulazimoglu Durmusoglu, Berrak C. Yegen and Ayca Yildiz-Pekoz
Pharmaceutics 2022, 14(11), 2375; https://doi.org/10.3390/pharmaceutics14112375 - 04 Nov 2022
Cited by 2 | Viewed by 1841
Abstract
Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients. Considering that the pulmonary route could provide a high drug concentration, and a safer application with [...] Read more.
Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients. Considering that the pulmonary route could provide a high drug concentration, and a safer application with less absorption into systemic circulation, it was aimed to elucidate whether favipiravir delivered via soft-mist inhaler has any deleterious effects on lung, liver and kidney tissues of healthy rats. Wistar albino rats of both sexes (n = 72) were placed in restrainers, and were given either saline or favipiravir (1, 2.5, 5 or 10 mg/kg in 1 mL saline) by inhalation within 2 min for 5 consecutive days. On the 6th day, electrocardiographic recording was obtained, and cardiac blood and lung tissues were collected. Favipiravir did not alter cardiac rhythm, blood cell counts, serum levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, urea or uric acid, and did not cause any significant changes in the pulmonary malondialdehyde, myeloperoxidase activity or antioxidant glutathione levels. Our data revealed that pulmonary use of favipiravir via soft-mist inhaler enables a high local concentration compared to plasma without oxidative lung injury or cardiac or hepatorenal dysfunction. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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22 pages, 3728 KiB  
Article
Formulation and Evaluation of Novel Additive-Free Spray-Dried Triamcinolone Acetonide Microspheres for Pulmonary Delivery: A Pharmacokinetic Study
by Mohammed Amran, El-Sayed Khafagy, Hatem I. Mokhtar, Sawsan A. Zaitone, Yasser M. Moustafa and Shadeed Gad
Pharmaceutics 2022, 14(11), 2354; https://doi.org/10.3390/pharmaceutics14112354 - 31 Oct 2022
Cited by 2 | Viewed by 1232
Abstract
This work aimed to establish a simple method to produce additive-free triamcinolone acetonide (TAA) microspheres suitable for pulmonary delivery, and therefore more simple manufacturing steps will be warranted. The spray-drying process involved the optimization of the TAA feed ratio in a concentration range [...] Read more.
This work aimed to establish a simple method to produce additive-free triamcinolone acetonide (TAA) microspheres suitable for pulmonary delivery, and therefore more simple manufacturing steps will be warranted. The spray-drying process involved the optimization of the TAA feed ratio in a concentration range of 1–3% w/v from different ethanol/water compositions with/without adding ammonium bicarbonate as a blowing agent. Characterization of the formulas was performed via scanning electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. Our results indicated that the size and morphology of spray-dried TAA particles were dependent on the feed and solvent concentrations in the spray-dried formulations. Furthermore, adding the blowing agent, ammonium bicarbonate, did not produce a significant enhancement in particle characteristics. We prepared additive-free TAA microspheres and found that TAA formulation #1 had optimal physical properties in terms of diameter (2.24 ± 0.27 µm), bulk density (0.95 ± 0.05), tapped density (1.18 ± 0.07), and flowability for deposition during the pulmonary tract, from a centric airway to the alveoli as indicated by Carr’s index = 19 ± 0.01. Hence, formulation #1 was selected to be tested for pharmacokinetic characters. Rats received pulmonary doses of TAA formula #1 and then the TTA concentration in plasma, fluid broncho-alveolar lavage, and lung tissues was determined by HPLC. The TAA concentration at 15 min was 0.55 ± 0.02 µg/mL in plasma, 16.74 ± 2 µg/mL in bronchoalveolar lavage, and 8.96 ± 0.65 µg/mL in lung homogenates, while at the 24 h time point, the TAA concentration was 0.03 ± 0.02 µg/mL in plasma, 1.48 ± 0.27 µg/mL in bronchoalveolar lavage, and 3.79 ± 0.33 µg/mL in lung homogenates. We found that TAA remained in curative concentrations in the rat lung tissues for at least 24 h after pulmonary administration. Therefore, we can conclude that additive-free spray-dried TAA microspheres were promising for treating lung diseases. The current novel preparation technology has applications in the design of preparations for TAA or other therapeutic agents designed for pulmonary delivery. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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21 pages, 7658 KiB  
Article
Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome
by Monica-Carolina Villa-Hermosilla, Sofia Negro, Emilia Barcia, Carolina Hurtado, Consuelo Montejo, Mario Alonso and Ana Fernandez-Carballido
Pharmaceutics 2022, 14(7), 1392; https://doi.org/10.3390/pharmaceutics14071392 - 30 Jun 2022
Cited by 5 | Viewed by 2242
Abstract
Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with [...] Read more.
Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with anti-inflammatory drugs as celecoxib (CXB). For this, CXB-loaded PLGA microparticles (MPs) for inhaled therapy and that are able to be internalized by alveolar macrophages, were developed. MPs were prepared with 5% and 10% initial percentages of CXB (MP-C1 and MP-C2). For both systems, the mean particle size was around 5 µm, which was adequate for macrophage uptake, and the mean encapsulation efficiency was >89%. The in vitro release of CXB was prolonged for more than 40 and 70 days, respectively. The uptake of fluorescein-loaded PLGA MPs by the RAW 264.7 macrophage cell line was evidenced by flow cytometry, fluorescence microscopy and confocal microscopy. CXB-loaded PLGA MPs did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of CXB (encapsulated and in solution) was evaluated by determining the IL-1, IL-6 and TNF-α levels at 24 h and 72 h in RAW 264.7 macrophages, resulting in a higher degree of reduction in the expression of inflammatory mediators for CXB in solution. A potent degree of gene expression reduction was obtained with the developed CXB-loaded MPs. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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13 pages, 1113 KiB  
Article
Preclinical Assessment of Nebulized Surfactant Delivered through Neonatal High Flow Nasal Cannula Respiratory Support
by Francesca Ricci, Arianna Mersanne, Matteo Storti, Marcello Nutini, Giulia Pellicelli, Angelo Carini, Ilaria Milesi, Marta Lombardini, Raffaele L. Dellacà, Merran A. Thomson, Xabier Murgia, Anna Lavizzari, Federico Bianco and Fabrizio Salomone
Pharmaceutics 2022, 14(5), 1093; https://doi.org/10.3390/pharmaceutics14051093 - 20 May 2022
Cited by 1 | Viewed by 1905
Abstract
High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, [...] Read more.
High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, the delivery efficiency of nebulized surfactant during HFNC has not been evaluated in vitro or in animal models of respiratory distress. We, therefore, performed first a benchmark study to compare the surfactant lung dose delivered by commercially available neonatal nasal cannulas (NCs) and HFNC circuits commonly used in neonatal intensive care units. Then, the pulmonary effect of nebulized surfactant delivered via HFNC was investigated in spontaneously breathing rabbits with induced respiratory distress. The benchmark study revealed the surfactant lung dose to be relatively low for both types of NCs tested (Westmed NCs 0.5 ± 0.45%; Fisher & Paykel NCs 1.8 ± 1.9% of a nominal dose of 200 mg/kg of Poractant alfa). The modest lung doses achieved in the benchmark study are compatible with the lack of the effect of nebulized surfactant in vivo (400 mg/kg), where arterial oxygenation and lung mechanics did not improve and were significantly worse than the intratracheal instillation of surfactant. The results from the present study indicate a relatively low lung surfactant dose and negligible effect on pulmonary function in terms of arterial oxygenation and lung mechanics. This negligible effect can, for the greater part, be explained by the high impaction of aerosol particles in the ventilation circuit and upper airways due to the high air flows used during HFNC. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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13 pages, 859 KiB  
Article
Early Effects of Low Molecular Weight Heparin Therapy with Soft-Mist Inhaler for COVID-19-Induced Hypoxemia: A Phase IIb Trial
by Mustafa Erelel, Mert Kaskal, Ozlem Akbal-Dagistan, Halim Issever, Ahmet Serhan Dagistanli, Hilal Balkanci, Merve Sinem Oguz, Aygun Qarayeva, Meltem Culha, Aybige Erturk, Nur Sena Basarir, Gokben Sahin, Ali Yagiz Uresin, Ahmet Ogul Araman, Alpay Medetalibeyoglu, Tufan Tukek, Mustafa Oral Oncul and Ayca Yildiz-Pekoz
Pharmaceutics 2021, 13(11), 1768; https://doi.org/10.3390/pharmaceutics13111768 - 22 Oct 2021
Cited by 11 | Viewed by 2849
Abstract
In COVID-19-induced acute respiratory distress syndrome, the lungs are incapable of filling with sufficient air, leading to hypoxemia that results in high mortality among hospitalized patients. In clinical trials, low-molecular-weight heparin was administered via a specially designed soft-mist inhaler device in an investigator [...] Read more.
In COVID-19-induced acute respiratory distress syndrome, the lungs are incapable of filling with sufficient air, leading to hypoxemia that results in high mortality among hospitalized patients. In clinical trials, low-molecular-weight heparin was administered via a specially designed soft-mist inhaler device in an investigator initiated, single-center, open-label, phase-IIb clinical trial. Patients with evidently worse clinical presentations were classed as the “Device Group”; 40 patients were given low-molecular-weight heparin via a soft mist inhaler at a dose of 4000 IU per administration, twice a day. The Control Group, also made up of 40 patients, received the standard therapy. The predetermined severity of hypoxemia and the peripheral oxygen saturation of patients were measured on the 1st and 10th days of treatment. The improvement was particularly striking in cases of severe hypoxemia. In the 10-day treatment, low-molecular-weight heparin was shown to significantly improve breathing capability when delivered via a soft-mist inhaler. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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15 pages, 1979 KiB  
Article
Surfactant-Assisted Distal Pulmonary Distribution of Budesonide Revealed by Mass Spectrometry Imaging
by Riccardo Zecchi, Pietro Franceschi, Laura Tigli, Barbara Pioselli, Valentina Mileo, Xabier Murgia, Fabrizio Salomone, Giuseppe Pieraccini, Haruo Usada, Augusto F. Schmidt, Noah H. Hillman, Matthew W. Kemp and Alan H. Jobe
Pharmaceutics 2021, 13(6), 868; https://doi.org/10.3390/pharmaceutics13060868 - 12 Jun 2021
Cited by 1 | Viewed by 2708
Abstract
Direct lung administration of budesonide in combination with surfactant reduces the incidence of bronchopulmonary dysplasia. Although the therapy is currently undergoing clinical development, the lung distribution of budesonide throughout the premature neonatal lung has not yet been investigated. Here, we applied mass spectrometry [...] Read more.
Direct lung administration of budesonide in combination with surfactant reduces the incidence of bronchopulmonary dysplasia. Although the therapy is currently undergoing clinical development, the lung distribution of budesonide throughout the premature neonatal lung has not yet been investigated. Here, we applied mass spectrometry imaging (MSI) to investigate the surfactant-assisted distal lung distribution of budesonide. Unlabeled budesonide was either delivered using saline as a vehicle (n = 5) or in combination with a standard dose of the porcine surfactant Poractant alfa (n = 5). These lambs were ventilated for one minute, and then the lungs were extracted for MSI analysis. Another group of lambs (n = 5) received the combination of budesonide and Poractant alfa, followed by two hours of mechanical ventilation. MSI enabled the label-free detection and visualization of both budesonide and the essential constituent of Poractant alfa, the porcine surfactant protein C (SP-C). 2D ion intensity images revealed a non-uniform distribution of budesonide with saline, which appeared clustered in clumps. In contrast, the combination therapy showed a more homogeneous distribution of budesonide throughout the sample, with more budesonide distributed towards the lung periphery. We found similar distribution patterns for the SP-C and budesonide in consecutive lung tissue sections, indicating that budesonide was transported across the lungs associated with the exogenous surfactant. After two hours of mechanical ventilation, the budesonide intensity signal in the 2D ion intensity maps dropped dramatically, suggesting a rapid lung clearance and highlighting the relevance of achieving a uniform surfactant-assisted lung distribution of budesonide early after delivery to maximize the anti-inflammatory and maturational effects throughout the lung. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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18 pages, 2346 KiB  
Article
Cylindrical Microparticles Composed of Mesoporous Silica Nanoparticles for the Targeted Delivery of a Small Molecule and a Macromolecular Drug to the Lungs: Exemplified with Curcumin and siRNA
by Thorben Fischer, Inga Winter, Robert Drumm and Marc Schneider
Pharmaceutics 2021, 13(6), 844; https://doi.org/10.3390/pharmaceutics13060844 - 07 Jun 2021
Cited by 13 | Viewed by 2940
Abstract
The transport of macromolecular drugs such as oligonucleotides into the lungs has become increasingly relevant in recent years due to their high potency. However, the chemical structure of this group of drugs poses a hurdle to their delivery, caused by the negative charge, [...] Read more.
The transport of macromolecular drugs such as oligonucleotides into the lungs has become increasingly relevant in recent years due to their high potency. However, the chemical structure of this group of drugs poses a hurdle to their delivery, caused by the negative charge, membrane impermeability and instability. For example, siRNA to reduce tumour necrosis factor alpha (TNF-α) secretion to reduce inflammatory signals has been successfully delivered by inhalation. In order to increase the effect of the treatment, a co-transport of another anti-inflammatory ingredient was applied. Combining curcumin-loaded mesoporous silica nanoparticles in nanostructured cylindrical microparticles stabilized by the layer-by-layer technique using polyanionic siRNA against TNF-α was used for demonstration. This system showed aerodynamic properties suited for lung deposition (mass median aerodynamic diameter of 2.85 ± 0.44 µm). Furthermore, these inhalable carriers showed no acute in vitro toxicity tested in both alveolar epithelial cells and macrophages up to 48 h incubation. Ultimately, TNF-α release was significantly reduced by the particles, showing an improved activity co-delivering both drugs using such a drug-delivery system for specific inhibition of TNF-α in the lungs. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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17 pages, 2919 KiB  
Article
Development and Characterization of Inhaled Ethanol as a Novel Pharmacological Strategy Currently Evaluated in a Phase II Clinical Trial for Early-Stage SARS-CoV-2 Infection
by Ana Castro-Balado, Cristina Mondelo-García, Letricia Barbosa-Pereira, Iria Varela-Rey, Ignacio Novo-Veleiro, Néstor Vázquez-Agra, José Ramón Antúnez-López, Enrique José Bandín-Vilar, Raquel Sendón-García, Manuel Busto-Iglesias, Ana Rodríguez-Bernaldo de Quirós, Laura García-Quintanilla, Miguel González-Barcia, Irene Zarra-Ferro, Francisco J. Otero-Espinar, David Rey-Bretal, José Ramón Lago-Quinteiro, Luis Valdés-Cuadrado, Carlos Rábade-Castedo, María Carmen del Río-Garma, Carlos Crespo-Diz, Olga Delgado-Sánchez, Pablo Aguiar, Gema Barbeito-Castiñeiras, María Luisa Pérez del Molino-Bernal, Rocío Trastoy-Pena, Rossana Passannante, Jordi Llop, Antonio Pose-Reino and Anxo Fernández-Ferreiroadd Show full author list remove Hide full author list
Pharmaceutics 2021, 13(3), 342; https://doi.org/10.3390/pharmaceutics13030342 - 05 Mar 2021
Cited by 6 | Viewed by 3891
Abstract
Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy [...] Read more.
Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19; EudraCT number: 2020-001760-29). Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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14 pages, 4999 KiB  
Article
Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops® High Dose Dry Powder Inhalation Device While Maintaining Dispersibility
by Imco Sibum, Paul Hagedoorn, Carel O. Botterman, Henderik W. Frijlink and Floris Grasmeijer
Pharmaceutics 2020, 12(7), 645; https://doi.org/10.3390/pharmaceutics12070645 - 09 Jul 2020
Cited by 8 | Viewed by 3096
Abstract
In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be [...] Read more.
In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used—an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 ± 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 ± 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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Review

Jump to: Research

21 pages, 369 KiB  
Review
Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease
by Niamh Woods and Ronan MacLoughlin
Pharmaceutics 2020, 12(10), 922; https://doi.org/10.3390/pharmaceutics12100922 - 26 Sep 2020
Cited by 10 | Viewed by 3927
Abstract
Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown [...] Read more.
Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery, Volume II)
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