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Pulmonary Delivery of Drugs and Biologics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 9596

Special Issue Editors

College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
Interests: drug discovery; drug repurposing; pulmonary drug delivery; lung cancer; pulmonary hypertension; respiratory pathophysiology
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY, USA
Interests: inhaled drug delivery; thermostable vaccines; nanomedicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug delivery via the pulmonary route enables the direct administration of drugs and biologics into the lung for the treatment of both local and systemic diseases. Lungs, as a delivery site, offer several advantages, such as a large surface area, dense vasculature, lower enzymatic activity than the gut, and a thin alveolar epithelium that allows for rapid absorption and the immediate onset of action. All of these benefits make it an excellent choice for a non-invasive route of administration. Furthermore, the presence of a high density of immune cells, particularly antigen-presenting cells such as alveolar macrophages and dendritic cells, make it ideal for vaccine delivery, and aid in the generation of a strong mucosal and systemic immunity.

For successful delivery into the lungs, the right combination of the formulation and the device is needed to generate particles or droplets of an appropriate size in order to achieve deposition in the respirable region of the airways. Recent advances in the field of formulation design and pharmaceutical engineering show significant progress in achieving efficient deep lung deposition.

In this review, we would like to focus on the latest advancements in the areas of nanoparticle-based pulmonary delivery, nebulizer- and dry powder-based formulations, pulmonary vaccine delivery, formulations containing drugs and biologics for lung delivery, and targeted delivery to specific regions of the lungs.

Dr. Vivek Gupta
Dr. Nitesh K. Kunda
Guest Editors

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Keywords

  • pulmonary drug delivery
  • nebulizers
  • metered-dose inhaler
  • dry powder inhaler
  • vaccine delivery
  • aerosol
  • inhalation
  • mucosal delivery

Published Papers (3 papers)

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Research

18 pages, 2579 KiB  
Article
Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes
Int. J. Mol. Sci. 2021, 22(9), 4783; https://doi.org/10.3390/ijms22094783 - 30 Apr 2021
Cited by 18 | Viewed by 3096
Abstract
There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer [...] Read more.
There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 × 103-fold after complexation with SBE-β-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-β-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<5 µm) and fine particle fraction: 83.3 ± 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment. Full article
(This article belongs to the Special Issue Pulmonary Delivery of Drugs and Biologics)
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17 pages, 8905 KiB  
Article
Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
Int. J. Mol. Sci. 2021, 22(2), 548; https://doi.org/10.3390/ijms22020548 - 07 Jan 2021
Cited by 9 | Viewed by 3114
Abstract
Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in [...] Read more.
Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil. Full article
(This article belongs to the Special Issue Pulmonary Delivery of Drugs and Biologics)
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20 pages, 4102 KiB  
Article
Different Sensitivity of Macrophages to Phospholipidosis Induction by Amphiphilic Cationic Drugs
Int. J. Mol. Sci. 2020, 21(21), 8391; https://doi.org/10.3390/ijms21218391 - 09 Nov 2020
Cited by 4 | Viewed by 2719
Abstract
Phospholipidosis (PLD), the intracellular accumulation of phospholipids, is an adaptive response to toxic stimuli and serves as an important parameter in the biological assessment of compounds. Cationic amphiphilic drugs are the main inducers of PLD and may impair the function of alveolar macrophages. [...] Read more.
Phospholipidosis (PLD), the intracellular accumulation of phospholipids, is an adaptive response to toxic stimuli and serves as an important parameter in the biological assessment of compounds. Cationic amphiphilic drugs are the main inducers of PLD and may impair the function of alveolar macrophages. In vivo and in vitro models are used for PLD screening but the choice of the cellular model may be important because PLD develops in a cell- and species-specific manner. In this study, a panel of different staining (LysoSensor, Acridine Orange, Nile Red, HCS LipidTOX, LysoID) was evaluated in murine (DMBM-2, J774, RAW264.7) and human (THP-1, monocyte-derived macrophages from peripheral blood) cells to identify the most sensitive and easy to analyze staining method and to detect species-specific differences in the reaction pattern. Amiodarone and chloroquine served as inducers of PLD. High content screening was used to compare number, area, and intensity of the staining. Due to the fast staining protocol and the sensitivity of the detection, LysoID proved to be the most suitable dye of the testing. The lower induction of PLD by chloroquine reported in vivo was also seen in this study. THP-1 macrophages, followed by DMBM-2 cells, produced the most similar reaction pattern to human monocyte-derived macrophages. Full article
(This article belongs to the Special Issue Pulmonary Delivery of Drugs and Biologics)
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