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Pharmaceuticals
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Drug Delivery to the Lungs: Challenges and Opportunities
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Drug Delivery to the Lungs: Challenges and Opportunities

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 13948

Special Issue Editor

Prof. Dr. Jinxiang Xi

E-Mail Website
Guest Editor
Department of Biomedical Engineering, Francis College of Engineering, University of Massachusetts, Lowell, MA 01854, USA
Interests: respiratory dynamics; inhalation toxicology; aerosol-based tumor diagnosis; personalized drug delivery; snoring and apnea; medical devices; machine learning

Special Issue Information

Dear Colleagues,

Many challenges exist in delivering mediations to the lungs. These include the complex lung network structure, the low delivery efficiency of current inhalation devices, large uncertainties in dosimetry, and the sophisticated pharmacokinetics of deposited drugs.  

Anatomically accurate lung models are needed to study inhalation therapies. Current CT-based patient-specific lung models are often limited to large branches due to low-resolution images, radiation exposure risks, and other ethical issues. It is not uncommon that based on on-shelf clinical chest CT scans, lung models can only be reconstructed to G3-G6, which cannot be used to study inhalation dosimetry in small airways. The knowledge of the dosimetry of drug products to both large and small airways is essential to develop a dose–outcome correlation. Moreover, lung anatomy and physiology can be significantly altered due to respiratory diseases, and the ensuing ventilation heterogeneity will change the dosimetry of inhaled medications, rendering previous correlations in healthy lungs less reliable.  

Many other sources of uncertainty exist, which may significantly bias the dose–outcome correlation, such as age, gender, health, poor adherence, and poor inhaler technique. Once deposited to the target tissue, the pharmaceuticals can still face physical, chemical, and immunological barriers before they are able to take effect. Studies to understand and strategies to mitigate the impacts from these barriers will help to unfold the full benefits of inhalation therapies to the lungs.  

In this Special Issue, we cordially invite submissions that tackle any aspects of these challenges, including but not limited to:

  • Advances in computational fluid dynamics and other dosimetry models;
  • Anatomical and physiological data of mammalian airways;
  • Deposition and clearance of soluble aerosols;  
  • Doses to target tissues, including small airways and alveoli;    
  • In vitro testing of lung dosimetry;
  • In vitro-in vivo correlation (IVIVC), animal models;   
  • Medical devices for pulmonary drug delivery;
  • Mucosal clearance, alveolar clearance, long-term retention;
  • Nanomedicines and vaccines;      
  • Pharmacokinetics of deposited medications;
  • Viral and other bioaerosols.

Prof. Dr. Jinxiang Xi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pulmonary drug delivery
  • lung remodeling
  • dosimetry to target tissues
  • lung clearance
  • bioaerosols
  • alveoli
  • pharmacokinetics
  • toxicology
  • animal models
  • data-driven diagnosis and therapy of lung diseases

Published Papers (7 papers)

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Research

17 pages, 4133 KiB  
Article
Achieving Targeted Delivery of Chemotherapeutic Particles to Small Airway Tumors via Pulmonary Route Using Endotracheal Catheters: A CFPD Study
by Mohammad Rashedul Islam and Yu Feng
Pharmaceuticals 2023, 16(2), 158; https://doi.org/10.3390/ph16020158 - 22 Jan 2023
Cited by 3 | Viewed by 1459
Abstract
Tracheobronchial tumors, while uncommon, are often malignant in adults. Surgical removal is the primary therapy for non-metastatic lung malignancies, but it is only possible in a small percentage of non-small-cell lung cancer patients and is limited by the number and location of tumors, [...] Read more.
Tracheobronchial tumors, while uncommon, are often malignant in adults. Surgical removal is the primary therapy for non-metastatic lung malignancies, but it is only possible in a small percentage of non-small-cell lung cancer patients and is limited by the number and location of tumors, as well as the patient’s overall health. This study proposes an alternative treatment: administering aerosolized chemotherapeutic particles via the pulmonary route using endotracheal catheters to target lung tumors. To improve delivery efficiency to the lesion, it is essential to understand local drug deposition and particle transport dynamics. This study uses an experimentally validated computational fluid particle dynamics (CFPD) model to simulate the transport and deposition of inhaled chemotherapeutic particles in a 3-dimensional tracheobronchial tree with 10 generations (G). Based on the particle release maps, targeted drug delivery strategies are proposed to enhance particle deposition at two lung tumor sites in G10. Results indicate that controlled drug release can improve particle delivery efficiencies at both targeted regions. The use of endotracheal catheters significantly affects particle delivery efficiencies in targeted tumors. The parametric analysis shows that using smaller catheters can deliver more than 74% of particles to targeted tumor sites, depending on the location of the tumor and the catheter diameter used, compared to less than 1% using conventional particle administration methods. Furthermore, the results indicate that particle release time has a significant impact on particle deposition under the same inhalation profile. This study serves as a first step in understanding the impact of catheter diameter on localized endotracheal injection for targeting tumors in small lung airways. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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16 pages, 3527 KiB  
Article
Hydroxysafflor Yellow A Phytosomes Administered via Intervaginal Space Injection Ameliorate Pulmonary Fibrosis in Mice
by Tingting Li, Dong Han, Zhongxian Li, Mengqi Qiu, Yuting Zhu, Kai Li, Jiawei Xiang, Huizhen Sun, Yahong Shi, Tun Yan, Xiaoli Shi and Qiang Zhang
Pharmaceuticals 2022, 15(11), 1394; https://doi.org/10.3390/ph15111394 - 12 Nov 2022
Cited by 2 | Viewed by 1426
Abstract
Idiopathic pulmonary fibrosis is a fatal interstitial disease characterized by fibroblast proliferation and differentiation and abnormal accumulation of extracellular matrix, with high mortality and an increasing annual incidence. Since few drugs are available for the treatment of pulmonary fibrosis, there is an urgent [...] Read more.
Idiopathic pulmonary fibrosis is a fatal interstitial disease characterized by fibroblast proliferation and differentiation and abnormal accumulation of extracellular matrix, with high mortality and an increasing annual incidence. Since few drugs are available for the treatment of pulmonary fibrosis, there is an urgent need for high-efficiency therapeutic drugs and treatment methods to reduce the mortality associated with pulmonary fibrosis. The interstitium, a highly efficient transportation system that pervades the body, plays an important role in the occurrence and development of disease, and can be used as a new route for disease diagnosis and treatment. In this study, we evaluated the administration of hydroxysafflor yellow A phytosomes via intervaginal space injection (ISI) as an anti-pulmonary fibrosis treatment. Our results show that this therapeutic strategy blocked the activation of p38 protein in the MAPK-p38 signaling pathway and inhibited the expression of Smad3 protein in the TGF-β/Smad signaling pathway, thereby reducing secretion of related inflammatory factors, deposition of collagen in the lungs of mice, and destruction of the alveolar structure. Use of ISI in the treatment of pulmonary fibrosis provides a potential novel therapeutic modality for the disease. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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14 pages, 1976 KiB  
Article
In Vitro Characterization of Aerosolized Albuterol Generated by a Jet Nebulizer and Delivered through a Heated Flow Nasal Cannula System
by Ariel Berlinski and Joshua Spiva
Pharmaceuticals 2022, 15(10), 1281; https://doi.org/10.3390/ph15101281 - 18 Oct 2022
Cited by 1 | Viewed by 1660
Abstract
Pediatric patients receiving respiratory support with heated flow nasal cannula (HFNC) systems frequently receive inhaled medications. Most available data have been obtained with vibrating mesh nebulizers that are expensive. Data are lacking regarding the feasibility of using less expensive devices such as continuous [...] Read more.
Pediatric patients receiving respiratory support with heated flow nasal cannula (HFNC) systems frequently receive inhaled medications. Most available data have been obtained with vibrating mesh nebulizers that are expensive. Data are lacking regarding the feasibility of using less expensive devices such as continuous output jet nebulizers. The characteristics of the aerosols generated by jet nebulizers operated at different conditions (6 and 9 L/min) were studied alone and connected to a HFNC system and different size cannulas using a cascade impactor and spectrophotometry (276 nm). Aerosol characteristics changed while traveling through the HFNC system. Initial size selection occurred at the exit of the circuit (before connecting to the cannula) with all aerosol <5 µm. Nasal cannula size further selected aerosols and reduced drug delivery. The operating flow of the nebulizer did not affect the delivered mass but higher flows generated smaller particle size aerosols. The addition of supplemental flow significantly reduced the delivered mass. The measured aerosol characteristics would likely result in intrapulmonary deposition. The delivery of aerosolized albuterol generated by a continuous output nebulizer placed in the inlet of a HFNC system and connected to large or XXL cannulas is feasible. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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13 pages, 4040 KiB  
Article
Flow Patterns and Particle Residence Times in the Oral Cavity during Inhaled Drug Delivery
by Brenda Vara Almirall, Kiao Inthavong, Kimberley Bradshaw, Narinder Singh, Aaron Johnson, Pippa Storey and Hana Salati
Pharmaceuticals 2022, 15(10), 1259; https://doi.org/10.3390/ph15101259 - 13 Oct 2022
Cited by 3 | Viewed by 1810
Abstract
Pulmonary drug delivery aims to deliver particles deep into the lungs, bypassing the mouth–throat airway geometry. However, micron particles under high flow rates are susceptible to inertial impaction on anatomical sites that serve as a defense system to filter and prevent foreign particles [...] Read more.
Pulmonary drug delivery aims to deliver particles deep into the lungs, bypassing the mouth–throat airway geometry. However, micron particles under high flow rates are susceptible to inertial impaction on anatomical sites that serve as a defense system to filter and prevent foreign particles from entering the lungs. The aim of this study was to understand particle aerodynamics and its possible deposition in the mouth–throat airway that inhibits pulmonary drug delivery. In this study, we present an analysis of the aerodynamics of inhaled particles inside a patient-specific mouth–throat model generated from MRI scans. Computational Fluid Dynamics with a Discrete Phase Model for tracking particles was used to characterize the airflow patterns for a constant inhalation flow rate of 30 L/min. Monodisperse particles with diameters of 7 μm to 26 μm were introduced to the domain within a 3 cm-diameter sphere in front of the oral cavity. The main outcomes of this study showed that the time taken for particle deposition to occur was 0.5 s; a narrow stream of particles (medially and superiorly) were transported by the flow field; larger particles > 20 μm deposited onto the oropharnyx, while smaller particles < 12 μm were more disperse throughout the oral cavity and navigated the curved geometry and laryngeal jet to escape through the tracheal outlet. It was concluded that at a flow rate of 30 L/min the particle diameters depositing on the larynx and trachea in this specific patient model are likely to be in the range of 7 μm to 16 μm. Particles larger than 16 μm primarily deposited on the oropharynx. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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16 pages, 7002 KiB  
Article
Stability of Inhaled Ciprofloxacin-Loaded Poly(2-ethyl-2-oxazoline) Nanoparticle Dry Powder Inhaler Formulation in High Stressed Conditions
by Mohammad Zaidur Rahman Sabuj, Md Abdur Rashid, Tim R. Dargaville and Nazrul Islam
Pharmaceuticals 2022, 15(10), 1223; https://doi.org/10.3390/ph15101223 - 02 Oct 2022
Cited by 3 | Viewed by 2018
Abstract
In this study, the stability of ciprofloxacin (CIP)-loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) was investigated at normal and high stressed conditions. The blank NPs were used to understand the intrinsic physicochemical properties of the polymer NPs under these storage conditions. The formulated NPs were [...] Read more.
In this study, the stability of ciprofloxacin (CIP)-loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) was investigated at normal and high stressed conditions. The blank NPs were used to understand the intrinsic physicochemical properties of the polymer NPs under these storage conditions. The formulated NPs were prepared by a coassembly reaction and dried by lyophilization. The powder NPs were stored at controlled room temperature (25 °C) with normal relative humidity (RH) (43%) and high temperature (40 °C) and RH (75%). The stored samples were analyzed by determining the particle sizes, morphology, solid-state properties, thermal behavior, drug-polymer interactions, and aerosol performances over six months. The chemical stability of the formulations was determined by X-ray diffraction, attenuated total refection-Fourier transform infrared (ATR-FTIR), and high-performance liquid chromatography (HPLC) over six months under both conditions. The particle size of the blank PEtOx NPs significantly (p < 0.05) increased from 195.4 nm to 202.7 nm after 3 months at 40 °C/75% RH due to the moisture absorption from high RH; however, no significant increase was observed afterward. On the other hand, the sizes of CIP-loaded PEtOx NPs significantly (p < 0.05) reduced from 200.2 nm to 126.3 nm after 6 months at 40 °C/75% RH. In addition, the scanning electron microscopy (SEM) images revealed that the surfaces of CIP-loaded PEtOx NPs become smoother after 3 months of storage due to the decay of surface drugs compared to the freshly prepared NPs. However, transmission electron microscopy (TEM) images could not provide much information on drug decay from the nanoparticle’s surfaces. The fine particle fraction (FPF) of CIP-loaded PEtOx NPs dropped significantly (p < 0.05) after three months at 25 °C/43% RH and 40 °C/75% RH conditions. The reduced FPF of CIP-loaded PEtOx NPs occurred due to the drug decay from the polymeric surface and blank PEtOx NPs due to the aggregations of the NPs at high temperatures and RH. Although the aerosolization properties of the prepared CIP-loaded PEtOx NPs were reduced, all formulations were chemically stable in the experimental conditions. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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18 pages, 9635 KiB  
Article
Lower Inspiratory Breathing Depth Enhances Pulmonary Delivery Efficiency of ProAir Sprays
by Mohamed Talaat, Xiuhua April Si and Jinxiang Xi
Pharmaceuticals 2022, 15(6), 706; https://doi.org/10.3390/ph15060706 - 03 Jun 2022
Cited by 3 | Viewed by 2094
Abstract
Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient’s breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability [...] Read more.
Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient’s breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability to perform the instructed breathing maneuver is one of the frequently reported issues during MDI applications; however, their effects on MDI dosimetry are unclear. The objective of this study is to systemically evaluate the effects of breathing depths on regional deposition in the respiratory tract using a ProAir-HFA inhaler. An integrated inhaler mouth-throat-lung geometry model was developed that extends to the ninth bifurcation (G9). Large-eddy simulation (LES) was used to compute the airflow dynamics due to concurrent inhalation and orifice flows. The discrete-phase Lagrangian model was used to track droplet motions. Experimental measurements of ProAir spray droplet sizes and speeds were used as initial and boundary conditions to develop the computational model for ProAir-pulmonary drug delivery. The time-varying spray plume from a ProAir-HFA inhaler into the open air was visualized using a high-speed imaging system and was further used to validate the computational model. The inhalation dosimetry of ProAir spray droplets in the respiratory tract was compared among five breathing depths on a regional, sub-regional, and local basis. The results show remarkable differences in airflow dynamics within the MDI mouthpiece and the droplet deposition distribution in the oral cavity. The inhalation depth had a positive relationship with the deposition in the mouth and a negative relationship with the deposition in the five lobes beyond G9 (small airways). The highest delivery efficiency to small airways was highest at 15 L/min and declined with an increasing inhalation depth. The drug loss inside the MDI was maximal at 45–60 L/min. Comparisons to previous experimental and numerical studies revealed a high dosimetry sensitivity to the inhaler type and patient breathing condition. Considering the appropriate inhalation waveform, spray actuation time, and spray properties (size and velocity) is essential to accurately predict inhalation dosimetry from MDIs. The results highlight the importance of personalized inhalation therapy to match the patient’s breathing patterns for optimal delivery efficiencies. Further complimentary in vitro or in vivo experiments are needed to validate the enhanced pulmonary delivery at 15 L/min. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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18 pages, 2982 KiB  
Article
Pulmonary Targeting of Levofloxacin Using Microsphere-Based Dry Powder Inhalation
by Turki Al Hagbani, Bhavya Vishwa, Amr S. Abu Lila, Hadil Faris Alotaibi, El-Sayed Khafagy, Afrasim Moin and Devegowda V. Gowda
Pharmaceuticals 2022, 15(5), 560; https://doi.org/10.3390/ph15050560 - 30 Apr 2022
Cited by 5 | Viewed by 2348
Abstract
The objective of the current study was to develop poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with the anti-tuberculosis (anti-TB) fluoroquinolone, Levofloxacin (LVX), in the form of dry powder inhalation (DPI). LVX-loaded microspheres were fabricated by solvent evaporation technique. Central Composite Design (CCD) was [...] Read more.
The objective of the current study was to develop poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with the anti-tuberculosis (anti-TB) fluoroquinolone, Levofloxacin (LVX), in the form of dry powder inhalation (DPI). LVX-loaded microspheres were fabricated by solvent evaporation technique. Central Composite Design (CCD) was adopted to optimize the microspheres, with desired particle size, drug loading, and drug entrapment efficiency, for targeting alveolar macrophages via non-invasive pulmonary delivery. Structural characterization studies by differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction analysis revealed the absence of any possible chemical interaction between the drug and the polymer used for the preparation of microspheres. In addition, the optimized drug-loaded microspheres exhibited desired average aerodynamic diameter of 2.13 ± 1.24 μm and fine particle fraction of 75.35 ± 1.42%, indicating good aerosolization properties. In vivo data demonstrated that LVX-loaded microspheres had superior lung accumulation, as evident by a two-fold increase in the area under the curve AUC0–24h, as compared with plain LVX. Furthermore, LVX-loaded microspheres prolonged drug residence time in the lung and maintained a relatively high drug concentration for a longer time, which contributed to a reduced leakage in the systemic circulation. In conclusion, inhalable LVX-loaded microspheres might represent a plausible delivery vehicle for targeting pulmonary tuberculosis via enhancing the therapeutic efficacy of LVX while minimizing its systemic off-target side effects. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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