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17 pages, 1371 KiB

Open AccessArticle

Biopharmaceutical Assessment of Mesh Aerosolised Plasminogen, a Step towards ARDS Treatment

by Lucia Vizzoni, Chiara Migone, Brunella Grassiri, Ylenia Zambito, Baldassare Ferro, Paolo Roncucci, Filippo Mori, Alfonso Salvatore, Ester Ascione, Roberto Crea, Semih Esin, Giovanna Batoni and Anna Maria Piras

Pharmaceutics 2023, 15(6), 1618; https://doi.org/10.3390/pharmaceutics15061618 - 30 May 2023

Viewed by 1709

Abstract

Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently [...] Read more.

Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently available. ARDS involves severe respiratory failure, fibrin deposition in both airways and lung parenchyma, with the development of an obstructing hyaline membrane drastically limiting gas exchange. Moreover, hypercoagulation is related to deep lung inflammation, and a pharmacological action toward both aspects is expected to be beneficial. Plasminogen (PLG) is a main component of the fibrinolytic system playing key roles in various inflammation regulatory processes. The inhalation of PLG has been proposed in the form of the off-label administration of an eyedrop solution, namely, a plasminogen-based orphan medicinal product (PLG-OMP), by means of jet nebulisation. Being a protein, PLG is susceptible to partial inactivation under jet nebulisation. The aim of the present work is to demonstrate the efficacy of the mesh nebulisation of PLG-OMP in an in vitro simulation of clinical off-label administration, considering both the enzymatic and immunomodulating activities of PLG. Biopharmaceutical aspects are also investigated to corroborate the feasibility of PLG-OMP administration by inhalation. The nebulisation of the solution was performed using an Aerogen^® Solo^TM vibrating-mesh nebuliser. Aerosolised PLG showed an optimal in vitro deposition profile, with 90% of the active ingredient impacting the lower portions of a glass impinger. The nebulised PLG remained in its monomeric form, with no alteration of glycoform composition and 94% of enzymatic activity maintenance. Activity loss was observed only when PLG-OMP nebulisation was performed under simulated clinical oxygen administration. In vitro investigations evidenced good penetration of aerosolised PLG through artificial airway mucus, as well as poor permeation across an Air–Liquid Interface model of pulmonary epithelium. The results suggest a good safety profile of inhalable PLG, excluding high systemic absorption but with good mucus diffusion. Most importantly, the aerosolised PLG was capable of reversing the effects of an LPS-activated macrophage RAW 264.7 cell line, demonstrating the immunomodulating activity of PLG in an already induced inflammatory state. All physical, biochemical and biopharmaceutical assessments of mesh aerosolised PLG-OMP provided evidence for its potential off-label administration as a treatment for ARDS patients. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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18 pages, 3096 KiB

Open AccessArticle

An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro

by Davide D’Angelo, Eride Quarta, Stefania Glieca, Giada Varacca, Lisa Flammini, Simona Bertoni, Martina Brandolini, Vittorio Sambri, Laura Grumiro, Giulia Gatti, Giorgio Dirani, Francesca Taddei, Annalisa Bianchera, Fabio Sonvico, Ruggero Bettini and Francesca Buttini

Pharmaceutics 2023, 15(3), 1023; https://doi.org/10.3390/pharmaceutics15031023 - 22 Mar 2023

Viewed by 1482

Abstract

This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in [...] Read more.

This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in terms of dissolution time and respirability was obtained starting from a concentration of ethanol of 45% (v/v) in the feedstock solution and 20% (w/w) of mannitol. This powder showed a faster dissolution profile (Weibull dissolution time of 59.5 min) than the poorly soluble raw material (169.0 min). The powder exhibited a fine particle fraction of 66.5% and an MMAD of 2.97 µm. The inhalable powder, when tested on A549 and THP-1, did not show cytotoxic effects up to a concentration of 10 µg/mL. Furthermore, the CsA inhalation powder showed efficiency in reducing IL-6 when tested on A549/THP-1 co-culture. A reduction in the replication of SARS-CoV-2 on Vero E6 cells was observed when the CsA powder was tested adopting the post-infection or simultaneous treatment. This formulation could represent a therapeutic strategy for the prevention of lung rejection, but is also a viable approach for the inhibition of SARS-CoV-2 replication and the COVID-19 pulmonary inflammatory process. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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18 pages, 5416 KiB

Open AccessArticle

Drug Combination of Ciprofloxacin and Polymyxin B for the Treatment of Multidrug–Resistant Acinetobacter baumannii Infections: A Drug Pair Limiting the Development of Resistance

by Junwei Wang, Marc Stegger, Arshnee Moodley and Mingshi Yang

Pharmaceutics 2023, 15(3), 720; https://doi.org/10.3390/pharmaceutics15030720 - 21 Feb 2023

Cited by 3 | Viewed by 1882

Abstract

Polymyxins are considered as last–resort antibiotics to treat infections caused by Acinetobacter baumannii. However, there are increasing reports of resistance in A. baumannii to polymyxins. In this study, inhalable combinational dry powders consisting of ciprofloxacin (CIP) and polymyxin B (PMB) were prepared [...] Read more.

Polymyxins are considered as last–resort antibiotics to treat infections caused by Acinetobacter baumannii. However, there are increasing reports of resistance in A. baumannii to polymyxins. In this study, inhalable combinational dry powders consisting of ciprofloxacin (CIP) and polymyxin B (PMB) were prepared by spray–drying. The obtained powders were characterized with respect to the particle properties, solid state, in vitro dissolution and in vitro aerosol performance. The antibacterial effect of the combination dry powders against multidrug–resistant A. baumannii was assessed in a time–kill study. Mutants from the time–kill study were further investigated by population analysis profiling, minimum inhibitory concentration testing, and genomic comparisons. Inhalable dry powders consisting of CIP, PMB and their combination showed a fine particle fraction above 30%, an index of robust aerosol performance of inhaled dry powder formulations in the literature. The combination of CIP and PMB exhibited a synergistic antibacterial effect against A. baumannii and suppressed the development of CIP and PMB resistance. Genome analyses revealed only a few genetic differences of 3–6 SNPs between mutants and the progenitor isolate. This study suggests that inhalable spray–dried powders composed of the combination of CIP and PMB is promising for the treatment of respiratory infections caused by A. baumannii, and this combination can enhance the killing efficiency and suppress the development of drug resistance. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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16 pages, 3204 KiB

Open AccessArticle

A Supine Position and Dual-Dose Applications Enhance Spray Dosing to the Posterior Nose: Paving the Way for Mucosal Immunization

by Amr Seifelnasr, Mohamed Talaat, Pranav Ramaswamy, Xiuhua April Si and Jinxiang Xi

Pharmaceutics 2023, 15(2), 359; https://doi.org/10.3390/pharmaceutics15020359 - 20 Jan 2023

Cited by 4 | Viewed by 1479

Abstract

Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the [...] Read more.

Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the caudal turbinate and nasopharynx. High-speed imaging was used to characterize the nasal spray plumes. Three-dimensional-printed transparent nasal casts were used to visualize the spray deposition within the nasal airway, as well as the subsequent liquid film formation and translocation. Influencing variables considered included the device type, delivery mode, release angle, flow rate, head position, and dose number. Apparent liquid film translocation was observed in the nasal cavity. To deliver sprays to the posterior nose, the optimal release angle was found to be 40° for unidirectional delivery and 30° for bidirectional delivery. The flow shear was the key factor that mobilized the liquid film. Both the flow shear and the head position were important in determining the translocation distance. A supine position and dual-dose application significantly improved delivery to the nasopharynx, i.e., 31% vs. 0% with an upright position and one-dose application. It is feasible to effectively deliver medications to the posterior nose by leveraging liquid film translocation for mucosal immunization. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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19 pages, 2878 KiB

Open AccessEditor’s ChoiceArticle

Dry Powder Comprised of Isoniazid-Loaded Nanoparticles of Hyaluronic Acid in Conjugation with Mannose-Anchored Chitosan for Macrophage-Targeted Pulmonary Administration in Tuberculosis

by Mahwash Mukhtar, Noemi Csaba, Sandra Robla, Rubén Varela-Calviño, Attila Nagy, Katalin Burian, Dávid Kókai and Rita Ambrus

Pharmaceutics 2022, 14(8), 1543; https://doi.org/10.3390/pharmaceutics14081543 - 25 Jul 2022

Cited by 17 | Viewed by 2815

Abstract

Marketed dosage forms fail to deliver anti-tubercular drugs directly to the lungs in pulmonary Tuberculosis (TB). Therefore, nanomediated isoniazid (INH)-loaded dry powder for inhalation (Nano-DPI) was developed for macrophage-targeted delivery in TB. Mannosylated chitosan (MC) and hyaluronic acid (HA) with an affinity for [...] Read more.

Marketed dosage forms fail to deliver anti-tubercular drugs directly to the lungs in pulmonary Tuberculosis (TB). Therefore, nanomediated isoniazid (INH)-loaded dry powder for inhalation (Nano-DPI) was developed for macrophage-targeted delivery in TB. Mannosylated chitosan (MC) and hyaluronic acid (HA) with an affinity for the surface mannose and CD44 receptors of macrophages were used in conjugation to prepare hybrid nanosuspension by ionic gelation method using cross-linker, sodium tri-polyphosphate (TPP) followed by freeze-drying to obtain a dry powder composed of nanoparticles (INH-MC/HA NPs). Nanoformulations were evaluated for aerodynamic characteristics, cytotoxicity, hemocompatibility, macrophage phenotype analysis, and immune regulation. Cellular uptake imaging was also conducted to evaluate the uptake of NPs. The nanopowders did not pose any significant toxicity to the cells, along with good compatibility with red blood cells (RBCs). The pro-inflammatory costimulatory markers were upregulated, demonstrating the activation of T-cell response. Moreover, the NPs did not show any tolerogenic effect on the macrophages. Furthermore, confocal imaging exhibited the translocation of NPs in the cells. Altogether, the findings present that nano-DPI was found to be a promising vehicle for targeting macrophages. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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23 pages, 2748 KiB

Open AccessArticle

Inhalable Mannosylated Rifampicin–Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy

by Juan M. Galdopórpora, Camila Martinena, Ezequiel Bernabeu, Jennifer Riedel, Lucia Palmas, Ines Castangia, Maria Letizia Manca, Mariana Garcés, Juan Lázaro-Martinez, Maria Jimena Salgueiro, Pablo Evelson, Nancy Liliana Tateosian, Diego Andres Chiappetta and Marcela Analia Moretton

Pharmaceutics 2022, 14(5), 959; https://doi.org/10.3390/pharmaceutics14050959 - 28 Apr 2022

Cited by 12 | Viewed by 2706

Abstract

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on [...] Read more.

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus^® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)–curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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19 pages, 2492 KiB

Open AccessArticle

Aggregates Associated with Instability of Antibodies during Aerosolization Induce Adverse Immunological Effects

by Thomas Sécher, Elsa Bodier-Montagutelli, Christelle Parent, Laura Bouvart, Mélanie Cortes, Marion Ferreira, Ronan MacLoughlin, Guy Ilango, Otmar Schmid, Renaud Respaud and Nathalie Heuzé-Vourc’h

Pharmaceutics 2022, 14(3), 671; https://doi.org/10.3390/pharmaceutics14030671 - 18 Mar 2022

Cited by 13 | Viewed by 2580

Abstract

Background: Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by [...] Read more.

Background: Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by inhalation, it is necessary to consider the interaction between aggregates resulting from the instability of the Ab during aerosolization and the lung mucosa. The aim of this study was to determine the impact of aggregates produced during aerosolization of therapeutic Ab on the immune system. Methods: Human and murine immunoglobulin G (IgG) were aerosolized using a clinically-relevant nebulizer and their immunogenic potency was assessed, both in vitro using a standard human monocyte-derived dendritic cell (MoDC) reporter assay and in vivo in immune cells in the airway compartment, lung parenchyma and spleen of healthy C57BL/6 mice after pulmonary administration. Results: IgG aggregates, produced during nebulization, induced a dose-dependent activation of MoDC characterized by the enhanced production of cytokines and expression of co-stimulatory markers. Interestingly, in vivo administration of high amounts of nebulization-mediated IgG aggregates resulted in a profound and sustained local and systemic depletion of immune cells, which was attributable to cell death. This cytotoxic effect was observed when nebulized IgG was administered locally in the airways as compared to a systemic administration but was mitigated by improving IgG stability during nebulization, through the addition of polysorbates to the formulation. Conclusion: Although inhalation delivery represents an attractive alternative route for delivering Ab to treat respiratory infections, our findings indicate that it is critical to prevent IgG aggregation during the nebulization process to avoid pro-inflammatory and cytotoxic effects. The optimization of Ab formulation can mitigate adverse effects induced by nebulization. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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19 pages, 2960 KiB

Open AccessArticle

Spray-Dried Powder Formulation of Capreomycin Designed for Inhaled Tuberculosis Therapy

by Zitong Shao, Waiting Tai, Yingshan Qiu, Rico C. H. Man, Qiuying Liao, Michael Y. T. Chow, Philip C. L. Kwok and Jenny K. W. Lam

Pharmaceutics 2021, 13(12), 2044; https://doi.org/10.3390/pharmaceutics13122044 - 30 Nov 2021

Cited by 6 | Viewed by 2470

Abstract

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB [...] Read more.

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It requires repeated intramuscular or intravenous administration five times per week. Pulmonary drug delivery is non-invasive with the advantages of local targeting and reduced risk of systemic toxicity. In this study, inhaled dry powder formulation of capreomycin targeting the lung was developed using spray drying technique. Among the 16 formulations designed, the one containing 25% capreomycin (w/w) and spray-dried at an inlet temperature of 90 °C showed the best overall performance with the mass median aerodynamic diameter (MMAD) of 3.38 μm and a fine particle fraction (FPF) of around 65%. In the pharmacokinetic study in mice, drug concentration in the lungs was approximately 8-fold higher than the minimum inhibitory concentration (MIC) (1.25 to 2.5 µg/mL) for at least 24 h following intratracheal administration (20 mg/kg). Compared to intravenous injection, inhaled capreomycin showed significantly higher area under the curve, slower clearance and longer mean residence time in both the lungs and plasma. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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13 pages, 3081 KiB

Open AccessArticle

Angiotensin-(1–7) Peptide Hormone Reduces Inflammation and Pathogen Burden during Mycoplasma pneumoniae Infection in Mice

by Katie L. Collins, Usir S. Younis, Sasipa Tanyaratsrisakul, Robin Polt, Meredith Hay, Heidi M. Mansour and Julie G. Ledford

Pharmaceutics 2021, 13(10), 1614; https://doi.org/10.3390/pharmaceutics13101614 - 04 Oct 2021

Cited by 4 | Viewed by 2010

Abstract

The peptide hormone, angiotensin (Ang-(1–7)), produces anti-inflammatory and protective effects by inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. While Ang-(1–7) has been shown to reduce inflammation and airway hyperreactivity in models of asthma, [...] Read more.

The peptide hormone, angiotensin (Ang-(1–7)), produces anti-inflammatory and protective effects by inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. While Ang-(1–7) has been shown to reduce inflammation and airway hyperreactivity in models of asthma, little is known about the effects of Ang-(1–7) during live respiratory infections. Our studies were developed to test if Ang-(1–7) is protective in the lung against overzealous immune responses during an infection with Mycoplasma pneumonia (Mp), a common respiratory pathogen known to provoke exacerbations in asthma and COPD patients. Wild type mice were treated with infectious Mp and a subset of was given either Ang-(1–7) or peptide-free vehicle via oropharyngeal delivery within 2 h of infection. Markers of inflammation in the lung were assessed within 24 h for each set of animals. During Mycoplasma infection, one high dose of Ang-(1–7) delivered to the lungs reduced neutrophilia and Muc5ac, as well as Tnf-

α

and chemokines (Cxcl1) associated with acute respiratory distress syndrome (ARDS). Despite decreased inflammation, Ang-(1-7)-treated mice also had significantly lower Mp burden in their lung tissue, indicating decreased airway colonization. Ang-(1–7) also had an impact on RAW 264.7 cells, a commonly used macrophage cell line, by dose-dependently inhibiting TNF-

α

production while promoting Mp killing. These new findings provide additional support to the protective role(s) of Ang1-7 in controlling inflammation, which we found to be highly protective against live Mp-induced lung inflammation. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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23 pages, 2179 KiB

Open AccessArticle

Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19

by Waiting Tai, Michael Yee Tak Chow, Rachel Yoon Kyung Chang, Patricia Tang, Igor Gonda, Robert B. MacArthur, Hak-Kim Chan and Philip Chi Lip Kwok

Pharmaceutics 2021, 13(8), 1260; https://doi.org/10.3390/pharmaceutics13081260 - 14 Aug 2021

Cited by 10 | Viewed by 6356

Abstract

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo [...] Read more.

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine by inhalation may be a promising alternative for direct targeting with minimal systemic exposure. This paper reports on the characterisation of isotonic, pH-neutral hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be prepared, sterilised, and nebulised for testing as an investigational new drug for treating this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3–5.2 µm, with about 50–60% of the aerosol by volume < 5 µm. The aerosol droplet size decreased (from 4.95 to 4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The emitted doses ranged from 9.1 to 75.9 mg, depending on the concentration and volume nebulised. The HCQS solutions appear suitable for preclinical and clinical studies for potential COVID-19 treatment. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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17 pages, 3260 KiB

Open AccessArticle

The Influence of Formulation Components and Environmental Humidity on Spray-Dried Phage Powders for Treatment of Respiratory Infections Caused by Acinetobacter baumannii

by Wei Yan, Ruide He, Xiaojiao Tang, Bin Tian, Yannan Liu, Yigang Tong, Kenneth K. W. To and Sharon S. Y. Leung

Pharmaceutics 2021, 13(8), 1162; https://doi.org/10.3390/pharmaceutics13081162 - 28 Jul 2021

Cited by 9 | Viewed by 2136

Abstract

The feasibility of using respirable bacteriophage (phage) powder to treat lung infections has been demonstrated in animal models and clinical studies. This work investigated the influence of formulation compositions and excipient concentrations on the aerosol performance and storage stability of phage powder. An [...] Read more.

The feasibility of using respirable bacteriophage (phage) powder to treat lung infections has been demonstrated in animal models and clinical studies. This work investigated the influence of formulation compositions and excipient concentrations on the aerosol performance and storage stability of phage powder. An anti-Acinetobacter baumannii phage vB_AbaM-IME-AB406 was incorporated into dry powders consisting of trehalose, mannitol and L-leucine for the first time. The phage stability upon the spray-drying process, room temperature storage and powder dispersion under different humidity conditions were assessed. In general, powders prepared with higher mannitol content (40% of the total solids) showed a lower degree of particle merging and no sense of stickiness during sample handling. These formulations also provided better storage stability of phage with no further titer loss after 1 month and <1 log titer loss in 6 months at high excipient concentration. Mannitol improved the dispersibility of phage powders, but the in vitro lung dose dropped sharply after exposure to high-humidity condition (65% RH) for formulations with 20% mannitol. While previously collected knowledge on phage powder preparation could be largely extended to formulate A. baumannii phage into inhalable dry powders, the environmental humidity may have great impacts on the stability and dispersion of phage; therefore, specific attention is required when optimizing phage powder formulations for global distribution. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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Review

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24 pages, 441 KiB

Open AccessEditor’s ChoiceReview

Inhaled Antifungal Agents for Treatment and Prophylaxis of Bronchopulmonary Invasive Mold Infections

by Kévin Brunet, Jean-Philippe Martellosio, Frédéric Tewes, Sandrine Marchand and Blandine Rammaert

Pharmaceutics 2022, 14(3), 641; https://doi.org/10.3390/pharmaceutics14030641 - 14 Mar 2022

Cited by 12 | Viewed by 4153

Abstract

Pulmonary mold infections are life-threatening diseases with high morbi-mortalities. Treatment is based on systemic antifungal agents belonging to the families of polyenes (amphotericin B) and triazoles. Despite this treatment, mortality remains high and the doses of systemic antifungals cannot be increased as they [...] Read more.

Pulmonary mold infections are life-threatening diseases with high morbi-mortalities. Treatment is based on systemic antifungal agents belonging to the families of polyenes (amphotericin B) and triazoles. Despite this treatment, mortality remains high and the doses of systemic antifungals cannot be increased as they often lead to toxicity. The pulmonary aerosolization of antifungal agents can theoretically increase their concentration at the infectious site, which could improve their efficacy while limiting their systemic exposure and toxicity. However, clinical experience is poor and thus inhaled agent utilization remains unclear in term of indications, drugs, and devices. This comprehensive literature review aims to describe the pharmacokinetic behavior and the efficacy of inhaled antifungal drugs as prophylaxes and curative treatments both in animal models and humans. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

32 pages, 23622 KiB

Open AccessReview

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

by Yoen-Ju Son, Danforth P. Miller and Jeffry G. Weers

Pharmaceutics 2021, 13(9), 1528; https://doi.org/10.3390/pharmaceutics13091528 - 21 Sep 2021

Cited by 10 | Viewed by 3961

Abstract

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (

T L D

) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the [...] Read more.

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (

T L D

) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the

T L D

of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the

T L D

divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet number) leads to the formation of higher density particles with high packing densities. This enables ultrahigh

T L D

(>100 mg of drug) to be achieved from a single receptacle. The emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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