Lung Deposition Research Articles

Inhalation Potential of Rifampicin-Loaded Novel Metal-Organic Frameworks for Improved Lung Delivery: Physicochemical Characterization, In Vitro Aerosolization and Antimycobacterial Studies.

Background: The aim of the current study was to examine the potential of a rifampicin-loaded metal-organic framework (RIF@ZIF-8) for management of tuberculosis. Materials and Methods: RIF@ZIF-8 was developed using a simple, economic, and environmentally friendly ultrasonication method. Furthermore, the developed metal-organic framework (MOF) formulations were subjected to physicochemical characterization analyses such as Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffractometry, thermogravimetric analysis, field emission-scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and UV spectroscopy. In addition, in vitro release, powder flow characterization, in vitro lung deposition, and efficacy studies against the Mycobacterium tuberculosis (MTB) H37Rv strain were performed. Results: Physicochemical characterization confirms its spherical shape and drug loading, whereas in vitro release analysis shows 80.5 ± 5.5% release of the drug from the loaded formulation within 48 hours. Furthermore, powder flow properties suggested that the nature of MOFs is free flowing. Additionally, in vitro lung deposition studies indicated an emission fraction of 88.02 ± 10.23% for the emitted dose and circa 21% fine particle fraction. The mass median aerodynamic diameter and geometric standard deviation were found to be 4.42 ± 0.07 μm and 1.55 ± 01 μm, respectively. The in vitro aerosol performance study demonstrated higher deposition at stages 3, 4, and 5 of the cascade impactors, which simulate deep lung delivery in terms of the trachea-primary bronchus and secondary and terminal bronchi of the human lung, respectively. Moreover, RIF@ZIF-8 exhibited improved antimycobacterial activity (0.0125 mg/mL) vis-à-vis an unformulated drug (0.025 mg/mL) against the MTB H37Rv strain, using the BACTEC 460TB system. Conclusions: Therefore, MOFs could be promising nanocarriers for targeting lungs and overcoming the hepatotoxicity associated with antituberculosis drugs requiring inhalation administration.

Afatinib liposomal dry powder inhaler: Targeted pulmonary delivery of EGFR inhibitor for the management of lung cancer

The present research work aims to prepare a liposomal dry powder inhaler (LDPI) of afatinib dimaleate for the treatment of non-small cell lung cancer through pulmonary delivery. The influence of formulation independent variables, lipid concentration (X1, mol%) and organic phase (X2, mL), on dependent variables, entrapment efficiency (%) and particle size (nm), were investigated using a three-level factorial design. The optimized drug encapsulated PEGylated liposomal batch of 2 mL prepared by ethanol injection method was further scaled up to 25 mL, to enable lyophilization used to convert liposomal dispersion into LDPI. Scale-up batch of liposomes was found to have an average particle size of 181.2 ± 5.0 nm, % entrapment efficiency of 75.31 ± 2.70%, and zeta potential of 9.65 ± 0.31 mV. LDPI manufactured with trehalose as a cryoprotectant and l-leucine as an antiadherent offered porous particles with smooth morphologies that improved aerodynamic efficiency. The prepared LDPI formulation exhibited 9.639 ± 1.369 μm of particle size distribution, 72.56 ± 1.04% drug content, and good flow properties. In vitro lung deposition study implied that particles could reach the deeper region of the lung with more than 85% dose emission from an inhaler device. In vitro drug release study revealed that the drug release profile in pH 7.4 buffer was lower than in pH 5.5 and pH 6.5 buffers, demonstrating the stability of LDPI in lung fluid. Cytotoxicity study utilizing A549 adenocarcinoma cell line uncovered the greater potential of liposomal formulation in inhibiting tumor cell growth as compared to plain drug solution. The cellular uptake across adenocarcinoma cells exhibited more intracellular uptake of fluorescein isothiocyanate (FITC) encapsulated afatinib liposomal formulation than plain FITC dye. Thus, the optimized LDPI can offer an excellent approach for managing lung cancer through site-specific delivery.

Aerosol Delivery of Lung Surfactant and Nasal CPAP in the Treatment of Neonatal Respiratory Distress Syndrome.

After shifting away from invasive mechanical ventilation and intratracheal instillation of surfactant toward non-invasive ventilation with nasal CPAP and less invasive surfactant administration in order to prevent bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome, fully non-invasive surfactant nebulization is the next Holy Grail in neonatology. Here we review the characteristics of animal-derived (clinical) and new advanced synthetic lung surfactants and improvements in nebulization technology required to secure optimal lung deposition and effectivity of non-invasive lung surfactant administration. Studies in surfactant-deficient animals and preterm infants have demonstrated the safety and potential of non-invasive surfactant administration, but also provide new directions for the development of synthetic lung surfactant destined for aerosol delivery, implementation of breath-actuated nebulization and optimization of nasal CPAP, nebulizer circuit and nasal interface. Surfactant nebulization may offer a truly non-invasive option for surfactant delivery to preterm infants in the near future.

Empirical Deposition Correlations.

Traditionally, empirical correlations for predicting respiratory tract deposition of inhaled aerosols have been developed using limited available in vivo data. More recently, advances in medical image segmentation and additive manufacturing processes have allowed researchers to conduct extensive in vitro deposition experiments in realistic replicas of the upper and central branching airways. This work has led to a collection of empirical equations for predicting regional aerosol deposition, especially in the upper, nasal and oral airways. The present section reviews empirical correlations based on both in vivo and in vitro data, which may be used to predict total and regional deposition. Equations are presented for predicting total respiratory deposition fraction, mouth-throat fraction, nasal, and nose-throat fractions for a large variety of aerosol sizes, subject age groups, and breathing maneuvers. Use of these correlations to estimate total lung deposition is also described.

Exposure Assessment of Silver and Gold Nanoparticles Generated During the Synthesis Process in a South African Research Laboratory.

During the synthesis of engineered nanomaterials (ENMs), various occupational exposures occur, leading to health consequences. To date, there is paucity of studies focused on modeling the deposition of nanoparticles emitted from ENMs synthesis processes. This study aimed to characterise and assess exposure to gold (AuNPs) and silver nanoparticles (AgNPs) during a synthesis process in a research laboratory in South Africa. AuNPs and AgNPs synthesis processes were monitored for an hour in a laboratory using a Scanning Mobility Particle Sizer. The monitoring was conducted at a height of 1.2–1.5 m (m) and 1.5 m away from the hood, assuming a 30 cm (cm) breathing circumference zone. Each synthesis process was monitored thrice to generate reliable point estimates, which were used to assess exposure over 8 hours. A time-weighted average concentration was calculated and compared to the derived 8-h occupational exposure limit (OEL) for AgNPs (0.19 μg/m3) and the proposed provisional nano reference value for AuNPs (20,000 particles/cm3). The Multiple-Path Particle Dosimetry model was used to calculate the deposition and retention of both AuNPs and AgNPs. NPs emitted during the synthesis process were dominant in the nuclei (79% for AuNPs and 54% for AgNPs), followed by the Aitken (12% for AuNPs and 29% for AgNPs), with fewer particles in the accumulation mode (9.2% for AuNPs and 17% for AgNPs). AuNPs and AgNPs generated during the synthesis process were determined at 1617.3 ± 102 cm3 (0.046 μg/m3) and 2,687 cm3 ± 620 (0.077 μg/m3), respectively. For the three exposure scenarios, none exceeded the occupational exposure limit for both AuNPs (provisional) and AgNPs (OEL). Workers in the synthesis laboratory are exposed to a concentration below the recommended occupational exposure limit for silver and the proposed provisional nano reference value for gold. Although, the concentrations to which laboratory workers are exposed to are below safe levels, the assessment of the lung deposition patterns indicate a high particle lung retention which raise concerns about long term safety of workers.

IBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10–6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

Nanotechnology-Assisted Metered-Dose Inhalers (MDIs) for High-Performance Pulmonary Drug Delivery Applications.

PurposeRespiratory disorders pose a major threat to the morbidity and mortality to public health. Here we reviewed the nanotechnology based pulmonary drug delivery using metered dose inhalers.MethodsMajor respiratory diseases such as chronic obstructive pulmonary diseases (COPD), asthma, acute lower respiratory tract infections, tuberculosis (TB) and lung cancer. At present, common treatments for respiratory disorders include surgery, radiation, immunotherapy, and chemotherapy or a combination. The major challenge is development of systemic delivery of the chemotherapeutic agents to the respiratory system. Conventional delivery of chemotherapy has various limitation and adverse side effected. Hence, targeted, and systemic delivery need to be developed. Towards this direction nanotechnology, based controlled, targeted, and systemic drug delivery systems are potential candidate to enhance therapeutic efficacy with minimum side effect. Among different route of administration, pulmonary delivery has unique benefits such as circumvents first pass hepatic metabolism and reduces dose and side effects.ResultsRespiratory disorders pose a major threat to the morbidity and mortality to public health globally. Pulmonary delivery can be achieved through various drug delivery devices such as nebulizers, dry powder inhalers, and metered dose inhalers. Among them, metered dose inhalers are the most interesting and first choice of clinician over others. This review focused on nanotechnology based pulmonary drug delivery using metered dose inhalers. This report focused on delivery of various types of therapeutics using nanocarriers such as polymeric nanoparticles and micelles, dendrimers, lipid nanocarriers such as liposomes, solid lipid nanostructures and nanostructured lipid carriers, and other using metered dose inhalers discussed comprehensively. This report provides insight about the effect of parameters of MDI such as co-solvent, propellants, actuators shape, nozzle diameters, and jet lengths, and respiratory flow rate, and particle size of co-suspension of drug on aerodynamics and lung deposition of formulation. This review also provided the insight about various metered dose inhalers market scenario and digital metered dose inhalers.ConclusionThis report concluded the clinical potential of metered dose inhalers, summary of current progress and future perspectives towards the smart digital metered dose inhalers development.

In Vitro Estimation of Tracheobronchial and Alveolar Doses Using Filters

To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.

FIDEPOC: Consensus on Inspiratory Flow and Lung Deposition as Key Decision Factors in COPD Inhaled Therapy.

PurposeThe pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy.MethodsA two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts’ consensus degree with each item.ResultsA high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations.ConclusionThis study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines.

Leucine improves the aerosol performance of dry powder inhaler formulations of siRNA-loaded nanoparticles

Thermostable dry powder inhaler (DPI) formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of inflammatory lung diseases. We recently demonstrated that lipidoid-polymer hybrid nanoparticles (LPNs) loaded with small interfering RNA (siRNA) directed against tumor necrosis factor alpha (TNF-α) mediate efficient intracellular siRNA delivery and reduce inflammation in vivo. Here, we show that mixtures of the stabilizing excipients trehalose (Tre) and dextran (Dex), in combination with the shell-forming dispersion enhancer leucine (Leu), stabilize TNF-α siRNA-loaded LPNs during spray drying into nanocomposite microparticles, and result in DPI formulations with high aerosol performance. At low Leu content (0 to 10%, w/w), the DPI formulations were amorphous, and exhibited poor aerosol performance. When the Leu content was increased from 20 to 60% (w/w), the surface content of Leu increased from 39.2 to 68.1 mol%, and the flowability was significantly improved. Microscopy analysis suggest that the improved powder dispersibility is the result of a wrinkled surface morphology, which reduces the surface area available for interparticle interactions. Increasing the Leu content further (to above 10%, w/w) did not influence the aerosol performance, and the aerosol yield was maximal at 30–40% Leu (w/w). Formulations containing 40% Leu and a Tre:Dex ratio of 10:90 (w/w) displayed a high fine particle fraction and aerosol properties suitable for inhalation. The chemical integrity of TNF-α siRNA was preserved in the solid state, and biodistribution studies in mice showed that pulmonary administration of DPI formulations with high aerosol performance resulted in homogenous deep lung deposition. Our results demonstrate that at optimal ratios, ternary excipient mixtures of Leu, Tre and Dex protect TNF-α siRNA-loaded LPNs during spray drying. Hence, this study shows that microparticles with an amorphous Tre/Dex matrix and a crystalline Leu shell efficiently stabilize the nanocomposite LPNs in the solid state, and ensure aerosol properties suitable for inhalation.

Effects of indoor air pollution on tribal community in rural India and health risk assessment due to domestic biomass burning: a realistic approach using the lung deposition model.

Indoor air pollution from the combustion of biomass fuel and associated health risks is a critical issue in developing countries. Concentrations of PM2.5 and PM10 are measured in Birbhum, West Bengal, during 2017-2018. PM2.5-bound elemental concentrations of twelve metals are determined in rural kitchens. The results showed higher toxicological risks in BMF (1.15) than the LPG users (0.14). The risk of non-carcinogenic exposure related with dermal contact and ingestion was observed in the acceptable limits (HQ < 1) for all age groups, and the risk associated with inhalation exposure from Cr, Ni, As, and Mn exceeded the acceptable limit. Results also suggest that carcinogenic risks from ingestion and dermal contact are within the acceptable limit (1 × 10-4-1 × 10-6) except Cr and As which were found to exceed the range. The deposition flux (Dφ) for multiple metals in the head airway region, tracheobronchial region, and alveolar regions was found to be higher in teenagers as compared to other groups, whereas the value was lower in infants. Further, it was notified from the Dφ that the metals could pass through the head airways and harm the tracheobronchial tree and alveolar region, increasing the risk of human health.

Radiolabeling Method for Lyophilizate for Dry Powder Inhalation Formulations

Human lung deposition data is non-mandatory for drug approval but very useful for the development of orally inhaled drug products. Lung deposition of inhaled drugs can be quantified by radionuclide imaging, for which one of the first considerations is the method used to radiolabel formulations. In this study, we report the development of a radiolabeling method for lyophilizate for dry powder inhalation (LDPI) formulations. TechneCoatTM is one method that can radiolabel drug particles without using solvents. In this method, particles are radiolabeled with a dispersion of 99mTc-labeled nanoparticles called TechnegasTM. Because a LDPI formulation is not comprised of particles but is a lyophilized cake aerosolized by air impact, the TechneCoat method cannot be used for the radiolabeling of LDPI formulations. We therefore modified the TechneCoat apparatus so that LDPI formulations were not aerosolized by the Technegas flow. Radiolabeling using a modified TechneCoat apparatus was validated with model LDPI formulations of interferon alpha (IFN). IFN of 99mTc-unlabeled, IFN of 99mTc-labeled, and 99mTc of 99mTc-labeled LDPI formulations showed similar behavior, and differences from IFN of 99mTc-unlabeled LDPI formulations were within ±15% in aerodynamic particle size distribution measurement. Our radiolabeling method for LDPI formulations may be useful for the quantification of drug deposition in human lungs.

Effects of airway deformation and alveolar pores on particle deposition in the lungs

The distal lung (G14–G23), which are composed of alveoli and bronchi, are responsible for almost all gas exchange and micro- and nanoparticle deposition in the lungs. In the existing research using computational fluid dynamics, the geometric modeling accuracy of the bronchial bifurcation structure is given priority, and then the alveoli are attached to bronchi as discrete spherical crowns. This method ignores the correlation between alveoli. In fact, the alveoli have a tessellated distribution, and adjacent alveoli are connected by several alveolar pores. Due to the huge number of alveoli, this seemingly small difference will be greatly amplified, which may lead to a large deviation in the prediction of the overall flow. Accordingly, the objective of this study is to construct a two-dimensional distal lung model including the bronchi, acini, and alveolar pores by using the methods of regular hexagonal tessellational subdivision, fusion, and coordinate transformation. A moving boundary is introduced to simulate the process of airflow and particle deposition in the distal lung, and the effects of bronchial deformation, respiratory frequency, and alveolar pores are obtained. The results show that there are significant differences in intrapulmonary flow patterns with and without alveolar pores. Alveolar pores can establish bypass ventilation downstream of a blockage, thus providing a pathway for particles to enter the airways downstream of the blockage. Changing the respiratory frequency and the amplitude of bronchial deformation will change the relative velocity between particles and moving wall, which, in turn, will change the particle deposition efficiency in the distal lung. To summarize this study, a geometric modeling method for the distal lung with alveolar pores is established, and the important roles of detailed characteristics of the distal lung are revealed. The findings of this study provide a reasonable hydrodynamic mechanism for the prevention of related respiratory diseases.

Influence of Particle Size and Particle Deposition of Inhaled Medication in Lung Disease: A Comrehensive Review

Drug particles less than 5 µm have the greatest probability of deposition in the lung, whereas those less than 2 µm tend to be concentrated in the alveoli. A large proportion of particles within the 2-5 μm range are present in the dose released from the inhaled drug, providing a relatively even distribution across the lungs. The efficient need for inhaled therapy highly depends on the essence of the method of drug delivery and the patient's ability to correctly use the system. A large range of inhaler products, each with positive and negative aspects, are on the market. It facilitates the administration of a lower dose; there is a quicker onset of action and less severe side effects. The deposition of the inhaled drug in the lung is dependent on particle size, inhalation technique and the type of inhaler device. Importance of particle size distribution and Particle aerodynamic diameter, Influence of environmental humidity on particle size Particle deposition in the airways, Methods to identify drug deposition in lungs, Physiological factors which affect the therapeutic efficacy of pulmonary delivery drugs. The nano and micro size particles is a mainstay of treatment for a variety of pulmonary diseases because they provide a platform to deliver drugs directly reliably and inexpensively to the disease site, thus allowing for a minimum amount of drug to be used and minimize side effects.

Dual targeting powder formulation of antiviral agent for customizable nasal and lung deposition profile through single intranasal administration

Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration. Spray freeze drying (SFD) and spray drying (SD) techniques were employed to prepare tamibarotene powder formulations, and cyclodextrin was used as the sole excipient to enhance drug solubility. With the employment of appropriate atomizing nozzles, particles of size above 10 μm and below 5 μm could be produced for nasal and lung deposition, respectively. The aerosol performance of the powder was evaluated using Next Generation Impactor (NGI) coupled with a glass expansion chamber and the powder was dispersed with a nasal powder device. By blending powder of two different particle sizes, a single powder formulation with dual aerosol deposition characteristic in both the nasal and pulmonary regions was produced. The aerosol deposition fractions in the nasal cavity and pulmonary region could be modulated by varying the powder mixing ratio. All dry powder formulations exhibited spherical structures, amorphous characteristics and improved dissolution profile as compared to the unformulated tamibarotene. Overall, a novel dual targeting powder formulation of tamibarotene exhibiting customizable aerosol deposition profile was developed. This exceptional formulation strategy can be adopted to deliver other antimicrobial agents to the upper and lower airways for the prevention and treatment of human respiratory infections.

Fate of inhaled aerosols under the influence of glottal motion in a realistic in silico human tracheobronchial tree model

Despite the prevalence of inhalation therapy in the treatment of various respiratory diseases, predicting and optimizing lung deposition fractions of inhaled drugs for maximal efficacy remains challenging due to the complex anatomical structures of the extra-thoracic airways, notably the glottal region. One of the widespread speculations in current insilico simulations lies in assuming a static glottis during inhalation, while in reality inhalation leads to significant glottis cross-sectional area expansion. The present work attempts to explore, insilico, the influence of transient movement of the glottal structures on inhalation therapy outcomes. To this end, we adopted a CT-based realistic human tracheobronchial tree (TB) model and explored transient airflows and deposition outcomes for a broad range of inhaled aerosols (i.e., dp=1-12 μm) under a dry powder inhaler (DPI) maneuver. Three different glottal expansion ratios, spanning static to 40 percent cross-sectional area expansion have been considered for the analysis. Our findings point to the tangible impact of glottal motion on airflow and particle deposition along the respiratory tract for a DPI maneuver, where a static glottis underpredicts the total particle deposition in the TB model for lower sized particles (dp≤ 3 μm) compared to predictions for all dynamic glottal motions. In contrast, for larger size particles (i.e., 5 ≤dp≤ 10 μm), a static glottis yields lower total deposition in the TB model compared with dynamic glottal motions. Our study also underlines that regional deposition of smaller micron-sized particles is most affected by glottal deformation in the conducting airways.

Characterisation of Particle Size and Viability of SARS-CoV-2 Aerosols from a Range of Nebuliser Types Using a Novel Sampling Technique.

Little is understood about the impact of nebulisation on the viability of SARS-CoV-2. In this study, a range of nebulisers with differing methods of aerosol generation were evaluated to determine SARS-CoV-2 viability following aerosolization. The aerosol particle size distribution was assessed using an aerosol particle sizer (APS) and SARS-CoV-2 viability was determined after collection into liquid media using All-Glass Impingers (AGI). Viable particles of SARS-CoV-2 were further characterised using the Collison 6-jet nebuliser in conjunction with novel sample techniques in an Andersen size-fractioning sampler to predict lung deposition profiles. Results demonstrate that all the tested nebulisers can generate stable, polydisperse aerosols (Geometric standard deviation (GSD) circa 1.8) in the respirable range (1.2 to 2.2 µm). Viable fractions (VF, units PFU/particle, the virus viability as a function of total particles produced) were circa 5 × 10−3. VF and spray factors were not significantly affected by relative humidity, within this system where aerosols were in the spray tube an extremely short time. The novel Andersen sample collection methods successfully captured viable virus particles across all sizes; with most particle sizes below 3.3 µm. Particle sizes, in MMAD (Mass Median Aerodynamic Diameters), were calculated from linear regression of log10-log10 transformed cumulative PFU data, and calculated MMADs accorded well with APS measurements and did not differ across collection method types. These data will be vital in informing animal aerosol challenge models, and infection prevention and control policies.

Development of a potential anti-cancer pulmonary nanosystem consisted of chitosan-doped LeciPlex loaded with resveratrol using a machine learning method

A novel self-assembled lecithin-based cationic nanocarrier (LeciPlex) doped with chitosan was prepared to improve Resveratrol solubility and anticancer efficacy. Using on a machine learning method based on regression analysis, LP5 (composed of lecithin, Peceol® and chitosan) was selected as the optimized one. This formula was spherical-shaped with a particle size of 59 nm, an encapsulation efficiency of 89% and a mean release time of 2.75 h together with a good mucoadhesive potential. Cascade impactor studies revealed the possible deep lung deposition of LP5 after nebulization. The safety of Resveratrol suspension and LP5 were checked on WISH cell line. Compared with Doxorubicin, both Resveratrol suspension and LP5 showed potent anticancer effects against the A549 cell line with IC50 values of 2.312, 2.200 and 1.708 μg/ml, respectively. These results indicated that the selected formula (LP5) significantly enhanced the crude drug anticancer effect by 63.2 fold and showed a higher anticancer selectivity index (>5.51). Furthermore, after 24 h, A549 up-took the LP5 more than the drug suspension by 40,000 fold. In addition, LP5 markedly induced the cellular apoptosis in A549 treated cells with a percentage of 73.1 compared to untreated cells. In conclusion, the results confirmed the enhanced lung anticancer effect, lower toxicity, and higher selectivity of the selected Resveratrol-loaded LeciPlex compared to the drug suspension. This study presents a potential nano-vesicular system for nebulization to combat lung cancer.

The proteasome-dependent degradation of ALKBH5 regulates ECM deposition in PM2.5 exposure-induced pulmonary fibrosis of mice

Long-term inhalation of fine particulate matter (PM2.5) can cause serious effects on the respiratory system. It might be attributed to the fact that PM2.5 could directly enter and deposit in lung tissues. We established models of PM2.5 exposure in vivo and in vitro to explore the adverse effects of ambient PM2.5 on pulmonary and its potential pathogenic mechanisms. Our results showed that PM2.5 exposure promoted the deposition of ECM and the increased stiffness of the lungs, and then led to pulmonary fibrosis in time- and dose- dependent manners. Pulmonary function test showed restrictive ventilation function in mice after PM2.5 exposure. After PM2.5 exposure, ALKBH5 was recognized by TRIM11 and then degraded through the proteasome pathway. ALKBH5 deficiency (ALKBH5-/-) aggravated restrictive ventilatory disorder and promoted ECM deposition in lungs of mice induced by PM2.5. And the YAP1 signaling pathway was more activated in ALKBH5-/- than WT mice after PM2.5 exposure. In consequence, decreased ALKBH5 protein levels regulated miRNAs and then the miRNAs-targeted YAP1 signaling was activated to promote pulmonary fibrosis induced by PM2.5.

Formulation, characterization and evaluation of inhalable effervescent dry powder of Rifampicin nanoparticles

BackgroundDry powder inhaler is a popular approach to pulmonary drug delivery to treat tuberculosis. Spray dried Nanoparticles using lactose carrier is extensively used for pulmonary drug delivery. Though lactose nanoparticles show deep lung deposition, they fail to uniformly disperse nanoparticles in its original form in alveoli. Rifampicin is one of the first line drugs in tuberculosis treatment. Lung targeted drug delivery system is an approach to reduce dose related side effects of rifampicin. Inhalable nanoparticles also help to target alveolar macrophages, thus improving treatment efficiency. MethodologyThis study focuses on rifampicin nanosuspension formulation and optimization using nano-precipitation method followed by characterizing effervescent DPI of rifampicin nanoparticles with effervescent pair (citric acid and sodium bicarbonate). Preliminary studies showed suitability of 4:5 solvent: antisolvent ratio and lecithin (1%) as stabilizer. The drug and stabilizer concentration in nanoparticles was successfully optimized using 3 ∗ 2 factorial design using DESIGN EXPERT software. The rifampicin nanoparticles were further converted to spray dried powder using effervescent carrier. ResultThe effervescent pair formulation was monodisperse and had a particle size of 1.5 microns (polydispersity index 0.289), thus showing better redispersibility than lactose nanoparticles. The mass median aerodynamic diameter and fine particle diameter of both spray dried formulations were similar and suitable for deep lung deposition. ConclusionThese findings are suggestive that effervescent technique can be successfully employed to improve redispersibility of rifampicin nanoparticles.