Aerodynamic Particle Size Distribution Research Articles

Real-time measurements and modeling of sodium combustion aerosol dynamics in test chamber to improve the evaluation of SFR containment aerosol behaviour

The initial size distribution and morphological parameters of sodium aerosols are critical in evaluating the accidental suspended aerosol behaviour in Sodium-cooled Fast Reactor (SFR) containment. Mass-based measurements were more familiar in characterizing the sodium aerosols. Real-time number size distribution measurements are carried out in this study. The sensitivity analysis of sodium aerosol effective density (ρe) in deriving the actual number size distributions from the measured Aerodynamic Particle Size Distributions (APSD) and predicting suspended aerosol dynamics is presented. Tests are conducted in a 1 m3 chamber at 47 ± 3% RH for different initial mass concentrations (M0) of 0.1, 1, and 2.9 g/m3. The initial APSDs measured just after the generation completions are observed to be polydisperse with the count median aerodynamic diameter (CMAD) < 1 μm. The literature reported ρe values of sodium aerosols, 2.27, 1.362, and 0.61 g/cm3 are used to derive mobility equivalent PSDs from APSD in each test. The real-time number concentration decay and size growth for four different PSDs are measured and compared with the estimate using nodal method-based code to ascertain the actual parameters. The validated parameters CMD = 0.66 μm, σg = 1.96, ρe = 1 g/cm3 and χ = 1 are used for improved estimation of sodium aerosol dynamics in Indian SFR containment with M0 = 4 g/m3 for severe accident scenarios.

Aerosol deposition and emission from a United States Pharmacopeia‐induction port when using a pressurized metered‐dose inhaler with and without a valved holding chamber

AbstractThe testing of pharmaceutical aerosols includes measuring the aerodynamic particle size distribution, which is usually performed on cascade impactors. In the next generation impactor (NGI), the aerosol dose is introduced through an induction port (IP), being separated into different aerodynamic diameter ranges by seven stages and a micro‐orifice collector. The IP plays an important role in estimating the oropharyngeal deposition fraction. While the IP retains mainly large particles, it also tends to retain particles in the respirable range. In this work, the deposition of particles in the IP of an NGI is studied, both experimentally and through computational fluid dynamic (CFD) simulations. Experimental tests are conducted both with the pressurized metered‐dose inhaler (pMDI) alone and in conjunction with a cylindrical valved holding chamber (VHC). For each case, the total mass deposition that occurs in the VHC, IP, and NGI stages is measured, as well as the mass median aerodynamic diameter of the aerosol leaving the IP. The CFD simulations show minimal variations in results regardless of the injection method due to the relatively low velocity and spray angle of the pMDI‐generated aerosol. If the flap‐valve is removed from the VHC, significant particle deposition occurs upstream or within the valve region, with downstream air recirculation contributing to small particle deposition. Based on the CFD results, a correlation is proposed to accurately predict the particle escape fraction of the IP and VHC, which allows estimation of the tannin distribution of particles collected in the NGI stages, especially those corresponding to the range of respirable particles.

Nebulization and In Vitro Upper Airway Deposition of Liposomal Carrier Systems.

Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 μm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.

Using Dry Dispersion Laser Diffraction to Assess Dispersibility in Spheronized Agglomerate Formulations.

In this study, dry dispersion laser diffraction was used to study the dispersibility of spheronized agglomerate formulations and identify geometric particle size metrics that correlated well with aerodynamic particle size distribution (APSD). Eleven unique batches of agglomerates were prepared for both laser diffraction and cascade impaction testing. Correlations between the particle size distribution (PSD) and aerodynamic particle size distribution (APSD) metrics for the eleven agglomerate batches were determined in a semi-empirical manner. The strongest correlation between APSD and PSD was observed between the impactor-sized mass (%ISM) and the cumulative PSD fraction <14.5 µm. The strongest correlation with fine particle fraction (FPF) was observed with the cumulative PSD fraction <0.99 micron (R-squared = 0.974). In contrast to the other APSD metrics, good correlations were not found between the mass median aerodynamic diameter (MMAD) and the cumulative PSD fractions. Overall, the implementation of laser diffraction as a surrogate for cascade impaction has the potential to streamline product development. Laser diffraction measurements offer savings in labor and turnaround time compared to cascade impaction.

Acceptance Testing of Used Cascade Impactor Stages Based on Pressure Drop Measurements in a Flow System Managed with a Critical Flow Venturi: Part I-Laboratory Proof-of-Principle.

Background: Cascade impactors are essential for measuring the aerodynamic particle size distribution delivered by metered dose, dry powder, and similar inhalable drug products. For quality control of used impactors, periodic optical inspection of the nozzles of each impactor stage (stage mensuration) is currently the only method sufficiently precise to test whether used impactors are suitable for continued use, in accord with pharmacopeial standards. Here, we demonstrate a new method for quality control of used impactors. The method combines stage-wise pressure-drop measurement with a critical flow venturi (CFV) for air flow management. This technique avoids the unacceptably large uncertainty in conventional air flow rate measurements and instead relies on pressure and temperature measurement upstream of the CFV. These measurements can be made precisely with affordable equipment. Methods: We placed a toroidally shaped CFV downstream of a Next Generation Impactor™** (NGI) and precisely measured the stagnation pressure (±0.02%) and temperature (±0.03%) upstream of this CFV at impactor inlet flow rates close to 60 L/min. Pressure-drop measurements (±0.25%) at stages 3-7 and the micro-orifice collector were made with capacitive diaphragm transducers and with a special lid to the NGI that allowed pneumatic connection to the interstage passageways before and after each impactor stage. Results: The measured pressure drop values matched, to fractional percentage precision, those predicted by the incompressible flow theory through the nozzles and the compressible flow theory through the CFV. Conclusions: Practical equipment has been assembled that measures, to fractional percentage precision, the pressure drop through impactor nozzles at precisely managed flow conditions. The experimental results support the relevant flow principles. The results, thereby, support the use of this method for quantifying whether used impactor stages are suitable for continued use in the testing of registered inhalable drug products, in accord with pharmacopeial standards.

Reconstituted dry powder formulations of ZnO-adjuvanted ovalbumin induce equivalent antigen specific antibodies but lower T cell responses than ovalbumin adjuvanted with Alhydrogel® or cationic adjuvant formulation 01 (CAF®01)

Most licensed human vaccines are based on liquid dosage forms but have poor storage stability and require continuous and expensive cold-chain storage. In contrast, the use of solid vaccine dosage forms produced by for example spray drying, extends shelf life and eliminates the need for a cold chain. Zinc oxide (ZnO)-based nanoparticles display immunomodulatory properties, but their adjuvant effect as a dry powder formulation is unknown. Here, we show that reconstituted dry powder formulations of ZnO particles containing the model antigen ovalbumin (OVA) induce antigen-specific CD8+ T-cell and humoral responses. By systematically varying the ratio between ZnO and mannitol during spray drying, we manufactured dry powder formulations of OVA-containing ZnO particles that displayed: (i) a spherical or wrinkled surface morphology, (ii) an aerodynamic diameter and particle size distribution optimal for deep lung deposition, and (iii) aerosolization properties suitable for lung delivery. Reconstituted dry powder formulations of ZnO particles were well-tolerated by Calu-3 lung epithelial cells. Furthermore, almost equivalent OVA-specific serum antibody responses were stimulated by reconstituted ZnO particles, OVA adjuvanted with Alhydrogel®, and OVA adjuvanted with the cationic adjuvant formulation 01 (CAF®01). However, reconstituted dry powder ZnO particles and OVA adjuvanted with Alhydrogel® induced significantly lower OVA-specific CD8+CD44+ T-cell responses in the spleen than OVA adjuvanted with CAF®01. Similarly, reconstituted dry powder ZnO particles activated significantly lower percentages of follicular helper T cells and germinal center B cells in the draining lymph nodes than OVA adjuvanted with CAF®01. Overall, our results show that reconstituted dry powder formulations of ZnO nanoparticles can induce antigen-specific antibodies and can be used in vaccines to enhance antigen-specific humoral immune responses against subunit protein antigens.

Preparing dry powder inhalation formulation of salbutamol sulfate using an ultrasonic atomizer device

Inhaled particles must possess certain morphological characteristics to ensure effective drug delivery to the targeted site in the lungs. A modified version of ultrasonic spray pyrolysis was employed to prepare salbutamol sulfate in the form of dry powder. A solution of salbutamol sulfate was atomized using ultrasonic nebulization, and the droplets were transformed into solid drug particles through exposure to high temperature airflow. The engineered salbutamol sulfate samples underwent physical characterization, including particle size, morphology, thermal behavior, and crystallinity analysis. The aerodynamic particle size distribution (APSD) and in vitro deposition of the dry powder inhalation formulation were assessed using the Next Generation Impactor (NGI). The salbutamol sulfate dry powder prepared by the ultrasonic atomizer exhibited an aerodynamic diameter ranging from 1 to 5 μm, as supported by the SEM images. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) results showed a significant drop in the crystallinity of the engineered particles. Aerosolization performance studies demonstrated a fine particle fraction (FPF) value (below 5 μm) of 25% for the engineered salbutamol sulfate produced using the ultrasonic atomizer technique, which is acceptable for inhalation purposes. Based on the observed results, this newly introduced method appears to be suitable for producing dry powder formulations of different drugs, with a minimized need for the use of surfactants or stabilizers in the formulation.

Modeled small airways lung deposition of two fixed-dose triple therapy combinations assessed with in silico functional respiratory imaging

BackgroundSmall airways disease plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and is a major cause of obstruction; therefore, it is a critical pharmacotherapy target. This study evaluated lung deposition of two inhaled corticosteroid (ICS)/long-acting β2-agonist/long-acting muscarinic antagonist single-inhaler triple therapies using in silico functional respiratory imaging (FRI). Deposition was assessed using real-world inhalation profiles simulating everyday use where optimal inhalation may be compromised.MethodsThree-dimensional airway models were produced from 20 patients with moderate-to-very severe COPD. Total, central, and regional small airways deposition as a percentage of delivered dose of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) 160/7.2/5 µg per actuation and fluticasone furoate/umeclidinium/vilanterol (FF/UM/VI) 100/62.5/25 µg were evaluated using in silico FRI based on in vitro aerodynamic particle size distributions of each device. Simulations were performed using multiple inhalation profiles of varying durations and flow rates representing patterns suited for a pressurized metered-dose inhaler or dry-powder inhaler (four for BGF, two for FF/UM/VI, with one common profile). For the common profile, deposition for BGF versus FF/UM/VI was compared post-hoc using paired t-tests.ResultsAcross inhalation profiles, mean total lung deposition was consistently higher with BGF (47.0–54.1%) versus FF/UM/VI (20.8–22.7%) and for each treatment component, with greater deposition for BGF also seen in the central large airways. Mean regional small airways deposition was also greater across inhalation profiles with BGF (16.9–23.6%) versus FF/UM/VI (6.8–8.7%) and for each treatment component. For the common profile, total, central, and regional small airways deposition were significantly greater for BGF versus FF/UM/VI (nominal p < 0.001), overall and for treatment components; notably, regional small airways deposition of the ICS components was approximately five-fold greater with budesonide versus fluticasone furoate (16.1% vs. 3.3%).ConclusionsBGF was associated with greater total, central, and small airways deposition for all components versus FF/UM/VI. Importantly, using an identical inhalation profile, there was an approximately five-fold difference in small airways deposition for the ICS components, with only a small percentage of the ICS from FF/UM/VI reaching the small airways. Further research is needed to understand if the enhanced delivery of BGF translates to clinical benefits.Graphical

A Technical Feasibility of Aqueous Aerosol Generation Based on the Flashing Jet: Effects of Overheat Degree, Jetting Rate, Jetting Volume, and Liquid Type

AbstractA previously established flashing jet inhaler prototype (FJ prototype) can produce an aqueous aerosol but cannot steadily provide inhalable aerosol (2–5 μm). This study aims to optimize the atomization performance of the FJ prototype and generate inhalable aqueous aerosols. The effects of overheat degree, jetting rate, jetting volume, and liquid type on atomization performance were assessed by determining output aerosol's mass median aerodynamic diameter (MMAD) and aerodynamic particle size distribution. Drug distribution of active ingredients in different liquid types was also measured. A Pari nebulizer was used as a reference device. Our data suggested that MMAD is negatively correlated with the overheat degree and jetting rate, but has no significant relationship with the jetting volume. The effect of jetting rate is weaker than that of the overheat degree. When normal saline was used as the atomization liquid, output aerosol's MMAD at the FJ prototype and Pari nebulizer were 1.98 ± 0.18 and 2.50 ± 0.81 μm, respectively. The addition of a surfactant significantly decreases MMAD both in solution and in suspension, but the suspended particles had no effect on the residual level and atomization performance of the FJ prototype. When ventolin was used as the atomization liquid, the MMAD of the FJ prototype and Pari nebulizer was 2.1 ± 0.2 and 1.7 ± 0.2 μm, respectively, while the fine particle dosage (FPD) in percent of the nominal dose (%ND) was 50.4 ± 3.1 and 53.1 ± 7.2%, respectively. When pulmicort respules was used as the atomization liquid, the MMAD of the FJ prototype and Pari nebulizer was 2.5 ± 0.5 and 4.6 ± 0.2 μm respectively, while the FPD (%ND) was 30.1 ± 5.6 and 58.6 ± 5.1%, respectively. The FJ prototype not only delivers inhalable aqueous aerosol but also has a potential advantage in the atomization of suspension or poorly soluble drugs.

A new method for investigating bioequivalence of inhaled formulations: A pilot study on salbutamol.

Purpose: An efficient, cost-effective and non-invasive test is required to overcome the challenges faced in the process of bioequivalence (BE) studies of various orally inhaled drug formulations. Two different types of pressurized meter dose inhalers (MDI-1 and MDI-2) were used in this study to test the practical applicability of a previously proposed hypothesis on the BE of inhaled salbutamol formulations. Methods: Salbutamol concentration profiles of the exhaled breath condensate (EBC) samples collected from volunteers receiving two inhaled formulations were compared employing BE criteria. In addition, the aerodynamic particle size distribution of the inhalers was determined by employing next generation impactor. Salbutamol concentrations in the samples were determined using liquid and gas chromatographic methods. Results: The MDI-1 inhaler induced slightly higher EBC concentrations of salbutamol when compared with MDI-2. The geometric MDI-2/MDI-1 mean ratios (confidence intervals) were 0.937 (0.721-1.22) for maximum concentration and 0.841 (0.592-1.20) for area under the EBC-time profile, indicating a lack of BE between the two formulations. In agreement with the in vivo data, the in vitro data indicated that the fine particle dose (FPD) of MDI-1 was slightly higher than that for the MDI-2 formulation. However, the FPD differences between the two formulations were not statistically significant. Conclusion: EBC data of the present work may be considered as a reliable source for assessment of the BE studies of orally inhaled drug formulations. However, more detailed investigations employing larger sample sizes and more formulations are required to provide more evidence for the proposed method of BE assay.

Inhalable Microparticles Embedding Biocompatible Magnetic Iron-Doped Hydroxyapatite Nanoparticles.

Recently, there has been increasing interest in developing biocompatible inhalable nanoparticle formulations, as they have enormous potential for treating and diagnosing lung disease. In this respect, here, we have studied superparamagnetic iron-doped calcium phosphate (in the form of hydroxyapatite) nanoparticles (FeCaP NPs) which were previously proved to be excellent materials for magnetic resonance imaging, drug delivery and hyperthermia-related applications. We have established that FeCaP NPs are not cytotoxic towards human lung alveolar epithelial type 1 (AT1) cells even at high doses, thus proving their safety for inhalation administration. Then, D-mannitol spray-dried microparticles embedding FeCaP NPs have been formulated, obtaining respirable dry powders. These microparticles were designed to achieve the best aerodynamic particle size distribution which is a critical condition for successful inhalation and deposition. The nanoparticle-in-microparticle approach resulted in the protection of FeCaP NPs, allowing their release upon microparticle dissolution, with dimensions and surface charge close to the original values. This work demonstrates the use of spray drying to provide an inhalable dry powder platform for the lung delivery of safe FeCaP NPs for magnetically driven applications.

Pressure Drop Characteristics of the Reduced NGI Configuration with Several Common Glass Fiber Filters.

Background: Measurement of aerodynamic particle size distribution, a clinically relevant in vitro attribute of inhalable drug products, involves multistage cascade impactors and is tedious and expensive. A leading candidate for a quicker method is the reduced NGI™ (rNGI). This method involves placing glass fiber filters on top of the nozzles of a chosen NGI stage, selected often to collect all particles with an aerodynamic diameter smaller than approximately five microns. These filters contribute additional flow resistance that can alter the flow rate start-up curve, potentially affecting the size distribution and mass of the drug product dispensed by passive dry powder inhalers (DPIs). The magnitude of these additional flow resistance measurements is currently unreported in the literature. Materials and Methods: We placed glass fiber filters on top of the stage 3 nozzles of an NGI, along with the necessary support screen and hold-down ring. We measured the pressure drop across NGI stage 3 with the assistance of a delta P lid and a high-precision pressure transducer. With each filter material type and multiple individual filters, we gathered eight replicates at flow rates of 30, 45, and 60 L/min. Results: The filters typically doubled the total pressure drop through the NGI. For example, at a flow rate of 60 L/min, the Whatman 934-AH filters introduced a pressure drop of about 9800 Pa at stage 3, reducing the absolute pressure exiting the NGI to about 23 kPa below ambient, compared with a typical value of 10 kPa for the NGI alone at this flow rate. Conclusions: The pressure drop across typical filters is approximately equal to that through the NGI alone and therefore will affect the flow start-up rate intrinsic to compendial testing of passive DPIs. This change in start-up rate could cause differences between results of the rNGI configuration and those of the full NGI and will increase the required vacuum pump capacity.

Study of glycopyrrolate dry powder behavior in new single dose inhalers under generic product development

With increasing environmental pollution and tendency to smoking, the number of patients suffering from chronic obstructive pulmonary disease is increasing and a demand for generic products for the treatment of chronic obstructive pulmonary disease (COPD) is growing. The long process of generic formulation development can be accelerated by using an inhaler with suitable fluid dynamics features. This paper presents a study of a newly patented single-dose Memmatec Mora® inhaler in two versions: with grid openings 1.0 (A) and 0.5 mm (B), using Seebri Breezhaler® as a reference product. The studies were conducted with inhalation powders containing 44μg glycopyrronium bromide placed in a capsule. The manuscript presents studies during the selection of a generic inhaler within the course of inhalation powder development by a pharmaceutical company. The fluid dynamics features of the inhalers and the dose delivered were determined. The aerodynamic particle size distribution (APSD) and the inhalable dose were tested using a cascade impactor. The delivery dose for the Breezhaler, Mora A and Mora B inhalers for a volumetric flow of 100 L×min-1 was 38.5, 40.5 40.3μg, respectively. Fine particle fraction of the inhalers tested was 22.3, 24.6 25.5μg, respectively. Results of the study indicate that increase of the glycopyrronium bromide inhalation dose can be achieved not only by changes in the manufacturing technology of inhalation powder, hard capsule technology or addition of best quality raw materials, but also by the use of a properly selected inhaler with specific fluid dynamics features.

Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

In vitro evaluation of the potential use of snake-derived peptides in the treatment of respiratory infections using inhalation therapy: A proof of concept study

Inhalation therapy using nebulisers is an attractive non-invasive route for drug delivery, particularly for the treatment of lung infections with anti-inflammatory and anti-microbial compounds. This study evaluated the suitability of three snake-derived peptides (termed Sn1b, SnE1 and SnE1-F), which we have recently shown have potent anti-inflammatory and bacteriostatic activities, for nebulisation using a vibrating mesh nebuliser (VMN). The effect of nebulisation on peptide concentration, stability and function were assessed, prior to progression to aerodynamic particle size distribution, and in vitro drug delivery in simulated adult spontaneous breathing and mechanical ventilated patient models. When nebulised, all three peptides exhibited similar functions to their non-nebulised counterparts and were found to be respirable during simulated mechanical ventilation. Based on the assessment of the droplet distributions of nebulised peptides using a Next Generation Impactor (NGI) demonstrated that if administered in vivo each peptide would likely be delivered to the lower airways. These data suggest that nebulisation using a VMN is a viable means of anti-microbial / anti-inflammatory peptide delivery targeting microbial respiratory infections, and possibly even systemic infections.

Performance Testing for Dry Powder Inhaler Products: Towards Clinical Relevance

It is well established that the critical performance metrics for aerosol products are aerodynamic particle size distribution (APSD) and delivered dose uniformity (DDU). In broad terms, these performance characteristics dictate the efficiency and reproducibility with which an aerosol is administered clinically. However, these properties alone do not support in-vitro, in-vivo correlations. There have been numerous publications attempting to more directly link product performance testing to physiological relevance or further to draw direct correlations of relevance to bioequivalence testing for the development of generic products. While these novel methods have been employed in product development activity, their suitability for compendial testing has yet to be established. This paper explores the potential to establish biologically relevant compendial standards for dry powder inhaler products while maintaining accuracy and reproducibility of data collected to support the quality and performance of the product.

A New Validated Method for Simultaneous Determination of Aerodynamic Particle Size Distribution of Drug Particles of Mometasone Furoate and Formoterol Fumarate Dihydrate in 200 mcg/5 mcg Inhalation Aerosol

Simultaneous determination of aerodynamic particle size distribution (APSD) of drug particles of mometasone furoate and formoterol fumarate dihydrate – 200 mcg/5 mcg inhalation aerosol (MDI) has been developed and reported in this work. The method was developed in consistent with USP &lt;601&gt; inhalation and nasal drug products e.g. aerosols, sprays and powders. The next generation impactor (NGI) was used and operated at 30 ± 5% L/min. The proposed method was demonstrated for sensitivity, minimum number of actuations, diluent volume optimization, mass balance and precision. The proposed method was found to be robust, accurate, linear and precise.

Spray-Dried Inhalable Powder Formulations of Gentamicin Designed for Pneumonic Plague Therapy in a Mouse Model.

Infection with Yersinia pestis (Y. pestis) may cause pneumonic plague, which is inevitably fatal without treatment. Gentamicin (GM), an aminoglycoside antibiotic, is a drug commonly used in the treatment of plague. However, it requires repeated intramuscular or intravenous administration. Pulmonary drug delivery is noninvasive, with the advantages of local targeting and reduced risk of systemic toxicity. In this study, GM powders were prepared using spray-drying technology. The powders displayed good physical and chemical properties and met the requirements for human pulmonary inhalation. The formulation of the powders was optimized using a 32 full factorial design. A formulation of 15% (w/w) of L-leucine was prepared, and the spray-drying process parameters using an inlet temperature of 120°C and a 15% pump rate were determined to produce the best powder. In addition, the optimized GM spray-dried powders were characterized in terms of morphology, crystallinity, powder fluidity, and aerodynamic particle size distribution analysis. In a mouse model of pneumonic plague, we compared the therapeutic effects among three administration routes, including subcutaneous injection, liquid atomization, and dry powder atomization. In conclusion, our data suggest that inhalation therapy with GM spray-dried powders is an effective treatment for pneumonic plague.

The pulmonary pharmacokinetics and anti-inflammatory effects after intratracheal and intravenous administration of Chuankezhi injection

BackgroundChuankezhi injection (CKZ) is a traditional Chinese medicine for the treatment of respiratory diseases and has been often used off-label as a nebulization therapy. However, little is known about the aerosolization performance and pulmonary fate of the inhaled CKZ. This study aimed to evaluate the aerodynamic characteristics of nebulizer generated aerosols and to compare the properties of pharmacokinetics, lung distribution and anti-inflammation effects of CKZ after intratracheal and intravenous administration. MethodsThe nebulization performance was evaluated in vitro based on the aerodynamic particle size distribution and aerosol output. The concentrations of epimedins A, B, C and icariin, the main active ingredients of CKZ, in plasma, bronchoalveolar lavage fluids (BALF) and lung tissues were measured by LC-MS/MS analysis. The pulmonary anti-inflammatory efficacy were tested using LPS-induced pulmonary inflammation mice model as indicated by the total cells counts, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in BALF. ResultsThe aerosols of CKZ generated by a commercial nebulizer showed excellent aerodynamic properties and delivery output. Following intratracheal instillation of CKZ, epidemins A, B and C, and icariin, were absorbed into the bloodstream with the mean absorption time varying from 101.8 min to 271.8 min, and their absolute bioavailabilities ranging from 26.4 % to 104 %. The instillation of CKZ increased the lung to plasma concentration ratios by 25.5–718 folds compared to intravenous administration, leading to improved and prolonged local anti-inflammatory effects. ConclusionNebulization therapy of CKZ could be a promising alternative to the injectable counterpart.

Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

PurposeTuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation.MethodsExcipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product.ResultsThe mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 μm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties.ConclusionThe spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11095-022-03393-w.