BACKGROUND:In spite of efforts to eradicate tuberculosis (TB), TB remains the deadliest infectious disease in the world; there is an urgent need for a thermostable, noninvasive TB vaccine suitable for distribution in the developing world. Spray-dried versions of a clinical-stage TB vaccine, ID93 + GLA-SE, are currently undergoing testing in baboons in both pulmonary and intranasal versions. We developed manufacturing processes and delivery systems to achieve delivery of each version to its intended site of action while avoiding off-target deposition. METHODS:Pulmonary ID93 + GLA-SE was manufactured in a custom research-scale spray dryer. Delivery efficiency using a custom intratracheal insufflator was measured gravimetrically, and aerodynamic performance was evaluated via cascade impaction. Intranasal ID93 + GLA-SE was manufactured in a pilot-scale spray dryer. In vitro regional deposition in the Alberta Idealized Nasal Inlet, measured by LC-MS/MS, was used as a surrogate for aerodynamic performance; total deposition was used to calculate a total delivered dose. For both powders, ID93 antigen content was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and GLA-SE adjuvant content was assessed via HPLC. RESULTS:No substantial processing losses of the antigen or adjuvant were observed after spray drying in either formulation. For the pulmonary powder, the emitted dose exiting the endotracheal tube across three tube sizes ranged from 15.9% to 21.4% of the nominal dose; for the 8 mm tube size, the emitted dose mass median aerodynamic diameter was 5.3 µm, which was deemed suitable for pulmonary administration. For the intranasal powder, the delivered dose was 88% ± 2% of nominal, and in vitro deposition in the posterior nasal cavity was 63% ± 10% of the emitted dose, with minimal anticipated lung deposition. CONCLUSIONS:Pulmonary and intranasal spray-dried ID93 + GLA-SE powders were successfully manufactured. The proposed dosing systems are expected to achieve exclusive pulmonary or intranasal delivery to nonhuman primates while requiring only a moderate amount of powder.

The size characterization of aerosols emitted from pressurized metered dose inhalers (pMDIs) is complicated by propellant evaporation and potential hygroscopic size changes in the presence of ambient humidity. This study used laser diffraction (LD) for in situ measurements of pMDI particle size distributions downstream of the Alberta Idealized Throat (AIT) and Alberta Idealized Child Throat (AICT) in low and high ambient humidity. In low humidity, agreement between LD-derived measurements and cascade impactor size distributions varied across inhalers. Extrathoracic deposition was higher in the AICT than the AIT. In high humidity, LD-derived particle sizes downstream of the model throats increased for one solution inhaler, but decreased for the remaining (suspension) inhalers. Experiments performed with a blank pMDI containing only propellant recorded non-zero size distributions downstream of the extrathoracic region in high humidity, suggesting that drug-free droplets may contribute to size distributions measured by LD for suspension pMDIs. Further experiments conducted using an extension tube downstream of the extrathoracic models to prolong exposure to high humidity demonstrated that hygroscopic size changes progressed slowly downstream of the extrathoracic airways. Differing drug deposition and particle sizes measured between the AIT and AICT underscore the importance of using age-appropriate extrathoracic models during size characterization of particles entering the lungs of adults and children. The use of LD for the measurement of pMDI aerosols should be considered on a product-specific basis. Size measurements in high humidity require careful interpretation, particularly for suspension pMDIs, as LD estimates could be impacted by the measurement of API-free droplets.Copyright (c) 2026 American Association for Aerosol Research

Laboratory-scale spray drying can be a useful tool in developing new dry powder formulations for the delivery of biologics such as therapeutic proteins or vaccines. Low-temperature drying is often used in these processes to prevent the exposure of biologics to harsh conditions that could potentially lead to degradation or instability of the final product. However, low-temperature drying on small-scale equipment can result in very low production rates that may not be practical for generating sufficient material for studies requiring larger sample quantities, such as key preclinical or toxicology studies. This study demonstrates a scale-up effort for a spray dried adjuvanted protein tuberculosis (TB) vaccine candidate using a custom lab-scale spray dryer. To achieve higher throughput without compromising the stability of the powder and biologic material, a process model for the spray dryer was used to determine optimal processing parameters and establish general vaccine powder manufacturing guidelines, such as minimizing exposure to high temperatures and relative humidity during drying. Maximizing dryer throughput and increasing overall feed concentration resulted in a tenfold increase in production rate using lab-scale equipment, such that 97.6 g of powder (the equivalent of about 5,000 human doses) could be produced using a lab-scale spray dryer in a single 6-hour spray drying run.

A nasal dry powder adjuvanted subunit COVID vaccine candidate was manufactured via spray drying and evaluated for physicochemical stability and aerosol performance over the course of 10 months under accelerated conditions. A nanoliposomal adjuvant system containing synthetic TLR 4 agonist GLA and synthetic TLR 7/8 agonist 3 M-052 and a trimeric SARS-CoV-2 spike protein antigen were encapsulated using trehalose and varying amounts of trileucine as excipients. 1 % and 3 % trileucine batches as well as a trehalose-only control batch were spray dried to achieve varying levels of particle surface modification and to study the overall effects on stability and aerosol performance. All batches achieved good yields and low processing losses on drying. Samples were held at 25 °C and 40 °C and monitored for physical and chemical stability. All three batches showed excellent performance over the course of the study. Overall morphology; solid phase; moisture content; contents of GLA and 3 M-052; and aerosol performance were largely maintained after exposure to high temperatures for 10 months. Spike protein antigen remained present in all samples after exposure, and liposomal size distributions remained within acceptable ranges for all but one of the samples. Overall, this vaccine candidate showed performance suitable for distribution independent of the cold chain and would be able to withstand high-temperature conditions encountered during last-mile delivery.

The recent COVID-19 pandemic, as well as the threat of a global pandemic caused by H5N1 avian influenza virus, has highlighted the need for the development of thermostable vaccines that can be manufactured and distributed rapidly to combat the next global pandemic. To address this need, we previously developed a replicon vaccine platform that utilizes a nanostructured lipid carrier (NLC) to protect and efficiently deliver antigen-expressing replicon molecules in vivo. The replicon-NLC vaccine platform uses readily sourced components and can be rapidly manufactured at scale with the potential for stockpiling, thus enhancing pandemic preparedness. Spray drying is a promising method of vaccine desiccation with reduced costs and increased scale-up capabilities compared to lyophilization. As proof of concept, we demonstrate for the first time the successful spray drying of a replicon-NLC vaccine complex designed to protect against H5N1 avian influenza A virus to enhance its long-term thermostability while maintaining vaccine immunogenicity in an in vivo mouse model. Several glass-forming disaccharide excipients were screened for formulation and process compatibility under low-temperature spray drying conditions, and it was determined that a suitable shell-forming excipient, L-leucine, was necessary to prevent excessive accumulation of replicon-NLC vaccine complexes on the dry powder surface and a subsequent loss in process yield. The spray dried replicon-NLC vaccine powders were chemically stable for 1 month of storage at 40 °C. Immunogenicity of the spray dried drug product was also well maintained for at least 3 months of storage at 4 °C when administered intramuscularly into C57BL/6 mice as a reconstituted liquid. Finally, we demonstrate the ability to precisely control the aerodynamic particle size of the spray dried vaccine product to generate dry powders that are theoretically suitable for nasal or pulmonary delivery without reconstitution. This work establishes the feasibility of spray drying a thermostable replicon-NLC vaccine for rapid pandemic response.

Background: Dry powders offer the potential to increase stability and reduce cold-chain requirements associated with the distribution of vaccines and other thermally sensitive products. The Alberta Idealized Nasal Inlet (AINI) is a representative geometry for in vitro characterization of nasal products that may prove useful in examining intranasal delivery of powders. Methods: Spray-dried trehalose powders were loaded at 10, 20, and 40 mg doses into active single-dose devices. Primary particle sizes (∼Dv50 = 10 µm for powder A and 25 µm for powder B), and sizes dispersed by devices, were evaluated using laser diffraction. The interior of the AINI was coated with a glycerol-surfactant mixture to mitigate particle bounce, and flow rates of 7.5 or 15 L/min were drawn through the AINI. Deposition of trehalose powder was determined in the four regions of the AINI (vestibule, turbinates, olfactory, and nasopharynx), a downstream preseparator, and an absolute filter (representing in vitro lung deposition) using liquid chromatography coupled with mass spectrometry. Results: Coating the AINI was effective in mitigating particle bounce for both trehalose powders. No difference in regional nasal deposition was observed when testing at a flow rate of 7.5 versus 15 L/min. A high fraction of both powders penetrated past the vestibule and deposited in the turbinates and nasopharynx for all loaded doses. For powder A, a non-negligible fraction of the recovered dose (up to 7%) is deposited on the filter, representing potential lung exposure. Conversely, a negligible fraction of the total recovered dose was deposited on the filter for powder B. Conclusion: Powders with a larger primary particle size showed reduced penetration through the nasal airways while maintaining high turbinate deposition. Optimized spray-dried powders offer the potential to target delivery to the peripheral nasal airways based on powder particle size while reducing lung exposure.

Switching to low-global warming potential (GWP) propellants for pressurized metered dose inhalers (pMDIs) is crucial in current inhalation product development, as it is crucial to safeguard patient access. This paper provides both theoretical and experimental evidence to advance the understanding of the relative performance of pMDIs using traditional HFA propellants (HFA-134a, HFA-227ea) versus new low-GWP propellant (HFO-1234ze, HFO-1234yf, HFC-152a) across three stages of pMDI actuation: discharge of propellant from the spray orifice, atomization of the bulk liquid into droplets, and interaction with the surrounding environment. The acoustic profiles, which represent the propellant discharge from the spray orifice, revealed that the plume duration and audio amplitude were mostly influenced by the diameter of the orifice and to a lesser extent by propellant type. The initial propellant droplet size produced after atomization of the discharged bulk liquid was evaluated by measuring content equivalent diameters at different ethanol concentrations and spray orifice diameters. Through a 0.32 mm spray orifice, propellant-only pMDIs produced droplets in the 9.0-13.5 mu m range, with HFC-152a yielding the largest droplets and HFO-1234yf the smallest, while all exhibited comparable dependence on ethanol concentration and spray orifice size. Modeling of moisture condensation on propellant droplets indicated that the amount of condensed water and droplet lifetime both depend strongly on ambient humidity and ethanol concentration and only weakly on the propellant type. Three suspension formulations in HFA-134a, HFO-1234ze, or HFC-152a, were tested under varying relative humidities to evaluate the impact of ambient humidity on the in vitro aerosol performance of suspension pMDIs.Copyright (c) 2024 American Association for Aerosol Research

Pressurized metered dose inhalers (pMDIs) require optimized formulations to provide stable, consistent lung delivery. This study investigates the feasibility of novel rugose lipid particles (RLPs) as potential drug carriers in pMDI formulations. The physical stability of RLPs was assessed in three different propellants: the established HFA-134a and HFA-227ea and the new low global-warming-potential (GWP) propellant HFO-1234ze. A feedstock containing DSPC and calcium chloride was prepared without pore forming agent to spray dry two RLP batches at inlet temperatures of 55 °C (RLP55) and 75 °C (RLP75). RLPs performance in pMDI formulations was compared to two reference samples that exhibit significantly different performance when suspended in propellants: well-established engineered porous particles and particles containing 80

The rapid growth and spread of multi-drug resistance (MDR) in Tuberculosis (TB) poses a severe threat to global public health. Existing antibiotics are increasingly ineffective against MDR-TB, contributing to millions of deaths each year. Recently, novel antituberculosis nanomaterials have been developed as innovative tools to combat MDR-TB. This review introduces several nanotechnology-based strategies aimed at addressing drug resistance in TB infections. Specifically, we highlight key elements in two critical areas: (1) the construction of nanoparticles with inherent mechanisms to overcome drug resistance, for instance, the newly discovered antimicrobial peptides and metal ions can achieve 60

Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be approved for inhalation soon and has been studied exhaustively. However, during stability, small fibers protruding from the particles of leucine-containing powders have occasionally been observed. To clarify the origin of these fibers and assess their potential influence on the performance of the powders, three different classes of spray-dried leucine-containing formulation systems were studied over an 8-month accelerated stability program. These systems consisted of a large molecule biologic (bevacizumab) in conjunction with a glass former (trehalose), an amorphous small-molecular mass active (moxidectin), and a crystallizing active (mannitol). It was determined that the appearance of the fibers was due to the presence of small quantities of leucine in higher energy states, either because these were amorphous or present as a less stable crystalline polymorph. It was further shown that the growth of these leucine fibers caused no significant physicochemical instability in the powders. Nor, more importantly, did it decrease their aerosol performance in a dry powder inhaler or reduce the concentration of their active pharmaceutical ingredients.

Background: Decontamination and reuse of respirators have been proposed to mitigate the shortage of respirators during pandemics. The U.S. National Institute for Occupational Safety and Health (NIOSH)'s respirator filtration efficiency (FE) test has been used to confirm that decontamination procedures maintain minimum FE above 95% for N95s and similar respirators. However, it was hypothesized that the limited range of test particle sizes may not include the most penetrating particle size (MPPS) for all respirators, especially after decontamination by moist heat incubation (MHI). Materials and Methods: A custom-designed apparatus was used to measure size-specific FE for respirators across particle size bins between aerodynamic diameter of 0.07 and 1.97 μm using an electrical low-pressure impactor. FEs were measured for two N95 respirator models before and after 10 cycles of MHI. In addition, pressure drop through the respirator materials and scanning electron microscope (SEM) images of respirator layers were obtained before and after MHI. Results: For Kimtech™ brand N95 respirators, FE was not reduced at any size after MHI. For Safe Life brand N95s, FE was below 95% before MHI and decreased significantly after MHI. The MPPS for this respirator was outside the range defined in NIOSH test protocol, and increased after MHI. There was no appreciable change to the pressure drop through the two respirator models after MHI, nor was any deterioration in fiber integrity visible in SEM images. Conclusions: Based on the results of the present study and other studies in the literature, MHI can be used to decontaminate respirators without significant decrease in FE. However, potential effects of MHI on FE need to be assessed for each respirator model. The ability to evaluate size-specific FE across a wide range of particle sizes is important in identifying the MPPS and associated FE of respirators before and after MHI.

Spray drying is gaining traction in the pharmaceutical industry as one of the processing methods of choice for the manufacture of solid dosage forms intended for pulmonary, oral, and parenteral delivery. This process is particularly advantageous because of its ability to produce engineered particles with improved efficacy and stability by combining active pharmaceutical ingredients or biologics with appropriate excipients. Moreover, due to its high throughput, continuous operation, and ability to produce thermostable solid powders, spray drying can be a manufacturing method of choice in the production of drugs and other formulations, including vaccines, for global distribution. Formulation design based on a mechanistic understanding of the different phenomena that occur during the spray drying of powders is complicated and can therefore make the use of available particle formation models difficult for the practitioner. This review aims to provide step-by-step guidance accompanied by critical background information for the successful formulation design of spray-dried microparticles. These include discussion of the tools needed to estimate the surface concentration of each solute during droplet drying, their times and modes of solidification, and the amount of glass stabilizers and shell formers required to produce stable and dispersible powders.

PURPOSE:To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids.METHODS:A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated.RESULTS:Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures.CONCLUSIONS:Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.

A paper-based microfluidic detection device for the detection of ethanol is demonstrated in this work. The method is based on a fluorophore consisting of short-chain conjugated molecular unit susceptible to the protonation of its terminal pyridine groups, along with a carboxyl-functionalized sidechain that acts as a binder and renders it water-soluble. The resulting fluorescent paper device yields large fluorescence changes when exposed to reactions that yield H2O2 in aqueous solutions. Using an enzyme-catalyzed rection that produces H2O2 from ethanol, we developed a two-zone, cut-out paper device containing a reaction zone in which the ethanol-containing analyte is placed, and an adjacent sensor zone where we observe a fluorescence color shift proportional to the ethanol concentration. The limit of detection of the fluidic ethanol biosensor was 0.05 v/v% and the dynamic range was 0.05–2 v/v%. This method was employed to detect the alcohol concentration of consumer vodkas using only a paper sensor and a smartphone camera.