Dry Powder Formulation Research Articles

Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses. Particles obtained spray drying dichloromethane-methanol mixtures yielded an aerodynamic diameter of about or smaller than 5 µm and were found to reach an emitted fine particle fraction (FPFEF) of at least 60 %. Pulmonary administration to rats using a dry powder insufflator revealed a nearly immediate therapeutic onset confirmed by the anticoagulant effects after 5 min in the plasma followed by a plateau over the next 4 h. Such rivaroxaban particles were further formulated in binary blends using different lactose carriers (Inhalac® 70/251/400). These interactive blends resulted in high emitted fractions of at least 87 %, and furthermore, the highest fine particle fraction − total dose (FPFTD) (60 %) of all tested formulations was achieved by using Inhalac® 400 as a carrier. The data strongly suggest a significant therapeutic potential of a rivaroxaban dry powder formulation, combining fast onset and a plateau of plasma concentrations turning it into a potential first aid therapeutic.

Impact of protein aggregation on the immunogenicity of a human monoclonal antibody following pulmonary administration in mice

Spray drying is a widely employed method for generating dry powder formulations for inhalation. Yet, it presents substantial challenges when applied to therapeutic proteins due to stability issues. The formation of protein aggregates during the atomization and the heating steps can diminish protein activity and raise immunogenicity concerns. Here, we assessed the impact of varying levels of protein aggregates generated during spray-drying on the fate and the immunogenicity of the human monoclonal antibody NIP228 following intratracheal administration in mice. Aggregate-free rhodamine labelled NIP228 was spray-dried with or without 1% polysorbate 80 surfactant, resulting in the generation of powder formulations with associated low and high protein aggregate levels, respectively. Confocal imaging highlighted the presence of aggregates in the lungs for both powders but not for the solution, while flow cytometry analysis designated alveolar macrophages as the main immune cells taking up rhod-NIP228 in the lungs with very little involvement of dendritic cells and interstitial macrophages following a single dose administration. Notably, repeated intratracheal administration of the three formulations in mice did not impact the magnitude of the anti-drug antibody response in sera or broncho-alveolar lavages. The pulmonary route appeared to evoke a more robust immune response when compared to subcutaneous administration. Overall, the level of NIP228 aggregation in this study did not appear to be the primary driver of NIP228 immunogenicity following delivery to the lungs in mice, shedding new light on the interplay between protein aggregation and immunogenicity in the context of the pulmonary delivery of therapeutic proteins.

Development of a dry powder formulation for pulmonary delivery of azithromycin-loaded nanoparticles.

The COVID-19 pandemic has raised concern regarding respiratory system diseases and oral inhalation stands out as an attractive non-invasive route of administration for pulmonary diseases such as chronic bronchitis, cystic fibrosis, COVID-19 and community-acquired pneumonia. In this context, we encapsulated azithromycin in polycaprolactone nanoparticles functionalized with phospholipids rich in dipalmitoylphosphatidylcholine and further produced a fine powder formulation by spray drying with monohydrated lactose. Nanoparticles obtained by the emulsion/solvent diffusion-evaporation technique exhibited a mean hydrodynamic diameter around 195-228nm with a narrow monomodal size distribution (PdI < 0.2). Nanoparticle dispersions were spray-dried at different inlet temperatures, atomizing air-flow, aspirator air flow, and feed rate, using lactose as a drying aid, resulting in a maximal process yield of 63% and an encapsulation efficiency of 83%. Excipients and the dry powder formulations were characterized in terms of morphology, chemical structure, thermal analyses and particle size by SEM, FTIR, DSC/TGA and laser light diffraction. The results indicated spherical particles with 90% at 4.06µm or below, an adequate size for pulmonary delivery. Aerosolization performance in a NGI confirmed good aerodynamic properties. Microbiological assays showed that the formulation preserves AZM antimicrobial effect against Staphylococcus aureus and Streptococcus pneumoniae strains, with halos above 18mm. In addition, no formulation-related cytotoxicity was observed against the human cell lines BEAS-2B (lung epithelial), HUVEC (endothelial) and HFF1 (fibroblasts). Overall, the approach described here allows the production of AZM-PCL nanoparticles incorporated into inhalable microparticles, enabling more efficient pulmonary therapy of lung infections.

Stabilization of microbial strains in long-lasting double emulsions as a new strategy for liquid biofertilizer formulation

The need for innovative biofertilizers has been increasing in recent years as a consequence of the loss of soil microbial biodiversity. In this context, symbiotic agriculture, which involves the application of beneficial microorganisms to the soil, is an emerging and promising reality. A key point is related to the choice of an adequate formulation strategy for the microbial systems to maintain their vitality and shelf-life. The use of a liquid formulation is an alternative to the traditional dry powder formulation, but currently a successful stabilization in a liquid biofertilizer is still not available. Therefore, the aim of this study is to stabilize different microorganisms by using a double emulsion to obtain a liquid product. The emulsion formulation and production conditions were optimized for strain encapsulation and emulsions were characterized by analysing droplet size distribution, concentration and vitality of microorganisms after the production process and stability of the product over time. A final product obtained by the mixture of the different emulsions was then obtained with the objective of delivering of a complete pool of beneficial microorganisms. The mixture was stable for 5 months at room temperature and microorganism concentration was maintained constant indicating that no antagonistic activity within the microbial consortium was present.

Development of inhaled moxifloxacin-metformin formulation as an alternative for pulmonary tuberculosis treatment

Resistant M. tuberculosis strains threaten pulmonary tuberculosis (P-TB) control since they limit drug options. Drug repositioning and new development strategies are urgently required to overcome resistance. Studies have already shown the beneficial role of the oral antidiabetic metformin as an anti-tuberculosis adjuvant drug. This work aimed to develop an inhalatory dry powder co-formulation of metformin and moxifloxacin to figure out a future option for P-TB treatment. Pre-formulation evaluations indicated the physicochemical compatibility of constituents, demonstrating powder crystallinity and acceptable drug content. Eight moxifloxacin-metformin dry powder formulations were produced by spray drying, and solid-state characterizations showed partial amorphization, ascribed to moxifloxacin. Four formulations containing L-leucine exhibited micromeritic and in vitro deposition profiles indicating pulmonary delivery suitability, like spherical and corrugated particle surface, geometric diameters < 5 μm, high emitted doses (>85 %), and mass median aerodynamic diameters between 1–5 μm. The use of a second spray dryer model further optimized the aerodynamic properties and yield of the best formulation, demonstrating the influence of the equipment used on the product obtained. Moreover, the final formulation showed high in vitro cell tolerability and characteristics in permeability studies indicative of good drug retention in the lungs.

Evaluating drug distribution in rat lung by mass spectrometry imaging after dry powder insufflation: Comparison of jet-milling, spray-drying, and thin film freezing

Uniform drug distribution within lungs is crucial for effective treatment of lung diseases when delivered via the pulmonary route. Imaging techniques such as gamma scintigraphy, positron emission tomography, and single-photon emission computed tomography, and others, have limitations, including the need for tagging, product reformulation, and in vitro validation. Mass Spectrometry Imaging (MSI) overcomes these drawbacks by visualizing drug distribution within lungs without tagging. In this study, voriconazole dry powder formulations for inhalation were prepared by three different methods: jet-milling, spray-drying, and thin film freezing (TFF). MSI was used to differentiate voriconazole distribution in rat lung after dry powder insufflation. The TFF-processed voriconazole powder, consisting of brittle, easily shearable nanoaggregates, exhibited the most homogeneous distribution in lung tissue, with the lowest airway-to-lung voriconazole deposition ratio (1.27), followed by spray-dried (1.76) and jet-milled (2.73). This enhanced distribution is attributed to the smaller particle size after disaggregation and rapid movements on the liquid surface. The results suggest that TFF dry powders for inhalation can enhance treatment efficiency and reduce toxicity for lung diseases, further supporting TFF as a promising method to formulate powder for pulmonary drug delivery.

Inhibition of influenza virus infection in mice by pulmonary administration of a spray dried antiviral drug

Increasing resistance to antiviral drugs approved for the treatment of influenza urges the development of novel compounds. Ideally, this should be complemented by a careful consideration of the administration route. 6′siallyllactosamine-functionalized β-cyclodextrin (CD-6′SLN) is a novel entry inhibitor that acts as a mimic of the primary attachment receptor of influenza, sialic acid. In this study, we aimed to develop a dry powder formulation of CD-6′SLN to assess its in vivo antiviral activity after administration via the pulmonary route. By means of spray drying the compound together with trileucine, a dispersion enhancer, we created a powder that retained the antiviral effect of the drug, remained stable under elevated temperature conditions and performed well in a dry powder inhaler. To test the efficacy of the dry powder drug against influenza infection in vivo, infected mice were treated with CD-6′SLN using an aerosol generator that allowed for the controlled administration of powder formulations to the lungs of mice. CD-6′SLN was effective in mitigating the course of the disease compared to the control groups, reflected by lower disease activity scores and by the prevention of virus-induced IL-6 production. Our data show that CD-6′SLN can be formulated as a stable dry powder that is suitable for use in a dry powder inhaler and is effective when administered via the pulmonary route to influenza-infected mice.

Novel inhalable nano-based/microparticles for enhanced sustained pulmonary delivery of remdesivir - A patient malleable treatment for coronaviruses infection: In vitro aerosolization, cytotoxicity assays and antiviral activity studies

Remdesivir (RDV) is an antiviral used in potential treatment of SARS-COV-2 infection during the COVID-19 pandemic worldwide. However, it is still limited to IV administration for hospitalized patients. Therefore, we report herein successful development of RDV-loaded nanosuspensions (NS) using polycaprolactone and pluronic® F127, for the first time. The optimized RDV-NS was further loaded into inhalable nano-based/microparticles (OLN-microparticles) via co-spray drying with hyaluronic acid and mannitol. OLN-microparticles exhibited high yield value ∼80.56 %, with satisfactory entrapment efficiency and drug loading percent ∼97.27 ± 1.84 % and 3.92 ± 0.07 %, respectively. Carr's index was equal to 22.7 ± 11.67 % indicating good flowability properties. Scanning electron microscopic analysis showed spherical-shaped particles. Transmission electron microscope demonstrated grape-shaped clumps surface porosity. OLN-microparticles exhibited excellent aerodynamic features including; emitted fraction ∼97.46 ± 1.70 %, respirable particle fraction 53.77 ± 0.2 %, effective inhalation index 72.39 ± 1.40 %, and mass median aerodynamic diameter 2.25 ± 0.01 μm. Compared to plain RDV, OLN-microparticles showed significantly enhanced sustained release (p < 0.0001) with 1.5 and 1.9 fold increase at 24 and 48 h, respectively in Gamble's solution. OLN-microparticles also showed favorable cytotoxic profile with CC50 ∼ 252.0 μg/mL, inhibitory concentration (IC50) 13.08 μg/mL, and safety index (SI) 19.26 which is 1.3 fold higher compared to plain RDV. The Optimal release profile of OLN-microparticles enabled controlled and sustained release with enhanced cellular uptake. Hence, OLN-microparticles represented an efficient alternative form of dry powder for inhalation for deep and targeted pulmonary delivery of RDV, outweighing limitations accompanied with IV administration. It can provide self-administered and malleable access of treatment for SARS-COV-2 infected patients.

Synergistic effect of magnesium stearate and fine lactose in improving aerosolization performance of fluticasone propionate in dry powder formulation

Magnesium stearate (MgSt) and lactose fines are often used as ternary components in carrier-based dry powder inhalers (DPIs) to improve fine particle fraction (FPF), but whether they act synergistically to improve aerosolization performance of DPI formulations is currently less studied. In addition, the applicability of utilizing powder rheological parameters to predict the FPF needs to be further verified. Thus, in this study, using fluticasone propionate (FP) as a model drug, effect of lactose fines addition in 0.5% MgSt containing DPI formulations on their powder and aerodynamic properties was explored. Influence of MgSt and fines mixing order on the DPIs performance was also investigated. The results showed that addition of lactose fines (1–10%) in 0.5% MgSt containing formulations could further improve flowability and enhance adhesion of the mixtures, and they could act synergistically to improve FPF. Moreover, the presence of 0.5% MgSt can greatly reduce the amount of lactose fines required to achieve the comparable FPF. The mixing order can affect distribution of MgSt on the carrier surface, with higher FPF noted when MgSt was mixed with carrier first, followed by lactose fines. A good linear relationship between powder rheological parameters such as basic flowability energy (BFE), Permeability and FPF was disclosed. In conclusion, in FP based DPIs, MgSt and lactose fines act synergistically to enhance FPF by tuning powder characteristics. Good flowability (27.39%) and strong adhesion (72.61%) contributed to the enhanced drug deposition in the lung.

Functional dry powders of connexin-containing extracellular vesicles

Extracellular vesicles (EVs) have emerged as a promising drug delivery system. Connectosomes are a specialized type of EVs that contain connexins in their membranes. Connexin is a surface transmembrane protein that forms connexin hemichannels. When a connexin hemichannel on a connectosome docks with another connexin hemichannel of a target cell, they form a gap junction that allows direct intracellular delivery of therapeutic cargos from within the connectosome to the cytoplasm of the recipient cell. In the present study, we tested the feasibility of converting connectosomes into dry powders by (thin-film) freeze-drying to enable their potential storage in temperatures higher than the recommended −80 °C, while maintaining their activity. Connectosomes were isolated from a genetically engineered HeLa cell line that overexpressing connexin-43 subunit protein tagged with red fluorescence protein. To facilitate the testing of the function of the connectosomes, they were loaded with calcein green dye. Calcein green-loaded connectosomes were thin-film freeze-dried with trehalose alone or trehalose and a polyvinylpyrrolidone polymer as lyoprotectant(s) to produce amorphous powders with high glass transition temperatures (>100 °C). Thin-film freeze-drying did not significantly change the morphology and structure of the connectosomes, nor their particle size distribution. Based on data from confocal microscopy, flow cytometry, and fluorescence spectrometry, the connexin hemichannels in the connectosomes reconstituted from the thin-film freeze-dried powder remained functional, allowing the passage of calcein green through the hemichannels and the release of the calcein green from the connectosomes when the channels were opened by chelating calcium in the reconstituted medium. The function of connectosomes was assessed after one month storage at different temperatures. The connexin hemichannels in connectosomes in liquid lost their function when stored at −19.5 ± 2.2 °C or 6.0 ± 0.5 °C for a month, while those in dry powder form remained functional under the same storage conditions. Finally, using doxorubicin-loaded connectosomes, we showed that the connectosomes reconstituted from thin-film freeze-dried powder remained pharmacologically active. These findings demonstrate that (thin-film) freeze-drying represents a viable method to prepare stable and functional powders of EVs that contain connexins in their membranes.

Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) – Part I: In Vitro Testing and Characterization

PurposeImproving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments.MethodsA new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals.ResultsThe best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7–17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min.ConclusionsA high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.

Evaluation of Cytotoxicity and Metabolic Profiling of Synechocystis sp. Extract Encapsulated in Nano-Liposomes and Nano-Niosomes Using LC-MS, Complemented by Molecular Docking Studies.

Liposomes and niosomes can be considered excellent drug delivery systems due to their ability to load all compounds, whether hydrophobic or hydrophilic. In addition, they can reduce the toxicity of the loaded drug without reducing its effectiveness. Synechocystis sp. is a unicellular, freshwater cyanobacteria strain that contains many bioactive compounds that qualify its use in industrial, pharmaceutical, and many other fields. This study investigated the potential of nano-liposomes (L) and nano-niosomes (N) for delivering Synechocystis sp. extract against cancer cell lines. Four different types of nanoparticles were prepared using a dry powder formulation and ethanol extract of Synechocystis sp. in both nanovesicles (N1 and N2, respectively) and liposomes (L1 and L2, respectively). Analysis of the formed vesicles using zeta analysis, SEM morphological analysis, and visual examination confirmed their stability and efficiency. L1 and L2 in this investigation had effective diameters of 419 and 847 nm, respectively, with PDI values of 0.24 and 0.27. Furthermore, the zeta potentials were found to range from -31.6 mV to -43.7 mV. Regarding N1 and N2, their effective diameters were 541 nm and 1051 nm, respectively, with PDI values of 0.31 and 0.35, and zeta potentials reported from -31.6 mV to -22.2 mV, respectively. Metabolic profiling tentatively identified 22 metabolites (1-22) from the ethanolic extract. Its effect against representative human cancers was studied in vitro, specifically against colon (Caco2), ovarian (OVCAR4), and breast (MCF7) cancer cell lines. The results showed the potential activities of the prepared N1, N2, L1, and L2 against the three cell lines, where L1 had cytotoxicity IC50 values of 19.56, 33.52, and 9.24 µg/mL compared to 26.27, 56.23, and 19.61 µg/mL for L2 against Caco2, OVCAR4, and MCF7, respectively. On the other hand, N1 exhibited IC50 values of 9.09, 11.42, and 2.38 µg/mL, while N2 showed values of 15.57, 18.17, and 35.31 µg/mL against Caco2, OVCAR4, and MCF7, respectively. Meanwhile, the formulations showed little effect on normal cell lines (FHC, OCE1, and MCF10a). All of the compounds were evaluated in silico against the epidermal growth factor receptor tyrosine kinase (EGFR). The molecular docking results showed that compound 21 (1-hexadecanoyl-2-(9Z-hexadecenoyl)-3-(6'-sulfo-alpha-D-quinovosyl)-sn-glycerol), followed by compounds 6 (Sulfoquinovosyl monoacylgycerol), 7 (3-Hydroxymyristic acid), 8 (Glycolipid PF2), 12 (Palmitoleic acid), and 19 (Glyceryl monostearate), showed the highest binding affinities. These compounds formed good hydrogen bond interactions with the key amino acid Lys721 as the co-crystallized ligand. These results suggest that nano-liposomes and nano-niosomes loaded with Synechocystis sp. extract hold promise for future cancer treatment development. Further research should focus on clinical trials, stability assessments, and pharmacological profiles to translate this approach into effective anticancer drugs.

Dry powder formulations of hyperimmune serum.

Effective strategies against the spread of respiratory viruses are needed, as tragically demonstrated during the COVID-19 pandemic. Apart from vaccines, other preventive or protective measures are necessary: one promising strategy involves the nasal delivery of preventive or protective agents, targeting the site of initial infection. Harnessing the immune system's ability to produce specific antibodies, a hyperimmune serum, collected from an individual vaccinated against SARS-CoV-2, was formulated as a dry powder for nasal administration. The selection of adequate excipients and process are key to maintaining protein stability and modulating the aerodynamic properties of the powders for reaching the desired respiratory regions. To this end, a hyperimmune serum was formulated with trehalose and mannitol as bulking agents during spray drying, then the ability of the redissolved immunoglobulins to bind Spike protein was verified by ELISA; foetal bovine serum was formulated in the same conditions as a reference. Moreover, a seroneutralization assay against SARS-CoV-2 pseudoviruses generated from different variants of concern was performed. The neutralizing ability of the serum was slightly reduced with respect to the starting serum when trehalose was used as a bulking agent. The powders were loaded in hypromellose capsules and aerosolized employing a nasal insufflator in an in vitro model of the nasal cavity connected to a Next Generation Impactor. The analysis of the powder distribution confirmed that all powders were inhalable and could target, at the same time, the upper and the lower airways. This is a preliminary proof-of-concept that this approach can constitute an effective strategy to provide broad coverage and protection against SARS-CoV-2, and in general against viruses affecting the airway. According to blood availability from donors, pools of hyperimmune sera could be rapidly formulated and administered, providing a simultaneous and timely neutralization of emerging viral variants.

Evaluating the effect of sodium alginate and sodium carboxymethylcellulose on pulmonary delivery of levofloxacin spray-dried microparticles.

Patients with cystic fibrosis commonly suffer from lung infections caused by Pseudomonas aeruginosa. Recently, the Levofloxacin (LVF) nebulizing solution (Quinsair®) has been prescribed for the antimicrobial management. The sustained-release (SR) dry powder formulation of LVF is a convenient alternative to Quinsair®. It has the potential to enhance patient convenience and decrease the likelihood of drug resistance over time. In this paper, we set forth to formulate and evaluate the potential application of sodium alginate (SA) and sodium carboxymethylcellulose (SCMC) for sustained pulmonary delivery of LVF. The spray-dried (SD) LVF microparticles were formulated using SCMC and SA along with L-leucine (Leu). The microparticles were analyzed in terms of particle size, morphology, x-ray diffraction (XRD), in-vitro drug release, and aerodynamic properties. Selected formulations were further proceeded to short-term stability test. The polymer-containing samples displayed process yield of 33.31%-39.67%, mean entrapment efficiency of 89% and volume size within the range of 2-5 μm. All the hydrogel microparticles were amorphous and exhibited rounded morphology with surface indentations. Formulations with a drug-to-excipient ratio of 50:50 and higher, showed a 24-h SR. The aerodynamic parameters were fine particle fraction and emitted dose percentage ranging between 46.21%-60.6% and 66.67%-87.75%, respectively. The short-term stability test revealed that the formulation with a 50:50 drug-to-excipient ratio, containing SA, demonstrated better physical stability. The selected formulation containing SA has the potential to extend the release duration. However, further enhancements are required to optimize its performance.

Influence of In-Process Emulsion Size on the Stability of PFH-VAP, a Stable Vitamin A Palmitate Dry Powder Formulation Developed for Use in Food Fortification

Influence of In-Process Emulsion Size on the Stability of PFH-VAP, a Stable Vitamin A Palmitate Dry Powder Formulation Developed for Use in Food Fortification

Promising brain biodistribution of insulin via intranasal dry powder for nose-to-brain delivery

Nose-to-brain delivery (NTBD) offering potential benefits for treating Alzheimer's disease. In previous research, insulin dry powder (IDP) formulation for NTBD was developed, exhibiting favorable stability. This study aims to conduct in vitro and ex vivo assessment of release, permeation, mucoadhesion and histopathology, as well as an in vivo biodistribution study to produce IDP for NTBD and evaluate brain biodistribution. Spray-freeze-dried IDP formulations with varying weight ratios of trehalose-to-inulin were produced and analyzed. The release study was carried out in PBS with a pH of 5.8 stirred at 50 rpm and maintained at 37 °C ± 0.5 °C. Goat nasal mucosa was used for ex vivo permeation and mucoadhesion testing under similar conditions. An ex vivo histopathological examination and an in vivo study using enzyme-linked immunosorbent assay, were also performed. The IDP dissolution study demonstrated complete release of all IDPs within 120 min. The permeation study indicated that steady-state conditions were observed between 30 and 240 min. The mucoadhesion study unveiled that IDP F5 exhibited the fastest mucoadhesion time and the least force required within the fastest time of 43.60 ± 2.57 s. The histopathological study confirmed that none of the tested IDPs induced irritation in the nasal mucosa. Furthermore, the biodistribution study demonstrated the absence of detectable insulin in the plasma, while IDP F3 exhibited the highest deposited concentration of insulin within both the olfactory bulb and the whole brain. The extensive evaluation of the IDP formulations through in vitro, ex vivo, and in vivo studies implies their strength non-invasive NTBD. IDP F3, with a 1:1 wt ratio of trehalose to inulin, exhibited favorable brain biodistribution outcomes and was recommended for further investigation and development in the context of NTBD.

Influence of particle diameter on aerosolization performance and release of budesonide loaded mesoporous silica particles

The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 µm) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 µm) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.

Design of Experiment (DoE) Approach for Developing Inhalable PLGA Microparticles Loaded with Clofazimine for Tuberculosis Treatment.

Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (-31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance.

Archaeosomes for Oral Drug Delivery: From Continuous Microfluidics Production to Powdered Formulations.

Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from Sulfolobus acidocaldarius. The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for oral drug delivery, with a focus on powdered formulations. The archaeosomes were negatively charged with a size of approximately 100 nm and a low polydispersity index. To assess their suitability for oral delivery, the archaeosomes were loaded with two model drugs: calcein, a fluorescent compound, and insulin, a peptide hormone. The archaeosomes demonstrated high stability in simulated intestinal fluids, with only 5% of the encapsulated compounds being released after 24 h, regardless of the presence of degrading enzymes or extremely acidic pH values such as those found in the stomach. In a co-culture cell model system mimicking the intestinal barrier, the archaeosomes showed strong adhesion to the cell membranes, facilitating a slow release of contents. The archaeosomes were loaded with insulin in a single-step procedure achieving an encapsulation efficiency of approximately 35%. These particles have been exposed to extreme manufacturing temperatures during freeze-drying and spray-drying processes, demonstrating remarkable resilience under these harsh conditions. The fabrication of stable dry powder formulations of archaeosomes represents a promising advancement toward the development of solid dosage forms for oral delivery of biological drugs.

Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.