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Author(s):  
Keiji Hirota ◽  
Yutaka Hirai ◽  
Takehisa Nakajima ◽  
Satoru Goto ◽  
Kimiko Makino ◽  
...  

Abstract Purpose Pulmonary administration of dry drug powder is a considered promising strategy in the treatment of various lung diseases such as tuberculosis and is more effective than systemic medication. However, in the pre-clinical study phase, there is a lack of devices for effective delivery of dry powders to the lungs of small rodents. In this study, an administration device which utilizes Venturi effect to deliver dry powders to the lungs homogeneously was developed. Methods A Venturi-effect administration device which synchronizes with breathes by use of a ventilator and aerosolizes the dry powders was created. Pulmonary distribution of inhalable dry powders prepared by spray-drying poly(lactic-co-glycolic) acid and an antituberculosis agent rifampicin and anti-tuberculosis effect of the powders on mycobacteria infected rats by administration with the Venturi-effect administration device and a conventional insufflation device were evaluated. Results Homogeneous distribution of the dry powders in the lung was achieved by the Venturi-effect administration device due to efficient and recurring aerosolization of loaded dry powders while synchronizing with breathes. Amount of rifampicin delivered to the lungs by the Venturi-effect administration device was three times higher than that by a conventional insufflation device, demonstrating three times greater antimycobacterial activity. Conclusions The Venturi-effect administration device aerosolized inhalable antituberculosis dry powders efficiently, achieved uniform pulmonary distribution, and aided the dry powders to exert antituberculosis activity on lung-residing mycobacteria.


Materials ◽  
2021 ◽  
Vol 14 (24) ◽  
pp. 7558
Author(s):  
Wacław Brachaczek ◽  
Adam Chleboś ◽  
Zbigniew Giergiczny

This paper presents the results of research on the influence of polymer modifiers: styrene-acrylic copolymer, vinyl acetate/ethylene (EVA), vinyl acetate/acrylic copolymer (VAAc), and VA/VeoVa/acrylic terpolymer on the water permeability and adhesion of cement-containing waterproofing mortars in concrete. The content of the polymers in the composition of the mortars was 15, 20 and 26% (m/m) in relation to the weight of the dry ingredients. Using microscopic methods, an attempt was made to analyse the relationship between the microstructure of the mortars and the properties of these polymers. The EVA and the vinyl acetate/acrylic copolymer, which were used in the form of dry powders, had the most favourable effect on water permeability and adhesion to the concrete substrate. They may prove to be useful for the production of one-component cement-containing waterproofing mortars. On the other hand, the VA/VeoVa/acrylic terpolymer modifier had the least favourable effect on the tested properties. For mortars with this modifier, the desired water-permeability parameters were not achieved. Depending on the amount of polymer modifier, the mortars were characterized by differences in watertightness, as established on the basis of changes in porosity and differences in the adhesion of the cement-polymer paste to the surface of aggregate grains. It was determined that the type of polymer and its dispergation properties influence the water permeability of mortars, as well as their adhesion to concrete substrates.


2021 ◽  
Author(s):  
Huy M. Dao ◽  
Sawittree Sahakijpijarn ◽  
Robert R. Chrostowski ◽  
Chaeho Moon ◽  
Filippo Mangolini ◽  
...  

ABSTRACTBiological macromolecules, especially therapeutic proteins, are delicate and highly sensitive to degradation from stresses encountered during the manufacture of dosage forms. Thin-film freeze-drying (TFFD) and spray freeze-drying (SFD) are two processes used to convert liquid forms of protein into dry powders. In the production of inhalable dry powders that contain proteins, these potential stressors fall into three categories based on their occurrence during the primary steps of the process: (1) droplet formation (e.g., the mechanism of droplet formation, including spray atomization), (2) freezing, and (3) frozen water removal (e.g., sublimation). This study compares the droplet formation mechanism used in TFFD and SFD by investigating the effects of spraying on the stability of proteins, using lactoferrin as a model. This study considers various perspectives on the degradation (e.g., conformation) of lactoferrin after subjecting the protein solution to the atomization process using a pneumatic two-fluid nozzle (employed in SFD) or a low-shear drop application through the nozzle. The surface activity of lactoferrin was examined to explore the interfacial adsorption tendency, diffusion, and denaturation process. Subsequently, this study also investigates the secondary and tertiary structure of lactoferrin, the quantification of monomers, oligomers, and ultimately, aggregates. The spraying process affected the tertiary structure more negatively than the tightly woven secondary structure, resulting in a 1.5 nm red shift in peak position corresponding to the Tryptophan (Trp) residues. This conformational change can either (a) be reversed at low concentrations via relaxation or (b) proceed to form irreversible aggregates at higher concentrations. Interestingly, when the sample was allowed to progress into micron-sized aggregates, such a dramatic change was not detected using methods such as size-exclusion chromatography, polyacrylamide gel electrophoresis, and dynamic light scattering at 173°. A more complete understanding of the heterogeneous protein sample was achieved only through a combination of 173° and 13° backward and forward scattering, a combination of derived count rate measurements, and micro-flow imaging (MFI). Finally, compared to the low-shear dripping used in the TFFD process, lactoferrin underwent a relatively fast conformational change upon exposure to the high air-water interface of the two-fluid atomization nozzle used in the SFD process as compared to the low shear dripping used in the TFFD process. The interfacial induced denaturation that occurred during spraying was governed primarily by the size of the atomized droplets, regardless of the duration of exposure to air.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1855
Author(s):  
Danforth P. Miller ◽  
Thomas E. Tarara ◽  
Jeffry G. Weers

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1831
Author(s):  
Jelisaveta Ignjatović ◽  
Tijana Šušteršič ◽  
Aleksandar Bodić ◽  
Sandra Cvijić ◽  
Jelena Đuriš ◽  
...  

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). The aim of this study was to compare the designed CFD-DPM outcomes with the results of three in vitro methods for aerodynamic assessment of solid lipid microparticle DPIs. The model was able to simulate particle-to-wall sticking and estimate fractions of particles that stick or bounce off the inhaler’s wall; however, we observed notable differences between the in silico and in vitro results. The predicted emitted fractions (EFs) were comparable to the in vitro determined EFs, whereas the predicted fine particle fractions (FPFs) were generally lower than the corresponding in vitro values. In addition, CFD-DPM predicted higher mass median aerodynamic diameter (MMAD) in comparison to the in vitro values. The outcomes of different in vitro methods also diverged, implying that these methods are not interchangeable. Overall, our results support the utility of CFD-DPM in the DPI development, but highlight the need for additional improvements in these models to capture all the key processes influencing aerodynamic performance of specific DPIs.


2021 ◽  
Author(s):  
Stephanie Hufnagel ◽  
Haiyue Xu ◽  
Sawittree Sahakijpijarn ◽  
Chaeho Moon ◽  
Laura Q.M. Chow ◽  
...  

Thin-film freeze-drying (TFFD) is a rapid freezing and then drying technique used to prepare inhalable dry powders from the liquid form for drug delivery to the lungs. We report the preparation of aerosolizable dry powders of monoclonal antibodies (mAbs) by TFFD. We first formulated IgG with lactose/leucine (60:40 w/w) or trehalose/leucine (75:25). IgG 1% (w/w) formulated with lactose/leucine (60:40 w/w) in phosphate buffered saline (PBS) (IgG-1-LL-PBS) and processed by TFFD was found to produce the powder with the most desirable aerosol properties. We then replaced IgG with a specific antibody, anti-programmed cell death protein (anti-PD-1 mAb), to prepare a dry powder (anti-PD1-1-LL-PBS), which performed similarly to the IgG-1-LL-PBS powder. The aerosol properties of anti-PD1-1-LL-PBS were significantly better when TFFD was used to prepare the powder as compared to conventional shelf freeze-drying (shelf FD). The dry powder had a porous structure with nanoaggregates. The dry powder had a Tg value between 39-50 degree Celsius. When stored at room temperature, the anti-PD-1 mAb in the TFFD powder was more stable than that of the same formulation stored as a liquid. The addition of polyvinylpyrrolidone (PVP) K40 in the formulation was able to raise the Tg to 152 degree Celsius, which is expected to further increase the storage stability of the mAbs. The PD-1 binding activities of the anti-PD-1 mAbs before and after TFFD were not different. While protein loss, likely due to protein binding to glass or plastic vials and the TFF apparatus, was identified, we were able to minimize the loss by increasing mAb content in the powders. Lastly, we show that another mAb, anti-TNF-alpha;, can also be converted to a dry powder with a similar composition by TFFD. We conclude that TFFD can be applied to produce stable aerosolizable dry powders of mAbs for pulmonary delivery.


2021 ◽  
Author(s):  
Jelisaveta Ignjatovic ◽  
Tijana Austersic ◽  
Sandra Cvijic ◽  
Aleksandar Bodic ◽  
Jelena Duris ◽  
...  

Author(s):  
Danforth P. Miller ◽  
Thomas E. Tarara ◽  
Jeffry G. Weers

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1377
Author(s):  
Estefanía Fernández-Paz ◽  
Lucía Feijoo-Siota ◽  
Maria Manuela Gaspar ◽  
Noemi Csaba ◽  
Carmen Remuñán-López

In this work, we propose chitosan (CS)-based nanocapsules (NCs) for pulmonary gene delivery. Hyaluronic acid (HA) was incorporated in the NCs composition (HA/CS NCs) aiming to promote gene transfection in the lung epithelium. NCs were loaded with a model plasmid (pCMV-βGal) to easily evaluate their transfection capacity. The plasmid encapsulation efficiencies were of approx. 90%. To facilitate their administration to the lungs, the plasmid-loaded NCs were microencapsulated in mannitol (Ma) microspheres (MS) using a simple spray-drying technique, obtaining dry powders of adequate properties. In vivo, the MS reached the deep lung, where the plasmid-loaded CS-based NCs were released and transfected the alveolar cells more homogeneously than the control formulation of plasmid directly microencapsulated in Ma MS. The HA-containing formulation achieved the highest transfection efficiency, in a more extended area and more homogeneously distributed than the rest of tested formulations. The new micro-nanostructured platform proposed in this work represents an efficient strategy for the delivery of genetic material to the lung, with great potential for the treatment of genetic lung diseases.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1162
Author(s):  
Wei Yan ◽  
Ruide He ◽  
Xiaojiao Tang ◽  
Bin Tian ◽  
Yannan Liu ◽  
...  

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


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