Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 μm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 μm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40–12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17–10.16% w/w).

Effects of lower alcohols on nanocomposite particles for inhalation prepared using O/W emulsion

BACKGROUND: Inhalable nanocomposite particles using O/W emulsions were studied. The effect of the composition of the dispersed phase on the nanoparticles in the nanocomposite particles was reported, however, the effect on the inhalation characteristics of nanocomposite particles has not been investigated. OBJECTIVE: The aim of this study was to study the effects of lower alcohols in the dispersed phase of O/W emulsions on inhalable nanocomposite particles. METHODS: Nanocomposite particles were prepared using a spray dryer from O/W emulsion. A mixed solution of dichloromethane and lower alcohols in which rifampicin (RFP) and poly(L-lactide-co-glycolide) were dissolved was used as a dispersed phase, and an aqueous solution in which arginine and leucine were dissolved was used as a continuous phase. RESULTS: We succeeded in preparing non-spherical nanocomposite particles with an average diameter of 9.01–10.91 μm. The results of the fine particle fraction (FPF) measurement showed that the higher the hydrophobicity of the lower alcohol mixed in the dispersed phase, the higher the FPF value. The FPF value of the nanocomposite particles was significantly increased by using ethanol and 1-propanol. CONCLUSIONS: The results were revealed that mixing 1-propanol with the dispersed phase increased the amount of RFP delivered to the lungs.

Obtaining and research of pharmaceutical properties of antiemetics in a form of powder for inhalation

Samples of antiemetic drugs (ondansetronum, palonosetronum, metoclopramidum) in the form of powder for inhalation have been developed by the method of spray drying. The granulometric composition, hygroscopicity and aerodynamic distribution of aerosol particles of the drugs have been investigated. The dosage form of the powder for inhalation of antiemetics (ondansetronum and palonosetronum) in terms of its particle size distribution, hygroscopicity and content of the agent corresponds to those for inhalation using dry powder inhalers. In the study of the phase-dispersed composition of aerosol, ondansetronum and palonosetronum in the dosage form of powder for inhalation as part of the HandiHaler inhaler (at a flow rate of 60 l / min) showed high rates of the released dose up to 72-76%, respirable particle fraction (up to 5 m) up to 54 -56% and a mass median particle size of about 3 microns. Obtaining the inhaled form of metoclopramide requires optimization of the production method for receiving the product with acceptable pharmaceutical properties.

Ruminant Milk-Derived Extracellular Vesicles: A Nutritional and Therapeutic Opportunity?

Milk has been shown to contain a specific fraction of extracellular particles that are reported to resist digestion and are purposefully packaged with lipids, proteins, and nucleic acids to exert specific biological effects. These findings suggest that these particles may have a role in the quality of infant nutrition, particularly in the early phase of life when many of the foundations of an infant’s potential for health and overall wellness are established. However, much of the current research focuses on human or cow milk only, and there is a knowledge gap in how milk from other species, which may be more commonly consumed in different regions, could also have these reported biological effects. Our review provides a summary of the studies into the extracellular particle fraction of milk from a wider range of ruminants and pseudo-ruminants, focusing on how this fraction is isolated and characterised, the stability and uptake of the fraction, and the reported biological effects of these fractions in a range of model systems. As the individual composition of milk from different species is known to differ, we propose that the extracellular particle fraction of milk from non-traditional and minority species may also have important and distinct biological properties that warrant further study.

Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and β forms behaved in the same manner (11–13% for SS; 53–58% for BUD) and better than lactose (8 and 13% for SS; 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance.

Inspiratory flows and the aerosol cloud from dry powder inhalers

The relationship between the delivered dose, the fine particle fraction and the fine particle dose and the value of inspiratory flow generated by the patient is one of the most important features of dry powder inhalers (DPIs). It significantly affects the amount of pulmonary deposition of the inhaled drug and the clinical effect of the drug. The results of research evaluating these relationships for popular in Poland dry powder inhalers are presented. Flow-dependent, relatively flow-dependent and relatively flow-independent inhalers are demonstrated.

Influences of Increased Pressure Foaming on the Cellular Structure and Compressive Properties of In Situ Al-4.5%Cu-xTiB2 Composite Foams with Different Particle Fraction

Metallic foams have drawn increasing attention in applications ranging from lightweight structures to energy absorption devices. Mechanical properties of metallic foams depend on both their microstructure and cellular structure. In situ Al-4.5%Cu-xTiB2 composites were used as start materials for fabrication of closed-cell foams through liquid route under atmosphere pressure and increased pressure, aiming at simultaneously strengthening the cell wall material and optimizing the cellular structure. Macro-structural features of the foams were determined by micro X-ray computed tomography (µCT); results exhibit that increasing weight ratio of in situ TiB2 particles leads to coarsened cell structure for foams made under atmosphere pressure, due to the increase in critical thickness of cell wall rupture. Significant reduction of cell size and increase in cell circularity were observed for foams fabricated under increased pressure. Quasi static compression test results indicate that yield strength of foam samples increases with increasing particle fraction and refinement of cell structure. Microstructure observation shows that the continuous network at interdendritic regions consists of in situ TiB2 particles and intermetallic compounds are responsible for the reduced ductility of cell wall materials and the reduction in energy absorption efficiency of foams with high particle fraction. The influences of cell structure on the normalized strength and specific energy absorption were also discussed, and it was found that the improvement of yield strength and energy absorption of composite foams attributes to both the reinforcement of in situ TiB2 particles and the refinement of cellular structure.