Deposition of Nacystelyn from a Dry Powder Inhaler in Healthy Volunteers and Cystic Fibrosis Patients

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with ^99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 ± 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 ± 7.0% for adults and 16.5 ± 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.     

Numerical investigation of powder dispersion mechanisms in Turbuhaler and the contact electrification effect

Powder dispersion in dry powder inhalers (DPI) is affected by factors such as device design and flow rate, but also electrification due to particle–particle/device collisions. This work presented a CFD-DEM study of powder dispersion in Turbuhaler®, aiming to understand the effect of electrostatic charge on the dispersion mechanisms. The device geometry was reconstructed from CT-scan images of commercial Turbuhaler device. Different work functions were applied to the active pharmaceutical ingredient (API) powder and the device wall. Electrostatic charges were accumulated on the API particles due to contact potential difference (CPD) between the particles and the device wall. Results showed that both the chamber and the spiral mouthpiece played an important role in de-agglomeration of powders caused by particle–wall impactions. With increasing flow rates, the performance of the device was improved with higher emitted dose (ED) and fine particle fractions (FPF). The electrostatic charging of the particles was enhanced with higher CPD and higher flow rates, but the electrostatic charging had a minimum effect on powder dispersion and deposition with slight reduction in ED and FPF. In conclusion, the van der Waals force is still the dominant adhesive inter-particle force, and the dispersion efficiency is affected by the flow rate rather than contact electrification of particles. Future work should focus on the effect of highly charged particles emitted from the inhaler on the deposition in the airway.     

In Vitro and in Vivo Deposition of Drug Particles Inhaled from Pressurized Aerosol and Dry Powder Inhaler

Abstract

Disodium cromoglycate particles were labelled with a pure ζ-radiator ^99mTc using a novel co-precipitation technique based on spray drying. Metered dose aerosols as well as a dry powder dosage form were prepared using these labelled drug particles. Fractional deposition of the drug particles was determined in vivo by means of gamma camera. Inhalation patterns of seven healthy volunteers were compared to deposition patterns evaluated in vitro using a modified cascade impactor. On average only 9 per cent of the aerosol dose deposited in a whole lung area and about 81 per cent in the upper airways of the volunteers. The in vitro results showed clearly greater deposition of the drug particles into the imitated bronchial and alveolar stages. The physiological factors of the human respiratory tract as well as the individual differences in the inhalation techniques seemed to have a significant influence to the deposition and aerodynamic behaviour of the inhaled drug particles. The in vitro results indicated, however, the similar differences between the two inhalation dosage forms as the in vivo evaluation did.     

Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro–in silico lung deposition results

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways – carrier-based, carrier-free, and novel combined formulation – and thereby to compare their physicochemical and in vitro–in silico aerodynamical properties before and after storage. Presenting a novel combined technology in the field of DPI formulation including the carrier-based and carrier-free methods, it is the most important reason to introduce this stable formulation for the further development of DPIs.

Methods: The structure, the residual solvent content, the interparticle interactions, the particle size distribution and the morphology of the samples were studied. The aerodynamic values were determined based on the cascade impactor in vitro lung model. We tested the in silico behavior of the novel combined formulated samples before and during storage.

Results: The physical measurements showed that the novel combined formulated sample was the most favorable. It was found that thanks to the formulation technique and the use of magnesium stearate (MgSt) has a beneficial effect on the stability compared with the carrier-based formulation without MgSt and carrier-free formulations. The results of in vitro and in silico lung models were consistent with the physical results, so the highest deposition was found for the novel combined formulated sample during the storage.

Conclusions: It can be established that after the storage a novel combined formulated DPI contained amorphous drug to have around 2.5?μm mass median aerodynamic diameter and nearly 50% fine particle fraction predicted high lung deposition in silico also.     

Nicotine-loaded chitosan nanoparticles for dry powder inhaler (DPI) formulations – Impact of nanoparticle surface charge on powder aerosolization

The aim of this study is to demonstrate the role of surface charge of nicotine loaded or unloaded chitosan (CS) nanoparticles on the dispersibility from dry powder inhaler (DPI) formulations. The nanoparticles were prepared using glutaraldehyde crosslinking of the amino groups of chitosan in a water-in-oil emulsion. Using dynamic light scattering (DLS) the particle size, size distribution and the zeta potential of nanoparticles were measured. The morphological characteristics were studied using SEM. The fine particle fractions (FPFs) of nanoparticles were determined by a twin stage impinger (TSI) using a Rotahaler at 60?L/min flow rate. The FPF of nanoparticles could be correlated to the surface charge i.e., FPFs were increased with increasing surface charge, which reduced with increased concentration of the drug. The FPF from the large carrier (lactose) based formulations was significantly higher (p?<?0.001) than those of formulations without carriers. The higher FPF from the large carrier-based formulations was independent of zeta potential and thought to be associated with high impaction. These results suggested the mechanism of nicotine loaded CS nanoparticle dispersion without large carriers was dependent on the zeta potential, which was linked to the agglomeration or deagglomeration behaviour of particles.     

Methods for reduction of cohesive forces between carrier and drug in DPI formulation

Dry powder inhaler (DPI) has become a well accepted drug delivery for pulmonary system to treat many related diseases including symptomatic and life threatening diseases. Successful delivery of dry powder to the lung requires careful consideration of powder production process, formulation and inhaler device. The formulation of DPI mostly comprises of lactose as a carrier for drug delivery. In DPI formulation, particulate interactions within the formulation govern both the drug dissociation from carrier particles and the disaggregation of drug into primary particles with a capacity to penetrate deep into lung. Two contradictory requirements must be fulfilled for this type of dry powder formulation. On one hand, adhesion between carrier and drug must be sufficient for the blend drug/carrier to be stable. On the other hand, adhesion drug/carrier has to be weak enough to enable the release of drug from carrier during patient inhalation. Thus the carrier use restricted due to detachment problem. Different methods are proposed to reduce the cohesive forces between drug and carrier to desired level. Various studies conducted for understanding the mechanism of deposition into lungs and making formulation with optimum carrier drug cohesive force. This review provides information on various processes involved in reducing the cohesive forces between drug and carrier, to a required level.     

A particle technology approach toward designing dry-powder inhaler formulations for personalized medicine in respiratory diseases

Compared with oral and parenteral formulations, inhaled formulations are attractive because of their great benefit and potential to enhance therapeutic effects of medications. Among the available inhaled formulations, powders used with dry-powder inhalers (DPIs) have become a preferred option because of their many advantages over other inhaled formulations. Additionally, a powder technological approach is required and available for sophisticated design of DPI formulations. To provide appropriate treatment using a DPI formulation, inhaled particles containing drugs should be delivered to the appropriate sites in the lungs of individual patients. It is indispensable that the design of DPI formulations specify particle properties suitable for a specific disease and the appropriate positions in the lungs to which the inhaled particles must be delivered. This article focuses on the current particle technological approach toward designing DPI formulations and numerical simulation analysis of behavior and deposition of inhaled particles in the lungs. As a future perspective from the viewpoint of pharmaceutical particle technology, a combination of experimental and simulation approaches is expected to improve the ability to obtain maximum lung delivery as well as target the site of deposition in the lungs of individual patients.     

Thermal and mechanical behaviour of flexible polyurethane foams modified with graphite and phosphorous fillers

Flexible polyurethane foams (FPF) are polymer materials that have high flammability. Fyrol PNX (FPNX) and expandable graphite (EG), have been used to modify the properties of these materials. The aim of this study was to assess the possibility of improving the thermal stability and flame retardancy of FPF by the addition of FPNX and EG fillers. The prepared foams were characterised by their apparent density, hardness, flexibility, irreversible strain and linear flammability, as well as thermogravimetric analysis (TGA), dynamic mechanical analysis, Fourier transform infrared spectroscopy (FT-IR) and pyrolysis combustion flow calorimetry (PCFC) measurements. The apparent density, hardness, flexibility and irreversible strain results showed that the addition of graphite and phosphorous fillers to the FPF makes slight changes to the mechanical properties, which remain within the acceptable norms. It was also observed that reducing the amount of Fyrol PNX and replacing it with the same amount of EG allowed similar values of linear flammability to be obtained with a simultaneous increase in thermal stability, as shown in the TGA study and the PCFC test. Moreover, it was found that the modification of flexible polyurethane foam by the addition of a mixture of FPNX and EG fillers allows the best properties of this type of materials to be obtained. This result indicates that this type of modification could be an effective way to improve the thermal stability of FPF.     

Optimizing the primary particle size distributions of pressurized metered dose inhalers by using inkjet spray drying for targeting desired regions of the lungs

Conventional suspension pressurized metered dose inhalers (pMDIs) suffer not only from delivering small amounts of a drug to the lungs, but also the inhaled dose scatters all over the lung regions. This results in much less of the desired dose being delivered to regions of the lungs. This study aimed to improve the aerosol performance of suspension pMDIs by producing primary particles with narrow size distributions. Inkjet spray drying was used to produce respirable particles of salbutamol sulfate. The Next Generation Impactor (NGI) was used to determine the aerosol particle size distribution and fine particle fraction (FPF). Furthermore, oropharyngeal models were used with the NGI to compare the aerosol performances of a pMDI with monodisperse primary particles and a conventional pMDI. Monodisperse primary particles in pMDIs showed significantly narrower aerosol particle size distributions than pMDIs containing polydisperse primary particles. Monodisperse pMDIs showed aerosol deposition on a single stage of the NGI as high as 41.75?±?5.76%, while this was 29.37?±?6.79% for a polydisperse pMDI. Narrow size distribution was crucial to achieve a high FPF (49.31?±?8.16%) for primary particles greater than 2?µm. Only small polydisperse primary particles with sizes such as 0.65?±?0.28?µm achieved a high FPF with (68.94?±?6.22%) or without (53.95?±?4.59%) a spacer. Oropharyngeal models also indicated a narrower aerosol particle size distribution for a pMDI containing monodisperse primary particles compared to a conventional pMDI. It is concluded that, pMDIs formulated with monodisperse primary particles show higher FPFs that may target desired regions of the lungs more effectively than polydisperse pMDIs.     

CF-CNTs多尺度增强体的制备及CF-CNTs/环氧树脂复合材料力学性能

利用化学气相沉积(CVD)法在碳纤维(CF)表面生长碳纳米管(CNTs),制备了CF-CNTs多尺度增强体,增强体与环氧树脂(EP)结合得到CF-CNTs/EP复合材料。采用场发射扫描电镜(FESEM)、高分辨透射电镜(HRTEM)等方法研究了不同CVD工艺参数对CF-CNTs多尺度增强体的影响,并研究了不同CVD时间对CFCNTs/EP复合材料力学性能的影响。结果表明:沉积温度为500℃、沉积时间为10min、反应压力为0.02 MPa时,制备得到的多尺度增强体性能最好。CF-CNTs多尺度增强体较未生长CNTs的碳纤维与环氧树脂的浸润性明显提高。在CVD时间为10min时,所得CF-CNTs/EP复合材料的界面剪切强度(IFSS)最大可提高90.6%,层间剪切强度(ILSS)最大可提高24.4%。同时,在制备环氧树脂复合材料过程中碳纤维的不加捻与加捻相比,其ILSS提高了11.3%。     

Nanocrystalline diamond coating on carbon fibers produced at different temperatures: Morphological, structural and electrochemical study

In this paper, the morphological, structural and electrochemical properties of nanocrystalline diamond (NCD) films grown on carbon fibers (CF) were investigated. The CF substrates were produced at three different heat treatment temperatures (HTT):1000, 1500 and 2000 °C. The HTT variation promoted different organization indexes on the CF structures. Consequently, the NCD coating formation was strongly affected by the substrate HTT. The changes in the properties of the diamond films were discussed as a function of the film morphology evolution using CH₄ flow rate of 0.25, 0.5 and 1.0 sccm in the feed gas. The X-ray diffraction measurements for the CF and NCD/CF composites were determinant to characterize the crystallinity of the NCD films as a function of the CF HTT and of the CH₄ addition. Based on the diffractograms, the Scherrer's equation was applied to the (111) NCD peak, resulting in grain size values varying from 11.0 to 5.0 nm depending on the CH₄ flow rate and on the CF HTT. The scanning electron microscopy images confirmed the deposition of a continuous NCD coating with high nucleation rate covering the whole CF, while their quality was analyzed by Raman spectroscopy measurements. The NCD grain agglomerates increased as a function of the increase in the CH₄ flow rate from 0.25 to 1.0 sccm, showing similar film morphology to that of the unfaceted diamond balls obtained by chemical vapor deposition. This behavior confirmed the expected tendency by decreasing the diamond quality with the CH₄ addition, especially for the films grown on CF treated at 1500 and 2000 °C. This performance was also corroborated by the cyclic voltammetry measurements concerning the electrode potential window and their responses in a redox couple.     

Surface treatment effect of carbon fiber fabric counter electrode in dye sensitized solar cell

Dye sensitized solar cells (DSSC) with surface modified carbon fiber fabric (CF) counter electrodes were prepared and tested. Four different type of CF were used; carbon fiber (CF); carbon fiber etched with NaOH (ECF); carbon fiber with thermally deposited platinum (CFPt); and carbon fiber etched with NaOH followed by thermal deposition of platinum (ECFPt). For comparison, DSSC with thermally Pt deposited fluorine doped tin oxide (FTO/Pt) glass counter electrode was also prepared and tested. Scanning electron microscope (SEM) proved that surface morphology of the carbon fiber was roughened by the etching process and platinum deposition process. The I-V curves of each DSSC were measured under simulated light (1 Sun, AM 1.5) to get open circuit voltage (Voc), short circuit current density (Jsc), fill factor (FF) and efficiency (eta). Electrochemical impedance spectroscopy of each cell was measured also. It was found that higher efficiency is obtained in order of using ECFPt > CFPt > FTO/Pt > ECF > CF counter electrode.     

Measurement of conformational changes in the structure of transglutaminase on binding calcium ions using optical evanescent dual polarisation interferometry

The conformational changes occurring when the protein transglutaminase binds calcium ions have been studied using the optical evanescent technique of dual polarization interferometry (DPI) implemented via a dual slab waveguide structure. Immobilized transglutaminase layers of 4-5 nm in thickness were obtained, which when challenged with calcium ions underwent a contraction of approximately 0.5 nm (depending on the concentration of calcium) and an increase in refractive index of approximately 1 x 10-2. The affinity constant for the calcium binding was found to be in the range of 0.95 +/- 0.2 mM. The results reported are in good agreement with those found in the literature obtained by other techniques. It has also been shown that the structural changes occurring during the binding event are considerably larger than the mass changes that take place; thus, DPI offers a potentially valuable method to study real-time structural changes occurring to proteins when they bind metal ions.     

Micronized drug powders in binary mixtures and the effect of physical properties on aerosolization from combination drug dry powder inhalers

Objectives: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. Methods: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. Results: The median SS particle diameter was larger than BDP (4.33?±?0.37 µm compared to 2.99?±?0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. Conclusions: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

Aerosol assisted fabrication of metallic film/carbon fiber and heat treatment to form crystalline alloy film

Carbon fiber (CF) was catalytically activated with spark generated Pd aerosol nanoparticles. Metal (Ag, Au, Cu, and Pd) and alloy (Ni-P, Ni-Cu-P) electroless films were deposited on Pd aerosol activated CF using a range of deposition parameters including deposition rate in an electroless deposition bath. Sintering was applied to the alloy films on the CF to examine the crystallization behavior at 400 °C in a nitrogen atmosphere. Ni-Cu-P had a higher crystallinity than Ni-P after the treatment.     

Diamond growth with CF4 addition inhot-filament chemical vapour deposition

Tetrafluoromethane (CF4) was added to standard CH4/H2 mixtures for diamond growth in hot-filament-assisted chemical vapour deposition. CF4 concentrations in the range of 0.3%–3% were studied. Mass spectrometry of the exhaust gas showed that only a small fraction (< 15%) of CF4 was thermally dissociated for filament temperatures over 1800 °C. The observed stable products of its dissociation were mainly C2H2, CH4 and HF. This CF4 addition considerably enhanced the nucleation and growth characteristics on silicon and molybdenum. Diamond growth was observed with substrate temperature as low as 390 °C. A comparative study for the growth dependence on substrate temperature with and without CF4 addition in the gas mixture is presented. The growth rate was measured by post-growth weighing with a micro balance. An activation energy of 11 kcal mol-1 for growth with CF4 addition was obtained. Raman spectra and atomic force microscopy were used to characterize the diamond films. This revised version was published online in November 2006 with corrections to the Cover Date.     

Current status of patient radiation doses from computed tomography examinations in Tanzania

The aim of this study was to assess the magnitude of radiation dose imparted to patients undergoing CT (computed tomography) examinations in Tanzania. The effective doses to patients undergoing five common CT examinations were obtained from eight health centres. The doses to patients were estimated using measurements of CTDI, exposure-related parameters and the CTDOSE software based on NRPB conversion factors. The mean effective doses in Tanzania for CT examinations of head, lumbar spine, chest, abdomen and pelvis were 2.2+/-0.9, 5.4+/-2.3, 12.2+/-3.4, 15.3+/-6.0 and 13.4+/-7.3 mSv, respectively. The mean effective doses and the variations in dose between hospitals in Tanzania were mostly comparable with reported values in the literature for six different countries from Europe. The observed wide variation in mean effective dose for similar CT examination among hospitals was largely influenced by different CT scanning protocols employed among hospitals. In view of the observed causes of variation in patient doses, it was concluded that further studies are needed to investigate the methods that can reduce dose to patients without affecting image quality.     

Enhanced field emission from aligned multistage carbon nanotube emitter arrays

In this work we report on the synthesis and field emission properties of carbon nanotube multistage emitter arrays grown on porous silicon by catalytic thermal chemical vapor deposition. The vertically oriented multistage array structures consisted of SWNTs and thin MWNTs grown on MWNTs, confirmed by TEM and Raman analysis. Higher field emission current ～32 times and low threshold field ～1.5 times were obtained for these structures in comparison to only MWNT arrays. The enhanced field emission results for these multistage emitters are a consequence of higher field concentration, which is ～3 times more than MWNTs.     

Growth of carbon nanofibers on carbon fabric with Ni nanocatalyst prepared using pulse electrodeposition

The pulse electrodeposition (PED) technique was utilized to deposit nanosized (≤10?nm) Ni catalysts on carbon fabric (CF). Via an in?situ potential profile, the PED technique can control the Ni catalyst loading, which is an important parameter for the growth of carbon nanofibers (CNFs) on CF. The preparation of CNF-coated CF (carpet-like CF) was carried out in a thermal chemical vapor deposition system with an optimum loading of Ni catalysts deposited in the PED pulse range from 20 to 320 cycles. CNFs grown at 813?K using different pulse cycles had a narrow diameter distribution, around 15 ± 5?nm to 29 ± 7?nm; they have a hydrophobic surface, like lotus leaves. Transmission electron microscopy images confirmed the graphene structural transformation of CNFs with the growth temperature. Solid wire CNFs were initially grown at 813?K with graphene edges exposed on the external surface. At elevated growth temperatures (1073 and 1173?K), bamboo-like CNFs were obtained, with herringbone structures and intersectional hollow cores.