撞击器法测定吸入粉雾剂空气动力学粒径分布颗粒反弹的研究

目的 对撞击器(cascade impactor,CI)法检测吸入粉雾剂空气动力学粒径分布(aerodynamic particle size distributions,APSDs)时颗粒反弹和二次夹带进行研究,为涂层材料的选择提供方法.方法 用甘油、硅油分别对收集杯/盘进行涂层或不涂层处理后,分别在30~90 L·min-1流速下,按照《美国药典》601项下规定进行样品收集并分析检测结果.结果 对收集杯/盘进行涂层处理能明显减少滤膜沉积率;用硅油涂层后,相同流速下质量平均空气动力学粒径(mass median aerodynamic diameter,MMAD)不随收集剂量的变化而变化,APSDs也较稳定.结论 使用撞击器法检测吸入粉雾剂APSDs时,对收集表面进行涂层很大程度上能够消除颗粒反弹和二次夹带;新一代碰撞取样器(next generation impactor,NGI)检测格隆溴铵吸入粉雾剂APSDs时,用硅油对收集杯进行涂层,可使检测结果更准确.     

Loading Effect on Particle Size Measurements by Inertial Sampling of Albuterol Metered Dose Inhalers

Purpose. The purpose of this study is to investigate the albuterol loading effect on particle size measurements by studying the effect of the amount of albuterol delivered, the number of puffs used, and the sampling techniques used in particle size measurement. Methods. Particle size distribution profiles for different albuterol loadings were evaluated using an 8-stage cascade impactor and a sensitive HPLC electrochemical assay method. A commercial albuterol MDI (Proventil^R) and other specially prepared albuterol MDIs were used in the study. Results. As the amount of albuterol was increased, either by increasing the number of puffs or the amount delivered per puff, the measured MMAD increased. This increase was more prominent in some formulations (Proventil^R) than others. Further, albuterol particles previously deposited on the valve and/or actuator didn't play a role in the observed multi-puff/loading effect. Conclusions. The collection of the least amount of aerosol in a cascade impactor provides a better estimate of MMAD, as it minimizes modifications of the collection surfaces.     

Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and Next Generation pharmaceutical impactors and their USP methods

The particle sizing performance of a Next Generation Pharmaceutical Impactor (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of Vanceril MDIs containing beclomethasone dipropionate (BDP) was used throughout. MDIs were sampled into NGI and ACI in accordance with USP recommendations, at 30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or without a silicone cup or stage coating, to determine the apparent particle size distributions (PSD) of BDP. The mass balance and the statistical comparability of drug deposits were assured on a "per actuation basis" across all experiments, demonstrating "good cascade impactor practices." Interstage deposition or "wall losses" in NGI were found to be lower than those in ACI, although their determination was laborious in NGI. The PSD profiles for Vanceril from a single actuation were distinguishable between NGI and ACI, when uncoated collection surfaces were used, most specifically for drug mass <4-microm aerodynamic diameter (p < 0.05). Silicone coating of collection surfaces and an increased number of actuations were shown to result in PSD profile shifts for both NGI and ACI. Such effects were most pronounced for NGI, although coating the collection surfaces and/or increasing the number of actuations improved drug retention significantly on the upper stages of NGI, and thereby, minimized the effects of particle bounce of BDP from Vanceril MDIs. PSD profiles from a single actuation could be determined reliably in either of these impactors, provided that coated collection surfaces were employed; also, cumulative % mass undersize profiles were similar between instruments. However, small differences in PSD profiles still existed to support NGI's design claims for reduced "overlap" in its stage collection efficiency curves.     

Determination of Tablet Coating Distribution by Deconvolution of Uncoated and Coated Tablet Weight Distributions

Purpose. The purpose of this research is to obtain the tablet coating distribution from weight distributions of uncoated and coated tablets. Methods. The method of deconvolution with digital smoothing was used to calculate the distribution of coating applied to a tablet population from separate random measurements of individual uncoated and coated tablets. Results. It was demonstrated that the calculated coating weight distribution agrees well with the measured distribution. The effect of the smoothing factor on the solution is illustrated. Conclusions. This method can be used during development to facilitate process scale-up/optimization. In routine production, the method can assess the reproducibility and consistency of a coating process.     

Aerodynamic particle size of metered-dose inhalers determined by the quartz crystal microbalance and the Andersen cascade impactor.

Given the rapid sizing capability and high sensitivity, the quartz crystal microbalance (QCM) cascade impactor has been evaluated for the size determination of metered-dose inhaler (MDI) aerosols. The effects of surfactants present in MDI formulations, crystal coating, particle bounce and crystal overloading on the QCM cascade impactor are investigated. To reduce particle bounce, it is necessary to coat the crystals and use new coated surfaces for each measurement. Mass median aerodynamic diameters (MMADs) obtained from the QCM cascade impactor are compared to those from the commonly used Andersen cascade impactor. For MDI formulations containing little or no surfactants, MMADs obtained from the QCM and Andersen cascade impactors are comparable. For MDI formulations containing a significant amount of surfactant (or any non-volatile excipients), the QCM cascade impactor measures the combined size distribution of the drug and non-volatile excipients. A technique is devised in this study to deduce the drug-only size distribution from the QCM impactor for surfactant-containing MDI formulations and show comparable results to the Andersen cascade impactor except for high drug load Intal. The QCM impactor has proved to be a useful tool for rapid size measurement of MDI formulations.     

Protein Inhalation Powders: Spray Drying vs Spray Freeze Drying

Purpose. To develop a new technique, spray freeze drying, for preparing protein aerosol powders. Also, to compare the spray freeze-dried powders with spray-dried powders in terms of physical properties and aerosol performance. Methods. Protein powders were characterized using particle size analysis, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffractometry, and specific surface area measurement. Aerosol performance of the powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger or an Anderson cascade impactor. Two recombinant therapeutic proteins currently used for treating respiratory tract-related diseases, deoxyribonuclase (rhDNase) and anti-IgE monoclonal antibody (anti-IgE MAb), were employed and formulated with different carbohydrate excipients. Results. Through the same atomization but the different drying process, spray drying (SD) produced small (3 m), dense particles, but SFD resulted in large (8–10 m), porous particles. The fine particle fraction (FPF) of the spray freeze-dried powder was significantly better than that of the spray-dried powder, attributed to better aerodynamic properties. Powders collected from different stages of the cascade impactor were characterized, which confirmed the concept of aerodynamic particle size. Protein formulation played a major role in affecting the powder's aerosol performance, especially for the carbohydrate excipient of a high crystallization tendency. Conclusions. Spray freeze drying, as opposed to spray drying, produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties.     

Reducing bounce effects in the Andersen cascade impactor

The collection efficiency of the Andersen cascade impactor (ACI) can be affected by particle bounce, overload and re-entrainment (or blow-off), collectively referred to as bounce effects. Reduction of bounce effects in the ACI operated at 60 LPM was investigated for placebo large porous particles. Aerodynamic particle size distributions (aPSDs) obtained with the ACI and multi-stage liquid impinger (MSLI) were compared by observation of modes and statistical comparisons of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (sigmag). Particle bounce effects were prevalent in the ACI with uncoated plates, i.e., bi-modal distribution with statistically significant differences in MMAD and sigmag (P<0.05). Coating the impaction plates with a thin layer of vacuum grease and decreasing the ACI stage jet velocities reduced, but did not minimize bounce effects. Bounce effects were minimized using 20-microm pore glass fiber filters saturated in water placed on inverted impaction plates, with good agreement obtained between the ACI and MSLI aPSDs, i.e., mono-modal with no statistically significant differences in MMAD and sigmag (P>0.05). Selection of the impaction substrate material and solvent must be evaluated with the drug product and analytical methods to minimize bounce effects and obtain an accurate measure of the aPSD.     

Evaluation of coat uniformity and taste-masking efficiency of irregular-shaped drug particles coated in a modified tangential spray fluidized bed processor

Objective: To explore the feasibility of coating irregular-shaped drug particles in a modified tangential spray fluidized bed processor (FS processor) and evaluate the coated particles for their coat uniformity and taste-masking efficiency.

Methods: Paracetamol particles were coated to 20%, w/w weight gain using a taste-masking polymer insoluble in neutral and basic pH but soluble in acidic pH. In-process samples (5, 10 and 15%, w/w coat) and the resultant coated particles (20%, w/w coat) were collected to monitor the changes in their physicochemical attributes.

Results: After coating to 20%, w/w coat weight gain, the usable yield was 81% with minimal agglomeration (< 5%). Some aerodynamic modifications to particle shape and surface morphology were observed for the in-process samples with 5 and 10% coat compared with the uncoated particles. A 15%, w/w coat was optimal for inhibiting drug release in salivary pH with subsequent fast dissolution in simulated gastric pH.

Conclusion: The FS processor shows promise for direct coating of irregular-shaped drug particles with wide size distribution. The coated particles with 15% coat were sufficiently taste masked and could be useful for further application in orally disintegrating tablet platforms.     

Aerosol Electrostatics I: Properties of Fine Powders Before and After Aerosolization by Dry Powder Inhalers

Purpose. To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. Methods. Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohalerand prototype Dryhaler. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. Results. Both inhalers conferred triboelectric FPD charges during aerosolization in the range –400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate albuterol beclomethasone dipropionate. Conclusions. While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.     

In Situ Determination of Delavirdine Mesylate Particle Size in Solid Oral Dosage Forms

Purpose. The in-situ particle size of delavirdine mesylate in dry mix and tablets was determined. Methods. Optical microscopy and fluorescence microscopy combined with image analysis were used for qualitative and quantitative measurements. Results. Using optical microscopy, it was demonstrated qualitatively that fragmentation of the large drug particles was occurring during tablet compression. Quantitative comparisons between dry mix and tablet samples showed that in the dry mix, drug particles remain intact, with particle lengths exceeding 200 m. In the tablets, no particles longer than 100 m had been observed. Analysis of multiple tablet lots revealed consistent in-situ drug particle size distributions, regardless of the original bulk drug particle size. Conclusions. Bulk drug particle size of delavirdine mesylate is not predictive of the particle size in the tablet due to fragmentation of particles during compression. Optical and fluorescence microscopy are valuable tools for probing in-situ particle size in complex matrices.     

Adhesion of Powders for Inhalation: An Evaluation of Drug Detachment from Surfaces Following Deposition from Aerosol Streams

Purpose. To evaluate micronized powder retention and detachment from inhaler surfaces following reproducible deposition by impaction, coupled with centrifugal particle detachment (CPD). Methods. Micronized albuterol sulfate (AS) and beclomethasone dipropionate (BDP) were aerosolized as dry powders and deposited by cascade impaction onto different contact surfaces. Drug detachment from the surfaces was characterized using CPD, coupled with HPLC assay and scanning electron microscopy. Results. Drugs which accumulated as aggregates on model surfaces detached with distinctive profiles for % remaining vs. applied centrifugal force; each profile showed reproducible values for the minimum force required to initiate drug detachment, F_yield. While differences occurred in the observed detachment profiles for different drugs and contact surfaces (polyacetal vs. aluminum), the deposited drug particle size had the most significant effect on these profiles, e.g., F_yield for AS (2.1-3.3 m) was 383 12.7 N compared with 18 13.8 N for AS (4.7-5.8 m). Conclusions. A technique was developed which enabled the experimental review, and subsequent data analysis, of the adhesive properties between different DPI construction materials and drug substances deposited from aerosol clouds. The technique appears to be of greater relevance to inhaler design decisions than earlier studies in the literature claiming to show differences in the adhesion of single drug particles to surfaces.     

Hollow Porous Particles in Metered Dose Inhalers

Purpose. To assess the physical stability and aerosol characteristicsof suspensions of hollow porous microspheres (PulmoSpheres) inHFA-134a. Methods. Cromolyn sodium, albuterol sulfate, and formoterol fumaratemicrospheres were prepared by a spray-drying method. Particle sizeand morphology were determined via electron microscopy. Particleaggregation and suspension creaming times were assessed visually,and aerosol performance was determined via Andersen cascadeimpaction and dose uniformity studies. Results. The hollow porous particle morphology allows the propellantto permeate freely within the particles creating a novel form ofsuspension termed a homodispersion, wherein the dispersed and continuousphases are identical, separated by an insoluble interfacial layer of drugand excipient. Homodispersion formation improves suspension stabilityby minimizing the difference in density between the particles andthe medium, and by reducing attractive forces between particles. Theimproved physical stability leads to excellent dose uniformity. Excellentaerosolization efficiencies are also observed with PulmoSpheresformulations, with fine particle fractions of about 70%. Conclusions. The formation of hollow porous particles provides anew formulation technology for stabilizing suspensions of drugs inhydrofluoroalkane propellants with improved physical stability, contentuniformity, and aerosolization efficiency.     

A comparison of the pharmacokinetics of two different formulations of extended-release niacin

ABSTRACT

Objective: The objective of this study was to compare pharmacokinetic parameters of niacin extended-release tablets (NER uncoated)^* and niacin extended-release caplet formation (NER coated)^?.

Research design and methods: Twenty-five healthy male and female subjects were enrolled in a four-period, open-label, randomized, crossover study. Both NER uncoated and NER coated were given as 1 × 1000 mg or 2 × 500 mg tablets. Similarity of NER coated 1 × 1000 mg and NER uncoated 2 × 500 mg was declared if 90% confidence intervals for the geometric mean ratio (GMR) for nicotinuric acid (NUA) C_max fell within the pre-specified bounds of [0.7, 1.43].

Results: The GMRs for NUA C_max demonstrated similarity in the pharmacokinetics of NER uncoated 2 × 500 mg, NER coated 1 × 1000 mg, and NER coated 2 × 500 mg. Although less stringent comparability bounds were prespecified for the primary pharmacokinetic endpoint (i.e., C_max of plasma NUA), inspection of the primary comparison of interest indicated that a hypothesis with more stringent bioequivalence bounds of [0.8, 1.25] would have been satisfied. The NUA C_max for NER uncoated 1 × 1000 mg was approximately 40% higher than that seen for the other three treatments. In contrast, total urinary excretion of niacin and its metabolites, an approximate measure of bioavailability, was similar for all four treatments.

Conclusion: The pharmacokinetic profile of the original NER uncoated formulation dosed as 2 × 500 mg was similar to the new film-coated formulation, NER coated, dosed as 1 × 1000 mg.     

Cascade impactor practice for a high dose dry powder inhaler at 90 L/min: NGI versus modified 6-stage and 8-stage ACI

The compendial methods of particle size distribution (PSD) profile determination for dry powder inhalers (DPIs) were compared between the Next Generation Pharmaceutical Impactor (NGI) and the Andersen Cascade Impactor (ACI). Relenza Rotadisk (zanamivir) and Diskhaler was used as a model DPI and sampled into each impactor via its preseparator (PS), at 90 L/min under various protocols. In the NGI, silicone coating was shown to be indispensable to prevent or minimize particle bounce and reentrainment, and to reduce wall losses to the levels acceptable to the compendia (5%). In contrast, the ACI exceeded this 5% limit, regardless of coating, implying different wall loss mechanisms from the NGI. Particle bounce occurred in both impactors, inaccurately undersizing the PSD profiles for Relenza, unless the collection surfaces were coated or an increased number of doses were employed. Hence, the PSD profile for Relenza following single dose collection in the stage-coated NGI was the most accurate. In contrast, the use of the ACI and its PS for Relenza at 90 L/min suffered from several problems, even though the poorly designed PS still resulted in consistent impactor dose and PSD profiles, compared to those obtained from the NGI and its PS.     

The Role of Serum Complement on the Organ Distribution of Intravenously Administered Poly (methyl methacrylate) Nanoparticles: Effects of Pre-Coating with Plasma and with Serum Complement

Purpose. The organ distribution of radiolabeled poly (methyl methacrylate) (PMMA) nanoparticles coated with plasma proteins and serum complement in rats was studied in order to determine the effect of serum complement on the particle phagocytosis by the organs of the reticulo-endothelial system (RES). Methods. PMMA-nanoparticles were coated overnight with plasma proteins or serum complement, and injected into Wistar rats. The body distribution of nanoparticles was measured by means of scintillation counting of organ samples. In addition, proteins adsorbed to the particle surface were inactivated by heat treatment prior to injection, and the particles's distribution was measured as described above. Results. Whereas uncoated nanoparticles (control group) were mainly taken up by the Kupffer cells in the liver, incubation of the particles in plasma for 12 h followed by heat inactivation reduced the particle concentrations in the liver to merely 22% after 30 min. After 120 min, liver concentrations were still lower than the control group, and almost 30% of the administered dose of the heat-inactivated particle group was present in non-RES organs and tissues. Particles with non-inactivated complement were accumulated in the lung at concentrations of 29% after 30 min, which increased to 71% after 120 min, whereas those coated with inactivated complement reached lung concentrations above 70% already after 30 min. Conclusions. Particles coated with plasma components are able to avoid uptake by the RES, especially after heat inactivation of the plasma components adsorbed. Adsorption and heat inactivation of complement proteins alone, however, does not have the same result as coating with plasma proteins followed by heat inactivation. Therefore, it is concluded that plasma components other than complement proteins take part in the process of RES activation and phagocytosis of injected nanoparticles.     

The Effect of Low Concentrations of Molecularly Dispersed Poly(Vinylpyrrolidone) on Indomethacin Crystallization from the Amorphous State

Purpose. To investigate the effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) (PVP) on indomethacin (IMC) crystallization from the amorphous state using particle size effects to identify possible mechanisms of crystallization inhibition. Methods. Different particle sizes of amorphous IMC and 1, 2, and 5% PVP were stored dry at 30°C for 84 days. PXRD was used to calculate the rate and extent of crystallization and the polymorph formed. Results. Crystallization from amorphous IMC and IMC/PVP molecular dispersions yielded the polymorph of IMC. Crystallization rates were reduced at larger particle size and in the presence of 1, 2, and 5%PVP. Crystallization did not reach completion in some IMC/PVP samples, with the quantity of uncrystallized amorphous phase proportional to particle size. Conclusions. Low concentrations of molecularly dispersed PVP affected IMC crystallization from the amorphous state. Formation of -IMC at rates dependent on particle size indicated that surface nucleation predominated in both the absence and presence of PVP. Excellent correlation was seen between the extent of crystallization and simulated depths of crystal penetration, supporting the hypothesis that increasing local PVP concentration inhibits crystal growth from surface nuclei into the amorphous particle.     

Preparation and evaluation of slow-release pan-coated indomethacin granules

Abstract

Granules containing indomethacin crystals are coated with Eudragit solutions of different RL/RS ratios using a pan coating technique. The process is reproducible with regard to drug content, inexpensive and the formed granules were directly compressed into tablets. In vitro release of indomethacin from coated granules, tablets and capsules was studied as a function of different ratios of Eudragit RL/RS in the coating solution. The release of the drug was significantly reduced by the coating process in comparison with a formulation made from uncoated granules, prepared using 10 per cent gelatin solution as a binder. Release data were found to follow a diffusion-controlled model.     

Influence of Hydrodynamics and Particle Size on the Absorption of Felodipine in Labradors

Purpose. To study the influence of GI hydrodynamics and drug particle size on felodipine absorption in the dog. Methods. Labradors fistulated at midjejunum were used to selectively study the influence of hydrodynamics and particle size on the in vivodissolution and absorption of the poorly soluble, lipophilic drug felodipine. A combination of infusion and oral administration of either normal saline or a 5% glucose solution was used to maintain fasted and establish fed state motility patterns, respectively. The absorption characteristics of both a micronized (8 m) and a coarse fraction (125 m) of felodipine were subsequently studied under these two motility patterns. Results. A reduction in particle size led up to an approximate 22-fold increase in maximum plasma concentration and up to an approximate 14-fold increase in area under the curve, with a commensurate decrease in the time at which the maximum plasma concentration occurred. Although the absorption of felodipine from the solution and micronized suspension was not influenced by a change in the hydrodynamics, felodipine was absorbed from the coarse suspension almost twice as well in the fed state as under fasted conditions. Conclusions. Absorption from coarse suspensions of felodipine was sensitive to luminal hydrodynamics, whereas micronized suspensions were not. However, the particle size seems to have a much more important influence on the bioavailability of felodipine than the hydrodynamics per se.     

The Effects of Milling on the Surface Properties of Form I Paracetamol Crystals

Purpose The effects of milling and particle size on surface energies of form I paracetamol crystals are reported.Methods Paracetamol crystals (75–850 μm) were obtained by cooling methanol and acetone saturated solutions. Additionally, macroscopic (>2 cm) single crystals were grown by slow solvent evaporation from saturated solutions, ball milled and sieved into different particle size fractions. Surface properties were characterised using Inverse Gas Chromatography and compared with those calculated from sessile drop contact angle measurements on macroscopic single crystals.Results Dispersive surface energies, for milled samples increased by 20% with decreasing particle size. With decreasing particle size acceptor numbers, K _A values were constant but donor numbers, K _B decreased. For unmilled materials K _B was comparable to K _A but with a significantly lower of only 33 mJ/m². Milling resulted in fracture along the crystal's lowest attachment energy plane (010), exposing facets of different surface chemistry to that of the native external facets. θ for the (010) fracture plane confirmed a higher compared to external facets such as (011) of single crystals.Conclusions Milling exposes a hydrophobic surface for paracetamol form I crystals which becomes increasingly more dominant with decreasing particle size.     

Study of the Hygroscopic Properties of Selected Pharmaceutical Aerosols Using Single Particle Levitation

Purpose. To use a single particle levitation technique to investigate the equilibrium water sorption characteristics in both the evaporation and growth of four respiratory drugs at 37°C: atropine sulfate (AS), isoproterenol hydrochloride (IPHC) and isoproterenol hemisulfate (IPHS) and disodium cromoglycate (DSCG). Methods. The equilibrium water content was measured as a function of relative humidity (RH) by a single particle levitation technique using an electrodynamic balance (EDB). The change of water content was determined by the voltage required to balance the weight of the levitated particle electrostatically. The water activities of bulk samples were also measured. Growth ratios were determined and compared with values in the literature. Results. Crystallization or deliquescence was not observed for AS, IPHC and IPHS. The hysteresis in the water cycle was not observed for any of the drugs. At RH 0%, AS particles still contain about 5% water but IPHC and IPHS particles do not contain any residual water. The aerodynamic growth ratio from RH 0% to 99.5% is 2.60, 2.86, 2.42 and 1.26 for AS, IPHC, IPHS and DSCG, respectively. Super- saturated droplets of IPHC and IPHS are expected to exist in the am- bient conditions. DSCG is in a solid state in the RH range of 10-90%. Conclusions. It is expected that some aerosolized drugs of low solubility may experience supersaturation before they enter the human body and this could exert a significant influence both on particle loss before inhalation and on the deposition of the drugs in the lungs. The EDB is a convenient and reliable tool for studying the hygroscopic properties of pharmaceutical aerosols, especially for supersaturated solutions.