Particle Size Distribution of Single and Multiple Sprays of Salbutamol Metered-Dose Inhalers (MDIs)

Pharmaceutical Research -     

鼻用喷雾剂/气雾剂生物等效性评价及其统计学应用考量

目的 系统阐述局部作用的鼻用喷雾剂和鼻用气雾剂生物等效性（bioequivalence,BE）评估背景,以及美国、欧盟和中国监管机构对该类复杂药械组合BE评估的基本要求。方法 详细解释美国食品药品监督管理局（Food and Drug Administration,FDA）采用的创新性证据加权理念,和该类制剂BE评估的统计学原理、方法和考量。通过FDA颁布的布地奈德吸入混悬液指导原则和丙酸氟替卡松鼻用喷雾剂指导原则草案中的计算方法,通过R语言编程计算双侧和单侧群体生物等效性（population bioequivalence,PBE）计算统计学参数,并提供计算程序的伪代码。介绍了欧盟和中国对于鼻用喷雾剂和鼻用气雾剂相关的指导原则和评审理念。结果与结论 局部作用的鼻用喷雾剂/鼻用气雾剂为近年来新药及仿制药开发的热点,本文为该类制剂的研发、质量控制以及仿制制剂BE评价提供有益的思路与参考。     

Assessment of the Twin Impinger for Size Measurement of Metered-Dose Inhaler Sprays

The calibration of the first stage of the twin-stage impinger, an instrument proposed for use in measuring the spray size from metered-dose inhalers, was performed with monodisperse aerosols by a standard technique for cascade impactors. The mean cut point was found to be not particularly sensitive to operating variables which may be expected to occur in practice. The cut point was close to that reported previously, although the collection efficiency curve was found to be slightly sharper. Calculations are reported on the expected results of measurements on aerosols in a two-stage instrument with an idealized perfect collection efficiency curve as well as the curve measured for the twin impinger. These results indicate that important characteristics of spray size distribution cannot be distinguished with an ideal two-stage instrument; the twin impinger is less capable than an ideal instrument.     

Prediction and Assessment of Flammability Hazards Associated with Metered-Dose Inhalers Containing Flammable Propellants

Several potential replacements for chlorofluorocarbons (CFCs) in metered-dose inhalers (MDIs) are flammable. The flammability hazard associated with their use was assessed using a range of MDIs containing 0–100% (w/w) n-butane (flammable) in HFC-134a (nonflammable) fitted with either 25-, 63-, or 100-µl metering valves or continuous valves. In flame projection tests each MDI was fired horizontally into a flame, and the ignited flume length emitted from the MDI was measured. Flame projections of 60 cm were produced by all formulations fitted with continuous valves which contained 40% (w/w) n-butane in HFC-134a. Using metering valves the maximum flame projection obtained was 30 cm. This was observed with a formulation containing 90% (w/w) n-butane in HFC-134a and a 100-µl valve. For a particular formulation, smaller metering valves produced shorter flame projections. Because many MDIs are used in conjunction with extension devices, the likelihood of accidental propellant vapor ignition was determined in Nebuhaler and Inspirease reservoirs and a Breathancer spacer. Ignition was predictable based on propellant composition, metered volume, number of actuations, and spacer capacity. Calculated n-butane concentrations in excess of the lower flammability limit [LFL; 1.9% (v/v)] but below the upper flammability limit [UFL; 8.5% (v/v)] were usually predictive of flammability following ignition by a glowing nichrome wire mounted inside the extension device. No ignition was predicted or observed following one or two 25-µl actuations of 100% n-butane into large volume Nebuhaler (750 ml) or Inspirease (660 ml) devices. Additionally, several other formulations containing lower proportions of n-butane also remained nonflammable, due to failure to reach the LFL. In the small-volume Breathancer spacer (140 ml), nonflammability was usually due to n-butane exceeding its UFL. In this situation further dilution during respiration could result in a flammable mixture. Using a carefully selected propellant blend, metering volume, and spacer design, environmentally acceptable flammable propellants may have considerable utility in MDIs reformulated without CFCs.     

Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays

Purpose

Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution.

Methods

In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 \( \mu \mathrm{g} \) / \( \mu \kern-.5pt \mathrm{L} \) IPBr.

Results

Instantaneous concentration measurements were obtained with 1 ms temporal resolution and 5 \( \mu \mathrm{m} \) spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo.

Conclusions

Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.

     

高效液相法测定盐酸氮卓斯汀鼻喷剂的含量

目的：建立测定盐酸氮卓斯汀鼻喷剂中盐酸氮卓斯汀含量的高效液相色谱方法。方法：色谱柱：Diamonsil C_（18）柱（250 mm×4.6 mm,5μm）;流动相：4%三乙胺（用醋酸调节pH至6.0）-乙腈-甲醇（45：21：34）;检测波长：289 nm;流速：1.0ml·min~（-1）;柱温：30℃。结果：盐酸氮卓斯汀在80~800μg·ml~（-1）范围内呈良好的线性关系（r=1.000 0）,平均加样回收率为99.93%,RSD=0.82%（n=9）。结论：本方法操作简便,灵敏,结果准确可靠,可用于盐酸氮卓斯汀鼻喷剂的质量控制。     

复方氧氟沙星酮替芬鼻用喷雾剂的制备及质量控制

目的:制备复方氧氟沙星酮替芬鼻用喷雾剂并建立其质量控制方法。方法:以氧氟沙星、富马酸酮替芬、盐酸麻黄碱为主药制备鼻用喷雾剂;采用高效液相色谱法测定其中主药含量。结果:该制剂各项检查均符合鼻用喷雾剂的有关规定;检测浓度氧氟沙星在30～300mg.L-1(r=0.9999)、富马酸酮替芬在20～200mg.L-1(r=0.9998)、盐酸麻黄碱在100～1000mg.L-1(r=0.9998)范围内呈良好的线性关系,平均回收率分别为99.29%(RSD=1.08%)、100.1%(RSD=1.61%)、99.98%(RSD=1.23%)。结论:本制剂制备工艺简单,性质稳定,质量可控。     

高效液相色谱法测定鲑鱼降钙素鼻喷剂的含量

目的用高效液相色谱法(HPLC法)测定鲑鱼降钙素鼻喷剂的含量及有关物质。方法采用HypersilODS-C18柱(100mm×4.6mm,5μm),以pH=3.0的1mol/L氢氧化四甲基铵-水-乙腈(4∶346∶150)为流动相,紫外检测波长为210nm,流速为1.0mL/min,柱温为40℃,按外标法以峰面积计算含量。结果辅料和降解产物等对主药测定无干扰,鲑鱼降钙素浓度在3.0～30.0μg/mL范围内与峰面积线性关系良好,回归方程为Y=53043.65X-11917.89,r=0.9996,最低检出浓度为0.5μg/mL,平均回收率为99.81%(n=5)。结论HPLC法准确、可靠、重现性好,可用于鲑鱼降钙素鼻喷剂的含量及有关物质的测定。     

HPLC法测定复方芩苍鼻喷雾剂中黄芩苷的含量

目的:建立测定复方芩苍鼻喷雾剂中黄芩苷含量的方法。方法:采用高效液相色谱法。色谱柱为Waters Symmetry C18(150mm×4.6mm,5μm),流动相为甲醇-水-磷酸(47:53:0.2,V/V/V),流速为1.0ml/min,检测波长为280nm,柱温为20℃。结果:黄芩苷的质量浓度在6.2～310.0μg/ml范围内与峰面积积分值呈良好线性关系(r=0.9993);平均加样回收率为98.72%,RSD=0.89%(n=9)。结论:本方法简便、快速、准确、重复性好,可用于复方芩苍鼻喷雾剂中黄芩苷的含量测定。     

Single-Puff Particle-Size Analysis of Albuterol Metered-Dose Inhalers (MDIs) by High-Pressure Liquid Chromatography with Electrochemical Detection (HPLC-EC)

Pharmaceutical Research -     

RP-HPLC法测定单硝酸异山梨酯鼻腔喷雾剂的含量和有关物质

目的:建立测定单硝酸异山梨酯鼻腔喷雾剂含量及有关物质的方法。方法:采用反相高效液相色谱法。色谱柱为Di-amonsil C18柱,流动相为甲醇-水(30∶70),流速为1.0mL·min-1,检测波长为210nm,进样量为20μL;峰面积定量采用外标法。结果:单硝酸异山梨酯回归方程为Y=7892.7X+2980.7(r=0.9999),检测浓度在5～150μg·mL-1范围内与峰面积积分值线性关系良好;最低检出浓度为20ng·mL-1;高、中、低浓度日内、日间精密度的RSD在0.31%～0.93%之间;重复性试验RSD=0.69%(n=9);样品的平均回收率为101.02%(RSD=1.12%,n=9)。结论:该法准确、可靠、重复性好,可用于单硝酸异山梨酯鼻腔喷雾剂的含量及有关物质的测定。     

糠酸莫米松鼻喷雾剂联合孟鲁司特治疗变应性鼻炎效果观察

目的：观察糠酸莫米松鼻喷雾剂与孟鲁司特联合治疗变应性鼻炎（AR）的疗效及预防复发作用。方法：74例AR患者随机分为观察组和对照组。观察组患者予糠酸莫米松鼻喷剂联合孟鲁司特片治疗,对照组患者仅予糠酸莫米松鼻喷剂治疗,两组疗程均为4周。观察并比较两组临床疗效及药品不良反应,随访1年后比较两组复发率。结果：观察组总有效率（94.59%）明显高于对照组（78.38%）,1年内复发率（22.86%）明显低于对照组（48.28%）,差异均有统计学意义（P〈0.05）。两组药品不良反应发生率比较,差异无统计学意义（P〉0.05）。结论：糠酸莫米松鼻喷剂联合孟鲁司特治疗AR疗效优于单用糠酸莫米松治疗,能降低AR复发率,且安全性好。     

中国鼻用喷雾剂注册临床试验近10年现状分析

目的 分析中国近10年鼻用喷雾剂注册临床试验现状及特点,结合国际研究现状,探讨中国鼻用喷雾剂药物的未来发展趋势。方法 检索国家药品监督管理局药物临床试验登记与信息公示平台（http：//www.chinadrugtrials.org.cn/index.html）,收集开放注册日（2012年11月1日）至2023年3月29日中国鼻用喷雾剂药物临床试验信息,使用Microsoft Office Excel软件进行系统性分析,从临床试验状态、适应证、地域分布和试验分期、试验设计类型等多个方面分析鼻用喷雾剂临床试验的现状与特点。结果 共80项鼻用喷雾剂临床试验,均为国内试验,其中Ⅰ期24项（30.0%）,Ⅱ期15项（18.8%）,Ⅲ期13项（16.3%）,Ⅳ期3项（3.8%）,生物等效性试验17项（21.3%）,其他（药动学/药效学研究）共8项（10.0%）。临床试验状态有进行中（尚未招募）13项（16.3%）、进行中（招募完成）7项（8.8%）、进行中（招募中）15项（18.8%）、已完成44项（55.0%）、主动终止1项（1.3%）。Ⅰ~Ⅳ期临床试验共56项,其中平行分组试验41项（73.2%）,交叉设计试验14项（25.0%）,单臂试验1项（1.8%）。化学药品共65项（81.3%）、生物制品7项（8.8%）和中药/天然药物8项（10.0%）。适应证包括过敏性鼻炎、镇静、干眼、阵发性室上心动过速等共15种。结论 中国鼻用喷雾剂研发尚处于早期阶段,但紧跟国际,自主创新能力不断加强,未来应探索更多新的鼻用喷雾剂临床研究方向与策略,助力鼻用喷雾剂发展,满足更多患者的需求。     

Measurement of Drug in Small Particles from Aqueous Nasal Sprays by Andersen Cascade Impactor

Purpose

To determine if cascade impactor (CI) measurement of drug in small particles from aqueous nasal sprays, described in FDA’s 2003 draft Nasal Bioavailability/Bioequivalence Guidance, can be optimized to reduce measurement variability. To examine the influence of flow rate configurations and number of impactor stages on CI deposition and explore the importance of inlet volume.

Methods

A total of eight assemblies and manual vs. automatic actuation were tested for deposition on the sum of all stages of the CI, and for Group 2 total drug mass per the Guidance. Mean deposition and variance about the mean were determined for each assembly.

Results

The path length for a spherical 1?l inlet was too short to allow adequate aerosol formation. Data variance was reduced by a factor of two or more by using an automatic actuator relative to manual actuation. Impactor assembly modification did not improve variance over the standard assembly.

Conclusions

Use of a spherical inlet (≥2?l volume) and automatic actuation are recommended for comparative measurements of drug in small particles arising from aqueous nasal sprays. The standard (8-stage) 28.3?lpm CI flow rate configuration is recommended when using the Andersen Cascade Impactor (ACI), as no other assembly showed a distinct advantage.     

Evaluation of Disintegration Testing of Different Fast Dissolving Tablets Using the Texture Analyzer

The in vitro disintegration behavior of fast dissolving systems manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument. Quantitative parameters were employed to characterize the effect of the major test variables on the disintegration profiles. The average disintegration profiles of the products were compared using the test conditions that minimized these effects and at the same time mimicked the in vivo situation in the patient's mouth. The differences in the disintegration mechanisms of the fast dissolving systems were reflected in the shape of their disintegration profiles and in the parameters derived from the profiles. The differences were explained in relation to the technology and/or formulation characteristics involved in the manufacture of each product. The in vitro disintegration times obtained under the simulated in vivo conditions were correlated with the reported in vivo disintegration times.     

压力定量吸入剂的质量评价与影响因素

综述在设计和制备压力定量吸入剂产品时,其质量评价内容及处方和装置的影响因素。压力定量吸入剂的处方设计包括药物、抛射剂、表面活性剂、助溶剂等的应用,对产品的质量起着至关重要的作用,尤其是氯氟烃类抛射剂逐步被淘汰后,其替代品种呈现多元化,致使处方因素对产品质量的影响变得复杂和不可预知。     

Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways

Pharmaceutical Research - Nasal delivery is a favorable route for vaccination against most respiratory infections, as antigen deposited in the nasal turbinate and Waldeyer’s ring areas induce...     

In Vitro Evaluation of the Effect of Metered-Dose Inhaler Administration Technique on Aerosolized Drug Delivery

The administration of aerosolized metered-dose inhalers (MDIs) to mechanically ventilated patients is labor intensive due to the large number of activations required and the currently recommended 30- to 60-second “wait and shake” between each puff. No studies have been published that assess the relationship between this delay between puffs and drug delivery. To address this issue, we conducted an in vitro, randomized, single-blind study using fenoterol MDI containing technetium-99m pertechnetate. Four modes of MDI administration were tested in triplicate by random sequence. Eight activations of the MDI were performed for each mode according to the following procedures: rapid succession (5 sec apart); 30-second intervals and shaking MDI between two rapid activations; 30-second intervals and shaking between each activation; and 60-second intervals and shaking between each activation. Two closed in vitro systems were designed to collect and measure the radiolabeled aerosol. In the first system, the MDI was activated into a plastic collection container; with the second system, the MDI was administered through an aerosol holding chamber with attached circuit filter positioned on the inspiratory line of the ventilator circuit. Sixty-second intervals between each activation were not tested with the second system. Radioactivity was measured before and after each mode of testing. No difference was found between the various modes of administration other than a 14% decrease in the amount of radioactivity released with the 60-second waiting period between puffs, compared with their rapid succession when using the plastic collection container system. Our results support the hypothesis that the delay after each activation of a MDI may not be necessary.     

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r² values ranged between 0.46 and 0.90 and the secondary OA increased the r² values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r² 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.     

InVitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort^® Turbuhaler^®, and Sultanol^® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort^® Turbuhaler^® (DPI). Conversely, lower PFR is desirable for Sultanol^® Inhaler (pMDI).