载体对微粉型粉雾剂呼吸道沉降的影响

目的：研究载体对微粉型粉雾剂呼吸道沉降的影响，筛选适合的载体组成和制备工艺。方法：以硫酸沙丁胺醇为模型药物，选用双冲程碰撞试验仪，评价以乳糖、甘露醇为载体的微粉型粉雾剂对药物在呼吸道沉降的影响。结果：含药甘露醇溶液喷雾干燥微粉，在模拟肺部药和沉降量最大（30．2％），明显高于两者分别喷雾干燥微粉的物理混合物（4．9％），处方中加入2％泊洛沙姆，并不显著增加药物沉降量；而以乳糖为载体时，呼吸道沉降量并不受乳糖介入方式的影响，但处方加入2％洛沙姆有助于提高药物在模拟肺部沉降。结论：选用甘露醇为载体以喷雾干燥法可制得较理想的微粉型粉雾剂。     

粉雾剂中乳糖对药物在模拟呼吸道沉降部位的影响

以硫酸沙丁胺醇为模型药物,以休止角为流动性指标。选用双冲程碰撞试验仪,评价乳糖的类型、大小对粉雾剂流动性以及对药物在呼吸道沉降的影响。结果显示,重结晶乳糖休止角较市售乳糖小,并优选其粒径54-100μm的为粉雾剂载体,呼吸道沉降研究结果显示,在各粒径区域,以粒径54-100μm重结晶乳糖为载体的物理混合型粉雾剂在模拟肺部沉降量最大。     

盐酸丙卡特罗粉雾剂治疗支气管哮喘中度急性发作的疗效观察

目的客观评价盐酸丙卡特罗粉雾剂治疗支气管哮喘中度急性发作的疗效。方法以硫酸沙丁胺醇气雾剂为阳性药物平行对照比较两种药物之间的有效性。结果共343例完成研究,其中使用盐酸丙卡丙卡特罗粉雾剂172例,使用硫酸沙丁胺醇气雾剂171例,经统计学分析,两种药物对哮喘症状改善维持率差异无统计学意义。结论盐酸丙卡特罗粉雾剂治疗支气管哮喘中度急性发作安全有效,与硫酸沙丁胺醇气雾剂相似。     

硫酸沙丁胺醇缓释胶囊的研制

以硬脂酸为主要辅料,采用熔融制粒法,制备了硫酸沙丁胺醇绥释胶囊,并对其溶出度进行了研究。     

沙丁胺醇吸入粉雾剂与气雾剂治疗支气管哮喘的随机对照多中心研究

目的比较沙丁胺醇吸入粉雾剂与吸入气雾剂治疗中、重度支气管哮喘的临床疗效和安全性。方法采用随机、单盲、多中心阳性对照临床试验方法。共入选219例中、重度支气管哮喘患者,随机分为两组。试验组患者通过茜乐装置吸入沙丁胺醇吸入粉雾剂400μg(2吸),对照组通过储雾罐吸入沙丁胺醇气雾剂400μg(4吸)。检测两组吸药后15、30、45、60、120、180、240 min不同时间点第一秒用力呼气容积(FEV1)、用力肺活量(FVC)和最大呼气流速(PEF)值,计算FEV1、FVC和PEF曲线下面积,观察肺部症状及体征变化及不良事件发生情况。结果吸药后两组各时间点FEV1、FVC和PEF均较治疗前改善(P<0.05),作用均可持续4 h,组间无显著差异(P>0.05),两组FEV1、FVC和PEF曲线下面积亦无显著差异(P>0.05)。两组患者吸药后咳嗽、呼吸困难及肺部干啰音均有不同程度的改善,组间无显著差异(P>0.05)。两组不良事件的发生率相似,试验组为11.4%,对照组为13.4%,与药物相关不良事件的发生率分别为0.9%和对照组5.4%,组间差异均无显著意义(P>0.05)。整个研究过程两组均无严重不良事件发生。结论同等剂量沙丁胺醇吸入粉雾剂与气雾剂通过茜乐干粉吸入器和储雾罐吸入,均可明显改善中、重度支气管哮喘患者的肺功能和肺部症状,安全性较好。     

HPLC法测定硫酸左旋沙丁胺醇缓释微丸胶囊的含量及其有关物质

目的：建立HPLC测定硫酸左旋沙丁胺醇缓释微丸胶囊含量及其有关物质。方法：色谱柱：Chirex（s）-ICAand（R）-NEA（250mm×4．6mm,5μm）,流动相：正己烷-二氯甲烷-甲醇-三氟乙酸（240：240：20：1）,检测波长：278nm,流速：1ml·min^-1,柱温：30℃,进样量：20μl。结果：硫酸左旋沙丁胺醇检测浓度的线性范围为1．00～6．03μg（r=0．9995）;平均回收率为99．94％（RSD：0．1％）。结论：本方法简便、准确、专属性强,可用于该制剂的质量控制。     

吸气流速对载体型粉雾剂分散行为影响的考察

本试验考察了吸入气流大小对以HandiHaler(R)为药物递送装置的载体型粉雾剂中粉末分散、沉积表现的影响.将载体乳糖Lactohale LH206与微粉化马来酸氯苯那敏混合,制得制剂粉末模型,利用新一代撞击器分析制剂粉末在20、30、40、50、60 L/min流速下的分散表现.同时,运用计算流体力学耦合离散元建模...     

左旋沙丁胺醇盐酸盐的合成

目的研究左旋沙丁胺醇盐酸盐的合成方法。方法以水杨醛和溴乙酰氯为原料经Friedel-Crafts酰基化反应、取代反应合成5-[[(1,1-二甲基乙基)胺基]乙酰基]-2-羟基苯甲醛盐酸盐(4),再经手性铑配合物催化的不对称氢转移反应协同还原得到左旋沙丁胺醇(5),最后与盐酸成盐制得左旋沙丁胺醇盐酸盐(1)。结果与结论以水杨醛计,4步反应总收率为35.6%,对映体过量值达92%,该合成路线易行。目标产物的结构经质谱、红外光谱和核磁共振氢谱确证。     

盐酸左旋沙丁胺醇治疗轻、中度支气管哮喘的随机双盲对照多中心临床研究

目的 评价盐酸左旋沙丁胺醇(β2受体激动剂,治疗支气管哮喘药)治疗轻、中度支气管哮喘的有效性和安全性.方法 用随机、双盲、对照临床研究,122例轻、中度支气管哮喘患者随机分为2组,试验组口服盐酸左旋沙丁胺醇片1.15 mg,对照组口服硫酸沙丁胺醇2 mg,每日3次,疗程(14±2)天.结果 与治疗前相比,试验组的第1秒用力呼气容积占预计值(FEV1%)、第1秒用力呼气容积值(FEV1)和第1秒用力呼气容积与用力肺活量的比值(FEV1/FVC)均有明显升高,具有显著的统计学差异(P≤0.05);对照组治疗前后无明显变化.试验组与对照组的不良反应发生率分别为12.5%和15.3%,2组间比较无显著性差异.结论 治疗轻中、度支气管哮喘2组具有相同的临床疗效和安全性;但试验组在肺功能改善方面明显优于对照组.     

影响吸入粉雾剂分散性能的制剂因素

综述了影响吸入粉雾剂分散性能的主要制刺因素，简要介绍了近年来提高粉雾剂性能的制剂方法的研究进展和有关研发和评价的新技术。     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

干粉吸入剂的研究进展

干粉吸入剂（DPI）具有独特的吸收方式和药动学特点,与定量气雾剂相比优点突出。粉体工学性质和给药装置设计一直是制约该剂型发展的重要因素。近十几年来随着药物微粉化技术和新型给药装置研究的不断进步,其应用范围越来越广,在国际药物制剂研发方面呈快速发展趋势。现参考国内外研究文献,对DPI给药方式的药物作用特点、DPI药物及载体粉末性质以及目前吸入装置的种类及主要特点等进行综述。     

干粉吸入剂的有效性及质量评价

综述了影响干粉吸入剂有效性的因素,并对其体内外测定方法及质量控制进行了概述.     

新型肺部给药系统-吸入粉雾剂

吸入粉雾剂 (又名粉雾吸入剂、干粉吸入剂、粉雾剂) 是一种新型的肺部给药系统, 具有稳定性好, 不含抛射剂氟里昂等优点, 近年来受到人们的广泛关注。粉雾剂由粉末吸入装置和供吸入用的干粉组成。本文就近年来粉雾剂的研究进展, 包括吸收机制, 粉雾剂品种, 吸入装置, 制备技术和评价特征参数等进行了综述。     

吸入粉雾剂的处方研究和制备工艺

吸入粉雾剂在治疗肺部疾病,如哮喘、慢性阻塞性肺病中应用广泛.文中广泛查阅欧盟、美国等国的吸入粉雾剂研发的要求,结合国内该剂型的研发和审批情况,对吸入粉雾剂的组成、处方筛选以及制备工艺进行详细的阐述.对吸入粉雾剂在处方筛选与制备过程中的影响因素加以详细讨论,为研发粉雾剂药学工作者提供有益的参考.     

The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers

Previous studies have reported that carrier:drug ratio and carrier size influence the aerosol performance of dry powder inhalation systems. These previous studies were complicated by the heterogeneous nature of the carriers used, making it difficult to define an explicit relationship between parameters and performance. Here, the authors studied the influence of drug loading and carrier size on drug aerosol performance using homogeneous spherical model carriers. Different formulations containing drug (salbutamol sulphate) and carriers (polystyrene beads with median diameters of 82.8 μm, 277.5 μm and 582.9 μm, respectively) were prepared by varying the ratio of carrier to drug (from ∼5:1 to ∼85:1). The surface morphology of the carrier particles and force of adhesion were investigated using atomic force microscopy, while the aerosol performance was evaluated using a multi-stage liquid impinger. The carrier surface morphology for all carrier sizes was homogenous with root-mean square roughness values ≤112 nm. No significant difference in the force of adhesion between salbutamol sulphate and the three carrier sizes was observed. Significant differences in aerosol performance of salbutamol sulphate (measured as fine particle dose (FPD) and fraction (FPF) ≤ 5 μm) from the carriers were observed. Specifically, as carrier size increased FPF decreased. In comparison, as drug loading increased there was no change in FPF until a critical threshold was exceeded. Such observations suggest that: (A) aerosolisation performance is governed by carrier collisions and (B) when homogeneous carriers are used, the aerosol performance remains constant with respect to drug concentration, until the formulation transitions from an ordered mix to an agglomerated and/or segregated powder bed.     

Low density,good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

Background: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency.

Methods: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations.

Results: The optimal formulation of CRBC (R₄) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R₄ was c.a. 5% which was far lower than spray-dried raffinose (R₀, c.a. 65%). R₄ exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R₀. The pulmonary and plasmatic bioavailability of R₄ were significantly higher than R₀ (p < 0.05).

Conclusion: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.     

干粉吸入剂的粉末定量分装设备浅析

干粉吸入剂是一种新兴呼吸道给药剂型,其吸入粉末的分装装置不同于常见的口服固体粉末分装装置。本文综述国际上常用的干粉吸入剂的粉末定量分装装置,包括标准定量器装置装置、真空滚筒分装装置、Xcelodose精确粉末微定量装置等,同时介绍几种较新的、处于研发阶段的粉末分装装置。     

盐酸氨溴索干粉吸入剂的制备工艺

目的优化盐酸氨溴索干粉吸入剂的制备工艺。方法采用喷雾干燥法制备盐酸氨溴索干粉吸入剂,采用双层液体碰撞器测定盐酸氨溴索干粉吸入剂体外沉积率,扫描电镜观察粉粒的形态,激光粒度测定仪测定粒径大小,以产品收率、粉末的空气动力学径、休止角及体外沉积率为考察指标,通过正交设计结合多指标综合评价法优化最佳制备工艺。结果通过正交试验-多指标综合评价,最佳制备工艺为:进口温度110℃、喷液速度1.8 mL.min-1、泵压170 kPa、气流量0.7 m3.min-1。结论按最佳制备工艺制得的干粉收率的质量分数为62.10%,空气动力学径Da 3.05μm,休止角36.16°,沉积率32.05%。正交实验结合多指标综合评价法用于盐酸氨溴索干粉吸入剂制备工艺的优化实用有效。