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.     

呼吸道给药的新剂型——粉雾剂

粉雾剂因不含抛射剂及可避免使用时的协同困难而越来越受到人们的重视，并有取代气雾剂的趋势。早在８０年代初国外即已对偻雾剂进行了深入的研究，而国内尚处于起步阶段。本文概述粉雾剂的发展，比较了粉雾剂与氯雾剂优缺点，对组成粉雾剂的药物粉末的处方设计及呼入装置进行了论述，并指出用于吸入疗法的粉雾剂的研究开发应用从三个文献考虑：粉末的雾化、吸入装置的转运性能和病人的肿气产生的雾化能量。     

雾化吸入用液体制剂的研究与应用

目前,吸入疗法越来越受欢迎,已成为治疗哮喘和慢性阻塞性肺病的常用治疗手段。临床上常用的吸入制剂包括吸入气雾剂、吸入粉雾剂和雾化吸入用液体制剂。其中,雾化吸入用液体制剂不仅可避免吸入气雾剂中抛射剂污染环境、呼吸和启动雾化协调性要求较高等问题,还可避免吸入粉雾剂吸湿性强、对吸气流速要求较高等缺点。近几年来雾化吸入用液体制剂在药物种类、治疗疾病类型等方面都有了进一步的发展,本文就该类制剂雾化器的种类和临床应用等方面进行综述。     

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。     

吸入粉雾剂产业化过程中的质量控制

吸入制剂尤其是吸入粉雾剂结构和功能的特殊性，决定其在产业化过程中质量控制的特异性。讨论吸入粉雾剂产业化过程中原辅料、包材、中间体、终产品及稳定性考察过程中的质量控制特异性考察项目及标准设定。     

吸入装置辅导视频制作及效果评价

目的:评估用药辅导视频对提高离院患者吸入装置正确使用能力的效果。方法:制作空气压缩雾化机、压力定量气雾剂+储雾罐(面罩)和吸入粉雾剂(都保)的用药辅导视频,对用药辅导视频的使用效果进行问卷调查,每项调查选取100例患者,先让患者观看药品及空气压缩雾化机使用说明书,进行评分(评分1),后让患者观看视频后学习使用,进行评分(评分2)。应用SPSS 22.0统计学软件分析评分结果。结果:相较于单纯阅读说明书,辅导视频可以有效提高空气压缩雾化机(Z=-8.231,P<0.01)、压力定量气雾剂+储雾罐(面罩,Z=-8.518,P<0.01)和吸入粉雾剂(都保)的正确使用率(Z=-8.145,P<0.01)。结论:用药辅导视频可以有效提高患者正确使用空气压缩雾化机、压力定量气雾剂+储雾罐(面罩)和吸入粉雾剂(都保)的能力。     

布地奈德粉雾剂的制备及质量控制

目的将布地奈德制备成胶囊型吸入粉雾剂,并对其进行初步质量研究,为同类制剂提供质量研究参考。方法采用SCF技术进行原料药微粉化,选用乳糖作载体,以处方量制备粉雾剂,并以粉体的休止角、排空率,胶囊药物含量及均匀度为指标对6批样品测定其质量性能。结果微粉粒径均在0.5～5μm,以每粒胶囊含主药0.2mg,含载体25mg的处方量,采用等量倍增稀释法混合制成粉雾剂,测得6批样品的休止角Ф<40°,排空率均在95%以上。结论按选定的制备方法和处方制得的粉雾剂粒子细小且分布均匀,流动性更好,分散性更强,含量及均匀度合格,有利于生产和使用。     

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。     

吸入粉雾剂的研究进展

综述了提高吸入粉雾剂雾化性能的方法、粉雾剂的体外评价手段和生物药剂学研究方法等方面的进展状况.着重介绍了大多孔粒子和纳米粒的聚合物对提高粉雾剂物化性能的作用.     

经口吸入制剂的研究进展

经口吸入制剂是由不同原理的气溶胶发生装置与相应药物形态结合成的药械组合产品,是目前防治哮喘、慢性阻塞性肺疾病(COPD)等呼吸道疾病的首选.吸入制剂不仅制剂的研发具有技术挑战,其使用也存在诸多困难.本研究总结了国内外近年来关于经口吸入制剂在改善患者用药依从性、克服递送剂量限制、控制颗粒特性以改善雾化效果和拓展治疗领域的...     

Latest advances in the development of dry powder inhalers

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.     

吸入粉雾剂工程颗粒技术研究

对于吸入粉雾剂来说,由于活性药物成分（API）较小的粒径和较高的表面能,导致微粉易于团聚,难以分散。微粒间的内聚力和微粒与乳糖间的粘附力导致粉雾剂产品较低的微细粒子比例（FPF）。通过工程颗粒可以改善API微粒的物化性质,进而显著提高DPI产品的递送效率。概述通过工程颗粒的制备API微粉的方法,包括反溶剂结晶、湿法粉碎/研磨、喷雾/冷冻干燥、超临界流体等方法,可以显著提高粉雾剂的雾化性能。     

A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.     

Bovine serum albumin as a lyoprotectant for preparation of DNA dry powder formulations using the spray-freeze drying method

The development of efficient and selective therapeutic gene delivery methods is a potential medical treatment for intractable diseases. Dry powder inhalers (DPIs) can efficiently deliver drugs locally to the lung. Many reports discuss preparation methods for DPIs. Spray-freeze drying is a method by which highly porous particulates can be prepared. However, altered physical properties after preparation may result in changes in gene expression. In this study, bovine serum albumin (BSA) was added as a lyoprotectant, and 1,2-dioleoyl-3-trimethylammonium propane/cholesterol liposomes/pCMV-Luc DPIs (lipoplex DPIs) were prepared by spray-freeze drying. The mean particle sizes of the lipoplex DPIs prepared without BSA increased by approximately 6.7-fold compared with that of the lipoplexes solution. In contrast, the mean particle sizes of the lipoplex/BSA DPIs increased only slightly. Gene expression was evaluated after the intratracheal administration of the lipoplexes solution, with maximum gene expression observed at 12?h after the administration. In contrast, maximum gene expression of the lipoplex/BSA DPIs occurred at 6?h after administration. The gene expression associated with the lipoplex DPIs was significantly lower compared with that of the lipoplex/BSA DPIs at 6 (p<0.01), 12 (p<0.01), and 24?h (p<0.05). These variances may be due to the difference in mean particle size between the DPI formulations. The results suggest that BSA is a useful lyoprotectant for dry powder formulation preparations of DNA using the spray-freeze drying method, given that the preparation results in minimal variation of physical properties and gene expression.     

Highly reproducible powder aerosolisation for lung delivery using powder-specific electromechanical vibration

Dry powder inhalers (DPIs) have been in use since the 1970s, but it is only within the past few years that their use has constituted > approximately 10% of the inhaler units sold worldwide. Similarly, active DPIs have been in development for more than a decade, but no active device has yet been approved. Oriel is developing an active DPI technology that uses a very simple physical design coupled with a complex knowledge of powder flow and dispersion characterisation. The DPI uses electromechanical vibration with frequencies determined through the analysis of powder flow properties. Results so far have shown highly reproducible, efficient performance. The technology lends itself to both unit-dose and multidose platforms in a targeted cost-effective DPI.     

Highly reproducible powder aerosolisation for lung delivery using powder-specific electromechanical vibration

Dry powder inhalers (DPIs) have been in use since the 1970s, but it is only within the past few years that their use has constituted > ～ 10% of the inhaler units sold worldwide. Similarly, active DPIs have been in development for more than a decade, but no active device has yet been approved. Oriel is developing an active DPI technology that uses a very simple physical design coupled with a complex knowledge of powder flow and dispersion characterisation. The DPI uses electromechanical vibration with frequencies determined through the analysis of powder flow properties. Results so far have shown highly reproducible, efficient performance. The technology lends itself to both unit-dose and multidose platforms in a targeted cost-effective DPI.     

Dose emissions from marketed dry powder inhalers

The dose emission characteristics of eight marketed dry powder inhalers (DPIs: Intal Spinhaler®, Ventolin and Becotide Diskhalers®, Ventolin and Becotide Rotahalers®, Bricanyl and Pulmicort Turbohalers®, Berotec Inhalator® have been investigated using the proposed USP dosage unit sampling apparatus for DPIs. Intra- and inter-device variation in emitted doses was determined at air flow rates of 60 and 100 1/min using a 4 1 air throughput in each case except Inhalator®, which was tested at 30 l/min only. The sampling apparatus was found to be suitable for quantifying single emitted doses from all of these devices which comprise examples of low, medium and high airflow resistance DPIs (Table 1 footnote). Dose emissions from the DPIs are presented as percentages of the manufacturers' label claims. Under all test flow conditions variability was high, when compared to the uniformity of content standards usually applied to pharmaceutical products; in some cases relative standard deviations (RSD) were greater than 15%, both within and between devices. However, under the proposed USP test flow rate conditions, the total RSD (n = 25) was < 15% around the average emitted dose in all cases except Pulmicort Turbohaler®; such variance (RSD< 15%) is proposed to be acceptable for DPIs delivering current medications. Only the Intal Spinhaler® emitted an average dose similar to its label claim. Testing at 100 1/min vs 60 1/min significantly increased DPI drug emission and reduced the device retention of both the Ventolin® and Becotide® versions of the low resistance devices, Rotahaler® and Diskhaler®. Using these same flow rates for testing the dose emissions from the medium resistance Bricanyl and Pulmicort Turbohalers®, there was no significant difference in drug output between the two flow rates.     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.     

Review of dry powder inhalers

The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.