多肽和蛋白质及疫苗类药物干粉吸入给药的研究进展

针对多肽和蛋白质类药物体内过程和药学性质的特殊性，介绍了多肽和蛋白质类药物非注射给药途径研究现状，干粉吸入剂的剂型优点和制剂工艺技术特点，以及多肽和蛋白质类药物干粉吸入剂的研究进展，着重介绍了胰岛素等全身作用类药物、局部作用类药物及疫苗药物的干粉吸入给药的研究现状。     

影响干粉吸入剂肺沉积的制剂因素

干粉吸入剂的制剂因素包括药物粉末的处方组成、给药装置类型等,是影响药物肺沉积的主要因素。文中按照药物处方组成将干粉吸入剂分成无载体、药物-载体、药物-添加剂、药物-载体-添加剂4种类型,并分别对其影响肺沉积的制剂因素进行了分析。     

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。     

乳糖在干粉吸入剂中的应用

目的综述了乳糖在干粉吸入剂(dry powder inhalers,DPI)中的应用,为DPI的研究和开发提供思路。方法查阅国内外相关文献,综述了载体乳糖(coarse carrier)的不同性质及加入微粉化乳糖(fine particles)对DPI肺部沉积的影响。结果 DPI中的药物经微粉化后,其雾化性能下降。乳糖应用于DPI中的研究分析表明,乳糖可以有效改善DPI中药物的雾化性能,从而提高药物在肺部的沉积效率,发挥最佳药效。结论加入不同性质的载体乳糖和微粉化乳糖可以有效改善药物在肺部的沉积效率。     

肺部给药系统的研究进展

介绍了呼吸道的特殊生理特征和功能以及药物的吸收过程,综述了近年来国内外肺部给药系统的进展,包括定量吸入剂、喷雾剂、干粉吸入剂、微球和脂质体的肺部给药。     

载药纳米粒在干粉吸入剂中的应用

本文分析了载药纳米粒在干粉吸入剂上缺乏商业吸引力的原因,以及与常规干粉吸入剂相比存在的优势;介绍了纳米粒-载体复合物、大粒径中空纳米粒聚集体两种干粉吸入剂的制备方法及形成机制。由于纳米粒干粉吸入制剂具备优良的分散性能和肺沉积性能,并同时拥有纳米粒作为药物载体的独特性能,使其在干粉吸入剂上具有强大的优势和广阔的发展空间。     

质量源于设计(QbD)在干粉吸入剂开发中的应用

干粉吸入剂具有避免首过效应、生物利用度高、给药方便等优点.但由于粉体的高度变异性,实现药物剂量的准确递送较为困难.而且,干粉吸入剂作为一种药械组合的剂型,处方和装置设计同样需要认真考量.应用包括风险分析、实验设计、过程分析技术、预测科学在内的质量源于设计(QbD)工具可有效降低干粉吸入剂的粉体学变异、提升肺部沉积率,最...     

干粉吸入剂空气动力学分散模型的建立和验证

在Weiler干粉粒子聚集体全分散理论模型基础上,以硫酸沙丁胺醇为模型药物,建立了一种更加深入的千粉吸入剂空气动力学分散模型.硫酸沙丁胺醇干粉吸入剂体外沉积试验表明,该模型可预测干粉粒子的空气动力学分散行为,并可结合计算流体动力学,估算干粉吸入剂在吸入装置中的分散及微细粒子分数.     

低密度多孔性颗粒在干粉吸入剂中的应用

评述了低密度多孔性颗粒能从改善药物的给药剂量重现性、提高沉积性能和降低巨嗜细胞的吞噬作用等多方面提高干粉吸入剂的性能,并介绍了它的几种制备方法。     

阿奇霉素干粉吸入剂的制备及稳定性考察

摘要：目的:制备阿奇霉素干粉吸入剂并考察其稳定性。方法:采用气流粉碎法制备阿奇霉素干粉吸入剂,以粉末收率、粒子空气动力学粒径、休止角和阿奇霉素干粉吸入剂的细微粒子剂量为考察指标,通过正交设计结合多指标综合评价法优化最佳制备工艺,并考察阿奇霉素干粉吸入剂的稳定性。结果:通过正交试验-多指标综合评价,最佳制备工艺为:分选频率25Hz;进料量80 g;粉碎次数1次;粉碎压力1.0 MPa。在稳定性考察中阿奇霉素干粉吸入剂的各项指标在观察期内无明显变化。结论:所制备的阿奇霉素干粉吸入剂适合肺部吸入给药,且具有较好的稳定性。     

Practical,regulatory and clinical considerations for development of inhalation drug products

The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).     

Carriers in drug powder delivery

The performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol. Multiple factors associated with drug and carrier particles are known to influence dry powder performance. Elucidation of a mechanistic understanding of particulate system properties and how these relate to powder performance and the disruption of inter-particulate forces that cause aggregation has not yet been achieved. However, the complexity of interactions within dry powder formulations has not restricted research in this area. Various strategies of overcoming inter-particulate forces have been devised, ranging from active inhaler designs to powder engineering approaches. The influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop DPI systems that perform as device-independent formulations and/or provide patient-independent delivery (controlled carrier systems). It seems likely that the future of DPI systems will combine both of these strategies with future developments in device design (formulation independency).     

Dry powder inhalers in COPD,lung inflammation and pulmonary infections

Introduction: The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow.

Areas covered: These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug–device combination product is critical. Aerosol medicine products are drug–device combination products. Device design and compatibility with the formulation are key drug–device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections.

Expert opinion: There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.     

Physico-chemical aspects of lactose for inhalation

A dry powder inhaler (DPI) is a dosage form that consists of a powder formulation in a device which is designed to deliver an active ingredient to the respiratory tract. It has been extensively investigated over the past years and several aspects relating to device and particulate delivery mechanisms have been the focal points for debate. DPI formulations may or may not contain carrier particles but whenever a carrier is included in a commercial formulation, it is almost invariably lactose monohydrate. Many physicochemical properties of the lactose carrier particles have been reported to affect the efficiency of a DPI. A number of preparation methods have been developed which have been claimed to produce lactose carriers with characteristics which lead to improved deposition. Alongside these developments, a number of characterization methods have been developed which have been reported to be useful in the measurement of key properties of the particulate ingredients. This review describes the various physicochemical characteristics of lactose, methods of manufacturing lactose particulates and their characterization.     

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

Purpose

The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device.

Methods

DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices.

Results

The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI.

Conclusions

High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD?<?1.5 μm, FPF_<5μm/ED?>?90%, and ED?>?80%.     

Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?

The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols’ behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.     

Determination of the Relative Bioavailability of Salbutamol to the Lungs Following Inhalation from Dry Powder Inhaler Formulations Containing Drug Substance Manufactured by Supercritical Fluids and Micronization

Purpose The relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS™) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler™, Innovata Biomed). Materials and Methods Twelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS™ particles (three batches) and micronized particles (Asmasal™ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV₁. Physicochemical evaluation of the three SEDS™ batches revealed inter-batch differences in particle size and shape. Results There was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS™ formulation and the Asmasal™ inhaler in volunteers and patients, respectively. SEDS™ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS™ batches containing elongated particles. Conclusions Active Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.     

Formulation of novel dry powder inhalation for fluticasone propionate and salmeterol xinafoate with capsule-based device

The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose^® SV003, Respitose^® SV010, and Respitose^® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.     

Active and intelligent inhaler device development

The dry powder inhaler, which has traditionally relied on the patient's inspiratory force to deaggregate and deliver the active agent to the target region of the lung, has been a successful delivery device for the provision of locally active agents for the treatment of conditions such as asthma and chronic obstructive pulmonary disease (COPD). However, such devices can suffer from poor delivery characteristics and/or poor reproducibility. More recently, drugs for systemic delivery and more high value compounds have been put into DPI devices. Regulatory, dosing, manufacturing and economic concerns have demanded that a more efficient and reproducible performance is achieved by these devices. Recently strategies have been put in place to produce a more efficient DPI device/formulation combination. Using one novel device as an example the paper will examine which features are important in such a device and some of the strategies required to implement these features. All of these technological advances are invisible, and may be irrelevant, to the patient. However, their inability to use an inhaler device properly has significant implications for their therapy. Use of active device mechanisms, which reduce the dependence on patient inspiratory flow, and sensible industrial design, which give the patient the right clues to use, are important determinants of performance here.