吸入粉雾剂粒径测定方法的评价:3种撞击器的比较

目的:分析和比较两级玻璃撞击器、Andersen多级撞击器(Andersen cascade impactor,ACI)和多级液体采样器(Multi-stage liquid impinger,MSLI)的粒度分布测定结果。方法:分别采用两级玻璃撞击器、ACI和MSLI测定了环索奈德吸入粉雾剂的粉雾粒度分布。结果:两级玻璃撞击器操作简单,能快速获得空气动力学直径小于6.4μm的细颗粒药物剂量,却不能获得药物颗粒的空气动力学粒度大小分布;ACI和MSLI均既能获得空气动力学直径在不同大小范围内的细颗粒药物剂量,又能获得药物颗粒的空气动力学粒度大小分布,但ACI不适合在高于28.3 L.min-1的流速下操作,且药物颗粒在ACI各级间的损耗高于MSLI。结论:与两级玻璃撞击器和ACI相比,MSLI在评价吸入粉雾剂质量时更为完善。     

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。     

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。     

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.     

Equivalent lung deposition of budesonide in vivo: a comparison of dry powder inhalers using a pharmacokinetic method

AIMS: The aim of this study was to compare lung deposition of budesonide administered from two dry powder inhalers, Giona Easyhaler 200 microg/dose and Pulmicort Turbuhaler 200 microg/dose by utilizing a pharmacokinetic method. METHODS: This was an open, randomized, crossover study in 33 healthy subjects. The study consisted of four treatment periods separated by at least 4 wash-out days. Equivalence in lung deposition was assessed after a single inhaled 1000 microg (5 x 200 microg) dose of budesonide from Giona Easyhaler and from Pulmicort Turbuhaler. Concomitant oral charcoal administration (40 g) was used to prevent gastrointestinal (GI) absorption of budesonide. The efficacy of the charcoal was studied after oral administration of a budesonide 2 mg capsule. The subjects were trained to inhale the study drugs with controlled flow rates, which resulted in an equal pressure drop (4 kPa) across both inhalers. Venous blood samples for the determination of budesonide concentrations in plasma were drawn before and at predetermined time points up to 8 h after drug administration. Budesonide concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Several pharmacokinetic parameters were estimated, the area under the budesonide concentration in plasma vs time curve from dosing to infinity (AUC(0, infinity)) being the primary response variable. Equivalence in lung deposition was concluded if the 90% confidence interval (CI) for the Easyhaler : Turbuhaler ratio of AUC(0, infinity) fell within the limits of 0.8-1.25. RESULTS: The mean AUC(0,infinity) value after Easyhaler treatment was 3.48 (standard deviation (SD) 0.93) ng ml(-1) h and after Turbuhaler treatment 3.46 (1.13) ng ml(-1) h. The Easyhaler : Turbuhaler AUC(0, infinity) ratio was 1.02 and the 90% CI was from 0.96 to 1.09. The mean C(max) values (SD) for budesonide in plasma after Easyhaler and Turbuhaler treatments were 1.22 (0.41) ng ml(-1) and 1.29 (0.44) ng ml(-1), respectively. There was no statistically significant difference (P = 0.39) between the median t(max) for Easyhaler (30 min) and Turbuhaler treatment (23 min). Charcoal impaired the GI absorption of budesonide by 96%. The occurrence of adverse events was similar during both treatments. CONCLUSIONS: The results show that the lung deposition of budesonide from Giona Easyhaler 200 microg/dose and Pulmicort Turbuhaler 200 microg/dose dry powder inhalers is equivalent. The charcoal block used to prevent GI absorption of swallowed budesonide was found to be effective.     

Influence of crystal form of ipratropium bromide on micronisation and aerosolisation behaviour in dry powder inhaler formulations

Objectives This study aimed to investigate the relationship between the mechanical properties of anhydrous and monohydrate ipratropium bromide (IB) crystals, their processing behaviour upon air‐jet micronisation and aerosolisation performance in dry powder inhaler (DPI) formulations. Methods IB monohydrate and anhydrous crystals were produced from seed crystals and supercritical carbon dioxide crystallisation, respectively. Young's modulus of anhydrous and monohydrate IB crystals was determined using nanoindentation. For air‐jet micronised crystals, the physicochemical and surface interfacial properties via the cohesive–adhesive balance (CAB) approach were investigated. These data were correlated to in‐vitro aerosolisation performance of carrier‐based DPI formulations containing either anhydrous or monohydrate IB. Key findings Particle size and Young's modulus of both crystals were similar and this was reflected in their similar processing upon micronisation. Particle size of micronised anhydrous and monohydrate crystals were similar. CAB measurements of the micronised particles of monohydrate or anhydrous forms of IB with respect to lactose were 0.70 (R² = 0.998) and 0.77 (R² = 0.999), respectively. These data suggested that both samples had similar adhesion to lactose, which correlated with their similar in‐vitro aerosolisation performance in DPI formulations. Conclusions Monohydrate and anhydrous crystals of IB exhibited similar mechanical properties and interfacial properties upon secondary processing. As a result, the performance of the DPI formulations were similar.     

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.     

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.     

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder

Purpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PS_bud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 g budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min^-1 (PS_bud25), and 50 L·min^-1 (PS_bud50), and 800 g of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min^-1(TH_bud60). PS_bud powder was radiolabeled with ^99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PS_bud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min^-1, respectively. Mean peak plasma budesonide levels were 4.7 (PS_bud25), 4.0 (PS_bud50), and 2.2 ng·ml^-1 (TH_bud60). Median t_max was 5 min after both PS_bud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PS_bud25), 5.9 (PS_bud50), and 6.0 (TH_bud60) ng·h·ml^-1. The engineered PS_bud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min^-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PS_bud relative to TH_bud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.     

Design of ciprofloxacin-loaded nano-and microcomposite particles for dry powder inhaler formulations: preparation,in vitro characterisation,and antimicrobial efficacy

Abstract

In this study, ciprofloxacin hydrochloride (CIP)-loaded poly-ε-caprolactone (PCL) nanoparticles were prepared for pulmonary administration. CIP-loaded PCL nanoparticles were prepared using solid-in-oil-in-water (s/o/w) emulsion solvent evaporation method, and the effects of various formulation parameters on the physicochemical properties of the nanoparticles were investigated. PCL nanoparticles showed spherical shapes with particle sizes around 143–489?nm. Encapsulation efficiency was found to be very low because of water-solubility properties of CIP. However, the surface modification of nanoparticles with chitosan caused an increase in the encapsulation efficiency of nanoparticles. At drug release study, CIP-loaded PCL nanoparticles showed initial burst effect for 4?h and then continuously released for 72?h. Nanocomposite microparticles containing CIP-loaded PCL nanoparticles were prepared freeze-drying method and mannitol was used as carrier material. Tapped density and MMADt results show that nanocomposite microparticles have suitable aerodynamic properties for pulmonary administration. Antimicrobial efficacy investigations showed that CIP-encapsulated PCL nanoparticles and nanocomposite microparticles inhibited the growth of bacteria. Also, when the antimicrobial activity of the nanoparticles at the beginning and at the sixth month was examined, it was found that the structure of the particulate system was still preserved. These results indicated that nanocomposite microparticles containing CIP-loaded PCL nanoparticles can be used for pulmonary delivery.     

治疗急性肺损伤的莪术油和莪术醇粉雾剂的比较研究

本文制备了莪术油粉雾剂(zedoary turmeric oil dry powder inhalers,ZDPIs)及其有效化合物莪术醇粉雾剂(curcumol dry powder inhalers,CDPIs),经大鼠气管给药后,比较两者对脂多糖(lipopolysaccharide,LPS)致急性肺损伤(acute lung injury,ALI)的治疗作用。分别制备莪术油和莪术醇纳米乳,加入5%甘露醇,冻干后得到ZDPIs和CDPIs。两者均为疏松白色粉末,空气动力学粒径(aerodynamic diameter,D_a)分别为3.02和2.67μm,均适合肺吸入给药。所有动物实验经军事科学院军事医学研究院辐射医学研究所伦理委员会批准且实验均按照相关指导原则和规定进行。大鼠气管喷入5 mg·mL^-1LPS溶液0.2 mL,建立ALI模型。分别将ZDPIs(含莪术油0.5 mg)和CDPIs(含莪术醇0.5 mg)经气管给药。两者均能减少ALI大鼠肺组织出血,并且显著降低肺组织中炎症因子(肿瘤坏死因子α、白介素-6和总蛋白)的含量(P&...     

Rational design of a dry powder inhaler: device design and optimisation

Objectives As part of the development of a dry powder inhalation system for the treatment of asthma and chronic obstructive pulmonary disease, this work specifically aimed at the systematic, however, cost-effective and efficient development of an inhalation device. Methods Based on theoretical design considerations and an initial inhaler prototype, the concept of a modular inhaler was developed. The modular inhaler was used for the systematic evaluation of the influence of the inhaler's inner dimensions on the resistance to the air flow and the in-vitro deposition characteristics of the inhalation system by using statistical design of experiments and cascade impaction analysis. Key findings A reliable statistical model enabled the accurate prediction of the device resistance of any combination of inner dimensions of the inhaler. In conjunction with results from in-vitro deposition studies, this allowed for the definition of optimised inner dimensions of the inhaler to maximise the fine particle fraction and minimise oropharyngeal deposition within the desired range of the inhaler's resistance to air flow. Conclusions The concept of the modular inhaler and statistical design and evaluation of experiments proved to be important tools for an efficient and successful product development. Eventually, the approaches described and the knowledge obtained enabled the cost-effective development and design of a technically feasible and competitive dry powder inhaler.     

Non-steroidal anti-inflammatory drug for pulmonary administration: Design and investigation of ketoprofen lysinate fine dry powders

Pulmonary inflammation is an important therapeutic target in cystic fibrosis (CF) patients, aiming to limit and delay the lung damage. The purpose of the present research was to produce respirable engineered particles of ketoprofen lysinate, a non-steroidal anti-inflammatory drug able to fight lung inflammatory status by direct administration to the site of action. Micronized drug powders containing leucine as dispersibility enhancer were prepared by co-spray drying the active compound and the excipient from water or hydro-alcoholic feeds. Microparticles were fully characterized in terms of process yield, particle size distribution, morphology and drug content. The ability of the drug to reach the deepest airways after aerosolization of spray-dried formulations was evaluated by Andersen cascade impactor, using the monodose DPI as device. In order to investigate the behaviour of the drug once in contact with lung fluid, an artificial CF mucus was prepared. Drug permeation properties were evaluated interposing the mucus layer between the drug and a synthetic membrane mounted in Franz-type diffusion cells. Finally, the effect of the engineered particles on vitality of human airway epithelial cells of patients homozygous for ΔF 508 CF (CuFi1) was studied and compared to that of raw active compound. Results indicated that powders engineering changed the diameter and shape of the particles, making them suitable for inhalation. The mucus layer in the donor compartment of vertical diffusion cells slowed down drug dissolution and permeation, leucine having no influence. Cell proliferation studies evidenced that the spray drying process together with the addition of leucine reduced the cytotoxic effect of ketoprofen lysine salt as raw material, making the ketoprofen lysinate DPI a very promising product for the inflammation control in CF patients.     

沙美特罗替卡松干粉吸入剂治疗咳嗽变异性哮喘的疗效观察

目的观察沙美特罗替卡松干粉（舒利迭）吸入剂治疗咳嗽变异性哮喘（cough variant asthma,CVA）患者的临床疗效。方法 32例CVA给予舒利迭（沙美特罗/替卡松50μg/250μg）吸入治疗8周后的咳嗽变化情况及肺功能改善情况。结果患者咳嗽严重程度持续下降,症状改善迅速,昼夜呼气峰值流速变异率≤20%,差异有统计学意义（P〈0.05）。结论舒利迭吸入剂可快速有效改善CVA患者症状,应用方便安全。     

Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices

Objective: The environmental concerns surrounding the use of chlorofluorocarbons (CFC) have led to a resurgence of interest in dry powder inhaler devices. The aim of our study was to compare two commonly used dry powder inhaler devices, namely the Turbuhaler and Diskus. Methods: Eight healthy volunteers with a mean (SEM) age of 21 years (0.8) were studied using a randomised single-investigator blind crossover design. Single doses of 1.2 mg salbutamol as Turbuhaler (12 × 100 μg) and Diskus (6 × 200 μg) were administered over 6 min. Mouth rinsing was performed after every inhalation. Lung delivery from each device was assessed by measuring the early plasma salbutamol profile at 5, 10, 15 and 20 min after inhalation. Results: Significant differences in lung delivery were found between the Diskus and the Turbuhaler for salbutamol C_max 3.21 vs 4.04 ng · ml⁻¹, respectively and C_av 2.65 vs 3.73 ng · ml⁻¹, respectively. This amounted to a 1.28-fold difference (95% CI 1.09 to 1.45) between these devices for C_max and a 1.42-fold difference (95% CI 1.57 to 1.66) for C_av. Conclusion: We have demonstrated that, in vivo, the Turbuhaler dry powder inhaler produces significantly greater lung delivery of salbutamol than the Diskus. This illustrates that dry powder inhaler devices may have different in vivo deposition characteristics. Received: 27 January 1997 / Accepted in revised form: 21 May 1997     

Identical efficacy of terbutaline multidose dry powder inhaler prior to and after 4 weeks of use by asthmatic patients

We investigated whether the terbutaline multidose dry powder inhaler (Turbuhaler) has the same efficacy after routine daily use as it has when new. Thirty-three adult asthmatic patients were tested on two occasions. The bronchodilatory effect of inhalations of 0.5, 0.5 and 1.0 mg terbutaline at 40-min intervals from the same device was determined prior to and after using the device at least three times a day for 4 weeks. When tested for the second time, 116–186 doses had been inhaled.Although baseline forced expiratory volume in 1 s (FEV₁) was slightly higher after the 4-week treatment period, the bronchodilatory effect of the inhaled terbutaline doses was identical.We conclude that the multidose dry powder inhaler is as effective in delivering terbutaline after a period of routine daily use as it is when new.     

新型环索奈德胶囊型干粉吸入剂的研制及其质量研究

目的:研制用于治疗哮喘的环索奈德胶囊型干粉吸入剂,建立其含量测定方法,并对其稳定性进行初步考察。方法:用高效液相色谱-紫外法检测环索奈德干粉吸入剂中主药环索奈德及其有关物质的含量。将主药与辅料混合后,以含量均匀度和肺部沉积率为指标进行处方筛选,考察制剂的有关物质和影响因素,并进行了加速稳定性和长期留样稳定性试验。结果:建立的高效液相色谱法,色谱条件如下:色谱柱为Alltima C18(250 mm×4.6mm,5μm);流动相为乙醇-水(65∶35);流速为1.2 mL.min-1;检测波长为243 nm。最后选择乳糖作为辅料,确定了最佳处方和工艺,获得了较好的含量均匀度和肺部沉积率(约19%)。稳定性结果显示,本制剂应置于阴凉、干燥处保存,在室温下保存至少在1年内稳定,长期放置稳定性在继续考察。结论:建立的高效液相色谱法适合于环索奈德胶囊型干粉吸入剂的日常质量控制,研制的制剂处方稳定。     

胰岛素吸入粉雾剂的制备及其体外沉积性质

目的采用喷雾干燥法制备胰岛素吸入粉雾剂,并对其体外沉积性质做出评价。方法以产品收率,粉末的空气动力学径、休止角及水分含量为考察指标,采用正交设计Z综合评价法优化喷雾干燥制备方法中各工艺参数,同时采用双层液体碰撞器测定该工艺所制备的胰岛素吸入粉雾剂的有效部位沉积量,并通过扫描电镜观察产品的形态。结果优选出的工艺参数为:气流量为0.6 m3.min-1,进口温度为100℃,喷液速度为5.0 mL.min-1,泵压为130 kPa,溶液质量分数为0.75%。体外有效部位沉积质量高达60%。结论采用本法制备胰岛素肺部吸入粉雾剂重现性好,所得粉雾剂的有效部位沉积量高,提示大部分粒子能够到达肺部。     

Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery

Nowadays, growing attention has been paid to the pulmonary region as a target for the delivery of peptide and protein drugs, especially macromolecules with systemic effect like insulin, since the pulmonary route exhibits numerous benefits to be an alternative for repeated injection. Furthermore, encapsulation of insulin into liposomal carriers is an attractive way to increase drug retention time and control the drug release in the lung; however, its long-term stability during storage in the reservoir and the process of aerosolization might be suspected when practically applied. Thus, the aim of this study was to design and characterize dry powder inhalation of insulin-loaded liposomes prepared by novel spray-freeze-drying method for enhanced pulmonary delivery. Process variables such as compressed air pressure, pump speed, and concentration were optimized for parameters such as mean particle diameter, moisture content, and fine particle fraction of the produced powders. Influence of different kinds and amounts of lyoprotectants was also evaluated for the best preservation of the drug entrapped in the liposome bilayers after the dehydration–rehydration cycle. The in vivo study of intratracheal instillation of insulin-loaded liposomes to diabetic rats showed successful hypoglycemic effect with low blood glucose level and long-lasting period and a relative pharmacological bioavailability as high as 38.38% in the group of 8 IU/kg dosage.     

NEXThaler,an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma

Introduction: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease.

Areas covered: The present review deals with the recently developed fixed dose drug combination of beclometasone dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler®. The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs.

Expert opinion: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and supports the broad utility of the NEXThaler DPI in patients with asthma. Overall, all the effectiveness, efficiency and satisfaction outcomes demonstrate the NEXThaler DPI is easy to use.