In Vitro Cell Integrated Impactor Deposition Methodology for the Study of Aerodynamically Relevant Size Fractions from Commercial Pressurised Metered Dose Inhalers

Purpose

The purpose of this study was to present a modified Andersen cascade impactor (ACI) as a platform to evaluate the deposition and subsequent transport of aerosol micropaticles across airway epithelial cells.

Methods

The impaction plate of an ACI was modified to accommodate up to eight Snapwells. Aerodynamic particle size distribution of the modified ACI was investigated with two commercially available formulations of Ventolin® (salbutamol sulphate) and QVAR® (beclomethasone dipropionate). Deposition and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells were also studied.

Results

The modified ACI demonstrated reproducible deposition patterns of the commercially available pressurised metered dose inhalers compared to the standard ACI. Furthermore, the Calu-3 cells could be placed in different stages of the modified ACI. No significant effect was observed among the transport rate of different particle sizes deposited on Calu-3 cells within the range of 3.3 to 0.4 μm.

Conclusions

The use of the cell compatible ACI to assess the fate of microparticles after deposition on the respiratory epithelia may allow for better understanding of deposited microparticles in vivo.     

Electrostatics of pharmaceutical inhalation aerosols

Objectives This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics. Key findings Data from limited in‐vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectrification, that is contact or friction for solids and flowing or spraying for liquids. Thus, particles and droplets emitted from pulmonary drug delivery devices (dry powder inhalers, metered dose inhalers with or without spacers, and nebulisers) are inherently charged. Apparatus with various operation principles have been employed in the measurement of pharmaceutical charges. Aerosol charges are dependent on many physicochemical parameters, such as formulation composition, device construction, relative humidity and solid‐state properties. In some devices, electrification has been purposefully applied to facilitate powder dispersion and liquid atomisation. Summary Currently, there are no regulatory requirements on characterising electrostatic properties of inhalation aerosols. As research in this area progresses, the new knowledge gained may become valuable for the development and regulation of inhalation aerosol products.     

In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices.

Experiments were performed to determine the effect of different pharmaceutical aerosol inhalation devices on the deposition of monodisperse aerosols in an idealized mouth and throat geometry. The devices included two dry powder inhalers (Diskus and Turbuhaler), two nebulizers (Pari LC STAR and Hudson T-Updraft), and a metered dose inhaler with attached holding chamber (Aerochamber), in addition to a straight tube (1.7 cm inner diameter). Aerosol particles (DL-alpha tocopheryl acetate) of diameters of 2.5, 5, and 7 microm generated by a vibrating orifice generator were inhaled at steady air flow rates of Q = 5-90 L/min through the devices and into the mouth-throat. Deposition in the mouth-throat and after-filter were determined by ultraviolet (UV) spectrophotometric assay. The amount of deposition in the mouth and throat region was found to depend on the type of device that the aerosol entered through. Deposition in the extrathoracic region with the two types of jet nebulizers did not differ significantly (p > 0.1) from that of a straight tube or each other over their entire tested range of 590 > or = pd2Q > or = 11,375, where p is particle density (in g/cm3), d is particle diameter (in microm), and Q is flow rate (in cm3/s). The metered dose inhaler with attached holding chamber was found to differ from the straight tube only at two intermediate values of pd2Q = 5,145 and 16,033. The deposition occurring for the dry powder inhalers was found to be significantly greater than for the straight tube for all values of pd2Q > or = 10,954 for the Diskus and pd2Q > or = 9,435 for the Turbuhaler. Deposition with the dry powder inhalers was found to be up to 14 times greater than that with the straight tube. Thus, the inhaler geometry that the aerosol passes through prior to entering the mouth and throat region can greatly affect the deposition in the mouth-throat.     

Inhaled corticosteroid delivery systems: clinical role of a breath-actuated device

Several devices have been developed to overcome the need to co-ordinate actuation with inhalation required during use of a pressurised metered dose inhaler (MDI) and to improve drug delivery to the lung. These include spacer attachments for MDIs, dry powder inhalers and breath-actuated MDIs. The breath-actuated Autohaler (3M Pharmaceuticals) is a compact, multidose inhaler device that, unlike dry powder inhalers, does not rely on the patient's inspiratory effort to aerosolise the dose of medication. Due to its simple operation, the Autohaler is suitable for patients unable to operate a conventional MDI efficiently, including the elderly, children, patients with arthritis and patients with low inspiratory flow rates. The mandatory replacement of chlorofluorocarbon propellants with non-ozone-depleting propellants has given the opportunity to improve drug delivery characteristics of MDIs. Recently, a formulation of beclomethasone dipropionate in hydrofluoroalkane-134a (HFA-BDP), has been developed in a conventional MDI that delivers most of the emitted dose to the lung. Drug deposition studies show that the HFA-BDP formulation in the Autohaler device has a similar lung deposition pattern to drug delivered from the MDI, when used correctly, and dose delivery is consistent across a wide range of inspiratory flow rates. Furthermore, HFA-BDP Autohaler has similar clinical benefits to CFC-BDP Autohaler but at less than half the dose. HFA-BDP Autohaler offers a useful CFC-free delivery option for patients challenged by the conventional MDI device.     

肺部吸入给药制剂及临床应用

目的:分析和综述肺吸入制剂的分类、现状及其临床用药。方法:收集国内外发表出版的相关论文及专著,对肺部吸入给药的特点及临床药物制剂进行了分析总结。结果与结论:肺部吸入给药是防治哮喘、慢性阻塞性肺病等呼吸道疾病的首选给药方式。常见的吸入给药制剂包括定量吸入气雾剂、干粉吸入剂和雾化吸入剂,所用药物主要为β2受体激动剂、抗胆碱药物、吸入性糖皮质激素及复方药物等。     

Artificial neural network prediction of the patterns of deposition of polydisperse aerosols within human lungs

For optimum therapeutic response from drug administered to the lungs, it is paramount that the aerosolised drug is able to deposit in the lower airways. The filtering characteristics of the respiratory tract, however, make this a particularly challenging task. Computational tools afford a cost-effective means of studying the problem, and here we report on the development of a rapid and reliable method for predicting the pattern of deposition of polydisperse aerosols within human lungs using artificial neural networks (ANNs). Literature (experimental) data on lung deposition of monodisperse aerosols were used to train a single ANN to allow for simultaneous predictions of regional and total aerosol particle deposition patterns in human lungs. When used in modelling the fate of polydisperse aerosols in human lungs, the trained ANN was found to give highly accurate predictions for all lung regions, and all (pharmaceutically relevant) particle sizes and breathing conditions (with errors typically <0.025%). Further testing of the ANN, using 'unseen' in vitro and in vivo data, gave good agreement of lung dosages. It is thus concluded that the ANN produced can be used to provide highly reliable estimates of particle deposition from polydisperse pharmaceutical aerosols generated from breath-actuated dry powder inhalers, nebulizers and metered dose inhalers with spacers.     

A novel cell compatible impingement system to study in vitro drug absorption from dry powder aerosol formulations

A modified Astra type multistage liquid impinger (MSLI) with integrated bronchial cell monolayers was used to study deposition and subsequent drug absorption on in vitro models of the human airway epithelial barrier. Inverted cell culture of Calu-3 cells on the bottom side of cell culture filter inserts was integrated into a compendial MSLI. Upside down cultivation did not impair the barrier function, morphology and viability of Calu-3 cells. Size selective deposition with subsequent absorption was studied for three different commercially available dry powder formulations of salbutamol sulphate and budesonide. After deposition without size separation the absorption rates from the aerosol formulations differed but correlated with the size of the carrier lactose particles. However, after deposition in the MSLI, simulating relevant impaction and causing the separation of small drug crystals from the carrier lactose, the absorption rates of the three formulations were identical, confirming the bioequivalence of the three formulations.     

Pulmonary drug delivery from the Taifun dry powder inhaler is relatively independent of the patient's inspiratory effort.

The Taifun dry powder inhaler (Leiras OY, Turku, Finland) is a breath-actuated, multidose device, each metered dose containing 200 micrograms of budesonide. A two-way randomized crossover gamma scintigraphic study was performed in 10 asthmatic patients to determine the in vivo deposition pattern of budesonide inhaled from the Taifun. In vitro radiolabelling validation studies demonstrated that the radiolabel could be used as an accurate marker to assess in vivo drug deposition. Patients used either maximal inspiratory effort (targeted peak inhalation flow 30 L/min) or submaximal inspiratory effort (targeted peak inhalation flow 15 L/min) on each study day. Mean (S.D.) whole lung deposition (% of metered dose) was 34.3 (5.8)% and 29.6 (5.9)% for the two inhalation flows. The intersubject coefficient of variation in lung deposition was less than 20% on both study days. Drug was deposited uniformly across the central, intermediate, and peripheral lung regions for maximal and submaximal inspiratory efforts. The study suggests that the Taifun is a superior drug delivery device compared with many other inhalers, in terms of the amount of drug deposited in the lungs, the reproducibility of the lung dose, and the relative flow--independence of lung deposition.     

Innovations and perspectives of metered dose inhalers in pulmonary drug delivery.

The phase-out of chlorofluorocarbons (CFCs) has spurred the development of alternative pulmonary drug delivery systems to pressurized metered dose inhalers (MDIs), such as dry powder inhalers and pocket size nebulizers. Reformulation of CFC-MDIs with hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely accepted systems with respect to ease of handling, compliance, dosing, and more reliable and efficient lung deposition. MDIs have the advantage to protect the drug substance from external parameters such as temperature and humidity and to meter and de-agglomerate the drug independent from patients inspiratory flow rates. Novel formulation technologies combined with improved valves and actuators should help to overcome dose uniformity and priming problems and will increase the percentage of fine particles capable of reaching the deeper regions of the lungs. Spacer mouthpieces can reduce the cold freon effect and undesired oropharyngeal deposition caused by the rapid evaporation of the propellant and plume velocity of the aerosol cloud. More advanced delivery devices may allow the patient to inhale at predetermined flow rates (fast/slow) to target the deposition of fine drug particles (1-6 microm) to specific sites into the lungs. Breath-actuated devices make these systems more effective and patient friendly. The above features in combination with numerical counters showing the remaining number of shots, and built-in blocking mechanisms to avoid tail-off dependent dose uniformity problems of the last labeled shots, should help to improve both acceptance and compliance of pMDIs compared to other inhalation devices. However, only those inhalation systems, which are accepted and appreciated by patients and offering an ambulatory treatment at reasonable cost, will be successful in a more and more competitive market. These issues must be considered in the development of future devices and formulations.     

The role of particle properties in pharmaceutical powder inhalation formulations.

Pharmaceutical aerosol delivery is undergoing dramatic changes in both inhaler device and formulation aspects. There is a rapid move from the traditional propellant-driven metered dose inhalers to the high performance liquid atomizers and dry powder inhalers (DPIs). DPIs involving the dispersion of powders into aerosols by an inhaler device are particularly attractive as dry powders generally have greater chemical stability than liquids used in atomizers. Delivery of therapeutic proteins as dry powder aerosols is of high commerical interest. However, production and formulation of dry powders for inhalation can be difficult and challenging due to the potential physical instability of the powder. Dry powders consisting of micro- or nano-sized particles are inherently adhesive and cohesive, leading to highly variable dose accuracy and poor aerosol performance. Particle engineering via the use of appropriate pharmaceutical excipients and processing parameters can produce particles of optimal morphologies and surface properties which would enhance aerosol generation. Some of the key determinants for successful dispersion of pharmaceutical powders suitable for inhalation are reviewed with an emphasis on the practical significance.     

Formation, characterization, and fate of inhaled drug nanoparticles

Nanoparticles bring many benefits to pulmonary drug delivery applications, especially for systemic delivery and drugs with poor solubility. They have recently been explored in pressurized metered dose inhaler, nebulizer, and dry powder inhaler applications, mostly in polymeric forms. This article presents a review of processes that have been used to generate pure (non polymeric) drug nanoparticles, methods for characterizing the particles/formulations, their in-vitro and in-vivo performances, and the fate of inhaled nanoparticles.     

Nebulizer possibilities and limitations.

The ban of chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDIs) gives rise to many alternatives and innovations: 1. CFC substitution by non-CFC propellants in MDIs. 2. battery driven miniaturized mechanical and piezoelectric nebulizers 3. revitalization of hand driven pocket nebulizers 4. self actuated dry powder inhalers (DPI's). All devices can be used with or without spacers. The choice for solid or liquid particles, e.g. powder or droplet aerosols, will also depend on the drug properties and the availability on the market for aerosol use. The nebulizer device will be chosen according to the medical need (emergency or long term treatment), the technical alternatives available in different countries, the possibility of patient cooperation (children, severely ill patients), and last not least marketing strategies and costs. The bronchial circulation is an important distribution system for medicine deposited by aerosol routes in the lung.     

In vitro aerosol characterization of Staccato(®) Loxapine

Medicinal aerosol products (metered dose and dry powder inhalers) require characterization testing over a wide range of use and pre-operating stress scenarios in order to ensure robust product performance and support submissions for regulatory approval. Aerosol characterization experiments on Staccato^® Loxapine for inhalation (Staccato Loxapine) product (emitted dose, particle size, and purity) were assessed at different operating settings (flow rates, ambient temperature and humidity, altitude, and orientation) and at nominal test conditions following exposure to various stresses on the device (mechanical shock, vibration, drop, thermal cycling, and light exposure). Emitted dose values were approximately 90% of the coated dose at every condition, meeting target specifications in each case. Aerosol purity was consistently >99.5% for every test setting, with no reportable impurities according to ICH standards (>0.1%). Particle size averaged 2 μm (MMAD) and was independent of the different test conditions with the exception of different airflow rates. Particle size decreased slightly with airflow, which may assist in maintaining constant deep lung deposition. The combination of high emitted dose efficiency and a particle size range ideally suited for lung deposition, along with the consistency of these key aerosol attributes, suggests that the Staccato system has distinct advantages over more traditional aerosol systems.     

Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ～50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution-absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.     

驱动器的规格与吸入辅助装置对气雾剂体外沉积性质的影响

目的 考察驱动器的规格——孔径、孔长以及吸入辅助装置的使用对气雾剂体外沉积性质的影响.方法 以自制丙酸氟替卡松混悬型气雾剂为模型药物,装配不同规格的驱动器,使用Andersen多级撞击器(Andersen cascade impactor,ACI)测定体外沉积率;将丙酸氟替卡松气雾剂装配筛选好的特定规格的驱动器,分别在不使用吸入辅助装置与使用吸入辅助装置的情况下,对体外沉积性质进行对比研究.结果 在孔径固定的情况下,随着孔长的延长,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.在孔长固定的情况下,随着孔径的增加,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.根据试验结果、混悬型气雾剂本身的剂型特点以及驱动器的实际使用情况,最终,将0.42 mm孔径、0.70 mm孔长的驱动器作为优选驱动器;在使用吸入辅助装置的情况下,Andersen多级撞击器装置L型连接管的沉积量极大地降低,微细粒子剂量增加,原来沉积在L型连接管的大粒子很大一部分被截留在吸入辅助装置当中.结论 驱动器的规格会对吸入气雾剂的体外沉积产生一定的影响,在药品研发的过程中,可根据气雾剂产品的具体特点(溶液型或混悬型,原料药的粒径大小等)进行驱动器的筛选;吸入辅助装置的使用可以提高气雾剂的药物利用率,推荐患者用药时使用.     

Inhalation therapy: technological milestones in asthma treatment

The humble origins of the propellant driven metered dose inhaler, as a response to a child's enquiry, initiated an industry which supplies approximately a half billion inhalers globally for the treatment of asthma. These inhalers fall into three major groups: nebulizers; propellant driven metered dose inhalers and dry powder inhalers. Each requires drug formulation, metering and device technology to be successful. In recent years there have been several new developments in the field including auxiliary systems to improve drug delivery from the device to the patient and new categories of device, notably single breath aqueous systems. As device technology improves and our understanding of the disease leads to new drugs the only barrier to therapy is the patient. Patient training and compliance will continue to be important factors in the success, or failure, of inhaled therapy and the role of health care professionals will depend on who sponsors their intervention.     

New aerosol drug delivery systems for the treatment of immune-mediated pulmonary diseases

In the lung, unchecked immune responses mediated predominantly by T-lymphocytes and concurrent inflammation can lead to the development of different pathological conditions such as parenchymal disease, interstitial fibrosis, hypersensitivity pneumonitis, bronchiolitis obliterans and bronchiolar asthma. Targeted modulation of uncontrolled T-cell activation and inhibition of cytokine production within different pulmonary compartments is the challenge for the development of novel methods for immunotherapeutic intervention. Utilization of aerosol technology for pulmonary drug delivery represents new potential opportunities for therapeutic application for such immune-mediated pulmonary diseases. For targeted aerosol pulmonary drug delivery, continuous-flow jet nebulizers have several advantages over metered dose or dry powder inhalers since they are the simplest and most effective for aerosol droplet deposition into the peripheral lung tissues. At the present, the major limitations for targeted pulmonary immunosuppression through effective utilization of nebulizer technology has been the conspicuous lack of suitable formulations. The development of liposomal formulations compatible with aerosol delivery with jet nebulizers has expanded the potential for more effective utilization with an array of potent and effective immunosuppressive drugs. For pulmonary therapy, the utilization of liposomes for aerosol delivery has many potential advantages, including universal carrier suitability for most lipophilic drugs, aqueous compatibility, sustained pulmonary release or depot and intracellular delivery. Drug liposomes may also prevent local irritation in the lung, and increase potency with reduced systemic toxicity. Successful utilization of potent immunosuppressive drugs, like cyclosporin, tacrolimus (FK-506), rapamycin, mycophenolate and budesonide, in a variety of immunopathological conditions for other indications demonstrates their potential efficacy for the treatment of many different immune-mediated pulmonary diseases. The route of delivery to the pulmonary tissues can potentially limit adverse effects and markedly affect localized immunosuppressive activity in the lung. Combination of liposomal formulations with topical aerosol delivery to the central and peripheral lung tissues has expanded potential for more effective utilization with these lipophilic immunosuppressive (and antiinflammatory) drugs. Synergistic combinations can also be developed for localized and sustained delivery of therapeutic drug concentrations within the lung to provide multisite immunosuppression. Drug liposome aerosol technology represents one readily available approach for more effective therapeutic intervention in the lung using cyclosporin, FK-506, rapamycin, mycophenolate, budesonide and other lipophilic drugs.     

Back to the Future: Inhaled Drug Products

Inhaled therapeutic aerosols continue to be an important treatment for asthma and pulmonary diseases. A variety of dosage forms are employed for different indications and demographics including pressurized or propellant-driven metered dose inhalers, dry powder inhalers, and nebulizers/nebules. Research and development in this field has shown remarkable innovation in the past decade. Important new drug products for the treatment of asthma, chronic obstructive pulmonary disease, cystic fibrosis, diabetes, and a range of neurological disorders have been developed. New devices in each of the dosage form categories also have been developed, and new formulation technologies have been adopted. Unlike many other dosage forms, as new inhaled products appeared few of the existing products were converted to generic form. This may be explained by the formulation and device complexity, the implications for degree of difficulty in obtaining regulatory approval, and the prevalence of intellectual property in the field. After the setback of the initial approval and subsequent withdrawal of the Exubera® -inhaled insulin, there appeared to be reluctance to consider the pulmonary route of administration for systemically acting agents, particularly peptides and proteins. However, recent product development activities and approvals suggest that attitudes may be changing in favor of systemic delivery following inhaled aerosol administration. The new inhaled drug technologies seem to be driving reconsideration of therapeutic categories for indications that were of interest at the inception of modern inhaled drug therapy in the past century. We should embrace the opportunity to use new drugs and technologies to go back to the future!.     

SCF-engineered powders for delivery of budesonide from passive DPI devices

The objective of this study was to develop SEDS-engineered budesonide particles suitable for dry powder inhalation delivery and to evaluate their aerosol performance across a range of passive dry powder inhalers (DPI). SEDS budesonide powders were manufactured in Nektar's SCF manufacturing plant and compared to the micronized drug and commercial powder (Pulmicort Turbuhaler, AstraZeneca). Aerosol performance was evaluated by determining emitted dose (ED) by a variation of the USP method and fine particle fraction (FPF) using Andersen cascade impaction. The SCF powder dispersed best in the Turbospin and Eclipse devices, exhibiting high EDs (70%-80%) and relatively low variability (RSD 8%-13%). Regardless of the device, the SEDS material outperformed both the micronized drug and the commercial powder, while exhibiting good batch-to-batch reproducibility (RSD <5%). All powders exhibited flow rate-dependent ED, albeit for the SEDS material it was minimized at reduced fill weights. This was attributed to inadequate and variable powder clearance from the capsules at low inspiratory flow rates, which was more pronounced in the Eclipse and Cyclohaler. The results demonstrate that SEDS is an attractive particle-engineering process that may enhance pulmonary performance of budesonide and possibly facilitate development of other small molecule pulmonary products in passive DPI.