A dry powder inhaler with reduced mouth-throat deposition.

A novel, compact, and highly efficient dry powder inhaler (DPI) with low mouth-throat deposition is described. The performance of this DPI was evaluated by measuring both (1) the total aerosol deposition in and distal to an idealized mouth-throat cast and (2) the fine particle fraction (FPF) using a standard Mark II Anderson impactor. Ultraviolet (UV) spectroscopy techniques were used in the aerosol deposition measurements. Two inhalation aerosol powders, namely budesonide (extracted from a Pulmicort/Turbuhaler multi-dose device, 200 microg/dose) and ciprofloxacin + lipid + lactose (in-house), were dispersed by the DPI at a steady inhalation flow rate of 60 L/min. The newly developed DPI had a total aerosol delivery distal to the mouth-throat cast of 50.5% +/- 3.04% and 69.7% +/- 1.5% for the budesonide and ciprofloxacin + lipid + lactose aerosols, respectively. This is a significant improvement over the Turbuhaler original device delivery of 34.5% +/- 5.2%, particularly considering that in vitro mouth-throat deposition dropped from 27.5% +/- 5.4% with the budesonide Turbuhaler to 11.0% +/- 3.5% with the present inhaler. The different lung deliveries from the same inhaler for the two formulations above also confirm that the overall performance of an inhaler is optimizable via powder formulations.     

The development of a novel dry powder inhaler

A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 μg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (<4.7 μm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction.     

影响干粉吸入剂雾化和沉积性能的制剂因素

干粉吸入剂是近年来肺部给药制剂研发的热点。随着微粉化技术不断成熟,新型给药装置日益涌现,干粉吸入剂的应用范围越来越广。本文从微粉化的药物、载体和干粉吸入器等3个方面综述了干粉吸入剂的处方组成,并重点介绍了影响药物粉末雾化和沉积性能的几个关键因素。     

Particle Size and Charge Distribution Analysis of Pharmaceutical Aerosols Generated by Inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 μC/g, the individual particles were charged with a relatively high charge: ?2 to + 2 μC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3–5 μm.     

Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 microC/g, the individual particles were charged with a relatively high charge: -2 to + 2 microC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3-5 microm.     

Novel alternative methods for the delivery of drugs for the treatment of asthma

Successful delivery of dry powder aerosols to the lung requires careful consideration of the powder production process, formulation and inhaler device. Newer production methods are emerging to prepare powders with desirable characteristics for inhalational administration. The conventional formulation approach of adding coarse lactose carriers to the drug to form binary powder systems to enhance powder flow and dispersion properties has been expanded to using finer carrier particles and hydrophobic materials, as well as ternary systems. Particle morphology and surface properties have also been explored to enhance powder performance. For the inhaler device, the new generation inhalers are designed to reduce or completely decouple the influence of air flow on the aerosol generation. Each of these determinants for powder aerosol delivery is reviewed with a strong focus on the patent literature that contains enormous information about the latest development in this field.     

Particle characteristics and lung deposition patterns in a human airway replica of a dry powder formulation of polylactic acid produced using supercritical fluid technology.

Polylactic acid (PLA) powders have been used as vector particles to carry pharmaceutical material. Drugs incorporated in the PLA powder can be retained in the lung for a longer period and may be more effective than free-form drugs. A new formulation of L-PLA dry powder, which was easy to disperse in the air, was produced by using a supercritical technology. The L-PLA powder was characterized in terms of physical particle size and aerodynamic size as generated with a Turbuhaler dry powder inhaler (DPI). Electron microscopy analysis of the particles indicated that they were individual particles in bulk form and became aggregate particles after generation by the Turbuhaler. Aerodynamic particle size analysis using both an Aerodynamic Particle Sizer (APS) aerosol spectrometer and Andersen impactor showed that the aerodynamic size decreased as the flow rate in the Turbuhaler increased from 28.3 to 90 L min(-1). Deposition patterns in the human respiratory tract were estimated using a realistic physical replica of human airways. Deposition of the L-PLA was high (80.8%) in the oral airway at 28.3 L min(-1) and an average of 73.4% at flow rates of 60 and 90 L min(-1). In the lung region, the deposition totaled 7.2% at 28.3 L min(-1), 18.3% at 60 L min(-1), and 17.6% at 90 L min(-1). These deposition patterns were consistent with aerodynamic size measurement, which showed 76 to 86% deposition in the USP/EP (US Pharmacopoeia/European Pharmacopoeia) induction port. As the flow rate increased, fewer aggregates were formed resulting in the smaller aerodynamic particles. As a result, more particles penetrated the oral airways and were available for deposition in the lung. Our results showed that L-PLA particles as manufactured by the supercritical technology could be used in a DPI that does not require the use of carrier particles to facilitate aerosol delivery.     

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%.     

Lung deposition of mannitol powder aerosol in healthy subjects.

Mannitol as a dry powder aerosol is used for bronchoprovocation testing and to enhance mucus clearance in people with excessive airway secretions. The dose and distribution of the deposited aerosol in the lung was investigated using fast single photon emission tomography (SPECT) imaging. Mannitol powder (3 microm particle size) was produced by spray drying and radiolabeled with (99m)Tc-DTPA. Approximately 60 mg of radiolabeled mannitol (containing 52-68 MBq of (99m)Tc-DTPA) was administered to 10 healthy subjects using the Inhalator dry powder inhaler (DPI), and SPECT images (1 min each) were collected. Thirteen percent to 31% of the dose of mannitol loaded in the inhaler deposited in the lungs and the deposited dose correlated positively with the peak inhalation air flow. The regional aerosol lung distribution, as expressed by the penetration index (i.e., ratio of peripheral to central deposition in the lung) varied from 0.31 to 0.88, which however showed no dependency on any flow parameters. The variation in response to the same dose of mannitol within the asthmatic population may in part be explained by these findings.     

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).     

Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler

This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm³, 55.99 mm³, and 133.04 mm³, and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI.     

Delivery of theophylline as dry powder for inhalation

Theophylline (TP) is a very well established orally or intravenously delivered antiasthma drug with many beneficial effects. This study aims to improve asthma treatment by creating a dry powder inhalable (DPI) formulation of TP to be delivered directly to the lung, avoiding the side effects associated with conventional oral delivery. The DPI TP formulation was investigated for its physico-chemical characteristics using scanning electron microscopy, laser diffraction, thermal analysis and dynamic vapour sorption. Furthermore, aerosol performance was assessed using the Multi Stage Liquid Impinger (MSLI). In addition, a Calu-3 cell transport assay was conducted in vitro using a modified ACI to study the impact of the DPI formulation on lung epithelial cells. Results showed DPI TP to be physico-chemically stable and of an aerodynamic size suitable for lung delivery. The aerosolisation performance analysis showed the TP DPI formulation to have a fine particle fraction of 29.70 ± 2.59% (P < 0.05) for the TP formulation containing 1.0% (w/w) sodium stearate, the most efficient for aerosolisation. Regarding the deposition of TP DPI on Calu-3 cells using the modified ACI, results demonstrated that 56.14 ± 7.62% of the total TP deposited (13.07 ± 1.69 µg) was transported across the Calu-3 monolayer over 180 min following deposition, while 37.05 ± 12.62% of the deposited TP was retained in the cells. This could be due to the presence of sodium stearate in the current formulation that increased its lipophilicity. A DPI formulation of TP was developed that was shown to be suitable for inhalation.     

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。     

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.     

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.     

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.     

Investigation of Electrostatic Behavior of Dry Powder-Inhaled Model Formulations

The accumulation of electrostatic charge on drug particles and excipient powders arising from interparticulate collisions or contacts with other surfaces can lead to agglomeration and adhesion problems during the manufacturing process, filling, and delivery of dry powder inhaler (DPI) formulations. The objective of the study was to investigate the role of triboelectrification to better understand the influence of electrostatic charge on the performance of DPIs with 2 capsule-based dimensionally similar devices constructed with different materials. In addition, strategies to reduce electrostatic charge build up during the manufacturing process, and the processes involved in this phenomenon were investigated. Electrostatic charge measurements showed that there was a significant difference in electrostatic charge generated between tested formulations and devices. This affects particle detachment from carrier and thus significantly impacts aerosol performance. Conditioning fluticasone DPI capsules at defined temperature and humidity conditions reduced electrostatic charges acquired during manufacturing. Conditioning salmeterol DPI capsules at same conditions seemed disadvantageous for their aerosol performance because of increasing capillary forces and solid bridge formation caused by water absorption. Knowledge and understanding of the role of electrostatic forces in influencing DPI formulation performance was increased by these studies.     

Dry powder inhalation: past,present and future

Introduction: Early dry powder inhalers (DPIs) were designed for low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied to achieve acceptable lung deposition with these poorly designed inhalers.

Areas covered: The consequences of the choices made for early DPI development with respect of efficacy, production costs and safety and the tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures are discussed. Also newly developed particle manufacturing and powder formulation processes are presented as well as the challenges, objectives, and new tools available for future DPI design.

Expert opinion: Improved inhaler design is desired to make DPIs for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the lungs, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimizing the use of unnecessary excipients and designing simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation maneuver. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred.     

Effect of particle size of dry powder mannitol on the lung deposition in healthy volunteers

There is a lack of in vivo studies focusing on the effect of particle size of dry powder aerosols on lung deposition and distribution. We investigated the dose and distribution of radiolabelled powder aerosols of mannitol in the lungs using single photon emission tomography (SPECT). Three different sized radiolabelled powders were produced by co-spray drying mannitol with 99mTc-DTPA. The primary particle size distribution of the powders measured by laser diffraction showed a volume median diameter of 2, 3 and 4 microm with span 2.3, 2.0 and 2.1, respectively, which corresponded to an aerodynamic diameter of 2.7, 3.6, 5.4 microm and geometric standard deviation of 2.6, 2.4 and 2.7 when the powders were dispersed using an Aeroliser dry powder inhaler. Three capsules each containing approximately 20mg (i.e. a total of 60 mg containing 60-90 MBq) of each of the radiolabelled powders were inhaled by eight healthy volunteers using the Aeroliser inhaler. Images of aerosol deposition in the lungs were acquired using fast, multi-bed position SPECT. The lung dose markedly decreased with increasing aerosol particle size (mean+/-S.E.M.: 44.8+/-2.4, 38.9+/-0.9, 20.6+/-1.6% for 2.7, 3.6, 5.4 microm, respectively, p<0.0001). The sites of deposition of the 2.7 and 3.6 microm aerosols were similar (penetration index, PI=0.63+/-0.05, 0.60+/-0.03, respectively, p>0.3), but different to the 5.4 microm aerosols (PI=0.52+/-0.04, p<0.02). The lung dose followed the in vitro powder dispersion performance, with the % lung dose being related to fine particle fraction by a slope of 0.8 for a regression with intercepts forced through the origin. The SPECT results provide direct evidence that the lung deposition of dry powder aerosols depends on the particle size. The lung dose of the 2.7 and 3.6 microm aerosols using the Aeroliser was double compared to that of the 5.4 microm aerosols and the deposition of the smaller particles was more peripheral.     

An Investigation into the Dispersion Mechanisms of Ternary Dry Powder Inhaler Formulations by the Quantification of Interparticulate Forces

Purpose To investigate the dispersion mechanism(s) of ternary dry powder inhaler (DPI) formulations by comparison of the interparticulate adhesions and in vitro performance of a number of carrier–drug–fines combinations. Materials and Methods The relative levels of adhesion and cohesion between a lactose carrier and a number of drugs and fine excipients were quantified using the cohesion–adhesion balance (CAB) approach to atomic force microscopy. The in vitro performance of formulations produced using these materials was quantified and the particle size distribution of the aerosol clouds produced from these formulations determined by laser diffraction. Results Comparison between CAB ratios and formulation performance suggested that the improvement in performance brought about by the addition of fines to which the drug was more adhesive than cohesive might have been due to the formation of agglomerates of drug and fines particles. This was supported by aerosol cloud particle size data. The mechanism(s) underlying the improved performance of ternary formulations where the drug was more cohesive than adhesive to the fines was unclear. Conclusions The performance of ternary DPI formulations might be increased by the preferential formation of drug–fines agglomerates, which might be subject to greater deagglomeration forces during aerosolisation than smaller agglomerates, thus producing better formulation performance.