Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

Measuring charge and mass distributions in dry powder inhalers using the electrical Next Generation Impactor (eNGI)

The electrical Next Generation Impactor (eNGI) was assessed against the electrical low-pressure impactor (ELPI) and next generation impactor (NGI) for its capability to characterise particle size and electrostatic charge properties of dry powder inhaler (DPI) formulations. Following assessment, the relationship between inhalational air flow rate and drug powder charge was explored using the eNGI. At a vacuum flow rate of 30 L/min, doses of Pulmicort^® (budesonide 400 μg) and Bricanyl^® (terbutaline 500 μg) were dispersed into the ELPI, NGI and eNGI, from which particle size profiles and charge profiles were ascertained. Further doses of Pulmicort and Bricanyl were fired into the eNGI at vacuum air flow rates of 45, 60, 75 and 90 L/min, and the resultant size and charge profiles were determined. Particle size profiles at 30 L/min were found to be comparable between the NGI and eNGI, while charge profiles were comparable between the eNGI and ELPI. As air flow rate increased from 30 to 90 L/min, in vitro aerosol performance improved before reaching a peak at 45 L/min (Pulmicort) and 60 L/min (Bricanyl). Net charge also increased with flow rate, the cause of which may be a combination of increased turbulence and aerosol performance. This study demonstrates that the eNGI is capable of electrostatic and particle size characterization of commercial drug-only DPI products.     

Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and Next Generation pharmaceutical impactors and their USP methods

The particle sizing performance of a Next Generation Pharmaceutical Impactor (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of Vanceril MDIs containing beclomethasone dipropionate (BDP) was used throughout. MDIs were sampled into NGI and ACI in accordance with USP recommendations, at 30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or without a silicone cup or stage coating, to determine the apparent particle size distributions (PSD) of BDP. The mass balance and the statistical comparability of drug deposits were assured on a "per actuation basis" across all experiments, demonstrating "good cascade impactor practices." Interstage deposition or "wall losses" in NGI were found to be lower than those in ACI, although their determination was laborious in NGI. The PSD profiles for Vanceril from a single actuation were distinguishable between NGI and ACI, when uncoated collection surfaces were used, most specifically for drug mass <4-microm aerodynamic diameter (p < 0.05). Silicone coating of collection surfaces and an increased number of actuations were shown to result in PSD profile shifts for both NGI and ACI. Such effects were most pronounced for NGI, although coating the collection surfaces and/or increasing the number of actuations improved drug retention significantly on the upper stages of NGI, and thereby, minimized the effects of particle bounce of BDP from Vanceril MDIs. PSD profiles from a single actuation could be determined reliably in either of these impactors, provided that coated collection surfaces were employed; also, cumulative % mass undersize profiles were similar between instruments. However, small differences in PSD profiles still existed to support NGI's design claims for reduced "overlap" in its stage collection efficiency curves.     

A new approach to characterise pharmaceutical aerosols: Measurement of aerosol from a single dose aqueous inhaler with an optical particle counter

An in-line sampling system with dilution units for aqueous droplet aerosols from single dose inhalers (Berodual Respimat^®, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany) for an optical particle counter is described. The device has been designed to interface with a white light aerosol spectrometer (welas^® digital 2100, Palas^® GmbH, Germany) that allows the time-resolved measurement of highly concentrated aerosols. Performance of the sampling system with regard to the measured particle size distribution (PSD) is compared to Next Generation Impactor (NGI) and to laser diffraction measurements (Sympatec Inhaler and open bench). Optimal settings of the sampling system lead to PSDs that correspond well to those measured by the evaporation minimising NGI approach (15 L/min, cooled) and laser diffraction. The better accuracy of the new dilution unit in presence of an additional aerosol sampling filter in comparison to a previously described aerosol sampling system is shown for different settings of the sampling system. This allows a more precise quantification of the delivered drug amount which is also well correlated to the aerosol volume measured by the welas^® system. In addition, using time-resolved welas^® measurements provides insight into droplet size, evaporation and size changes of aerosol clouds delivered by liquid inhalers.     

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles

Purpose

This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations.

Methods

Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (R_a) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor.

Results

Fluid-bed processing resulted in a modest increase in the R_a from 562 to 907 nm while roller compaction led to significant increases in R_a?>?1300 nm. The roller compacted carriers exhibited FPF?>?35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60–200% whereas only?<?30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air.

Conclusions

The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

     

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.     

Effects of formulation and operating variables on Zanamivir dry powder inhalation characteristics and aerosolization performance

Abstract

The objective of this study was to investigate the influence of formulation and operating variables on the physical characteristics and aerosolization performance of zanamivir spary-dried powders for inhalation. Spray-dried samples of zanamivir, zanamivir/mannitol and zanamivir/mannitol/leucine were prepared from their corresponding aqueous solutions under the same conditions to study the influence of the composition, and zanamivir/mannitol/leucine (1/1/3 by weight) formulation was used for investigation of the effect of the preparation process. Dry powders were characterized afterwards for different physical properties, including morphology, particle size, flowability, density and moisture absorption. The in vitro deposition was also evaluated after the aerosolization of powders at 100?L?min^?1 via the Aerolizer® into a Next Generation Impactor (NGI). The highest FPF of 41.40?±?1.1% was obtained with a zanamivir/mannitol/leucine ratio of 1/1/3, which had an average D_g of 3.11?±?0.13?μm and an angle of repose of 36°^?±?1. It was found that the influence of the preparation process on zanamivir spary-dried powders characteristics and aerosolization properties was relatively small, but the influence of the composition was relatively large. Optimization of DPI can be achieved by selecting the most appropriate formulation and preparation process.     

Adhesion forces in interactive mixtures for dry powder inhalers--evaluation of a new measuring method.

Dry powder inhalers mostly contain carrier based formulations where micronized drug particles are adhered to coarse carrier particles. The performance of the dry powder inhaler depends on the inhaler device, the inhalation manoeuvre and the formulation. The most important factor influencing the behaviour of the formulation is the adhesion force acting between the active ingredient and the carrier particles, which can be measured using different methods, for example the centrifuge technique or atomic force microscopy. In this study the tensile strength method, usually applied to determine cohesion forces between powder particles of one material, is optimized for adhesion force measurements between powder particles of unlike materials. Adhesion force measurements between the carrier materials lactose or mannitol and the drug substance salbutamol sulphate using the tensile strength method and the atomic force microscopy show higher values with increasing relative humidity. Consequently, the fine particle fraction determined using the Next Generation Impactor decreases with increasing relative humidity as a result of the enhanced interparticle interactions.     

Comparative analysis of methods to measure aerosols generated by a vibrating mesh nebulizer.

Different approaches have been employed for in vitro assessment of the aerosol particle size generated by inhalation devices. In this study, aerosols from the Omron MicroAir vibrating mesh (VM) nebulizer were measured by cascade impaction (CI) using the MSP Next Generation Pharmaceutical Impactor (NGI), the ThermoAndersen Cascade Impactor (ACI), and by time-of-flight (TOF) analysis with the TSI 3321 Aerodynamic Particle Sizer Spectrometer (APS). The VM nebulizer was evaluated with sodium fluoride (NaF; 2.5%) and with generic albuterol (0.083%). Aerosol particle size (MMAD), respirable fractions (RF < 5 microm), and fine particle fractions (FPF < 3.3 microm) were determined with each method at room temperature (RT) and 4 degrees C using 50% average relative humidity. By NGI at either RT or 4 degrees C, aerosol particle sizes were similar for both NaF and albuterol (4.3-4.5 microm MMAD) with 55-61% RF and 27-43% FPF. With ACI, the distribution of particles at RT was similar except at the extremes of the dispersion and the MMAD was smaller (3.3 microm MMAD; p = 0.03). At 4 degrees C, particle sizes determined by ACI results were similar to the NGI (MMAD 4.1 microm; p > 0.05). TOF analysis by APS with albuterol gave significantly larger calculated MMAD (cMMAD) than either CI method (7.2 microm; p < 0.001). TOF measurements of nebulized albuterol at RT and 4 degrees C were equivalent. In summary, the results of VM nebulized NaF and albuterol were more consistent and generally equivalent when determined by NGI (at RT and 4 degrees C) and ACI analysis (at 4 degrees C). In contrast, aerosol particle sizes measured by TOF in the APS at both RT and 4 degrees C were larger than results obtained by CI. Differences in aerosol particle distribution obtained by different analysis methods should be considered while evaluating the in vitro performance of VM nebulizers.     

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS

An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values (R² = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.     

Investigating improving powder deagglomeration via dry powder inhalers at a low inspiratory flow rate by employing add-on spacers

The aim of this study was to investigate whether small add-on spacers alone or equipped with a passive deagglomerating component would improve aerosol performances of passive low airflow resistance dry powder inhalers (DPIs) at a low inhalation flow rate. Depositions of beclometasone dipropionate (BDP) and salbutamol sulphate (SS) via the Asmabec Clickhaler and Asmasal Clickhaler at 30 L/min airflow rate in an oropharyngeal model and attached filter were determined. Three add-on spacers, one with 5.0 cm length, and the other with the same features but incorporating a fine mesh, and the third one with the length of 8.5 cm (long add-on spacer) were used. Incorporating mesh did not improve the filter dose for SS, and significantly reduced this dose for BDP. The long add-on spacer was the most efficient spacer as it had minimal effects on the filter doses, also significantly reduced drug depositions in the model. In conclusion, an optimum length of an add-on spacer is required to minimise oropharyngeal drug deposition via a low airflow resistance DPI at a low inspiratory flow rate without considerable reduction of the respirable dose. Incorporating sieves within add-on spacers may diminish aerosol performances of the DPIs at low airflow rates.     

Cascade impactor practice for a high dose dry powder inhaler at 90 L/min: NGI versus modified 6-stage and 8-stage ACI

The compendial methods of particle size distribution (PSD) profile determination for dry powder inhalers (DPIs) were compared between the Next Generation Pharmaceutical Impactor (NGI) and the Andersen Cascade Impactor (ACI). Relenza Rotadisk (zanamivir) and Diskhaler was used as a model DPI and sampled into each impactor via its preseparator (PS), at 90 L/min under various protocols. In the NGI, silicone coating was shown to be indispensable to prevent or minimize particle bounce and reentrainment, and to reduce wall losses to the levels acceptable to the compendia (5%). In contrast, the ACI exceeded this 5% limit, regardless of coating, implying different wall loss mechanisms from the NGI. Particle bounce occurred in both impactors, inaccurately undersizing the PSD profiles for Relenza, unless the collection surfaces were coated or an increased number of doses were employed. Hence, the PSD profile for Relenza following single dose collection in the stage-coated NGI was the most accurate. In contrast, the use of the ACI and its PS for Relenza at 90 L/min suffered from several problems, even though the poorly designed PS still resulted in consistent impactor dose and PSD profiles, compared to those obtained from the NGI and its PS.     

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。     

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.     

Preparation and Evaluation of Single and Co-Engineered Combination Inhalation Carrier Formulations for the Treatment of Asthma

Two combination dry powder inhalation formulations were engineered via spray drying and co-spray drying salbutamol base (SB) and beclomethasone dipropionate (BDP). The aerosol performances of the individual drugs, a physical mix and the co-spray-dried particle systems were investigated after blending with conventional lactose carrier, under realistic dose regimes. Furthermore, each system was evaluated in terms of the physicochemical properties and via high-throughput Raman microscopy (to study co-association and deposition patterns after in vitro aerosolisation studies). In general, analysis of the aerosol performance (measured using a next-generation impactor) of the single drug and physical mix formulations suggested that SB and BDP have significantly different stage-deposition profiles. Such observations were further substantiated by scanning electron microscopy, where SB–BDP agglomeration could be observed in the physical mix. Stage deposition from the SB–BDP co-spray-dried powders were different than that for the physical mix, wherein the amount of SB and BDP on each stage was equivalent; suggesting that the two drugs could be targeted and deposited at the same location on the lung epithelia. Raman microscopy of the physical mix and co-spray-dried formulations also confirmed the differences in stage deposition between formulations and co-localised deposition for the co-spray-dried formulation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4267–4276, 2012     

An in vitro investigation into the effect of glycosaminoglycans on the skin partitioning and deposition of NSAIDs

Beclomethasone dipropionate (BDP) liposomes were prepared from various lipids, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and hydrogenated soybean phosphatidylcholine (Epikuron 200 SH). A lipid with a low transition temperature (T(m)) (DLPC) incorporated a higher amount of BDP than lipid with a high T(m). The nebulisation of rehydrated freeze-dried BDP liposomes was carried out using a Pari LC Plus nebuliser and the generated aerosol characterised by an Andersen Cascade Impactor operated at 28.3 l/min. The rehydrated BDP-DLPC liposomes showed a higher output (78.3%) and a higher fine particle fraction (FPF) (75.0%) and smaller mass median aerodynamic diameter (MMAD) (3.31 microm) than the other rehydrated liposome preparations. Liposomes containing lipid with a high T(m) (DPPC and Epikuron) underwent aggregation during nebulisation. This was shown by the large increase in size of the DPPC liposomes from 15.78 to 47.51 microm and the Epikuron liposomes from 5.84 to 46.70 microm.     

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.     

Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers.

The effects of formulation parameters on the product performance characteristics of solution metered dose inhalers (MDIs) were determined using ethanol as the cosolvent and HFA 134a as the propellant. Solubility of beclomethasone dipropionate (BDP) was determined in various blends of 134a and ethanol and was shown to increase with ethanol concentration. Product performance was assessed using the APS Model 3306 Impactor Inlet in conjunction with APS Model 3320 Aerodynamic Particle Sizer (APS). Nine solution formulations containing various BDP and ethanol concentrations were studied. Chemical analysis of the Impactor Inlet was performed in order to determine the "respirable" deposition of the MDI system. With increased ethanol concentration, the throat deposition and plate deposition increased and the respirable deposition decreased. The mass median aerodynamic diameter (MMAD) increased with the increasing drug concentration, but did not show a significant increase with an increase in ethanol concentration. This indicates that the efficiency of solution MDIs decreases with increased ethanol concentration. A Maximum Respirable Mass (MRM) was calculated based on the drug solubility at a particular ethanol concentration and the respirable deposition for a 50mcl valve and QVAR actuator for that ethanol concentration. The MRM represents the maximum amount of a given drug that can be delivered to the lungs theoretically and is very sensitive to the solubility profile of the drug. The MRM increased with the increasing ethanol concentration in the formulation until a plateau was reached at an ethanol concentration of 10-15% w/w. The MRM initially increases with increase in ethanol concentration due to the increase in drug solubility. However, at higher ethanol concentrations the increase in drug solubility was negated by a decrease in the respirable deposition. This study illustrates the importance of considering both formulation properties and product performance characteristics when optimizing a metered dose inhaler drug delivery system.     

Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles

Objective: To design and characterize aerosol microparticles (MP) to provide sustained release of the water-soluble compound sulforhodamine B (SRB) and achieve effective aerosol dispersion.

Significance: Modulating the release of water-soluble compounds remains a challenge in pulmonary drug delivery.

Methods: SRB and water made up an aqueous solution, while acetalated dextran (Ac-Dex) and isopropyl alcohol made up an organic solution. The two solutions were mixed together, and the solution was spray dried to produce MP. MP were characterized for morphology, size, release kinetics, aerosol dispersion, and cellular interactions.

Results: Ac-Dex MP exhibited corrugated morphology and aerodynamic diameters from 2.06 to 2.86?μm. MP deposited in all stages of a Next Generation Impactor, with >90% fine particle fraction. MP exhibited encapsulation efficiencies >129% with SRB loading values up to 16.7?μg SRB/mg MP. MP exhibited sustained release of SRB at pH 7 and fast release at pH 5. In vitro experiments showed minimal cytotoxicity, successful uptake of MP in epithelial cells, and no disruption to the integrity of epithelial monolayers.

Conclusions: Ac-Dex MP systems demonstrated the ability to provide sustained the release of a water-soluble therapeutic in addition to effective aerosol dispersion for pulmonary applications.