Qi (Tony) Zhou

Emerging inhalation aerosol devices and strategies: where are we headed?

Novel inhaled therapeutics including antibiotics, vaccines and anti-hypertensives, have led to innovations in designing suitable delivery systems. These emerging design technologies are in urgent demand to ensure high aerosolisation performance, consistent efficacy and satisfactory patient adherence. Recent vibrating-mesh and software technologies have resulted in nebulisers that have remarkably accurate dosing and portability. Alternatively, dry powder inhalers (DPIs) have become highly favourable for delivering high-dose and single-dose drugs with the aid of advanced particle engineering. In contrast, innovations are needed to overcome the technical constrains in drug-propellant incompatibility and delivering high-dose drugs with pressurised metered dose inhalers (pMDIs). This review discusses recent and emerging trends in pulmonary drug delivery systems.

Drug–lactose binding aspects in adhesive mixtures: Controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations.

Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach

The aim of this study is to investigate the changes in physical and chemical surface properties of a fine lactose powder, which has been processed by a mechanical dry coating approach. A commercially available milled lactose monohydrate powder (median diameter around 20 μm) was dry coated with a pharmaceutical lubricant, magnesium stearate (MgSt). Substantial changes in bulk behavior have been shown previously and the purpose of the current work was to understand the relationship between these bulk changes and physico-chemical changes in the surface. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry results demonstrated both qualitatively and quantitatively how the chemical properties of the lactose particle surfaces had been altered. The characterization results indicated that a high-level coverage of a thin coating layer of MgSt has been created through the coating. Inverse gas chromatography was used to probe the surface energetic changes, and at conditions of finite dilution, provided a new insight into surface energy changes. This work demonstrated that the modifications of the surface physical and chemical properties correlated with the reduction in powder cohesion and improvement in powder flow.

Improving Powder Flow Properties of a Cohesive Lactose Monohydrate Powder by Intensive Mechanical Dry Coating

The objective of this study was to improve the cohesive lactose powder flowability. A cohesive lactose monohydrate powder was processed in either a tumbling blender or an intensive mechanical processor with either magnesium stearate or fumed silica. No substantial changes in particle size were detected by laser diffraction following either treatment. The untreated lactose sample exhibited very poor powder flow. Only limited improvements in powder flowability were indicated after the tumbling blending, intensive mechanical processing with the fumed silica or without additives. However, the intensive mechanical processing of the lactose sample with magnesium stearate demonstrated exceptionally large increases in both poured and tapped density as well as notable improvements in all powder flowability indicators examined. Our findings support the use of intensive mechanical processing technique as an effective method to coat cohesive pharmaceutical powders with selected additives, modify the surface nature of the particles, reduce the interparticle cohesive forces and hence improve powder flowability. The subtle differences in powder flow behaviour of lactose samples between the untreated and tumbling blended powders with magnesium stearate were only detected by the powder rheometer using its dynamic mode, indicating its potential advantages over traditional powder flow characterisation approaches.

Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties.

The objective of this study was to investigate if the coating extent created by a mechanofusion process corresponded with observed changes in bulk powder properties. A fine lactose powder (approximate median diameter 20 μm) was dry coated with magnesium stearate using from 0.1 to 5% (w/w) content. An ultra-thin coating layer of magnesium stearate was anticipated, but previous attempts to determine such thin layers on these fine particles have had limited success, with poor resolution. In this study, the surface coating was examined using the state-of-the-art XPS and ToF-SIMS systems. The powder flow was characterized by Carr index and shear cell testing. XPS was successfully applied to demonstrate variations in surface coverage, as a function of additive levels, and indicated near complete coating coverage at additive levels of 1% (w/w) and above. ToF-SIMS results supported such coating coverage assessment, and indicated coating uniformly across the fine particle surfaces. The flow metrics employed could then be related to the coating coverage metrics. The mechanofusion process also modified the apparent surface roughness observed by SEM and BET. It was suggested that the changes in the surface chemical composition exerted a more evident and direct impact on the powder cohesion and flow characteristics than the changes in the surface morphological properties after the mechanofusion in this study.

Synergistic Antibiotic Combination Powders of Colistin and Rifampicin Provide High Aerosolization Efficiency and Moisture Protection

For many respiratory infections caused by multidrug-resistant Gram-negative bacteria, colistin is the only effective antibiotic despite its nephrotoxicity. A novel inhaled combination formulation of colistin with a synergistic antimicrobial component of rifampicin was prepared via co-spray drying, aiming to deliver the drug directly to the respiratory tract and minimize drug resistance and adverse effects. Synergistic antibacterial activity against Acinetobacter baumannii was demonstrated for the combination formulation with high emitted doses (96%) and fine particle fraction total (FPFtotal; 92%). Storage of the spray-dried colistin alone formulation in the elevated relative humidity (RH) of 75% resulted in a substantial deterioration in the aerosolization performance because the amorphous colistin powders absorbed significant amount of water up to 30% by weight. In contrast, the FPFtotal values of the combination formulation stored at various RH were unchanged, which was similar to the aerosolization behavior of the spray-dried rifampicin-alone formulation. Advanced surface chemistry measurements by XPS and ToF-SIMS demonstrated a dominance of rifampicin on the combination particle surfaces, which contributed to the moisture protection at the elevated RH. This study shows a novel inhalable powder formulation of antibiotic combination with the combined beneficial properties of synergistic antibacterial activity, high aerosolization efficiency, and moisture protection.

Effect of Surface Coating with Magnesium Stearate via Mechanical Dry Powder Coating Approach on the Aerosol Performance of Micronized Drug Powders from Dry Powder Inhalers

The objective of this study was to investigate the effect of particle surface coating with magnesium stearate on the aerosolization of dry powder inhaler formulations. Micronized salbutamol sulphate as a model drug was dry coated with magnesium stearate using a mechanofusion technique. The coating quality was characterized by X-ray photoelectron spectroscopy. Powder bulk and flow properties were assessed by bulk densities and shear cell measurements. The aerosol performance was studied by laser diffraction and supported by a twin-stage impinger. High degrees of coating coverage were achieved after mechanofusion, as measured by X-ray photoelectron spectroscopy. Concomitant significant increases occurred in powder bulk densities and in aerosol performance after coating. The apparent optimum performance corresponded with using 2% w/w magnesium stearate. In contrast, traditional blending resulted in no significant changes in either bulk or aerosolization behaviour compared to the untreated sample. It is believed that conventional low-shear blending provides insufficient energy levels to expose host micronized particle surfaces from agglomerates and to distribute guest coating material effectively for coating. A simple ultra-high-shear mechanical dry powder coating step was shown as highly effective in producing ultra-thin coatings on micronized powders and to substantially improve the powder aerosolization efficiency.

Use of surface energy distributions by inverse gas chromatography to understand mechanofusion processing and functionality of lactose coated with magnesium stearate

The purpose was to employ a new finite dilution approach to determine total surface energy distributions of mechanofused powders by inverse gas chromatography (IGC) to contribute to the understanding of their improved flow properties and to help optimise the magnesium stearate (MgSt) coating. Pharmatose 450M was mechanofused with between 0.1 and 8% (w/w) of MgSt. The non-polar, polar and total surface energies and work of cohesion at infinite dilution and the energy distributions at finite dilution were constructed using IGC. Brunauer-Emmet-Teller (BET) surface area and particle morphology were determined by IGC and scanning electron microscope, respectively. Surface energies determined at finite dilution appeared more consistent with the observed flow behaviour of mechanofused powders than comparative surface energy determination at infinite dilution. Polar and total surface energy distributions together with BET surface area measurements were the lowest when lactose was mechanofused with 1-2% MgSt (w/w). In conclusion, the surface energy distribution profiles measured at finite dilution were argued to be more informative and useful in reporting the surface energy changes during mechanofusion, optimising MgSt concentration in the mechanofusion process, and the flow behaviour of mechanofused powders.

Colistin powders with high aerosolisation efficiency for respiratory infection: preparation and in vitro evaluation.

In many respiratory infections caused by multi-drug-resistant Gram-negative bacteria, colistin is often the last-line drug for treatment despite its nephrotoxicity when administered parenterally. Inhalation therapy of colistin has great potential to improve the efficacy while reducing adverse effects. In this study, inhalable powder formulations of colistin (sulphate) were produced via spray drying. The colistin powders were found to have intact antimicrobial activity against Acinetobacter baumannii measured by broth micro-dilution. Both the raw material and spray-dried formulations were amorphous and absorbed significant amount of water up to 30% (w/w) at relative humidity (RH) of at least 70%. The spray-dried formulations were physically stable in the amorphous form at 60% RH and 25°C, having a high aerosol efficiency (emitted dose >86% and fine particle fraction total >83%) which remained unchanged after a 3-month storage. Storage at an elevated RH of 75% resulted in the aerosolisation performance significantly decreased, and at RH 90%, the formulation particles fused together (but without re-crystallisation). Although spray drying has been extensively used for generating inhalable drug particles, this is the first report that colistin powder can be physically stable in the amorphous form at ambient conditions, indicating that spray-drying approach is suitable for producing inhalable colistin powder formulation.

How Much Surface Coating of Hydrophobic Azithromycin Is Sufficient to Prevent Moisture-Induced Decrease in Aerosolisation of Hygroscopic Amorphous Colistin Powder?

ABSTRACTAerosolisation performance of hygroscopic particles of colistin could be compromised at elevated humidity due to increased capillary forces. Co-spray drying colistin with a hydrophobic drug is known to provide a protective coating on the composite particle surfaces against moisture-induced reduction in aerosolisation performance; however, the effects of component ratio on surface coating quality and powder aerosolisation at elevated relative humidities are unknown. In this study, we have systematically examined the effects of mass ratio of hydrophobic azithromycin on surface coating quality and aerosolisation performance of the co-spray dried composite particles. Four combination formulations with varying drug ratios were prepared by co-spray drying drug solutions. Both of the drugs in each combination formulation had similar in vitro deposition profiles, suggesting that each composite particle comprises two drugs in the designed mass ratio, which is supported by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) data. XPS and ToF-SIMS measurements also revealed that 50% by weight (or 35% by molecular fraction) of azithromycin in the formulation provided a near complete coating of 96.5% (molar fraction) on the composite particle surface, which is sufficient to prevent moisture-induced reduction in fine particle fraction (FPF)recovered and FPFemitted. Higher azithromycin content did not increase coating coverage, while contents of azithromycin lower than 20% w/w did not totally prevent the negative effects of humidity on aerosolisation performance. This study has highlighted that a critical amount of azithromycin is required to sufficiently coat the colistin particles for short-term protection against moisture.