Susan Hoe

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 30L/min, doses of Pulmicort (budesonide 400 microg) and Bricanyl (terbutaline 500 microg) 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.

Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics

A series of co-spray dried microparticles containing di-sodium cromoglycate (DSCG) and polyvinyl alcohol (PVA - 0%, 30%, 50%, 70% and 90% w/w, respectively), were prepared as potential controlled release (CR) viscous/gelling vehicles for drug delivery to the respiratory tract. The microparticles were characterised in terms of particle size, crystal structure, density, surface morphology, moisture sorption, surface energy and in vitro aerosolisation efficiency. The co-spray dried particles were amorphous in nature and had spherical geometry. High-resolution atomic force microscopy analysis of the surfaces of the DSCG/PVA suggested no significant differences in roughness between microparticles containing 30-90% w/w PVA (ANOVA, p<0.05), while no specific trend in either size or density was observed with respect to PVA concentration. In comparison, a linear decrease in the relative moisture sorption (R2=0.997) and concurrent increase in total surface free energy (R2=0.870) were observed as PVA concentration was increased. Furthermore a linear increase in the aerosolisation efficiency, measured by inertial impaction, was observed as PVA concentration was increased (R2=0.993). In addition, the increase in aerosolisation efficiency showed good correlation with equilibrium moisture content (R2=0.974) and surface energy measurement (R2=0.905). These relationships can be attributed to the complex interplay of particle forces at the contiguous interfaces in this particulate system.

Does carrier size matter? A fundamental study of drug aerosolisation from carrier based dry powder inhalation systems

There is plenty of evidence supporting the notion that the size of the carrier influences the aerosolisation performance of drug from a drug-carrier blend. Interestingly, that evidence is contradictory in places and the study of such mechanisms is fraught by the compounding variables associated with comparing crystalline powders (e.g. as size is varied so may the shape, surface chemistry, roughness and the amount of fine excipients). To overcome these limitations, a series of model polystyrene spheres were used to study the influence of size on aerosol performance. Three polystyrene sphere carriers (TS-80, TS-250 and TS-500, describing their approximate diameters) were characterised using laser diffraction, atomic force microscopy, colloid probe microscopy, electron microscopy, true density and dynamic vapour sorption. The model carriers were blended with micronized salbutamol sulphate (67.5:1 ratios) and the aerosolisation performance was tested using a multistage liquid impinger at a range of flow rates (40-100 lmin(-1)). Physico-chemical analysis of the carriers indicated that all carriers were spherical with similar roughness and densities. Furthermore, the adhesion force of drug to the carrier surfaces was independent of carrier size. Significant differences in drug aerosolisation were observed with both flow rate and carrier size. In general, as carrier size was increased, aerosol performance decreased. Furthermore, as flow rate was increased so did performance. Such observations suggest that higher energy processes drive aerosolisation, however this is likely to be due to the number of impaction events (and associated frictional and rotational forces) rather than the actual collision velocity (since the larger carriers had increased momentum and drag forces). This study shows that, in isolation of other variables, as carrier size increases, a concurrent decrease in drug aerosolisation performance is observed.

Use of a Fundamental Approach to Spray-Drying Formulation Design to Facilitate the Development of Multi-Component Dry Powder Aerosols for Respiratory Drug Delivery

PurposeA fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach.MethodsFormulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured.ResultsThe design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations.ConclusionsTheoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.

Respirable bacteriophages for the treatment of bacterial lung infections.

This review article discusses the development of respiratory therapeutics containing bacteriophages indicated for lung infections, specifically those that have become increasingly difficult to treat because of antibiotic resistance. Recent achievements and remaining problems are presented for each step necessary to develop a bacteriophage-containing dosage form for respiratory drug delivery, including selection of appropriate bacteriophages for therapy, processing and purification of phage preparations, formulation into a stable, solid dosage form, and delivery device selection. Safety and efficacy studies in animals and human subjects are also reviewed.

A Review of Electrostatic Measurement Techniques for Aerosol Drug Delivery to the Lung: Implications in Aerosol Particle Deposition

Electrostatic properties of formulation components play an important role in inhalation products. Suitable measurement of charge distribution will, therefore, lead to better control of inhalation formulation manufacture. Advances in this field have been made in the past few years but, real time, direct techniques still need to be developed further to obtain a precise, accurate and easy to use measurement of electrically charged aerosolised powders. This short review presents an overview of the various techniques present in literature for measurement of charge applicable to inhalation dosage forms.

Manufacturing and device options for the delivery of biotherapeutics.

Biotherapeutic aerosol formulations are an intense area of interest for systemic and local drug delivery. This article provides a short overview of typical factors required specifically for biotherapeutic aerosol formulation design, the processing options open for consideration, and the issue of inhalation device selection. Focusing on spray drying, four case studies are used to highlight the relevant issues, describing investigations into: (1) the mechanical stresses occurring in bacteriophage formulations during spray-dryer atomization; (2) modeling of the spray-dryer process and droplet drying kinetics, to assist process design and predictions of formulation stability; (3) a predictive approach to the design and processing of a five-component dry powder aerosol formulation; and (4) the survival of bacteriophages after pressurized metered dose inhaler atomization.

Dynamic electrostatic charge of lactose-salbutamol sulphate powder blends dispersed from a Cyclohaler®

Context: Electrostatic forces have been claimed to be a mechanism for aerosol deposition in the lungs. However, the extent of its influence on aerosol performance is not clear, particularly for carrier-drug formulations. Objectives: To prepare lactose-salbutamol powder blends, varying in blend ratio, and identify any relationships between salbutamol dose, electrostatic characteristics and in vitro aerosol performance. Methods: Decanted lactose and micronized salbutamol sulfate was mixed to produce five blends (equivalent to 50, 100, 200, 300 and 400 µg salbutamol per 33 mg of powder). 33 ± 1 mg of a blend was loaded into a Cyclohaler™ and dispersed into the electrical Next Generation Impactor (eNGI) at an air flow rate of 60 L/min. This was conducted in triplicate for all five lactose-salbutamol blends. Results: Fine particle fraction increased with salbutamol dose, from 5.89 ± 1.42 to 21.35 ± 2.91%. Specific charge (charge divided by mass) distributions for each blend were greatest in magnitude for the 50 µg blend and similar in magnitude between all other blends. However, in eNGI Stage 1 (>8.06 µm), specific charge decreased from 100 µg (−170.4 ± 45.8 pC/µg) to 400 µg (−10.0 ± 9.1 pC/µg). Conclusions: The improvement in fine particle fraction with increased salbutamol dose was indicative of fine drug binding to high and low energy sites on the lactose carrier surface. This finding was supported by electrostatic charge results, but the aerosol charge itself was not found to influence aerosol performance by electrostatic forces.

Macro-Raman spectroscopy for bulk composition and homogeneity analysis of multi-component pharmaceutical powders

&NA; A new macro‐Raman system equipped with a motorized translational sample stage and low‐frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi‐component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi‐pass cavity of the macro‐Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02 &mgr;L to about 0.4 &mgr;L. A stochastic model simulating the random sampling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide® 250 and Seretide® 500 simulated for different sampling volumes with experimentally measured compositions verified that the effective sample volume of a single point macro‐Raman measurement in the multi‐pass cavity of this instrument was between 0.3 &mgr;L and 0.5 &mgr;L. The macro‐Raman system was also successfully used for blend uniformity analysis. It was concluded that demixing occurred in the binary mixture of L‐leucine and D‐mannitol from the observation that the sampling errors indicated by the standard deviations of measured leucine mass fractions increased during mixing, and the standard deviation values were all larger than the theoretical lower limit determined by the simulation. Since sample volume was shown to have a significant impact on measured homogeneity characteristics, it was concluded that powder homogeneity analysis results, i.e., the mean of individual test results and absolute and relative standard deviations, must be presented together with the effective sample volumes of the applied testing techniques for any measurement of powder homogeneity to be fully meaningful. Graphical abstract Figure. No caption available. HighlightsMacro‐Raman systems are suitable for bulk composition and blend uniformity analysis.Two methods of evaluating macro‐Raman effective sample volumes were proposed.Uniformity analysis results strongly rely on the effectively tested sample volumes.

Quantitative Macro-Raman Spectroscopy on Microparticle-Based Pharmaceutical Dosage Forms:

Quantitative macro-Raman spectroscopy was applied to the analysis of the bulk composition of pharmaceutical drug powders. Powders were extracted from seven commercial lactose-carrier-based dry-powder inhalers: Flixotide 50, 100, 250, and 500 μg/dose (four concentrations of fluticasone propionate) and Seretide 100, 250, and 500 μg/dose (three concentrations of fluticasone propionate, each with 50 μg/dose salmeterol xinafoate). Also, a carrier-free pressurized metered-dose inhaler of the same combination product, Seretide 50 (50 μg fluticasone propionate and 25 μg salmeterol xinafoate per dose) was tested. The applicability of a custom-designed dispersive macro-Raman instrument with a large sample volume of 0.16 μL was tested to determine the composition of the multicomponent powder samples. To quantify the error caused by sample heterogeneity, a Monte Carlo model was developed to predict the minimum sample volume required for representative sampling of potentially heterogeneous samples at the microscopic level, characterized by different particle-size distributions and compositions. Typical carrier-free respirable powder samples required a minimum sample volume on the order of 10−4 μL to achieve representative sampling with less than 3% relative error. In contrast, dosage forms containing non-respirable carriers (e.g., lactose) required a sample volume on the order of 0.1 μL for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation.