Nora Y.K. Chew

Use of Solid Corrugated Particles to Enhance Powder Aerosol Performance

AbstractPurpose. To study the dispersion performance of non-porous corrugated particles, with a focus on the effect of particle surface morphology on aerosolization of bovine serum albumin (BSA) powders. Methods. The solid-state characteristics of the spray-dried BSA powders, one consisting of smooth spherical particles and another corrugated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, thermogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler® and the Dinkihaler® coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size ≤5 μm collected from the liquid impinger. Results. Apart from the morphology and morphology-related properties (specific surface area, envelope density), the corrugated particles and spherical particles of BSA had very similar solid-state characteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler®, the FPFs of the corrugated particles were 10-20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dispersed by the Rotahaler®, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. Conclusions. Enhanced aerosol performance of powders can be obtained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact between the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles.

How Much Particle Surface Corrugation Is Sufficient to Improve Aerosol Performance of Powders

No HeadingPurpose.The current study aimed to quantify the different degree of particle surface corrugation and correlate it to the aerosol performance of powders.Methods.Powders of different degree of surface corrugation were prepared by spray drying under varying conditions. The solid-state properties of the powders including particle size, morphology, crystal form, true density, and moisture content were characterized. The degree of surface corrugation was quantified by the surface fractal dimension (DS) obtained by light scattering. The aerosol performance was studied by dispersing the powders using the Rotahaler at 60 L/min into a multi-stage liquid impinger. Fine particle fraction (FPF) was expressed as the wt% of BSA particles of size ≤5 μm in the aerosol.Results.Four powders of increasing degree of particle surface corrugation were prepared, with DS ranging from 2.06 for the least corrugated to 2.41 for the most corrugated. The powders had a similar size distribution (VMD 3 μm, span 1.4–1.5) and solid-state properties. Increasing the surface corrugation, DS, slightly from 2.06 to 2.18 enhanced the FPF significantly from 27% to 41%. This was explained by the reduced area of contacts and increased separation distance between the particles. Further increase of corrugation (DS ≥ 2.18) did not improve FPF.Conclusion.Powders with varying degrees of corrugation were successfully obtained by spray drying with their surface roughness quantified by fractal analysis. It was shown that only a relatively small degree of surface corrugation was sufficient to accomplish a considerable improvement in the aerosol performance of the powder.

Evidence of mast cell activation and leukotriene release after mannitol inhalation

The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction. Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before andfor90 min after challenge. The urinary concentrations of leukotriene (LT)E4, the prostaglandin (PG)D2 metabolite and the mast cell marker 9α,11β‐PGF2 weremeasured by enzyme immunoassay. Nτ‐methylhistamine was measured by radioimmunoassay. In asthmatic subjects, inhalation of a mean±sem dose of 272±56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5±2.1%. This was associated with increases in urinary 9α,11β‐PGF2 (91.9±8.2 versus 66.9±6.6 ng·mmol creatinine−1, peak versus baseline) and LTE4 (51.3±7.5 versus 32.9±4.7). In nonasthmatic subjects, the reduction in FEV1 was 1.0±0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9α,11β‐PGF2 (68.4±6.9 versus 56.0±5.8 ng·mmol creatinine−1) and LTE4 (58.5±5.3 versus 43.0±3.3 ng·mmol creatinine−1) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of Nτ‐methylhistamine in the nonasthmatics, but not in the asthmatics. The increased urinary levels of 9α,11β‐prostaglandin F2 support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects.

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.

Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing

Mannitol inhalation increases urinary excretion of 9α,11β-prostaglandin F2 (a metabolite of prostaglandin D2 and marker of mast cell activation) and leukotriene E4. The present study tested the hypothesis that β2-adrenoreceptor agonists and disodium cromoglycate (SCG) protect against mannitol-induced bronchoconstriction by inhibition of mast cell mediator release. Fourteen asthmatic subjects inhaled mannitol (mean dose 252±213 mg) in order to induce a fall in forced expiratory volume in one second (FEV1) of ≥25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 µg), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9α,11β-prostaglandin F2 and leukotriene E4. The maximum fall in FEV1 of 32±10% on placebo was reduced by 95% following formoterol and 63% following SCG. Following placebo, there was an increase in median urinary 9α,11β-prostaglandin F2 concentration from 61 to 92 ng·mmol creatinine−1, but no significant increase in 9α,11β-prostaglandin F2 concentration in the presence of either formoterol (69 versus 67 ng·mmol creatinine−1) or SCG (66 versus 60 ng·mmol creatinine−1). The increase in urinary leukotriene E4 following placebo (from 19 to 31 ng·mmol creatinine−1) was unaffected by the drugs. These results support the hypothesis that the drug effect on airway response to mannitol is due to inhibition of mast cell prostaglandin D2 release.

Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols.

AbstractPurpose. To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. Methods. Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler® and Dinkihaler®, connected to a multistage liquid impinger at different air flows. Results. Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 μm and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm3 and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler® increasing the flow (60−120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 μm powder, and decreased the FPF for the 7.3 μm powder; whereas the FPF for 5.0 μm powder was unaffected. With the Dinkihaler®, all the powders were near complete dispersion at ≥60 L/min. Conclusions. The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.

Effect of particle size, air flow and inhaler device on the aerosolisation of disodium cromoglycate powders

Recently, the dispersion of mannitol powders has demonstrated the importance of particle size, air flow and inhaler device (Chew and Chan, 1999). The aim of the present study is to extend our investigation to a different compound, disodium cromoglycate (DSCG) powders. Solid state characteristics of the powders were assessed by particle sizing, scanning electron microscopy, X-ray powder diffraction, moisture content, particle density determination and freeze fracture. The aerosol behaviour of the powders was studied by dispersion using Rotahaler(R) and Dinkihaler(R), connected to a four-stage liquid impinger operating at 30-120 l/min. Three amorphous powders with a mass median diameter (MMD) of 2.3, 3.7, 5.2 microm and a similar polydispersity were prepared. The particles were nearly spherical with a particle density of 1.6 g/cm(3) and moisture content of 6.6 wt.%. Using Rotahaler(R), the maximum fine particle fraction (FPF(max)) for all three powders was only 15 wt.%, attained at the highest flow of 120 l/min. Using Dinkihaler(R), the FPF(max) was two to four times higher, being 36 and 29 wt.% for the 2.3 and 3.7 microm powder, respectively, at 60 l/min; and 18 wt.% for the 5.2 microm powder at 120 l/min. Hence, the study shows that the FPF in the DSCG powder aerosols was determined by the interaction of the particle size, air flow and inhaler design. The attribution of the amorphous nature and the different physico-chemical properties of the powder may explain the incomplete and low dispersibility of DSCG.

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.

In Vitro Aerosol Performance and Dose Uniformity between the Foradile® Aerolizer® and the Oxis® Turbuhaler®

Dry powder inhalers for eformoterol fumarate dihydrate, a long-acting beta-2 agonist for bronchodilation, are currently available as the Foradile Aerolizer and the Oxis Turbuhaler. The two products are different in the formulation, the aerosol production mechanism, and the device resistance to air flow. These disparities are likely to lead to different aerosol characteristics. Our objective was to compare the in vitro performance of these two inhalers in producing eformoterol aerosols. Emitted dose uniformity was measured using a sampling apparatus described in the British Pharmacopaeia. Ten individual doses (dose number 2, 3, 15, 16, 30, 31, 45, 46, 59, and 60) of the entire content (60 doses) were collected from the Aerolizer and the Turbuhaler (six inhalers each). Particle size distribution of the aerosols generated by the two inhalers were measured by a multiple stage liquid impinger at four different air flows (30-120 L/min). Eformoterol collected from the sampling devices was measured by HPLC. Fine particles are those of < or = 1.7-5.0 microm in size in the aerosols obtained by interpolation of the data at the specified air flow. The Aerolizer showed a slight dependence of the emitted dose on the air flow, with the average emitted dose increased from 80% (at 30 L/min) to 90% (at higher flows) of the 12-microg label claim as compared with 60% for the Turbuhaler. When the emitted dose was normalized by the average emitted dose value, the Aerolizer showed less variation in the normalized emitted dose uniformity than the Turbuhaler. At high air flows, 90 and 120 L/min, both inhalers produced similar amounts (4 microg) of fine particles in the aerosol per dose discharged. As the flow as decreased to 30 and 60 L/min, both inhalers produced significantly less fine particles (p < 0.05), with the Oxis Turbuhaler producing lesser amounts than the Foradile Aerolizer. However, due to the different device resistance, comparing the inhaler performance at the same inspiratory effort may be more appropriate. At a comfortable effort of 40 cm H2O, the Foradile Aerolizer would produce a significantly higher fine particle mass in the aerosols. We conclude that the two inhalers were dissimilar in the emitted dose uniformity. The fine particle mass of eformoterol produced by the two inhalers was equivalent at high but not at low air flows. The disparities may be due to the difference in the formulation and the aerosol generation mechanism of the inhalers.

Aerosolization of protein solutions using thermal inkjet technology

Vapotronics Inc. is developing the thermal inkjet (TIJ) technology used extensively in the printer industry to create a digital aerosol inhaler for the inhalation of therapeutics for local and systemic delivery. The operation of thermal inkjet printers requires generation of high temperatures and vaporization of the liquid formulation to effect droplet ejection. A study was conducted to develop formulations that would permit the generation of aerosols of therapeutic proteins without damage to the inkjet system or degradation of the proteins. Two proteins, human growth hormone and insulin, were formulated and aerosolized. The aerosol was collected and subjected to assays to compare the physicochemical and biological activities of these proteins before and after aerosolization. In each case, there was no significant changes to the proteins as a result of the aerosolization, providing evidence that TIJ can be used for aerosolizing solutions of protein therapeutics.