Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler

Abstract

The purpose of this study was to evaluate the effect of carrier particle size on properties of dry powder and its effect on dry powder inhaler (DPI) performance. Commercial α-lactose-monohydrate, a commonly used carrier in DPI formulations, was carefully sieved to obtain different lactose size fractions, namely Lac A (90–125 μm), Lac B (63–90 μm), Lac C (45–63 μm), Lac D (20–45 μm), and Lac E (< 20 μm). The lactose samples were analysed in terms of size, shape, solid state, density, and flowability. Lactose particles were blended with budesonide (< 5 μm) powder to generate five different formulations. These formulations were then evaluated in terms of budesonide–lactose adhesion properties, drug content homogeneity, and in vitro aerosolisation performance. The results demonstrated that lactose samples with smaller particle volume mean diameter have higher amorphous lactose content, higher true density (linear, r2 = 0.9932), higher surface smoothness (linear, r2 = 0.8752), smaller angularity (linear, r2 = 0.921), smaller bulk density, higher porosity (linear, r2 = 0.914), poorer flowability, and higher specific surface area. In general, the smaller the lactose particles the smaller are the budesonide–lactose adhesion properties. Budesonide formulated with smaller lactose particles exhibited smaller aerodynamic diameter and higher amounts of budesonide were delivered to lower stages of the impactor indicating improved DPI aerosolisation performance. However, the use of lactose particles with smaller volume mean diameter had a detrimental effect on budesonide content homogeneity and caused an increase in the amounts of budesonide deposited on oropharyngeal region. Therefore, particle size of the lactose within dry powder inhaler formulations should be selected carefully. Accordingly, higher drug aerosolisation efficiency of lactose particles with smaller size may have to be balanced due to considerations of other disadvantages including poorer flowability, reduced formulation stability, higher potential side effects, and higher dose variability

Combined control of morphology and polymorph in spray drying of mannitol for dry powder inhalation

“…In order to aerosolize the drug particles, the properties of both the carriers and the API particles are of great importance since the drug-carrier adhesive forces need to be overcome by the patient's inspiratory force [4]. Studies have reported on the impact of particle mean size [5], particle size distribution [6], morphology [7,8], crystal form [9], surface roughness [10] and surface energy [11] on the performance of inhalable dry powders. Indeed, the particle size, size distribution, morphology and polymorphism of carriers have been found to exert a major impact on the efficiency of dry powder inhalation (DPI) [12,13], although results have not been consistent.…”

“…Indeed, the particle size, size distribution, morphology and polymorphism of carriers have been found to exert a major impact on the efficiency of dry powder inhalation (DPI) [12,13], although results have not been consistent. For instance, Podczeck [14] found that small particles improved aerosol performance, while Kaialy et al [5] observed that large particles had such an effect. Further, Maas et al [15] and Kaialy et al [16] found that smooth carriers provided a higher fine particle fraction (FPF) than rough carriers, while Littringer et al [17] showed that rough surface carriers improved the FPF.…”

DEM analysis of particle adhesion during powder mixing for dry powder inhaler formulation development

“…The particle-particle interaction forces have to be sufficiently strong that fine API particles can adhere with the carriers or form large agglomerates to be transported, but weak enough that they can be detached or dispersed by a deagglomeration process and thus allow the delivery of the API particles into the respiratory tracts and lungs. Therefore, particle-particle interactions play a significant role in controlling the performance of DPIs and hence many studies have been performed to explore the dependency of these interactions on particle size [7,8], material properties [9,10], particle concentration [11,12], particle morphology [13,14], particle surface roughness [15,16], storage conditions [17,18], surface area [19], density and porosity [20], and crystal form [21]. For example, Kaialy et al [7] experimentally examined the influence of the particle size of lactose carrier on the DPI performance and demonstrated that the DPI performance improved with decreasing carrier particle size.…”

“…Therefore, particle-particle interactions play a significant role in controlling the performance of DPIs and hence many studies have been performed to explore the dependency of these interactions on particle size [7,8], material properties [9,10], particle concentration [11,12], particle morphology [13,14], particle surface roughness [15,16], storage conditions [17,18], surface area [19], density and porosity [20], and crystal form [21]. For example, Kaialy et al [7] experimentally examined the influence of the particle size of lactose carrier on the DPI performance and demonstrated that the DPI performance improved with decreasing carrier particle size. Young et al [11] investigated the relationship between API dosage (drug/lactose ratio) and aerosolisation performance of conventional carrier based formulations using the twin stage impinger and found that the fine particle fraction (FPF) decreased with increasing API dosage for small values of the parameter (10-135 µg/50 mg), while the FPF increased with increasing API dosage at large values of the API dosage (135-450 µg/50 mg).…”

Development of Nicotine Loaded Chitosan Nanoparticles for Lung Delivery

“…Presence of lactose monohydrate types and sieve fractions as carriers is a strategy to improve dispersion properties of inhalation particles (Kaialy, Alhalaweh, Velaga, & Nokhodchi, 2012;Patil, Mahadik, & Paradkar, 2015). Blending drugs with coarse lactose not only enhances the bulk of the formulations; also it improves separation of fine drug particles from formulation to improve dosing consistency of the DPI formulations (Prime et al, 1997).…”