New mechanisms to explain the effects of added lactose fines on the dispersion performance of adhesive mixtures for inhalation

Abstract

Fine excipient particles or 'fines' have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of 'fine lactose fines' (FLF, X50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.

Figure 1. Representative SEM images of the pure mixture components.

Figure 2. Representative SEM images of mixtures.

Top: mixtures containing 4% budesonide and 4% fine lactose fines. Bottom: mixtures containing 4% budesonide and 4% coarse lactose fines. Images on the right hand side are a magnification of images on the left hand side.

Figure 3. The effects of added lactose fines on drug detachment over a range of flow rates.

A) effects of 4% fine lactose fines (FLF) or 4% coarse lactose fines (CLF) on drug detachment of 0.4% budesonide mixtures and B) for 4% budesonide mixtures. Error bars represent maximum and minimum values measured (n = 5).

Figure 4. Drug detachment of 4% budesonide mixtures at 30 L/min as a function of added fines content.

FLF =  fine lactose fines; CLF =  coarse lactose fines. Error bars represent maximum and minimum values measured (n = 5).

Figure 5. The influence of mixing order on the effects of added fines on drug detachment.

A) mixtures containing 0.4% budesonide and 4% fine lactose fines (FLF); B) mixtures containing 0.4% budesonide and 4% coarse lactose fines (CLF); C) mixtures containing 4% budesonide and 4% CLF. Drug detachment versus flow rate profiles of mixtures containing only 0.4% or 4% of budesonide (mixed for 5 or 10 minutes) are shown as a reference. Fine components were mixed separately by mixing one component with the carrier for 5 minutes, after which the second component was added and mixing was continued for another 5 minutes. Simult.  =  drug and fines mixed simultaneously with the carrier material for 5 or 10 minutes. Error bars represent maximum and minimum values measured (n = 5).