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.
Highlights
The dispersion performance of adhesive mixtures for inhalation may be modified by the addition of a third, fine particulate component or ‘fines’ [1]
Studies described in this paper address the hypotheses that, analogous to the effect of drug content, the effect of added lactose fines on the dispersion performance of adhesive mixtures can be explained by a balance between multiple mechanisms and that these mechanisms may include an increase of the effectiveness of press-on forces or the formation of coherent networks
The carrier classification method used in this study may better represent the practical situation, since commercial carrier products will always contain a certain amount of intrinsic lactose fines too
Summary
The dispersion performance of adhesive mixtures for inhalation may be modified by the addition of a third, fine particulate component or ‘fines’ [1]. Fines generally improve the dispersion performance of adhesive mixtures, and different hypotheses have been proposed to explain this finding (Table 1). The exact working mechanisms of added fines are largely unknown to date. This is the result of a limited number of techniques available to measure relevant powder properties. Interactions may explain why contradictory results have been obtained between studies on the working mechanisms of fines that were performed under different conditions, and why the plethora of available data has not led to a fundamental understanding of powder performance [2]
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