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.

Complexity in Pharmaceutical Powders for Inhalation: A perspective

“…However, the inability to separate these forces in the heterogeneous systems of which pharmaceutical formulations are composed has confounded efforts to reduce the problem to basic principles. Various groups have chosen to examine the problem from the perspective of probing powder systems experimentally to derive data on performance that can inform models that allow prediction of behavior (Hickey A. and Xu Z., 2013;Steckel H. and Bolzen N., 2004;Jones M. and Price R., 2006;Grasmeijer F. et al, 2013Grasmeijer F. et al, , 2014.…”

On the effects of blending, physicochemical properties, and their interactions on the performance of carrier-based dry powders for inhalation — A review

“…Finally, it should be kept in mind that the effects of blending conditions on the aerosolisation performance of adhesive mixtures depend on many variables such as inhalation flow rate [74], carrier payload [60,94,128], drug type [70], and size distribution of the fine excipient particulates [129] (Fig. 1).…”

“…In brief, some mechanisms that has been proposed include the saturation of 'highly active sites' theory [12,[165][166][167][168][169][170] (Section 3.1.3), the agglomeration theory (i.e. the formulation of readily dispersible multiplets of fine particulates) [62,91,93,112,[171][172][173][174][175], the buffer theory [129,130,169], and the fluidisation (or the tensile strength) theory [156]. In the buffer theory, when fine excipient ternary additives are slightly larger than drug particulates, they act Fig.…”

“…The mechanism by which fine drug particulates exert their influence on aerosolisation performance has been argued to be similar to that exerted by fine excipient particulates. Such similarity was expressed in the 'total fines concept' [279], and it has been shown to be dependent on their similarity in size distribution [129]. In another study, Young et al [142] showed that above a certain concentration, drug concentration has no further promoted aerosol performance.…”

Extrinsic lactose fines improve dry powder inhaler formulation performance of a cohesive batch of budesonide via agglomerate formation and consequential co-deposition

“…However, to date, the exact mechanism for how these fine lactose particles alter the formulation performance has remained unclear, with active sites (El-Sabawi et al, 2006;Ganderton, 1992;Young et al, 2005), drug-lactose fine agglomerate formation (Lucas et al, 1998), and increased cohesion (Shur et al, 2008) theories attempting to explain the phenomenon. Due to the shortcomings of each of these theories, more recently it has also been suggested that all these three theories may be at play simultaneously (Grasmeijer et al, 2014). The concept of total fines, which also takes the concentration of the drug in the formulation into 5 account when defining fines, has also been introduced as an explanation for the improved performance in the presence of a fine particle component (Thalberg et al, 2012).…”