The effect of carrier surface and bulk properties on drug particle detachment from crystalline lactose carrier particles during inhalation, as function of carrier payload and mixing time

Abstract

The effect of carrier payload and mixing time on the redispersion of drug particles from adhesive mixtures during inhalation for two different drugs (budesonide and disodium cromoglycate) has been investigated. A special test inhaler which retains carrier crystals during inhalation was used at 30 and 60 l/min. The special inhaler enabled the analysis of residual drug on the carrier yielding so called carrier residue (CR) values. Mixtures with carrier size fractions of 32–45; 150–200 and 250–355 μm, derived from marketed lactose brands, with increasing carrier payload (0.4–6.0% w/w of drug) were prepared. It was found that with increasing carrier payload, the CR increases for the coarse carrier fraction, decreases for the fine fraction and remains roughly constant for the intermediate fraction at 30 l/min. At 60 l/min, the CR decreased for all carrier fractions with increasing payload. The effect of powder bulk properties on the adhesive forces between drug and carrier (during mixing) as well as changes in the balance between adhesion and separation forces (during inhalation) explain the results found. An improved understanding of the different effects is obtained through the recently introduced force distribution concept. The ratio of (mean) separation force to (mean) adhesion force increases with the flow rate. The adhesive forces (during mixing) increase with increasing carrier diameter (higher press-on and kneading forces) and longer mixing time.