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  • Therefore HNE is an attractive therapeutic


    Therefore, HNE is an attractive therapeutic target and the design of new HNE inhibitors is a demanding field that has been extensively investigated in order to provide inhibitors with new molecular architectures, including the potent oxo-β-lactam class [14]. In the present work, a coumarin-based oxo-β-lactam was designed as to be an irreversible HNE inhibitor that behaves as a turn-on probe as upon HNE inhibition releases the fluorescent hydroxy-coumarin, allowing appropriate signalization for Q-VD(OMe)-OPh permeation studies. Based on our previous studies the purpose of this study was to develop starch nanocapsules for topical delivery of a novel HNE inhibitor (ER143) presenting low water solubility and putative anti-inflammatory action, in order to increase its bioavailability [8], [14], [15]. A quality by design (QbD) approach was performed to extract the maximum amount of information from the collected data, to establish the influence of several factors on the nanoformulation critical quality attributes. The in vitro release and permeation, and the in vivo studies allowed demonstrating the successful application of starch nanocapsules and highlighting their potential as a nanobiomaterial suitable for topical delivery of therapeutically relevant HNE inhibitors.
    Materials and methods
    Results and discussion
    Conclusions A novel elastase inhibitor with anti-inflammatory properties – ER143 – was successfully formulated in starch-based nanocapules with adequate pharmaceutical attributes (particle Q-VD(OMe)-OPh size distribution, surface charge and encapsulation efficiency) for topical application, as demonstrated by the in vitro studies. The starch nanocapsules increased drug skin permeation with maximum efficacy in the treatment areas. The improved pharmacological performance resulting from ER143 nanoencapsulation was confirmed in vivo and compared to a commercial lotion containing an anti-inflammatory corticosteroid. Overall these studies demonstrate that the incorporation of ER143 into starch-based nanocapsules has scientific merit, and is a promising strategy for the treatment of inflammatory skin diseases.
    Introduction The steroid hormone cortisol is found in blood bound to the transport proteins corticosteroid-binding globulin (CBG), albumin (Alb), and in the free form with a distribution of 70%, 20% and 10%, respectively [4]. Although free and bound cortisol contribute to the total concentration of cortisol in blood, only free cortisol is considered bioactive [5], [4]. By equilibrium dialysis, gel filtration or ultrafiltration direct measurement of free cortisol in human plasma can be done. However, the methods are both time-consuming and labour-intensive [6]. Thus, in most clinical procedures for measuring cortisol levels only the total cortisol concentration is measured [4]. Afterwards conservation and equilibrium assumptions are used to calculate concentrations of free and bound cortisol [3], [2]. The most often used formula for calculating free cortisol is the Coolens formula, which includes solving a second order polynomial [1], [2]. Coolens et al. [1] considered cortisol, CBG and albumin only and assumed the relevant reactions to be in equilibrium as well as conservation of the corresponding substances. Furthermore, the ratio of total albumin to its affinity for cortisol was assumed constant. Later Dorin et al. [2] developed an improved, cubic model with total albumin and its affinity for cortisol included as input variable and parameter, respectively, and by this excellent work demonstrated the importance of albumin concentration in cases with combined albumin and CBG deficiencies [2]. Nguyen et al. [3] extended the model further by considering two states of CBG: high-affinity, native CBG and low-affinity, elastase-cleaved CBG (CBG*), assuming equilibrium of the relevant reactions and conservation of the total amounts of the corresponding substances. This was elegantly generalized to a fourth order formula [3]. In their formula Nguyen et al. [3] ignored the actual enzymatic reaction cleaving CBG into CBG* and instead took the total amounts of each of CBG and CBG* to be conserved.