A systematic approach to the formulation of anti-onychomycotic nail patches

Nail patches have a potential role as drug carriers for the topical treatment of nail diseases such as onychomycosis, a common condition. O ur aim was therefore to develop a systematic and novel appr oach to the formulat ion of a simple drug -in-adhesive ungual patch. Twelve pressure -sensitive adhesives (PSAs), four backing membranes, two release liners and three drugs were screened for pharmaceutical and mechanical properties . From this initial screeni ng, two PSAs, two drugs, one backing membrane and one release liner were selected for further investigation. Patches were prepared by solvent -casting and characterised. The patches had good uniformity of thickness and of drug content, and showed minimal drug crystallisation during six month s of storage. Meanwhile, the d rug stability in the patch upon storage and patch adhesion to the nail was influenced by the nature of the drug, the PSA and the backing membrane . The reported methodology paves the way for a systematic formulation of ungual nail patches to add to the armamentarium of nail medicines . Further , from this work, the best patch formulation has been identified

Mechanisms of burst release from pH-responsive polymeric microparticles.

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of the prepared microparticles and investigated the underlying mechanisms responsible for the “burst release” effect. Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Although, spray drying is an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method is superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allows adequate time for drug and polymer redistribution in the microparticles and reduces uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated non-porous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release

Application of Hansen Solubility Parameters to predict drug-nail interactions, which can assist the design of nail medicines

We hypothesised that Hansen solubility parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: i) determine the HSPs (δD, δP, δH) of the nailplate, the hoof membrane (a model for the nailplate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, ii) predict nail-drug interactions by comparing drug and nail HSPs, and iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nailplate and hoof. Many solvents caused no change in the mass of nailplates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs’ affinities to keratin. We therefore propose that drug and nail Hansen solubility parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research

Development of a rapid, reliable and quantitative method: "SPOTi" for testing antifungal efficacy

A reference method for the antimicrobial susceptibility testing of common fungal pathogens such as dermatophytes, is currently lacking. In this study, we report the successful adaptation of solid agar-based spot culture growth inhibition assay (SPOTi) for dermatophytes, currently being used as a gold-standard in the anti-tubercular drug discovery field. The fungal-SPOTi assay correlated with the disc-diffusion method, and is validated using mycelial plugs. We propose the fungal-SPOTi as a high-throughput alternative to the disc-diffusion and broth micro-dilution anti-fungal assays to screen novel anti-fungals

Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin

Epidemic Spreading and Digital Contact Tracing: Effects of Heterogeneous Mixing and Quarantine Failures

Contact tracing via digital tracking applications installed on mobile phones is an important tool for controlling epidemic spreading. Its effectivity can be quantified by modifying the standard methodology for analyzing percolation and connectivity of contact networks. We apply this framework to networks with varying degree distributions, numbers of application users, and probabilities of quarantine failures. Further, we study structured populations with homophily and heterophily and the possibility of degree-targeted application distribution. Our results are based on a combination of explicit simulations and mean-field analysis. They indicate that there can be major differences in the epidemic size and epidemic probabilities which are equivalent in the normal SIR processes. Further, degree heterogeneity is seen to be especially important for the epidemic threshold but not as much for the epidemic size. The probability that tracing leads to quarantines is not as important as the application adoption rate. Finally, both strong homophily and especially heterophily with regard to application adoption can be detrimental. Overall, epidemic dynamics are very sensitive to all of the parameter values we tested out, which makes the problem of estimating the effect of digital contact tracing an inherently multidimensional problem

The Unreasonable Effectiveness of Contact Tracing on Networks with Cliques

Contact tracing, the practice of isolating individuals who have been in contact with infected individuals, is an effective and practical way of containing disease spread. Here, we show that this strategy is particularly effective in the presence of social groups: Once the disease enters a group, contact tracing not only cuts direct infection paths but can also pre-emptively quarantine group members such that it will cut indirect spreading routes. We show these results by using a deliberately stylized model that allows us to isolate the effect of contact tracing within the clique structure of the network where the contagion is spreading. This will enable us to derive mean-field approximations and epidemic thresholds to demonstrate the efficiency of contact tracing in social networks with small groups. This analysis shows that contact tracing in networks with groups is more efficient the larger the groups are. We show how these results can be understood by approximating the combination of disease spreading and contact tracing with a complex contagion process where every failed infection attempt will lead to a lower infection probability in the next attempts. Our results illustrate how contract tracing in real-world settings can be more efficient than predicted by models that treat the system as fully mixed or the network structure as locally tree-like.Comment: 15 pages, 13 figures, 4 table

A systematic approach to the formulation of anti-onychomycotic nail patches

Nail patches have a potential role as drug carriers for the topical treatment of nail diseases such as onychomycosis, a common condition. Our aim was therefore to develop a systematic and novel approach to the formulation of a simple drug-in-adhesive ungual patch. Twelve pressure-sensitive adhesives (PSAs), four backing membranes, two release liners and three drugs were screened for pharmaceutical and mechanical properties. From this initial screening, two PSAs, two drugs, one backing membrane and one release liner were selected for further investigation. Patches were prepared by solvent-casting and characterised. The patches had good uniformity of thickness and of drug content, and showed minimal drug crystallisation during six months of storage. Meanwhile, the drug stability in the patch upon storage and patch adhesion to the nail was influenced by the nature of the drug, the PSA and the backing membrane. The reported methodology paves the way for a systematic formulation of ungual nail patches to add to the armamentarium of nail medicines. Further, from this work, the best patch formulation has been identified