Poly(pseudo)rotaxanes formed by mixed micelles and α-cyclodextrin enhance terbinafine nail permeation to deeper layers

This work aimed to develop water-based formulations for onychomycosis topical treatment using micelles of small pegylated surfactants associated with α-cyclodextrin (αCD) to deliver terbinafine to the nail. Kolliphor® RH40 (RH40) and Gelucire® 48/16 (GEL) single and mixed micelles (RH40:GEL 1:1) were prepared. αCD was added to the surfactants dispersions to form poly(pseudo)rotaxanes (PPR). Formulations were characterized in terms of drug solubilization (3 to 34-fold increase), particle size (9–11 nm) and Z-potential (+0.3 − +1.96 mV), blood compatibility (non-hemolytic), rheological behavior (solid-like viscoelastic properties after 5–10% αCD addition), drug release and interaction with the nail plate. GEL micelles and surfactant-10% αCD PPRs notably hydrated the nail plate.

Highlights

• RH40, GEL and their mixed micelles increased 3-fold and 34-fold TB solubility in water and citrate buffer, respectively.

• Addition of αCD (5–10%) led to PPR formation and viscoelastic supramolecular gels without decrease in TB solubilization.

• PPR formulations with 10% αCD enhanced nail plate hydration, increasing its porosity.

• Compared to mixed micelles, PRP showed slower release rate but promoted TB accumulation in deeper regions of hooves.

The high viscosity of PPR led to a slower drug release, except for RH40:GEL +10% αCD that surprisingly released terbinafine faster. The RH40:GEL +10% αCD formulation delivered twice more amount of terbinafine to deeper regions of nail plate compared to other formulations. The results evidenced the potential of PPR formed by small pegylated surfactants as a water-based formulation for nail drug delivery.

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Materials

Terbinafine hydrochloride (TB) (327.17 g/mol; ≥ 99%) was obtained from Acros Organics™ (New Jersey, USA). Gelucire® 48/16 (1766 g/mol) (GEL) was provided by Gattefossé (Lyon, France), and Kolliphor® RH40 (2500 g/mol) (RH40) was purchased from BASF (Ludwigshafen, Germany). α-Cyclodextrin (αCD) (Cavamax W6 Pharma, lot 60P304, 972.84 Da) was obtained from Wacker Chemie (Munich, Germany). All solvents and reagents were of analytical grade.

Anna Paula Krawczyk-Santos, Ricardo Neves Marreto, Angel Concheiro, Carmen Alvarez-Lorenzo, Stephânia Fleury Taveira,
Poly(pseudo)rotaxanes formed by mixed micelles and α-cyclodextrin enhance terbinafine nail permeation to deeper layers,
International Journal of Pharmaceutics: X, Volume 4, 2022, 100118, ISSN 2590-1567,
https://doi.org/10.1016/j.ijpx.2022.100118.