Development of terbinafine solid lipid nanoparticles as a topical delivery system

Abstract

To resolve problems of long treatment durations and frequent administration of the antifungal agent terbinafine (TB), solid lipid nanoparticles (SLNs) with the ability to load lipophilic drugs and nanosize were developed. The SLNs were manufactured by a microemulsion technique in which glyceryl monostearate (GMS), glyceryl behenate (Compritol(®) 888; Gattefossé), and glyceryl palmitostearate (Precirol(®) ATO 5; Gattefossé) were used as the solid lipid phases, Tween(®) and Cremophor(®) series as the surfactants, and propylene glycol as the cosurfactant to construct ternary phase diagrams. The skin of nude mice was used as a barrier membrane, and penetration levels of TB of the designed formulations and a commercial product, Lamisil(®) Once™ (Novartis Pharmaceuticals), in the stratum corneum (SC), viable epidermis, and dermis were measured; particle sizes were determined as an indicator of stability. The optimal SLN system contained a <5% lipid phase and >50% water phase. The addition of ethanol or etchants had no significant effect on enhancing the amount of TB that penetrated the skin layers, but it was enhanced by increasing the percentage of the lipid phase. Furthermore, the combination of GMS and Compritol(®) 888 was able to increase the stable amount of TB that penetrated all skin layers. For the ACP1-GM1 (4% lipid phase; Compritol(®) 888: GMS of 1:1) formulation, the amount of TB that penetrated the SC was similar to that of Lamisil(®) Once™, whereas the amount of TB of the dermis was higher than that of Lamisil(®) Once™ at 12 hours, and it was almost the same as that of Lamisil(®) Once™ at 24 hours. It was concluded that the application of ACP1-GM1 for 12 hours might have an efficacy comparable to that of Lamisil(®) Once™ for 24 hours, which would resolve the practical problem of the longer administration period that is necessary for Lamisil(®) Once™.

Keywords: solid lipid nanoparticle; terbinafine; topical delivery system.

Figure 1

A representative ternary phase diagram of the microemulsion system that is capable of forming solid lipid nanoparticles (SLNs).

Figure 2

Changes of particle sizes for various solid lipid nanoparticle (SLN) formulations at different time points. Abbreviations: GMS, glyceryl monostearate; CP, Compritol^® 888; RH40, Cremophor RH40; PG, 1,2-propylene glycol.

Figure 3

Scanning electron microscopy photography of the stratum corneum of nude mice that had been tape-stripped 0, 1, 5, 10, 15, and 20 times, after in vitro transdermal penetration was magnified at 50× (A1, B1, C1, D1, E1, F1), respectively; and 200× (A2, B2, C2, D2, E2, F2), respectively.

Figure 4

Amounts of terbinafine (TB) that penetrated into various skin layers at different time points after treatment with Lamisil^® Once™. Abbreviations: SC, stratum corneum, VE, viable epidermis.

Figure 5

Amounts of terbinafine (TB) that penetrated into different skin layers after treatment with various solid lipid nanoparticle (SLN) formulations for 24 hours. Abbreviations: SC, stratum corneum; VE, viable epidermis; GMS, glyceryl monostearate; CP, Compritol^® 888; RH40, Cremophor RH40; PG, 1,2-propylene glycol.

Figure 6

Amounts of terbinafine (TB) that penetrated into the stratum corneum (SC) (A), variable epidermis (VE) (B), and dermis (C) versus time profile after treatment with various solid lipid nanoparticle (SLN) formulations. Abbreviations: GMS, glyceryl monostearate; Concn, concentrations; CP, Compritol^® 888; RH40, Cremophor RH40; PG, 1,2-propylene glycol.