gamma-cyclodextrin and fludrocortisone-acetate

Numerous reports on the enhancement effect of cyclodextrins (CDs) on the skin permeation of dermally applied drugs exist, the majority of which is based on in vitro diffusion cell studies. The specific experimental setup of such studies may skew the obtained results, which is rarely discussed in the context of CD studies. Thus, the aim of this work was to conduct a systematic in vitro investigation of the permeation enhancement potential of γ-CD on a steroidal drug from a nanoemulsion. The role of critical diffusion cell parameters such as the dose of application, occlusive conditions, the nature of the receptor medium and the skin thickness were investigated. The results showed that significantly enhanced skin permeation rates of fludrocortisone acetate were indeed caused by 1% (w/w) of γ-CD at both finite and infinite dose conditions. At 0.5% (w/w) of γ-CD, significant enhancement was only achieved at infinite dose application. Additional in vitro tape stripping experiments confirmed these tendencies, but the observed effects did not reach statistical significance. It may be concluded that the full permeation enhancement potential of the CD as observed in the Franz-cell setup can only be realised at infinite dose conditions while preserving the formulation structure.

Topics: Animals; Biological Assay; Chemistry, Pharmaceutical; Diffusion; Dose-Response Relationship, Drug; Drug Compounding; Emulsions; Fludrocortisone; gamma-Cyclodextrins; In Vitro Techniques; Kinetics; Nanoparticles; Nanotechnology; Permeability; Skin; Skin Absorption; Steroids; Swine; Technology, Pharmaceutical

Nanoemulsions aimed at dermal drug delivery are usually stabilised by natural lecithins. However, lecithin has a high tendency towards self-aggregation and is prone to chemical degradation. Therefore, the aim of this study was to develop nanoemulsions with improved structure and long-term stability by employing a natural sucrose ester mixture as sole surfactant. A thorough comparison between the novel sucrose stearate-based nanoemulsions and corresponding lecithin-based nanoemulsions revealed that the sucrose ester is superior in terms of emulsifying efficiency, droplet formation as well as physical and chemical stability. The novel formulations exhibited a remarkably homogeneous structure in cryo TEM investigations, as opposed to the variable structure observed for lecithin-based systems. The in vitro skin permeation rates of lipophilic drugs from sucrose stearate nanoemulsions were comparable to those obtained with their lecithin-based counterparts. Furthermore, it was observed that addition of γ-cyclodextrin led to enhanced skin permeation of the steroidal drug fludrocortisone acetate from 9.99±0.46 to 55.10±3.67 μg cm(-2) after 24 h in the case of sucrose stearate-based systems and from 9.98±0.64 to 98.62±24.89 μg cm(-2) after 24 h in the case of lecithin-based systems. This enhancement effect was significantly stronger in formulations based on lecithin (P<0.05), which indicates that synergistic mechanisms between the surfactant and the cyclodextrin are involved. Cryo TEM images suggest that the cyclodextrin is incorporated into the interfacial film, which might alter drug release rates and improve the droplet microstructure.

Topics: Abdomen; Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Cyclodextrins; Drug Compounding; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Stability; Emulsions; Excipients; Fludrocortisone; gamma-Cyclodextrins; Models, Chemical; Nanoparticles; Particle Size; Permeability; Skin; Skin Absorption; Solubility; Sucrose; Surface Properties; Surface-Active Agents; Swine