Formulation-by-Design of Efinaconazole Spanlastic Nanovesicles for Transungual Delivery Using Statistical Risk Management and Multivariate Analytical Techniques

Abstract

As regulatory and technical landscapes for pharmaceutical formulation development are rapidly evolving, a risk-management approach using multivariate analysis is highly essential for designing a product with requisite critical quality attributes (CQA). Efinaconazole, a newly approved poorly water-soluble antifungal triazole drug has poor permeability. Spanlastics, new-generation surfactant nanovesicles, being fluidic, help improve the permeability of drugs. Therefore, we optimized efinaconazole spanlastics using the concepts of Formulation-by-Design (FbD) and explored the feasibility of transungual delivery for the management of onychomycosis. Using the Ishikawa fishbone diagram, the risk factors that may have an impact on the CQA of efinaconazole spanlastic vesicles were identified. Application of the Plackett–Burman experimental design facilitated the screening of eight different formulation and process parameters influencing particle size, transmittance, relative deformability, zeta potential, entrapment efficiency, and dissolution efficiency. With the help of Pareto charts, the three most significant factors were identified, viz., vesicle builder (Span), edge activator (Tween), and mixing time. The levels of these three critical variables were optimized by FbD to reduce the particle size and maximize the transparency, relative deformability, encapsulation efficiency, and dissolution efficiency of efinaconazole spanlastic nanovesicles. Bayesian and Lenth’s analysis and mathematical modeling of the experimental data helped to quantify the critical formulation attributes required for getting the formulation with optimum quality features. The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery. This explorative study provides an example of the application of principles of risk management, statistical multivariate analysis, and the FbD approach in developing efinaconazole spanlastic nanovesicles.

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“…However, at lower concentrations, they may prove insufficient to coat the entire vesicle surface. Consequently, vesicles can accumulate until the surface area is adequately reduced for the surfactant to cover it entirely, resulting in a stable dispersion containing relatively large vesicles ( Almuqbil et al, 2022 ).…”

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“…Additionally, the permeation coefficients for gel were calculated by dividing flux with the total amount of TEF in the donor apartment. The experiment was carried out in triplicate and the results were reported as the mean ± SD [ 17 ]. All trials were made in agreement with the standard institutional guiding principles duly proved by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) at Jamia Hamdard Animal Centre (New Delhi, India).…”

“…It also includes the determination of the quality target product profile (QTPP) using Failure Mode Effect Analysis (FMEA) for each quality attribute (QA) of the product. However, QTPP-based risk assessment necessitates the evaluation of the impact of material attributes and process parameters on the critical quality attributes (CQAs), which are described by the Ishikawa diagram [ 16 , 17 ]. Finally, central composite design (CCD) was employed to determine optimized formulation.…”