QbD-Based Investigation of Dermal Semisolid in situ Film-Forming Systems for Local Anaesthesia

Drug Des Devel Ther. 2020 Nov 18:14:5059-5076. doi: 10.2147/DDDT.S279727. eCollection 2020.

Abstract

Purpose: The aim of our research work was to develop dermally applicable, lidocaine hydrochloride (LID-HCl)-containing semisolid in situ film-forming systems (FFSs) using the Quality by Design (QbD) approach to increase drug permeation into the skin.

Methods: Silicones were used to improve the properties of formulations and to increase the permeation through the skin. The QbD approach was applied to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs).

Results: During the initial risk assessment, four high-risk CQAs, namely in vitro drug release, in vitro drug permeation, drying properties, and mechanical properties, and three medium-risk CQAs, namely pH, viscosity, and film appearance were identified and investigated. Moreover, four high-risk CMAs were also considered during the formulation: permeation enhancing excipients, drying excipients, film-forming excipients, and emollients. During the experiments, LID-HCl influenced these critical parameters highly, thereby reducing the drying time. The formulation containing 25% silicone showed the best mechanical properties (49 mN skin adhesion, 20.3% film flexibility, 1.27 N film burst strength), which could predict better patient adherence. In addition, in vitro permeation studies showed that formulation containing 50% silicone has the fastest permeation rate. The flux of diffused API was 6.763 µg/cm2/h, which is much higher compared to the silicone-free formulation (1.5734 µg/cm2/h), and it can already be observed in the lower part of the dermis in 0.5 hour.

Conclusion: Our results show that LID-HCl has great influence on the critical parameters of FFSs. The silicone content can improve the applicability of formulations and has a favorable effect on the permeation rate of LID-HCl into the skin.

Keywords: Quality by Design; formulation excipients; in situ film-forming system; local anaesthesia.

MeSH terms

  • Administration, Cutaneous
  • Anesthesia, Local*
  • Female
  • Humans
  • Lidocaine / administration & dosage
  • Lidocaine / pharmacology*
  • Skin / drug effects*
  • Skin Absorption / drug effects*

Substances

  • Lidocaine

Grants and funding

This research was funded by the Gedeon Richter’s Talentum Foundation (Gyömrői Street 19-21), Budapest, Hungary, 1103) and project EFOP 3.6.3-VEKOP-16-2017-00009. The article publishing charge was funded by The University of Szeged Open Access Fund (FundRef, Grant No. 4943).