Evaluation of topical econazole nitrate formulations with potential for treating Raynaud's phenomenon

Pharm Dev Technol. 2019 Jul;24(6):689-699. doi: 10.1080/10837450.2019.1578371. Epub 2019 Apr 26.


The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud's phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase® cream, and F4_Lipoderm® Activemax™ Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10-20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_HPMC dispersion could be further explored as a treatment option for RP.

Keywords: Raynaud’s phenomenon; TRPM-8; econazole nitrate; permeation; topical.

MeSH terms

  • 14-alpha Demethylase Inhibitors / administration & dosage*
  • 14-alpha Demethylase Inhibitors / pharmacokinetics
  • Administration, Topical
  • Animals
  • Antifungal Agents / administration & dosage*
  • Antifungal Agents / pharmacokinetics
  • Crystallization
  • Drug Compounding / methods
  • Econazole / administration & dosage*
  • Econazole / pharmacokinetics
  • Humans
  • Hypromellose Derivatives / chemistry
  • Pharmaceutical Vehicles / chemistry*
  • Raynaud Disease / drug therapy*
  • Raynaud Disease / metabolism
  • Skin Absorption
  • Swine


  • 14-alpha Demethylase Inhibitors
  • Antifungal Agents
  • Pharmaceutical Vehicles
  • Hypromellose Derivatives
  • Econazole