Tailoring novel soft nano-vesicles 'Flexosomes' for enhanced transdermal drug delivery: Optimization, characterization and comprehensive ex vivo - in vivo evaluation

Int J Pharm. 2019 Apr 5:560:101-115. doi: 10.1016/j.ijpharm.2019.01.072. Epub 2019 Feb 10.


The transdermal route is a convenient non-invasive way for drug delivery, however, the hydrophobic compact nature of stratum corneum (SC) forms an obstacle hindering the diffusion of drugs particularly hydrophilic ones. Hence, the purpose of this study was to develop novel soft nano-vesicles, entitled Flexosomes, amalgamating two penetration enhancers, ethanol and one edge activator (EA) from various types and different hydrophilic-lipophilic balances. The tailored vesicles were loaded with tropisetron hydrochloride (TRO), a potent highly-soluble anti-emetic, and compared with ethosomes. Aiming to preclude the formation of rigid non-deformable mixed micelles, all critical parameters; EA type, phosphatidylcholine-to-EA molar ratio, and cholesterol concentration, were optimized proving their influences on vesicle-to-micelle transitions. The prepared formulations were characterized in terms of visual inspection, particle size, polydispersity, zeta potential, turbidity measurements, entrapment efficiency, and vesicle morphology. The permeation mechanisms were assessed by differential scanning calorimetry on isolated SC. The modified vesicles, based on ethanol and either vitamin E or PEGylated castor oil derivatives exhibited the highest transdermal fluxes confirmed by a deeply tracking to dermis using confocal laser microscopy. Both vesicles demonstrated higher bioavailability relative to ethosomes, topical and oral aqueous solutions. The findings endorsed the effectiveness of tailored nano-vesicles in boosting TRO skin transport suggesting their applicability with various drug entities for enhanced transdermal delivery.

Keywords: Cetyl trimethyl ammonium bromide (PubChem CID: 5974); Cholesterol (PubChem CID: 5997); Cremophor RH 40 (CAS-RN: 61788-85-0); D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) (PubChem CID: 71406); Edge activator; Ethanol (PubChem CID: 702); Ethosomes; Ex vivo permeation; In vivo pharmacokinetics; Micelles; Nano-vesicles; Phosphatidylcholine (PubChem CID: 24779388); Sodium cholate (PubChem CID: 23668194); Sodium deoxycholate (PubChem CID: 23668196); Span 85 (PubChem CID: 9920343); Transdermal delivery; Tropisetron hydrochloride (PubChem CID: 656664); Tween 80 (PubChem CID: 443315).

Publication types

  • Comparative Study

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Antiemetics / administration & dosage*
  • Antiemetics / pharmacokinetics
  • Biological Availability
  • Calorimetry, Differential Scanning
  • Chemistry, Pharmaceutical / methods
  • Drug Delivery Systems*
  • Ethanol / chemistry
  • Excipients / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Male
  • Micelles
  • Microscopy, Confocal
  • Nanoparticles*
  • Particle Size
  • Rats
  • Skin / metabolism
  • Skin Absorption
  • Tropisetron / administration & dosage*
  • Tropisetron / pharmacokinetics


  • Antiemetics
  • Excipients
  • Micelles
  • Ethanol
  • Tropisetron