Semifluorinated Alkane Based Systems for Enhanced Corneal Penetration of Poorly Soluble Drugs

Int J Pharm. 2018 Mar 1;538(1-2):119-129. doi: 10.1016/j.ijpharm.2018.01.019. Epub 2018 Jan 12.

Abstract

Semifluorinated alkanes (SFAs) are amphiphilic liquids that can dissolve hydrophobic drugs to form clear solutions. This study evaluated the potential of two SFAs to act as vehicle for topical ocular drug delivery. After confirming ocular safety, an ex vivo corneal penetration model was developed to determine drug distribution and corneal bioavailability. Hydrophobic dye distribution in the different corneal layers was visualised under a confocal microscope. Corneal bioavailability of cyclosporine A (CsA) dissolved in perfluorobutylpentane (F4H5) or perfluorohexyloctane (F6H8) was compared to commercially available CsA ophthalmic emulsions, Restasis® and Ikervis®. Precorneal residence of the four test vehicles containing the hydrophobic dye was also compared using an ex vivo corneal tissue model. Preferential accumulation of the hydrophobic dye in the corneal epithelium was observed with higher amounts detectable when delivered via the SFAs compared to Restasis or Ikervis. A significant improvement in corneal CsA penetration was observed after application of a single dose of 0.05% CsA in F4H5 and F6H8 when compared to Restasis with the area under curve over 4 h (AUC(0-4h)) being at least 8-fold greater for both SFAs (p < .0001). Moreover, the AUC(0-4h) of 0.1% CsA in F4H5 was almost 5-fold greater than Ikervis (p < .0001). Finally, the precorneal residence time of both SFA solutions was significantly longer than that of the commercial emulsions with the AUC(0-60min) being 2- to 11-fold greater. This study demonstrated that SFAs can significantly improve the local bioavailability of hydrophobic drugs by increasing corneal penetration as well as prolonging precorneal residence. They therefore offer a promising new platform for topical drug delivery to the eye.

Keywords: Corneal penetration; Cyclosporine A; Ex vivo tissue models; Precorneal residence time; Semifluorinated alkanes.

Publication types

  • Comparative Study

MeSH terms

  • Alkanes / chemistry
  • Animals
  • Area Under Curve
  • Biological Availability
  • Cornea / metabolism
  • Cyclosporine / administration & dosage*
  • Cyclosporine / chemistry
  • Cyclosporine / pharmacokinetics
  • Drug Carriers / chemistry
  • Drug Delivery Systems
  • Emulsions
  • Epithelium, Corneal / metabolism*
  • Fluorocarbons / chemistry*
  • Hydrophobic and Hydrophilic Interactions
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacokinetics
  • Ophthalmic Solutions
  • Solubility
  • Swine

Substances

  • Alkanes
  • Drug Carriers
  • Emulsions
  • Fluorocarbons
  • Immunosuppressive Agents
  • Ophthalmic Solutions
  • perfluorobutylpentane
  • perfluorohexyl-octan
  • Cyclosporine