Synergy between chemical permeation enhancers and drug permeation across the tympanic membrane

J Control Release. 2018 Nov 10:289:94-101. doi: 10.1016/j.jconrel.2018.06.019. Epub 2018 Jun 19.

Abstract

Chemical permeation enhancers (CPEs) can enable antibiotic flux across the tympanic membrane. Here we study whether combinations of CPEs (sodium dodecyl sulfate, limonene, and bupivacaine hydrochloride) are synergistic and whether they could increase the peak drug flux. Synergy is studied by isobolographic analysis and combination indices. CPE concentration-response (i.e. trans-tympanic flux of ciprofloxacin) curves are demonstrated for each CPE, isobolograms constructed for pairs of CPEs, and synergy demonstrated for all three pairs. Synergy is much greater at earlier (6 h) than later (48 h) time points, although the effect sizes are greater later. Synergy is also demonstrated with the three-drug combination. Combinations of CPEs also greatly enhance the maximum drug flux achievable over that achieved by individual CPEs.

Keywords: Chemical permeation enhancers; Otitis media; Trans-tympanic permeation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / metabolism*
  • Bupivacaine / chemistry
  • Bupivacaine / metabolism
  • Chinchilla
  • Ciprofloxacin / administration & dosage
  • Ciprofloxacin / metabolism*
  • Drug Delivery Systems
  • Drug Synergism
  • Humans
  • Hydrogels
  • Ketamine / pharmacology
  • Limonene / chemistry
  • Limonene / metabolism
  • Male
  • Pentobarbital / pharmacology
  • Permeability
  • Polymerization
  • Sodium Dodecyl Sulfate / chemistry
  • Sodium Dodecyl Sulfate / metabolism
  • Tympanic Membrane / metabolism*
  • Xylazine / pharmacology

Substances

  • Anti-Bacterial Agents
  • Hydrogels
  • Xylazine
  • Sodium Dodecyl Sulfate
  • Ciprofloxacin
  • Ketamine
  • Limonene
  • Pentobarbital
  • Bupivacaine