Improving the ocular absorption of phenylephrine

An oxazolidine prodrug of phenylephrine and the base form of phenylephrine were synthesized, suspended in sesame oil, and tested for mydriatic activity against phenylephrine HCl. The HCl salt was formulated as a viscous aqueous solution and as a sesame oil suspension. A dosing volume of 10 microliter was instilled into rabbit eyes and the pupillary diameter was measured over time. A 0.045 M prodrug suspension was judged equal in mydriatic activity to a 0.45 M viscous solution of phenylephrine HCl with the exception that the time of maximum response occurred 60 min earlier with the prodrug. When phenylephrine base was suspended in sesame oil at 0.045, 0.12, and 0.45 M, the mydriatic activity was also greater than equimolar suspensions of phenylephrine HCl. The pH of tear fluids was also measured over time and found to rise 1.1, 0.70, and 0.30 pH units for 0.45, 0.12, and 0.045 M suspensions of the base form but remain unchanged when phenylephrine HCl was instilled in the rabbit eye. The greater activity associated with the base form of phenylephrine was judged a result of the change in pH to favour the absorption of phenylephrine. This latter approach should be applicable to either weak acids or weak bases with pKa values outside of the normal pH range (7-8) of the tears and in concentrations greater than 0.045 M suspended in a non-aqueous vehicle.