The use of cyclodextrins in ophthalmic formulations of dipivefrin

Dipivefrine (dipivalyl epinephrine, DPE) is a dipivalic acid ester prodrug of epinephrine. The present study evaluates the possible use of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or sulfobutyl ether beta-cyclodextrin ((SBE)(7m)-beta-CD) in ophthalmic formulations of DPE in order to increase the aqueous stability of DPE. The solubility of DPE was determined by phase-solubility method at pH 7.4 while the stability of DPE was investigated as a function of temperature (37-70 degrees C) and CD concentrations at pH 5.0 and 7.4. The effect of HP-beta-CD and (SBE)(7m)-beta-CD on the aqueous phase to organic phase transfer kinetics was studied with an aqueous buffer/n-octanol system, while the effect of (SBE)(7m)-beta-CD on (in vitro) corneal uptake of DPE was studied with isolated rabbit corneas in order to predict the ophthalmic bioavailability of DPE in the presence of CD. The negatively charged (SBE)(7m)-beta-CD formed significantly stronger inclusion complexes with the positively charged DPE (pK(a) = 9.01) and enhanced the aqueous stability of DPE significantly more compared to the neutral cyclodextrin HP-beta-CD. At room temperature and al pH values of 5.0 and 7.4, 9.2 mM (SBE)(7m)-beta-CD increased the aqueous stability of DPE about 20- and 100-fold, respectively, while 9.2 mM HP-beta-CD increased the stability about four to five times. The phase-transfer and in vitro corneal uptake studies suggested that the complexation of DPE with both CDs may decrease the ophthalmic availability of DPE. (C) 1997 Elsevier Science B.V.