THE USE OF CYCLODEXTRINS IN OPHTHALMIC FORMULATIONS OF DIPIVEFRIN

Dipivefrine (dipivalyl epinephrine, DPE) is a dipivalic acid ester pro drug of epinephrine. The present study evaluates the possible use of h ydroxypropyl-beta-cyclodextrin (HP-beta-CD) or sulfobutyl ether beta-c yclodextrin ((SBE)(7m)-beta-CD) in ophthalmic formulations of DPE in o rder to increase the aqueous stability of DPE. The solubility of DPE w as 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 an d (SBE)(7m)-beta-CD on the aqueous phase to organic phase transfer kin etics was studied with an aqueous buffer/n-octanol system, while the e ffect of (SBE)(7m)-beta-CD on (in vitro) corneal uptake of DPE was stu died with isolated rabbit corneas in order to predict the ophthalmic b ioavailability of DPE in the presence of CD. The negatively charged (S BE)(7m)-beta-CD formed significantly stronger inclusion complexes with the positively charged DPE (pK(a) = 9.01) and enhanced the aqueous st ability 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 stab ility about four to five times. The phase-transfer and in vitro cornea l uptake studies suggested that the complexation of DPE with both CDs may decrease the ophthalmic availability of DPE. (C) 1997 Elsevier Sci ence B.V.