Objective. The lactone moiety of camptothecin (CPT) is unstable in vivo, but essential for anti-tumor efficacy. CZ48, CPT-C20-propionate, was synthesized to improve the lactone stability, and exerts anti-neoplastic activity after its hydrolysis to CPT. The study was to formulate microemulsions of CZ48 for transdermal delivery and perform proof-of-concept in vitro permeation evaluations. Methods. Microemulsion formulations were developed and optimized to achieve solubility of 0.24 to 4.44 mg/ml, with various combinations of oils, surfactants, and co-surfactants. Six formulations were evaluated for their comparative in vitro transdermal permeation characteristics of CPT and CZ48 lactone moieties through surgically excised full-thickness rat skin barrier, using Franz diffusion cells with finite doses of CZ48 microemulsions. CZ48 saturated solutions in a co-solvent of DMSO, PEG 400 and ethanol (2:2:1 by volume) was the reference. The permeated drug concentrations in diffusate samples of 0.2% Tween 80 containing phosphate buffered saline were monitored up to 72 hr, using a developed HPLC assay with a reversed phase C8 column and a fluorescent detection, capable of simultaneous quantifications of CPT and CZ48 lactone forms at 10 ng/ml and higher. The permeation profiles of both permeants were constructed. The steady state flux and permeation parameters of lag time, permeability constant, diffusion coefficient and partition coefficient of both permeants from each formulation were derived from the profiles. The significance of differences in parameters among formulations were evaluated by ANOVA at p<0.05. Results. Four of the six formulations resulted in significantly higher transdermal permeation of CZ48 than that of the reference. All formulations demonstrated transdermal conversions of CZ48 into CPT. A flux of CZ48 up to 81.5 ng/cm2/hr was achieved as compared to 29.7 ng/cm2/hr from the reference. CZ48 permeability constant increased 100 times with the microemulsion formulations from 2.4 x 10-6 to 231.7 x 10-6 cm/hr. The lag time was comparable to that of the reference, ranging from 6-13 hr. Diffusion coefficients were 5.5 –9.4 x 10-3 hr-1 for the microemulsions and 13.3 x 10-3 hr-1 for the reference. Partition coefficients of CZ48 from the microemulsion formulations were enhanced from 0.2 to 47.4 x 10-3 cm as normalized by skin thickness. Conclusions. Microemulsion formulations of CZ48 are promising for transdermal delivery. The CZ48 were efficiently converted to active CPT. The formulation effort significantly enhanced the permeation flux resulting from the favorable partition of CZ48 from microemulsions into the skin stratum corneum.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]