ABSTRACT
The purpose of this study was to determine the permeation of the hydrophilic compound 5-fluorouracil through human epidermal membranes, Ehrlich Ascites Carcinoma (EAC) cells were used as a model cell line to evaluate the cytotoxic concentration and anti-tumor activity of 5-fluorouracil (5-FU) through transdermal drug delivery for tumors. Cytotoxicity was assessed by exposing cell suspension to increased concentration of drug from 20-100 microg/ml and measuring the viable cell count by tryphan blue exclusion method. Results confirmed that 100 microg/ml of 5-FU was cytotoxic. The increase in the life span (ILS) was 87.05% with maximum survival time of 30.5+/-1.87 days. For 5-fluorouracil monolithic matrix transdermal patch, the results were statistically significant (p<0.05) compared to untreated control, anti-tumor activity was very effective compared to intravenous therapy. Patches did not show any sign of erythema, vesiculations or bullaous reaction. Mean cumulative skin irritation and adherence scoring for both animal and humans proved that none of the irritation sensitization reactions score were zero and less than one, while good adherence score was 0, with complete adherence to the skin, without leaving any adhesive residue on skin with scores = 0 in human subjects. Transdermal patches showed 100% flatness, thickness 150+/-0.03 mm, good content uniformity, folding endurance (>500 foldings), smoothness, transparency, flexibility and appearance. Pharmacokinetic studies of 5-FU transdermal patch in rabbits showed half-life 95+/-0.5 min, C(max) (ng/ml) 863.25,AUC(0-infinity) (ng/ml/h)1567+/-36 and T(max) (h) 1.5 with controlled release for 24 h which was very significant (p<0.001) compared to intravenous route. Recent patents has been reported for suitable treatment of tumors and cancer, by topical and transdermal applications. Velcro protection jackets were suitable for this study and protected our applied transdermal patched from being licked, scratched and rubbed off.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Adhesiveness , Administration, Cutaneous , Animals , Antimetabolites, Antineoplastic/pharmacokinetics , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Drug Delivery Systems , Fluorouracil/pharmacokinetics , Humans , Irritants/toxicity , Mice , Mice, Inbred BALB C , Rabbits , Survival AnalysisABSTRACT
Carboxymethyl guar (CMGS), an anionic semisynthetic guar gum derivative was evaluated for its suitability of use in transdermal drug-delivery systems. Terbutaline sulfate (TS) was used as a model drug. The diffusion of terbutaline sulfate from CMGS solution was relatively slower at pH 5 than at pH 10. It is most likely that the interaction between CMGS and terbutaline sulfate at pH 5 is physical, involving static interaction. The ability of such interactions in modifying the release kinetics of drug from the CMGS transdermal films was studied. The release was exponential from pH 5 formulations whereas the release rate followed zero or Higuchian order from pH 10 formulations. However, the diffusion kinetics of both pH 5 and pH 10 formulations followed zero order across human cadaver epidermis. Such an interaction was also found to alter the pharmacokinetic parameters of the drug. The steady-state concentration of TS was relatively consistent and the bioavailability was approximately 50% higher in pH 5 formulations than pH 10. The elimination rate constant/half-life was significantly different between pH 5 and pH 10 formulations.
