Approaches to reducing toxicity of parenteral anticancer drug formulations using cyclodextrins.
Mitomycin C (MMC) is a clinically useful anticancer drug which can cause severe dermatological problems upon injection. It can cause delayed erythema and/or ulceration occurring either at or distant from the injection site for weeks or even months after administration. In an attempt to reduce the skin necrosis, complexation of MMC with cyclodextrins was studied in order to help increase patient compliance and acceptance. The complexation of MMC with 2-Hydroxypropylbetacyclodextrin (HPBCD) in the presence and absence of mannitol was studied and it was found that the mannitol present in the commercial formulation caused an increase in the binding of MMC to HPBCD. Isotonicity adjustment of hypotonic MMC formulations by the addition of normal saline did not change the degree of complexation with MMC. The complexed formulations were then tested to determine their antitumor efficacy using the B-16 melanoma cell model. No difference in antitumor activity between the complexed and uncomplexed MMC formulations was observed. Different MMC formulations were tested for their potential to produce skin irritation and/or toxicity using intradermal injections in a BALB/c mouse model in order to find the most suitable formulation. The skin ulceration studies indicated that there were no significant differences between the isotonic MMC solution and isotonic formulations of MMC complexed with HPBCD.
Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721, USA.
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Bhardwaj
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Dorr
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Blanchard
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000008:administration & dosage*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D012867:Skin / Q000187:drug effects; D012995:Solubility; D047392:beta-Cyclodextrins
D000903:Antibiotics, Antineoplastic; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D016685:Mitomycin