Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity--drug supersaturation, toxicity on TR146 cells and release from a delivery system.
The dissolution rate, the toxicity and the release from chewing gum of miconazole and econazole cyclodextrin products and complexes were investigated. The dissolution rate studies showed that an amorphous miconazole hydroxypropyl-beta-cyclodextrin product gave drug supersaturation, whereas drug supersaturation was not present during dissolution rate testing of an econazole hydroxypropyl-beta-cyclodextrin product. The miconazole hydroxypropyl-beta-cyclodextrin product and genuine cyclodextrin inclusion complexes of miconazole, econazole and clotrimazole were toxic on a human TR146 buccal cell culture model. The toxicity was probably due to drug supersaturation, thereby increasing the bioavailability of the antimycotics. The econazole hydroxypropyl-beta-cyclodextrin product and physical mixtures of miconazole or econazole and beta-cyclodextrin did not give supersaturation and were not as toxic as the above-mentioned compounds. Neat econazole and miconazole, a genuine econazole beta-cyclodextrin complex and the miconazole hydroxypropyl-beta-cyclodextrin product were incorporated in chewing gum. The miconazole hydroxypropyl-beta-cyclodextrin gum had a much higher drug release in vitro than the neat miconazole gum. The genuine econazole beta-cyclodextrin complex only increased the drug release moderately when compared with the release from the neat econazole gum. The release studies were performed on a mastication device.
Jacobsen
J
J
Department of Pharmaceutics, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Bjerregaard
S
S
Pedersen
M
M
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D002176:Candida albicans / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002610:Cheek; D002638:Chewing Gum; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D016503:Drug Delivery Systems; D004464:Econazole / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000556:secondary; D006801:Humans; D007700:Kinetics; D008825:Miconazole / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D008855:Microscopy, Electron, Scanning; D009061:Mouth Mucosa / Q000187:drug effects; D009062:Mouth Neoplasms / Q000473:pathology; D012995:Solubility; D014407:Tumor Cells, Cultured; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D002638:Chewing Gum; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D004464:Econazole; D008825:Miconazole