A mucoadhesive, cyclodextrin-based vaginal cream formulation of itraconazole.
The development of vaginal medications, especially antifungal medications, requires that the drug is solubilized as well as retained at or near the mucosa for sufficient periods of time to ensure adequate bioavailability. Itraconazole is a broad-spectrum antifungal agent, which has been used for some time orally and intravenously but for which a vaginal formulation has not yet been developed. We present here a novel itraconazole formulation intended for vaginal use based on hydroxypropyl-beta-cyclodextrin (HPbetaCD), a functional excipient that increases drug solubility and generates a mucoadhesive system in the presence of other ingredients. An aqueous phase was prepared by solubilizing itraconazole with HCl in the presence of propylene glycol and then adding an aqueous solution of HPbetaCD. After pH adjustment, the itraconazole/HPbetaCD solution was added to the oil phase (paraffin oil, trihydroxystearate, and cetyl dimethicon copolyol) and the desired cream containing 1%, 2%, and 2.5% drug obtained by homogenization. Primary irritation studies and subchronic toxicity studies using a rabbit vaginal model indicated that the formulation was safe, well tolerated, and retained in the vaginal space. Clinical investigations indicated that application of 5 g of a 2% cream was very well tolerated and itraconazole was not systemically absorbed. Additional studies in women found that the itraconazole cream was highly effective in reducing or eliminating fungal cultures with few adverse effects. These studies suggested that an HPbetaCD-based, emulsified wax cream formulation was a useful and effective dosage form for treating vaginal candidiasis.
Francois
Marc
M
Department of Pharmaceutical Development, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
Snoeckx
Eric
E
Putteman
Peter
P
Wouters
Fons
F
De Proost
Eddy
E
Delaet
Urbain
U
Peeters
Jef
J
Brewster
Marcus E
ME
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001682:Biological Availability; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D003505:Cyclodextrins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D004304:Dosage Forms; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D011817:Rabbits; D012995:Solubility; D012996:Solutions / Q000737:chemistry / Q000627:therapeutic use; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000627:therapeutic use; D014623:Vaginal Diseases / Q000188:drug therapy / Q000382:microbiology; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D003505:Cyclodextrins; D004304:Dosage Forms; D012996:Solutions; D014622:Vaginal Creams, Foams, and Jellies; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole