KEYWORDSItraconazole, vaginal, cyclodextrin, mucoadhesive, toxicity, clinical investigation, candidiasisThe 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-ȕ-cyclodextrin (HPȕCD), 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 HPȕCD. After pH adjustment, the itraconazole/HPȕCD 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 HPȕCD-based, emulsified wax cream formulation was a useful and effective dosage form for treating vaginal candidiasis.

Complexation of various equipotent doses of fentanyl-like opioids in hydroxypropyl-6-cyclodextrin (HP-P-CD) results in a potentiation of the spinal activity of these opioids after both epidural and intrathecal administration in a fixed diluent volume o f 10 p,l. The first active and most optimal concentrations of HP-(3-CD after epidural administration differed between the opioids and varied from 1 to 20% HP-P-CD. The duration of deep surgical analgesia increased at optimal concentrations of HP-P-CD with a factor 3 for fentanyl (15% HP-P-CD), 3.6 for sufentanil (5-10% HP-p-CD), and 2.2, 6.0, and 1.4 for carfentanil (5% HP-P-CD), alfentanil (20% HP-p-CD), and lofentanil (15% HP-P-CD), respectively. Increasing the concentrations of HP-P-CD above these optimal concentrations did not further potentiate the analgesic activity of the opioids. The complexation of the opioids in HP-P-CD also increased the duration o f supraspinal side-effects. However, except for lofentanil, the potentiations o f the analgesic activity were always longer lasting than those for the secondary side-effects. As a consequence, there was a gain in the total time of analgesia without side-effects. After intrathecal administration, there was no gain in the duration of deep surgical analgesia after complexation of fentanyl, carfentanil, and alfentanil in HP-P-CD. For both sufentanil and lofentanil, maximal potentiation of analgesia was measured at 10% HP-P-CD with, respectively, 2.8-and 1.7-fold increases in the duration of analgesia. Also intrathecally, there was some gain in the duration o f duration o f analgesia without supraspinal side-effects. These results on the potentiation of the opioids with HP-P-CD are discussed in relation to the lipophilicity of the tested opioids. o 1993 Wiley-Liss, Inc