口腔内投与型クロナゼパム半固形製剤の開発

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A semisolid dosage form of clonazepam (CZP), administered to the oral cavity between the lower gum and bottom lip with small volume of saline, was developed to obtain the stable dosage which can replace the injection dosage form. Semisolid dosage forms were prepared using a mixture of CZP/(polyethylene glycol 1500 (PEG))/(oleic acid (OA)) at the ratios of 1/39/0, 1/37/2 and 2/36/2 (w/w), named CZP1-PEG, CZP1-PEG-OA and CZP2-PEG-OA, respectively, and were evaluated in vitro and in vivo. No crystal of CZP was observed in CZP1-PEG-OA for at least 8 days, while CZP crystal appeared before administration for CZP2-PEG-OA. When a small volume of saline was added to CZP1-PEG-OA just before the oral cavity administration, more than 80% (w/w) was found to exist in the soluble form. Each semisolid dosage form (40 mg) was administered to the oral cavity in rats, and CZP 1 mg suspension in 0.5% (w/v) sodium carboxymethylcellulose aqueous solution was administered into rat stomach as a control. CZP1-PEG-OA gave the plasma concentrations of more than 5 ng/ml and 12 ng/ml at 30 min and 1 h after administration, respectively, which might be near the plasma levels effective for the suppression of epileptic seizures in human, while the plasma concentration was less than 5 ng/ml at 30 min or did not reach 10 ng/ml at 1 h for the other formulations. It is proposed that the semisolid dosage form CZP1-PEG-OA should be a possibly useful preparation for the antiepileptic or sedative medication.

口腔内投与型クロナゼパム半固形製剤の開発

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