Norio Takasugi

Determination of timiperone in rat plasma by high-performance liquid chromatography with electrochemical detection

We report a sensitive new method for the determination of timiperone in rat plasma by using high-performance liquid chromatography with electrochemical detection. The method involves extraction of plasma samples with heptane-isoamyl alcohol at pH > 8, followed by back-extraction into dilute acetic acid. Separation was accomplished by reversed-phase high-performance liquid chromatography on an ODS column with the mobile phase consisting of 0.1 M phosphate buffer (pH 3.5)-acetonitrile-methanol (65:20:15, v/v). Recovery was greater than 80%. Calibration curve was linear over the concentration range 0.5-50.0 ng/ml. The limit of quantitation of timiperone was 0.5 ng/ml plasma.

Pharmacological activities of timiperone transdermal dosage forms composed of water-soluble polymer matrix in rats.

To prevent the emesis associated with anticancer therapy with chemotherapeutic drugs, various investigations have been conducted into transdermal dosage forms containing timiperone, antipsychotics and strong antiemetics. In the present study, we used the water-soluble polymers as a matrix for transdermal dosage forms. Further, we also evaluated the effect of matrix pH on the inhibition action of timiperone on apomorphine-induced stereotyped behavior in an in vivo model in rats, and compared pharmacological activity with these water-soluble matrices to that obtained with a plaster formulation. Inhibition of timiperone on apomorphine-induced stereotyped behavior was used as an index of percutaneous absorption of timiperone. Results showed that pharmacological activity increased with increasing matrix pH. This finding suggests that the percutaneous absorption of timiperone is pH-dependent. At 4 h after the administration of water-soluble polymer matrices, the pharmacological activity of timiperone was closely similar to that at the same time-point after oral administration of the drugs. Further, this activity was maintained for up to about 8 h after administration. These findings suggest that the transdermal dos age form of timiperone prepared from these water-soluble polymers is effective and longer-acting preparations to prevent the emesis associated with anticancer therapy with chemotherapeutic drugs.

Preliminary Preformulation Studies of a 2-(3,4-Dimethoxyphenyl)ethylamine Derivative for Oral Administration at an Exploratory Stage of New Drug Development.

Preliminary preformulation studies of a 2-(3,4-dimethoxyphenyl)ethylamine derivative were investigated. The hydrochloride form showed incompatibility with the excipients used for oral dosage forms. There were several crystal forms of the free base, namely, alpha-anhydrate, beta-anhydrate, monohydrate, and trihydrate. The trihydrate form was unstable. The degree of crystallinity of the beta-anhydrate form was difficult to control. The monohydrate form was difficult to manufacture with constant quality. The serum levels of the compounds in rats were almost related to the dissolution rates in the JP 1st disintegration medium from the discs. The serum level of alpha-anhydrate was the lowest. However, the dissolution rates from the formulations of alpha-anhydrate were improved. After oral administration of the improved formulation, the serum level of alpha-anhydrate in beagle dogs was almost triple that after the oral administration of the capsule of the hydrochloride form.