著者

加藤 日出男 永田 治 山崎 昌弘 鈴木 利広 仲野 善久

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.122, no.1, pp.57-69, 2002-01-01 (Released:2003-02-13)

参考文献数

15

被引用文献数

18 17

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β2-Adrenergic agonists have been widely used to treat patients with asthma. Usually, oral dosage forms of β2-agonists have been used, but side effects such as palpitation and tremor have been reported because of excessive serum levels around Tmax. It is said that circadian variations exist in the manifestation of asthma with maximum incidence of asthma attacks in early morning at around 4 a.m., the so-called morning dip. Chronotherapy for asthma based on circadian rhythm should be more efficient and have a lower frequency of side effects. Accordingly we developed a transdermal delivery system of the β2-agonist tulobuterol adapted to the circadian rhythm. The system is designed to administer the appropriate dose of the drug at an optimal time using the so-called Crystal Reservoir System. The superiority of the transdermal formulation of tulobuterol over the current therapy using oral formulations of β2-stimulants was indicated by its excellent pharmacokinetic profile, and confirmed by the results of clinical trials. This formulation is the first transdermal chrono-delivery system reported anywhere in the world, and is expected to provide more effective and safe treatment of asthma and related diseases not only in adults, but also especially in children.

著者

斎藤 勝 籔 晴夫 山崎 昌弘 松村 阜子 加藤 日出男

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.30, no.2, pp.652-658, 1982-02-25 (Released:2008-03-31)

参考文献数

17

被引用文献数

3 5

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The existence of four crystalline forms (forms I, II and III, and a hydrate) and an amorphous form of tulobuterol hydrochloride was confirmed by X-ray powder diffraction, infrared spectroscopy and thermal analyses (DSC and TG). The hydrate was found to be the monohydrate by elemental analysis and measurement of water content. From the DSC measurement, it was found that forms I and II melted at 163°C and 170°C, and their heats of fusion were 5.15 kcal/mol and 4.76 kcal/mol, respectively. Form III, the amorphous form and the hydrate transformed into form II at 135°C, 90°C and 75°C, respectively. Activation energy for the dehydration of the hydrate determined by Kissinger's method was 56.1 kcal/mol. No crystal changes were observed in the four crystalline forms when they were ground in a mortar or compressed at high pressure ; however, after such mechanical treatments form I transformed into form II on being heated. The investigation of phase transitions of the four crystals showed that form II was the most stable among them.