Kato Hideo, Nagata Osamu, Yamazaki Masahiro, Suzuki Toshihiro, Nakano Yoshihisa
Hokuriku Seiyaku Co., Ltd., 37-1-1, Inokuchi, Katsuyama, Fukui 911-8555, Japan and NITTO DENKO CORPORATION, 1-1-2, Shimohozumi, Ibaraki, Osaka 567-8680, Japan.
Yakugaku Zasshi. 2002 Jan;122(1):57-69. doi: 10.1248/yakushi.122.57.
beta 2-Adrenergic agonists have been widely used to treat patients with asthma. Usually, oral dosage forms of beta 2-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 beta 2-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 beta 2-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.
β2肾上腺素能激动剂已被广泛用于治疗哮喘患者。通常使用β2激动剂的口服剂型，但由于在达峰时间（Tmax）左右血清水平过高，已报告出现心悸和震颤等副作用。据说哮喘的发作存在昼夜变化，在凌晨4点左右的清晨哮喘发作发生率最高，即所谓的清晨低谷。基于昼夜节律的哮喘时间治疗应该更有效且副作用发生率更低。因此，我们开发了一种适应昼夜节律的β2激动剂妥洛特罗透皮给药系统。该系统旨在使用所谓的晶体储库系统在最佳时间给予适当剂量的药物。妥洛特罗透皮制剂相对于目前使用β2兴奋剂口服制剂的疗法的优越性体现在其优异的药代动力学特征上，并得到了临床试验结果的证实。这种制剂是世界上首个报道的透皮定时给药系统，预计不仅能为成人，尤其是儿童提供更有效、安全的哮喘及相关疾病治疗。
