Mizoguchi Masashi, Nakatsuji Masatoshi, Inoue Haruka, Yamaguchi Keisuke, Sakamoto Atsushi, Wada Koichi, Inui Takashi
Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan; Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
Eur J Pharm Sci. 2015 Jul 10;74:77-85. doi: 10.1016/j.ejps.2015.04.012. Epub 2015 Apr 20.
Lipocalin-type prostaglandin D synthase (L-PGDS), a member of the lipocalin superfamily, possesses the function of forming complexes together with various small lipophilic molecules. In this study, we chose telmisartan as a model drug due to its pH dependent poor water solubility, and developed and characterized a novel solubilized formulation of telmisartan using a complex formulation with L-PGDS. The solid state of the complex formulation was prepared using a spray-drying process. The spray-dried formulation of telmisartan/L-PGDS powder showed a typical spray-dried particle without any change in the secondary and tertiary structures of L-PGDS. Furthermore, the complex formulation showed a high rate and level of drug release in pH 1.2, 5.0, and 6.8 solutions in comparison with the active pharmaceutical ingredient (API) and commercial product. To validate the potential for oral administration of the telmisartan/L-PGDS complex in vivo, the pharmacokinetic and pharmacodynamic profiles were assessed in spontaneous hypertensive rats. An animal study revealed that the complex formulation led to a significant improvement of AUC and Cmax as compared with API, and the prolonged pharmacologic effect on blood pressure reduction was comparable with the commercial product. These results, taken together, demonstrate that this novel approach is feasible for the solubilized solid oral formulation and it can be applied to poorly water-soluble drugs to enhance oral bioavailability.
脂联素型前列腺素D合成酶（L-PGDS）是脂联素超家族的成员之一，具有与各种亲脂性小分子形成复合物的功能。在本研究中，我们选择替米沙坦作为模型药物，因其在pH值依赖性下水溶性较差，并使用与L-PGDS的复合制剂开发并表征了一种新型的替米沙坦增溶制剂。复合制剂的固态通过喷雾干燥工艺制备。替米沙坦/L-PGDS粉末的喷雾干燥制剂呈现出典型的喷雾干燥颗粒，L-PGDS的二级和三级结构没有任何变化。此外，与活性药物成分（API）和市售产品相比，复合制剂在pH 1.2、5.0和6.8的溶液中显示出较高的药物释放速率和水平。为了验证替米沙坦/L-PGDS复合物口服给药的体内潜力，在自发性高血压大鼠中评估了其药代动力学和药效学特征。一项动物研究表明，与API相比，复合制剂导致AUC和Cmax显著改善，并且对血压降低的延长药理作用与市售产品相当。综上所述，这些结果表明这种新方法对于增溶固体口服制剂是可行的，并且可以应用于水溶性差的药物以提高口服生物利用度。
