Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies
Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies
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DOI：
10.1016/j.ijpharm.2006.02.056
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发表时间：
2006-07-24
影响因子：
5.8
通讯作者：
Takada, Kanji
中科院分区：
文献类型：
--
作者：
Ito, Yukako;Kusawake, Tomohiro;Takada, Kanji
口服抗凝治疗肝素已挑战，制定肝素在口服固体制剂。肝素选用低分子量肝素（LMWH）。用自微乳化给药系统（SMEDDS）用表面活性剂PEG-8己烯/己烯甘油酯（Labrasol）分散低分子wh，并用三种吸附剂(微孔硅酸钙（Florite (TM) RE）、硅酸铝镁（Neusilin (TM) US2）和二氧化硅（Sylysia (TM) 320）对混合物进行固化。体外释放试验表明，Sylysia 320的T50%为3.2 +/- 0.1 min， Florite RE为4.6 +/- 0.2 min， Neusilin US2为13.7 +/- 0.1 min。大鼠体内吸收研究表明，Florite RE体系的C-max最高，为0.42 +/- 0.01 IU/mL， AUC最高，为0.15 +/- 0.02 IU h/mL，其中血浆低分子肝素水平为抗xa活性。其他制剂的C-max和AUC分别为Neusilin US2的0.12 +/- 0.01 IU/mL和0.15 +/- 0.02 IU h/mL， Sylysia 320的0.25 +/- 0.02 IU/mL和0.40 +/- 0.03 IU h/mL。通过与另一组大鼠静脉注射低分子肝素（40 IU/kg）获得的AUC比较，低分子肝素微孔硅酸钙制剂Florite RE在大鼠体内的生物利用度（13A）为18.8%。以低分子肝素200 IU/kg的剂量口服Eudragit s100肠胶囊后，对Florite RE系统进行了评价。血浆抗xa活性较高，即C-max为0.48 +/- 0.11 IU/mL， AUC为1.64 +/- 0.32 IU h/mL。这些结果表明，吸附剂系统可作为低分子肝素等难吸收药物的口服固体递送系统。(c) 2006 Elsevier B.V.版权所有
Oral anticoagulant therapy with heparin has been challenged by formulating heparin in oral solid preparation. As heparin, low molecular weight heparin (LMWH) was used. LMWH was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with three kinds of adsorbents, microporous calcium silicate (Florite (TM) RE), magnesium alminometa silicate (Neusilin (TM) US2 ) and silicon dioxide (Sylysia (TM) 320). The in vitro release study showed that the T50% were 3.2 +/- 0.1 min for Sylysia 320, 4.6 +/- 0.2 min for Florite RE, 13.7 +/- 0.1 min for Neusilin US2. The in vivo rat absorption study showed that Florite RE system had the highest C-max, 0.42 +/- 0.01 IU/mL and AUC, 0.15 +/- 0.02 IU h/mL, where plasma LMWH levels were measured as anti-Xa activity. Other preparations had the C-max and AUC, 0.12 +/- 0.01 IU/mL and 0.15 +/- 0.02 IU h/mL for Neusilin US2 and 0.25 +/- 0.02 IU/mL and 0.40 +/- 0.03 IU h/mL for Sylysia 320, respectively. The bioavailability (13A) of LMWH from the microporous calcium silicate preparation, Florite RE, was 18.8% in rats by comparing the AUC obtained after i.v. injection of LMWH, 40 IU/kg to another group of rats. Florite RE system was evaluated in dogs after oral administration in an enteric capsule made of Eudragit S 100 at the LMWH dose of 200 IU/kg. High plasma anti-Xa activity levels were obtained, i.e., the C-max was 0.48 +/- 0.11 IU/mL and AUC was 1.64 +/- 0.32 IU h/mL. These results suggest that adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as LMWH. (c) 2006 Elsevier B.V. All rights reserved.