Development and evaluation of novel biodegradable transdermal penetration enhancers

新型可生物降解透皮渗透促进剂的开发与评价

• 批准号: 09672281
• 负责人: KUBO Kazuyoshi
• 金额: $ 1.92万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672281/
• 关键词: Skin permeation; Penetration enhancer; Biodegradable; Ion pair; Partition coefficient; 経皮吸収促進剤; イオン対形成; 透過速度; 透過係数; 血中濃度予測; 分配係数

This studies were aimed to develop the transdermal therapeutic system of highly ionizable drugs by ion pair formation with novel biodegradable counter ions.The following results were obtained.(1) Novel biodegradable triglycerides having quaternary ammonium group (YKS) were synthesized as counter ions for ion pair complexation with salicylate or cromoglicate (SCG) (model anionic drugs).The permeability of these anionic drugs through the rat skin was significantly increased by lipophilic ion pair formation in the presence of the YKS.(2) The biodegradability of YKS were illustrated by the pH-stability experiments.Judging from the primary irritation indices, YKS-21 had less cutaneous irritancy compared with Azone.(3) The combination of pretreatment with YKS and ion pair formation was more effective for ion pair transport.(4) The maximum flux and permeability coefficient of SCG from SCG-YKS ion pair in propylene glycol/isopropyl alcohol/isopropyl myristate(15 : 75 : 1O)were about 15 and 3 times respectively higher than those of SCG alone in the same vehicle mixture.(5) The plasma concentrations after topical application to the rat were simulated using obtained permeation and disposition parameters.Although there were some differences in the time course patterns, it was found that the percutaneous penetration of SCG was increased by ion pair formation with YKS in vivo as well.The results of this study suggest that it may be possible through the selection of appropriate counter ions to improve the efficiency of transdermal penetration of other highly ionized drugs, and that ion pair formation is an important consideration in the formulation of ionized drugs.

本研究旨在通过与新型可生物降解的反离子形成离子对，开发高电离药物的透皮治疗系统。得到了以下结果：(1)合成了具有季铵盐基团（YKS）的新型可生物降解甘油三酯，作为与水杨酸盐或异丙酸盐（SCG）（模型阴离子药物）离子对络合的反离子。这些阴离子药物通过大鼠皮肤的渗透性明显增加，在YKS存在下形成亲脂离子对。(2)通过ph稳定性实验验证了YKS的生物降解性。从主要刺激指标来看，YKS-21与Azone相比具有较低的皮肤刺激性。(3)预处理与YKS结合，离子对形成更有效。(4) SCG- yks离子对在丙二醇/异丙醇/肉豆酸异丙酯（15:75:10）混合物中的最大通量和渗透系数分别比单独使用SCG的最大通量和渗透系数高约15倍和3倍。(5)使用获得的渗透和处置参数模拟大鼠外用后的血浆浓度。虽然在时间过程模式上存在一些差异，但我们发现，体内与YKS形成离子对也会增加SCG的经皮穿透。本研究结果提示，通过选择合适的反离子可以提高其他高电离药物的透皮渗透效率，离子对的形成是电离药物配方中的一个重要考虑因素。

项目成果

Kadono M et al.: "Enhanced in Vitro Percutaneous Penetration of Salicytlate by Ion Pair Formation with Alkylamines." Biol.Pharm.Bull.21. 599-603 (1998)

Kadono M 等人：“通过与烷基胺形成离子对增强水杨酸盐的体外经皮渗透。”

久保一義: "イオン対形成による皮膚透過性制御と皮膚ターゲッテングの可能性" Fragrance Jounal. 26巻9号. 71-78 (1998)

Kazuyoshi Kubo：“通过离子对形成控制皮肤渗透性和皮肤靶向的可能性”《香水杂志》第 26 卷，第 9. 71-78 期（1998 年）。

Masanori Kadono: "Enhanced いn Vitro Percutaneous Penetration of Salicylate by lon Pair Formation with Alkylamines" Biol.Pharm.Bull.21巻6号. 599-603 (1998)

Masanori Kadono：“通过与烷基胺形成离子对增强水杨酸盐的体外经皮渗透”Biol.Pharm.Bull.Vol. 21，No. 6. 599-603 (1998)

Masanori Kadono: "Enhanced in Vitro Percutaneous Penetration of Salicylate by Ion Pair Formation with Alkylamines" Biol.Pharm.Bull.21巻6号. 599-603 (1998)

Masanori Kadono：“通过与烷基胺形成离子对增强水杨酸盐的体外经皮渗透”Biol.Pharm.Bull.Vol. 21，No. 6. 599-603 (1998)

Kubo K.et al.: "Possibility of Dynamic Control of Skin Permeability by Ion Pair Formation in Topical Drug Targeting" Fragrance Journal. 26. 71-78 (1998)

Kubo K.等人：“局部药物靶向中离子对形成动态控制皮肤渗透性的可能性”《香水杂志》。