Enhancement of skin permeation of ketotifen by supersaturation generated by amorphous form of the drug
Enhancement of skin permeation of ketotifen by supersaturation generated by amorphous form of the drug
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DOI：
10.1016/j.jconrel.2005.08.008
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发表时间：
2005-11-28
影响因子：
10.8
通讯作者：
Sugibayashi, K
中科院分区：
文献类型：
--
作者：
Inoue, K;Ogawa, K;Sugibayashi, K
制备含有无定形酮替芬的压敏粘合剂（PSA）基质，并评价其增强的药物皮肤渗透性。采用使用硅酮型PSA的溶剂浇铸法，并且使用正己烷（PSA的原始溶剂）和一种或多种溶剂二氯甲烷、四氢呋喃、丙酮、乙酸乙酯或甲苯，以使酮替芬完全溶解并高度分散在药物的无定形状态中。基于从基质的体外药物释放速率判断无定形形式的存在。因此，选择二氯甲烷和四氢呋喃作为适当的稀释溶剂。通过离体无毛小鼠皮肤的体外渗透实验表明，从无定形酮替芬分散基质的稳态通量约为结晶酮替芬分散基质的5倍，并且增强比与药物的无定形与结晶形式的溶解度比良好一致。两种不同药物含量的无定形酮替芬分散基质的皮肤渗透曲线的比较表明，稳态通量不受药物含量的影响。此外，在两种药物含量下，稳态渗透的时间与无定形药物从基质中耗尽的时间一致。这些结果表明，酮替芬从PSA基质中的皮肤渗透的增加是由于无定形形式产生的过饱和，并且无定形形式在施用期间是稳定的。(c)2005 Elsevier B.V.保留所有权利。
Pressure sensitive adhesive (PSA) matrices containing amorphous ketotifen were prepared and evaluated for enhanced skin permeability of the drug. A solvent casting method using silicone-typed PSA was employed, and n-hexane, an original solvent for the PSA and one more solvent, dichloromethane, tetrahydrofuran, acetone, ethyl acetate or toluene, were used for complete dissolution of ketotifen and high dispersion in an amorphous state of the drug. Presence of the amorphous form was judged based on the in vitro drug release rate from the matrix. As a result, dichloromethane and tetrahudrofuran were selected as appropriate dilution solvents. In vitro permeation experiments through excised hairless mouse skin revealed that the steady-state flux from the amorphous ketotifen-dispersed matrices was about five times greater than that of the crystalline ketotifen-dispersed matrices, and that the enhancement ratio was in good agreement with the solubility ratio of the amorphous to crystalline form of the drug. Comparison of the skin permeation profiles of amorphous ketotifen-dispersed matrices between two different drug contents suggested that the steady-state flux was not influenced by the drug content. In addition, at both drug contents, the period of the steady-state permeation coincided with the time until the amorphous drug was depleted from the matrix. These results suggest that the increase in skin permeation of ketotifen from PSA matrix was due to the supersaturation generated by amorphous form, and that the amorphous form was stable during the application period. (c) 2005 Elsevier B.V. All rights reserved.