烷基羰氧基甲基（ACOM）醚作为酚类新型前药用于局部给药的体外评价：对乙酰氨基酚的ACOM前药

In vitro evaluation of alkylcarbonyloxymethyl (ACOM) ethers as novel prodrugs of phenols for topical delivery: ACOM prodrugs of acetaminophen.

作者信息

Thomas Joshua D, Sloan Kenneth B

机构信息

Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, MD 21702, USA.

出版信息

Int J Pharm. 2008 Jan 4;346(1-2):80-8. doi: 10.1016/j.ijpharm.2007.06.007. Epub 2007 Jun 14.

DOI:10.1016/j.ijpharm.2007.06.007

PMID:17629641

Abstract

The fluxes (J(IPM)) of a series of alkylcarbonyloxymethyl (ACOM) ethers of acetaminophen (APAP) were measured through hairless mouse skin from suspensions of each prodrug in isopropyl myristate (IPM). Solubilities in IPM, estimated solubilities in pH 4.0 buffer (S(4.0)) and flux data for the 4-ACOM-APAP prodrugs were incorporated into the Roberts-Sloan (RS) database to give new estimates for the independent variables of the RS equation: logJ(IPM)=x+ylogS(IPM)+(1-y)logS(4.0)-zM(W). All but one of the 4-ACOM-APAP derivatives hydrolyzed completely on permeation through mouse skin. Three out of the five prodrugs permeated the skin better than APAP, with a maximum fourfold increase in flux. Biphasic solubility - not solubility in a single solvent - was shown to have the greatest impact on flux. A fit of the new n=66 database to the RS equation gave the following values for x, y, z, and r(2): x=-0.545, y=0.511, z=0.00253, r(2)=0.915. These results demonstrate that the topical delivery of a model phenol, acetaminophen, can be improved by transiently masking the phenolic hydroxyl group as an ACOM ether.

摘要

通过将对乙酰氨基酚（APAP）的一系列烷基羰氧基甲基（ACOM）醚在肉豆蔻酸异丙酯（IPM）中的悬浮液透过无毛小鼠皮肤，测量了它们的通量（J(IPM)）。将在IPM中的溶解度、在pH 4.0缓冲液中的估计溶解度（S(4.0)）以及4-ACOM-APAP前药的通量数据纳入罗伯茨-斯隆（RS）数据库，以给出RS方程自变量的新估计值：logJ(IPM)=x+ylogS(IPM)+(1-y)logS(4.0)-zM(W)。4-ACOM-APAP衍生物中除一种外，其余在透过小鼠皮肤渗透时均完全水解。五种前药中有三种比APAP的皮肤渗透性更好，通量最大增加了四倍。结果表明，双相溶解度而非在单一溶剂中的溶解度对通量影响最大。新的n = 66数据库对RS方程的拟合得出x、y、z和r(2)的以下值：x = -0.545，y = 0.511，z = 0.00253，r(2)=0.915。这些结果表明，作为模型酚的对乙酰氨基酚的局部给药可通过将酚羟基暂时掩蔽为ACOM醚来改善。