Soft Alkyl Ether Prodrugs of a Model Phenolic Drug: The Effect of Incorporation of Ethyleneoxy Groups on Transdermal Delivery

Molecules

Joshua Denver Thomas¹  Susruta Majumdar¹ 

[1] ¹Laboratory of Medicinal Chemistry, NCI, NIH, NCI – Frederick, Frederick, MD 21702, USA ²Laboratory of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA ³Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, FL 32610, USA

关键词: topical delivery;    Roberts-Sloan equation;    water solubility;    lipid solubility;    prodrugs;   

DOI  :  10.3390/molecules14104231

来源: mdpi

【 摘 要 】

Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, S_IPM, and water, S_AQ, partition coefficients between IPM and pH 4.0 buffer, K_IPM:4.0, and the delivery of total species containing APAP through hairless mouse skin from IPM, J_MMIPM, have been measured for the prodrugs. The J_MMIPM values were accurately predicted by the Roberts-Sloan (RS) equation. Only modest increases in JMMIPM were realized (about 1.4 times) by each type. The only prodrug that was more water soluble and more lipid soluble than APAP did not improve J_MMIPM of APAP. This result may be due to the strong association of water molecules with the ethyleneoxy groups, and especially the triethyleneoxy derivative, which dramatically increases the molecular weight and depresses J_MMIPM.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.