In vitro evaluation of alkylcarbonyloxymethyl (ACOM) ethers as novel prodrugs of phenols for topical delivery: ACOM prodrugs of acetaminophen.
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.
Thomas
Joshua D
JD
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, MD 21702, USA.
Sloan
Kenneth B
KB
D000082:Acetaminophen / Q000737:chemistry / Q000378:metabolism*; D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems; D004987:Ethers / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D008954:Models, Biological; D010636:Phenols / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D012995:Solubility; D044366:Transition Temperature
D004987:Ethers; D010636:Phenols; D011355:Prodrugs; D000082:Acetaminophen