7-Alkylcarbonyloxymethyl prodrugs of theophylline: topical delivery of theophylline

Correlation of aqueous and lipid solubilities with flux for prodrugs of 5‐fluorouracil, theophylline, and 6‐mercaptopurine: A potts–Guy approach

“…The buffer contained 0.11% formaldehyde as a preservative to prevent microbial growth and maintain the integrity of the skins during the course of the experiment. 8 The surface area of the diffusion cells was 4.9 cm 2 , and the receptor phase volume was 20 mL. After contact with the receptor phase for 48 h to condition the skins, aliquots of a suspension of the prodrug in IPM (usually 0.5 mL) were applied to the epidermal side of three skins (n ) 3) for 48 h. The receptor phases were continuously stirred during the entire experiment and were changed every 3 h during the time when steady-state fluxes were measured which was usually from 19 to 33 h. Variation in flux values was less than 30% except from the 6ACOM-6-MP series where the variation was less than 50%.…”

“…The methods used to determine the values for flux (JM), solubilities (SIPM, SAQ), and partition coefficients between IPM and water (KIPM:AQ) are described in the original papers for each series of prodrugs: 1-alkylcarbonyloxymethyl-5-FU (ACOM-5-FU), 5 1-alkyloxycarbonyl-5-FU (AOC-5-FU), 3 1-alkylcarbonyl-5-FU (AC-5-FU), 4 1-alkylaminocarbonyl-5-FU (AAC-5-FU), 2 7-alkylcarbonyloxymethyltheophylline (ACOM-Th), 8 6-alkylcarbonyloxymethyl-6-MP (6ACOM-6-MP), 7 and 6,9-bis(alkylcarbonyloxymethyl)-6-MP (6,9ACOM-6-MP). 6 In each series only straight chain homologues were completely characterized and evaluated except for the ACOM-5-FU series where one branched chain homologue was characterized and evaluated: 1-pivaloyloxymethyl-5-FU (pivA-COM-5-FU).…”

“…1 Examples where different types of promoieties have been used with one parent drug, [2][3][4][5] or where one type of promoiety has been used with a number of different parent drugs, [5][6][7][8] show that, for an homologous series of more lipid soluble prodrugs, the more water soluble member or members of the series are the more efficient at delivering the parent drug topically. Although the greatest accumulation of data supporting this axiom exists for prodrugs of heterocycles such as a fluorouracil (5-FU), 2-5 theophylline (Th), 8 6-mercaptopurine (6-MP), 6,7 and arabinofuranosyladenine, 9,10 ample supporting data can also be found from experiments using prodrugs of lipophilic drugs such as levonorgestrel 11 and indomethacin. 12 In one comparison of variables affecting flux, the axiom holds regardless of the polarity of the vehicle used to deliver the prodrug, 6,7 while in another comparison, the axiom holds regardless of the type of skin that is used in the experimentssmouse 2-8 or human skin.…”

Prodrugs of Theophylline Incorporating Ethyleneoxy Groups in the Promoiety: Synthesis, Characterization, and Transdermal Delivery

“…1. Diffusion through hairless mice skins for a series of theophylline prodrugs (1)(2)(3)(4)(5)8) larger J MMIPM than 16 for those prodrugs containing two ethyleneoxy groups. Previously, the only APAP prodrug containing multiple ethyleneoxy groups in the promoiety that had been evaluated in diffusion cell experiments using IPM as the vehicle was a soft alkyl alkyloxycarbonyloxymethyl-type derivative containing three ethyleneoxy groups (15).…”

“…Theophylline (Th-H) was the first amide/imide for which prodrugs were synthesized and characterized for their ability to enhance the topical delivery of their parent drug from a lipid vehicle isopropyl myristate (IPM) (1,2). A lipid vehicle was chosen because lipids comprise the continuous phase in many topical formulations.…”