7-Alkylcarbonyloxymethyl prodrugs of theophylline: topical delivery of theophylline

Five members of an homologous series of 7-n-alkylcarbonyloxymethyl (ACOM) prodrugs (C-1 to C-5, acetyl- to hexanoyloxymethyl) of a potential topical antiproliferative drug, theophylline (Th, 1) have been synthesized, characterized and evaluated for their abilities to deliver Th into and through hairless mouse skin from suspensions in isopropyl myristate (IPM). The synthesis used a tertiary amine quaternary salt of the ACOM chlorides (2) as the alkylating agent to give about twice the percent yields as previously reported. Although all of the members of the 7-ACOM-Th prodrugs (C-1 to C-5, 3a to 3e) were more soluble in LPM than Th (10-200 times), the most water soluble members (C-1 and C-3, acetyl- and butyryloxymethyl) were only about 0.25 times as soluble as Th; C-2 (propionyl-oxymethyl) was only about 0.1 times as soluble. In addition to being almost as water soluble as C-1, C-3 was almost 10 times more lipid soluble than C-1 or C-2. Thus, the C-3 prodrug exhibited the best biphasic solubility properties in the series. In the diffusion cell experiments, the C-3 prodrug was the only member that was significantly (2 times) more effective than Th at delivering total Th species-(J(i)). In addition, all of the prodrugs of the series delivered significant amounts of intact prodrug through the skin (J(p)): J(p)/J(i) for C-1 = 47%, C-2 = 29%, C-3 = 32%, C-4= 7% and C-5 = 1%. None of the prodrugs delivered as much Th into the skin (C-s) as Th itself. Fluxes of Th from propylene glycol (J(j)) subsequent to the initial application of prodrug or Th/LPM were all of a similar magnitude, so that the differences in J(i) were not caused by differences in damage to the skins from the initial applications. 7-Hydroxymethyltheophylline (7-HOCH2-Th, 4) which was as lipid soluble as C-1 and C-2, but 10 times more water soluble than Th gave a J(i) which was 2 times that of Th and a C-s value that was 2 times that of Th. 7-HOCH2-Th was the best prodrug studied for increasing the delivery of Th. (C) 1998 Elsevier Science B.V. All rights reserved.