7-ALKYLCARBONYLOXYMETHYL PRODRUGS OF THEOPHYLLINE - TOPICAL DELIVERY OF THEOPHYLLINE

Five members of an homologous series of 7-n-alkylcarbonyloxymethyl (AC OM) prodrugs (C-1 to C-5, acetyl- to hexanoyloxymethyl) of a potential topical antiproliferative drug, theophylline (Th, 1) have been synthe sized, characterized and evaluated for their abilities to deliver Th i nto and through hairless mouse skin from suspensions in isopropyl myri state (IPM). The synthesis used a tertiary amine quaternary salt of th e ACOM chlorides (2) as the alkylating agent to give about twice the p ercent yields as previously reported. Although all of the members of t he 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, a cetyl- 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 ti mes more lipid soluble than C-1 or C-2. Thus, the C-3 prodrug exhibite d the best biphasic solubility properties in the series. In the diffus ion cell experiments, the C-3 prodrug was the only member that was sig nificantly (2 times) more effective than Th at delivering total Th spe cies-(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. Fl uxes of Th from propylene glycol (J(j)) subsequent to the initial appl ication 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 th e 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 m ore 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 prod rug studied for increasing the delivery of Th. (C) 1998 Elsevier Scien ce B.V. All rights reserved.