Abstract. Two different types of derivatives of theophylline (Th-H) incorporating ethyleneoxy groups into the promoiety have been synthesized. One is a soft alkyl type where N-methyl-N-methoxyethyleneoxycarbonylaminomethyl chlorides have been used to alkylate Th-H in the 7 position. The other is in an acyl type where methoxyethyleneoxycarbonyl chlorides have been used to acylate Th-H in the 7 position. All of the prodrugs were more soluble in the lipid isopropyl myristate (IPM) than Th-H, and three were more soluble in water (AQ) than Th-H. The most water-soluble prodrug gave the highest maximum delivery of total species containing Th-H through hairless mouse skin from IPM (maximum flux, J MMIPM )-more than seven times that of Th-H, while the other two gave more than three times that of Th-H. The acyl-type prodrugs delivered only Th-H, while the soft alkyl types delivered 60-70% Th-H plus intact prodrug. The Roberts-Sloan equation was able to predict the best performer for each type with an average of the absolute difference between the experimental logJ MMIPM and calculated logJ MMIPM (ΔlogJ MMIPM ) of 0.253 log units. The values for the present prodrugs and previously reported prodrugs that had not been previously included in the Roberts-Sloan data base (n=23) were included in the previous n=71 data base to give n=94. New coefficients for the Roberts-Sloan equation have been obtained.KEY WORDS: ethyleneoxy groups; lipid solubility; maximum flux; Roberts-Sloan equation; theophylline; water solubility. INTRODUCTIONTheophylline (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. Although 7-alkylcarbonyloxymethyl soft alkyl prodrugs of Th-H (7-ACOM-Th) were the first prodrugs to be made, the performance of the best member of the series was not much better than Th-H itself: two times that of Th-H (1,2). Their relatively poor delivery of their parent Th-H had been attributed to their lack of adequate water solubility, S AQ (3). Although they were 10-100 times more soluble in the lipid vehicle, IPM, the most water-soluble 7-ACOM prodrug, exhibited only 25% of the solubility of Th-H in water. The next most water-soluble member of their series (20% of Th-H) actually delivered the greater amount of total species containing Th-H through hairless mouse skin from their suspensions in IPM: maximum flux, J MMIPM . The slightly less water-soluble member compensated for its slightly lower S AQ by being 10 times more soluble in IPM than the most water-soluble member. Thus, as more series of prodrugs were synthesized, characterized, and evaluated in diffusion cell experiments using an IPM vehicle, it became obvious that the prodrug exhibiting the best balance of lipid and aqueous solubilities gave the highest flux value in the series and not necessarily the member that wa...
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