Application to Functional Groups

There are four functional groups found in drug molecules for which the greatest number of promoieties have been designed, synthesized, characterized (solubility, stability, purity), and evaluated in diffusion cell experiments. These four functional groups are the amide or imide (O = C-NH), the thioamide (S = C-NH), the hydroxy group (OH) substituted on aliphatic or aromatic carbons, and the carboxylic acid (O = C-OH) mentioned above. For each functional group there are two general types of promoieties possible; these are the acyl and soft alkyl types also mentioned above and described in detail elsewhere (Sloan, 1989, 1992, Sloan and Wasdo, 2003). Since a recent review of various combinations of functional group and promoiety is available, we will limit our discussion to those prodrugs that have played a role in developing general synthetic approaches to modifying the physicochemical properties of the parent drug or that contribute to databases (Table 1) from which models for topical permeation have been derived that form the basis for the design of better prodrugs.

Parent drugs that contain an amide- or imide-like functional group provide good opportunities for a prodrug approach to significantly change their physico-chemical properties by masking the polarized N-H group. These types of parent drugs are generally characterized as exhibiting high melting points and poor lipid and aqueous solubilities. Thus, masking the polarized N-H group by replacing the H with a non-polarized promoiety can dramatically increase the lipid and aqueous solubilities and, hence, potentially increase the topical delivery of the parent drug.

Alkylcarbonyloxymethyl (ACOM)

The first report of the use of ACOM prodrugs to enhance the topical delivery of a parent drug containing an amide- or imide-like functional group was for 7-ACOM derivatives to deliver theophylline (Th) (Bodor and Sloan, 1977). The evaluation of only two members of the complete series (3 and 6) was reported initially (Sloan and Bodor, 1982). The characterization and evaluation of the complete series (1 to 6) was reported later (Table 1) (Kerr et al., 1998). The results were typical of what has been observed for most other ACOM derivatives of heterocyclic parent drugs containing amide- or imide-like functional group. All of the prodrugs were much more lipid soluble (increased SIPM) than Th, varying from 8 times for 1 to 75 times for 3 to 230 times for 5. Although in many series at least one member was more soluble in pH 4.0 buffer (increased S4.0) than the parent, in this series the best S4.0 values were 0.27 and 0.22 times that of Th for 1 and 3, respectively. The trend in solubilities followed the trend in melting points (mp): 2 exhibited a higher than expected mp and lower than expected SIPM and S4.0. 3, which exhibited almost the same S4.0 value as 1 (and over twice the S4.0 values of the other members) and a SIPM value 9 times that of 1, gave the best flux value from IPM as would be predicted (Sloan, 1989, 1992); 3 exhibited the best balance of S40 and SIPM. 4 and 5, which exhibited the greatest SIPM values, did not give the greatest fluxes. The percent of intact prodrug measured in the receptor phases from the diffusion cell experiments varied from 47% for 1 to 7% for 4 and 2% for 5 (data not shown). This result was also typical for ACOM derivatives. The longer chain members of the series underwent more complete conversion to the parent drug even if the total amount permeated was about the same as in 1 versus 4.

The initial report of 7-ACOM-Th derivatives (Sloan and Bodor, 1982) also described the synthesis of ACOM derivatives that contained other types of functional groups substituted on or into the alkyl chain that were designed to further enhance topical delivery or enhance stability. Examples in which a dialky-lamino group or a dialkylaminocarbonyl group were substituted on the alkyl chain were described. Both substituents were designed to increase both lipid and aqueous solubility, but were never evaluated in diffusion cell experiments. Another example where an oxygen was substituted into the alkyl chain to give an alkyloxycarbonyoxymethyl derivative (AOCOM) was described, but was never evaluated. Because the ACOM derivatives of the O = C-NH functional group are not always effective at delivering the parent drug through skin, evaluation of an even more stable carbonate analogue (AOCOM) is probably not warranted unless transdermal sustained systemic delivery is desired.

The second report of the use of ACOM type promoieties to deliver a parent drug containing an amide- or imide-like functional group topically was for 1-ACOM to deliver 5-FU (Mollgaard et al., 1982). Again, only two members (9 and 14) were evaluated initially, and propylene glycol (PG) was used as vehicle instead of IPM. The characterization and evaluation of the complete series (7 to 14) was published later (Table 1) (Taylor and Sloan, 1998). Although all of the prodrugs were more lipid soluble than 5-FU, because 5-FU was much less lipid soluble than Th (0.14 times SIPM) the increases in SIPM values were relatively much greater for the ACOM derivatives of 5-FU than for Th, especially for the first few members of the series: 70-, 200- and 300 times that of 5-FU for 7, 8 and 9, respectively. However, among these, only the C2 member 8 was substantially more lipid soluble than the corresponding C2 member 2 of the 7-ACOM-Th. On the other hand, the aqueous solubility (S40) of 5-FU was about twice that of Th and the C1 (7) and C2 (8) members were 2.4 and 1.8 times, respectively, more soluble in water than 5-FU. So the 1-ACOM-5-FU members were much more water soluble than the corresponding 7-ACOM-Th derivatives: 16 times for 7, 30 times for 8, and 5 times for 9 compared to 1, 2 and 3, respectively. The balance between increased S4.0and SIPM values was better for the 5-FU ACOM derivatives. The result was that the flux values for the 5-FU derivatives from IPM were also greater than those for the Th derivatives: 5 times for 7, 12 times for 8, and 2.5 times for 9 compared to 1, 2 and 3, respectively. Within the 1-ACOM-5-FU series, 8 exhibited the best balance between S4.0 and SIPM values (1.8 times greater S4.0 and 200 times greater SIPM than 5-FU) and, hence, exhibited the greatest increase in flux values compared to 5 FU, as would be predicted (Sloan, 1989, 1992), 16 times. The percent of intact prodrug measured in the receptor phase from diffusion cell experiments varied from 55% for C1 (7), 50% for C2 (8), and 29% for C4 (10) to 12% for C7 (12). Thus, the most effective prodrugs were delivering only about 50% of the parent drug.

The 3-ACOM-5-FU prodrugs (15 to 20) were designed (Roberts and Sloan, 2003) not only to be more soluble in lipids and water than 5-FU but also to deliver more 5-FU topically than the 1-ACOM prodrugs; this was based on reports that the C1 member of the 3-ACOM series, 15, was 5 times more labile enzymatically than the corresponding 1-ACOM member, 7. Complete characterization of the members of the 3-ACOM series (Table 1) found that they were also more lipid soluble and water soluble than the members of the 1-ACOM series except for the C1 member (15 versus 7). Based on those solubilities, the results that the C1 member of the 3-ACOM series gave a much lower flux value from IPM than did the C1 member of the 1-ACOM series and that the C3 to C7 members of the 3-ACOM series gave higher flux values than the corresponding member of the 1-ACOM series were expected (Sloan, 1989, 1992). However, the result that the C2 member of the 3-ACOM series (16), which was more soluble in lipid and water than the C2 member of the 1-ACOM series (8), gave only 0.60 times the flux of 8 was unexpected and could not be explained. It could have been argued that 16 also exhibited the best balance of lipid and aqueous solubilities in the 3-ACOM series, yet 17, which was almost twice as soluble in IPM as 16 but only 0.50 times as soluble in water, gave the greatest flux value for the series. As expected, the 3-ACOM series was more effective at delivering more parent drug (5-FU) than the 1-ACOM series. Intact prodrug varied from 20% for C1 (15), 31% for C2 (16), 22% for C3 (17) and about 6% for 18 through 20. Thus, the 3-ACOM-5-FU series, except for 16, behaved as expected based on their measured solubilities and reported hydrolyses.

Since Th itself is 7 times more soluble in IPM and only half as soluble in water as 5-FU, Th gave about twice the flux as 5-FU from IPM. On the other hand, although SIPM values for the 7-ACOM-Th prodrugs were comparable to those of the corresponding ACOM-5-FU prodrugs, their S4.0 values were much lower. The balance between SIPM and S40, which was better for Th, was worse for its ACOM prodrugs compared to those for 5-FU. Thus, it would be predicted (Sloan, 1989, 1992) that not only would the increase in flux for the 7-ACOM-Th derivatives compared to Th be less than the increase in flux for the ACOM-5-FU derivatives compared to 5-FU, but the absolute values for the 7-ACOM-Th derivatives would be much less than for the ACOM-5-FU derivatives; their absolute S4.0 values were less.

Dialkylaminomethyl (AAM)

The dialkylaminomethyl (AAM) or N-Mannich base derivatives represent another type of soft alkyl derivative which is complementary to the ACOM derivatives. While the ACOM derivatives generally undergo enzymatic hydrolysis to the parent drug, the AAM derivatives are chemically labile; the mechanism for their hydrolysis is described in detail elsewhere (Sloan, 1992). Generally, the AAM derivatives are more soluble in lipids than the parent drug because the promoiety masks the highly polarized O = C-NH group. The facile chemical hydrolysis of the AAM derivatives precludes a realistic, accurate measurement of their aqueous solubilities. However, aqueous solubilities for some N-Mannich bases have been reported under acidic conditions where they are more stable (Johansen and Bundgaard, 1980). Based on those results, which show that the N-Mannich bases are much more soluble in water than the parent amide or imide, it was anticipated that the AAM derivatives would also generally be more soluble in water at physiological pH. Although N-Mannich bases have the potential to increase both aqueous and lipid solubility and hence flux (especially from a nonprotic vehicle such as IPM in which they would be stable), they are not sufficiently stable (even in IPM) to give a reasonable shelf-life and, upon hydrolysis, they liberate a secondary amine that may be irritating to the skin. Thus, their commercial use may be limited to applications where the functional group to be masked is a higher pKa amide for which the promoiety would be more stable and where the secondary amine is a proline derivative which, as an amino acid, should be less toxic.

N-Mannich base derivatives of Th (Sloan et al., 1984, 1988), 5-FU (Sloan et al., 1984, 1988), 6-MP (Siver and Sloan, 1988), 5-fluorocytosine (Koch and Sloan, 1987a) and 5 iodocytidine (Koch and Sloan, 1987b) have been synthesized, characterized and evaluated in diffusion cell experiments. In all examples, the derivatives exhibited higher solubility in IPM than did the parent drugs, as expected, and enhanced delivery of the parent drug through hairless mouse skin from suspensions in IPM. Data for Th and 6-MP, which are typical, are given in Table 2. It is interesting that the most effective N-Mannich base derivatives of Th (22 and 23) were over 300 to 1000 times more soluble in IPM than Th and up to

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