946
Wasdo and Sloan
2. A. L. Stinchcomb, A. Paliwal, R. Dua, H. Imoto, R. W. Woodard,
and G. L. Flynn. Permeation of buprenorphine and its 3-alkyl-
ester prodrugs through human skin. Pharm. Res. 13:1519–1523
(1996).
3. K. C. Sung, R.-Y. Han, O. Y. P. Hu, and L.-R. Hsu. Controlled
release of nalbuphine prodrugs from biodegradable polymeric
matrices: influences of prodrug hydrophilicity and polymer com-
position. Int. J. Pharm. 172:17–25 (1998).
4. A. L. Stinchcomb, P. Swaan, O. Ekabo, K. K. Harris, J. Browe, P.
D. Hammell, T. A. Cooperman, and M. Pearsall. Straight-chain
naltrexone ester prodrugs: diffusion and concurrent esterase bio-
transformation in human skin. J. Pharm. Sci. 91:2571–2578
(2002).
5. K. B. Sloan, S. Wasdo, U. Ezike-Mkparu, T. Murray, D. Nickels,
S. Singh, T. Shanks, J. Tovar, K. Ulmer, and R. Waranis. Topical
delivery of 5-fluorouracil and 6-mercaptopurine by their alkyl-
carbonyloxymethyl prodrugs from water: vehicle effects on de-
sign of prodrugs. Pharm. Res. 20:639–645 (2003).
6. L. W. Dittert, H. C. Caldwell, H. J. Adams, G. M. Irwin, and J. V.
Swintosky. Acetaminophen prodrugs I. Synthesis, physicochem-
ical properties and analgesic activity. J. Pharm. Sci. 57:774–780
(1963).
7. W. J. Roberts and K. B. Sloan. Correlation of aqueous and lipid
solubilities with flux for prodrugs of 5-fluorouracil, theophylline
and 6-mercaptopurine: a Potts-Guy approach. J. Pharm. Sci. 88:
515–532 (1999).
8. H. D. Beall, J. J. Getz, and K. B. Sloan. The estimation of relative
water solubility for prodrugs that are unstable in water. Int. J.
Pharm. 93:37–47 (1993).
9. H. D. Beall and K. B. Sloan. Topical delivery of 5-fluorouracil
(5-FU) by 3-alkylcarbonyl-5-FU prodrugs. Int. J. Pharm. 217:127–
137 (2001).
43 coefficients; the 3-alkylcarbonyloxymethyl-5-fluorouracil
(3-ACOM-5-FU) series did as well (19), where the average
error of predicting log JMIPM was ⌬ log JЈMIPM ס
0.19 0.09
log units. In order to update the original database for the
Roberts-Sloan equation and also to see what effect the inclu-
sion of two new series, both of which underperformed, in the
database would have on the calculated performance of the
other series, the members of the 4-AOC-APAP series, the
3-ACOM-5-FU series, (19) and the 3-alkylcarbonyl-5-FU (9)
series (Table V) were added to the original database to give
n ס
61, and new coefficients for the Roberts-Sloan equation
were calculated. The new values for the x, y, and z coefficients
were –0.322, 0.530, and 0.00337, respectively, for the n ס
61
database (Fig. 3). The average error in calculating log JMIPM
(experimental log JMIPM – calculated log JMIPM ס
⌬ log
J
MIPM) was 0.15 0.11 log units for n ס
61, which was some-
what larger than the average ⌬ log JMIPM for the n ס
43
database: 0.13 0.09 log units using the n ס
43 coefficients.
Although the average error in calculating log JMIPM did not
change more than 0.01 log units for most of the series, there
were three series that did change substantially. The average ⌬
log JMIPM for the 1-alkylcarbonyloxymethyl-5-FU series (1-
ACOM-5-FU) worsened from 0.12 to 0.17 log units, whereas
the average ⌬ log JMIPM for the 3-ACOM-5-FU and the
4-AOC-APAP series improved from 0.19 to 0.15 and from
0.27 to 0.24 log units, respectively.
10. K. B. Sloan, S. A. M. Koch, K. G. Siver, and F. P. Flowers. The
use of solubility parameters of drug and vehicle to predict flux. J.
Invest. Dermatol. 87:244–252 (1986).
11. K. B. Sloan, H. D. Beall, W. R. Weimar, and R. Villaneuva. The
effect of receptor phase composition on the permeability of hair-
less mouse skin in diffusion cell experiments. Int. J. Pharm. 73:
97–104 (1991).
12. R. F. Fedors. A method for estimating both the solubility param-
eters and molar volumes of liquids. Polym. Eng. Sci. 14:147–154
(1974).
13. A. Martin, P. L. Wu, and T. Velasquez. Extended Hildebrand
solubility approach: sulfonamides in binary and ternary solvents.
J. Pharm. Sci. 74:277–282 (1985).
14. E. Merck. Zur kenntnis der einwirkung von phosgen bxw
chlorkohlensaure ester auf p-acetylaminophenole und p-
oxyphenylurethane. Chem. Zentralbl. I:468–469 (1897).
15. K. B. Sloan. Prodrugs for dermal delivery. Adv. Drug Del. Rev.
3:67–101 (1989).
16. K. B. Sloan. Functional group considerations in the development
of prodrug approaches to solving topical delivery problems. In K.
B. Sloan (ed.), Prodrugs. Topical and Ocular Drug Delivery, Mar-
cel Dekker, New York, 1992, pp. 17–116.
17. K. B. Sloan and S. Wasdo. Designing for topical delivery: pro-
drugs can make the difference. Med. Res. Rev. 23:763–793 (2003).
18. H. D. Beall, R. J. Prankerd, and K. B. Sloan. Transdermal deliv-
ery of 5-fluorouracil (5-FU) through hairless mouse skin by 1-al-
kyloxycarbonyl-5-FU prodrugs: physicochemical characterization
of prodrugs and correlations with transdermal delivery. Int. J.
Pharm. 111:223–233 (1994).
19. W. J. Roberts and K. B. Sloan. Topical delivery of 5-fluorouracil
(5-FU) by 3-alkylcarbonyloxymethyl-5-FU prodrugs. J. Pharm.
Sci. 92:1028–1036 (2003).
CONCLUSIONS
The delivery of the total acetaminophen (APAP) con-
taining species (JMIPM) by its alkyloxycarbonyl (AOC) de-
rivatives from IPM, although reasonably predicted by the
Roberts-Sloan equation, did not give substantially higher
JMIPM values than by APAP. Again, the more water soluble
members of this more lipophilic series were the most effective
at enhancing delivery of total APAP species through mouse
skin from IPM (15–17). The addition of the 4-AOC-APAP
series data and that of two other series to the database for the
Roberts-Sloan equation and the subsequent fitting of all the
data (n ס
61) to the Roberts-Sloan equation resulted in the
determination of new coefficients for the parameters that are
not substantially different from the previous coefficients, but
do account for the two underperforming series (3-ACOM-5-
FU and 4-AOC-APAP) better. Although these results, which
reinforce the importance of SAQ on predicting flux from a
lipid vehicle, are based on in vitro hairless mouse data, re-
gression analysis of in vivo data for the delivery of nonsteroi-
dal anti-inflammatory drugs from mineral oil through human
skin also showed a significant and substantial dependence on
S
AQ (0.28 vs. 0.47 for hairless mouse skin data) (20). Regard-
less of the difference in degree of hydration between in vitro
and in vivo, and between hairless mouse skin and human skin,
water solubility is an important parameter in predicting flux
from lipid vehicles such as IPM and mineral oil.
20. W. J. Roberts and K. B. Sloan. Application of the transformed
Potts-Guy equation to in vivo human skin data. J. Pharm. Sci.
90:1318–1323 (2001).
REFERENCES
1. J. Drustrup, A. Fullerton, L. Christrup, and H. Bundgaard. Uti- 21. K. B. Sloan, H. B. Beall, H. E. Taylor, J. J. Getz, R. Villaneuva,
lization of prodrugs to enhance the transdermal absorption of
morphine. Int. J. Pharm. 71:105–116 (1991).
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