Bioreversible derivatives of 5-fluorouracil (5FU) : improving dermal and transdermal delivery with prodrugs

176 Pages·1991·3.1 MB·English

by  Beall, Howard D.

BIOREVERSIBLE DERIVATIVES OF 5-FLUOROURACIL (5FU)
IMPROVING DERMAL AND TRANSDERMAL DELIVERY
WITH PRODRUGS
3Y
HOWARD D. BEALL
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1991
Copyright 1991
by
Howard D. Beall
. .
ACKNOWLEDGEMENTS
I would like to thank the members of my supervisory
committee, Dr. Kenneth Sloan, Dr Margaret James, Dr. Koppaka
Rao, Dr. Richard Prankerd, and Dr. John Zoltewicz for their
guidance and expert advice over the past four years. My
sincerest thanks go to my research advisor and committee
chairman, Dr. Sloan, for sharing his enthusiasm for teaching
and science. I am especially grateful for his patience and
understanding during my seemingly endless questions and
interruptions
I would also like to acknowledge the enthusiastic
support of Dr. Noel Meltzer of Hoffmann-La Roche. This
project was partially funded by a grant from Hoffmann-La
Roche
My special thanks go to my parents for their love and
support throughout my life and to my two-year-old son,
Michael, who could make me laugh when it was the last thing I
felt like doing. But most of all, I want to thank my wife,
Donna, whose love, support, and countless sacrifices made my
return to school and the completion of this project possible.
iii
.
TABLE OF CONTENTS
ACKNOWLEDGEMENTS
iii
LIST OF TABLES
vi
LIST OF FIGURES
viii
KEY TO ABBREVIATIONS
ix
ABSTRACT
X
INTRODUCTION
1
Fluorouracil
Fluorouracil Derivatives'.'..., 1
Fluorouracil Metabolism 2
Structure of the Skin 3
Mechanisms of Transdermal Penetration
Passive Diffusion 8f
Enhancement of Skin Penetration U10
Prodrugs and Skin Penetration
Dermal versus Transdermal Delivery }l
Cutaneous Metabolism 16
RTeJs:elalrecSht Pn°roUpSoesaSlkin as a M°dei'Membrane.'.'.' \1l8
20
1-ALKYLOXYCARBONYL DERIVATIVES
Introduction
Materials and Methods'.'.'.'.'. 23
Results and Discussion 25
Summary . . . 35
1-ACYL DERIVATIVES
53
Introduction
Materials and Methods...... 53
Results and Discussion....... 53
Summary... 64
80
1,3-BIS-ACYL DERIVATIVES
82
Introduction
Materials and Methods 82
Results and Discussion. .. 84
Summary . . 93
107
3-ACYL DERIVATIVES 109
Introduction 109
Materials and Methods.. . Ill
Results and Discussion. .120
146
Summary .
SUMMARY AND CONCLUSIONS . . . 148
LIST OF REFERENCES . 153
BIOGRAPHICAL SKETCH . 160
LIST OF TABLES
Table 1-1. Structures of 5FU and prodrug derivatives
of 5FU 21
Table 2-1. Structures of 1-alkyloxycarbonyl
derivatives 24
Table 2-2. Melting points (MP), lipid solubilities
(Sipm) i and aqueous solubilities (Saq) for
1-alkyloxycarbonyl derivatives 39
Table 2-3. Solubility ratios (SR) partition
cfooreff1i-caileknytlsoxy(cPCa)rb,onaynld hdeyrdirvoapthio,vbeiscity parameters (71) 40
Table 2-4. Pseudo-first-order rate constants (k) and
half-lives (ti/2> for hydrolysis of 1-methyloxy-
carbonyl-5FU in 0.05 M phosphate buffer (pH=7.1,
1=0.12) with and without formaldehyde at 32 CC 44
Table 2-5. Fluxes (J), lag times (tjj and skin
,
accumulation (SA) values for 1-alkyloxycarbonyl
derivatives 48
Table 2-6. Second application fluxes (J) and lag times
(tL> for 1-alkyloxycarbonyl derivatives 49
Table 3-1. Structures of 1-acyl derivatives 54
Table 3-2. Melting points (MP), lipid solubilities
(Sipm) , and aqueous solubilities (Saq) for 1-acyl
derivatives 68
Table 3-3. Partition coefficients (PC) and hydropho-
bicity parameters (7C) for 1-acyl derivatives 69
Table 3-4 Pseudo-first-order rate constants (k) and
half-li.ves (ti/2) for hydrolysis of 1-acyl derivatives
in 0.05 M phosphate buffer (pH-7.1, 1=0.12) at 32 °C 71
. . . .
Table 3-5. Pseudo-first-order rate constants (k) and
half-lives (ti/2) for hydrolysis of l-acetyl-5F0 in
0.05 M phosphate buffer (pH=7.1, 1=0.12) with and
without formaldehyde at 32 °C 72
vi
Table 3-6. Fluxes (J), lag times (tj,) , and skin
accumulation (SA) values for 1-acyl derivatives 77
Table 3-7. Second application fluxes (J) and lag times
(ti,) for 1-acyl derivatives 78
Table 4-1. Structures of 1,3-bis-acyl derivatives 83
Table 4-2. Melting points (MP), lipid solubilities
(Sipm) i an<i aqueous solubilities (Saq) for 1,3-bis-
acyl derivatives 98
Table 4-3. Pseudo-first-order rate constants (k) and
half-lives (ti/2) for hydrolysis of 1,3-bis-acetyl-5FU
in 0.05 M phosphate buffer (pH=7.1, 1=0.12) with and
without formaldehyde at 32 °C 100
Table 4-4. Fluxes (J), lag times (ti,) , and skin
accumulation (SA) values for 1,3-bis-acyl
derivatives 104
Table 4-5. Second application fluxes (J) and lag times
(tL> for 1,3-bis-acyl derivatives 105
Table 5-1 Structures of 3-acyl derivatives 110
.
Table 5-2. Melting points (MP), lipid solubilities
(Sipm) / and aqueous solubilities (Saq) for 3-acyl
derivatives 127
Table 5-3. Solubility ratios (SR) partition
coefficients (PC) , and hydropho,bicity parameters (JC)
for 3-acyl derivatives 128
Table 5-4 Pseudo-first-order rate constants (k) and
.
half-lives (ti/2) for hydrolysis of 3-acyl derivatives
in 0.05 M phosphate buffer (pH=7.1, 1=0.12) with and
without formaldehyde at 32 °C 134
Table 5-5. Reaction products formed during hydrolysis of
3-acetyl-5FU in 0.05 M phosphate buffer (pH=7.1,
1=0.12) with formaldehyde at 32 °C 135
Table 5-6. Fluxes (J), lag times (ti,) , and skin
accumulation (SA) values for 3-acyl derivatives 142
Table 5-7. Second application fluxes (J) and lag times
(tL) for 3-acyl derivatives 143
vii
J
LIST OF FIGURES
Figure 2-1. Plots of ln(C) versus time (rain) for
hydrolysis of l-methyloxycarbonyl-5FU in 0.05 M
phosphate buffer (pH=7.1, 1=0.12) with and without
formaldehyde at 32 °C 4
Figure 2-2. Plots of cumulative amount of total 5FU
species that diffused (Jlmol) versus time (h) for
compounds 1, 2, 3, and 5FU 46
Figure 2-3. Plots of cumulative amount of total 5FU
species that diffused (Jlraol) versus time (h) for
compounds 4, 5, 6, and 5FU 47
Figure 3-1. X-ray structure of l-acetyl-5FU (unprimed) . ... 66
Figure 3-2. X-ray structure of l-acetyl-5FU (primed) 67
Figure 3-3. Plot of pseudo-first-order rate constant (k)
versus formaldehyde concentration (M) for hydrolysis
of l-acetyl-5FU in 0.05 M phosphate buffer (pH-7.1,
73
1=0.12) at 32 °C
Figure 3-4. Plots of cumulative amount of total 5FU
species that diffused (Hmol) versus time (h) for
compounds 7, 8, 9, and 5FU 75
Figure 3-5. Plots of cumulative amount of total 5FU
species that diffused (|imol) versus time (h) for
compounds 10, 11, 12, and 5FU 76
Figure 4-1. X-ray structure of 1,3-bis-acetyl-5FU 95
Figure 4-2. Plots of ln(At-A<„) versus time (min) for
hydrolysis of 1,3-bis-acetyl-5FU in 0.05 M phosphate
buffer (pH=7.1, 1=0.12) with and without formaldehyde "
at 32 °C
Figure 4-3. Plots of cumulative amount of total 5FU
species that diffused (timol) versus time (h) for
compounds 13, 14, and 5FU 102
Figure 4-4. Plots of cumulative amount of total 5FU
species that diffused (nmol) versus time (h) for
compounds 15, 16, and 5FU 103
Figure 5-1. Possible scheme for thermal decomposition of
3-acetyl-5FU 123
Figure 5-2. Possible scheme for thermal intramolecular
rearrangement for 3-acetyl-5FU to l-acetyl-5FU 124
Figure 5-3. Plot of In(At-A«>) versus time (min) for
hydrolysis of 3-acetyl-5FU in 0.05 M phosphate buffer
(pH-7.1, 1=0.12) at 32 °C 130
Figure 5-4. Plot of ln(At-A°°) versus time (min) for
hydrolysis of 3-propionyl-5FU in 0.05 M phosphate
buffer (pH-7.1, 1=0.12) at 32 °C 131
Figure 5-5. Plots of ln(C) versus time (min) for
hydrolysis of 3-acetyl-5FU in 0.05 M phosphate buffer
(pH=7.1, 1=0.12) with (n=2) and without (n=3)
formaldehyde at 32 °C 132
Figure 5-6. Plots of ln(C) versus time (min) for
hydrolysis of 3-acetyl-5FU in 0.05 M phosphate buffer
(pH=7.1, 1=0.12) at 32 °C using actual concentration
(Ct) and concentration corrected for secondary
degradation (Ccorr) 133
Figure 5-7. Possible scheme for reaction of 3-acetyl-5FU
with formaldehyde to form l-acetyloxymethyl-5FU and
3-acetyloxymethyl-5FO 136
Figure 5-8. Plots of cumulative amount of total 5FU
species that diffused (Hmol) versus time (h) for
compounds 17, 18, and 5FU 140
Figure 5-9. Plots of cumulative amount of total 5FU
species that diffused (|lmol) versus time (h) for
compounds 19, 20, and 5FU 141
KEY TO ABBREVIATIONS
bs broad singlet
CDCI3 chloroform-d
(CD3>2SO dimethylsulfoxide-d6
CH3CN acetonitrile
d doublet
dec decomposition
dist t distorted triplet
m multiplet
q quartet
Rf retention factor
t triplet