Escolar Documentos
Profissional Documentos
Cultura Documentos
Delivery Systems
A symposiu
the Division of Medicinal
Chemistry at the 168th
Meeting of the American
Chemical Society,
Atlantic City, N . J . ,
September 10, 1974.
ACS S Y M P O S I U M SERIES
14
Library of Congress
Data
V . Title.
615'.7
ISBN 0-8412-0291-5
75-11721
ACSMC8 14 1-245
Copyright 1975
American Chemical Society
All Rights Reserved
PRINTED I N T H E U N I T E D STATES O F AMERICA
FOREWORD
The ACS SYMPOSIU
PREFACE
'his volume contains the papers presented during the Symposium on
Pro-drugs held at Atlantic City, September 10,1974 under the sponsorship of the Division of Medicinal Chemistry. No serious effort was made
in organizing the program to provide a comprehensive treatment of the
subject matter. Rather it was hoped that the material presented would
stimulate greater interest in this chemical approach to the problem of
drug delivery.
A short review of the subject sets forth some of the basic underlying
concepts and approaches
array of antibiotics are then discussed. The remainder of the volume
details chemical and biological studies on pro-drug candidates developed
in our own laboratories.
We apologize for the limited coverage of the subject matter contained in this book. This was caused more by necessity than by choice.
At the time the program was formulated we were forced to depend
largely on projects completed or being carried out in our several facilities
or in those of our collaborators. This was in large part due to the sensitive
nature of pro-drug research programs in established drug houses and
their reluctance to publicize their early efforts in the field. In any case,
the examples have been selected to illustrate the real utility of this
approach.
I would like to take this opportunity to thank all those who took
part in the program and Naida Jimenez and her able secretarial assistants
for their help in preparing the manuscript.
A
University of Kansas
TAKERU HIGUCHI
Lawrence, Kans.
March 11, 1975
ix
1
Pro-drugs: An Overview and Definition
V. STELLA
University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, Kans. 66044
(I)
(II)
formaldehyde and salicylic acid respectively. Use of
salicylic acid as an analgesic and anti-inflammatory
agent was somewhat limited by its corrosiveness which
was in part overcome with the use of II. Formaldehyde, although a useful topical antiseptic, could not
be used orally as a urinary tract antiseptic until i t
was converted to I and formulated in an enteric coated
tablet.
The chemical modification of drugs to overcome
pharmaceutical problems has also been termed "drug
1
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
PRO-DRUGS
1.
STELLA
DRUG
A
TEMPORARY
TRANSPORT
MOIETY
C
LINKAGE
CHI)
ff
!!
PRO-DRUGS
DRUG
DOSAGE
FORM
41
Scheme I
TISSUE
COMPARTMENT
21
w
13
"31
FAT DEPOT
OR "DEEP"
COMPARTMENT
CENTRAL
COMPARTMENT
l4
kV
ELIMINATION
PRODUCT
2 - ^ e x c r e t i o n ^metabolism
other
f = f r a c t i o n of dose absorbed
TARGET
ORGAN
a.
PRO-DRUGS
PARENT
DRUG
PRO-DRUG
PRO-DRUG METABOLITE
(Inactive)
DRUG METABOLITE
(Inactive)
Scheme I I
1.
STELLA
PRO-DRUGS
LACK OP SITE
SPECIFICITY
TOXICITY IF
ABSORBED AS
SUCH
FORMULATION
PROBLEMS, E.G.,
LIQUID-TABLET
FORMULATION
DESIRED
METABOLIZED AT
ABSORPTION SITE
WATER INSOLUBLE
NOT ABSORBED NOT CAPABLE OF
DIRECT IV
INJECTION
ABSORBED TOO
QUICKLY SUSTAINED RELEASE
DESIRED
Figure 1
1.
STELLA
10
PRO-DRUGS
HO
(IV)
s u f f e r i n g from Parkinson's disease. I t has been
stated that dopamine i t s e l f cannot be used because i t
i s incapable of bein absorbed
th BBB
fact
primarily attribute
h i g h l y i o n i z e d s t a t e at p h y s i o l o g i c a l pH. A precursor
or a pro-drug of dopamine, L-Dopa (V) or L-3,4-dihydroxyphenylalanine, has repeatedly been found to be
e f f e c t i v e i n the treatment of Parkinson's disease
(41-50). L-Dopa i s absorbed from the GI t r a c t and
DOPA DECARBOXYLASE
DOPAMINE
i n t o the CNS through the a c t i v e transport mechanism
f o r amino acids (51-52). I n the CNS, Dopa decarboxylase can convert L-Dopa to the d e s i r e d dopamine. I t
has been assumed that the poor absorption of dopamine
i s due t o i t s p o l a r i t y and h i g h l y i o n i z e d s t a t e . However, r a p i d enzymatic metabolism of c a t e c h o l molecules
v i a conjugation mechanisms such as s u l f a t i o n , g l u c u r o n i d a t i o n and O-methylation c o n t r i b u t e h e a v i l y t o
the r a p i d l o s s of dopamine i f dopamine i s administered
o r a l l y , i . e . , dopamine given o r a l l y probably never
reaches the BBB. Even w i t h L-Dopa, approximately only
20% of an o r a l l y administered dose reaches general
c i r c u l a t i o n as L-Dopa since i t can be r a p i d l y conjugated, decarboxylated, O-methylated and o x i d i z e d i n
the GI t r a c t and mucosa (53-60). The degree of t h i s
so c a l l e d " f i r s t pass" e f f e c t i n any given i n d i v i d u a l
1.
STELLA
11
(VI):
R = a l k y l substituent
a n d
a r e
(00)
Scheme I I I
m i
12
PRO-DRUGS
^^^
* *******
^| *mmimmmfi\ OH
Scheme IV
branes, then the percentage of t o t a l drug present at
p h y s i o l o g i c a l pH of 7
(00) w i l l b
functio
f
the various microscopi
cussion of the i n t e r r e l a t i o n s h i p s of the microscopic
and macroscopic constants see references 6 2 - 6 6 ) . The
f o l l o w i n g drugs were subjected to a n a l y s i s of 35(00.)
present at p h y s i o l o g i c a l pH; tyramine ( V I I ) , t y r o s i n e
e t h y l e s t e r ( V I I I ) , epinephrine ( I X ) , dopamine ( I V ) ,
and morphine ( X ) . An estimate of , pK2, pk]_, and
pk2 f o r a t y p i c a l L-Dopa e s t e r (VI) was made and ap
proximate $(00) c a l c u l a t e d at p h y s i o l o g i c a l pH. Table
I gives the pK]_, pK2, pk]_, pk2, R(where R i s the r a
t i o (+-)/(00) and equals k]_/k2) and $(00) at physio
l o g i c a l pH f o r these compounds. As i s r e a d i l y appar
ent from t h i s t a b l e l i t t l e passive absorption from the
(VII)
(VIII)
(X)
1.
STELLA
13
Table I
Compound
pK
PK
8.87
IV
10.63
pk
8.90
pk
10.06
7.21
9.44
VII
9.61
10.65
VIII
7.33
9.80
9.42
7.33
IX
8.66
8.31
9.51
8.87
8.45
8.76*
9.70
7.22
10.32
0.21
15
VI
$(00)
0.03
*
60.2
4.2
0.008
0.12
53.1
0.38
7.98
14
PRO-DRUGS
CH C0
o
(XIII)
of C r e v e l i n g et a l . ( 9 , 7 0 ) who had shown that 3 , 4 ,
-triacetyl (XIIT, and 3 , 4 , 3 - t r i ( t r i m e t h y l s i l y l )
(XIV) d e r i v a t i v e s of norepinephrine caused prolonged
release of the parent catecholamine i n mice b r a i n s .
However, as pointed out by C r e v e l i n g et_ a l . ( 6 9 , 7 0 )
even though both X I I I and XIV r e a d i l y entered the CNS,
the d e r i v a t i v e s survived as noncatechol e n t i t i e s f o r
long periods i n the b r a i n . For example, when H 3
tagged X I I I was given I.V. to mice approximately 20$
of t o t a l b r a i n r a d i o a c t i v i t y could be a t t r i b u t e d to
catechol species while the remaining 80$ was noncatechol s p e c i e s . In the hearts of the same animals the
reverse was the case, i . e . , the d e r i v a t i v e appeared to
be q u i c k l y converted to c a t e c h o l species. This tends
to suggest that enzymatic regeneration of the n o r e p i nephrine from X I I I may not be f a c i l e i n the CNS.
Borgman et a l . (Jl)
have r e c e n t l y synthesized a s e r i e s
of 0 , 0 - d i a c e t y l d e r i v a t i v e s of v a r i o u s dopaminergic
catecholamines i n c l u d i n g dopamine. The i n a b i l i t y of
XI to antagonize oxotremorine-induced tremor i n mice
( 7 1 ) , reserpine-induced depression ( 7 1 ) or to cause
hypothermia ( 7 1 ) i n mice suggests that P i n d e r s proposal that XI should penetrate the CNS may be e r r o neous.
The use of I.V. dopamine i n the treatment of
shock ( 7 2 , 7 3 ) suggests that dopamine pro-drugs such as
XI and other 0 , 0 - d i a c y l ( 1 1 , 7 4 ) and amino a c i d amides
d e r i v a t i v e s of dopamine (75.) might provide u s e f u l ,
f
1.
STELLA
15
CH 3
(XV)
Water soluble v i t a m i n s . Many of the water s o l u
ble vitamins such as thiamine (vitamin , XVI),
r i b o f l a v i n (vitamin B 2 , XVII) and p y r i d o x i n e (vitamin
B6, XVIII) are h i g h l y polar and a c t i v e l y absorbed
agents.
Thiamine, being a water soluble compound w i t h a
quaternary n i t r o g e n , i s poorly absorbed i n t o the CNS
(83) and poorly absorbed from the GI t r a c t ( 8 4 - 8 7 ) .
Thiamine passes through these b a r r i e r s because both
i n CNS and o r a l a b s o r p t i o n , i t i s a c t i v e l y absorbed.
However, a c t i v e absorption processes are saturable
and/or e a s i l y i n h i b i t e d . I n h i b i t i o n of the o r a l ab
s o r p t i o n of thiamine by chronic a l c o h o l consumption
has been i m p l i c a t e d i n Wernicke's encephalopathy ( 8 8 )
and i n h i b i t e d CNS absorption of thiamine has been im
p l i c a t e d i n the Leigh's disease (89.,0) Thomson
16
PRO-DRUGS
0
(XVII)
et a l . (88) have shown that chronic a l c o h o l consumpt i o n and long d i e t a r y d e f i c i e n c y may reduce the i n t e s t i n a l absorption of thiamine. Thiamine undergoes
a r a t h e r unusual second i o n i z a t i o n (Scheme V) t o a
t h i o l a t e i o n (XIX), i n v o l v i n g the consumption of two
moles of hydroxide i o n f o r each mole of thiamine.
D e r i v a t i z a t i o n of XIX leads t o many l i p i d s o l u b l e prodrugs o f (a) the d i s u l f i d e type, such as thiamine prop y l d i s u l f i d e (TPD, XX), thiamine t e t r a f u r f u r y l d i s u l f i d e (TTPD, XXI) and 0,0 -dibenzoylthiamine d i s u l f i d e
( X X I I ) ; (b) d i a c y l type, such as 0,S-diacetylthiamine
(DAT, X X I I I ) ; and (c) 0,S- and S-carbonate e s t e r s of
thiamine, such as 0,S-diethoxycarbonylthiamine (DECT,
XXIV). These and many other d e r i v a t i v e s have been
synthesized i n Japan since the e a r l y 1950 s (91) The
synthesis of these d e r i v a t i v e s was not n e c e s s a r i l y
aimed at p r e f e r e n t i a l GI or CNS absorption of thiamine
but was geared mainly t o the p o s s i b l e use of these
l i p i d s o l u b l e thiamine d e r i v a t i v e s as s t a b l e food add i t i v e s . The p o l i s h i n g of r i c e had l e d t o some t h i a mine d e f i c i e n c y i n Japan. Thiamine i t s e l f could not
be used as a food a d d i t i v e f o r r i c e because i t i s too
water s o l u b l e , thus e a s i l y washed from r i c e . I t i s
a l s o chemically unstable (92) and very poorly absorbed.
f
1.
STELLA
17
(XIX)
Scheme V
Compounds l i k e (XX-XXIV) and t h e i r homologues do
not possess a quaternized n i t r o g e n so a l l o w i n g them to
be p a s s i v e l y absorbed from the GI t r a c t . Each are
q u a n t i t a t i v e l y converted t o thiamine once i n the body
(93).
XXIII and XXIV and t h e i r homologues are converted t o thiamine by t h i o e s t e r a s e s and esterases
(93).
The d i s u l f i d e compounds (XX-XXII) and t h e i r
homologues are converted to thiamine by a d i s u l f i d e
exchange mechanism i m p l i c a t i n g g l u t a t h i o n e and g l u t a thione reductase ( 9 4 - 9 7 ) . Grode et a l . (9.8) r e c e n t l y
speculated that d i s u l f i d e thiamine pro-drugs might be
s u s c e p t i b l e to i n t e r a c t i o n with serum p r o t e i n s v i a a
d i s u l f i d e exchange r e a c t i o n and p r e c i p i t a t e antibody
formation. Their r e s u l t s show that long term dosing
of XXI i n r a b b i t s d i d not e l i c i t antibody formation.
Thomson et a l . (8J3) have presented some e x c e l l e n t
data on thiamine blood and CNS l e v e l s i n Wernicke's
encephalopathy as w e l l as lowered blood and CNS l e v e l s
of thiamine i n a l c o h o l i c s having symptoms s i m i l a r to
but not n e c e s s a r i l y s u f f e r i n g from Wernicke's disease.
Their r e s u l t s show that XX on s i n g l e o r a l dosing r e s u l t e d i n increased, and i n some cases normal, red
blood c e l l (RBC) t r a n s k e t o l a s e a c t i v i t y i n a l c o h o l i c ,
thiamine d e f i c i e n t p a t i e n t s while thiamine i t s e l f had
CH
^NH
C-CH CH OH
S-SR
2
(XX) : R
C H
3
(XXI) : R = -CH 2
J3H
CH-
I
CH
NH $
C-CH CH 0CR
o
0
(XXIII) : R = -CH.
(XXIV) : R = -OC H
2
C H
^ ^
^CH.
CH ^N3
CH
CH
I
I
N,
0
II
C-CH CH 0C
I
S
0
i
C-CH CH oB
2~ 2
:
2 o
CH.
CK
(XXII)
1.
STELLA
19
* 24
TIME (hours)
Annals of Internal Medicine
mission
showing
thiamine
dose of
20
PRO-DRUGS
46 2 4
TIME (HOURS)
9
Figure 3. Comparison of clinical and laboratory abnormalities response to 50 mg of thiamine hydrochloride followed
by XX in thiamine deficient ahoholics (88)
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
1.
STELLA
21
Blood
13
0 13
0 13
TIME (hours)
Vitamins (Kyoto)
22
PRO-DRUGS
1.
STELLA
23
(XXV): R = -H
(XXVI): R = - C O C H 3
(XXVII): R = -COC^H
24
PRO-DRUGS
(142).
Welch (134) ha
o r a l l y every 8 hours and
s completely absorbed. O
o r a l dosing, XXVI i s excreted 80$ as XXV and 11% as i t s
5 - a c e t y l d e r i v a t i v e w i t h only traces of XXVI excreted.
O r a l l y administered XXVI caused the same c l i n i c a l e f f e c t s as a molar equivalent dose of XXV given I.V.
The poor o r a l b i o a v a i l a b i l i t y of the n u c l e o s i d e ,
p s i c o f u r a n i n e , (XXVIII), has been a t t r i b u t e d to the
b a s i c i t y of i t s 6-amino group, and i t s n o n l i p o p h i l i c
character (143). Various acetate esters of XXVIII were
prepared i n c l u d i n g t h ^ t e t r a a c e t a t e e s t e r (XXIX).
Oral
CD50 studies with S. hemolyticus i n f e c t e d mice showed
XXIX to be twice as e f f e c t i v e as the parent compound
XXVIII. Figure 5 gives human serum l e v e l s of XXVIII as
f
OR
OR
(XXVIII) :
(XXIX) :
R = -H
R = -COCH
1.
STELLA
25
>
J. -L
12
3 4 5
TIME (hours)
26
PRO-DRUGS
NHR-
?
(XXX):
(XXXI):
(XXXII):
(XXXIII):
R
R
R
R
OR
1
= R = -COC H
=~COC H , R2 = -H
= -COC^H^, R = -H
3
1.
STELLA
27
CH.
CH
"(CH )
Ik
(XXXIV)
CH
CH_
I
( C H2'5) - N
Br ( C H ) - N
0
( C H ^ Br
56
(XXXV)
CH,
CH,
(CH )
2
16.8
(XXVI)
CH
CH.
I 3,
I 3
C I ( CH ) ^ - N ( CH ) N ( CH ) - C l
0
21
(XXXVII)
28
PRO-DRUGS
CH
(XXXIX)
CH
(XXXVIII)
1.
STELLA
29
(XL)
(XLI)
Scheme VI
Scheme VI was the general r e a c t i o n studied. The dura
t i o n and i n t e n s i t y of l o c a l anesthesia using i n vivo
and i n v i t r o t e s t s , f o r both XL and XLI, were studied.
Chemical studies of the e f f e c t of and -x on the con
v e r s i o n of XL t o XLI and the l o c a l anesthetic a c t i v i t y
of both the t e r t i a r y analog i t s e l f and the formed qua
ternary compound suggested that the formed quaternary
compounds c o n t r i b u t e t o the d u r a t i o n of the anesthesia
(155*157). The l o c a l anesthetic e f f e c t s of XL and XLI
on the s c i a t i c nerve of guinea p i g s , i n v i v o , and
f r o g , i n v i t r o , showed that sustained l o c a l anesthetic
a c t i v i t y occurred f o r compounds where = 5 and =
30
PRO-DRUGS
3
0
CH^ ^^"2
(CH ) N
3
(XLII):
(XLIII):
R = -H
R = -COCH,
1.
STELLA
31
TIME (hours)
Antibiotics Annual
32
PRO-DRUGS
(XLIV): erythromycin
erythromycin
A, C
FT
B, R*
R
=
=
=
=
-OH,
-H
-H,
-H
1.
STELLA
CH
H
33
(XLV) : R = R = -H
?
(XLVI) : 1
R and/or R = a c y l or
alkoxycarbonyl s u b s t i t u e n t
2,7-dicarbonate e s t e r s were found to be i n a c t i v e i n
v i t r o but had i n v i v o a c t i v i t y a f t e r S.C. i n j e c t i o n and
o r a l dosing i n S. aureus i n f e c t e d mice. A number of
the d e r i v a t i v e s (both a c y l and carbonate e s t e r s ) were
shown to achieve the o r i g i n a l o b j e c t i v e of the authors,
i . e . , a t a s t e l e s s lincomycin d e r i v a t i v e with i n v i v o
a c t i v i t y comparable to lincomycin base (185)
Mlek et a l . (l86) have attempted to increase del i v e r y of p o l a r a n t i b i o t i c s such as p e n i c i l l i n to p u l monary t i s s u e and lymph nodes by d e r i v a t i v e formation.
The authors argue that d e l i v e r y to the lymphatic system might be achieved i f drugs such as streptomycin,
neomycin and viomycin were a s s o c i a t e d as macromolecular
s a l t s with c a r b o x y l , s u l f o n y l or phosphoryl high molec u l a r weight polymers.
They conclude that these macromolecules, w i t h t h e i r c o l l o i d a l p r o p e r t i e s , have a high
a f f i n i t y f o r the lymphatic system. The authors prepared a number of macromolecular s a l t s of the various
a n t i b i o t i c s (the authors termed the r e s u l t a n t s a l t s
"antibiolymphins") i n c l u d i n g (a) p o l y a c r y l a t e s a l t s ,
(b) s a l t s w i t h s u l f o n y l and phosphorylated polysacchar i d e s , and (c) s a l t s w i t h n a t u r a l p o l y c a r b o x y l i c acids
of the polyuronic and polysaccharide s e r i e s . A f t e r
I.M., I.P., I.V., and i n t r a p l u r a l a d m i n i s t r a t i o n of the
macromolecular s a l t s of streptomycin, neomycin and v i o mycin, l e v e l s of the various drugs i n the lymphatic
system appeared to be higher than l e v e l s obtained from
a d m i n i s t r a t i o n of an equivalent dose of the nonderiva-
34
PRO-DRUGS
t i z e d drug.
The o r a l absorption of heavy metal c h e l a t i n g
agents such as ethylenediaminetetraacetic
a c i d (EDTA,
XLVII) and diethylenetriaminepentaacetic
a c i d (DTPA,
XLVIII) had been shown to be l e s s than k% of the t o t a l
dosage (187). The r e l a t i v e l y poor e f f e c t i v e n e s s of a
number of c h e l a t i n g agents t o promote r a d i o a c t i v e metal
m o b i l i z a t i o n has been a t t r i b u t e d t o t h e i r poor permeability characteristics. The chelating agents (2-hydroxyethylenediamine-N,N,N-triacetic acid (HEDTA, LXIX) and N,N'-bis(2-hyHOOCCH
^CH COOH
\cH CH N
HOOCCH
(XLIX)
.0
Hr-COOCCH
NCHCHN
H C OOCCH
5
(LI)
CH^COOH CH C00H
o
(LII)
1.
STELLA
35
droxycyclohexyl)-ethylenediamine-N,N -diacetic a c i d
(DOC L) have been d e r i v a t i z e d to the l e s s polar compounds LI and L I I r e s p e c t i v e l y . A f t e r I.V. administrat i o n of L I , m o b i l i z a t i o n of various radiometals from
the l i v e r of Ce ^^ dosed cats was f a r s u p e r i o r to an
equivalent dose of XLIX. LI administered o r a l l y was as
e f f i c i e n t at radiometal m o b i l i z a t i o n as an equivalent
I.V. dose of L I . The increased o r a l b i o a v a i l a b i l i t y
and increased p e r m e a b i l i t y to various organs of LI and
LII were a t t r i b u t e d to the l e s s polar nature of the der i v a t i v e s and t h e i r ready conversion to the parent compound . The increased m o b i l i z a t i o n of radiometals by
LI was a t t r i b u t e d to the formed XLIX because LI was
shown to have no heav i o c h e l a t i n capacit (188)
5
CHCH NH(CH )
(CH ) CC0
Q
(LIII)
n e u t r a l molecule present at p h y s i o l o g i c a l pH should not
be g r e a t l y a f f e c t e d by the a c y l a t i o n , the l i p i d s o l u b i l i t y of L I I I i s f a r superior to i t s parent compound,
IX. Since corneal absorption i n v o l v e s transport
through a l i p o i d a l b a r r i e r , the greater l i p o p h i l i c i t y
of L I I I may account f o r i t s superior therapeutic e f f e c t i v e n e s s . The use of the d i p i v a l y l e s t e r was necessary
not only to increase the l i p o p h i l i c i t y of the compound
but a l s o to help guarantee adequate aqueous s t a b i l i t y .
Percutaneous absorption of p o l a r drug e n t i t i e s .
The absorption of drugs i n t o and through the s k i n i s an
area of study which has achieved wide coverage but
which i s not, as y e t , f u l l y understood. I t i s generall y accepted that only n e u t r a l , r e l a t i v e l y l i p o i d a l drug
36
PRO-DRUGS
1>=0
H-
-OH
H-
-OH
H
(LIV);
(LV):
R = -H
R = -P0 H
3
1.
STELLA
37
( L V I I ) ; X = CI
(LVIII); X =
CH3COO
i n Scheme V I . Whethe
depend on whether i s a weak or strong base or wheth
er LVII or L V I I I i s i n buffered s o l u t i o n s . Since the
acetate anion i s a much stronger base than the c h l o r i d e
anion, the e q u i l i b r i u m i s forced t o the r i g h t f a v o r i n g
the formation of LVI. L V I I I i s considered a pro-drug
of LVI, yet i t i s simply a s a l t of LVI and regeneration
of LVI from L V I I I i n v o l v e s simple d i s s o c i a t i o n .
S t e r o i d s are an area where the pro-drug approach
has been apparently s u c c e s s f u l l y u t i l i z e d i n attempts
to promote t o p i c a l or percutaneous absorption. Ste
r o i d s such as triamcinolone ( L I X ) , f l u o c i n o l o n e (LX)
and f l u c l o r o l o n e have been d e r i v a t i z e d t o t h e i r acetonide d e r i v a t i v e s (192), triamcinolone acetonide
Scheme VI
38
PRO-DRUGS
1.
STELLA
39
(LXb)
Scheme V I I
a c t i v e when the percentage of propylene g l y c o l i n the
v e h i c l e was >55$ These d i f f e r e n c e s were a t t r i b u t e d t o
d i f f e r e n c e s i n s o l u b i l i t i e s of LXb and LXc i n the ve
h i c l e as a f u n c t i o n of propylene g l y c o l concentration.
LXb (0.025$) was completely soluble i n the v e h i c l e when
the percentage of propylene g l y c o l was >20-40$ while
LXc (0.025$) d i d not d i s s o l v e completely i n the v e h i c l e
u n t i l the percentage of propylene g l y c o l reached ap
proximately 80$. The importance of v e h i c l e composi
t i o n , see Poulsen (194) f o r a complete d i s c u s s i o n of
t h i s problem, i n the anti-inflammatory a c t i v i t y of s t e
r o i d s and t h e i r d e r i v a t i v e s was r e c e n t l y re-emphasized
by the study of Barry and Woodford (192).
M a i s t r e l l o et a l . ( 1 9 5 ) have r e c e n t l y attempted t o
quantitate the t o p i c a l anti-inflammatory e f f e c t s of
various s t e r o i d a l agents administered as s o l u t i o n s i n
2-(2-ethoxyethoxy)ethanol.
The greater a c t i v i t y of LXa
r e l a t i v e to LIX was r e a d i l y apparent.
The pro-drug approach has been s u c c e s s f u l i n im
proving the anti-inflammatory c l i n i c a l e f f i c a c y of per
cutaneously administered s t e r o i d s as can be seen by the
large number of s t e r o i d s c u r r e n t l y a v a i l a b l e as e i t h e r
esters or acetonide d e r i v a t i v e s ( r e l a t i v e to nonderivat i z e d s t e r o i d s ) . However, the r o l e of the v e h i c l e i n
the success of these products has only r e c e n t l y begun
to be understood and f u l l y appreciated (194) .
40
PRO-DRUGS
1.
STELLA
41
0
II
OH H
However, the studies of Rietbock e_t a l . (204) confirm
that demethylation of L X I I I does occur. Whether any of
these d e r i v a t i v e s , monoalkyl ( 2 0 3 - 2 0 5 ) monoacyl ( 2 0 6 214), or p o l y a c y l ( 2 1 6 ) , have any r e a l advantage over
d i g o x i n i t s e l f i s debatable. White and G r i s v o l d ( 2 1 7 )
claim good o r a l absorption p r o p e r t i e s f o r LXII i n cats
and LXII i s marketed as Acylanid (Sandoz) i n the
United S t a t e s .
Recently, Hussain and R y t t i n g ( 2 1 8 ) argued that
a l l o p u r i n o l (LXIV) owed i t s low water s o l u b i l i t y of
0 . 7 8 mg/ml to strong i n t e r m o l e c u l a r hydrogen bonding i n
i t s c r y s t a l l a t t i c e . A melting point of 3 6 5 f o r LXIV
seemed to confirm t h i s assumption. D i s r u p t i o n of the
c r y s t a l l a t t i c e by t r a n s i e n t pro-drug formation was
suggested as a means of i n c r e a s i n g the aqueous s o l u b i l i t y of a l l o p u r i n o l . The authors synthesized 1e t h o x y e t h y l - 4 - a l l o p u r i n y l ether (LXV) and 2 - t e t r a h y d r o p y r a n y l - 4 - a l l o p u r i n y l ether (LXVI) and demonstrated
the improved d i s s o l u t i o n r a t e from a constant surface
area p e l l e t of LXV and LXVI when compared to LXIV.
LXV and LXVI were shown to regenerate LXIV under a c i d i c
0
42
PRO-DRUGS
(LXIV):
R = -H
(LXV):
(LXVI):
form of the drug. I f the determining f a c t o r t o poor
aqueous s o l u b i l i t y i s the strength of the c r y s t a l l a t t i c e of the drug, and t h i s c r y s t a l energy i s not s u f f i c i e n t l y r e l i e v e d by s o l v a t i o n energy on d i s s o l u t i o n ,
then d i s r u p t i o n of the c r y s t a l l a t t i c e by pro-drug f o r mation may provide a s i g n i f i c a n t increase i n aqueous as
w e l l as l i p i d s o l u b i l i t y .
The strong c r y s t a l l a t t i c e energies of the hydant o i n s , 5*5-diphenylhydantoin and n i t r o f u r a n t o i n , and
various pro-drug forms of these drugs w i l l be discussed
l a t e r by S t e l l a et a l .
The a n t i f u n g a l agent, g r i s e o f u l v i n (LXVII), has
been shown to be poorly absorbed a f t e r o r a l administrat i o n t o man as w e l l as animals (219-225) The study by
Bates et a l . (226) has shown that the absorption of
g r i s e o f u l v i n can be g r e a t l y enhanced by the concomital
a d m i n i s t r a t i o n of f a t s . I t appears that the incomplete
b i o a v a i l a b i l i t y of LXVII i s a f u n c t i o n of i t s low water
s o l u b i l i t y . This can be traced t o i t s high l i p o p h i l i c i t y , a contrast to the c r y s t a l l a t t i c e s t r u c t u r e problems associated with the e a r l i e r examples. F i s c h e r and
Riegelman (227) attempted t o increase the aqueous s o l u b i l i t y of LXVII by pro-drug formation. The d e r i v a t i v e s
1.
STELLA
43
studied were g r i s e o f u l v i n - 4 ' - a l c o h o l ( L X V I I I ) , g r i s e o f u l v i n - ^ -oxime (LXIX), griseofulvin-4'-carboxymethoxime (LXX) and griseofulvin-4'-hemisuccinate (LXXI).
In a l l d i s c u s s i o n s thus f a r , most of the d e r i v a t i v e s
were e s t e r s of the parent compound where regeneration
of the parent compound was p o s s i b l e by the known presence and abundance of esterases i n the body. The s a l t
and complex pro-drugs reverted to the parent compounds
by d i s s o c i a t i o n (a nonenzymatic process). In the case
of g r i s e o f u l v i n pro-drugs, the conversion of LXVIII to
CI
(LXVII):
(LXVIII):
(LXIX):
(LXX):
(LXXI):
CH
R
R
R
R
R
=
=
=
=
=
=0
-OH
=N0H
=N0CH C00H
-OCOCHpCHpCOOH
p
44
PRO-DRUGS
OH
(LXXII): R = -H
(LXIII):
R =
-CH
1.
STELLA
45
46
PRO-DRUGS
CH 0H
I
c=o
o
2
ilu
1.
STELLA
ary
a m i c a l Society
47
48
PRO-DRUGS
(LXXIX):
(LXXX);
(LXXXI)
(LXXXII)
Rt
K: = -COCHo, R^ = -H
R^ = -H,
R = -COCH.
R = R = -COCH^
2
CH
N-
(LXXXIII):
(LXXXIV):
R = -H
R = -COCH
1.
STELLA
49
50
PRO-DRUGS
Ca(H 0)
J 2
(LXXXVI)
Lj yu \
(LXXXVII)
KYNURENINE
FORMAMIDASE
(LXXXVIII)
Scheme V I I I
1.
STELLA
51
Prolonged
52
PRO-DRUGS
OH
(LXXXIX):
(XC);
R = -H
R = a c y l substituent
of s t e r o i d therapy.
Recently Tanaka et a l . ( 2 6 3 ) have
attempted to q u a n t i t a t e f a c t o r s which a f f e c t the prol o n g a t i o n of a c t i v i t y of drug i n j e c t e d I.M. i n o i l y
s o l u t i o n s . James et a l . ( 2 6 4 ) showed that f o r a s e r i e s
of testosterone (XCI) esters the b i o l o g i c a l h a l f l i f e
f o r the r e l e a s e of testosterone and i t s esters from an
I.M. o i l i n j e c t i o n was c l o s e l y r e l a t e d to the o i l / w a t e r
d i s t r i b u t i o n c o e f f i c i e n t of the d e r i v a t i v e s . The o i l
used by James ejb a l . ( 2 6 4 ) was e t h y l o l e a t e . I t was
i n t e r e s t i n g to note that the homologous s e r i e s of f o r myl through v a l e r y l esters of testosterone had approximately equal s o l u b i l i t y i n the e t h y l oleate showing
that the d i s t r i b u t i o n c o e f f i c i e n t was l a r g e l y determined by the decrease i n water s o l u b i l i t y . Apart from
these i n t e r e s t i n g b a s i c s t u d i e s , the r e s u l t s of many
workers have shown that longer duration of a c t i o n of
testosterone from an I.M. i n j e c t i o n could be e f f e c t e d
by a c y l a t i o n of the 173-hydroxy group ( 2 6 5 - 2 8 8 ) .
Increasing chain length of the a c y l group e f f e c t i v e l y i n creased the d u r a t i o n of a c t i o n , i . e . , the testosterone
esters are thought to gradually leach out of the I.M.
i n j e c t i o n s i t e ( o i l based I.M. i n j e c t i o n ) , regenerate
testosterone i n the general c i r c u l a t i o n which then
exerts i t s androgenic a c t i v i t y ( 2 6 4 ) .
1.
STELLA
53
0
(XCI)
-H
(XCIII)
-COC H
(XCIV)
-C0CH C0C H
-C0C H
(XCVIII)
(XCIX)
(C)
(XCII)
10
21
(XCV)
(XCVI)
(XCVII)
C
6 i3
H
54
PRO-DRUGS
1.
STELLA
55
of nandrolone f o r anabolic a c t i v i t y .
Depot forms (I.M. i n j e c t i o n i n an o i l v e h i c l e ) of
other s t e r o i d s are a l s o quite common. The weekly use
of dromostanolone propionate i n the treatment of
breast carcinoma was discussed by Seay e_t a l . (297)
Long a c t i n g estrogenic s t e r o i d s u s e f u l i n the t r e a t ment of estrogen d e f i c i e n c y i n women has been a goal
of many workers. D e r i v a t i v e s of e s t r a d i o l (CIV), such
as the oligemeric d e r i v a t i v e s (CV longest a c t i n g der i v a t i v e ) of Kuhl ert a l . (298), p o l y e s t r a d i o l phosphate (CVI) of D i c z f a l u s y et a l . (299), e s t r a d i o l 3benzoate-17-cyclooctenyl ether (CVII) of P a l c o n i et
a l . (300), 3- and/or 17-acyl d e r i v a t i v e s of e s t r a d i o l
of F e r r i n (301), and others (302-310) were a l l shown
to have prolonged estrogeni
t r a t i o n . CVI was a l s
treatment of p r o s t a t i c carcinoma. Prolonged release
forms of dihydroxy progesterone f o r b i r t h c o n t r o l
(acetophenide d e r i v a t i v e s ) have been found u s e f u l
(311-313) while the caproate e s t e r of hydroxyprogesterone (Delalutin) i s used as a long a c t i n g s t e r o i d
i n amonorrhea (314).
The use of desoxycorticosterone acetate and t r i methylacetate i n adrenal i n s u f f i c i e n c y (Addison's d i s ease) has proven s u c c e s s f u l (315)
Desoxycorticosterone t r i m e t h y l a c e t a t e (CIX, Percorten p i v a l a t e ) has
a very prolonged a c t i o n and should not be administered
more than once a month (316).
Long a c t i n g , pro-drug r e p o s i t o r y i n j e c t a b l e forms
of c o r t i c o s t e r o i d s u s e f u l i n the treatment of i n f l a m mation are betamethasone acetate, methylprednisolone
acetate (Depo-Medrol), f l u o r o c o r t i s o n e acetate ( F l o r inef a c e t a t e ) , hydrocortisone cypionate (Cortef) and
triamcinolone hexacetonide (Aristocort), to name a
few
(316).
(CVI): R = e s t r a d i o l
molecule
1.
STELLA
57
TIME, (DAYS)
Acta Pharmacologica et Toxicologica
PRO-DRUGS
58
(CX):
R = -H
(CXI)
(CXII): R = - C O C H
n
(CXIII): R = -H
(CXIV):
R = -COC H
Q
C H CH C H /
2
\ c H CH 0 R
S0 N(CH )
2
(CXV):
R = -H
(CXVI): R = - C O C
(CXVII):
1 5
R = -C0C
i n
3 1
o l
1.
59
STELLA
(CXIX)
(CXX):
R = -COC H
15
31
0
CH CHN-^/
3
(CXXIII)
60
PRO-DRUGS
Cl
(CXXII)
(CXXI)
1.
STELLA
61
oc
a
tu
H
LU
I-
- S
Ui
ce
Lu
g *
X
Lu
LU
LU
8"
|i
CO
Lu
62
PRO-DRUGS
(CXXIV)
the l e a s t squares l i n e described by equation 1.
l o g PMW
= -0.71
+ 0.11
l o g S + 0.077
The
(eq.
1)
1.
STELLA
63
r
ol
Li
12
15
18
21
24
27
30
DAY
AFTER INJECTION
American Journal of Clinical Nutrition
P a r e n t e r a l l y sustained r e l e a s e of a c i d substances
such as p e n i c i l l i n has s i m i l a r l y been e f f e c t e d by the
use of s p a r i n g l y soluble s a l t s of p e n i c i l l i n such as
benzathine and procaine p e n i c i l l i n (7-11). The spar-
64
PRO-DRUGS
1.
STELLA
65
CH 0C0CH
I
CH-OCOCEL
CH OCOCH
o
(CXXIX)
HOCH NHCNHCH OH
2
(CXXX)
H(?H
i n vivo
H
3
CH
c
I
(CXXXII)
C= 0
1
NCH OH
2
(CXXXI)
RCO(CH CH 0) CR
2
i|
R = NH
(CXXXIII)
(H C ) NCH CH OC
5
('
COCH CH N(C H )
2
NH
(CXXXIV)
66
PRO-DRUGS
1.
STELLA
67
R-P-OH
(
Na
(CXXXV)
i n vivo
Na
( CXXXVI
where R = c o r t i c o s t e r o i d molecule
Although prednisolone hemisuccinate sodium s a l t
(CXXXIX) i s the current commercially a v a i l a b l e water
s o l u b l e form of prednisolone (CXXXVIII), other water
s o l u b l e d e r i v a t i v e s such as prednisolone-21-m-sulfobenzoate sodium s a l t (XCLI) and prednisolone-21-disodium
phosphate (XCL) have a l s o been synthesized and t e s t e d
(377-379). S i m i l a r l y , methylprednisolone sodium s u c c i
nate (316,380), hydrocortisone-21-phosphate (379,381),
-21-succinate (316,379*381-382), -21-aminoalkylcarboxyl a t e s (383), -21-m-sulfobenzoates (384) , and -21-sulf a t e s (384), dexamethasone sodium phosphate (316,379)*
betamethasone disodium phosphate (316) have been syn
t h e s i z e d and found to be water s o l u b l e , p a r e n t e r a l l y
b i o a v a i l a b l e forms of the parent s t e r o i d s .
The succinate e s t e r s of the various s t e r o i d s are
u s e f u l but s u f f e r somewhat from s t a b i l i t y problems,
i . e . , the drug must be s u p p l i e d as a l y o p h i l i z e d powder
f o r r e c o n s t i t u t i o n (316). Flynn et. a l . (385)> i n d i s
cussing the s o l v o l y s i s and f a c t o r s a f f e c t i n g the s t a
b i l i t y of corticosteroid-21-phosphate e s t e r s , s t a t e s
that " a d d i t i o n a l l y , some types of phosphate e s t e r s are
s u f f i c i e n t l y s t a b l e to allow the f o r m u l a t i o n of s o l u
t i o n s with p r a c t i c a l s h e l f - l i v e s . " Another added ad
vantage of phosphate e s t e r s as opposed to the succinate
esters i s t h e i r very r a p i d conversion to the parent
s t e r o i d . Melby et a l . (379) i n a very i n t e r e s t i n g
study showed that I.M. administered hydrocortisone-21phosphate ( X C L I I ) , (XCL), dexamethasone-21-phosphate
(XCLIII) and I.V. administered XCLII a l l produced
higher plasma l e v e l s of the parent s t e r o i d than the
corresponding 21-succinate e s t e r s , (see Figure 10).
68
PRO-DRUGS
0
RCNHCH CCP
(CXXXVII):
R = various s t e r o i d molecules
CH 0R
C=0
-OH
o
(CXXXVIII): R
(CXXXIX): R
(XCL): R
-COCH CH COO
2
-PO
Na
2Na
(XCLI): R =
so
Na
1.
STELLA
69
250
TIME (minutes)
Metabolism
70
PRO-DRUGS
0
Il
0 A
I I
2
i
C=0
I
CHC1
H
2 2
(XCLIV)
i n vivo
CH CH COO*
Na
2
CHCHCH 0H
I I 2
OHNH
I
c=o
I
CHC1
o
^CH
I
NH
I
(XCLV)
CHC1
(XCLVI)
Scheme IX
(XCLVIII)
(XCLIX)
Scheme X
1.
STELLA
71
(CLII) : R = -H
( C L I I I ) : R = -COCH CH COO Na
0
72
PRO-DRUGS
(CLIV)
(CLV): R = -COH
9
(CLVII): R = -H
8
(CLVIII): R = -COCHgCHgCOoSla
1.
STELLA
73
HN\
(CLIX)
in vivo/in vitro
-c=o
HC5
CH^
II
0
(CLX)
74
PRO-DRUGS
NH
.NH
(CLXII)
(CLXIII)
OH
1.
STELLA
75
OCH.
'3
OH
0
NH
(CLXIV): R
(CLXV): R
-H
-COC^H
7"15
76
PRO-DRUGS
problem e s p e c i a l l y i n p a t i e n t s t r e a t e d f o r inflammatory
diseases. S a l i c y l a t e s i n c l u d i n g a c e t y l s a l i c y l i c a c i d
or a s p i r i n , as w e l l as s a l i c y l i c a c i d i t s e l f , have been
known to induce g a s t r i c bleeding, u l c e r a t i o n and genera l GI i r r i t a t i o n (430-441). Attempts to modify s a l i c y l i c and a c e t y l s a l i c y l i c a c i d i r r i t a t i o n by the prodrug approach has a long h i s t o r y . None of the products
studied appears to hold any great advantage over acet y l s a l i c y l i c a c i d e i t h e r i n a c t i v i t y or decreased gast r i c i r r i t a n t properties.
However, p o t e n t i a l decreased
g a s t r i c i r r i t a n t properties with the use of some of the
pro-drugs have been claimed by some of t h e i r promoters
(442-445).
Other s a l i c y l i
benzoi a c i d e r i v a t i v e whic
have shown g a s t r i c i r r i t a n
c a l l y modified i n attempts to decrease t h e i r i r r i t a n t
properties.
The g l y c e r y l ester of N - a r y l a n t h r a n i l i c
a c i d apparently has lower g a s t r i c i r r i t a n t p r o p e r t i e s
than the parent compound (446), while various b i o r e v e r s i b l e d e r i v a t i v e s of n i c o t i n i c a c i d showed no advantage or showed marginal advantages over n i c o t i n i c a c i d
(447-448).
1.
STELLA
77
(CLXVI): R = -COOH
(CLXVII): R =
-COH
78
PRO-DRUGS
0
II
(CLXIX)
Ca ++
2
(CLXX)
1.
STELLA
79
PRO-DRUGS
80
1. STELLA
81
to be t a s t e l e s s
(492).
82
PRO-DRUGS
CH CHN-^
0 <^
^)
(CLXXVII)
+
H /H 0
2
(CLXXVI)
1.
STELLA
83
9H
C1CCH
3
C1_CCH0H
OH
(CLXXVIII)
(CLXXX)
ClgCCHgO Na
OH
(CLXXXI)
CH CHNF
3
(CLXXXII)
yOCOCH CCl
2
(CLXXXIII)
The Use of Pro-Drugs to Promote S i t e S p e c i f i c D e l i v e r y
of a Drug
I d e a l l y , pro-drugs might be u s e f u l i n promoting
s i t e s p e c i f i c i t y f o r a given drug by l o c a l i z i n g the
drug i n a target organ by u t i l i z i n g e i t h e r some s p e c i f
i c p h y s i c a l or chemical property of the s i t e . For ex
ample, tumor c e l l s are postulated to contain a higher
concentration of phosphatase and amidase enzymes than
normal c e l l s (510). Therefore, i f a c y t o t o x i c drug i s
phosphorylated (assuming a s u i t a b l e f u n c t i o n a l group
f o r attachment i s a v a i l a b l e ) , the tumor c e l l s w i l l pro
v i d e a " s i n k " f o r the drug thus promoting a somewhat
s p e c i f i c accumulation of the drug at that s i t e .
Phosp h o r y l d e r i v a t i v e s of c y t o t o x i c agents such as d i e t h y l s t i l b e s t e r o l (CLXXXIVa and CLXXXIVb) and e s t r a d i o l
(CVI) have been found u s e f u l i n the treatment of pro
s t a t i c carcinoma (299,389-397) presumably due to t h i s
s p e c i f i c i t y . Phosphate esters of cytosine arabinoside
(511,512) and adenine arabinoside (43,44) have not
proven to be any more a c t i v e than the parent compounds.
The dicarbamate of CLXXXIVa, (CLXXXV), has a l s o been
suggested f o r the treatment of p r o s t a t i c carcinoma
(513). The parent compounds i n each of these cases are
84
PRO-DRUGS
RO
OR
(CLXXXIVa):
( CLXXXIVb): R
(CLXXXV): R
the a c t i v e agent with the precursors having l i t t l e i n trinsic activity.
L o c a l i z a t i o n of drugs at a s i t e has received some
success with the bowel s t e r i l a n t s , s u c c i n y l and phthal o y l s u l p h a t h i a z o l e (514). Both these d e r i v a t i v e s are
monoamides of sulphathiazole which, due t o t h e i r p o l a r i t y , are not w e l l absorbed from the GI t r a c t . I n the
lower i n t e s t i n e and colon, both r e l e a s e s u l p h a t h i a z o l e
which then acts as the bowel s t e r i l a n t . Another prodrug which has shown some s i t e s p e c i f i c i t y i s oxyphenis a t i n and i t s d i a c e t a t e d e r i v a t i v e (CLXXXVII). CLXXXVI
OR
(CLXXXVI): R = -H
(CLXXXVII): R = -COCH
1.
STELLA
85
PRO-DRUGS
86
1.
STELLA
87
CH NH CH CH NH CH
2
Penicillin
(CLXXXIX)
y L
< c
Penicillin
(XCC)
CH
CH NH CH CH NH CH
CH.
CH(CH )
3
(CH ) CH
3
Penicillin
J 2
(XCCI)
88
PRO-DRUGS
CH.
(CH ) NHCH CH
(j)CC H
2
"
C H
2 6 5
C
6 5
H
(XCCIII)
HO-^
\-CHCH NH ( CH ) fh^
HO
CHCH NH( CH )
2
n u
(XCCIV)
(XCCV)
l i z e d b i o r e v e r s i b l e d e r i v a t i v e of IX.
Ascorbic a c i d or v i t a m i n C i s very s u s c e p t i b l e to
o x i d a t i o n both i n s o l u t i o n and to some degree i n the
s o l i d s t a t e . This o x i d a t i o n w i l l take place only i f
the 2 , 3 - d i o l system of ascorbic a c i d i s f r e e , i . e . ,
not d e r i v a t i z e d . Such d e r i v a t i v e s as 2 and/or 3 - a c y l
( 5 2 1 ) , -benzoyl ( 1 2 9 - 1 3 2 ) , -phosphoryl ( 1 8 9 , 5 2 2 - 5 2 4 ) ,
and s u l f a t e d e r i v a t i v e s (525) have been shown to be
more stable i n s o l u t i o n and to provide s i m i l a r v i t a m i n
C a c t i v i t y as ascorbic a c i d i t s e l f . S i m i l a r l y , various
b i o r e v e r s i b l e d e r i v a t i v e s of hydrocortisone have been
shown to be quite s t a b l e ( 3 8 2 - 3 8 4 ) , whereas h y d r o c o r t i
sone i t s e l f i s quite s u s c e p t i b l e to degradation ( 5 . 2 6 ) .
S o l i d state degradations can a l s o be a problem
with some drugs. Highly unsaturated hydrocarbons, such
as v i t a m i n A and v i t a m i n D, are s u s c e p t i b l e to degrada
t i o n . G u i l l o r y and Higuchi (527) studied the s o l i d
s t a t e s t a b i l i t y of some v i t a m i n A d e r i v a t i v e s . They
found that the s o l i d s t a t e s t a b i l i t y was i n v e r s e l y pro
p o r t i o n a l to the melting point of the s o l i d , i . e . , the
higher the melting point of the d e r i v a t i v e the more
s t a b l e the product. However, as stated by the authors,
the higher melting point d e r i v a t i v e s a l s o had the lower
aqueous s o l u b i l i t y so the b i o a v a i l a b i l i t y of the more
s t a b l e products might present some problems.
Forlano et a l . ( 5 2 8 - 5 3 0 ) studied the e f f e c t of
a c y l a t i o n of v i t a m i n A a l c o h o l on the s t a b i l i t y of
v i t a m i n A. The ,-dimethylpalmityl d e r i v a t i v e was
found to be quite s t a b l e . The b i o l o g i c a l a v a i l a b i l i t y
1.
STELLA
89
(91-93).
.CH.
H0CH CH N^
CH.
2
CSC^
II 2 5
(XCCVII)
(XCCVIII)
^CH^
H0CH CH N
\m
2
CH CNH
3
C-0
(XCCIX)
90
PRO-DRUGS
NH 2
(CC)
AZO-REDUCTAZE
(CCI)
1.
STELLA
91
92
PRO-DRUGS
nal agents.
All the implications just discussed make the area
of pro-drugs an exciting and fruitful field for con
tinued study. It is an area where the pharmaceutical
chemist, with his knowledge and expertise in solubility
theory, pharmacokinetics and formulation variables, the
medicinal chemist, with his knowledge of synthesis, SAR
and metabolism, and the pharmacologist, with his know
ledge of mechanisms and sites of drug action and toxi
city can cooperate to optimize the delivery of an ac
tive drug to its site of action while minimizing toxi
city and unfavorable reactions to the drug. Many prob
lems associated with drugs can be overcome by the use
of pro-drug approach and i t is the hope of this author
that this review wil
this area.
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97
98
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155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
99
100
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
PROD
- RUGS
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(1973), 62, 1757.
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Antibiot. Ann
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101
102
PROD
- RUGS
224. Bedford, C., Busfield, D., Child, K. J., Mac
Gregor, I., Sutherland, P., and Tomich, E. G.,
Arch. Dermatol. (1960), 8 1 , 735.
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230. Karim, S. M.
Gynaec. Commun
231. Schedl, H. P., and Clifton, J . ., Gastroenterol.
(1961), 41, 491.
232. Tanabe, ., and Bigley, B . , J. Amer. Chem. Soc.
(1961), 83, 756.
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P., and Sabo, E. F . , J . Amer. Chem. Soc. (1958),
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247.
248.
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
103
^04
PROD
- RUGS
268.
1. STELLA
105
106
PROD
- RUGS
1. STELLA
107
108
PROD
- RUGS
365.
366.
1. STELLA
109
110
PROD
- RUGS
1. STELLA
111
112
PROD
- RUGS
460.
1. STELLA
114
503.
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
514.
515.
516.
517.
518.
519.
520.
521.
522.
523.
524.
PROD
- RUGS
"American Hospital Formulary Service", American
Society of Hospital Pharmacists, Washington, D.C.
(1974), 8, 08.
"American Hospital Formulary Service", American
Society of Hospital Pharmacists, Washington, D.C.
(1974), 28, 16.08.
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(1974), 56, 20.
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C., Toxicol. Appl. Pharmacol. (1971), 19, 445.
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F., and Scholz
(1971), 19, 480.
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(1962), 51, 172.
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1. STELLA
115
2
Application of the Pro-drug Approach to Antibiotics
A. A. SINKULA
Research Laboratories, The Upjohn Co., Kalamazoo, Mich. 49001
2.
SINKULA
117
118
PRO-DRUGS
2.
SINKULA
119
B i o l o g i c a l . Although p i v a m p i c i l l i n i s s t a b l e i n n e u t r a l
s o l u t i o n , i t i s r a p i d l y hydrolyzed to a m p i c i l l i n i n the presence
o f e s t e r a s e s d e r i v e d from a v a r i e t y o f mammalian sources ( 2 ) .
Esterases obtained from rodent sources, e.g. r a t and mouse, exh i b i t a high degree of h y d r o l y t i c a c t i v i t y while e s t e r a s e enzymes
o f dog and man show a somewhat lower a c t i v i t y . Table I summarizes
the i n v i t r o enzyme h y d r o l y s i s s t u d i e s conducted with pivampicillin.
These s t u d i e s , while i n d i c a t i v e o f the f a t e o f the e s t e r i n
serum and whole blood, do not provide c o n c l u s i v e proof t h a t the
same e s t e r w i l l behave s i m i l a r l y i n the i n t a c t organism. Human
s u b j e c t s dosed, i n a c r o s s o v e r experiment, with 250 mg. o f amp i c i l l i n and 358 mg. o f p i v a m p i c i l l i n (*250 mg o f a m p i c i l l i n )
showed a b s o r p t i o n o f th
concentrations of ampicilli
The e s t e r was absorbed almost q u a n t i t a t i v e l y (a t h r e e - f o l d i n crease i n peak serum l e v e l s when administered as the e s t e r ) . I t
was f u r t h e r noted t h a t 99% o f the drug i n blood was present as
a m p i c i l l i n 15 minutes a f t e r a d m i n i s t r a t i o n . S p e c u l a t i o n centered
on the f a c t t h a t , due to the inherent l a b i l i t y o f the p i v a l o y loxymethyl e s t e r , h y d r o l y s i s i n v i v o proceeded v i a Sequence I.
A f t e r a b s o r p t i o n o f the e s t e r , h y d r o l y s i s to the hydroxymethyl
e s t e r occurred f o l l o w e d by f u r t h e r degradation to a m p i c i l l i n and
formaldehyde.
Hetacillin. Hetacillin
{6-(2,2-dimethyl-5-oxo-4-phenyl-li m i d a z o l i d i n y l ) p e n i c i l l a n i c acid} V [ represents another type o f
prodrug o f a m p i c i l l i n ( 3 ) .
0
II
T h i s a n t i b i o t i c d e r i v a t i v e was prepared by the condensation o f
acetone with a m p i c i l l i n and was o r i g i n a l l y designed to enhance
the g a s t r o i n t e s t i n a l a b s o r p t i o n of a m p i c i l l i n . I t i s a l s o u t i l i z e d as a s t a b l e form o f a m p i c i l l i n f o r use i n i n f u s i o n s o l u t i o n s
f o r a d m i n i s t r a t i o n over extended periods o f time.
Chemistry. Several methods have been devised whereby H can
be prepared from commercially a v a i l a b l e intermediates (Scheme I I ) .
103
<1
<1
50
23
50
10
5
<5
5
5
5
3-4
Ha1f-life
(min)
"
None
Mouse serum, 1%
Rat serum, 1%
Dog serum, 5%
Dog serum, 10%
Human serum, 10%
Homogenate o f g a s t r i c mucosa from t h e dog, 10%
Homogenate o f i n t e s t i n a l mucosa from the dog, 10%
L i v e r homogenate from the dog, 10%
Homogenate o f human g a s t r i c mucosa, 10%
Homogenate o f human duodenal mucosa, 10%
Human whole blood
Whole blood from the dog
Enzyme Source
TABLE I
2.
SINKULA
121
HN
2
~^C00CH20C0CMe3
0
0 - CHCCi
H
I
NH2
HCI
O-CH2CNH-1fy:
*0
6.
0E1
0-CHCNH-i-Y ><
C00CH 0C0CMe
2
CICH20C-CMe3
Chloromethylpivolate
Nol
H30+
NH
N_
^C00CH 0C0CMe
2
0
^-CHCNH
<f
0"
-r-f^Y
Scheme I
0
I
/
IIIl
f > C H - c - N :
: .
v
7/
/
CH3
^C00CH 0CC(CH3)
5
Pivampicillin
non-specific esterases
0
Il
n
/rv
2
0
<^H-C~N
v i
CH
C
a _ h
3
"
^COOH + C H 0
H
Ampicillin
Antimicrobial Agents and Chemotherapy
122
PRO-DRUGS
2. SINKULA
-? " !
NH
<f
~~^COONa
CH CCH
3
I. H2O
_ _ _ _ _
3
1 1
r f
H^^CHs ^
N
>
C H
-^0
CICH 0CCMe
2
fV-HC-c'
'
I I
H C CH3
CH3CCH3
^COOH
A_ -cci
N-|-YS<
123
r Q
^C00CH 0C0CMe
><
L,
1\
Il
V V0CH C-NH-ir >:
.
Il
(' V o C H ^ - N H - r - r - S Y
P-CcOON.
'
methoxymethyl
chloride
.F^C0OCH 0CH
2
chemical or
enzymatic
H N-f <
S^SST
>*
9>
0
fi^i-CH-CCI
^ N HNH
HCI
2
^-"- TT Y
NH
CH "CH3
3
^C00CH 0CH
^COOCHoOCHx
2
v**
,
*
H C CH
^C00CH 0CH
, , 7/ ~~^Cl
3
Scheme III
HETACILLIN
AMPICILLIN
CENTRAL
COMPARTMENT
|2
*T~~
21
PERIPHERAL
COMPARTMENT
BILE AND
METABOLISM
URINE
12
21
124
PRO-DRUGS
TABLE II
D i s t r i b u t i o n and E l i m i n a t i o n Parameters o f the Two-Compartment
Open Model f o r A m p i c i l l i n
Intravenous
A m p i c i l l i n (SD)
Parameter
A m p i c i l l i n from
H e t a c i l l i n (SD)
D i s t r i b u t i o n volumes, 1
12.0 (1.9)
17.9 (1.5)
12.5 (2.8)
19.3 (2.9)
341 (91)
335 (56)
296 (91)
350 (102)
0.384 (0.185)
0.733 (0.163)
1.73 (0.49)
1.55 (0.47)
0.17 (0.12)
1.29 (0.11)
0.419 (0.180)
0.728 (0.161)
1.68 (0.30)
1.58 (0.31)
0.10 (0.13)
1.34 (0.20)
0.899 (0.075)
0.939 (0.076)
22.7 (5.2)
22.9 (7.6)
0.581 (0.133)
0.297 (0.081)
0.878 (0.151)
0.581 (0.118)
0.355 (0.102)
0.921 (0.141)
Clearances, ml./mi.
Rate c o n s t a n t s , hr.
k
k
1 2
2 1
pi
e
b
Slow th hr.
Fraction (f )
excreted i n u r i n e
Plasma l e v e l
_-.
a r e a , meg. hr. ml.
Integral c o e f f i c i e n t s , hr.
k
K
2.
SINKULA
125
C a r b e n i c i l l i n . C a r b e n i c i l l i n (-carboxybenzylpenicillin)
17
i s an important p e n i c i l l i n analog having unique b i o a c t i v i t y
a g a i n s t pseudomonas aeruginosa and i n d o l e - p o s i t i v e Proteus species
which are u s u a l l y r e s i s t a n t to a m p i c i l l i n . C a r b e n i c i l l i n i s
u s u a l l y administered p a r e n t e r a l l y due to i t s poor g a s t r o i n t e s t i n a l
absorption c h a r a c t e r i s t i c s . A d d i t i o n a l l y , i t i s rendered i n a c
t i v e i n the g a s t r i c contents due to i t s a c i d l a b i l i t y . Many
d e r i v a t i v e s , p r i m a r i l y e s t e r s , of t h i s , a n t i b i o t i c have been pre
pared i n an attempt to overcome these shortcomings inherent i n
the parent molecule.
126
PRO-DRUGS
SINKULA
127
J!
Scheme V
CO H
Z
f 3
---
CH C00CHCI
\oC\
HaN-r-fSC
J-N-<C02H
0
-CH
TEA
J-N^ 00CH0C0CH
0
j
C
12.
20
< ^ C H - C N H y - f
*
C0 H
CH3
~~^C00CH0C0CH
CI H
3
21
Scheme VI
-CHCOCI
. =0
^
CH0C0CH
I
CH
^ C H - C - N H ^ S ^
M ~~^C00H
A= 0
CH0C0CH
I
CH
22
21
Scheme VII
CH3
<_ ~"~ _
C02Na
/ ~~^C02Na
0
2CH3C00CHC1
0- -"- t_
23
nh
M
0
C=0
,
0
f
CH
"C0 CH0C0CH
,
2
CH
C
24
Scheme VIII
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
128
PRO-DRUGS
SINKULA
OH
15%
HO
<0
HO
^0
I
OH
iJO
Antimicrobial Agents and
10%
Chemotherapy
Scheme X
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
Oral
25
Absorption
26
17,18
1,2,19-22
3,8,23
32
24
Absorption
Absorption
Absorption
Absorption
Absorption
Absorption
16
15
Absorption
Oral
Absorption
Reference
14
Property
Modified
Absorption
Route o f
Administration
Oral
3. P e n i c i l l i n , general s t r u c t u r e D i e t h y l aminoethyl e s t e r s ,
Oral
alkoxymethyl e s t e r s , ether
O r a l , IV
a. Azide
4. -Aminobenzyl p e n i c i l l i n
b. Acyloxymethyl e s t e r s
Oral
c.
N,N-isopropylidene
Oral
adduct
Oral
d. P h t h a l i d y l e s t e r
IM
Amide
5. P e n i c i l l i n G
Penicillin V
6. -Amino ( o r ureido)
Acyloxymethyl e s t e r s
Oral
cyclohexad i e n y l a l k y l
penicillin
esters
Chemical
Modification
Pivaloyloxymethyl e s t e r
Parent Molecule
1. 6-N '-Cyanoamidopeni c i 11i
Carbenicillin
9.
14. P e n i c i l l i n , general s t r u c t u r e
13.
12. -Aminobenzyl p e n i c i l l i n
11. A c e t a m i d o p e n i c i l l i n s
penicillin
10. 6-(3-Thienyloxyacetamido)
Hetacillin
Molecule
8.
Parent
Chalcon-4-yl
Amide
b.
salt
a.
Probenecid
Dibenzyl ethylene
diamine s a l t
Carboxamido e s t e r
esters
Resistance t o p e n i
cillinase
Resistance to peni
cillinase
Oral
Oral
Bitterness
Duration o f a c t i v i t y
Duration o f a c t i v i t y
Oral
IM
IM
Oral
34
33
30
29
28
31
10
9,12
27
Absorption
Absorption
Absorption
Absorption,
duration of a c t i v i t y
Absorption
Oral
Reference
Property
Modified
Route o f
Administration
ester
Acetoxymethyl e s t e r
a.
b.
c.
Pivaloyloxymethyl
Chemical
Modification
TABLE I I I . (Continued)
00
ST
*
QTQ
>
132
PRO-DRUGS
SINKULA
25
^CHCH 0C0CI
-I^U
CH2CNH
i-Nvj^CH 0C0CH .
C00C00CH Crf
^CH
3 ct
32
Scheme XII
1. DCC
2. CH CHC00C(CH
,
" ' )3
'
VV
N H
C H
C N H
T /-N>f^CH20C0CH3
T J
0
C0NHCHC00C(CH3)3
33
CH3
Scheme XIII
8
JVW^^
CH CNH-p^
2
c H 2 0 c o c H 3
C0NHCH C00C H
2
36
Scheme XIV
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
134
PRO-DRUGS
amino a c i d e s t e r s r e a c t i n s i m i l a r f a s h i o n .
Another s e r i e s o f i n t e r e s t i n g s y n t h e t i c r o u t e s designed t o
p r o v i d e b i o r e v e r s i b l e Ca c e p h a l o s p o r i n e s t e r s a r e r e p o r t e d by
Binderup e t . a l . (49). S t i m u l a t e d by the success achieved with
acyloxymethyl e s t e r s o f a m p i c i l l i n , these i n v e s t i g a t o r s attempted
to repeat the e a r l i e r achievements with c e p h a l o g l y c i n . U t i l i z i n g
the sodium s a l t o f c e p h a l o t h i n as t h e i r s t a r t i n g p o i n t , t h e
and acetoxymethyl e s t e r s were made by treatment with c h l o r o
methyl a c e t a t e . (Scheme XV). T h i s mixture was o x i d i z e d t o the
s u l f o x i d e 37, as p r e v i o u s l y d e s c r i b e d , and subsequently reduced
to acetoxymethyl-7-(2'-thienylacetamido) cephalosporanate 38 with
phosphorus t r i c h l o r i d e .
Acetoxymethyl-7-aminocephalosporanate
39 was produced by treatment o f 38 with phosphorus p e n t a c h l o r i d e
and n-propanol. The h y d r o c h l o r i d e s a l t o f 39 was formed by the
a d d i t i o n o f IN HC1. T
chloride to yield
acetoxymethyl-7-(D-a
cephalosporanate 40 which was subsequently hydrogenated with 10%
palladium/carbon t o y i e l d
acetoxymethyl-7-(D-a-aminophenylacetamido) cephalosporanate 4K
The p i v a l o y l o x y m e t h y l e s t e r was s y n t h e s i z e d by combining
f e a t u r e s o f s e v e r a l syntheses p r e v i o u s l y d e s c r i b e d . T h i s e s t e r
was i n i t i a l l y prepared by treatment o f potassium 7-(D-a-azidophenylacetamido) cephalosporanate 42 with c h l o r o m e t h y l p i v a l a t e .
A mixture o f t h e 43 and e s t e r s were formed by t h i s proce
dure. Treatment o f the mixture f i r s t with m-chloroperbenzoic
a c i d t o form t h e s u l f o x i d e e s t e r and secondly with sodium
d i t h i o n i t e / a c e t y l c h l o r i d e gave t h e r e q u i s i t e p i v a l o y l o x y m e t h y l 7-(D-a-azidophenylacetamido) cephalosporanate 44 e x c l u s i v e l y as
the isomer. Reduction o f 44 by c a t a l y t i c hydrognation a f forded pivaloyloxymethyl-7-(D-a-aminophenylacetamido)
cephalosporanate 45.
Many o t h e r c e p h a l o s p o r i n d e r i v a t i v e s have been made u t i l i z i n g s y n t h e t i c pathways s i m i l a r t o those p r e v i o u s l y d i s c u s s e d
(50-53).
2
2.
SINKULA
135
136
PRO-DRUGS
CO3H
0
O Ss . CH CNH-|f |
/-Nxj^
0
frtrtUn
b N
CICH20C0CH3
Chloromethylacetate
C H 2 0 A c
5 ,
0
f
^
ff\
^ c A ,
PCI3
* N-f^CH 0Ac
C00CH 0C0CH3
L
J~ Y^CH 0Ac
COCH2OCOCH3
II
0
N
0
VAru-Lu
0
J
L PCI /quinoline
2. PrOH
5
^S
/)-N^CH 0Ac
C00CH 0C0CH3
2
S^CH CNH-r-Y h
3. H 0
3
37
- f "h
H 2 N- - r!
// N>f^CH 0Ac
-HC0C
U2
d'C00CH 0C0CH3
2
11 _
J-Nf^CH 0Ac
2
39
fnnrMonmnHi
0
NH
/r Y^CH 0Ac
C00CH 0C0CH3
N
2
0
il
Scheme XV
Scheme XVI
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
2.
SINKULA
137
esters
esters
C^-acyloxybenzyl
Oral
Oral
62
63
Absorption
Absorption
61
Absorption,
decreased
toxicity
Oral
C^-acyloxyalkyl esters
3. 7-Acylami nocephalosporani c
acid
59
60
Absorption
Reference
Absorption
Oral
Property
Mod i f i ed
Oral
Route o f
Administration
C.-p-alkoxycarbonyloxybenzyl
esters
c.
b.
a.
Chemical
Modification
2. 7-Acylami nocephalosporani c
acid
1. 7-Acylcephalosporanic Acid
Parent Molecule
7 - S u b s t i t u t e d cephalosporanic
S u b s t i t u t e d 7-3-aminocephemol- C . - p h y s i o l o g i c a l l y l a b i l e
4-carboxylic acid
esters
8.
9.
Oral
Oral
Oral
Oral
Route o f
Administration
^-Aminoacyloxymethyl e s t e r s
C.-acyloxymethyl e s t e r s
7.
Imino ether
Chemical
Modification
Molecule
(Continued)
6.
Parent
TABLE IV.
65
Absorption
67-69
Absorption,
i n c r e a s e d water
solubility,
66
decreased s i d e
effects
Absorption
6 4
Reference
Decreased
toxicity,
resistance to
3-lactamase
Property
Modified
140
PRO-DRUGS
Cephaloglycin
41 H CI (Acetoxy methyl ester)
- -
Journal of Antibiotics
Figure 1. Mean serum levels of cephaloglycin in fasting, healthy volunteers following oral administration of
200 mg of cephaloglycin and equimolar amounts of 41
HCI and 45 HCI (49)
Scheme XVII
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
2.
siNKULA
141
142
PRO-DRUGS
Scheme XVIII.
Clindamycin-2-monoesters
CH
'ISh
49
II
ROC C I ,
Base
-25C
CH
H-C-CI
I
C-NH-CH
S
ROC
HO^o
SCH
OH
Acylation
Pyridine.R.T.
690 (69)
2-hexanoate h y d r o c h l o r i d e
330 (33)
2-hexylcarbonate h y d r o c h l o r i d e
20 (2.0)
2-laurate hydrochloride
21 (2.1)
2-palmitate h y d r o c h l o r i d e
<4 (<0.4)
2-hexadecylcarbonate h y d r o c h l o r i d e
55 (5.5)
2-(p-benzoyl) benzoate h y d r o c h l o r i d e
7 (0.7)
2-(o-benzoyl) benzoate h y d r o c h l o r i d e
180
(18)
3-pentylcarbonate h y d r o c h l o r i d e
2,3-bis (hexylcarbonate) h y d r o c h l o r i d e <4 (<0.4)
0.67
1.31
1.36
0.43
<0.28
<0.1
<0.3
0.21
<0.1
0.23
1.67
0.54
<0.15
0.29
0.37
0.67
0.60
0.18
JOURNAL OF PHARMACEUTICAL
SCIENCES
Clindamycin
Clindamycin
Clindamycin
Clindamycin
Clindamycin
Clindamycin
Clindamycin
Clindamycin
Clindamycin
In V i t r o
A c t i v i t y , . R e l a t i v e Median P r o t e c t i v e Dose ( C D )
mcg./mg.
Subcutaneous
Oral
Antibacterial Activity
144
PRO-DRUGS
2.
siNKULA
145
TABLE VI
Pharmacokinetic Parameters Estimated from Serum Clindamycin B i o a c t i v i t y Concentrations Following Oral A d m i n i s t r a t i o n (150 mg.)
o f Clindamycin-2-Palmitate ( A ) , Clindamycin-2-Hexadecylcarbonate
(B), and Clindamycin H y d r o c h l o r i d e (C)
Parameter
K. ( h r . " )
2.81(0.92)
1.23-4.38&
1.53(0.94)
0.75-3.41
7.65(7.56)
1.03-22.92
A, ( h r . )
0.28(0.11)
0.16-0.56
0.25
0.58(0.25)
0.20-0.93
0.76
0.19(0.18)
0.03-0.67
0.15
Estimated time o f
1.16(0.24)
maximum c o n c e n t r a t i o n ( h r . ) 0.86-1.62
1.15
1.67(0.32)
1.09-2.09
1.80
0.86(0.53)
0.19-1.88
0.78
Estimated maximum
c o n c e n t r a t i o n (yg/ml)
1.99(0.61)
1.29-3.34
1.97
1.47(0.48)
0.97-2.33
1.44
2.61(1.14)
1.75-5.75
2.38
Observed maximum
c o n c e n t r a t i o n (pg/ml)
2.05(0.66)
1.33-3.38
2.05
1.47(0.54)
0.96-2.39
1.42
2.80(1.26)
1.67-6.40
2.39
- 1
0.25(0.07)
0.17-0.35
0.24
0.35(0.19)
0.17-0.81
0.36
0.26(0.07)
0.18-0.35
0.23
E, ( h r . )
*
2.94(0.83)
2.00-4.08
2.83
2.48(1.14)
0.85-4.17
1.95
2.84(0.76)
2.00-3.93
3.04
(hr. )
Area, 0 ( p g
hr./ml)
146
PRO-DRUGS
JOURNAL OF ANTIBIOTICS
1.23 mcg/ml a t 45 mi
74 5
0.76
136 32
Clindamycin-2-P0
2.25 mcg/ml a t 30 mi
72 10
1.00
177 30
Clindamycin
Mean time o f
Max. cone.(mcg/ml)
50% area 2 S E '
a t time t
Area under , x
curve 2 SE '
R e l a t i v e area
o f curves '
dose o f c l i n d a m y c i n and
Antibiotic
TABLE VII
148
PRO-DRUGS
Scheme XXI
4
Hr. after 1st Dose
8j
7.5
| 0
43rd Dose
Journal of Clinical Pharmacology
siNKULA
20fl
18
Clindamycin bioactivity
"Total" clindamycin +
clindamycin phosphate)
\/
/
/
/
/
-Total"
^Clindamycin phosphate
Clindamycin-
10
12
150
PRO-DRUGS
Acknowledgements
The author wishes to express his appreciation to Dr.
W. Morozowich for helpful suggestions concerning the synthesis
of clindamycin phosphate. Special thanks are also extended to
D. Harling for typing and to E.E. Beals for preparation of the
schemes and figures used throughout the manuscript.
Literature Cited
SINKULA
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
151
2.
152
PROD
- RUGS
2. sN
i KULA
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
153
3
The Chemistry of a Novel 5,5-Diphenylhydantoin
Pro-drug
V. STELLA, T. HIGUCHI, A. HUSSAIN, and J. TRUELOVE
University of Kansas, Department of Pharmaceutical Chemistry and
INTERx Research Corp., Lawrence, Kans. 66044
Phenytoin or 5,5-diphenylhydantoin (DPH), a
widely used anticonvulsan
primaril i
the treatment of gran
erratic absorption and dissolution patterns as well
as possible precipitation in the body after intravenous (I.V.) infusions of highly alkaline solutions
of its sodium salt (1-6). It was the objective of
this work to find a water soluble pro-drug (7,8)
form of DPH which would revert to DPH in the body.
The aim was to improve both the parenteral and oral
bioavailability of DPH.
A number of hydantoins including DPH, mephenytoin
or 5-ethyl-3-methyl-5-phenylhydantoin (I), and nitrofurantoin or 1-(5-nitro-2-furfurylindene) aminohydantoin (II) are widely used as drugs. Their uses,
however, have been hampered by their low water solubility combined with their weakly acidic nature.
Orally the bioavailability of DPH from capsules
has been erratic (1-3). The P a of DPH, approximately 8.3 (1,9), allows DPH to be formulated as its
mono-sodium salt. Formulations of DPH as the free
acid are also available. A report before a congressional investigation committee in 1967 suggested
that a brand change of DPH resulted in increased convulsive seizures due to lower bioavailability from
the new formulation. Similarly differences between
products have been noted by Martin et al. (2) and by
Arnold et al. (1). The dependency of DPH blood levels
after oral dosing on differences, in the rate of
metabolism of DPH, particle size, and various generic
and trade name products has recently been discussed
by Glazko (10). DPH has an aqueous solubility of
between 1-4 mg/100 ml (1)and it appears that this
poor aqueous solubility is the major cause of the
erratic absorption and dissolution rates (1) of
K
154
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
3.
STELLA
E T
AL.
(ID
v a r i o u s DPH p r e p a r a t i o n s .
The low aqueous s o l u b i l i t y o f DPH can be a t t r i b u t e d t o i t s s t r o n g c r y s t a l
l a t t i c e (mp. 293) r e s u l t i n g from i n t e r m o l e c u l a r h y d r o gen b o n d i n g (11).
That the s t r o n g c r y s t a l l a t t i c e i s
a major f a c t o r i n the d e t e r m i n a t i o n o f s o l u b i l i t y i s
a l s o e x e m p l i f i e d by the poor l i p i d s o l u b i l i t y o f DPH.
DPH i s g i v e n p a r e n t e r a l l y as i t s mono-sodium s a l t
in a reconstituted i n j e c t i o n with a solvent consist i n g o f "40% p r o p y l e n e g l y c o l and 10% a l c o h o l i n water
f o r i n j e c t i o n and i s b u f f e r e d t o pH 10 t o 12 w i t h
sodium h y d r o x i d e " (12) .
Blum e t a l . (_5,6) and o t h e r s
(13) n o t e d s e v e r e s i d e e f f e c t s " T h dogs and man when
DPH i n j e c t i o n s were g i v e n i n t r a v e n o u s l y .
A subsequent
autopsy o f the dogs used i n the experiments o f Blum
e t a l . (5^,6) showed p r e c i p i t a t i o n o f DPH i n the l u n g s ,
I T e . , the i n j e c t i o n o f sodium DPH o f pH 12 on m i x i n g
w i t h b l o o d b u f f e r e d a t pH 7.4 r e s u l t e d i n the p r e c i p i t a t i o n o f DPH as the f r e e a c i d .
Precautions i n
the I . V . use o f i n j e c t a b l e DPH i n the t r e a t m e n t o f
s t a t u s e p i l e p t i c u s and d i g i t a l i s i n t o x i c a t i o n
(13)
and i n the attempted p r e p a r a t i o n o f l a r g e volume I . V .
155
156
PRO-DRUGS
N-C-OC H .
HN
XT
(III)
3.
STELLA
E T
AL.
/ 2 5
OC H -N-H
C
NHCNHC
I
CH
C H
2
(IV)
pH = 7 . 4 , = 37<
t i = 20 m i n .
C H -C
2
(I)
The s y n t h e s i s , c h e m i s t r y , p h y s i c a l p r o p e r t i e s
and f o r m u l a t i o n problems o f a s i m i l a r d e r i v a t i v e t o
IV b u t f o r DPH w i l l be p r e s e n t e d a t t h i s t i m e .
Rationale
E s t e r s o f h y d a n t o i c a c i d s were known t o c y c l i z e
v i a an i n t r a m o l e c u l a r r e a c t i o n under b a s i c c o n d i t i o n s
t o t h e i r r e s p e c t i v e h y d a n t o i n (scheme I) b u t no
a c t u a l k i n e t i c d a t a was a v a i l a b l e .
K i n e t i c d a t a was
a v a i l a b l e on the c y c l i z a t i o n o f e s t e r s o f the r e l a t e d
O - u r e i d o b e n z o i c a c i d i n water i n the n e u t r a l t o a l k a
l i n e pH range (31).
I n t r a m o l e c u l a r c y c l i z a t i o n s had
been p o s t u l a t e d as a means o f l a t e n t i a t i o n by L e v i n e
157
158
PRO-DRUGS
R
OH
HN^
CNH
R"
I
C1
Il
4
-COR^
2 I
R-C-
HN
NCH-
Scheme I
e t a l . (32) i n t h e i r work on the c o n v e r s i o n s o f - h a l o alkylamines to t h e i
many d e r i v a t i v e s o f drugs formed t h r o u g h an e s t e r l i n k
age have been dependent on e n z y m a t i c r e a c t i o n s t o r e
l e a s e the p a r e n t compound (3J3,_34) .
The c y c l i z a t i o n s o f
the e s t e r s o f h y d a n t o i c a c i d a r e i n t r a m o l e c u l a r r e a c
t i o n s and t h e s e are known t o be many o r d e r s o f m a g n i
tude f a s t e r than t h e i r i n t e r m o l e c u l a r e q u i v a l e n t .
This
forms a b a s i s f o r the f o r m a t i o n o f the p a r e n t drug from
i t s p r o - d r u g which i s n o t dependent on e n z y m a t i c m e d i a
tion.
P r o c e d u r e and R e s u l t s
Because o f the a p p a r e n t s u c c e s s o f compound IV i n
p r o d u c i n g a water s o l u b l e p r o - d r u g o f I a s i m i l a r d e
r i v a t i v e t o IV b u t f o r DPH was s y n t h e s i z e d .
The com
pound o f i n t e r e s t was V .
(V)
The s y n t h e s i s o f V was a c c o m p l i s h e d v i a the
f o l l o w i n g p r o c e d u r e and pathway.
The f i r s t s t e p i n
v o l v e d the r e a c t i o n o f 2 , 2 - d i p h e n y l g l y c i n e w i t h e t h y l c h l o r o f o r m a t e under aqueous a l k a l i n e c o n d i t i o n s .
Ini
t i a l l y the s y n t h e s i s o f 2 , 2 - d i p h e n y l g l y c i n e was accom
p l i s h e d by t h e method o f D u s c h i n s k y (35.) which i n v o l v e d
the a c t u a l h y d r o l y s i s o f DPH i n 20% sodium h y d r o x i d e
3.
STELLA
E T A L .
159
160
PRO-DRUGS
3.
STELLA ET A L .
V-cCOOH
c=o
HN
C0C Hc
o
(VIII)
To HCI Trap
HCI
(gas)
Oil
Bath
Magnetic
Heater
Stirrer/
162
PRO-DRUGS
o c c a s i o n a l l y observed at t h i s p o i n t .
This material
may be saved by washing t h o r o u g h l y w i t h c h l o r o f o r m ,
f i l t e r i n g , and a d d i n g i t to the c h l o r o f o r m s o l u t i o n
o f X i m m e d i a t e l y p r i o r t o the NaOH e x t r a c t i o n
procedure below.
The c h l o r o f o r m f i l t r a t e was p l a c e d on a r o t a r y
e v a p o r a t o r and a p p r o x i m a t e l y 50 ml o f c h l o r o f o r m were
removed.
Any e x c e s s HCI d i s s o l v e d i n the r e a c t i o n
m i x t u r e was removed by t h i s p r o c e d u r e .
The r e
m a i n i n g c h l o r o f o r m " r e a c t i o n m i x t u r e " s o l u t i o n was
then e x t r a c t e d w i t h aqueous NaOH u n t i l the aqueous
l a y e r had a pH > 11.
Each f r a c t i o n (aqueous and o r
g a n i c ) was b a c k - e x t r a c t e d and the c h l o r o f o r m l a y e r s
combined w i t h anhydrous sodium s u l f a t e .
A f t e r d r y i n g , th
c h l o r o f o r m removed w i t h the a i d o f a r o t a r y e v a p o r a t o r .
The r e s u l t i n g c l e a r y e l l o w o i l s h o u l d be n e a r l y pure
X as the f r e e b a s e .
The o i l y p r o d u c t may c o n t a i n
u n r e a c t e d , - d i e t h y l a m i n o e t h a n o l , which was r e a d i l y
d e t e c t e d by NMR. I f the a m i n o a l c o h o l was p r e s e n t
the o i l y m a t e r i a l was washed by the f o l l o w i n g
procedure :
To the p r o d u c t , i n a l a r g e s e p a r a t o r y f u n n e l ,
was added 250 ml c o l d ( ^ 4 ) w a t e r .
The m i x t u r e was
shaken g e n t l y and the l a y e r s a l l o w e d t o s e p a r a t e .
V i g o r o u s s h a k i n g r e s u l t e d i n a e m u l s i o n which s e p a
r a t e d very s l o w l y .
The o i l y l a y e r was then s e p a r a t e d
and added t o a f l a s k c o n t a i n i n g a p p r o x i m a t e l y 200 ml
c h l o r o f o r m o v e r anhydrous sodium s u l f a t e .
After
d r y i n g , the s o l u t i o n was f i l t e r e d and the c h l o r o f o r m
removed on the r o t a r y e v a p o r a t o r .
The r e s u l t i n g o i l
was X.
The r e a c t i o n sequence f o r s t e p I I I i s o u t l i n e d
on the f o l l o w i n g page and u s u a l l y r e s u l t e d i n 95-100%
o f the t h e o r e t i c a l y i e l d :
Step I V .
X, a p p r o x i m a t e l y 65 g , was d i s s o l v e d
i n 170 ml g l a c i a l a c e t i c a c i d .
The s o l u t i o n was
s t i r r e d i n an i c e b a t h u n t i l a c l e a r s o l u t i o n r e
sulted.
W h i l e v i g o r o u s l y s t i r r i n g the a c e t i c s o l u
t i o n , 17.8 g (0.22 moles) p o t a s s i u m i s o c y a n a t e was
g r a d u a l l y added.
The s o l u t i o n was a l l o w e d t o s t i r
f o r 15 minutes i n the i c e b a t h and t h e n an a d d i t i o n a l
t h r e e hours a t room t e m p e r a t u r e .
The p r o d u c t $ - N ' , N - d i e t h y l a m i n o e t h y l - 2 , 2 d i p h e n y l h y d a n t o a t e (XI) was i s o l a t e d as the HSO4
s a l t by the f o l l o w i n g p r o c e d u r e :
A f t e r t h r e e hours s t i r r i n g a t room t e m p e r a t u r e ,
125 ml methanol was added to the r e a c t i o n m i x t u r e .
To a s e p a r a t e 125 ml p o r t i o n o f m e t h a n o l , 16.7 ml
(30 g , 0.3 moles) c o n c e n t r a t e d (98%)
sulfuric
,
3.
STELLA
E T
AL.
C= 0
HOC H -N
(IX)
HCI
M
/
C-OC H -N
2
NH 2
CO
2
(X)
a c i d was c a r e f u l l y added.
A f t e r the s u l f u r i c
a c i d / m e t h a n o l s o l u t i o n had c o o l e d t o room temperat u r e , i t was added t o the methanol r e a c t i o n m i x t u r e
s o l u t i o n with vigorous s t i r r i n g .
The HSO4 s a l t o f
p r o d u c t , X I , was t h e n p r e c i p i t a t e d by the a d d i t i o n
of e t h e r .
(Ether was added u n t i l no f u r t h e r p r e c i p i t a t i o n occurred.
Up t o 2 l i t e r s o f e t h e r may be
required.)
The r e a c t i o n sequence i s o u t l i n e d on the f o l lowing page:_
The HSO4 s a l t (XI) was c o n v e r t e d t o the S 0
salt
(XII) by the f o l l o w i n g p r o c e d u r e :
P r o d u c t X I , 47 g (0.1 m o l e ) , was d i s s o l v e d i n
1500 ml water (a c l e a r s o l u t i o n may n o t r e s u l t i f
p r o d u c t , X I , was i m p u r e ) .
Ammonium s u l f a t e , 1425 g ,
was d i s s o l v e d i n 2000 ml water and the s o l u t i o n
filtered.
The s o l u t i o n o f XI was t h e n f i l t e r e d
i n t o the same f l a s k and the m i x t u r e s t i r r e d .
After
c r y s t a l l i z a t i o n had commenced, the f l a s k was c o o l e d
t o 0 - 5 and l e f t f o r 3-4 hours a t t h i s temperature
or stored overnight i n a r e f r i g e r a t o r .
The c r y s t a l s were r e c o v e r e d by f i l t r a t i o n .
After
the c r y s t a l s had been d r i e d on the f i l t e r , the
c r y s t a l s were added t o 10 ml o f the w a t e r .
The m i x t u r e was s t i r r e d t h o r o u g h l y and the w a t e r removed by
vacuum f i l t r a t i o n .
=
163
164
PRO-DRUGS
1)KCN0/CH C00H
3
O C
2 4~
H
N <
(X)
HSO
(XI)
A f t e r a l l apparent t r a c e s o f m o i s t u r e had been
removed, the c r y s t a l s were t r a n s f e r r e d t o a f l a s k
c o n t a i n i n g 750 ml o f 95% e t h a n o l and s t i r r e d t h o r
oughly.
A t t h i s s t a g e , a c l e a r s o l u t i o n may n o t
r e s u l t due t o the p r e s e n c e o f (NH4)2S04.
The s o l u t i o n
was f i l t e r e d and the p r o d u c t X I I was p r e c i p i t a t e d by
the a d d i t i o n o f e t h e r ( a p p r o x i m a t e l y 2 l i t e r s was
required).
The e t h a n o l / e t h e r s o l u t i o n was s t i r r e d
f o r s e v e r a l hours o r o v e r n i g h t a t room temperature
and the c r y s t a l l i n e p r o d u c t r e c o v e r e d by f i l t r a t i o n .
The p e r c e n t a g e y i e l d i n the f i n a l c o n v e r s i o n t o
p r o d u c t XII was u s u a l l y q u i t e low (30-50%).
I t should
be p o i n t e d o u t t h a t t h i s s t e p c o u l d be improved by
a r e c y c l i n g o f the aqueous s o l u t i o n .
Compound, X I I , o r the h e m i - s u l f a t e s a l t o f - ' ,
N - d i e t h y l a m i n o e t h y l - 2 , 2 - d i p h e n y l h y d a n t o a t e w i l l be
r e f e r r e d t o as Pro-DPH f o r c o n v e n i e n c e ; t h i s was the
d e r i v a t i v e used i n a l l subsequent s t a b i l i t y and
animal s t u d i e s .
T a b l e I g i v e s the m e l t i n g p o i n t s , m o l e c u l a r
w e i g h t s , % e q u i v a l e n t o f DPH and s o l u b i l i t y o f a
number o f - , N - d i e t h y l a m i n o e t h y l - 2 , 2 - d i p h e n y l hydantoate s a l t s at 2 5 i n water.
The s u p e r i o r
aqueous s o l u b i l i t y o f t h e h e m i - s u l f a t e s a l t made i t
the c a n d i d a t e o f c h o i c e f o r i n i t i a l s c r e e n i n g
for anticonvulsant a c t i v i t y .
N o t e , t h a t DPH has
a s o l u b i l i t y o f a p p r o x i m a t e l y 2 mg/100 ml
,
3.
STELLA
E T A L .
H2
(XII)
or 0.02 mg/ml i n aqueous s o l u t i o n at pH pK at
25 which means that the increase i n aqueous s o l u
b i l i t y of Pro-DPH over DPH i s about a f a c t o r of
15,000 or 9,000 i n terms of DPH equivalents.
a
Table I
Some p h y s i c a l properties of various s a l t forms of
-', -diethylaminoethyl-2,2-diphenylhydantoate.
1
Mol.
Wt.
%Equivalence Melting
Pt.
of Diphenylhydantoin
Solu- *
bility
at 25 C
HN0
432
58.3
173(dec)
22 mg/ml
HCL
405.5
62.1
188
23 mg/ml
49.7
138
8 mg/ml
145
301 mg/ml
Salt
S a l i c y l a t e 507
Sulfate
837.01
60.28
S o l u b i l i t y r e f e r s to the s o l u b i l i t y of the s a l t
i t s e l f and not DPH equivalence.
** This gives an aqueous s o l u t i o n of pH ^ 3.3.
165
166
PRO-DRUGS
fc
[DPHft
= 2k [Pro-DPHl
(eq. 1)
^ t
o
/ci [DPHN
where V d s
is the i n i t i a l rate of formation of DPH
from Pro-DPH, [Pro-DPH] i s the i n i t i a l concentration
of Pro-DPH and k i s the pseudo f i r s t order observed
rate constant f o r the conversion of Pro-DPH to DPH
under the designated experimental conditions. I f
d[DPHf\ i s expressed as mg/ml/hr and [Pro-DPH]
d
(.
3.
STELLA ET
AL.
CO
-H
>
I
m
r-i
rd
--
rH
Cfl
0
^!
m
m
<d
*"
CM
4J
\
(d
4J
(d
<
>
En
CO
LO
C0
00
CO
C0
CM
00
rd
-
Cl
CO
m
CM
CM CO
I
i
m
CM
-
fd
CM
Q
0
-M
ffi
CM
*
CO
M
P4
CM
CO
I
C0
*>
CM
as
00
CM
00
Q
1
0
M-l
00
CM
00
CO
rH
CM
>
0
**
167
168
PRO-DRUGS
= k [Pro-DPH]
1
2 )
(eq. 3)
p p t e
p p
Table I I I
Apparent zero order i n i t i a l rate of formation of
DPH from Pro-DPH as a function of i n i t i a l Pro-DPH
concentration at 25 and pH 3 and the p o t e n t i a l
t
based on Equations 1-3 and a s o l u b i l i t y of
Dt>! at 25 and pH 3 of 2 mg/100 ml.
t
t .
(min)
PPte
[Pro-DPH]
[d[DPH]/dt)
25 mg/ml
50 mg/ml
52 min
26
100 mg/ml
13
200 mg/ml
1.85 lO^mg/ml/hour
p p
3.
STELLA
ET
AL.
-51
0
I
1
I
2
I
3
I
4
I
5
I
6
1
7
i
8
1
9
L
10
PH
169
170
PRO-DRUGS
Table IV
Experimental Determination of T u r b i d i t y Time as a
Function of I n i t i a l Pro-DPH Concentration.
Concentration of Pro-DPH i n
mg/ml i n d i s t i l l e d water
pH
Time f o r T u r b i d i t y
Development
83.25
3.6
36 Minutes
83.25
3.7
15 Minutes
1 Hour 10 Minutes
208.1
2 Hours 10 Minutes
246.75
3.5
36 Minutes
124.84
166.5
3.
STELLA
E T
AL.
solubility.
The c y c l i z a t i o n o f Pro-DPH t o DPH a t
2 5 and pH 4.5 (the pH n e c e s s a r y t o m i n i m i z e d i s s o c i a
t i o n o f Pro-DPH s a l i c y l a t e ) has a h a l f - l i f e o f 180
hours o r k k
i s 3.85 10"3 h o u r s " .
The i n i t i a l
r a t e o f f o r m a t i o n o f DPH o r ( d [ D P H ] / d t ) from t h i s
s a t u r a t e d s o l u t i o n would be 0.015 mg/ml/hour, i . e . ,
i t would be 1.3 hours b e f o r e DPH would b e g i n
p r e c i p i t a t i n g out.
T a b l e V shows the e f f e c t
o f added s a l i c y l a t e a n i o n on the s o l u b i l i t y o f P r o DPH s a l i c y l a t e .
In the p r e s e n c e o f 0.1 M sodium
s a l i c y l a t e , the s o l u b i l i t y i s lowered t o 1 mg/ml so
t h a t the i n i t i a l r a t e o f f o r m a t i o n o f DPH becomes
0.0010 mg/ml/hour and i t would be 10.5 hours b e f o r e
DPH would b e g i n t o p r e c i p i t a t e .
The c a l c u l a t e d
s o l u b i l i t y product o
d a t a was found t o be 3.04 1 0 ~ M .
0
S c i
Table V
Aqueous S o l u b i l i t y o f Pro-DPH S a l i c y l a t e as
F u n c t i o n o f Added S a l i c y l a t e A n i o n
Pro-DPH s a l i c y l a t e
s o l u b i l i t y i n mg/ml
6.8
0.01
2.9
0.05
1.5
0.10
S i n c e the pK
s o l u b i l i t y product w i l l
o f about two
(^ 1.5
SP
3.04xlO" M
4
of s a l i c y l i c i s ^ 3.0,
as the pH i n c r e a s e s ,
Calculate
Cone, o f
added Sodium S a l i
cylate
8.7
or
the
n o t change s i g n i f i c a n t l y
but w i l l
1"
d e c r e a s e by a
factor
M ) a t pH 3 . 0 .
2
Discussion
The s y n t h e s i s o f Pro-DPH was n o t s h o r t b u t a t
the same time d i d n o t r e q u i r e any h i g h degree o f
sophistication.
On a commercial b a s i s , the c o n v e r
s i o n o f V I , 2 , 2 - d i p h e n y l g l y c i n e , t o IX might be
e f f e c t e d by a one s t e p r e a c t i o n w i t h phosgene r a t h e r
than the two s t e p approach t a k e n .
O b v i o u s l y the c o s t
o f p r o d u c i n g the Pro-DPH would be h i g h e r than DPH
171
172
PRO-DRUGS
3.
STELLA
E TA L .
obsd
[ H + ] a
-OH
r
k ' - ^ ] (1-a)
(eq. 4)
where k b s d i s the o b s e r v e d r a t e c o n s t a n t f o r t h e
c o n v e r s i o n o f Pro-DPH a t a g i v e n t e m p e r a t u r e , k +
i s an a c i d c a t a l y z e d c o n s t a n t , k i s a spontaneous
o r water c a t a l y z e d r a t e c o n s t a n t , k is a specific
base c a t a l y z e d r a t e c o n s t a n t r e p r e s e n t i n g t h e a t t a c k
o f the u r e i d o a n i o n
p r o t o n a t e d form o f Pro-DPH and k ' is a specific
base c a t a l y z e d r a t e c o n s t a n t r e p r e s e n t i n g t h e a t t a c k
o f t h e u r e i d o a n i o n a t t h e e s t e r l i n k a g e o f the u n p r o t o n a t e d form o f P r o - D P H .
A l t h o u g h w i t h Pro-DPH
no s o p h i s t i c a t e d p h y s i c a l o r g a n i c study was c a r r i e d
o u t ( t h a t was n o t t h e o b j e c t i v e o f t h i s study) by
i n f e r e n c e t o o u r e a r l i e r more d e t a i l e d k i n e t i c
s t u d y o f the c o n v e r s i o n o f IV t o I the l o g k
v e r s u s pH p r o f i l e and E q u a t i o n 4 were c o n s i s t e n t w i t h
Scheme I I .
A t p H ' s g r e a t e r t h a n 5 b u t l e s s t h a n the p K
o f t h e amino g r o u p , t h e r a t e d e t e r m i n i n g s t e p appears
t o be t h e i n t r a m o l e c u l a r a t t a c k o f t h e u r e i d o a n i o n
on the n e i g h b o r i n g e s t e r l i n k a g e .
T h i s was c o n s i d e r e d
t o be t h e most l i k e l y mechanism because o f t h e l a c k
o f b u f f e r c a t a l y s i s (30).
The spontaneous r a t e c o n
s t a n t k p r o b a b l y i n v o l v e s the a t t a c k o f t h e n e u t r a l
u r e i d o group a g a i n v i a an i n t r a m o l e c u l a r r e a c t i o n on
the n e i g h b o r i n g e s t e r l i n k a g e .
These r e a c t i o n s
o f c o u r s e i n v o l v e Pro-DPH c o n v e r t i n g t o DPH w i t h t h e
subsequent e x p u l s i o n o f t h e , - d i e t h y l a m i n o e t h a n o l
leaving group.
The minor n a t u r e o f t h e a p p a r e n t
s p e c i f i c a c i d c a t a l y z e d pathway which i n v o l v e s t h e
a t t a c k o f t h e u r e i d o group on the p r o t o n a t e d e s t e r
f u n c t i o n i s p r e d i c t a b l e i n t h a t p r o t o n a t i o n o f the
e s t e r f u n c t i o n would n o t be f a v o r a b l e due t o e l e c t r o
s t a t i c r e p u l s i o n . The d i m i n u t i v e n a t u r e o f t h i s
pathway i s c o n s i s t e n t w i t h e a r l i e r h y d r o l y s i s s t u d i e s
on o t h e r amino e s t e r s such as p r o c a i n e (.37) and
a t r o p i n e (38^,39) t where l i t t l e s p e c i f i c a c i d c a t a l y z e d
h y d r o l y s i s was s i m i l a r l y n o t e d .
These r e a c t i o n s
d i d n o t i n v o l v e an i n t r a m o l e c u l a r r e a c t i o n
b u t were normal i n t e r m o l e c u l a r h y d r o l y s i s r e a c t i o n s .
T a b l e I n o t e d t h e 15,000 f o l d i n c r e a s e i n aqueous
s o l u b i l i t y o f Pro-DPH o v e r DPH. I n terms o f DPH
Q
Q H
0 H
o t ) S d
H 0
R,
2 5 2
K,
( C
C-OC H -N(C H )
+H
O R
li i
- 2 4-7
NH-C-NH
\ /
-H
Scheme
II
HYDANTOIN
+H
+H
-H
K
2
-H
i - \
\ /
R_
NH-C-N
+H
O R
II l
NH-C-NH
C-OCJ.-N(C
3.
STELLA
ET
AL.
t e
Conclusion
The o r i g i n a l objective of t h i s work was to u t i l i z e the pro-drug approach to produce a b i o - r e v e r s i b l e
DPH d e r i v a t i v e with good aqueous s o l u b i l i t y . I t was
hoped that the d e r i v a t i v e would have good i n vivo
DPH release c h a r a c t e r i s t i c s (see the paper of Glazko
et a l . following) and lead to a superior form of DPH.
A water soluble b i o r e v e r s i b l e pro-drug of DPH was
synthesized and i t s p h y s i c a l and chemical properties
studied. The pro-drug was an a c y c l i c form of DPH
which underwent an intramolecular reaction to regenerate the parent compound, DPH.
Under simulated
p h y s i o l o g i c a l conditions, the h a l f - l i f e f o r the conversion of the Pro-DPH to DPH was approximately seven
minutes i l l u s t r a t i n g that enzyme mediation i n the r e generation of the parent compound was unnecessary.
The r e l a t i v e s t a b i l i t y of Pro-DPH under a c i d i c s o l u t i o n s , pH ^ 3, allowed a l y o p h i l i z e d powder to be
formed. When reconstituted with water, the extremely
poor aqueous s o l u b i l i t y of the gradually formed DPH
did create problems by producing t u r b i d solutions rel a t i v e l y q u i c k l y . The e f f e c t of the counter anion
175
176
PRO-DRUGS
3.
STELLA
E T
A L .
R
2
I II
R-C-C-0
+H
NHCNH3
Il
K'
a
(A )
R
I II
CCOH
2
R CCOH
.+
+H
NHCNH
O
NHCNH
O R
(HA)
\
(H A )
2
,
product
I
C
/ '2
k
C=0
1
HN
NR
II
o
(H)
Scheme
III
where R , R , R = a l k y l ,
hydrogen s u b s t i t u e n t s .
1
aryl,
and/or
177
178
PRO-DRUGS
w e l l as a p o s s i b l e i n c r e a s e i n water s o l u b i l i t y .
E n g l i s h e t a l . ( 1 ) t e s t e d b o t h t h e i n v i t r o and
in vivo a c t i v i t y of various 3 - a l k y l , 3-acyl,
3-acyloxym e t h y l , and 3 - a l k o x y c a r b o n y l d e r i v a t i v e s (see s t r u c t u r e
below) o f t h e h y d a n t o i n , n i t r o f u r a n t o i n (II) a g a i n s t
v u l g a r i s .
They n o t e d l i t t l e c o r r e l a t i o n between i n
(ID
where R = - a l k y l ;
- C R where R i s an
a l k y l , a r y l o r a l k o x y g r o u p ; and - O ^ O R
where R
i s an a l k y l o r a c y l g r o u p .
1
1 1
3.
STELLA E T A L .
C= 0
HN
N C - 0 C H
'
Il
o
(III)
had a mp o f 138-140, i . e . , a c y l a t i o n a t t h e 3 p o s i t i o n
o f DPH caused a d e c r e a s e i n mp o f a p p r o x i m a t e l y 1 6 0
when compared t o DPH. T h i s o c c u r r e d as t h e a c y l group
d i s p l a c e d t h e most a c i d i c p r o t o n o f DPH [ p K 8 . 3 ,
(1/9.)] r e s u l t i n g i n d e c r e a s e d i n t e r m o l e c u l a r hydrogen
bonding i n the c r y s t a l l a t t i c e .
S e v e r a l s t u d i e s have
s u g g e s t e d t h a t 1 - a c y l - and l , 3 - d i a c y l - 5 , 5 - d i p h e n y l h y d a n t o i n s had l i t t l e a n t i c o n v u l s a n t a c t i v i t y and were
e s s e n t i a l l y e x c r e t e d as 1 - a c y l - 5 , 5 - d i p h e n y l h y d a n t o i n
whereas 3 - a c y l d e r i v a t i v e s had c o n s i d e r a b l e a n t i c o n v u l s a n t a c t i v i t y and i n t h e c a s e o f I I I t h e a c t i v i t y a p p e a r e d t o be g r e a t e r than DPH i t s e l f .
These r e s u l t s
suggest t h a t 3 - a c y l d e r i v a t i v e s are converted to the
p a r e n t h y d a n t o i n whereas t h e 1 - a c y l d e r i v a t i v e s a r e r e s i s t a n t to b i o t r a n s f o r m a t i o n to the parent hydantoin.
Nakamura e t a l . (26-29) have shown t h a t I I I demonstrat e d h i g h e r b l o o d l e v e l s and h i g h e r CNS l e v e l s o f DPH i n
r a t s and dogs when compared t o DPH i t s e l f .
Both drugs
were g i v e n as o r a l s u s p e n s i o n s .
Two human t r i a l s comparing I I I t o DPH by K i s h i e t
a l . (48) and Taen e t a l . ( 9 ) were e n c o u r a g i n g e s p e c i a l l y i n t h e i r conclusions of diminished side e f f e c t s
o f I I I r e l a t i v e t o DPH.
We have r e c e n t l y s y n t h e s i z e d a s e r i e s o f 3 - a l k o x y c a r b o n y l - 5 , 5 - d i p h e n y l h y d a n t o i n d e r i v a t i v e s w i t h a view
o f u t i l i z i n g t h e lower m e l t i n g p o i n t s and h i g h e r l i p i d
s o l u b i l i t i e s o f the d e r i v a t i v e s t o e f f e c t a s o f t g e l a t i n c a p s u l e dosage form o f DPH.
3-Hexoxycarbonyl-5,5d i p h e n y l h y d a n t o i n (XV) has a m e l t i n g p o i n t o f 8 6 and
was found t o be s o l u b l e and s t a b l e i n sesame o i l , p e a nut o i l , e t c .
XV was a l s o s t a b l e i n t h e b l a n d o i l s i n
the p r e s e n c e o f s u r f a c t a n t s such as Tween 80.
The b i o a
180
PRO-DRUGS
6 13
(XV)
a v a i l a b i l i t y o f DPH
form o f XV w i l l be r e p o r t e d a t a l a t e r d a t e .
The h y d a n t o i n , 5 - e t h y l - 5 - p h e n y l h y d a n t o i n (XVI) o r
N i r v a n o l was marketed as an a n t i c o n v u l s a n t drug b u t
f e l l i n t o d i s f a v o r and was removed from the market b e
cause o f h i g h t o x i c i t y .
I i s d e m e t h y l a t e d i n man and
dog t o XVI and i t seems l i k e l y t h a t the a n i t c o n v u l s a n t
a c t i v i t y o f I (see Scheme IV) i s , i n p a r t , due t o i t s
d e m e t h y l a t e d p r o d u c t , XVI (5JD) .
T h e r e f o r e , i t would
seem t h a t I i t s e l f i s a p r o - d r u g o f X V I .
P r o - d r u g s o f h y d a n t o i n s are not numerous.
This
s e c t i o n has r e v i e w e d what d e r i v a t i v e s have been attemp
t e d w i t h the hope t h a t i t might s t i m u l a t e f u r t h e r i n
v e s t i g a t i o n i n t o more e f f i c i e n t l y absorbed h y d a n t o i n
pro-drugs.
C= 0
N - CH
HN
oxidation
in vivo
C=0
C-
NH
HN
II
II
(XVI)
(I)
Scheme IV
3. STELLA ET AL.
Literature Cited
1. Arnold, ., Gerber, ., and Levy, G., Can. J.
Pharm. Sci. (1970), 5, 89.
2. Martin, C. ., Rubin, M., O'Malley, W., Garaguai,
V. F., and McCauley, C. ., Pharmacologist (1968),
10, 167.
3. Rail, L., Med. J. Aust. (1968), ii, 339.
4. Suzuki, T., Saitoh, ., and Hishihara, ., Chem.
Pharm. Bull. (1970), 18, 405
5. Blum, M. R., Riegelman, S., and McGilveray, I.,
Paper 12 presented to the Basic Pharmaceutics
Section, APhA Academy of Pharmaceutical Sciences
San Francisco,
6. Blum, M. R., Riegelman, ,
,
, Pape
12 presented to the Basic Pharmaceutics Section,
APhA Academy of Pharmaceutical Sciences, San
Francisco, 1971.
7. Albert, ., Nature (1958), 182, 421.
8. Albert, ., "Selective Toxicity", 2nd. Ed., p.
30, Wiley, New York, N.Y., 1960.
9. Agarwal, S. P., and Blake, M. I., J. Pharm. Sci.
(1968), 57, 1434.
10. Glazko, A. J., Pharmacology (1972), 8, 163.
11. Sohar, P., Acta Chim. Acad. Sci. Hung. (1968),
57, 425.
12. "Dilantin", Formulary Monograph from Parke,
Davis and Co., Detroit, Michigan 48232.
13. Atkinson, Jr., A. J., and Davison, R., Ann. Rev.
Med. (1974), 25, 99.
14. Frank, J. T., Drug Intel. Clin. Pharm. (1973),
7, 287.
15. Sachtler, G., Drug Intel. Clin. Pharm. (1973).
7, 418.
16. Tobias, D. C., and Kellick, . ., Drug Intel.
Clin. Pharm. (1973), 7, 418.
17. Catania, P. ., Drug Intel. Clin. Pharm. (1973),
7, 418.
18. Chan, N. L., Drug Intel. Clin. Pharm. (1973),
7, 419.
19. Frank, J. T., Drug Intel. Clin. Pharm. (1973),
7, 419.
20. Baldwin, J., and Amerson, . ., Amer. J. Hosp.
Pharm. (1973), 30, 837.
21. Rowland, ., "Clinical Pharmacology", p.27,
Macmillan Co., New York, N.Y., 1972.
22. Serrano, E., Roye, D., Hammer, R., and Wilder,
B., Neurology (1973), 23, 311.
182
PROD
- RUGS
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
3. STELLA ET AL.
4
The Metabolic Disposition of a Novel
5,5-Diphenylhydantoin Pro-drug
A. J. GLAZKO, W. A. DILL, R. H. WHEELOCK, R. M. YOUNG,
A. NEMANICH, and L. CROSKEY
Research Laboratories, Parke, Davis, and Co., Ann Arbor, Mich. 48106
V. STELLA and T. HIGUCHI
University of Kansas, Lawrence, Kans. 66044
5,5-Diphenylhydantoin (DPH; phenytoin; Dilantin )
has been used extensivel
oral and parenteral
its low water solubility (about 20 g/ml at 25 C),
parenteral formulations are dissolved in40%propylene
glycol and10%alcohol in water for injection, adjusted
to pH 12 to convert the acid to the sodium salt. A l
though this solution has been adequate for intravenous
use, there are clinical indications that intramuscular
use may result in slow absorption and low plasma levels
of DPH. One approach to this problem is based upon the
observation of Kozelka and Hine (1) that diphenylhydantoic acid undergoes ring closure to form DPH when heat
ed with strong acids. However, ring closure of diphenylhydantoic acid proceeds very slowly under physiolog
ical conditions.
Stella and Higuchi (2) studied a number of water
-soluble hydantoate esters and found that cyclization
occurred rapidly in neutral and alkaline solutions at
room temperature, apparently due to a specific base
-catalyzed intramolecular closure. As an outgrowth of
this work, Stella and Higuchi prepared the diethylami
noethanol ester of diphenylhydantoic acid, first as the
nitrate salt, and later as the hemisulfate (Pro-DPH).
These preparations were tested in the Parke-Davis Lab
oratories, and preliminary observations on metabolic
disposition were reported elsewhere (3). The structure
of this compound is shown in Figure 1.
*
4.
GLAZKO
ET
AL.
185
186
PRO-DRUGS
HN
X c /
NH
li
0
MOLECULAR WEIGHT (SULFATE SALT)
= 837.01
OF SULFATE SALT.
1 ml Plasma
+ 0.5 g NaHCO^
+ 7 ml EDC
(10)
5 ml EDC
+ 3 ml 0.1N HCI
( d i s c a r d aqueous) ^ _
(5 )
ml EDC
+ 3 ml IN NaOH
(5)
2 ml HCI
2 ml NaOH
(discard EDC)
PRO-DPH
DPH
Figure 2. Extraction scheme for separation of ProDPH and DPH. The extracts are then subjected to
permanganate oxidation to form benzophenone, which
is assayed by thefluorometrictechnicque. described
elsewhere (4).
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
4.
GLAZKO
ET
AL.
187
188
PRO-DRUGS
4. GLAZKO ET AL.
HOURS
189
190
PRO-DRUGS
Tissue D i s t r i b u t i o n Studies
Albino r a t s were given intramuscular doses of ProDPH s u l f a t e equivalent to 50 mg DPH per Kg body weight,
GLAZKO ET AL.
192
PRO-DRUGS
4. GLAZKO ET AL.
100
<
PRO-DPH ASSAY
DPH ASSAY
10
'-
F /
0.1
V
10
30
90
10
TIME AFTER DOSING
30
MINUTES
KIDNEY
SPLEEN
LUNG
LIVER
FAT
BRAIN
90
193
194
PRO-DRUGS
TABLE 1
ASSAY OF 22-HOUR RAT URINE AFTER A SINGLE 50 MG/KG
INTRAMUSCULAR DOSE OF PRO-DPH OR DPH
DRUG
ADMINISTERED
URINARY EXCRETION
PER CENT OF DOSE
RAT
NO.
PRO-DPH
DPH
TOTAL
(*)
{%)
(%)
PRO-DPH
k.2
2.0
6.2
DPH
0.15
0.15
0.05
0.05
4. GLAZKO ET AL.
5
Case Histories of the Development of Pro-drugs for
Use in the Formulation of Cytotoxic Agents in
Parenteral Solutions
ARNOLD J. REPTA
Department of Pharmaceutical Chemistry, School of Pharmacy,
University of Kansas, Lawrence, Kans. 66044
Introduction
The pro-drug approac
drug delivery through a number of related but distinctly different mechanisms. These might include use of a
pro-drug in attempting 1) to alter the rate of metabolism of the drug, 2) to alter the rate of release from
a dosage form or depot site, and/or 3) to deliver the
drug to a specific site or organ in the body. The
achievement of any one or a combination of two or more
of these objectives would be expected to have significant effects on the concentration vs time profile of
the drug at the receptor site. Although the technology
for achieving any one or more such goals could probably
be developed for a given drug substance, a good deal of
data would have to be available relative to the metabolism, site of action, toxicity and desired concentration-time profile for that drug in the body. Only on
the basis of such information would i t be possible to
define the specific properties and characteristics that
need be incorporated in the pro-drug. Obviously, the
application of pro-drug approaches in order to attain
such objectives requires that there be both a great
deal of interest in the drug and considerable advantage
to be gained before one could justify committing the
resources necessary for the design and development of a
suitable pro-drug.
A more common and presumably more achievable objective, which would involve the use of pro-drugs for
improved drug delivery, would be that concerned with the
enhancement of the absorption or bioavailability of a
drug through some reversible alteration of the properties of the drug. Pro-drugs used for such a purpose
would normally exhibit an apparent increase in the solubility or stability of the drug which in turn would
196
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
5.
REPTA
197
198
PRO-DRUGS
t o r s g i v i n g r i s e t o the gross problem being confronted?" The answer t o t h i s question i s u s u a l l y m u l t i f a c eted and often cannot be answered with complete cert a i n t y . Usually the answer requires o b t a i n i n g and
e v a l u a t i n g various p h y s i c a l and chemical data about the
candidate drug. The p a r t i c u l a r nature of the data
needed depends on the problem type. For i n s t a n c e , i f
the problem i s one of the low aqueous s o l u b i l i t y of the
substance, then information on the melting behavior,
the s o l u b i l i t y i n a v a r i e t y o f s o l v e n t s , the s t r u c t u r a l
f e a t u r e s , e t c . , are important.
I f the problem i s s t a b i l i t y r e l a t e d , then the nature of the degradation
products, the k i n e t i c order of the degradation process,
information r e l a t i v t r e a c t i o mechanis
d
d
a l l other data p e r t a i n i n
are u s e f u l . The c a r e f u
type
information and s i m i l a r information on r e l a t e d compounds often allows one t o s p e c i f y with some degree of
c e r t a i n t y the basic f a c t o r s causing the problem. For
example, the low aqueous s o l u b i l i t y of a r a t h e r p o l a r
compound which has a high melting point and a low s o l u b i l i t y i n v i r t u a l l y a l l solvents could perhaps be a t t r i b u t e d t o strong i n t e r m o l e c u l a r hydrogen bonding i n t e r a c t i o n s i n the c r y s t a l l i n e s t a t e . This would cause
the thermodynamic a c t i v i t y of the solute phase to be
low which i n t u r n gives r i s e t o the observed low s o l u b i l i t y . A second example, i n v o l v i n g a s t a b i l i t y problem, might be a s i t u a t i o n where the data may suggest
that i n t e r - or i n t r a m o l e c u l a r c a t a l y s i s by some funct i o n a l group i n the drug molecule i s responsible f o r
the r a p i d degradation.
A f t e r answering the second question, one can proceed to the next question which i s , "What s p e c i f i c type
of manipulation of the molecule or system can be accomp l i s h e d so that the basic cause or causes w i l l be suff i c i e n t l y ameliorated so as t o solve the gross problem?"
Normally the generic answer t o t h i s question i s
not a d i f f i c u l t one. This i s p a r t i c u l a r l y true i f the
previous question ( r e l a t i v e t o the basic causes of the
problem) was answered i n unequivocal terms. As an example, a s o l u t i o n t o the above described s o l u b i l i t y
problem, which stemmed from hydrogen bonding, might be
the d i s r u p t i o n of the hydrogen bonding by preparing a
chemical d e r i v a t i v e which would be incapable of a c t i n g
as a hydrogen donor. S i m i l a r l y an answer to the s t a b i l i t y problem p r e v i o u s l y described might i n v o l v e using
some p h y s i c a l or chemical a l t e r a t i o n of the system
which would t i e up the f u n c t i o n a l group responsible f o r
the c a t a l y s i s of the decomposition r e a c t i o n .
5.
REPTA
199
The f o u r t h and f i n a l (and perhaps the most d i f f i c u l t ) question to be asked i s , "What s p e c i f i c pro-drug
approach can be used to achieve the desired e f f e c t on
the p r o p e r t i e s of the drug substance and y e t , while
being s u f f i c i e n t l y stable i n the dosage form, w i l l rapi d l y release the parent drug i n the body upon administ r a t i o n ? " The answer to t h i s question i s often a d i f f i c u l t one since i t r e q u i r e s that the approach to be
used must s a t i s f y the general aims of the answer to
question three and a d d i t i o n a l l y i t must contain a
b u i l t - i n r e l e a s i n g mechanism which i s t r i g g e r e d by some
agent or event encountered upon a d m i n i s t r a t i o n of the
pro-drug. This t r i g g e r must dependently and r a p i d l y
allow or cause the pro-drug to r e v e r t to the free par
ent drug.
I t appears that there are at l e a s t three such po
t e n t i a l t r i g g e r i n g mechanisms which are encountered i n
the a d m i n i s t r a t i o n of intravenous s o l u t i o n s . The f i r s t
of these i s the various enzymes i n the blood and other
t i s s u e s (3.) I f one designs a pro-drug which w i l l
serve as a substrate f o r one or more of the enzymes
found i n the body and i f t o t a l enzymatic a c t i v i t y i s
s u f f i c i e n t l y l a r g e , then the release of the drug from
the pro-drug w i l l be much enhanced.
Another p o t e n t i a l t r i g g e r i s the event i n v o l v i n g
the d i l u t i o n of the pro-drug formulation upon administ r a t i o n of the s o l u t i o n i n t o the bloodstream. Such d i l u t i o n r e s u l t s i n reduced concentrations of components
and thus causes s h i f t s i n e q u i l i b r i a . An example of a
pro-drug system f o r which t h i s t r i g g e r would be s u i t able i s one i n v o l v i n g complexation which i s subject to
the law of mass a c t i o n (4_).
The buffered and r e l a t i v e l y constant value of the
p h y s i o l o g i c a l pH (= 7 . 4 ) i s a t h i r d f a c t o r which may be
u s e f u l i n t r i g g e r i n g the release of a drug from a prodrug. In those cases where the pH and b u f f e r capacity
of the blood i s to be used to advantage, i t would seem
to be necessary that the p r o - d r u g K i r u g r e a c t i o n be
very pH s e n s i t i v e , and that the pro-drug formulation
used be at a pH value appreciably d i f f e r e n t than
pH 7 . 4 .
In view of the l i m i t e d number of t r i g g e r i n g mechanisms a v a i l a b l e one must c a r e f u l l y consider the p h y s i co-chemical c h a r a c t e r i s t i c s of the v a r i o u s p o t e n t i a l
pro-drug approaches w i t h a view toward s e l e c t i n g only
those pro-drug systems which w i l l be most responsive to
one or more of the a v a i l a b l e t r i g g e r s encountered upon
intravenous a d m i n i s t r a t i o n of the f i n a l formulation.
When a l l of the above four questions have been
s a t i s f a c t o r i l y answered, the pro-drug system must be
f
200
PRO-DRUGS
OH
I
ara~A
OH
OH
II
adenosine
Some c l i n i c a l t e s t i n g of ara- as a cancer chemotherapeutic agent has been attempted but a f u l l scale
e v a l u a t i o n has been severely l i m i t e d because of prob
lems associated with the a d m i n i s t r a t i o n of the drug.
Human adult doses of 2.5 grams have been suggested and
a c t u a l l y administered as an aqueous intravenous i n f u
s i o n , but the low s o l u b i l i t y value of ^0.5 mg per ml of
water (8_) found f o r ara- have n e c e s s i t a t e d the use of
5 t o 6 l i t e r s of such s o l u t i o n s . Obviously, such a
large volume of s o l u t i o n r e q u i r e s a d m i n i s t r a t i o n over a
prolonged period of time ( 9 ) .
5.
REPTA
201
III
ara-H
IV
ara-A-5 -formate
1
202
PRO-DRUGS
adenosine
ara-a
ara-A-5 -formate
1
*
^
^
0.02
0.0018
0.12a
235
^ 260
* 175
267
267
295
5.
REPTA
203
donor capacity at that p o s i t i o n . Although an ether der i v a t i v e would a l s o be e f f e c t i v e i n e l i m i n a t i n g the hydrogen donor a c t i v i t y , the ester was p r e f e r e n t i a l l y seLected because of i t s greater ease of h y d r o l y s i s , esp e c i a l l y i n the presence of the various esterases which
abound i n blood and other t i s s u e s (3.).
Such enzymatic
assistance could therefore serve as the t r i g g e r i n the
release of the drug from the pro-drug.
The choice of the 5 hydroxyl as the s i t e of
e s t e r i f i c a t i o n was based on the general knowledge that
esters of primary a l c o h o l s are normally more e a s i l y hydrolyzed than the corresponding e s t e r s of secondary a l cohols such as are found at the 2 and 3 p o s i t i o n s of
ara-A. An a d d i t i o n a l
fo desirin
derivativ
of the 5 hydroxyl wa
d e r i v a t i v e s of compound
poo
substrates f o r adenosine deaminase (.6,10.) and thus the
5 e s t e r of ara-A would probably not undergo appreciable metabolism p r i o r to h y d r o l y s i s . While t h i s i s an
added bonus i t i s not an e s s e n t i a l f a c t o r i n so f a r as
achieving an increased molar s o l u b i l i t y i s concerned.
The choice of the formate e s t e r r a t h e r than some
other e s t e r was made on the b a s i s of the compact and
r e l a t i v e l y p o l a r nature of the formate group which was
not expected to n o t i c e a b l y a l t e r the o v e r a l l h y d r o p h i l i c character of the pro-drug r e l a t i v e to the parent
compound. The f a c t that formate e s t e r s are normally
more r a p i d l y hydrolyzed than corresponding homologs was
a l s o important ( 1 5 ) .
The reasons f o r choosing the monoformate e s t e r i n
preference to the diformate or t r i f o r m a t e esters
stemmed mainly from a d e s i r e to use as simple a system
as p o s s i b l e i n order to be able to f o l l o w u l t i m a t e l y
the regeneration of the drug. I f the t r i e s t e r was to
be used as the pro-drug, ( p r o v i d i n g i t was s u f f i c i e n t l y
s o l u b l e ) random h y d r o l y s i s of the esters would potent i a l l y r e s u l t i n three d i f f e r e n t diformate esters which
i n t u r n would hydrolyze to y i e l d three d i f f e r e n t monoe s t e r s . This k i n e t i c sequence would then r e s u l t i n the
simultaneous existence of s e v e r a l pro-drug species
which would be present i n amounts r e l a t e d to t h e i r
r a t e s of formation and degradation.
The s i t u a t i o n i s
somewhat simpler f o r the diformate d e r i v a t i v e s , but
s t i l l p o t e n t i a l l y q u i t e complicated when compared to
that to be expected with the 5 monoformate.
Ara-A-5'-formate was prepared (8_) and the aqueous
s o l u b i l i t y was found to change i n the a n t i c i p a t e d d i f
204
PRO-DRUGS
5. REPTA
205
to a h a l f - l i f e of about 4 hours. At pH 4 . 2 to 4 . 5 ,
which was the pH range of greatest s t a b i l i t y , the observed h a l f - l i f e was approximately 1 0 days.
Although i t was obvious from the data that the
pro-drug could not be formulated as an aqueous s o l u t i o n with acceptable long term s t a b i l i t y , the formate
TIME (minutes)
Journal of Pharmaceutical Sciences
206
PRO-DRUGS
41
3
PH
Journal of Pharmaceutical Sciences
5.
REPTA
207
V
Hexamethylmelamine
VI
G e n t i s i c Acid
208
PRO-DRUGS
Water
,-Diethylacetamide
Dimethylsulfoxide
Ethanol
Ethylacetate
Propylene g l y c o l
Polyethylene g l y c o l 400
Chloroform
Benzene
D i e t h y l ether
'V/O.l
30-50
a>5
^15
*15
<2
<2
^200
^10 6
5.
REPTA
209
( e q
1 )
mS + nL
= [S L ]/[S] [L]
m
(eq. 2 ) .
210
PRO-DRUGS
u b i l i t y , [ S ] , may be expressed as
T
[S]
= [S] + m [ S L ]
m
(eq. 3 ) .
[S]
= [ S ] = m[S L ]
Q
(eq. 4 ) .
5.
REPTA
211
s o l u b i l i t y f o r hexamethylmalamine at these pH v a l u e s ,
the abrupt d i s c o n t i n u i t i e s and the apparent s e n s i t i v i t y
of the observed s o l u b i l i t y to s l i g h t compositional
212
PRO-DRUGS
OCH
OCH
HO
CH3
3
VII
VIII
Acronycine
Acronycinium Ion
5.
REPTA
213
systems ( 2 5 ) .
However, the low water s o l u b i l i t y (^2
mg/liter)T?6) has presented b i o a v a i l a b i l i t y problems
and t h i s has made the c l i n i c a l e v a l u a t i o n of t h i s agent
extremely d i f f i c u l t . The only p r e v i o u s l y reported a t tempt (27.) made to s o l u b i l i z e acronycine i n v o l v e d the
preparation of a c o p r e c i p i t a t e c o n t a i n i n g p o l y v i n y l
pyrrolidone (5 parts by weight) and acronycine (1 part
by weight). When the c o p r e c i p i t a t e was d i s s o l v e d i n
water, an apparent 5 f o l d increase i n the s o l u b i l i t y of
acronycine was obtained and the c o p r e c i p i t a t e demons t r a t e d enhanced antitumor a c t i v i t y when administered
i n t r a p e r i t o n e a l l y as a suspension. Whether or not the
enhanced a c t i v i t y was due to an increase i n the e q u i l i b r i u m s o l u b i l i t y of acronycin
(a
prob
ably the case) to a
c o p r e c i p i t a t e r e l a t i v e to acronycine alone was not
c l e a r . Nevertheless, because of the r a t h e r l a r g e a n t i cipated acronycine dose of 100 to 200 mg, and a d e s i r e
f o r that dose to be contained i n a volume of about 100
mis or l e s s ( 2 8 ) , the approach using the p o l y v i n y l p y r r o l i d o n e c o p r e c i p i t a t e apparently was not found s u i t able f o r intravenous use. Therefore i t was necessary
to pursue other means of s o l u b i l i z i n g acronycine.
The s o l u b i l i t y of acronycine i n a v a r i e t y of simple and mixed solvent systems was determined (29.) as
shown i n Table I I I . Prom such data i t was obvious that
Table I I I - Approximate Apparent S o l u b i l i t y of Acronycine i n Various Solvents at about 25 (29)
Solvent
S o l u b i l i t y (mg/ml)
chloroform
water
benzene
acetone
25% (v/v) acetone i n water
40$ (v/v) propylene g l y c o l i n
water
275
0.002
40
32
20
8
214
PRO-DRUGS
5.
REPTA
215
loool
600
400
2001-
CM
100
60
40
J3
20
10
6
4
6
PH
10
216
PRO-DRUGS
IX
Acylacronycinium
Ion
5.
REPTA
217
Solubilit
f Variou
(29).
acetylacronycine s a l t
perchlorate
sulfate
phosphate
bromide
chloride
a
a
s o l u b i l i t y (mg/ml)
^ .25
^ 1.5
^12
^ 6
^12
The r e a c t i o n of acetylacronycinium p e r c h l o r a t e i n
water and aqueous b u f f e r was studied and i t was found
that the regeneration of acronycine from the a c e t y l a c
ronycinium i o n was q u a n t i t a t i v e ( 2_9) K i n e t i c studies
demonstrated that the rate of h y d r o l y s i s of the e s t e r
linkage was e s s e n t i a l l y independent of both pH and buf
f e r concentration over a range o f pH 0-7 However, at
pH greater than 8, hydroxide c a t a l y s i s was observed.
Some of the k i n e t i c data obtained (2) i s shown i n F i g .
5 where i t can be seen that at 25 the h y d r o l y t i c r a t e
at pH values below 8 i s about 2.8 1 0 " minute" which
corresponds to a h a l f - l i f e of about 25 minutes. From
studies of the temperature dependence of the h y d r o l y s i s
r e a c t i o n (29.), i t appeared that at a body temperature
of 37, the i n v i t r o h a l f - l i f e f o r h y d r o l y s i s would be
only about 5 minutes. Although such r a p i d h y d r o l y s i s
i s d e s i r e d f o l l o w i n g p a r e n t e r a l a d m i n i s t r a t i o n , the
o v e r a l l i n s t a b i l i t y presents problems i n the prepara
t i o n of the intravenous formulation. The d i f f i c u l t y
a r i s e s from a combination of f a c t o r s which include the
low s o l u b i l i t y of acronycine, the high apparent concen
t r a t i o n of acronycine (as the acetylacronycinium per2
218
PRO-DRUGS
c h l o r a t e ) d e s i r e d , and the r a t h e r r a p i d h y d r o l y s i s of
the acetylacronycinium i o n . As an i l l u s t r a t i o n of the
problem, consider a s o l u t i o n c o n t a i n i n g the a c e t y l a c r o nycinium perchlorate at a concentration corresponding
to the equivalent of 0.2 mg of acronycine per ml. Upon
h y d r o l y s i s of 5% of the acetylacronycinium s a l t , which
would occur i n only about 2 minutes (at room temperature) a f i v e f o l d supersaturated s o l u t i o n of acronycine
would r e s u l t . Moreover, the above example i s an o p t i m i s t i c one i n that no c o n s i d e r a t i o n was given to the
h y d r o l y s i s l i k e l y to occur during the preparation of
the s o l u t i o n .
In l i g h t of the above s t a b i l i t y problems, i t was
necessary to conside approache b which th h y d r o l y t
i c s t a b i l i t y of the
could be increased. In view of the p H - p r o f i l e ( F i g .
5), the s t a b i l i t y could not be enhanced by pH a d j u s t ment and thus more elaborate approaches had to be considered.
I n i t i a l l y , i t was f e l t that the i n t r o d u c t i o n of a
more bulky a c y l group would reduce the r a t e of hydrolys i s through s t e r i c e f f e c t s (15.). In order to evaluate
t h i s approach, the p e r c h l o r i d e s a l t s of IXb, IXc, and
IXd were prepared and the h y d r o l y s i s of each was studi e d at 25 and pH 7.0 or 7.5.
Somewhat s u r p r i s i n g l y ,
the r e s u l t s showed that the h y d r o l y t i c r a t e s f o r a l l
four of the acetylacronycinium perchlorate s a l t s were
e s s e n t i a l l y independent of the nature of the a c y l group
and the h a l f - l i f e f o r a l l was about 25 minutes. This
apparent complete l a c k of any dependence of the s t a b i l i t y on the s t r u c t u r e of the a c y l group prompted the
c o n s i d e r a t i o n of an a l t e r n a t i v e method f o r a t t a i n i n g
greater s t a b i l i t y .
E a r l i e r work by Higuchi and a s s o c i a t e (31332,33)
had shown that complex formation between organic spec i e s i n s o l u t i o n could a l t e r t h e i r chemical behavior
such as the s u s c e p t i b i l i t y to h y d r o l y s i s . Those r e s u l t s l e d to the c o n s i d e r a t i o n of complexing as a pot e n t i a l method f o r s t a b i l i z i n g the acetylacronycinium
ion.
For many of the same reasons mentioned i n Case I I ,
g e n t i s i c a c i d was chosen as a p o t e n t i a l l i g a n d and i t s
e f f e c t s on the s t a b i l i t y of acetylacronycinium i o n were
s t u d i e d . Some of the r e s u l t s obtained (29.) are shown
i n F i g . 6.
The observed decrease i n h y d r o l y t i c r a t e which occurs with i n c r e a s i n g gentisate concentration can be a t t r i b u t e d to the formation of complexes between the gent i s a t e and acetylacronycinium i o n s . Such complex spec i e s appear to decrease the s u s c e p t i b i l i t y of the acet-
5.
REPTA
219
30H
. 0 8 O T W
.02
.04
.06
Gentisate Concentration [moles/liter]
Figure 6. Plot of the effects of the gentisate on the observed
first order rate constant for the hydrolysis of the acetylacronycinium ion at 25 (29, 30)
220
PRO-DRUGS
5. REPTA
221
Cytotoxic Agents in Parenteral Solutions
222
PROD
- RUGS
5.
31.
32.
33.
34.
REPTA
223
6
The Effect of a Pro-drug of Epinephrine (Dipivalyl
Epinephrine) in GlaucomaGeneral Pharmacology,
Toxicology, and Clinical Experience
DAVID A. McCLURE
Alergan Pharmaceuticals, Irvine, Calif. 92664
Epinephrine ha
treatment of the conditio
is a disease where the pressure within the eye increases to a point where damage to the visual apparatus occurs and, if left unchecked, could lead to
a significant deminuation in visual acuity and eventually, blindness.
The reasons for this pressure increase are
numerous and we will touch on these shortly. However,
first, let us examine the anatomy of the eye and how
glaucoma comes about. Figure 1 shows a cross section
of an eye. From the crystalline lens backward is one
chamber filled with a thick, viscus fluid that does
not move. Another chamber, that is in front of the
lens and the Zonule ligament, is actually composed of
two chambers with fluid circulating between. This
fluid is called the aqueous humor. The path of the
aqueous humor is from the ciliary body, through the
pupil, and out the trabecular meshwork and an area
called the Canal of Schlemm. Figure 2 is a close-up
of the area of fluid circulation and drainage.
Now, we mentioned earlier that glaucoma results
from an increase in the intraocular pressure (IOP).
The normal IOP averages around 17 mmHg. This pressure
can increase in 3 ways: 1) a greater influx of fluid
into the envelope of the eye while maintaining a constant outflow, 2) a decreased outflow while maintaining a constant inflow or, 3) a combination of the
two. We are concerned primarily (in simple primary
glaucoma) with a decrease in the outflow of aqueous
fluid. Now what happens if the IOP goes up 10 to 20
mmHg from normal and is maintained at that level? In
224
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
6.
MC CLURE
225
226
PRO-DRUGS
Figure 1
Figure 2
Figure 3
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
6.
MCCLURE
227
Table 1
Problems o f E p i n e p h r i n e use i n Glaucoma
I.
II.
III.
IV.
Duration of Action
Side E f f e c t
A.
Ocular
B.
Systemic
Bioavailability
Stability
Duration of a c t i o n .
When a d m i n i s t e r e d i n t r a v e n o u s l y , the c a r d i o v a s c u l a r , pulmonary and o t h e r
e f f e c t s from e p i n e p h r i n e are o v e r w i t h i n 10 m i n u t e s .
When i n s t i l l e d i n t o the e y e , a d i l a t e d p u p i l o c c u r s
i n 10 t o 15 minutes and the d i l a t i o n l a s t s up t o an
hour.
The d u r a t i o n o f l o w e r i n g o f IOP from e p i n e p h r i n e can be seen i n F i g u r e 4.
The c o n c e n t r a t i o n o f
e p i n e p h r i n e (2%) used i n t h e s e d a t a r e p r e s e n t s the
highest concentration a v a i l a b l e .
It i s presented
h e r e t o demonstrate the peak a c t i v i t y time o f 4 hours
and a d u r a t i o n o f a c t i o n o f between 12 and 24 h o u r s .
The m e t a b o l i c pathways f o r e p i n e p h r i n e can be seen
i n F i g u r e 5.
The s i d e e f f e c t s o c c u r r i n g from e p i n e p h r i n e
t o p i c a l l y a p p l i e d t o the eye are b o t h l o c a l o c u l a r
s i d e e f f e c t s and s y s t e m i c .
T a b l e 2 i l l u s t r a t e s some
of these e f f e c t s .
To g e t around a l l t h e s e problems w i t h e p i n e p h r i n e , we were f o r t u n a t e t o get a chance t o examine
an analogue o f e p i n e p h r i n e and p o s s i b l y what i s f e l t
t o be a p r o - d r u g o f e p i n e p h r i n e .
F i g u r e 6 shows the
c h e m i c a l s t r u c t u r e o f e p i n e p h r i n e and i t s p r o - d r u g ,
d i p i v a l y l e p i n e p h r i n e (DPE).
228
PRO-DRUGS
40
30
-A
20
AVERAGE OF
44 UNTREATED
GLAUCOMATOUS
EYES
10
1
TIME (HOURS)
Archives of Ophthalmology
Figure 5
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
6. MCCLURE
Table 2
Ocular Side E f f e c t s
of T o p i c a l Epinephrine
I . Hyperemia
II. Mydriasis
-r-r-r
V . Browache
(Photophobia)
I I I . C o r n e a l Edema
_ _..
.
_
.
IV. A l l e r g i c S e n s i t i v i t y
Systemic
I.
V I . Adrenochrome
DepOSltS
. -,
Side E f f e c t s
V I I . Tolerance
VIII.
Maculaopathy
of T o p i c a l Epinephrine
Cardiovascula
A . Cardiac Arrhythmias
B. Blood Pressure E l e v a t i o n
C. Cerebrovascular
II. Pallor,
Dizziness,
Accidents
Tremor
Tenseness,
Restlessness
CH-CH -N
2
CH,
Figure 6
229
230
PRO-DRUGS
Table 3
Proposed Advantages o f DPE
I.
II.
Increased Duration o f A c t i o n
Increased B i o a v a i l a b i l i t y
III.
Increased
Potency
IV.
Decreased
Side
V.
Increased
Stability
Effects
ON
N CO
CHCHgNHCH
NO
METANEPHRINE
CHCN NHCH
2
NO
3.4 Dl HYDROXY
MANDELIC
ALDEHYDE
Figure 7
In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1975.
6. MCCLURE
231
Why an i n c r e a s e d b i o a v a i l a b i l i t y ? I t i s v e r y
e v i d e n t t h a t DPE i s much more l i p o p h i l i c than e p i n e p h r i n e by v i r t u e o f t h e two l a r g e p i v a l y l groups a t t a c h e d t o t h e two h y d r o x y l s o f e p i n e p h r i n e .
In a d d i t i o n , DPE m a i n t a i n s a h i g h degree o f h y d r o p h i l i c i t y .
T h e r e f o r e , by i t s d u a l s o l u b i l i t i e s , i t f i t s i n v e r y
n i c e l y t o t h e p r e s e n t day a b s o r p t i o n t h e o r i e s . The
c o r n e a o f t h e eye i s t h e b a r r i e r drugs must overcome
i n o r d e r t o be absorbed i n t o t h e e y e . The c o r n e a i s
composed o f t h r e e l a y e r s :
an e p i t h e l i u m and an e n d o t h e l i u m , b o t h o f w h i c h r e q u i r e drugs t o be l i p o p h i l i c
i f t h e y a r e t o be absorbed a n d , t h e s t r o m a ; s a n d wiched between t h e e p i t h e l i u m and e n d o t h e l i u m t h a t
r e q u i r e d a d r u g t o be h y d r o p h i l i c f o r p e n e t r a b i l i t y .
By t h e d u a l s o l u b i l i t
the eye i s g r e a t e r t h a n t h e l e s s l i p o p h i l i c e p i n e phrine molecule.
20,
TIME IN HOURS
Why an i n c r e a s e d potency?
I f more m a t e r i a l g a i n s
a c c e s s t o t h e i n s i d e o f t h e eye i t w i l l t h e n , on a
r e l a t i v e b a s i s , be more p o t e n t .
F i g u r e 8 shows a
comparison between 0.5% e p i n e p h r i n e and 0.16% DPE
DPE on t h e IOP o f u n a n e s t h e t i z e d r a b b i t s .
The e f f e c t s
232
PRO-DRUGS
are o b v i o u s . F i g u r e 9 i l l u s t r a t e s a dose-response o f
DPE on c a u s i n g p u p i l l a r y d i l a t i o n .
On t h e d i f f e r e n t i a l s i d e e f f e c t s t u d i e s , a
comparison o f DPE t o e p i n e p h r i n e r e l a t i v e t o b l o o d
bJ 01
If
TIME-(HOURS)
j
< kl
p r e s s u r e and h e a r t r a t e e f f e c t s a f t e r i n t r a v e n o u s
a d m i n i s t r a t i o n was c a r r i e d o u t i n dogs and c a t s .
F i g u r e s 10 and 11 compare t h e e f f e c t s o f i n t r a
v e n o u s l y a d m i n i s t e r e d DPE and e p i n e p h r i n e on t h e
b l o o d p r e s s u r e and h e a r t r a t e i n a n e s t h e t i z e d d o g s .
I t i s e v i d e n t t h a t DPE has s i g n i f i c a n t l y l e s s e f f e c t
on b l o o d p r e s s u r e and h e a r t r a t e t h a n e p i n e p h r i n e .
In a s i m i l a r f a s h i o n , t h e e f f e c t o f DPE and e p i n e
p h r i n e on t h e b l o o d p r e s s u r e o f a n e s t h e t i z e d a t r o p i n i z e d c a t s may be seen i n F i g u r e 12.
MCCLURE
TIME (MINUTES)
Figure 11. Effect of I.V. epinephrine and DPE on heart rate in dogs
234
PRO-DRUGS
DOSE (XIO-SMOLES/KC)
Figure 12. The effect of epinephrine and DPE on the arterial blood
pressure of the anesthetized atropinized cat
F i n a l l y , t h e e f f e c t o f DPE on humans w i t h
glaucoma may be seen i n F i g u r e 13.
I t c a n be seen
t h a t t h e response e l i c i t e d by DPE i s p r o n o u n c e d .
If
one s u b t r a c t s t h e c o n t r a l a t e r a l c o n t r o l eye (normal
d i u r n a l response) from t h e t r e a t e d e y e , i t c a n be
see t h a t DPE produced a marked r e d u c t i o n i n IOP.
6. MCCLURE
Summary
The dipivalyl analogue of epinephrine has been
shown to produce fewer side effects and greater
potency than the parent compound. These results have
been found in both animal and human studies. More
studies are to be carried out which will amplify
these data and perhaps lead to a better understanding
of the mechanism of action of this epinephrine prodrug.
Literature Cited
1. L. L. Garner, W. W. Johnstone, E. J.
Ballintine, M. E. Carroll, Arch Opth. (1959), 62, 230.
INDEX
A
Absorption barriers
9
Absorption of drugs
4,196
Accidental pro-drugs
90
Acetamidopenicillins
131
Acetaminophen
81,90
O-acyl and O-carbonate esters of ....
81
2- ( p- Aeetaminophenoxy ) tetrahydropyran
81
Acetonide formation .,
38
a-Acetoxyethyl phenylmalonyl
chloride
126
Acetoxymethyl-7-aminocephalosporanate
13
Aeetoxymethyl-7- ( D-a-aminophenylacetamido)cephalosporanate
134
Acetoxymethyl-7- ( D-a-azidophenylacetamido)cephalosporanate
134
Acetoxymethyl-7- ( 2'-thienylacetamido) cephalosporanate
134
Acetylacronycine salts
217
Acetylacronycinium
complexes
212
ion
215,219
perchlorate
216
salts
212
4"'-Acetyldigoxin
40
3- Acetyl-5,5-diphenylhydantoin
178
Acetylsalicylic acid
76
Acidic media
126
Acronycine, pro-drug of
212
Acronycine, solubility of
213,214
Acronycinium ion
212,216
7-Acylacephalosporanic acid
138
7-Acylaminocephalosporanic acid 138,139
7-Acylaminodesacetoxy cephalosporanic acid
138
Acylanid
41
Adamantoyl esters
26
Addison's disease
47,55
Adenine arabinoside, 5' phosphate of
71
Adenosine
200,202
3',5'-Adenosine monophosphate
25
Adrenergic agents
225
Adrenergic mechanism
225
Adriamycin-14-octanoate
75,91
Aglycone
2
Alcoholic patients
19
Allopurinol
41
Amines
15
Amino acid carbamates
..
66
-Aminobenzyl penicillin
118,130,131
7-a-Amino cyclohexadienylalkyl
cephalosporanic acid
139
-Amino cyclohexadienylalkyl
penicillin
130
6-Aminopenicillanic acid
122,125
p-Aminosalicylic acid
49
Ammonium drugs, quaternary
26
Amodiaquine
59
Amphotericin
79
methyl ester
79
Ampicillin
30, 118, 122-124
deoxylincomyci
,
Antagonist, narcotic
62
Anthracene glycosides
2
Antibacterial activity
143
Antibiotics
^-lactam
118
macromolecular salts of
33
oral bioavailability of
30
polar
33
pro-drug approach to
116
Anticonvulsant
74,154,184
Anti-inflammatory agents,
nonsteroidal
76
Antifungal agent
42
Antihypercholesteremic agent
78
Antimicrobial agents, sulfonamide ...
90
Aqueous solubility ( See also Water
soluble)
40,66,73,155
Ara-A
200-202,205
-5' formate
201,202,205,206
Ara-H
201
l-/?-D-Arabinofuranosyladenine,
pro-drug of
200
a-Aryl-0-aminoethyIpenicillin
130
Ascorbic acid
22,36,88
3-phosphoryl ester of
36
Aspirin
1,76
6-Azauridine
23
Barrier(s)
blood brain
of drug to taget organ
physical, chemical, and social
Behavior, psychotic
Benzathine
penicillin
Benzoic acid derivatives
239
85
6
7
55
3
3,86
76
240
PRO-DRUGS
Benzophenone
185
Bioactivities
145, 147
Bioavailability
of antibiotics, oral
30
dose-dependent
44
of a drug
196
of steroids
45
Bioreversible
chemical modification of drugs
73
derivatives
1
pro-drugs, water soluble
175
Biotransformation
2
Birth control
5
,'-Bis ( 2-hydroxycyclohexyl ) -ethylenediamine-,' diacetic acid .... 35
Bis-trichloroethyl carbonate
82
Blood
ara-A-5' formate and ara-A i
brain barrier (BBB)
9,85
levels, thiamine
19,20
pressure of cats
234
pressure of dogs
233
of rats, bioactivities in
147
thiamine levels in
21
Brain dopamine
9
Buffers
187, 188
Burn therapy
36
N -Butanoyl derivatives
25
6
Calcium 4-benzamidosalicylate
49
Cancer chemotherapeutic agent
200
N-Carbamoyl-2,2-diphenylglycine,2( diethylamino ) ethyl ester,
hemisulfate
184,186
Carbenicillin
125,131
esters of
126,128
disodium salt
126
indanyl sodium-sodium 6-[2phenyl-2- ( 5-indanyloxycarbonyl)] acetamido peni
cillinate
125
N-Carbethoxychlorphentermine
15
N-Carbethoxy-2,2-diphenylglycine .... 160
3-Carbethoxy-5,5-diphenylhydantoin
156,178
N- ( Carbethoxymethyl ) -3-acetoxymethyl-7- ( 2'-thienylacetamido ) 2-cephem-4-carboxylic acid
amide
132
IV- [ 1-Carbo-t-butoxy ) ethyl] -7- ( 2'thienylacetamido ) cephalosporanic acid amide
132
-Carboxybenzylpenicillin
125
Carcinoma
55,69,83
Cat
234
Catecholamines
9,14,47
Catechol-0-methyl transferase
230
Central nervous system (CNS)
9,15,29
Cephaloglycin
135,140
Cephalosporin
128
C amides
132
C esters
128
C esters
132
GI absorption of
134
pro-drugs
135,138
Cerebrospinalfluidconcentration
20
Chelating agents, heavy metal
34
Chemotherapeutic agent, cancer
200
Chloral hydrate
81
Chloramphenicol
68,71,80
succinate
68, 71
Chloroguanide
59,60
p-Chlorophenoxyisobutyric acid
78
ethyl ester
78
Cholinergic agents
225
4
alkyl esters
141
bioactivity concentrations, serum ... 145
-2,3-biscarbonate ester
142
[7( S )-chloro-7-deoxylincomycin]
hydrochloride
137
-2-cyanoethyl phosphate
146
2,3-diesters
143
mean serum concentrations of . .148,149
-3-monocarbonate ester
142
-2-monoester
142,143
-2-phosphate
144,146,148,149
subcutaneous dose of
147
Codeine
2
Complex of a drug
3
Complexation
209
Corneal absorption
35
Corticosteroids
38
Covalent bond linkage
3
Covalent chemical modification
86
Crystal lattice energies
42
6-N'-Cyanoamidopenicillin
130
Cyanoethyl phosphate ester
intermediate
146
Cycloguanil
59,60
Cytosine arabinoside, 5'acyl
derivatives of
51
Cytotoxic agents
196
D
Darvon
Deanol
Degradations, solid state
Delivery
of polar anticiotics
problems of cytotoxic agents,
intravenous
site specific
Derivative
formation
in vivo liability of a drug
86
90
88
33
196
83
33
117
241
INDEX
Derivative (continued)
nontoxic
117
over the parent molecule,
advantage of
117
scale-up of
117
stability of
117
synthesis and purification of
116
Desacetylrifampicin
137
Desoxycorticosterone
47
trimethylacetate
55
Dexamethasone-21-phosphate
67
4,4'-Diaeetoamidodiphenylsulfone .... 59
,-Diacetyldopamine
13
3,6-Diacetylmorphine
48
0,S-Diacetylthiamine
16
4,4'-Diaminodiphenylsulfone
50,59
,-Dibenzoylthiamine disulfide
16
N -2'-0-Dibutanoyladenosine-3',5'
monophosphate, diburanoy
derivative
25
Dichloralphenazone
81
O-S-Diethoxycarbonylthiamine
16
Dilantin
184
^-N,N-Diethylaminoethyl-2,2diphenylglyoinate
161
^-iV,iV'-Diethylaminoethyl-2,2diphenylhydantoate
162,164
^-N',N-Diethylaminoethyl-2-ethyl-5methyl-2-phenylhydantoate
157
^N',N'-Diethylaminoethyl-5-methyl2,2-ethylphenylhydantoate
72
Diethyldithiolisophthalate
89
Diethylenetriaminepentaacetic acid .. 34
Diethylstilbesterol
69, 83
4,4'-Diformamidodiphenylsulfone
50
Digoxin
40
Dihydroxy groups in some steroids .... 38
L-3,4-Dihydroxyphenylalanine
10
N-N-Dimethylaminoethanol
90
Dimethylol urea
64
6- ( 2,2-Dimethyl-5-oxo-4-phenyl-limidazolidinyl) penicillanic acid 119
2,2-Diphenylglycine
159,171
5,5-Diphenylhydantoin (DPH)
pro-drug
154,175,184
aqueous and lipid solubility of
155
bioavailability
154
conversion of pro-DPH
to
165,169,185,187,188
in dogs
190,191,193
in rats
187-189, 191-193
separation of pro-DPH and
186
Diphenylmethane derivatives
185
4,4-Diphenyl-2,5-oxazolidinedione ... 160
Dipivalyl derivative
35
Dipivalyl epinephrine
(DPE)
227, 230-234
Distribution of drugs
4
0,0-Di(trimethylsilyl) dopamine
13
Dogjs)
effect of I.V. epinephrine and DPE
Dogs (continued)
on blood pressure and heart
rate of
233
plasma levels at DPH and
pro-DPH in
190, 191
tissue levels of pro-DPH and
DPH in
193
urine, indanol metabolites in
129
L-Dopa
10,44
esters
11
Dopamine
12,15
Dose dependent bioavailability
44
Dose-response
231
Drug(s)
absorption or bioavailability of
196
absorption, distribution, metabo
lism, and excretion of
4
242
PRO-DRUGS
Fluoinolone
acetonide-21-acetate
Fluphenazine decanoate
Fluphenazine dihydrochloride
Fluphenazine enanthate
-Fluphenthixol dihydrochloride
Formaldehyde
Formulation problems of drugs
9- ( 5-O-Formyl-0-D-arabinofuranosyl) adenine drug
3-Formyl rifamycin SV
37
38
55
55
55
57
1,64
85
200
137
G
Gastric irritants
76
Gastric ulceration, drug-induced
75
Gastrointestinal (GI) tract
9,134
Gentisate complex
3
Gentisic acid
207,209,21
Glaucoma
35,224,227,23
Griseofulvin
42
-4'-alcohol
43
-4'-carboxymethoxime
43
-4'-hemisuccinate
43
-4'-oxime
43
H
-Haloalkylamines
28
Heart rate in dogs
233
Heavy metal chelating agents
34
p-Heptyloxyhydrocinnamyltestosterone
54
Heroin
48
Hetacillin
119,122,123,131
Hexamethylmelamine
complexation of
209
-gentisic acid complexes
3,207
pro-drug of
3, 207
solubility of
208,210,211
3, Hexoxycarbonyl-5,-diphenylhydantoin
179
Human serum levels
24
Hydantoic acid
158,176
Hydantoins
176,180
Hydrocortisone-21-phosphate
67
Hydrolysis
43, 120, 121
Hydroxydione
71
2-Hydroxyethylenediamine-N,N,IVtriacetic acid
34
N-Hydroxyphthalimide
(phthaloxime)
132
I
Indanol
Indanylcarbenicillin
Indomethicin
Inflammation
Injection
direct aqueous I.V. or I.M
of ionic and colloidal iron
pain
vehicle
129
129
76,77
55
66
79
79
60
Intermediates, chemical
116
Intramuscular doses
187
Intraocular pressure
(IOP)
224,227,231,235
Intravenous
administration of hexamethyl
malamine
207
delivery problems of cytotoxic
agents
196
epinephrine to dogs,
233
solutions, problems of
197
Ionization constants, macroscopic
and microscopic
11
Iron, injection of ionic and colloidal 79
L
Latentiation
Leigh's disease
Leprosy
Lincomycin
Linkage, covalent bond
Lipid solubility
Lymph nodes
2
15,21
89
32
3
-9,155
33
M
Mafenide
36,49
acetate
3
Mephenytoin
72, 74, 154
Metabolic pathways
227
Metabolism
during oral absorption
43
enzymatic drug
201
time course of drug
4
Metabolic disposition
184
Metabolites
6, 49, 129
Metal chelating agents
34
Methanamine
1
Methoxymethyl-6-aminopenicillinate.. 122
Methoxymethyl hetacillin 16
122
4"'Methyldigoxin
40
15-Methyl F
44
3-Methylol-5,5-dimethylhydantoin
64
3- ( 4-Methylpiperazinyliminomethyl )
rifamycin SV
137
Milk
21
Modification, bioreversible chemical 73
Modification, covalent chemical
86
Morphine
2,12, 48, 49
2
Naloxone
pamoate
Nandrolone
decanoate
phenylpropionate
Narcotic antagonist
47,62
62
54
54
54
62
243
INDEX
Neoplastic diseases
Nirvanol
Nitrofuran
Nitrofurantoin
1- ( 5-Nitro-2-furfurylindene )
aminohydantoin
Nonsteroidal anti-inflammatory agents
Norepinephrine
Nucleosides and nucleotides
23
180
154
178
Pivaloyloxymethyl 6-aminopenicillinate
118
Pivaloyloxymethyl-7- ( D-a-aminophenylacetamido ) cephalosporanate
134
154 Pivaloyloxymethyl-7-(D--azidophen76
ylacetamido) cephalosporanate .. 134
14 Pivaloyloxymethyl benzylpenicillinate 118
23 Pivampicillin
119-121
Plasma
conversion of pro-DPH to
DPH in
187,188
N -Octanoyl derivatives
25
level, indomethicin
77
Ocular side effects of epinephrine .... 229
levels of pro-DPH and DPH in
Oleandomycin
30
rats and dogs
187-191
Opthalmic absorption
35
26
Opthalmic delivery
66 Polar compounds
Polar drugs
33,35
Oral
absorption
26
activity
45 Potassium
D-a-azidobenzylpenicillinate
118
bioavailability
30
7- ( D-a-azidophenylacetamido )
-fluphenthixol dihydrochloride
57
cephalosporanate
134
Organ, target
6
benzylpenicillinate
118
Oxazepame
71,90
7-(2'thienylaeetamido) cephalosodium succinate
71
sporadesate
132
Oxyphenisatin
84
Prednisolone
67
acetonide
45
cyclopentylidenedioxy
45
Pain, injection
79
-21-disodium phosphate
67
O-Palmitoylamodiaquine
59
hemisuccinate sodium salt
67
Pamoate salt of cycloguanil
60
-21-m-sulfobenzoate sodium salt .... 67
Parent
74
catecholamine
14 Primacolone
1
compound
2 Pro-agent
3, 64, 86
molecule
117 Procaine
164,165
Parenteral repository pro-drug
59 Pro-DPH
conversion of
165-169,185,187,188
Parenteral solutions ...
196
Parkinson s disease
9
in dogs, plasma levels of
190,191
Patient acceptance of drugs
80
in dogs and rats, tissue levels of
193
intramuscular doses of
187
Penicillin
3,118
properties of
184
delivery of
3
in rats, plasma levels
G
86,130
of
187,188,189,191
pro-drugs
130
salicylate
170,171
salts of
86
separation of
186
V
130
sulfate
190,192
Percorten
55
turbidity times for
168
Percutaneous absorption
35
Permanganate oxidation technique
185 Pro-drug(s)
Peroral administration
190
accidental
90
Pharmaceutical phase
4
approach to antibiotics
7,116,199
Pharmacodynamic phase
4
definition of
1
Pharmacokinetic phase
4
in the formulation of cytotoxic
Phenobarbitone
74
agents
196
Phenylbutazone
78
to increase the aqueous solubility
Phenylmalonic acid, indanyl ester of 125
of a drug
66
Phenytoin
154,184
to lower the toxicity of a drug
73
Physiological
fluids
60
metabolite
6
Pilocarpine
225
parenteral repository
59
Pipothiazine
57
rationale for use of
4
Pivaloyloxymethyl-D-a-aminobenzylretrospective
2
penicillinate
118,131
for sustained or prolonged release 51
6
244
PRO-DRUGS
Prontosil
Propoxyphene
Prostaglandins
Psicofuranine
Psoriasis
Psychotic behavior
Pulmonary tissue
Pupillary dilation
Pyridoxine (vitamin B )
palmitate esters of
6
Q
Quaternary
ammonium drugs
compounds
derivatives
Quaternized nitrogen
90
86
45
24
23
55
33
231
15
22
26
26,29
28
17
R
Rabbits, IOP effects in
231
Rate constant, first order
206
Rate determining step
173
Rats
bioactivities in blood of
147
plasma levels of pro-DPH and
DPH in
187-189, 191
tissue levels of pro-DPH and
DPH in
193
urinary excretion of DPH and
pro-DPH sulfate in
192
Release, sustained or prolonged
51
Repository pro-drug effect
59
Retina
226
Retrospective pro-drugs
2
Reversible alteration of drug
properties
196
Riboflavin (vitamin B2)
15
fatty acid esters of
22
Rifampicin
137
S
Salicylic acid
76
derivatives
1, 76
Salt(s)
of antibiotics, macromolecular
33
drug
3
sparingly water soluble
63
Scale-up of derivative, convenient .... 117
Selenium sulfide
85
Serum clindamycin bioactivity
concentrations
145
Serum levels
24,140,148,149
Shock treatment
15
Side effects
207,229
Site-specific delivery
83
Skin conditions
38
Sodium
ampicillin
122
O-benzoyl-7- ( 2thienylacetamido )
cephalosporadesate
132
/
Sodium (continued)
6- ( -phenoxyacetamido )
penicillinate
122
salt of chloramphenical
monosuccinate
71
Solid state degradations
88
Solubility aqueous
( See Aqueous Solubility and Water
soluble )
of drug in physiologicalfluidsand
in injection vehicle
60
lipid
9,155
Sparingly water soluble drugs
63, 66
Stability
of carbenicillin esters
126
of derivative
117
problems of drugs
67,85
bioavailability of
45
dihydroxy groups in
38
succinate esters of
67
therapy
52
Subacute necrotising encephalomyleopathy (SNE)
15,21
Substituted 7-/?-aminocephemol-4carboxylic acid
139
7-Substituted cephalosporanic acid .... 139
21-Succinate esters
67
6- ( D-a-Sulfoaminophenylacetamido )
penicillin
130
Sulfamylon
36
hydrochloride solution
36
Sulfanilamide
90
Sulfonamide antimicrobial agents .... 90
Systemic side effects of epinephrine 229
Target organ, barriers of drug to
6
Taste problem of drugs
80, 81
Temporary transport forms
2
Testosterone
-cyclopentylpropionate ester of
53
decanoylacetate
54
esters
24,52-54
phenyl propionate
54
propionate
54
2-Tetrahydropyranyl-4-allopurinyl
ether
41
Thiamine (vitamin B i )
15,26
blood levels in alcoholic patients .... 19
CNS absorption of
15
levels in milk and blood
21
pro-drugs
89
propyldisulfide
16
tetrafurfuryldisulfide
16
N- [7- ( 2'-Thienylacetamido ) cephalosporanoyloxy] phthalimide
132
7- ( 2'-Thienylacetamide ) cephalo
sporanic acid monoisobutylcarbonate anhydride
132
245
INDEX
Triclorphos
Triggering mechanisms
Tuberculosis
Tumors, solid
Turbidity times
Tyramine
Tyrosine ethyl ester
81
199
89
207
168
12
12
Ulceration, gastric
Ureido anion
Urinary excretion of DPH and proDPH sulfate in rats
Urine, indanol metabolites in dog ....
Vasoconstrictive mechanism
Vitamin
A
B
Bo
C
D
water soluble
2
75
173
192
129
225
88
15,89
15
15
88
88
15
W
Water solubility and taste of drugs .... 81
Water soluble
bioreversible pro-drug of DPH
175
drugs, sparingly
66
gentisate complex of hexamethyl
melamine
3
salts, sparingly
63
vitamins
15
Wernicke's disease
17