Effect of food on the bioavailability of griseofulvin from microsize and PEG ultramicrosize (GRIS-PEGR) plain tablets


Aoyagi, N.; Ogata, H.; Kaniwa, N.; Ejima, A.

Journal of Pharmacobio Dynamics 5(2): 120-124

1982


Effect of food on the bioavailability of griseofulvin from its two plain tablets, a commercial microsize product and a PEG ultramicrosize (GRIS-PEGR) one, was investigated. The drug was dissolved at a slower rate from ultramicrosize formulation than from microsize one in 18 1 of pH 7.2 buffer but at a little faster rate in 40% dimethylformamide. When administered to fasting subjects, the microsize product showed higher serum levels and peak serum level than ultramicrosize one but the extent of the bioavailability was nearly the same. A standard breakfast enhanced the rate of absorption of the drug from both the products, especially from ultramicrosize one, and those products were equivalent in the rate and extent of bioavailability after food ingestion. The peak serum level of ultramicrosize product in nonfasting was about twice higher than that in fasting subjects. The different intensities of food effect on the bioavailabilities from two dosage forms suggest that formulation factors should be considered for the evaluation of food effect.

1Pharm.Dyn.,4,120
—124
(1982)
EFFECT
OF
FOOD
ON
THE
BIOAVAILABILITY
OF
GRISEOFULVIN
FROM
MICROSIZE
AND
PEG
ULTRAMICROSIZE
(GRIS-PEGR)
PLAIN
TABLETS
NOBUO
AOYAGI,
HIROYASU
OGATA,
NAHOKO
KANIWA
AND
AKIRA
EJIMA
National
Institute
of
Hygienic
Sciences,
18-1,
Kamiyoga
1-chome,
Setagaya-ku,
Tokyo
158,
Japan
(Received
September
3,
1981)
Effect
of
food
on
the
bioavailability
of
griseofulvin
from
its
two
plain
tablets,
a
commercial
microsize
product
and
a
PEG
ultramicrosize
(GRIS-PEG
R
)
one,
was
investigat-
ed.
The
drug
was
dissolved
at
a
slower
rate
from
ultramicrosize
formulation
than
from
microsize
one
in
18
1
of
pH
7.2
buffer
but
at
a
little
faster
rate
in
40%
dimethylformamide.
When
administered
to
fasting
subjects,
the
microsize
product
showed
higher
serum
levels
and
peak
serum
level
than
ultramicrosize
one
but
the
extent
of
the
bioavailability
was
nearly
the
same.
A
standard
breakfast
enhanced
the
rate
of
absorption
of
the
drug
from
both
the
products,
especially
from
ultramicrosize
one,
and
those
products
were
equivalent
in
the
rate
and
extent
of
bioavailability
after
food
ingestion.
The
peak
serum
level
of
ultramicrosize
product
in
nonfasting
was
about
twice
higher
than
that
in
fasting
subjects.
The
different
intensities
of
food
effect
on
the
bioavailabilities
from
two
dosage
forms
suggest
that
formu-
lation
factors
should
be
considered
for
the
evaluation
of
food
effect.
Keywords—griseofulvin;
ultramicrosize
formulation;
microsize
formulation;
dis-
solution;
food
effect;
human
study;
bioavailability
INTRODUCTION
Bioavailabilities
of
drug
have
been
usually
es-
timated
in
a
fasting
state
to
avoid
the
complicat-
ed
interference
with
food.
However,
it
seems
im-
portant
to
investigate
the
availability
after
food
ingestion
because
drugs
are
often
or
mostly
ad-
ministered
after
food
intake,
and
alteration
of
the
bioavailability
due
to
food,
if
occurs,
may
cause
a
significant
change
in
the
clinical
re-
sponse.
There
is
a
considerable
evidence
to
indi-
cate
that
the
absorption
of
drugs
may
be
in-
fluenced
by
the
presence
of
food
in
the
gastroin-
testinal
tract'
)
but
most
of
the
investigations
have
been
carried
out
with
only
one
formulation
but
not
with
different
ones
without
any
detail
information
on
the
formulation
characteristics.
However,
food
effect
on
drug
bioavailabilities
from
its
dosage
forms
may
differ
by
the
lots
and
type
of
the
formulations
as
shown
in
nitrofuran-
toin
2)
and
erythromycin
formulations.
3,4)
In
our
previous
studies
on
chloramphenicol,
food
en-
hanced
the
bioavailability
from
sugar
coated
tablet
which
had
poor
availability
in
fasting
state
but
it
did
not
from
the
powder.
5)
Thus
it
should
be
necessary
to
consider
the
formulation
characteristics
and
pay
attention
as
to
whether
the
food
effect,
if
was
observed,
is
mainly
based
on
the
interactions
of
food
with
drug
itself
or
with
formulation
factors.
Considerable
interest
has
been
generated
con-
cerning
the
absorption
of
griseofulvin
because
of
the
low
water
solubility
and
hence
its
poor
bioa-
vailability.
The
absorption
of
griseofulvin
was
increased
by
fatty
meals
6,7)
probably
because
of
enhancement
of
the
solubility
and
decreased
gas-
tric
emptying
rate.
The
present
investigation
was
undertaken
to
study
how
food
ingestion
in-
fl
uences
the
bioavailability
of
griseofulvin
from
its
two
different
plain
tablets,
a
commercial
microsize
product
and
a
PEG
ultramicrosize
(GRIS-PEG
R
)
one.
5-1
°
)
METHODS
Formulations
—PEG
ultramicrosize
griseo-
Bioavailability
of
Griseofulvin
121
fulvin
tablet
(GRIS-PEG
R
)
(Dorsey
Laborato-
ries,
Division
of
Sandoz
Inc.)
which
is
formulated
with
the
drug
dispersed
in
polyethylene
glycol
6000
8-10)
and
a
commercial
plain
tablet
of
microsize
griseofulvin
in
Japan
were
used
in
this
study.
The
labellings
of
both
products
indicate
that
each
tablet
contains
125
mg
of
griseofulvin.
The
spectrophotometric
assay"
showed
that
the
contents
of
the
drug
in
a
tablet
of
the
ultra-
microsize
and
microsize
products
were
123
and
122
mg,
respectively.
Disintegration
Time
—Disintegration
times
of
the
tablets
were
determined
with
six
tablets
according
to
JP
-IX
specifications
using
pH
1.2
hydrochloric
acid
solution
and
pH
7.2
sodium
phosphate
buffer
(0.01
M).
Dissolution
Rate
—The
dissolution
rates
of
the
drug
from
its
dosage
forms
were
determined
with
one
tablet
at
37°C
in
18
1
of
pH
7.2
sodium
phosphate
buffer
(0.01
M)
and
in
900
ml
of
40%
(w/v)
dimethylformamide.
Eighteen
liters
of
pH
7.2
buffer
was
agitated
with
three
bladed
screw
type
impeller
(5.0
cm
i.d.)
at
512
rpm
in
the
middle
of
the
solvent
in
a
20
1
fl
at
-bottom
beaker
(29.0
cm
i.d.).
Dissolution
test
in
900
ml
of
40%
dimethylformamide
was
carried
out
by
paddle
method
(USP
XX)
at
120
rpm.
The
amount
of
the
drug
dissolved
was
monitored
spectrophotometrically
by
passing
the
solution
through
a
glass
filter
(porosity
G-3)
to
a
fl
ow
cell.
An
average
dissolution
rate
was
obtained
after
three
dissolution
runs.
Bioavailability—Four
healthy
male
subjects
participated
in
this
four
way
cross
-over
study
ranged
in
age
from
32
to
51
years
(mean
43),
in
height
from
160
to
172
cm
(mean
168)
and
in
weight
from
54
to
68
kg
(mean
60).
Each
subject
received
a
test
tablet
with
200
ml
of
water
after
fasted
overnight
or
15
minutes
after
ingestion
of
a
standard
breakfast
which
consists
of
100
g
of
bread,
20
g
of
butter,
35
g
of
cucumber,
200
ml
of
milk
and
a
boiled
egg.
No
foods
or
liquid
were
permitted
until
4
h
after
drug
administration.
Blood
samples
(5
ml)
were
obtained
at
1,
3,5,
8,
23.5,
33
and
47.5
h
after
dosing
and
serum
sam-
ples
were
stored
frozen
at
—15°C
until
assayed.
The
experiments
were
repeated
every
two
weeks.
Serum
griseofulvin
was
determined
by
gas
-chromatography.
1
2)
The
differences
among
the
treatments
in
serum
levels,
peak
serum
levels
(C
max
),
time
to
C
max
(
T
m
),
area
under
serum
concentration
-time
curves
from
zero
to
47.5
h
and
to
infinite
time
(AUC
47
.
5
and
AUC
OO
),
elim-
ination
rate
constants
(k
ei
)
and
half
li
ves
(
t
112
)
were
examined
statistically
by
analysis
of
vari-
ance
(ANOVA)
and
then
by
Tukey's
multiple
range
test.
The
C
max
and
T
max
were
observed
values
and
Ic
e'
or
t
112
was
calculated
from
the
serum
concentration
-time
curve
from
23.5
to
47.5
h.
AUC
47.5
and
AUG
QO
were
calculated
by
the
trapezoidal
rule
and
the
method
of
Wag-
ner,
13)
respectively.
RESULTS
The
dissolution
rates
of
griseofulvin
from
its
Percent
dissolved
60
40
20
I
10
Time
(min)
20
FIG.
1.
Dissolution
of
Griseofulvin
from
Microsize
(0)
and
Ultramicrosize
( •
)
Formulations
in
18
l
of
pH
7.2
Phosphate
Buffer
The
solid
and
dotted
lines
show
the
dissolution
curves
in
the
absence
of
surfactants
and
in
the
pre-
sence
of
O.
1%
(w/
polysorbate
80.
122
N.Aoyagi,
et
al.
dosage
forms
were
determined
in
18
1
of
aque-
ous
solvent
as
Katchen
et
al.
had
applied"
)
and
in
900
ml
of
40%
dimethylformamide
since
the
drug
is
practically
insoluble
in
water
and
the
use
of
partially
alcoholic
medium
was
described
for
the
dissolution
tests
of
poorly
soluble
drugs
in
USP
Pharmacopeial
Forum."
)
As
Fig.
1
shows,
the
drug
was
dissolved
slower
from
the
ultar-
microsize
product
than
from
microsize
one,
and
:Percent
dissolved:
60
40
20
5
10
15
Time
(min)
FIG.
2.
Dissolution
of
Griseofulvin
from
Microsize
( 0
)
and
Ultramicrosize
( • )
Formulations
in
900
ml
of
40%
Dimethylformamide
TABLE
I.
Disintegration
Times
(Min)
of
Microsize
and
Ultramicrosize
Griseofulvin
Tablets
Formulation
Solvent
pH
7.2
pH
1.2
Microsize
12.0
±-1.1
Ultramicrosize
11.8
-
±
-
2.7
7.3
±-.1.8
The
figures
show
means
±
standard
deviations
of
the
disintegration
times
determined
with
six
tab-
lets.
polysorbate
80
did
not
influence
the
dissolution
though
the
surfactant
was
expected
to
promote
the
dissolution
of
the
drug
due
to its
wetting
ac-
tion."
)
As
Fig.
2
shows,
in
40%
dimethylforma-
mide
solution
the
ultramicrosize
formulation
showed
faster
dissolution
than
microsize
one
contrary
to
the
dissolution
findings
in
pure
aque-
ous
medium.
This
indicates
that
the
high
solvent
capacity
of
dimethylformamide
having
lipophi-
lic
and
hydrophilic
properties
will
change
the
dissolution
behavior
of
griseofulvin
from
its
dosage
forms.
The
disintegration
time
of
the
ultramicrosize
product
was
as
fast
as
that
of
microsize
one
at
pH
7.2
and
was
a
li
ttle
faster
at
pH
1.2
(Table
I).
The
microsize
product
disintegrated
into
fine
particles
while
the
ultramicrosize
one
produced
relatively
large
particles
and/or
agglomerates
after
disintegration
at
either
pH
7.2
or
1.2,
which
may
be
related
with
slower
dissolution
from
ultramicrosize
product
in
aqueous
solvent.
Fig.
3
shows
the
mean
serum
concentration
of
griseofulvin
after
oral
administration
of
two
formulations
to
fasting
and
nonfasting
subjects,
and
Table
II
li
sts
the
mean
values
of
the
in
vivo
parameters.
When
administered
to
fasting
sub-
jects,
the
microsize
product
exhibited
higher
0.8
Ti
I".
OA
,
,
X)
O.
10
20
30
47.5
Time
(h)
FIG.
3.
Mean
Serum
Concentrations
of
Griseoful-
vin
after
Oral
Administration
of
Microsize
and
Ul-
tramicrosize
Formulations
to
Fasting
and
Nonfast-
ing
Human
Subjects
Ultramicrosize
formulation
( •
)
and
microsize
formulation
( 0
).
The
dotted
and
solid
lines
show
the
serum
levels
in
fasting
and
nonfasting
states
respectively.
The
vertical
lines
show
stan-
dard
errors.
Bioavailability
of
Griseofulvin
123
serum
levels
from
zero
to
8
h
after
dosing
and
C
max
than
ultramicrosize
one.
The
C.
of
ultra-
microsize
product
was
approximately
70%
of
microsize's
one
and
the
difference
was
statistical-
ly
significant.
No
significant
difference
was
ob-
served
between
the
AUC
,,,„s
of
both
tablets
given
in
fasting
state.
The
standard
breakfast
significantly
enhanced
the
serum
levels
at
3
and
5
h
and
C
max
of
micro
-
size
formulation.
The
Cmax
in
nonfasting
was
ap-
proximately
136%
that
in
fasting.
The
standard
breakfast
increased
more
the
serum
levels
at
ear-
lier
sampling
times
and
C
max
of
ultramicrosize
formulation,
and
the
C
max
was
about
twice
that
in
fasting.
Under
food
ingestion
condition,
the
bioavailability
of
ultramicrosize
formulation
was
nearly
equal
to
that
of
microsize
one.
The
food,
however,
did
not
significantly
influence
the
AUC„,,
and
T.
of
both
formulations
though
the
T.
s
in
nonfasting,
especially
that
of
ultramicrosize
one,
tended
to
decrease
in
com-
parison
with
that
in
fasting.
The
elimination
half
li
ves
of
griseofulvin
were
11
-13
h
which
agreed
with
that
reported
by
Rowland
et
al.'"
Food
ingestion
did
not
affect
the
elimination
rate
of
the
drug.
DISCUSSION
The
dissolution
and
hence
absorption
of
gri-
seofulvin
has
been
reported
to
be
enhanced
by
reducing
particle
size
of
the
crystals.
7,18)
Thus
a
microsize
powder
of
the
drug
is
used
in
commer-
cial
tablets
and
a
new
formulation
called
ultra-
microsize
griseofulvin
tablet
can
also
be
ob-
tained,
which
was
shown
to
have
twice
better
bi-
oavailability
than
that
of
microsize
one.
9,10)
However,
Straughn
et
al.
recently
found
lower
absorption
of
the
drug
from
ultramicrosize
formulations
than
that
from
microsize
ones.
19)
In
this
study,
the
drug
was
absorbed
at
a
slower
rate
from
ultramicrosize
product
than
from
microsize
one
in
fasting
subjects,
which
coincid-
ed
with
the
result
of
Straughn
et
al.'
9)
A
standard
breakfast
increased
the
serum
levels
in
absorption
phase
and
Cmax
of
both
formulations.
The
food,
especially
the
fat
in
it,
seems
to
directly
facilitate
the
dissolution
of
gri-
seofulvin
and
also
increase
it
indirectly
by
stimu-
lating
the
fl
ow
of
bile
containing
solubilizing
and
emulsifying
agents.
20)
The
breakfast
greatly
TABLE
II.
Serum
Concentrations,
C
max
,
T„,
,
AUC
and
Elimination
Rates
after
Oral
Administration
of
Microsize
and
Ultramicrosize
Griseofulvin
Tablets
to
Fasting
and
Nonfasting
Subjects
In
vivo
parameter
Treatment
Results
Ultramicrosize
product
Microsize
product
of
ANOVA
Fasting(a)
Nonfasting(A)
Fasting(b)
Nonfasting(B)
Tukey's
test
b)
p
<0.05
1.0h
0.131-1.
-
0.015
0.343-1.-0.121
0.219±0.053
0.478
±0.168
N.S
a)
0
3.0
5.0
-4475
8.0
E
151
23.5
0.264
±0.049
0.318
±0.067
0.235
±0.042
0.252
±0.027
0.684
±0.035
0.601
±0.067
0.480
±0.046
0.190
±0.031
0.479±0.050
0.460
±0.029
0.400
±0.044
0.227
±0.030
0.671
±0.048
0.671
±0.035
0.470
±0.060
0.174±0.026
p
<0.01
A>B>b>a
p
<0.01
B>A>b>a
p
<0.01
A>B>b>a
N.S
b3-3
33.0
0.159
±0.031
0.113
±0.025
0.130
±0.023
0.110±0.024
NS
47.5
0.082
±0.024
0.046
±0.009
0.056
±0.010
0.051
±0.016
N.S
C
max
(f-Lem0
0.359
±0.036
0.684±0.035
0.517
±0.032
0.703
±0.041
p<0.01
B>A
>b
>a
T
max
(h)
9.4±4.7
3.0
-
1=0.0
4.3
±1.3
3.0±1.2
N.S
AUC
47
.
5
(pg.h/m1)
9.34
±0.70
11.89
±1.24
10.93
±1.04
11.95
-
1
-
1.40
N.S
AUC
co
(tig.h/m1)
10.77
±1.14
12.67
±
1.37
11.90
±1.25
13.06
±1.87
N.S
k
e
i(ir
1
)
0.057
±0.004
0.060
±0.003
0.059
±0.002
0.057
±0.008
N.S
412(h)
12.3
±0.7
11.6±0.6
11.8±0.5
13.0
±1.9
N.S
The
figures
indicate
means
±
standard
errors.
a)
N.S:
not
significant.
b)
Treatments
underlined
by
a
common
line
did
not
differ
significantly.
124
N.Aoyagi,
et
al.
increased
the
absorption
rate
of
the
drug
from
ultramicrosize
formulation
and
it
was
nearly
equal
to
that
from
microsize
one
in
the
presence
of
food
though
lower
in
the
absence
of
it.
Ultra-
microsize
formulation
may
produce
relatively
large
particles
or
agglomerates
by
disintegration
in
fasting
state
as
shown
in
the
in
vitro
disintegra-
tion
test,
but
further
disintegration
and
deaggre-
gation
of
those
particles
may
be
accelerated
by
food
ingestion.
Previous
studies
on
chloramphe-
7)
nicol
suggested
the
strong
destructive
force
caused
by
food.°
On
the
other
hand,
the
fat
component
in
the
diet
may
make
the
difference
smaller
in
the
dissolution
rates
of
lipophilic
drugs
such
as
griseofulvin
from
different
formu-
lations,
together
with
enhancement
of
the
disso-
lution,
as
shown
in
nitrofurantoin
studies
2)
in
which
the
macrocrystalline
drug
was
absorbed
at
a
slower
rate
than
microcrystalline
one
in
fast-
ing
state
but
absorbed
at
the
same
rate
in
non
-
fasting
state.
The
in
vitro
dissolution
behaviors
of
griseofulvin
in
40%
dimethylformamide
may
suggest
the
dissolution
in
a
lipophilic
state.
T
max
s,
especially
of
ultramicrosize
formula-
tion,
tended
to
be
decreased
by
ingestion
of
the
breakfast.
It
will
be
the
net
result
of
counteract-
ing
effects
of
food
on
the
absorption
of
the
drug,
namely
the
retardation
of
gastric
emptying
rate'
)
and
enhancement
of
the
disintegration
and
dissolution
of
the
drug.
The
different
intensities
of
food
effect
on
the
bioavailabilities
from
microsize
and
ultramicro-
size
formulations
suggest
that
its
effect
on
the
absorption
of
the
other
drugs
may
also
differ
by
the
lots
and
type
of
the
formulations,
and
it
seems
necessary
to
pay
attention
whether
the
ob-
served
effect
of
food
will
be
attributed
to
the
in-
teraction
between
food
and
drug
itself,
or
that
between
food
and
formulation
factors.
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