Comparative bioavailability of a microsize and ultramicrosize griseofulvin formulation in man


Lin, C.; Lim, J.; DiGiore, C.; Gural, R.; Symchowicz, S.

Journal of International Medical Research 10(4): 274-277

1982


The bioavailability of 500 mg of a microsize formulation of griseofulvin has been compared to two new ultramicrosize griseofulvin formulations, two 165 mg tablets and a 330 mg tablet, in sixteen healthy, male, volunteers in a randomized crossover study design. Based on the griseofulvin plasma levels measured at specified times over a 48-hour period, the major bioavailability parameters (i.e., area under plasma concentration-time curve, maximum plasma concentration, and time to reach maximum plasma concentration) were determined and statistically evaluated. The results showed that one 330 mg ultramicrosize tablet is bioequivalent to two 165 mg ultramicrosize griseofulvin tablets and that either ultramicrosize griseofulvin dosage regimen is bioequivalent to 500 mg of the microsize griseofulvin formulation.

J
Int
Med
Res
(1982)
10,
274
Comparative
Bioavailability
of
a
Microsize
and
Ultramicrosize
Griseofulvin
Formulation
in
Man
C
Lin*,
PhD,
J
Lim,
MS,
C
DiGiore,
MT,
R
Gural,
PhD
and
S
Symchowicz,
PhD,
Drug
Metabolism
and
Pharmacokinetics,
Schering
Corporation,
60
Orange
Street,
Bloomfield,
NJ
07003,
USA
The
bioavailability
of
500
mg
of
a
microsize
formulation
of
griseofulvin
has
been
compared
to
two
new
ultramicrosize
griseofulvin
formulations,
two
165
mg
tablets
and
a
330
mg
tablet,
in
sixteen
healthy,
male,
volunteers
in
a
randomized
crossover
study
design.
Based
on
the
griseofulvin
plasma
levels
measured
at
specified
times
over
a
48
-hour
period,
the
major
bioavailability
parameters
(i.e.,
area
under
plasma
concentration
-time
curve,
maximum
plasma
concentration,
and
time
to
reach
maximum
plasma
concentration)
were
determined
and
statistically
evaluated.
The
results
showed
that
one
330
mg
ultramicrosize
tablet
is
bioequivalent
to
two
165
mg
ultramicrosize
griseofulvin
tablets
and
that
either
ultramicrosize
griseofulvin
dosage
regimen
is
bioequivalent
to
500
mg
of
the
microsize
griseofulvin
formulation.
Introduction
Griseofulvin
is
an
orally
effective
antifungal
agent
which
is
widely
used
in
the
treatment
of
ringworm
infections
of
the
skin,
hair,
and
nails.
Barrett
and
Bianchine
(1975)
have
reported
that
the
bioavailability
of
250
mg
ultramicrosize
griseofulvin
is
equivalent
to
a
500
mg
of
microsize
griseofulvin
formulation.
This
has
not
been
confirmed
in
a
more
recent
fi
nding
by
Straughn,
Meyer,
Raghow
and
Rotenberg
(1980),
who
concluded
that
250
mg
of
ultramicrosize
griseofulvin
was
not
bioequivalent
to
several
500
mg
microsize
griseofulvin
products.
This
study
was
designed
to
evaluate
the
bioavailability
of
griseofulvin
from
ultramicrosize
griseofulvin
tablet
formulations
and
a
microsize
griseofulvin
tablet
formulation.
*To
whom
reprint
requests
should
be
addressed.
Materials
and
Methods
(a)
Drug
Administration
Sixteen
normal,
healthy,
male,
volunteers
participated
in
the
study
at
St.
James
Hospital,
Dublin,
Ireland.
The
drug
was
administered
after
a
12
-hour
fast.
Each
subject
received
a
microsize
500
mg
griseofulvin
tablet,*
an
ultramicrosize
330
mg
griseofulvin
tablet,
*
or
two
ultramicrosize
165
mg
griseofulvin*
tablets
according
to
a
randomized,
crossover
study
design.
A
wash
-out
period
of
at
least
7
days
separated
the
various
phases
of
the
study.
Plasma
samples
were
collected
at
specific
time
intervals
and
kept
frozen
until
analyzed.
All
samples
were
coded
and
analyzed
without
reference
to
treatment.
*Fulvicin
P/G
Schering
Corporation's
(U.S.A.)
brand
of
ultramicrosize
griseofulvin
tablets.
tGrisovin
Glaxo
Laboratories
Ltd's
(United
Kingdom)
brand
of
microsize
griseofulvin
tablets.
0300-0605/82/040274-04
$02.00
©Cambridge
Medical
Publications
Limited
C
Lin
et
al
275
(b)
Analysis
of
Plasma
Concentration
of
Griseofulvin
Plasma
levels
of
griseofulvin
were
analyzed
by
a
gas
-liquid
chromatographic
(GLC)
method.
To
an
aliquot
(0.5
ml)
of
plasma
samples,
0.5
pg
of
isogriseofulvin
(as
Internal
Standard)
in
10
pl
ethanol
was
added.
The
mixture
was
extracted
with
2
ml
of
diethyl
ether,
and
2
pl
of
ether
were
then
injected
into
a
Varian
Aerograph
model
2100
GLC
unit.
The
GLC
was
equipped
with
Ni"
electron
capture
detectors
and
12
feet
long
U
-type
glass
columns,
packed
with
3%
OV-25
on
Supelcoport
(100/120).
The
temperature
was
maintained
at
280°C,
for
the
column,
320°C
for
detector
and
300°C
for
injector.
N
2
was
used
as
the
carrier
gas
at
a
rate
of
10
ml/min.
With
these
conditions,
a
retention
time
of
8
minutes
was
obtained
for
griseofulvin,
and
10
minutes
for
isogriseofulvin.
The
amount
of
griseofulvin
in
the
plasma
was
calculated
from
a
standard
curve
which
was
obtained
by
plotting
the
ratio
of
the
peak
height
of
griseofulvin
to
the
peak
height
of
isogriseo-
fulvin
(Internal
Standard)
against
the
concentration
of
griseofulvin.
This
method
is
very
sensitive
and
can
measure
griseofulvin
concentrations
as
low
as
5
ng/ml
with
good
accuracy
and
reproducibility.
The
specificity
of
the
method
has
been
established
by
comparison
with
the
retention
times
of
griseofulvin
analogs.
Based
on
the
plasma
concentrations,
the
area
under
the
plasma
concentration
-time
curve,
maximum
plasma
concentration,
and
time
to
reach
maximum
plasma
concentration
were
then
calculated
for
each
formulation.
(c)
Statistical
Analysis
The
area
under
the
plasma
concentration
-time
curve,
maximum
plasma
concentration,
time
to
reach
maximum
plasma
concentration,
and
concentration
at
each
time
period
were
compared
via
a
crossover
analysis
of
variance;
between
treatment
comparisons
were
made
using
Duncan's
Multiple
Range
test.
Results
and
Discussion
The
plasma
levels
of
griseofulvin
after
administration
of
various
tablet
formulations
are
illustrated
in
Figure
1.
Table
1
shows
that
there
were
no
significant
differences
in
plasma
drug
levels
between
two
165
mg
ultramicrosize
griseofulvin
tablets
and
one
330
mg
ultramicrosize
griseofulvin
tablet.
The
result
also
shows
that
at
most
time
periods
there
were
no
significant
differences
(p
>
0.05)
in
plasma
drug
levels
between
the
500
mg
microsize
griseofulvin
tablet
and
the
two
strengths
of
ultramicrosize
griseofulvin.
Two
165
mg
ultramicrosize
griseofulvin
tablets
produced
a
higher
drug
level
(p
<
0.05)
than
one
500
mg
microsize
griseofulvin
tablet
at
4
hours
while
the
microsize
tablet
yielded
drug
levels
higher
than
both
formulations
of
ultramicrosize
griseofulvin
at
36
and
48
hours
(p
<
0.05).
Based
on
the
plasma
drug
levels,
three
major
bioavailability
parameters
were
evaluated:
(1)
area
under
the
plasma
griseofulvin
concentration
-time
curve
(AUC),
(2)
observed
maximum
plasma
griseofulvin
concentration
(Cmax),
and
(3)
time
to
reach
the
observed
maximum
plasma
drug
concentration
(T
max
).
The
AUC,
which
reflects
the
relative
amounts
of
griseofulvin
absorbed
from
each
formulation,
was
determined
for
the
0-
to
48
-
hour
period.
As
shown
in
Table
2,
the
mean
AUC
was
similar
in
each
treatment
group
(15.5,
15.0,
and
16.8
µg-hr/ml
for
two
165
mg
ultramicrosize
griseofulvin
tablets,
a
330
mg
ultramicrosize
griseofulvin
tablet,
and
a
500
mg
microsize
griseofulvin
tablet,
respectively).
There
were
no
significant
differences
(p
>
0.10)
in
AUC
between
microsize
griseofulvin
and
either
ultramicrosize
griseofulvin
tablets
or
between
the
two
ultramicrosize
dosage
regimens.
The
Cmax,
which
is
the
highest
measured
drug
level,
is
a
function
of
both
the
rate
and
extent
of
drug
absorption.
The
mean
Cmax
was
0.84
pg/ml
for
two
165
mg
ultramicrosize
griseofulvin
tablets,
0.75
pg/ml
for
one
330
mg
ultramicrosize
griseofulvin
tablet,
and
0.71
g/ml
for
one
500
mg
microsize
griseofulvin
tablet
(Table
2).
The
statistical
analysis
indicated
no
significant
differences
(p
>
0.20)
in
C,„
ax
among
the
three
formulations.
The
Tmax,
which
is
the
time
of
maximum
concentration,
is
a
function
of
the
rate
of
drug
absorption.
The
mean
T.
for
all
three
formulations
was
between
4.5
and
5.4
hours.
The
statistical
analysis
showed
no
significant
differences
(p
>
0.10)
in
T.
among
the
three
treatments.
276
The
Journal
of
International
Medical
Research
z
_J
La.
0
-
cn
-J
W
2
a.
0.8
Two
165
mg
ultramicrosize
griseofulvin
tablets
One
330
mg
ultramicrosize
griseofulvin
tablet
One
500mg
microsize
griseofulvin
tablet
0
12
24
36
48
TIME
(hr)
Fig
1
Plasma
concentration
of
griseofulvin
after
a
single
oral
dose
in
human
volunteers.
Table
1
Plasma
concentrations
of
griseofulvin
(µg/ml)
at
various
time
periods
after
drug
administration
Mean
(To
coefficient
of
variation•)
One
330
mg
Two
165
mg
One
500
mg
ultramicro- ultramicro-
microsize
size
size
Time
griseofulvin: griseofulvin:
griseofulvin:
Statistical
significance
(hr)
Tablet
(A)
Tablet
(B)
Tablets
(C)
A
vs
B
A
vs
C
B
vs
C
0.5
0.09
(124)
0.10
(63)
0.10
(68)
N.S.*
N.S. N.S.
1
0.24
(65)
0.28
(51)
0.28
(55)
N.S.
N.S.
N.S.
2
0.42
(52)
0.48
(29)
0.52
(50)
N.S.
N.S.
N.S.
3
0.57
(29)
0.62
(23)
0.71
(36)
N.S. N.S.
N.S.
4
0.63
(29)
0.71
(34)
0.78
(31)
N.S.
Sig
S
N.S.
6
0.63
(23)
0.67
(33)
0.74
(27)
N.S.
N.S.
N.S.
8
0.55
(20)
0.57
(29)
0.64
(27)
N.S.
N.S.
N.S.
10
0.53
(20)
0.53
(26)
0.57
(30)
N.S.
N.S.
N.S.
12
0.49
(23)
0.47
(25)
0.50
(26)
N.S. N.S.
N.S.
16
0.40
(23)
0.38
(25)
0.39
(27)
N.S. N.S.
N.S.
24
0.32
(32)
0.27
(33)
0.27
(33)
N.S.
Sig
N.S.
36
0.27
(44)
0.18
(43)
0.16
(51)
Sig Sig
N.S.
48
0.15
(54)
0.09
(68)
0.08
(52)
Sig
Sig
N.S.
%Coefficient
of
variation
=
(S.D./Mean)
x
100.
tp
>
0.05.
S
p
<
0.05.
C
Lin
et
al
277
Table
2
Summary
for
major
bioavailability
parameters
and
statistical
analysis
Mean
(%
coefficient
of
variation')
A
UC
(µg-hr/ml)
Cmax(aglml)
T
max
(hr)
One
500
mg microsize
griseofulvin
tablet
(A)
One
330
mg
ultramicrosize
griseofulvin
tablet
(B)
Two
165
mg
ultramicrosize
griseofulvin
tablets
(C)
Percent
of
difference
[p
-Value]:
16.79
(23.0)
15.00
(24.1)
15.54
(24.7)
0.71
(23.3)
0.75
(31.0)
0.84
(29.0)
5.44
(52.0)
5.06
(41.1)
4.56
(38.4)
A
vs
B
10.7%
[
>
0.101
5.3%
[>
0.10]
7.0%
[>
0.10]
A
vs
C
7.4%
[>
040]
15.5%
[>
0.10]
16.2%
[>
0.10]
B
vs
C
3.5%
[>
0.10]
10.7%
[>
040]
9.9%
[>
0.10]
%Coefficient
of
variation
=
(S.D./Mean)
x
100.
Conclusions
Based
on
the
data
obtained
in
this
study,
it
is
concluded
that
one
330
mg
tablet
of
ultramicrosize
griseofulvin
is
bioequivalent
to
two
165
mg
tablets
of
ultramicrosize
griseofulvin,
and
that
330
mg
of
ultramicrosize
griseofulvin,
(either
as
a
one
330
mg
or
two
165
mg
tablets)
is
bioequivalent
to
500
mg
of
microsize
griseofulvin.
REFERENCES
Barrett
W
E
&
Bianchine
J
R
(1975)
The
bioavailability
of
ultramicrosize
griseofulvin
(Gris-PEG)
tablets
in
man.
Current
Therapeutic
Research
18,
501
Straughn
A
B,
Meyer
M
C,
Raghow
G
&
Rotenberg
K
(1980)
Bioavailability
of
microsize
and
ultramicrosize
griseofulvin
products
in
man.
Journal
of
Pharmacokinetics
and
Blopharmaceutics
8,
347