The bioavailability of ultramicrosize griseofulvin (Gris-Peg) tablets in man


Barrett, W.E.; Bianchine, J.R.

Current Therapeutic Research 18(3): 501-509

1975


In an effort to provide for a better absorption and a more predictale blood level of griseofulvin, the drug was incorporated into a PEG;6000 formulation. This ultramicrosize formulation (called Gris-PEG® tablets) was compared to commercially available microsize griseofulvin in normal male volunteers. The two studies reported were a double-blind, single-dose, parallel-group design and a crossover design. The results derived from these two studies indicate that the oral absorption of griseofulvin, in man, is significantly enhanced by the PEG formulation since essentially the same plasma levels were achieved with 250 mg. of the ultramicrosize griseofulvin (Gris-PEG®) as were achieved with a 500-mg. dose. of the marketed microsize form of griseofulvin. The bioavailability of 250 mg. of the ultramicrosize griseofulvin was equivalent to that of a 500-mg. dose of the microsize formulation.

CURRENT
THERAPEUTIC
RESEARCH
VOL.
18.
NO.
3,
SEPTEMBER,
1975
Laboratory
Study
THE
BIOAVAILABILITY
OF
ULTRAMICROSIZE
GRISEOFULVIN
(GRIS-PEG®)
TABLETS
IN
MAN
WALTER
E.
BARRETT,
PH.D.,*
Pharmaceutical
Research
and
Development,
Sandoz,
Inc.,
East
Hanover,
New
Jersey
and
JOSEPH
R.
BIANCHINE,
M.D.,
PH.D.,**
Department
of
Medicine,
John
Hopkins
University,
School
of
Medicine,
and
Baltimore
City
Hospital,
Baltimore,
Maryland
ABSTRACT
In
an
effort
to
provide
for
a
better
absorption
and
a
more
predictable
blood
level
of
griseofulvin,
the
drug
was
incorporated
into
a
PEG
-6000
formulation.
This
ultramicrosize
formulation
(called
Gris-PEG®
tablets)
was
compared
to
commercially
available
microsize
griseofulvin
in
normal
male
volunteers.
The
two
studies
reported
were
a
double-blind,
single
-dose,
parallel
-group
design
and
a
crossover
design.
The
results
derived
from
these
two
studies
indicate
that
the
oral
absorption
of
griseofulvin,
in
man,
is
significantly
enhanced
by
the
PEG
formulation
since
essentially
the
same
plasma
levels
were
achieved
with
250
mg.
of
the
ultramicrosize
griseofulvin
(Gris-PEG®)
as
were
achieved
with
a
500
-mg.
dose
of
the
marketed
micro
-
size
form
of
griseofulvin.
The
bioavailability
of
250
mg.
of
the
ultramicro-
size
griseofulvin
was
equivalent
to
that
of
a
500
-mg.
dose
of
the
microsize
formulation.
INTRODUCTION
There
is
evidence
that
griseofulvin
is
poorly
and
irregularly
absorbed
in
humansl
-1
°
and
it
is
possible
that
in
many
infections
unresponsiveness
to
griseofulvin
therapy
may
be
due
to
poor
absorption
of
the
drug.
Blood
-level
studies
carried
out
in
several
laboratories1,4,5,11-14
h
ave
shown
that
it
is
possible
to
improve
intestinal
absorption
of
griseofulvin
by
reducing
its
particle
size.
Plasma
levels
equal
to
those
resulting
from
a
full
dose
of
macrosize
griseofulvin
(10
microns
plus
in
diameter)
can
be
obtained
with
one
half
the
dose
of
microsize
griseofulvin
(2.7
micron
plus
in
diameter).
The
reduction
of
particle
size
can
be
accomplished
directly
by
several
**
Director,
Short
Term
Research
and
Development
Present
Address:
Professor
and
Chairman
of
the
Department
of
Pharmacology
and
Thera-
peutics,
Ohio
State
University,
School
of
Medicine,
Columbus,
Ohio
Reprint
Requests:
Walter
E.
Barrett,
Ph.D.
Received
for
publication
on
July
16,
1975.
Printed
in
U.S.A.
1975,
Therapeutic
Research
Press,
Inc.
Reproduction
in
whole
or
part
is
not
permitted.
[
501
]
THE
BIOAVAILABILITY
OF
ULTRAMICROSIZE
GRISEOFULVIN
(GRIS-PEG)
TABLETS
recognized
techniques.
The
resultant
fine
particles
may
not
produce
the
expected
faster
dissolution
rate
and
better•gastrointestinal
absorption
due
to
possible
aggregation
an
d
agglomeration
of
the
fine
particles.''
This
may
be
caused
by
the
electrostatic
charge
that
develops
on
the
solids
after
milling.'
5
The
application
of
solid
dispersion
systems
to
increase
rates
of
disso-
lution
and
oral
absorption
of
poorly
water-soluble
or
insoluble
drugs
was
proposed
by
Sekiguchi
and
Obi"
in
1961.
These
authors
described
the
formation
of
an
eutectic
mixture
which
consisted
of
a
physiologically
inert,
readily
soluble
carrier
plus
a
poorly
water-soluble
drug.
A
mixture
of
the
drug
and
the
carrier
was
melted
together
and
then
solidified
by
chilling
or
cooling
to
room
temperature.
At
room
temperature,
this
mate-
rial
was
a
solid
material.
When
such
a
solid
dispersion
system
was
exposed
to
water
or
gastrointestinal
fluids,
the
soluble
carrier
was
rapidly
dis-
solved,
releasing
finely
dispersed
particles
of
the
drug.
This
was
.based
upon
the
assumption
that
at
the
time
of
the
solidification,
only
very
small
particles
in
the
submicron
or
micron
range
would
be
formed.
Chiou
and
Riegelmanl
7
have
described
the
in
-vitro
characteristics
of
solid
dispersion
of
griseofulvin.
The
in
vivo
applications
with
griseofulvin
were
only
recently
demon-
strated
by
Chiou
and
Riegelman
in
dogs
and
human
subjects.
18,1
9
These
investigators
demonstrated
that
oral
administration
of
griseofulvin
in
the
solid
dispersion
formulations
gave
fast
and
almost
complete
absorption,
whereas
only
30
to
60
percent
of
the
commercially
available
microsize
formulation
was
absorbed.
In
their
studies,
they
used
polyethylene
glycol
(PEG
-6000)
as
the
dispersion
carrier.
The
human
bioavailability
studies
reported
in
this
paper
were
designed
to
corroborate
and
amplify
the
results
presented
by
Chiou
and
Riegelman
and
to
compare
quantitatively
the
oral
absorption
characteris-
tics
of
commercially
available
microsize
griseofulvin
tablets
and
ultra-
microsize
griseofulvin
(Gris-PEG®)
tablets
(griseofulvin
in
a
PEG
-6000
formulation).
A
group
of
thirty-six
male
volunteers
participated
in
Study
No.
1
which
was
a
double-blind
parallel
-group
design.
In
the
second
study,
Study
No.
1A,
a
group
of
eleven
male
subjects
participated
in a
double-blind
crossover
study.
METHODS
1.
Study
No.
1
In
this
first
bioavailability
study,
thirty-six
male
volunteers
were
randomly
assigned
to
one
of
three
groups
of
equal
size
by
means
of
a
table
of
random
numbers.
[
502
]
WALTER
E.
BARRETT,
PH.D.,
AND
JOSEPH
R.
BIANCHINE,
M.D.,
PH.D.
Group
A
(12
subjects)
received
a
single
oral
dose
of
500
mg.
of
a
commercial-
ly
available
formulation
(tablet)
of
microsize
griseofulvin.*
Group
B
(12
subjects)
received
two
125
mg.
ultramicrosize
griseofulvin**
tablets
(griseofulvin
in
a
PEG
-6000
formulation).
Group
C
(12
subjects)
received
four
125
mg.
ultramicro-
size
griseofulvin
tablets.
All
subjects
received
the
study
medications
at
8:00
a.m.
with
4
to
6
ounces
of
water.
Blood
samples
for
the
determination
of
the
concen-
tration
of
griseofulvin
in
plasma
were
obtained
at
zero
time
and
at
0.5,
1,
2,
4,
6,
8,
10,
12,
and
24
hours
after
the
oral
administration
of
the
study
medication.
2.
Study
No.
1A
Twelve
normal
healthy
male
volunteers
were
selected
to
participate
in
this
double-
blind,
single
-dose
crossover
study.
Eleven
subjects
actually
took
part
in
this
study.
One
subject
never
returned
after
the
initial
physical
examination.
Group
I
received
a
single
oral
dose
of
500
mg.
of
a
commercially
available
microsize
formulation
(tablet)
with
4
to
6
ounces
of
water
on
Study
Day
1.
Group
II
received
a
single
oral
dose
of
250
mg.
of
ultramicrosize
griseofulvin
with
4
to
6
ounces
of
water
on
Study
Day
1.
Assignment
of
subjects
to
a
treatment
group
was
based
on
a
table
of
random
numbers.
On
Study
Day
9,
following
a
washout
period,
which
extended
from
Study
Day
3
to
Study
Day
8,
the
subjects
were
crossed
over
and
received
the
second
study
medication.
Blood
samples
for
the
determination
of
the
concentration
of
griseofulvin
in
the
plasma
were
obtained
at
zero
time
and
at
0.5,
1,
2,
4,
6,
8,
10,
12,
24,
36,
48,
and
72
hours
after
the
oral
administration
of
the
study
medications.
The
following
variables
were
controlled
in
both
Study
No.
1
and
Study
No.
1A.
In
both
studies,
all
subjects
were
informed
about
the
purpose
and
design
of
the
experiment.
All
gave
written
consent
to
participate
in
these
studies.
Subjects
selected
indicated
a
willingness
and
good
motivation
to
cooperate.
All
subjects
were
between
the
ages
of
21
and
50
years,
weighed
between
140
and
200
pounds
and
were
within
±15
percent
of
the
normal
body
weight
for
their
frame
and
stature.
20
Additional
criteria
for
entrance
into
the
studies
included
a
normal
routine
physical
examination,
complete
blood
count,
urinalysis
and
auto-
mated
serum
chemistries.
Further,
all
subjects
were
totally
free
of
significant
clinical
illness
in
the
two
weeks
preceding
the
study;
had
no
surgical
or
medical
condition
which
might
interfere
with
the
absorption,
metabolism
or
excretion
of
the_
study
medications;
were
not
taking
any
other
medication.
During
the
pretreatment
phase
(control
period),
the
following
parameters
were
studied
in
each
subject:
a
12
-lead
ECG,
a
battery
of
hematology
tests,
including
a
determination
of
the
hemoglobin,
hematocrit
and
WBC
count.
Blood
chemistries
included
a
determination
of
the
following:
calcium,
inorganic
phos-
phorus,
fasting
blood
sugar,
BUN,
serum
uric
acid,
total
protein,
albumin,
cho-
lesterol,
total
bilirubin,
alkaline
phosphatase,
LDH
and
SGOT.
Subjects
with
abnormal
values
or
findings
were
not
admitted
into
these
studies.
These
paramaters
were
evaluated
again
on
Study
Day
2
in
Study
No.
1.
They
were
also
evaluated
again
in
Study
No.
1A
on
Study
Day
2,
at
the
end
of
the
washout
period
which
was
Study
Day
8
and
on
Study
Day
10.
No
concurrent
medication
was
permitted
during
the
course
of
either
Study
No.
1
or
No.
1A.
Each
subject
entered
the
Clinical
Unit
of
the
Baltimore
City
Hospital
the
night
before
the
study
was
initiated
and
subjects
fasted
overnight
but
were
*
Microsize
griseofulvin
tablets
were
purchased
from
available
commercial
supplies.
**
Ultramicrosize
griseofulvin
tablets
were
supplied
by
Sandoz,
Inc.
[
503
]
THE
BIOAVAILABILITY
OF
ULTRAMICROSIZE
GRISEOFULVIN
(GRIS-PEG)
TABLETS
allowed
water
ad
lib.
No
food
or
liquids
were
allowed
until
four
hours
after
the
ingestion
of
the
study
medications.
The
plasma
samples
were
labeled
with
a
five
-digit
number,
frozen
and
kept
frozen
until
the
time
of
the
assay.
Schwarz
et
a1.
21
have
recently
reported
upon
the
chemical
assay
method
employed
in
the
present
studies.
The
persons
who
performed
the
chemical
assays
were
not
aware
of
the
study
medications
received
by
any
subject.
In
Study
No.
1,
the
statistical
procedures
used
were
the
analysis
of
variance,
the
t
-test
against
zero
time
and
the
Krushall-Wallis
rank
sum
test.
For
Study
No.
1A,
the
data
from
the
plasma
samples
were
statistically
ana-
lyzed
using
the
analysis
of
variance
for
a
crossover
design.
Vital
signs
and
clinical
laboratory
data
were
analyzed
by
comparing
the
change
from
baseline
for
the
two
treatments.
RESULTS
After
the
plasma
assay
results
had
been
obtained,
the
following
para-
meters
were
subjected
to
a
statistical
analysis:
a..
peak
plasma
level;
b.
time
to
reach
peak
plasma
level;
c.
area
under
the
plasma
level
curve.
Study
No.
1
Parallel
-Group
Design
A
single
oral
dose
of
250
mg.
of
ultramicrosize
griseofulvin
produced
essentially
the
same
peak
plasma
concentration,
the
same
time
to
Figure
1
Study
No.
1,
the
plasma
concentration
of
griseofulvin
(mcg./ml.)
after
a
single
oral
dose
in
human
volunteers;
gas
chromatographic
assay.
1.0
mcg./ml.
Af
.
N.
4
\\.
-•..........
4
.......
4
........
0.5
A
•••/"......._
'
/
...
............
.M
.....
''".....,...
0.
/•
/
.w.....„.....:::
:
.......
El
,
a
.........
t
i1
f
=
microsize
griseofulvin
500
mg.
=
ultramicrosize
griseofulvin
250
mg.
A
=
ultramicrosize
griseofulvin
500
mg.
0
1
2
4
6
8
10
12
HOURS
24
[
504
]
WALTER
E.
BARRETT,
PH.D.,
AND
JOSEPH
R.
BIANCHINE,
M.D.,
PH.D.
reach
peak
concentration
and
the
same
area
under
the
plasma
level
curve
as
was
achieved
with
a
single
oral
dose
of
500
mg.
of
the
microsize
formulation
of
griseofulvin
(Fig.
1).
There
was
no
statis-
tically
significant
difference
between
the
plasma
levels
achieved
with
these
two
study
medications.
Following
the
oral
administration
of
a
single
500
-mg.
dose
of
ultramicrosize
griseofulvin
to
man,
the
peak
plasma
level
and
the
area
under
the
plasma
level
curve
were
significantly
enhanced
when
com-
pared
to
the
results
obtained
with
a
500
-mg.
dose
of
a
commercially
available
microsize
formulation
of
griseovulv
.
in
(Fig.
1).
Study
No.
lA
Crossover
Design
In
this
crossover
study,
an
oral
dose
of
250
mg.
of
ultramicrosize
griseofulvin
produced
essentially
the
same
peak
concentration,
the
same
time
to
reach
peak
concentration,
and
the
same
area
under
the
plasma
level
curve
as
was
achieved
with
a
single
oral
dose
of
500
mg.
of
a
commercially
available
microsize
formulation
of
griseofulvin.
The
differences
between
the
two
study
medications
were
not
significant
(Fig.
2).
Figure
2
Study
No.
1A,
the
plasma
concentration
of
griseofulvin
(mcg./m1.)
after
a
single
oral
dose
in
human
volunteers;
gas
chromatographic
assay.
0.7
0.6
0.5
0.4
0.3
0.2
0.1
mcg./ml.
11
1
.1
1
1
1
A
••••••
*v.
•••
41%
•vv.
••,„
I=
0
ultramicrosize
griseofulvin
250
mg.
microsize
griseofulvin
500
mg.
•••
•••
••••
••••
••••
•••
•••,
•••
0
3
6
9
12
24
36
48
HOURS
[
505
72
THE
BIOAVAILABILITY
OF
ULTRAMICROSIZE
GRISEOFULVIN
(GRIS-PEG)
TABLETS
The
numerical
values
for
the
bioavailability
parameters
studied
in
Studies
No.
1
and
No.
1A
have
been
summarized
in
Table
I.
Table
I
-Bioauctilability
Parameters
-
Average
Values
Area
Under
Plasma
Oral
Time
To
Peak
Plasma
Level
Curve
Study
No.
N
Group
Dose
-mg.
Peak
(Hr.)
Level
(mcg./m1.)
(Hrs.
mcg./ml.
No.
1
12
A
500
4.00
0.65
9.89
12
B
250
4.67
0.80
11.18
12
C
500
4.17
1.15
15.11
No.
1A
11
I
500
6.10
0.51
14.36
11
II
250
3.70
0.60
12.88
A
=
Microsize
Griseofulvin
-
500
mg.
B
=
Ultramicrosize
Griseofulvin
-
250
mg.
C
=
Ultramicrosize
griseofulvin
-
500
mg.
I
=
Microsize
Griseofulvin
-
500
mg.
II
=
Ultramicrosize
Griseofulvin
-
250
mg.
In
studies
No.
1
and
No.
1A,
no
adverse
effects
attributable
to
the
study
medications
were
observed
in
the
following
parameters:
vital
signs,
ECG,
hematology
parameters,
blood
chemistry
parameters
and
the
urinalysis
tests.
No
adverse
reactions
were
reported
during
the
course
of
these
two
studies.
Table
II
-
Study
No.
1
-
Summary
of
Background
Data
Mean
±
Standard
Deviation
Drug
Group
Age
In
Years
Weight
In
Lbs.
(Kg
.1
Height
In
Inches
(Cm.)
A
24.1
±2.4
160.3
±
15.8
69.4
±
2.4
(72.71
±7.1
kg.)
(1762
±
6.1
cm.)
B
27.2
±
5.3
160.4
±
16.4
69.1
±3.5
(72.76
±
7.4
kg.)
(175.5
±
8.8
cm.)
C
24.1
±
2.0
156.5
±
15.9
70.4
±
2.0
(70.99
±
7.2
kg.)
(178.8
±
5.1
cm.)
A
=
Microsize
Griseofulvin
-
500
mg.
B
=
Ultramicrosize
Griseofulvin
-
250
mg.
C
=
Ultramicrosize
Griseofulvin
-
500
Ong.
For
both
Studies
No.
1
and
No.
1A,
there
were
no
significant
differences
between
treatment
groups
in
terms
of
age,
body
weight
and
height
as
indicated
in
Tables
II
and
III.
[
506
]
WALTER
E.
BARRETT,
PH.D.,
AND
JOSEPH
R.
BIANCHINE,
M.D.,
PH.D.
Table
III
Study
No.
I
A
Summary
of
Background
Data
Mean
±
Standard
Deviation
Study
Day
0
N
Drug
Group
Age
in
Years
Weight
in
Lbs.
(Kg.)
Height
in
Inches
(Cm.)
5
I
25.6
±
3.5
150.0
±
9.2
70.2
±
1.9
(68.95
±
4.2
kg.)
(178.3
±4.8
cm.)
6
II
22.3
±
1.0
157.6
±
5.1
70.7
±
2.7
(71.49
±
2.3
kg.)
(179.5
±
6.8
cm.)
I
=
Microsize
Griseofulvin
500
mg.
II
=
Ultramicrosize
Griseofulvin
250
mg.
DISCUSSION
The
results
derived
from
these
two
studies
confirm
those
of
Chiou
and
Riegelman
18
and
indicate
that
the
oral
absorption
of
griseofulvin
in
man
is
significantly
enhanced
by
the
PEG
formulation
since
essentially
the
same
plasma
levels
were
achieved
with
250
mg.
of
ultramicrosize
griseo-
fulvin
as
were
achieved
with
a
500
-mg.
oral
dose
of
a
marketed
microsize
formulation
of
griseofulvin.
The
parameters
peak
plasma
level
and
area
under
the
plasma
level
curve
produced
by
an
oral
dose
of
500
mg.
of
the
ultramicrosize
griseo-
fulvin
were
1.48
times
as
large
as
those
obtained
with
a
500
-mg.
dose
of
the
microsize
griseofulvin
(Fig.
1),
P
=
<
0.01.
The
results
obtained
from
these
studies
conducted
in
man
indicate
that
the
PEG
formulation
significantly
enhanced
the
oral
absorption
of
griseofulvin
and
should
provide
for
a
better
absorption
and
for
a
more
predictable
blood
concentration.
Analysis
of
the
data
obtained
from
the
two
studies
reported
upon
in
this
paper
indicate
that
the
bioavailability
of
250
mg.
of
ultramicrosize
griseofulvin
(griseofulvin
in
a
PEG
-6000
formulation)
was
equivalent
to
the
bioavailability
of
a
500
-mg.
dose
of
a
commercially
available
micro
-
size
formulation
of
griseofulvin,
within
the
limits
of
the
pharmaceutical
tolerance.
The
increased
absorption
is
thought
to
be
due
to
the
ultramicrosize
particles
of
griseofulvin
obtained
with
the
PEG
-6000
formulation.
Acknowledgements
The
assay
of
the
plasma
samples
was
done
under
the
direction
of
Hans
J.
Schwarz,
Ph.D.,
Director,
Drug
Metabolism
Unit,
Biology
Department,
Pharmaceutical
Research
and
Development,
Sandoz,
Inc.,
East
Hanover,
New
Jersey.
The
statistical
analysis
was
done
under
the
supervision
of
Hans
[5071
THE
BIOAVAILABILITY
OF
ULTRAMICROSIZE
GRISEOFULVIN
(GRIS-PEG)
TABLETS
Mueller,
Ph.D.,
Director,
Department
of
Research
Data
Services,
Sandoz,
Inc.,
East
Hanover,
New
Jersey.
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M.D.,
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-
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