Note: Descriptions are shown in the official language in which they were submitted.
CA 02433962 2003-07-25
ANTIBACTERIAL C'.LARiTI-IROMYCIN COMPOSITIONS AND
PROCESSES FUR MAKING THE SAME
FIELD OF THE WVENTION
This invention is directed to abridged clarithromycin antibacterial
compositions
and methods for making the same.
5 BACKGROUND OF THE INVENTION
Clarithromycin is employed in the manufacture; of commercially-available
antibiotic compositions for human administration. For example, an orally-
administered
antibacterial composition of clarithromycin in tablet form consists
essentially of
clarithromycin and a number of excipients which, in toto, control the
bioavailability of the
10 antibiotic.
The removal of one or more of these excipients from the composition to provide
an
abridged antibacterial composition of clarithromycin with substantially
similar antibiotic
activity of the clarithromycin would provide a more streamlined, less costly
avenue toward
commercial-availability of the drug. in addition, an abridged antibacterial
composition of
15 clarithromycin, if smaller in size or offering other advantages, would be
better tolerated by
patients. Therefore, there is an existing need in the formulations art for an
abridged
antibacterial composition of clarithromycin.
SUMMARY OF THE INVENTION
The first embodiment of this invention, therefore, is directed to an abridged
20 antibacterial clarithromycin composition consisting essentially of
clarithromyein, water, an
infra-granular excipient, and an extra-granular excipient, in which the
granular excipient
consists essentially of povidone, sodium croscannellose, and microcrystailine
celluose,
and the extra-granular excipient consists essentially of sodium
croscarmellose,
microcrystalline celluose, colloidal silicon dioxide, and impalpable magnesium
stearate
2 5 powder.
A second embodiment of this invention is directed to a process for making an
abridged antibacterial clarithromycin composition,
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the process comprising the steps of:
(a) granulating a mixture consisting essentially of
povidone, clarithromycin, sodium croscarmellose, microcrystalline eelluose,
and water to
provide a wet infra-granular excipient;
5 (b) drying the wet intro-granular excipient to provide a dry infra-granular
excipient;
and
(c) mixing the dry infra-granular excipient and an extra-granular excipient,
the
extra-granular excipient consisting essentially of sodium croscanneliose,
microcrystalline
celluose, colloidal silicon dioxide, and impalpable magnesium stearate powder.
10 A third embodiment of this invention is directed to a medicament consisting
essentially of an abridged antibacterial clarithromycin composition.
A fourth embodiment of this invention is directed to use of an abridged
antibacterial clarithromycin composition
in the preparation of a medicament, the medicament being useful for
prophylaxis or
15 treatment of bacterial infections in a mammal.
DETAILED DESCRIPTIC)N OF THE 1T1VENTION
The currently commercially-available, non-abridged clarithromycin composition
consists essentially of the following components: ciarithromycin, colloidal
silicon dioxide,
D&C yellow dye No. 10, extra-g~ranufar sodium croscannellose, extra-granular
20 microcrystalline celluose (Avicel~ PH-l02), infra-granular sodium
croscarmellose, intra-
granular microcrystalline celluose (Avicel~ PH-101 ), magnesium stearute
powder,
povidone, pre-gelatinized starch, 200 proof alcohol, stearic acid, talc, and
water.
This invention is directed to abridged antibacterial clarithromycin
compositions,
hereinafter referred to as "abridged compositions," which contain any amount
of
25 clarithromycin and from which at least one of the aforementioned components
have been
omitted.
In a preferred first embodiment, the abridged compositions contain the same
amount of clarithromycin which is cuirendy available in non-abridged adult and
pediatric
formulations, such as, for example, 250 mg of clarithromycin or 500 mg of
clarithromycin
3 o for the adult formulations and aqueous solutions comprising 125 mg per 5
mL or 250 mg
per 5 mL of clarithromycin for the pediatric formulations.
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In still another preferred first embodiment, the 200 proof alcohol, stearic
acid, and
talc have been omitted from the abridged compositions.
In still yet another preferred first embodiment, the 200 proof alcohol,
stearic acid,
talc pre-gelatinized starch and D&C yellow dye No. 10 have been omitted from
the
abridged compositions.
In still even yet another preferred first embodiment, the microcrystalline
celluose
of the infra-granular excipient comprises Avicel~ PH-101.
In still even yet another preferred first embodiment, the microcrystalline
celluose
of the extra-granular excipient comprises Avicel~ PH-102.
In still even yet another preferred first embodiment, the colloidal silicon
dioxide of
the extra-granular excipient comprises Cab-O-SiITM M-5.
In still even yet another preferred first embodiment, the abridged
compositions
contain 4.0% to 5.9% by weight povidone, 3.0% to 6.8% by weight infra-granular
sodium
croscarmellose, 2.2% to 7.5% by weight infra-granular microcrystalline
celluose, 3.0% to
6.8% by weight extra-granular sodium croscarmellose, 6.9% to 15.9% by weight
extra-
granular microcrystalline celluose, 0.5% to 0.8% by weight, colloidal silicon
dioxide, and
1.5% to 2.5% by weight magnesium stearate powder.
In a more preferred first embodiment, the abridged compositions contain 4.9%
by
weight povidone, 4.9% by weight infra-granular sodium croscarmellose, 4.9% by
weight
2 0 extra-granular sodium croscarmellose, 11.6% by weight extra-granular
sodium
croscarmellose, 0.5% by weight colloidal silicon dioxide (Cab-O-SiITM M-5),
and 1.5% by
weight magnesium stearate powder.
In another preferred first embodiment, the abridged compositions are
substantially
bioequivalent to the non-abridged formulations.
2 5 In still another preferred first embodiment, the abridged compositions are
for oral
administration in tablet form, such as, for example, tablets which weigh 750
mg.
These preferred embodiments may combine to provide an abridged antibacterial
composition for the oral administration of clarithromycin in tablet form, the
tablet
weighing 750 mg and consisting essentially of 250 mg of clarithromycin, water,
an
3 0 infra-granular excipient, and an extra-granular excipient,
in which the granular excipient consists essentially of
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4.9% by weight povidone, 4,9% by weight sodium croscarmetlose, and
microcrystalline celluose (Avicel~ PH-101 ), and
the extra-granular excipient consists essentially of 4.9°lo by weight
sodium
croscarmellose> 11.6% by weight microcrystalline celluose (Avicel~ PH-l02),
U.5% by
5 weight colloidal silicon dioxide (Cab-O-Sil M-5), and 1.5°!n by
weight impalpable
magnesium stearate powder; and
an abridged antibacterial composition for oral administration of
clarithromycin in tablet
form, the tablet weighing 750 mg and consisting essentially of 500 mg of
clarithromycin,
water, an infra-granular excipient, and an extra-granular excipient, in which
the granular
10 excipient consists essentially of
4.9% by weight povidone, 4.9°k by weight sodium croscarmellose, and
microcrystalline eelluose (Avicel~ PH-101 )> and
the extra-granular excipient consists essentially of 4.996 by weight sodium
croscarmellose, 11.6% by weight microcrystailine celluose (Avicel~ PH-102),
0.5% by
15 weight colloidal silicon dioxide. ((:ab-O-Sil M-5). and 1.5% by weight
impalpable
magnesium stearate powder.
In a preferred second embodiment, the microcrystalline celluose of the intra-
granular excipient comprises AvicelU PH-101, the microcrystalline celluose of
the extra-
granular excipient comprises Avicel~ PH-102, and the colloidal silicon dioxide
of the
20 extra-granular excipient comprises Cab-O-Sil M-5.
In another preferred second embodiment, the process further comprises adding a
solution of povidone in water to the material to be granulated in step (a), in
which the
amount of water is present in 390!o by weight to 44~k~ by weight of the
material to be
granulated.
In a preferred third or fourth embodiment, the medicament is a 750 mg tablet
containing 250 mg clarithromycin, an infra-granular excipient, and an extra-
granular
excipient.
In another preferred third or fourth embodiment, the medicament is a 750 mg
tablet
2 5 containing 500 mg clarithromycin, an infra-granular excipient, and an
extra-granular
excipient.
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The following bioequivalenee study was conducted at Sea View Research, Ine.
(Miami, FL).
5 Fifty-six (56) healthy adult male and female subjects were enrolled in the
study.
Fifty-four (54) subjects completed all four periods of the study, Subject 6
received only
one dose of study drug and was terminated froth the study due to a positive
drug screen.
Subject 45 received three doses of the study drug and was terminated from the
study due to
adverse events. Neither of the terminated subjects had complete data for the
reference
10 formulation under nonfasting or fasting conditions. For the 54 subjects (36
males and 18
females) who completed the study, nine were Caucasian, three were Black, and
42 were
Hispanic. The mean age was 34.4 years (range: l9 to 49 years), the mean weight
was 71.4
kg (range: 52 to 89.5 kg) and the mean height was 167.2 cm (range: !49 to 196
cm).
15 DRUG FORMULATIONS
Formulation A: test clarithromycin SOU mg tablet formulation manufactured by
Abbott Laboratories (Abbott Park, 1L).
Formulation B: reference (BIAXIN~) clarithromycin 500 mg tablet formulation
manufactured by Abbott Health Products Inc. (Barceloneta, Puerto Rico).
STUDY DES1GN AND DOSE ADM1NISTRATIUN
This was a Phase I, single-dose, open-label, randomized, four-period, complete-
crossover study. Regimen A was defined as one tablet of Formulation A (test)
administered approximately 3U minutes after the start of breakfast. Regimen B
was
2 5 defined as one tablet of Formulation A (test) administered after an eight-
hour fast.
Regimen C was defined as one tablet of Formulation B (reference) administered
approximately 30 minutes after the start of breakfast. Regimen D was defined
as one
tablet of Formulation B (reference) administered after an eight-hour fast.
3 0 SAMPLE COLLEC.'TION
Blood samples (7 mL) were collected into heparinized evacuated collection
tubes
prior to dosing (0 hour) and at 0.5. 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12,
1S, 18 and 24 hours
after dosing in each study period.
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ANALYTICAL METHODOLOGY
Plasma samples were analyzed for clarithromycin at BAS Analytics (West
Lafayette, Indiana) using a validated HPLC procedure. 'fhe lower limit of
quantification
was 0.0156 pg/mL. The assays were conducted from December 19, 1997 through
January
28, 1998.
PHARMAGOKINETIC ANALYSES
Pharmacokinetic parameter values were estimated for clarithromycin using
noncompartmental methods. The pharmacokinetic parameters included maximum
observed plasma concentration (C",~,), the time of C",;,x {'I'",ax), the area
under the plasma
concentration-time curve from time (1 to the time of the lust measurable
plasma
concentration (AUCo_i~,), the AIJC extrapolated to infinite time (AUCo-~,),
the terminal
elimination rate constant (p) and the half-life (ti~~).
STATISTICAL ANALYSES
Analyses of variance (ANOVAs) were also performed for T",ax (hours) and the
natural logarithms of Cmax (pg/mL), AUCo_,;", {~g~h/mL), and AUCo_~ (pg~h/mL).
The
model included effects for sequence, subject nested within sequence, and
period and
regimen. Within the ANOVA modeling framework, the test formulation under
fasting
2 0 conditions (Regimen B) was compared to the reference formulation under
fasting
conditions (Regimen D), the test formulation under nonfasting conditions
(Regimen A)
was compared to the reference formulation under nonfasting conditions (Regimen
C), and
the test formulation under nonfasting conditions (Regimen A) was compared to
the test
formulation under fasting conditions (Regimen B), each with an alpha level of
0.05.
2 5 Within the framework of the ANOVA's for the logarithms of CmaX and AUC,
the
bioavailability of the test formulation under fasting conditions (Regimen B)
relative to the
reference formulation under fasting conditions (Regimen U) was assessed by the
two one-
sided tests procedure viu 90°/~ confidence intervals. The confidence
interval for relative
bioavailability was obtained by exponentiuting the endpoints of a confidence
interval for
3 0 the difference of logarithm means. Similarly, the bioavailability of the
test formulation
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under nonfasting conditions (Regimen A) relative to that of the test
formulation under
fasting conditions (Regimen B) was assessed vin 95% confidence intervals.
RESALTS
5 Summaries (mean ~ standard deviation) of the phannacokinetic parameter
estimates for clarithromycin are presented hereinbelow.
Regimen Cmax ~rmax AUCo_i;", AUC.'o_" 1n2
A 2.9811.12h'' 2.511.0' 16.816.(1 17.316.2 4.3
10 B 2.3810.86 1.910.8' 16.315.0 17.816.8 4.3
C 2.6511.17 2.4~0.6 2.416.5 16.116.6 4.3
D 2.3910.98 2.412,1 16.916.0 !7.616.1 4.7
3Significantly different (p<U.OS) From reference formulation under fasting
conditions
15 (Regimen D).
bSignificantly different (p<0.05) from reference formulation under nonfasting
conditions
(Regimen C).
'Significantly different (p<0.05) from test formulation under fasting
conditions (Regimen
B).
20 Half-life is presented as the harmonic mean: this parameter was not
subjected to statistical
analysis.
These data illustrate the bioequivalence of the abridged and non-abridged 500
mg
clarithromycin formulations.
25 The following will provide a better understanding of the compositions and
processes of this invention.
Both microcrystalline celluloses were purchased from FMC BioPolymer (Cork,
Ireland); Magnesium Stearate was purchased from Mallinckrodt-Baker, Inc (ST
Louis,
3 0 Mo); Collodial silicon dioxide was purchased from Cabot Corp. (Tuscola.
IL); povidone
was purchased from ISP Technologies (Texas City. TX); sodium croscarmellose
was
purchased from Noviant (Nijmegan, Netherlands); or from FMC BioPolymer
(Newark,
DE).
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GRANULATION
Povidone (K-value Range 29-32, 125.8() kg) was dissolved in purified water
(1384.89 kg) to prepare an approximately 8.33% w/w solution.
5 Clarithromycin bulk drug (1360.(X) kg), sodium croscarmellose (100.64 kg),
and
microcrystalline cellulose, (1'H-101, I(X>.64 kg) were charged into a high
intensity 1200L
Gral masser bowl, mixed for 5 minutes on low speed (chopper off), treated with
the 8.33%
w/w povidone in water (U.774 kg of solution per kg of material to be
granulated) at the rate
of 30 kg per minute at low speed (chupper and mixer), and granulated on high
speed
(chopper and mixer) for 4 minutes (9 minutes total granulation time).
A power increase from the baseline was determined, and if the significant
power
increase was observed, the next step was conducted immediately. If a
significant power
increase was not observed, further granulation was conducted using additional
purified
water. When significant power increase was attained, the mixture was
granulated for one
additional minute (chopper and mixer on high).
The contents of the high intensity masser were discharged into a fluid bed
dryer
bowl and dried to provide a loss on drying of not more than 0.8~7o using a
gravimetric
moisture tester. The bowl of wet granulation was positioned in an Aeromatic
Dryer, and
the filter bag was shaken manually, as needed, to keep most of the granulation
in the dryer
2 0 bowl. A shock cycle and/or agitator was used as needed to fluidize any
stationary
material.
The bowl was removed from the fluid bed dryer, and its contents were
discharged,
with an inverter cone-attached, into an impact mill, granulation mill dried
through a 2AA
band (or 14 mesh screen) at medium speed with knives Forward, and discharged
into
appropriate containers.
LUBRICATION
Approximately one-half of the granulation was charged into a V-blender
followed
by sodium croscarmellase (100.64 kg), microcrystallinc cellulose (PH-102,
236.64 kg),
magnesium stearate (29.92 kg), and colloidal silicon dioxide (1(1.88 kg)
through a 30 mesh
3 0 screen using a speed sifter, followed by transfer of the remainder of the
granulation, and
blended for at least 30 minutes using a 15U cubic foot V-blender or for at
least 20 minutes
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using a 75 cubic foot V-blender, and discharged into appropriate containers.
Room RH
control must not be more than 2~% Ior low setting) during this step.
COMPRESS1NG
5 The tablets were compressed using a rotary tablet compressing machine
installed
with ovaloid lower punch with Abbo Code KL and ovaloid upper punch with Abbott
Corporate Logo. A de-duster was employed, as necessary. The theoretical weight
of 10
tablets was 7.50g.
COLOR COAT>TIG LIQUID MANUFACTURE
A color coating liquid was prepared by adding a portion of purified water
(792.82L) into the mix tank, mixing at high speed while reducing speed, as
necessary to
minimize foaming, treating the mixture with Opadry Yellow~ (YS-5-12749, 85.65
kg)
and propylene glycol (21.63 kg), mixing until all solid dissolved, and mixing
the coating
liquid at least one hour prior to sampling.
The tablets were coated with 400 mL of color coating liquid per kg weight of
uncoated tablets using an Accela-Cota or equivalent size vented perforated pan
coater.
The target run size for 60" pan water is approximately 245 kg. Mixers were
used to
maintain motion in the liquids to keep the solids suspended. A distance
between the
nozzles and tablet bed was maintained while running. These parameters are
summarized
in TABLE 1 below.
TABLE 1
Parameter Set PointRange Unit
() of
Measure
Air Supply Upper Limit 95 NIA C
Temperature for
Color
Exhaust Air Temperature 48 5 C
for Color
Application
Supply Air Rate ~ 4000 NIA SCFM
Liquid Flow Rate, Volume,0.65 0.2 Kg/min
Color '
Atomization Pressure for 80 ~ 5 ~ PSIG
C."olor
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Pan Speed ~ 6 2 RPM
Distance Between Nozzles 9 1 Inches
and Tablet
Bed, Coior
The foregoing is merely illustrative of the invention and is not intended to
limit the
same to the disclosed compounds and processes. Variations and changes which
arc
obvious to one skilled in the art, as defined in the claims, are intended to
be within the
scope and nature of the invention.
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