Note: Descriptions are shown in the official language in which they were submitted.
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ANTIBIOTIC COMPOSIT10N
This invention relates to antibiotic compositions and the use thereof. More
parfiicularly, this invention relates to a composition for the delivery of two
or more
antibiotics, and the use thereof.
In many cases, it is desirable to employ two different antibiotics in the
treatment of a bacterial infection, in that such antibiotics may have
complementary
mechanisms of action that facilitate treatment of the bacterial infection.
The present invention is directed to a new and improved product that delivers
two antibiotics of specified antibiotic pairs, and the use thereof, with the
antibiotic
pairs being one of the following (1 ) a protein synthesis inhibiting
antibiotic and a non-
protein synthesis inhibiting antibiotic; (2) Tetracycline and Doxycycline; or
(3)
Ciprofoxacin and Metronidazole; or (4) Amoxicillin and Clarithromycin; or (5)
Amoxicillin and Dicloxacillin; or (6) Cephalosporin and Metronidazole, with
pair #4
being an example of pair #1.
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In accordance with an aspect of the present invention, there is provided an
antibiotic product for delivering at least two different antibiotics that is
comprised of at
least three dosage forms each comprised of at least one antibiotic and a
pharmaceutically acceptable carrier, with one of the dosage forms including at
least
one antibiotic of the antibiotic pair and at least one dosage form including
at least a
second antibiotic of the antibiotic pair.
Thus, for example, each of the dosage forms may include two antibiotics of
the pair, or one or two of the dosage forms may include only one of the two
antibiotics of the pair and each of the remaining dosage forms may include
only one
or two of the antibiotics of the pair. Thus, in accordance with this aspect of
the
invention, there is provided an antibiotic product for delivering at least two
of the
antibiotics of the hereinabove described antibiotic pairs wherein the product
includes
at least three dosage forms wherein each of the antibiotics of the pair is
present in at
least one of the three dosage forms and each of the three dosage forms
includes at
least one of the two antibiotics. In one preferred embodiment each dosage form
includes only one antibiotic.
In accordance with an embodiment of the present invention, there is provided
an antibiotic product for delivering at least two different antibiotics that
is comprised
of at least three dosage forms each comprised of at least one antibiotic and a
pharmaceutically acceptable carrier, with one of the dosage forms including at
least
one of the at least two antibiotics and at least one dosage form including at
least a
second antibiotic of the at least two antibiotics, wherein one of the least
two
antibiotics is one of the antibiotics of the hereinabove described antibiotic
pairs and
the other of the at least two different antibiotics is the other antibiotic of
such pair. In
a preferred embodiment each dosage form includes at least one of such two
antibiotics. In a particularly preferred embodiment, each dosage form includes
only
one of the two antibiotics with each of the two antibiotics being present in
at least
one of the three dosage forms.
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In a preferred embodiment each of the dosage forms of the product that
contains the antibiotic pairs has a different release profile, with one of the
dosage
forms being an immediate release dosage form.
In another aspect, the present invention is directed to treating a bacterial
infection by administering to a host in need thereof an antibiotic product as
hereinabove and hereinafter described.
Thus, in accordance with an aspect of the present invention, there is provided
a single or unitary antibiotic product that has contained therein at least
three
antibiotic dosage forms, each of which has a different release profile,
whereby the
antibiotic contained in each of the at least three dosage forms is released at
different
times, and wherein each of the dosage forms includes at least one of the
antibiotics
of the antibiotic pairs. One or more of the dosage forms may include more than
one
antibiotic.
In accordance with a further aspect of the invention, the antibiotic product
may
be comprised of at least four different dosage forms, each of which starts to
release
the antibiotic contained therein at different times after administration of
the antibiotic
product, with each of the dosage forms including at least one of the two
antibiotic of
an antibiotic pair and with each antibiotic of the pair being present in at
least one of
the dosage forms.
The antibiotic product generally does not include more than five dosage forms
with different release times.
In accordance with a preferred embodiment, the antibiotic product has an
overall release profile such that when administered the maximum serum
concentration of the total antibiotic released from the product is reached in
less than
twelve hours, preferably in less than eleven hours. In an embodiment, the
maximum
serum concentration of the total antibiotic released from the antibiotic
product is
achieved no earlier than four hours after administration.
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In accordance with one preferred embodiment of the invention, one of the at
least three dosage forms is an immediate release dosage form whereby
initiation of
release of antibiotic therefrom is not substantially delayed after
administration of the
antibiotic product. The second and third of the at least three dosage forms is
a
delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed
dosage form, depending on the type of antibiotic product), whereby antibiotic
released therefrom is delayed until after initiation of release of antibiotic
from the
immediate release dosage form. More particularly, antibiotic release from the
second of the at least two dosage forms achieves a Cmax (maximum serum
concentration in the serum) at a time after antibiotic released from the first
of the at
least three dosage forms achieves a Cmax in the serum, and antibiotic released
from
the third dosage form achieves a Cmax in the serum after the Cma,~ of
antibiotic
released from the second dosage form.
In one embodiment, the second of the at least two dosage forms initiates
release of antibiotic contained therein at least one hour after the first
dosage form,
with the initiation of the release therefrom generally occurring no more than
six hours
after initiation of release of antibiotic from the first dosage form of the at
least three
dosage forms.
In general, the immediate release dosage form produces a Cmax for antibiotic
released therefrom within from about 0.5 to about 2 hours, with the second
dosage
form of the at least three dosage forms producing a Cmax for antibiotic
released
therefrom in no more than about four hours. In general, the Cmax for such
second
dosage form is achieved no earlier than two hours after administration of the
antibiotic product; however, it is possible within the scope of the invention
to achieve
Amax in a shorter period of time.
As hereinabove indicated, the antibiotic product may contain at least three or
at least four or more different dosage forms. For example, the antibiotic
released
from the third dosage form reaches a Cmax at a time later than the Cmax is
achieved
for antibiotic released from each of the first and second dosage forms. In a
preferred
embodiment, release of antibiotic from the third dosage form is started after
initiation
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of release of antibiotic from both the first dosage form and the second dosage
form.
In one embodiment, CmaX for antibiotic release from the third dosage form is
achieved
within eight hours.
In another embodiment, the antibiotic product contains at least four dosage
forms, with each of the at least four dosage forms having different release
profiles,
whereby antibiotic released from each of the at least four different dosage
forms
achieves a C,naX at a different time.
As hereinabove indicated, in a preferred embodiment, irrespective of whether
the antibiotic contains at least three or at least four different dosage forms
each with
a different release profile, Cmax for all the antibiotic released from the
antibiotic
product is achieved in less than twelve hours, and more generally is achieved
in less
than eleven hours.
In a preferred embodiment, the antibiotic product is a once a day product,
whereby after administration of the antibiotic product, no further product is
administered during the day; i.e., the preferred regimen is that the product
is
administered only once over a twenty-four hour period. Thus, in accordance
with the
present invention, there is a single administration of an antibiotic product
with the
antibiotic being released in a manner such that overall antibiotic release is
effected
with different release profiles in a manner such that the overall CmaX for the
antibiotic
product is reached in less than twelve hours. The term single administration
means
that the total antibiotic administered over a twenty-four hour period is
administered at
the same time, which can be a single tablet or capsule or two or more thereof,
provided that they are administered at essentially the same time.
Thus in accordance with an aspect of the invention, there is provided a single
dosage antibiotic product comprised of at least three antibiotic dosage forms
each
having a different release profile with each of the dosage forms including at
least one
of the antibiotics of the hereinabove described antibiotic pairs and wherein
each
antibiotic of the pair is present in at least one of the dosage forms. Each of
the
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dosage forms of antibiotic in a pharmaceutically acceptable carrier may have
one or
more antibiotics.
In one embodiment the two different antibiotics comprise Tetracycline and
Doxycycline. In another embodiment the two different antibiotics comprise
Ciprofoxacin and Metronidazole. In another embodiment the two different
antibiotics
comprise Amoxicillin and Clarithromycin. In another embodiment the two
different
antibiotics comprise Amoxicillin and Dicloxacillin. In another embodiment the
two
different antibiotics comprise Cephalosporin and Metronidazole.
In one embodiment, the first dosage form contains one of the first antibiotics
of the antibiotic pair and is free of the other antibiotic of the antibiotic
pair, and in a
preferred embodiment contains only such one antibiotic; the second dosage form
contains the other antibiotic of the pair and is free of such one antibiotic
of the pair
and in a preferred embodiment contains only one antibiotic and the third
dosage
form contains such one antibiotic of the pair and is free of the other
antibiotic of the
pair and in a preferred embodiment contains only one antibiotic and if a
fourth
dosage form is used, such fourth dosage form contains such other antibiotic
and is
free of such one antibiotic and in a preferred embodiment bacteria are exposed
to
alternating pulses of the two antibiotics of the hereinabove described
antibiotic pairs.
It is to be understood that when it is disclosed herein that a dosage form
initiates release after another dosage form, such terminology means that the
dosage
form is designed and is intended to produce such later initiated release. It
is known
in the art, however, notwithstanding such design and intent, some "leakage" of
antibiotic may occur. Such "leakage" is not "release" as used herein.
If at least four dosage forms are used, the fourth of the at least four dosage
form may be a sustained release dosage form or a delayed release dosage form.
If
the fourth dosage form is a sustained release dosage form, even though CmaX of
the
fourth dosage form of the at least four dosage forms is reached after the
Cma,~ of
each of the other dosage forms is reached, antibiotic release from such fourth
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dosage form may be initiated prior to or after release from the second or
third
dosage form.
In one embodiment of the invention, one of the antibiotics of the antibiotic
pairs as hereinabove and hereinafter described is a protein synthesis
inhibiting
antibiotic and the other antibiotic of the antibiotic pair is a non-protein
synthesis
inhibiting antibiotic.
The terminology "protein synthesis inhibiting antibiotic" means an agent that
disrupts the bacterial ribosome cycle through which polypeptide chain
initiation and
elongation is normally effected. There are multiple points in the ribosome
cycle at
which this can occur.
The terminology "non-protein synthesis inhibiting antibiotic" means
antibiotics
other than protein synthesis inhibiting antibiotics.
As non-limiting representative examples of "protein synthesis inhibiting
antibiotics" there may be mentioned: the aminoglycosides such as streptomycin,
amileacin, and tobramycin; the macrolides such as erythromycin,
clarithromycin, and
lincomycin; the tetracyclines such as tetracycline, doxycycline,
chlortetracycline, and
minocycline; the oxaxolidinones such as linezolid; fusidic acid; and
chloramphenicol.
As non-limiting representative examples of "non-protein synthesis inhibiting
antibiotics" there may be mentioned: the beta-lactam penicillins such as
penicillin,
amoxicillin, dicloxacillin, and ampicillin; the beta lactam cephalsporins such
as
cefotaxime, cefuroxime, cefaclor, and ceftriaxone; the beta lactam carbapenems
such as imipenem and meropenem; the quinolones such as ciprofloxacin,
moxifloxacin, and levofloxacin; the sulfonamides such as sulfanilimide and
sulfamethoxazole; metronidazole; rifampin; vancomycin; and nitrofurantoin.
In a preferred embodiment such two antibiotics are delivered in alternating
pulses.
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In a particularly preferred embodiment of the present invention, there is
provided an antibiotic composition that includes three different dosage forms:
the
first dosage form providing an initial dosage of a first antibiotic that is a
protein
synthesis inhibiting antibiotic and wherein the first dosage form is free of
antibiotics
that are not protein synthesis inhibiting antibiotics and in one preferred
embodiment
contains only one antibiotic; the second dosage form providing an initial
dosage of a
second antibiotic that is not a protein synthesis inhibiting antibiotic and
wherein the
second dosage form is free of antibiotics that are protein synthesis
inhibiting
antibiotics and in one preferred embodiment contains only one antibiotic; and
the
third dosage form providing an additional dosage of said first antibiotic that
is a
protein synthesis inhibiting antibiotic and wherein the third dosage form is
free of
antibiotics that are not protein synthesis inhibiting antibiotics and in one
preferred
embodiment contains only one antibiotic. The first dosage form is an immediate
release dosage form; and the second and third dosage forms are delayed release
dosage forms.
In another preferred embodiment of the present invention, there is provided
an antibiotic composition that includes four different dosage forms: the first
dosage
form providing an initial dosage of a first antibiotic that is a protein
synthesis
inhibiting antibiotic and wherein the first dosage form is free of antibiotics
that are not
protein synthesis inhibiting antibiotics and in a preferred embodiment
contains only
one antibiotic; the second dosage form providing an initial dosage of a second
antibiotic that is not a protein synthesis inhibiting antibiotic and wherein
the second
dosage form is free of antibiotics that are protein synthesis inhibiting
antibiotics and
in a preferred embodiment contains only one antibiotic; the third dosage form
providing an additional dosage of said first antibiotic that is a protein
synthesis
inhibiting antibiotic and wherein the third dosage form is free of antibiotics
that are
not protein synthesis inhibiting antibiotics and in a preferred embodiment
contains
only one antibiotic; and the fourth dosage form providing an additional dosage
of
said second antibiotic that is not a protein synthesis inhibiting antibiotic
and wherein
the fourth dosage form is free of antibiotics that are protein synthesis
inhibiting
antibiotics and in a preferred embodiment contains only one antibiotic. The
first
dosage form is an immediate release dosage form; the second and third dosage
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forms are delayed release dosage forms; and the fourth dosage form is
optionally a
delayed release dosage form or a sustained release dosage form, preferably a
delayed release dosage form.
Particularly advantageous formulations of the immediately preceding
embodiments of the present invention are those that comprise Clarithromycin, a
protein synthesis inhibiting antibiotic as one of the antibiotics, and
Amoxicillin, a non-
protein synthesis inhibiting antibiotic as the other antibiotic. In these
formulations a
first, immediate release dosage form contains an initial dosage of
Clarithromycin and
is free of any non-protein synthesis inhibiting antibiotics; a second, delayed
release
dosage form contains an initial dosage of Amoxicillin and is free of any
protein
synthesis inhibiting antibiotics; and a third, delayed release dosage form
provides an
additional dosage of Clarithromycin and is free of any non-protein synthesis
inhibiting
antibiotics. An optional fourth, dosage form provides an additional dosage of
Amoxicillin and is free of any protein synthesis inhibiting antibiotics. This
fourth
dosage form is a delayed release or a sustained release dosage form,
preferably a
delayed release dosage form.
In formulating an antibiotic product in accordance with the invention, in one
embodiment, the immediate release dosage form of the product generally
provides
from about 20% to about 50% of the total dosage of antibiotic to be delivered
by the
product, with such immediate release dosage form generally providing at least
25%
of the total dosage of the antibiotic to be delivered by the product. In many
cases,
the immediate release dosage form provides from about 20% to about 30% of the
total dosage of antibiotic to be delivered by the product; however, in some
cases it
may be desirable to have the immediate release dosage form provide for about
45%
to about 50% of the total dosage of antibiotic to be delivered by the product.
The remaining dosage forms deliver the remainder of the antibiotic. If more
than one delayed release dosage form is used, in one embodiment, each of the
delayed release dosage forms may provide about equal amounts of antibiotic;
however, they may also be formulated so as to provide different amounts.
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In one embodiment, where the composition contains one immediate release
component and two delayed release components, the immediate release component
provides from 20% to 35% (preferably 20% to 30%), by weight, of the total
antibiotic;
where there is three delayed release components, the immediate release
component
provides from 15% to 30%, by weight, of the total antibiotic; and where there
are four
delayed release components, the immediate release component provides from 10%
to 25%, by weight, of the total antibiotic.
With respect to the delayed release components, where there are two delayed
release components, the first delayed release component (the one released
earlier in
time) provides from 30% to 60%, by weight, of the total antibiotic provided by
the two
delayed release components with the second delayed release component providing
the remainder of the antibiotic.
Where there are three delayed release components, the earliest released
component provides 20% to 35% by weight of the total antibiotic provided by
the
three delayed release components, the next in time delayed release component
provides from 20% to 40%, by weight, of the antibiotic provided by the three
delayed
release components and the last in time providing the remainder of the
antibiotic
provided by the three delayed release components.
When there are four delayed release components, the earliest delayed
release component provides from 15% to 30%, by weight, the next in time
delayed
release component provides from 15% to 30%, the next in time delayed release
component provides from 20% to 35%, by weight, and the last in time delayed
release component provides from 20% to 35%, by weight, in each case of the
total
antibiotic provided by the four delayed release components.
In accordance with another aspect of the present invention, there is provided
an antibiotic composition that is a mixture of antibiotic compositions or
dosage forms
wherein said composition contains a first composition or dosage form
comprising a
first antibiotic and a pharmaceutically acceptable carrier; a second
composition or
dosage form comprising the first antibiotic and a pharmaceutically acceptable
carrier;
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a third composition or dosage form comprising a second antibiotic different
from the
first antibiotic and a pharmaceutically acceptable carrier; and a fourth
composition or
dosage form comprising the second antibiotic and a pharmaceutically acceptable
carrier; wherein the second and third compositions each have a release profile
that
provides a maximum serum concentration of the first antibiotic released from
the
second composition and a maximum serum concentration for the second antibiotic
released from the third composition at a time after the first antibiotic
released from
the first composition reaches a maximum serum concentration, and wherein the
fourth composition has a release profile that provides for a maximum serum
concentration of the second antibiotic released from the fourth composition at
a time
after the antibiotics released from the second and third compositions reach a
maximum serum concentration. The first antibiotic and second antibiotic are
one of
the antibiotics of the hereinabove described antibiotic pairs.
In one embodiment, the release profiles of the second and third dosage forms
are such that the maximum serum concentration of the first antibiotic released
from
the second dosage form, and the maximum serum concentration of the second
antibiotic released from the third dosage form are reached at approximately
the
same time, or where the first antibiotic reaches a maximum serum concentration
before or after the second antibiotic reaches a maximum serum concentration.
In effect, in accordance with a preferred embodiment of the present invention,
there is provided a first pulse in which a first antibiotic reaches a maximum
serum
concentration, a second pulse wherein a further dosage of the first
antibiotic, and an
initial dosage of the second antibiotic reach a maximum serum concentration at
a
time after the first pulse of the first antibiotic reaches a maximum serum
concentration, and a third pulse wherein an additional dosage of the second
antibiotic reaches a maximum serum concentration at a time after the maximum
serum concentration is reached for each of the first and second antibiotic
dosages
provided in the second pulse.
In a preferred embodiment of the present invention, the first dosage of the
first
antibiotic achieves a maximum serum concentration within four hours after
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administration of the antibiotic composition; the second dosage of the first
antibiotic
and the first dosage of the second antibiotic each reach a maximum serum
concentration within four to eight hours after administration of the
antibiotic
composition; and the second dosage of the second antibiotic reaches a maximum
serum concentration within twelve hours after administration of the antibiotic
composition.
Thus, in accordance with an aspect of the present invention, there is provided
an antibiotic composition that includes four different dosage forms, with the
first
dosage form providing an initial dosage of a first antibiotic of the
hereinabove
described antibiotic pairs, the second dosage form providing a further dosage
of the
first antibiotic; the third dosage form providing an initial dosage of a
second antibiotic
of such pair; and the fourth dosage form providing an additional dosage of the
second antibiotic, wherein the antibiotics released from the second and third
dosage
forms reach a maximum serum concentration at a time after the antibiotic
released
from the first dosage form reaches a maximum serum concentration, and the
antibiotic released from the fourth dosage form reaching a maximum serum
concentration at a time after the times at which the antibiotics released from
each of
the first, second, and third dosage forms reach a maximum serum concentration.
In one embodiment of the invention, the first dosage form provides for
immediate release, the second and third dosage forms provide for a delayed
release
(pH or non pH dependent, with the second dosage form preferably being a pH
dependent release), and the fourth dosage form provides for pH dependent or
non
pH dependent release preferably non pH dependent release.
In formulating the antibiotic composition of the present invention, which
contains four different dosage forms, as hereinabove described that contains
the first
antibiotic of the antibiotic pair in the first and second antibiotic dosage
forms and the
second antibiotic of the antibiotic pair in the third and fourth dosage forms,
the first
dosage form generally contains from about 30 percent to about 80 percent of
the first
antibiotic; the second dosage form contains from about 30 percent to about 30
percent of the first antibiotic; the third dosage form contains from about 30
percent to
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about 80 percent of the second antibiotic, and the fourth antibiotic dosage
form
contains from about 30 percent to about 80 percent of the second antibiotic.
In
formulating a composition comprised of such four dosage forms or units, each
unit or
dosage form is present in an amount of at least 20 percent by weight, with
each
dosage form or unit being present in the overall composition in an amount that
generally does not exceed 60 percent by weight.
Each of the first and second dosage forms include from 20% to 80% of the
total dosage of the first antibiotic to be provided by the composition, and
each of the
first and second dosage forms may include the same or different dosages of the
first
antibiotic.
Each of the third and fourth dosage forms include from 20% to 80% of the
total dosage of the second antibiotic to be delivered by the composition, and
each of
the third and fourth units may have the same or different dosages of the
antibiotic.
In another embodiment the product as hereinabove described may also be
formulated in a manner such that the product contains at least three dosage
forms
wherein each of the three dosage forms is a delayed release dosage form, with
the
product being free of an immediate release dosage form. The product contains
the
antibiotic pairs as hereinabove described. In this embodiment the overall Cmax
is
reached within 12 hours after initial release of antibiotic, i.e. Cmax is
achieved in less
than about twelve hours after initial release of antibiotic. As hereinabove
described
this product may optionally contain a fourth dosage form. When such product
contains a fourth dosage form, such fourth dosage form is preferably a delayed
release dosage form, but may otherwise be a sustained release dosage form. As
hereinabove described, in a preferred embodiment, the antibiotic product is a
once a
day product, whereby after administration of the antibiotic product, no
further product
is administered during the day; i.e., the preferred regimen is that the
product is
administered only once over a twenty-four hour period. Thus, in accordance
with the
present invention, there is a single administration of an antibiotic product
with the
antibiotic being released in a manner such that overall antibiotic release is
effected
with different release profiles in a manner such that the overall CmaX for the
antibiotic
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product is reached in less than twelve hours from the initial release of
antibiotic. The
term single administration means that the total antibiotic administered over a
twenty-
four hour period is administered at the same time, which can be a single
tablet or
capsule or two or more thereof, provided that they are administered at
essentially the
same time.
The overall composition includes each of the antibiotics in a therapeutically
effective amount. The specific amounts) is dependant on the antibiotic used,
the
disease or infection to be treated, and the number of times of day that the
composition is to be administered.
The antibiotic composition of the present invention may be administered for
example, by any one of the following routes of administration: sublingual,
transmucosal, transdermal, parenteral, oral, preferably by oral
administration.
The antibiotic product of the present invention, as hereinabove described,
may be formulated for administration by a variety of routes of administration.
For
example, the antibiotic product may be formulated in a way that is suitable
for topical
administration; administration in the eye or the ear; rectal or vaginal
administration;
as nose drops; by inhalation; as an injectable; or for oral administration. In
a
preferred embodiment, the antibiotic product is formulated in a manner such
that it is
suitable for oral administration.
For example, in formulating the antibiotic product for topical administration,
such as by application to the skin, the at least two different dosage forms,
each of
which contains an antibiotic, may be formulated for topical administration by
including such dosage forms in an oil-in-water emulsion, or a water-in-oil
emulsion.
In such a formulation, the immediate release dosage form is in the continuous
phase, and the delayed release dosage form is in a discontinuous phase. The
formulation may also be produced in a manner for delivery of three dosage
forms as
hereinabove described. For example, there may be provided an oil-in-water-in-
oil
emulsion, with oil being a continuous phase that contains the immediate
release
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component, water dispersed in the oil containing a first delayed release
dosage form,
and oil dispersed in the water containing a third delayed release dosage form.
It is also within the scope of the invention to provide an antibiotic product
in
the form of a patch, which includes antibiotic dosage forms having different
release
profiles, as hereinabove described.
In addition, the antibiotic product may be formulated for use in the eye or
ear
or nose, for example, as a liquid emulsion. For example, the dosage form may
be
coated with a hydrophobic polymer whereby a dosage form is in the oil phase of
the
emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a
dosage form is in the water phase of the emulsion.
Furthermore, the antibiotic product with at least three different dosage forms
with different release profiles may be formulated for rectal or vaginal
administration,
as known in the art. This may take the form of a cream or emulsion, or other
dissolvable dosage form similar to those used for topical administration.
As a further embodiment, the antibiotic product may be formulated for use in
inhalation therapy by coating the particles and micronizing the particles for
inhalation.
In a preferred embodiment, the antibiotic product is formulated in a manner
suitable for oral administration. Thus, for example, for oral administration,
each of
the dosage forms may be used as a pellet or a particle, with a pellet or
particle then
being formed into a unitary pharmaceutical product, for example, in a capsule,
or
embedded in a tablet, or suspended in a liquid for oral administration.
Alternatively, in formulating an oral delivery system, each of the dosage
forms
of the product may be formulated as a tablet, with each of the tablets being
put into a
capsule to produce a unitary antibiotic product. Thus, for example, antibiotic
products may include a first dosage form in the form of a tablet that is an
immediate
release tablet, and may also include two or more additional tablets, each of
which
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provides for a delayed release of the antibiotic, as hereinabove described,
whereby
the C,nax of the antibiotic released from each of the tablets is reached at
different
times, with the Cmax of the total antibiotic released from the antibiotic
product being
achieved in less than twelve hours.
The formulation of an antibiotic product including at least three dosage forms
with different release profiles for different routes of administration is
deemed to be
within the skill of the art from the teachings herein. As known in the art,
with respect
to delayed release, the time of release can be controlled by the concentration
of
antibiotics in the coating and/or the thickness of the coating.
As hereinabove indicated, the first and second antibiotics employed in the
antibiotic composition may be a wide variety of products. In one embodiment,
the
combination of first and second antibiotics that are used in the composition
may be,
for example, a penicillin and an aminoglycoside, such as gentamycin,
tobramicin,
amikacin or vancomycin. Another antibiotic composition that may be employed is
a
combination of a sulfonamide, such as sulfamethoxasol, which would be combined
with trimethoporim. In a preferred embodiment, the first and second,
antibiotics are
different antibiotics and each is from a different class of antibiotic.
The Immediate Release Component
The immediate release portion of this system can be a mixture of ingredients
that breaks down quickly after administration to release the antibiotic. This
can take
the form of either a discrete pellet or granule that is mixed in with, or
compressed
with, the other three components.
The materials to be added to the antibiotics for the immediate release
component can be, but are not limited to, microcrystalline cellulose, corn
starch,
pregelatinized starch, potato starch, rice starch, sodium carboxymethyl
starch,
hydroxypropylcellulose, ydroxypropylmethylcellulose, hydroxyethylcellulose,
ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-
linked
chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,
sorbitol,
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dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone
(PVP),
acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols,
such a low
molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox)
with molecular weights above 20,000 daltons.
It may be useful to have these materials present in the range of 1.0 to 60%
(W/W).
In addition, it may be useful to have other ingredients in this system to aid
in
the dissolution of the drug, or the breakdown of the component after ingestion
or
administration. These ingredients can be surfactants, such as sodium lauryl
sulfate,
sodium monoglycerate, sorbitan monooleate, sorbitan monooleate,
polyoxyethylene
sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl
monobutyrate, one of the non-ionic surfactants such as the Pluronic line of
surfactants, or any other material with surface active properties, or~any
combination
of the above.
These materials may be present in the rate of 0.05-15% (W/W).
The Delayed Release Component
The components in this composition are the same immediate release unit, but
with additional polymers integrated into the composition, or as coatings over
the
pellet or granule.
Materials that can be used to obtain a delay in release suitable for this
component of the invention can be, but are not limited to, polyethylene glycol
(PEG)
with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as
white
wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene
glycol, and
ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this
component.
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The Enteric Release Component
The components in this composition are the same as the immediate release
component, but with additional polymers integrated into the composition, or as
coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to,
cellulose acetate phthalate, Eudragit L, and other phthalate salts of
cellulose
derivatives.
These materials can be present in concentrations from 4-20% (W/W).
The invention will be further described with respect to the following
examples;
however the scope of the invention is not limited thereby. All percentages
stated in
this specification are by weight, unless otherwise specified.
Examples
Immediate Release Component
Ingiredient Conc. (% WNV)
Example 1:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
Example 2:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Povidone 10
Croscarmellose sodium 10
Example 3:
Amoxicillin 65% (W/V1/)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
is
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Example 4:
Example 5:
Example 6:
Example 7:
Example 8:
Example 9:
Example 10:
Example 11:
Example 12:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Clarithromycin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Clarithromycin 75% (WNV)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Clarithromycin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Clarithromycin 75% (1N/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Ciprofoxacin 65% (V11NV)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Ciprofoxacin 75% (V1I/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Ciprofoxacin 75% (W/W)
Polyethylene glycol 4000 10
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Polytheylene glycol 2000 10
Hydroxypropylcellulose 5
Example 13:
Cirpofoxacin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 14:
Ceftibuten 75% (UVNV)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 15:
Ceftibuten 75% (W/W)
Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
Delayed Release Component (non-pH dependant)
Example 16:
Example 17:
Ingredient Conc. (% WNV)
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Polyox 10
Croscarmellose sodium 5
Amoxicillin 55% (WNV)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 18:
Amoxicillin 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 19:
Clarithromycin 70% (W/W)
Polyox 20
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 20:
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Gentamicin 20% (W/W)
Sodium lauryl sulfate 2
Sodium monoglycerides _ 10
Sodium diglycerides 20
Diethyleneglycolmethylether5
Microcrystalline cellulose43
Example 21:
Gentamicin 10% (WNV)
Glyvceryl behanate 30
Pluronic 10
Carbopol 94P 30
Microcrystalline cellulose20
Example 22:
Gentamicin 25% (W/W)
Carbopol 94P 35
Microcrystalline cellulose20
Vitamin E TPGS 15
Sodium monoglycerate 5
Example 23:
Amikacin 25% (W/W)
Carbopol 94P 10
Sodium monoglycerate 15
Sodium diglycerate 15
Pluronic 10
Lactose 25
Example 24:
Gentamicin 30% (WNV)
Triacetin 15
Capryol 90 5
Poloxamer Synperonic PE/F6610
Cab-O-Sil 5
Microcrystalline cellulose35
Enteric Release Component
Example 25:
Clarithromycin 70% (WNV)
Hydroxypropylcellulose 15
phthalate 10
Croscarmellose sodium
Example 26:
Clarithromycin 75% (W/W)
Polyethylene glycol 2000 10
Eudragit E 30D 15
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Example 27:
Clarithromycin 40% (W/W)
Lactose 50
Eudgragit E 30D 10
Example 28:
Ciprofoxacin 65% (WNV)
Microcrystalline Cellulose 20
Eudragit E 30D 10
Example 29:
Ciprofoxacin 75% (WNV)
Microcrystalline Cellulose 15
Hydroxypropylcellulose 10
phthalate
Example 30:
Ciprofoxacin 80% (W/W)
Lactose 10
Eudragit E 30D 10
Example 31:
Ciprofoxacin 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate phthalate 10
Example 32:
Example 33:
Example 34:
Example 35:
Example 36:
Ceftibuten 60% (WNV)
Polyethylene glycol 2000 10
Lactose 20
Eudragit E 30D 10
Ceftibuten 70% (WNV)
Microcrystalline cellulose 20
Cellulose acetate phthalate 10
Amoxicillin 65% (WNV)
Microcrystalline cellulose 20
Cellulose Acetate Phthalate 15
Amoxicillin 55% (WNV)
Microcrystalline cellulose 25
Cellulose Acetate Phthalate 10
Hydroxypropylmethylcellulose 10
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Amoxicillin 65% (1IV/W)
Polyox 20
Hydroxypropylcellulose 10
phthalate 5
Eudragit E30D
Example 37:
Amoxicillin 40% (W/W)
Microcrystalline Cellulose 40
Cellulose Acetate Phthalate 10
Example 38:
Gentamicin 20% (W/W)
Sodium lauryl sulfate 2
Sodium monoglycerides 10
Sodium diglycerides 20
Diethyleneglycolmethylether5
Microcrystalline cellulose30
Cellulose acetate phthalate13
Example 39:
Gentamicin 10% (WNV)
Glyceryl behanate 30
Pluronic 10
Carbopol 94P 10
Microcrystalline cellulose20
Eudragit E30D 20
Example 40:
Gentamicin 25% (WNV)
Carbopol 94P 15
Microcrystalline cellulose20
Vitamin E TPGS 15
Sodium Monoglycerate 5
Eudragit E30D 20
Example 41:
Amikacin 25% (WNV)
Carbopol 94P 10
Sodium monoglycerate 15
Sodium diglycerate 15
Pluronic 10
Lactose 15
Cellulose acetate phthalate10
Example 42:
Gentamicin 30% (W/W)
Triacetin 15
Capryol 90
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Poloxamer SynperonicPE/F66 10
Cab-O-Sil 5
Microcrystalline cellulose 25
Eudragit E30D 10
Three Pulses
Example 43.
1. Antibiotic Matrix Pellet Formulation and Preparation Procedure
(Immediate Release)
A. Pellet Formulation
The composition of the antibiotic matrix pellets provided in Table 1.
Table 1 Composition of Antibiotic Pellets
Component Percentage (%)
Antibiotic 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet
massing.
B. Preparation Procedure for antibiotic Matrix Pellets
1.2.1 Blend metronidazole and Avicel~ PH 101 using a Robot Coupe high shear
granulator.
1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend
under continuous mixing.
1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter
of the screen of the Bench Top Granulator was 1.0 mm.
1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
1.2.5 Dry the spheronized pellets at 50°C overnight.
1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
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The above procedure is used to make pellets of a first antibiotic and pellets
of
a second different antibiotic.
1.3 Preparation of an Eudragit~ L 30 D-55 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
antibiotic matrix pellets is provided below in Table 2.
Table 2 Eudragit~ L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
~
Eudragit~ L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
B. Preparation Procedure for an Eudragit~ L 30 D-55 Aqueous Dispersion
1.3.1 Suspend triethyl citrate and talc in deionized water.
1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700
high shear mixer.
1.3.3 Add the TEC/talc suspension slowly to the Eudragit~ L 30 D-55 latex
dispersion while stirring.
1.3.4 Allow the coating dispersion to stir for one hour prior to application
onto
the antibiotic matrix pellets.
1.4 Preparation of an Eudragit~ S 100 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit~ S 100 dispersion applied to the
antibiotic
matrix pellets is provided below in Table 3.
Table 3 Eudragit~ S 100 Aqueous Coating Dispersion
Component Percentage (%)
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Part A
Eudragit~ S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
B. Preparation Procedure for an Eudragit~ S 100 Aqueous Dispersion
Part I:
(i) Dispense Eudragit~ S 100 powder in deionized water with
stirring.
(ii) Add ammonium hydroxide solution drop-wise into the dispersion
with stirring.
(iii) Allow the partially neutralized dispersion to stir for 60 minutes.
(iv) Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.
Part II:
(i) Disperse talc in the required amount of water
(ii) Homogenize the dispersion using a PowerGen 700D high shear
mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
1.5 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters are used to coat matrix pellets with each of
the
Eudragit~ L 30 D-55 and Eudragit~ S 100 aqueous film coating.
Coating Equipment STREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature40 to 45 C
Outlet Air Temperature30 to 33 C
Atomization Air
Pressure 1.3 Bar
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Pump Rate 2 gram per minute
(i) Coat matrix pellets with L30 D-55 dispersion such that you apply
12% coat weight gain to the pellets.
(ii) Coat matrix pellets with S100 dispersion such that you apply
20% coat weight gain to the pellets.
1.6 Encapsulation of the Antibiotic Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%:
40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100
coated pellets respectively.
The capsule is filled with the three different pellets to achieve the desire
dosage.
The immediate release matrix pellets include the first antibiotic, the L30 D-
55
coated pellets are made by coating matrix pellets that contain the second
antibiotic
and the S100 coated pellets are made by coating matrix pellets that contain
the first
antibiotic.
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Three Pulses '
Example 44
Antibiotic Pellet Formulation and Preparation Procedure
44.1 Pellet Formulations for subsequent coating
The composition of the Antibiotictrihydrate matrix pellets provided in Table
4.
Table 4 Composition of AntibioticMatrix Pellets
Component Percentage (%)
AntibioticTrihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose,1.0
NF*
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution
during wet massing.
44.2 Preparation Procedure for Antibiotic Matrix Pellets
44.2.1 Blend Antibiotic and Avicel~ PH 101 using a low shear blender.
44.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
44.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
44.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
44.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer
until the
exhaust temperature reaches 40°C.
44.2.6 Pellets between 20 and 40 Mesh were collected for further processing.
44.2.7 The above procedure is used to produce pellets that contain a first
antibiotic and pellets that contain a second and different antibiotic.
44.3 Preparation of an Eudragit~ L 30 D-55 Aqueous Coating Dispersion
44.3.1 Dispersion Formulation
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The composition of the aqueous Eudragit L30D-55 dispersion applied to the
Antibiotic matrix pellets is provided below in Table 5.
Table 5 Eudragit~ L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
44.4 Preparation Procedure for an Eudragit~ L 30 D-55 Aqueous Dispersion
44.4.1 Suspend triethyl citrate and talc in deionized water.
44.4.2 The TEC/talc suspension is mixed using laboratory mixer.
44.4.3 Add the TEC/talc suspension from slowly to the Eudragit~ L 30 D-55
latex dispersion while stirring.
44.4.4 Allow the coating dispersion to stir for one hour prior to application
onto
the Antibiotic matrix pellets.
44.5 Preparation of an Eudragit~ S 100 Aqueous Coating Dispersion
44.5.1 Dispersion Formulation
The composition of the aqueous Eudragit~ S 100 dispersion applied to the
Antibiotic
matrix pellets is provided below in Table 6.
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Table 6 Eudragit~ S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit~ S 100 ~ 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
44.6 Preparation Procedure for an Eudragit~ S 100 Aqueous Dispersion
Part A:
44.6.1 Dispense Eudragit~ S 100 powder in deionized water with stirring.
44.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with
stirring.
44.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
44.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and
let stir
overnight prior to the addition of Part B.
Part B:
44.6.5 Disperse talc in the required amount of water
44.6.6 Stir the dispersion using an overhead laboratory mixer.
44.6.7 Part B is then added slowly to the polymer dispersion in Part A with a
mild stirring.
44.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters are used for both the Eudragit~ L 30 D-55 and
Eudragit~ S 100 aqueous film coating processes.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
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Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2-6 gram per minute
44.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20%
coat weight gain to the pellets.
44.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat
weight gain to the pellets.
44.8 Preparation of Antibiotic Granulation (Immediate Release Component) for
tabletting
Table 7 Composition of Antibiotic Granulation
Component Percentage (%)
AntibioticTrihydrate powder92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose,
NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution
during wet massing.
44.8.1 Blend Antibiotic and Avicel~ PH 101 using a low shear blender.
44.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
44.8.3 Dry the granulation at 60°C using a fluid bed dryer until the
exhaust
temperature reaches 40°C.
44.8.4 Granules between 20 and 40 Mesh are collected for further processing.
44.9 Tabletting of the Antibiotic Pellets
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Table 8 Composition of Antibiotic Tablets
Component Percentage (%)
First antibiotic granules
32.5
Avicel PH 200 5.0
Second antibioticL30D-55 coated pellets
First antibioticS100 coated pellets 30
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
44.9.1 Blend the Antibiotic granules, Avicel PH-200, Antibiotic pellets and
colloidal silicon dioxide for 15 minutes in a tumble blender.
44.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
44.9.3 Compress the blend on a rotary tablet press.
44.9.4 The fill weight should be adjusted to achieve the desired dosage.
Four pulses
Example 45.
1 Antibiotic Matrix Pellet Formulation and Preparation Procedure
45.1 Pellet Formulation
The composition of the antibiotic matrix pellets provided in Table 9.
Table 9 Composition of Antibiotic Pellets
Component Percentage (%)
Antibiotic 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet
massing.
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45.2 Preparation Procedure for Antibiotic Matrix Pellets
45.2.1 Blend antibiotic and Avicel~ PH 101 using a Robot Coupe high shear
granulator.
45.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend
under continuous mixing.
45.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0 mm.
45.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
45.2.5 Dry the spheronized pellets at 50°C overnight.
45.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
45.2.7 The above procedure is used to prepare pellets that contain a first
antibiotic and pellets that contain a second antibiotic.
45.3 Preparation of an Eudragit~ L 30 D-55 Aqueous Coating Dispersion
45.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
antibiotic matrix pellets is provided below in Table 10.
Table 10 Eudragit~ L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 3.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
45.4 Preparation Procedure for an Eudragit~ L 30 D-55 Aqueous Dispersion
45.4.1 Suspend triethyl citrate and talc in deionized water.
45.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700
high shear mixer.
45.4.3 Add the TEC/talc suspension slowly to the Eudragit~ L 30 D-55 latex
dispersion while stirring.
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45.4.4 Allow the coating dispersion to stir for one hour prior to application
onto
the antibiotic matrix pellets.
45.5 Preparation of an Eudragit~ S 100 Aqueous Coating Dispersion
45.5.1 Dispersion Formulation
The composition of the aqueous Eudragit~ S 100 dispersion applied to the
antibiotic
matrix pellets is provided below in Table 11.
Table 11 Eudragit~ S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit~ S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
45.6 Preparation Procedure for an Eudragit~ S 100 Aqueous Dispersion
Part A:
45.6.1 Dispense Eudragit~ S 100 powder in deionized water with stirring.
45.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with
stirring.
45.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
45.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir
for
about 2 hours prior to the addition of Part B.
Part B:
45.6.5 Disperse talc in the required amount of water
45.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
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45.6.7 Part B is then added slowly to the polymer dispersion in Part A with a
mild stirring.
45.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters are used for coating with each of the
Eudragit~ L
30 D-55 and Eudragit~ S 100 aqueous film coatings.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature40 to 45 C
Outlet Air Temperature30 to 33 C
Atomization Air
Pressure 1.8 Bar
Pump Rate 2 gram per minute
45.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12%
coat weight gain to the pellets.
45.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30%
coat weight gain to the pellets.
45.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat
weight gain to the pellets.
45.8 Encapsulation of the Antibiotic Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%:
20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12%
weight
gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets
respectively.
The capsule is filled with the four different pellets to achieve the desired
dosage.
The immediate release pellets contain the first antibiotic; the L30 D-55 12%
weight
gain coated pellets contain the second antibiotic; the L30 D-55 30% weight
gain
coated pellets contain the first antibiotic and the S100 coated pellets
contain the
second antibiotic.
Example 46
Tetracycline Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Tetracycline pellets provided in Table 12.
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Table 12 Composition of Tetracycline Pellets
Component Percentage (%)
Tetracycline 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
*Removed during processing
Preparation Procedure for Tetracycline Pellets
~ Blend Tetracycline, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
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Tetracycline Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Tetracycline
pellets
is provided below in Table 13.
Table 13 Opadry Clear Aqueous Coating Solution
Com_po_nent Percent_ag_e (%)
~ ~~
Opadry Clear 7.0
YS-1-7006
Purified Water* 93.0
Solid Content % . 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
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Preparation of an AQOAT AS-HF/Eudragit~ FS30D Aqueous Coating Dispersion
_Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion
applied to the Opadry coated Tetracycline pellets is provided below in Table
14.
Table 14 AQOAT AS-HFI Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudragit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing
Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aaueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add sodium lauryl sulfate into the triethyl citrate
dispersion with stirring.
~ Slowly add the AQOAT AS-HF powder to the dispersion above
and stir for a minimum of 30 minutes.
~ Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF
dispersion and continue to stir for a minimum of 1 hour.
~ Slowly add the talc to the coating dispersion and continue to stir
for at least 2 hours.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
38
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Coating Conditions for the Application of Opadry -and AQOAT/Eudraait FS30D
Aaueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat Tetracycline pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HFlEudragit FS30D film coating dispersion.
Coating Equipment STREA 1TM Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
~ Coat Opadry coated Tetracycline pellets with the AQOATAS-
HF/Eudragit FS30D coating dispersion such that you apply 32% coat
weight gain to the pellets. Dry the coated pellets in the fluid bed for 20
minutes at 50°C.
39
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Doxycycline hyclate pellets provided in Table 15.
Table 15 Composition of Doxycycline hyclate Pellets
Component Percentage (%)
Doxycycline hyclate 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
'Removed during processing
Preparation Procedure for Doxycycline hyclate Pellets
~ Blend Doxycycline hyclate, Avicel~ PH 101, and Methocel using
a Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Agueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55lEudragit NE 30D aqueous
coating dispersion applied to the Doxycycline hyclate pellets is provided
below in
Table 16.
Table 16 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Agueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
41
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
~ Continue to stir the dispersion until the coating process is complete.
42
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudragit L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating dispersion such that you apply 20% coat weight gain to the pellets.
43
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Colonic-Release Pellets Formulation and Preparation
Procedure
Preparation of an Eudragit~ FS30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Doxycycline hyclate pellets is provided below in Table 17.
Table 17 Eudragit~ FS 30D Apueous Coating Dispersion
Component Percentage (%)
~
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
"Kemoved during processing
Preparation Procedure for an Eudragit~ FS 30D Aqueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
44
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudragit FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Tetracycline and Doxycycline hyclate Tablets
Preparation of Tetracycline Granulation for tableting
Table 18 Composition of Tetracycline Granulation (Immediate Release)
Component Percentage (%)
Tetracycline 40.0
Lactose monohydrate, spray dried 39.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Tetracycline, lactose, and Avicel~ PH 101 using a high shear
mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
46
CA 02478121 2004-09-03
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Tabletina of the Tetracycline and Doxycycline hyclate
Table 19 Composition of Tetracycline and Doxycycline hyclate Tablets
Component Percentage (%)
Tetracycline granules 45.0
Avicel PH 200 7.4
Eudragit L30D-55/NE 30D coated Doxycycline
hyclate Pellets 9~2
AQOAT/Eudragit FS 30D coated Tetracycline
Pellets 25.9
Eudragit FS 30D coated Doxycycline hyclate
Pellets 10.0
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Tetracycline granules, Avicel PH-200, Tetracycline coated
pellets, Doxycycline hyclate coated pellets and colloidal silicon dioxide
for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 350 mg total dose
tablet.
Example 47.
Tetracycline Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Tetracycline pellets provided in Table 20.
Table 20 Composition of Tetracycline Pellets
Component - Percentage (%)
Tetracycline 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
*Removed during processing
47
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Preparation Procedure for Tetracycline Pellets
~ Blend Tetracycline, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
48
CA 02478121 2004-09-03
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Tetracycline Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Tetracycline pellets is provided below in
Table 21.
Table 21 Eudragit~ L 30 D-551Eudragit NE 30D Apueous Coating Dispersion
Component . Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
"Kemoved during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Aqueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
49
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Tetracycline pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
so
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Tetracycline Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Tetracycline
pellets
is provided below in Table 22.
Table 22 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
si
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Preparation of an Eudraait~ FS 30D/Eudraait L 30D-55 Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating
dispersion applied to the Opadry coated Tetracycline pellets is provided below
in
Table 23.
Table 23 AQOAT AS-HFI Eudragit FS 30D Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudragit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing
Preparation Procedure for Eudrag~it FS 30D/Eudragit L 30D-55 Aaueous
Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add talc into the triethyl citrate dispersion with stirring.
~ Slowly add the Eudragit L 30D-55 to the dispersion above and
stir for a minimum of 10 minutes.
~ Slowly add the Eudragit FS 30D dispersion to the Eudragit L
30D-55 dispersion and continue to stir for a minimum of 1 hour.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
52
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Opadry and Eudraait FS 30D/ Eudragit
L
30D-55 Aaueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat Tetracycline pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated Tetracycline pellets with the Eudragit FS30D/
Eudragit L 30D-55 coating dispersion such that you apply 32% coat
weight gain to the pellets.
53
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Tetracycline Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ FS30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Tetracycline pellets is provided below in Table 24.
Table 24 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
54
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Ap~~lication of Eudragiit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
ss
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Doxycycline hyclate pellets provided in Table 25.
Table 25 Composition of Doxycycline hyclate Pellets
Component Percentage (%)
Doxycycline hyclate 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
Removed during processing
Preparation Procedure for Doxycycline hyclate Pellets
~ Blend Doxycycline hyclate, Avicel~ PH 101, and Methocel using
a Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
56
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit~ L 30 D-55/Eudraait NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the doxycycline hyclate pellets is provided
below in
Table 26.
Table 26 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudrag~it~ L 30D-55/Eudra~it NE 30D Aaueous
_Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/lmwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30DITEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
s7
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudraait L30D-55/Eudra iq t NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55lEudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating dispersion such that you apply 20% coat weight gain to the pellets.
ss
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Doxycycline hyclate Delayed Enteric-Release Pellet Formulation and
Preparation Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Doxycycline
hyclate
pellets is provided below in Table 27.
Table 27 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
~
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
59
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Preparation of an Eudraait~ FS 30D/Eudragit L 30D-55 Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating
dispersion applied to the Opadry coated Doxycycline hyclate pellets is
provided
below in Table 28.
Table 28 AQOAT AS-HFI Eudragit FS 30D Coating Dispersion
Component Percentage(%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
Removed during processing
Preparation Procedure for Eudraait FS 30D/Eudragit L 30D-55 AcLueous
Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add talc into the triethyl citrate dispersion with stirring.
~ Slowly add the Eudragit L 30D-55 to the dispersion above and
stir for a minimum of 10 minutes.
~ Slowly add the Eudragit FS 30D dispersion to the Eudragit L
30D-55 dispersion and continue to stir for a minimum of 1 hour.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Opadry and Eudraait FS 30D/ Eudragit
L
30D-55 Aaueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat Doxycycline hyclate pellets with Opadry coating solution such that
you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated Doxycycline hyclate pellets with the Eudragit
FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 32%
coat weight gain to the pellets.
61
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Doxycycline hyclate Colonic-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit~ FS30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
doxycycline hyclate pellets is provided below in Table 29.
Table 29 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
~Kemoved during processing
Preparation Procedure for an Eudrag~it~ FS 30D Agueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
62
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudraait FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
63
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Tetracycline and Doxycycline hyclate Tablets
Preparation of Tetracycline and Doxycycline hyclate Granulation for tableting
Table 30 Composition of Tetracycline and Doxycycline hyclate Granulation
(Immediate Release)
Component Percentage (%)
Tetracycline 15.6
Doxycycline hyclate 6.2
Lactose monohydrate, spray dried 57.2
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF~ 1.0
Total 100
'~Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Tetracycline, Doxycycline hyclate, lactose, and Avicel~ PH 101
using a high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
64
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Tableting of the Tetracycline and DoxYcycline h clate
Table 31 Composition of Tetracycline and Doxycycline hyclate Tablets
Compo Percentage (
n %)
ent
__
_
_
_
Tetracycline/Doxycycline
hyclate granules
50.0
Avicel PH 200 2.5
Eudragit L30D-551NE 30D coated Tetracycline
Pellets 10.0
Eudragit L30D-55/NE 30D coated Doxycycline
hyclate Pellets 4.0
Eudragit FS 30D/Eudragit
L30D coated
Tetracycline Pellets 11.3
Eudragit FS 30D/Eudragit
L30D coated
Doxycycline hyclate Pellets
4.5
Eudragit FS 30D coated Tetracycline
Pellets
10.9
Eudragit FS 30D coated Doxycycline hyclate
Pellets 4.3
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Tetracycline/Doxycycline hyclate granules, Avicel PH-200,
Tetracycline coated pellets, Doxycycline hyclate coated pellets and
colloidal silicon dioxide for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 350 mg total dose
tablet.
In one embodiment, Tetracycline will be dosed in an alternate pulse to
Doxycycline. This will alternate the exposure to the bacteria in such a way as
to
make both antibiotics more effective than if they were co-administered, and
thereby
competing with each other for sites on the bacterial cell wall receptors, or
sites within
the bacterial cells.
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In addition, even when Tetracycline and Doxycycline are not delivered in
alternate pulses, the dosage forms as hereinabove described provide for
improved
treatment of infection.
Example 48.
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 32.
Table 32 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV
Purified Water
Total 100
'Removed during processing
Preparation Procedure for Metronidazole Pellets
~ Blend metronidazole, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
66
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Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Metronidazole pellets is provided below in
Table 33.
Table 33 Eudragit~ L 30 D-55/Eudragit NE 30D Apueous Coating Dispersion
Component _ Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 O,g
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
-rcemovea aunng processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudraait NE 30D Aaueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
67
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Coatina Conditions for the Application of Eudraait L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Qutlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
~ Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D
film coating dispersion such that you apply 20% coat weight gain to the
pellets.
68
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Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coatings Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole
pellets is provided below in Table 34.
Table 34 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Actueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
69
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Preparation of an AQOAT AS-HF/Eudragit~ FS30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion
applied to the Opadry coated metronidazole pellets is provided below in Table
35.
Table 35 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
--rcemovea aunng processing
Preparation Procedure for AQOAT AS-HF/ Eudragiit FS30D Agueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add sodium lauryl sulfate into the triethyl citrate
dispersion with stirring.
~ Slowly add the AQOAT AS-HF powder to the dispersion above
and stir for a minimum of 30 minutes.
~ Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF
dispersion and continue to stir for a minimum of 1 hour.
~ Slowly add the talc to the coating dispersion and continue to stir
for at least 2 hours.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
Coating Conditions for the Application of O~adry and AQOAT/Eudraqit FS30D
Aqueous Coating Dispersions
CA 02478121 2004-09-03
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The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat metronidazole pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated metronidazole pellets with the AQOATAS-
HF/Eudragit FS30D coating dispersion such that you apply 32% coat
weight gain to the pellets. Dry the coated pellets in the fluid bed for 20
minutes at 50°C.
71
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Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ FS 30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 36.
Table 36 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate O.g
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
FKemoved during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
72
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Coating Conditions for the Application of Eudraait FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
~utlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
73
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Ciprofloxacin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Ciprofloxacin pellets provided in Table 37.
Table 37 Composition of Ciprofloxacin Pellets
Component Percentage (%)
Ciprofloxacin 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
'Removed during processing
Preparation Procedure for Ciprofloxacin Pellets
~ Blend Ciprofloxacin, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
74
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Ciprofloxacin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Discersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Ciprofloxacin pellets is provided below in
Table 38.
Table 38 Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component _ Percentage (%)
_
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
--rcemovea aunng processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
CA 02478121 2004-09-03
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Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Ciprofloxacin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
76
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Ciprofloxacin Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Ciprofloxacin
pellets
is provided below in Table 39.
Table 39 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
77
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Preparation of an Eudraait~ FS 30D/Eudragiit L 30D-55 Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating
dispersion applied to the Opadry coated Ciprofloxacin pellets is provided
below in
Table 40.
Table 40 Eudragit FS 30D/Eudragit L 30D-55 Coating Dispersion
Component _ Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing
Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aaueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add talc into the triethyl citrate dispersion with stirring.
~ Slowly add the Eudragit L 30D-55 to the dispersion above and
stir for a minimum of 10 minutes.
~ Slowly add the Eudragit FS 30D dispersion to the Eudragit L
30D-55 dispersion and continue to stir for a minimum of 1 hour.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
7~
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit
L
30D-55 Aaueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat Ciprofloxacin pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated Ciprofloxacin pellets with the Eudragit FS30D/
Eudragit L 30D-55 coating dispersion such that you apply 32% coat
weight gain to the pellets.
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Ciprofloxacin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ FS 30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Ciprofloxacin pellets is provided below in Table 41.
Table 41 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
Removed during processing
Preparation Procedure for an Eudraait~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizes.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
so
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudraait FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
si
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WO 03/075852 PCT/US03/07118
Metronidazole and Ciprofloxacin Tablets
Preparation of Metronidazole and Ciprofloxacin Granulation for tableting
Table 42 Composition of Metronidazole and Ciprofloxacin Granulation
(Immediate Release)
Component Percentage (%)
Metronidazole Trihydrate powder 13.3
Ciprofloxacin 9.0
Lactose monohydrate, spray dried 56.7
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was aaaea as a
2.9% w/w aqueous solution during wet massing.
~ Blend Metronidazole, Ciprofloxacin, lactose, and Avicel~ PH 101 using
a high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
82
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Tableting of the Metronidazole and Ci~rofloxacin
Table 43 Composition of Metronidazole and Ciprofloxacin Tablets
Component Percentage (%)
MetronidazolelCiprofloxacin granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole
Pellets g.4
Eudragit L30D-55/NE 30D coated Ciprofloxacin
Pellets 5.6
AQOAT/ Eudragit FS 30D coated Metronidazole
Pellets g,5
Eudragit FS 30D / L30D coated Ciprofloxacin
Pellets 6.3
Eudragit FS 30D coated Metronidazole Pellets
9.1
Eudragit FS 30D coated Ciprofloxacin Pellets
6.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200,
Metronidazole coated pellets, Ciprofloxacin coated pellets and colloidal
silicon dioxide for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 625 mg total dose
tablet.
83
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Example 49.
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 44.
Table 44 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Metronidazole Pellets
~ Blend metronidazole, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
84
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Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coatinq
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Metronidazole pellets is provided below in
Table 45.
Table 45 Eudragit~ L 30 D-551Eudragit NE 30D Apueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
'Removed during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudraait NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
ss
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Coating Conditions for the Application of Eudragit L30D-55/Eudra iq t NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"~ Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
~utlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
'
Pump Rate 3-4 gram per minute
~ Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D
film coating dispersion such that you apply 20% coat weight gain to the
pellets.
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Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole
pellets is provided below in Table 46.
Table 46 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Agueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
a7
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Preparation of an AQOAT AS-HF/Eudraait~ FS30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion
applied to the Opadry coated metronidazole pellets is provided below in Table
47.
Table 47 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
Removed during processing
Preparation Procedure for AQOAT AS-HF/ Eudraait FS30D Aqueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add sodium lauryl sulfate into the triethyl citrate
dispersion with stirring.
~ Slowly add the AQOAT AS-HF powder to the dispersion above
and stir for a minimum of 30 minutes.
~ Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF
dispersion and continue to stir for a minimum of 1 hour.
~ Slowly add the talc to the coating dispersion and continue to stir
for at least 2 hours.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
Coating Conditions for the Application of Opadry and AQOAT/Eudra~it FS30D
Aaueous Coating Dispersions
ss
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The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat metronidazole pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated metronidazole pellets with the AQOATAS-
HF/Eudragit FS30D coating dispersion such that you apply 32% coat
weight gain to the pellets. Dry the coated pellets in the fluid bed for 20
minutes at 50°C.
89
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Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ FS 30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 48.
Table 48 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
CA 02478121 2004-09-03
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Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
91
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Metronidazole and Ciprofloxacin Tablets
Preparation of Metronidazole and Ciprofloxacin Granulation for tableting
Table 49 Composition of Metronidazole and Ciprofloxacin Granulation
(Immediate Release)
Component Percentage (%)_
Metronidazole 22.5
Ciprofloxacin 59.0
Lactose monohydrate, spray dried 10.0
Avicel PH 101 7.5
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
~'Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Metronidazole, Ciprofloxacin, lactose, and Avicel~ PH 101 using
a high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
92
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Tabletinq of the Metronidazole and Ciprofloxacin
Table 50 Composition of Metronidazole and Ciprofloxacin Tablets
Component Percentage (%)
Metronidazole/Ciprofloxacin granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole
Pellets 14.0
AQOAT/ Eudragit FS 30D coated Metronidazole
Pellets 15.8
Eudragit FS 30D coated Metronidazole Pellets
15.2
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200,
Metronidazole coated pellets and colloidal silicon dioxide for 15
minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 625 mg total dose
tablet.
In one embodiment, Ciprofoxacin will be dosed in an alternate pulse to
Metronidazole. This will alternate the exposure to the bacteria in such a way
as to
make both antibiotics more effective than if they were co-administered, and
thereby
competing with each other for sites on the bacterial cell wall receptors, or
sites within
the bacterial cells.
In addition, even when Ciprofoxacin and Metronidazole are not delivered in
alternate pulses, the dosage forms as hereinabove described provide for
improved
treatment of infection.
93
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Example 50
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 51.
Table 51 Composition of Amoxicillin Pellets
Component Percentage (%)
~
Amoxicillin Trihydrate 92
powder
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose,1.0
NF*
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor EL
were added as a 2.9% w/w aqueous solution during
wet massing.
**Removed during processing
Preparation Procedure for Amoxicillin Pellets
~ Blend Amoxicillin and Avicel~ PH 101 using a low shear blender.
~ Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil
binder solution slowly into the powder blend under continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
~ Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
~ Dry the spheronized pellets at 60°C using a fluid bed dryer until the
exhaust temperature reaches 40°C.
~ Pellets between 20 and 40 Mesh were collected for further processing.
94
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Amoxicillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the amoxicillin pellets is provided below in
Table 52.
Table 52 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraait~ L 30D-55/Eudragit NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/lmwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Coating Conditions for the Application of Eudraait L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
.
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
96
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Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an AQOAT AS-HF Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the amoxicillin pellets is provided below in Table 53.
Table 53 AQOAT AS-HF Aqueous Coating Dispersion
Component _ Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
'Removed during processing
Preparation Procedure for an AQOAT AS-HF Agueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete
97
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Coating Conditions for the Application of AQOAT AS-HF Aaueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
98
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Amoxicillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ FS 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Amoxicillin pellets is provided below in Table 54.
Table 54 Eudragit~ FS 30D Aqueous Coating Dispersion
Component . ~ Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
99
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Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature33 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
ioo
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Clarithromycin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the clarithromycin pellets provided in Table 55.
Table 55 Composition of Clarithromycin Pellets
Component____ Percentage (°/o)
Clarithromycin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water
Tota I 100
*Removed during processing
Preparation Procedure for Clarithromycin Pellets
~ Prepare the binder solution by adding the Polyoxyl to the purified water
while stirring. After that is mixed, slowly add the hydroxypropyl
methylcellulose and continue to stir until a solution is achieved.
~ Blend clarithromycin, lactose monohydrate, and croscarmellose sodium
using a Robot Coupe high shear granulator.
~ Add binder solution slowly into the powder blend under continuous
mixing.
~ Granulate the powders in the high shear granulator with the binder
solution.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0 mm.
~ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
~ Dry the spheronized pellets at 50°C until the moisture level is > 3%.
~ Pellets between 16 and 30 Mesh were collected for further processing.
ioi
CA 02478121 2004-09-03
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Clarithromycin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the clarithromycin pellets is provided below in
Table 56.
Table 56 Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Agueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
102
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Coating Conditions for the Application of Eudragit L30D-55/Eudra iq t NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating
dispersion such that you apply 20% coat weight gain to the pellets.
103
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Clarithromycin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an AQOAT AS-HF Agueous Coating Dispersion
Dis~oersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the clarithromycin pellets is provided below in Table 57.
Table 57 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water' 8g,7
Solid Content 11.3
Polymer Content 7.0
rcernovea aunng processing
Preparation Procedure for an AQOAT AS-HF Aaueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
104
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Coating Conditions for the Application of AQOAT AS-HF Aaueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
los
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Clarithromycin Colonic-Release Pellets Formulation and Preparation
Procedure
Preparation of an Eudragit~ FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
clarithromycin pellets is provided below in Table 58.
Table 58 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
106
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Coating Conditions for the Application of Eudragit FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
io7
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Amoxicillin and Clarithromycin Tablets
Preparation of Amoxicillin and Clarithromycin Granulation for tableting
Table 59 Composition of Amoxicillin and Clarithromycin Granulation
(Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Clarithromycin 22.0
Lactose monohydrate, spray dried 45.0
Avicel PH 101 10.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcemnose was aaaea as a
2.9% w/w apueous solution during wet massing.
~ Blend Amoxicillin, Clarithromycin, lactose, and Avicel~ PH 101 using a
high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
log
CA 02478121 2004-09-03
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Tableting of the Amoxicillin and Clarithromycin
Table 60 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Amoxicillin/Clarithromycin granules
45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Amoxicillin
Pellets 6.4
Eudragit L30D-55/NE 30D coated Clarithromycin
Pellets 7.6
AQOAT coated Amoxicillin Pellets 7.2
AQOAT coated Clarithromycin Pellets 8.6
Eudragit FS 30D coated Amoxicillin Pellets 6.9
Eudragit FS 30D coated Clarithromycin Pellets
8.3
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Amoxicillin/Clarithromycin granules, Avicel PH-200,
Amoxicillin coated pellets, Clarithromycin coated pellets and colloidal
silicon dioxide for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 500 mg total dose
tablet.
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Example 51
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 61.
Table 61 Composition of Amoxicillin Pellets
Component ~ -Percentage (%)
Amoxicillin Trihydrate powder92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose,1.0
NF*
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor EL
were added as a 2.9% w/w aqueous solution during
wet massing.
**Removed during processing
Preparation Procedure for Amoxicillin Pellets
~ Blend Amoxicillin and Avicel~ PH 101 using a low shear blender.
~ Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil
binder solution slowly into the powder blend under continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
~ Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
~ Dry the spheronized pellets at 60°C using a fluid bed dryer until the
exhaust temperature reaches 40°C.
~ Pellets between 20 and 40 Mesh were collected for further processing.
no
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an AQOAT AS-HF Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the amoxicillin pellets is provided below in Table 62.
Table 62 AQOAT AS-HF Apueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aaueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
111
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Coating Conditions for the Application of AQOAT AS-HF Aaueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating EquipmentSTREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6
Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
112
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Clarithromycin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the clarithromycin pellets provided in Table 63.
Table 63 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water
Total 100
*Removed during processing
Preparation Procedure for Clarithromycin Pellets
~ Prepare the binder solution by adding the Polyoxyl to the purified water
while stirring. After that is mixed, slowly add the hydroxypropyl
methylcellulose and continue to stir until a solution is achieved.
~ Blend clarithromycin, lactose monohydrate, and croscarmellose sodium
using a Robot Coupe high shear granulator.
~ Add binder solution slowly into the powder blend under continuous
mixing.
~ Granulate the powders in the high shear granulator with the binder
solution.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0 mm.
~ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until the moisture level is >
3%.
~ Pellets between 16 and 30 Mesh were collected for further processing.
113
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Clarithromycin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the clarithromycin pellets is provided below in
Table 64.
Table 64 Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water 38.6
Solid Content 20.6
Polymer Content 16.4
-wemovea aunng processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Aqueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
114
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Coating Conditions for the Application of Eudraait L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating
dispersion such that you apply 20% coat weight gain to the pellets.
us
CA 02478121 2004-09-03
WO 03/075852 PCT/US03/07118
Clarithromycin Colonic-Release Pellets Formulation and Preparation
Procedure
Preparation of an Eudraait~ FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
clarithromycin pellets is provided below in Table 65.
Table 65 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
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Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
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Amoxicillin and Clarithromycin Tablets
Preparation of Amoxicillin Granulation for tableting
Table 66 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Lactose monohydrate, spray dried 57.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Amoxicillin, lactose, and Avicel~ PH 101 using a high shear
mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
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Tableting of the Amoxicillin and Clarithromycin
Table 67 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Amoxicillin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Clarithromycin
Pellets 14.9
AQOAT coated Amoxicillin Pellets
14.0
Eudragit FS 30D coated Clarithromycin Pellets
16.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coated
pellets, Clarithromycin coated pellets and colloidal silicon dioxide for 15
minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 500 mg total dose
tablet.
In one embodiment, Amoxicillin will be dosed in an alternate pulse to
Clarithromycin. This will alternate the exposure to the bacteria in such a way
as to
make both antibiotics more effective than if they were co-administered, and
thereby
competing with each other for sites on the bacterial cell wall receptors, or
sites within
the bacterial cells.
In addition, even when Amoxicillin and Clarithromycin are not delivered in
alternate pulses, the dosage forms as hereinabove described provide for
improved
treatment of infection.
Clarithromycin and Amoxicillin Tablets
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Preparation of Clarithromycin Granulation for tabletina
Table 68 Composition of Clarithromycin Granulation (Immediate Release)
Component Percenfiage (%)
Clarithromycin powder 22.0
Lactose monohydrate, spray dried 57.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
Blend Clarithromycin, lactose, and Avicel~ PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder
blend
under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature
reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tabletina of the Amoxicillin and Clarithromycin
Table 69 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Clarithromycin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Amoxicillin
Pellets 14.9
AQOAT coated Clarithromy cin Pellets
14.0
Eudragit FS 30D coated Amoxicillin
Pellets
16.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Clarithromycin granules, Avicel PH-200, Amoxicillin coated
pellets, Clarithromycin coated pellets and colloidal silicon dioxide for 15
minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
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~ Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
Example 52
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 70.
Table 70 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose,1.0
NF*
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor EL
were added as a 2.9% w/w aqueous solution during
wet massing.
**Removed during processing
Preparation Procedure for Amoxicillin Pellets
~ Blend Amoxicillin and Avicel~ PH 101 using a low shear blender.
~ Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil
binder solution slowly into the powder blend under continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
~ Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
~ Dry the spheronized pellets at 60°C using a fluid bed dryer until the
exhaust temperature reaches 40°C.
~ Pellets between 20 and 40 Mesh were collected for further processing.
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Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation ofi an AQOAT AS-HF Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the amoxicillin pellets is provided below in Table 71.
Table 71 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 83.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aaueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
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Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Dicloxacillin pellets provided in Table 72.
Table 72 Composition of Dicloxacillin Pellets
Component Percentage (%)
Dicloxacillin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water
Total 100
*Removed during processing
Preparation Procedure for Dicloxacillin Pellets
~ Prepare the binder solution by adding the Polyoxyl to the purified water
while stirring. After that is mixed, slowly add the hydroxypropyl
methylcellulose and continue to stir until a solution is achieved.
~ Blend Dicloxacillin, lactose monohydrate, and croscarmellose sodium
using a Robot Coupe high shear granulator.
~ Add binder solution slowly into the powder blend under continuous
mixing.
~ Granulate the powders in the high shear granulator with the binder
solution.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0 mm.
~ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
~ Dry the spheronized pellets at 50°C until the moisture level is > 3%.
~ Pellets between 16 and 30 Mesh were collected for further processing.
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Dicloxacillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation ofi an Eudraait~ L 30 D-55/Eudraait NE 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Dicloxacillin pellets is provided below in
Table 73.
Table 73 Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30DrfEC/lmwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudragiit L30D-55/Eudraait NE
30DAaueous Coatin Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
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Dicloxacillin Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudraqit~ FS30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Dicloxacillin pellets is provided below in Table 74.
Table 74 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* . 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraait~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
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Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
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Amoxicillin and Dicloxacillin Tablets
Preparation of Amoxicillin Granulation for tabletina
Table 75 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 24.0
Lactose monohydrate, spray dried 55.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
°hyaroxypropyi metnylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Amoxicillin, lactose, and Avicel~ PH 101 using a high shear
mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
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Tableting of the Amoxicillin and Dicloxacillin
Table 76 Composition of Amoxicillin and Dicloxacillin Tablets
Component Percentage (%)
Amoxicillin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Dicloxacillin
Pellets 14.0
AQOAT coated Amoxicillin
Pellets
15.8
Eudragit FS 30D coated Dicloxacillin
Pellets
15.2
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coated
pellets, Dicloxacillin coated pellets and colloidal silicon dioxide for 15
minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 500 mg total dose
tablet.
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Example 53
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 77.
Table 77 Composition of Amoxicillin Pellets
Component __ Percentage (%)
Amoxicillin Trihydrate powder92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose,1.0
NF*
Purified Water **
Total 100
"Hydroxypropyl methylcellulose and Cremaphor EL
were added as a 2.9% w/w aqueous solution during
wet massing.
**Removed during processing
Preparation Procedure for Amoxicillin Pellets
~ Blend Amoxicillin and Avicel~ PH 101 using a low shear blender.
~ Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil
binder solution slowly into the powder blend under continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
~ Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
~ Dry the spheronized pellets at 60°C using a fluid bed dryer until the
exhaust temperature reaches 40°C.
~ Pellets between 20 and 40 Mesh were collected for further processing.
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Amoxicillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudraait NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the amoxicillin pellets is provided below in
Table 78.
Table 78 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component - Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
~Kemoved during processing
Preparation Procedure for an Eudragiit~ L 30D-55/Eudragit NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudragit L30D-55/Eudraait NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
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Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the amoxicillin pellets is provided below in Table 79.
Table 79 AQOAT AS-HF Aqueous Coating Dispersion
Component _ _ Percentage (%)
~~
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
~Kemoved during processing
Precaration Procedure for an AQOAT AS-HF Agueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of AQOAT AS-HF Aaueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
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Amoxicillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ FS 30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Amoxicillin pellets is provided below in Table 80.
Table 80 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you
apply
30% coat weight gain to the pellets.
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Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Dicloxacillin trihydrate pellets provided in Table 81.
Table 81 Composition of Dicloxacillin Pellets
Component Percentage (%)
Dicloxacillin 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Polyoxyl
35 Castor Oil
were added as a 2.9% w/w aqueous solution
during
wet massing.
**Removed during processing
Preparation Procedure for Dicloxacillin Pellets
~ Blend Dicloxacillin and Avicel~ PH 101 using a low shear blender.
~ Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil
binder solution slowly into the powder blend under continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
~ Spheronize the extrudate using a QJ-230 Spheronizer using a small
cross section plate.
~ Dry the spheronized pellets at 60°C using a fluid bed dryer until the
exhaust temperature reaches 40°C.
~ Pellets between 20 and 40 Mesh were collected for further processing.
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Dicloxacillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Dicloxacillin pellets is provided below in
Table 82.
Table 82 Eudragit~ L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component P_ ercentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
'Removed during processing
Preparation Procedure for an Eudragit~ L 30D-55/Eudragit NE 30D Aqueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudraait L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating
dispersion such that you apply 20% coat weight gain to the pellets.
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Dicloxacillin Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an AQOAT AS-HF Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied
to the Dicloxacillin pellets is provided below in Table 83.
Table 83 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aaueous Dispersion
~ Add triethyl citrate (TEC) to the purified water with stirring.
~ Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring
and completely until completely dissolved.
~ Add the AQOAT to the TEC/SLS dispersion and stir for at least 30
minutes.
~ Add the talc to the AQOAT dispersion and until completely mixed and
for at least 30 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of AQOAT AS-HF Aaueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film
coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature48 C
Outlet Air Temperature27 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with AQOAT AS-HF film coating dispersion such that
you
apply 30-35% coat weight gain to the pellets.
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Dicloxacillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ FS 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Dicloxacillin pellets is provided below in Table 84.
Table 84 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudraait FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating EquipmentSTREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6
Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
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Amoxicillin and Dicloxacillin Tablets
Preparation of Amoxicillin and Dicloxacillin Granulation for tabletina
Table 85 Composition of Amoxicillin and Dicloxacillin Granulation
(Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Dicloxacillin 22.0
Lactose monohydrate, spray dried 45.0
Avicel PH 101 10.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
~'Hydroxypropyl methylcellulose was added as a
2.9% wlw aqueous solution during wet massing.
~ Blend Amoxicillin, Dicloxacillin, lactose, and Avicel~ PH 101 using a
high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
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Tabletinc,~of the Amoxicillin and Dicloxacillin
Table 86 Composition of Amoxicillin and Dicloxacillin Tablets
Component Percentage (%)
Amoxicillin/Dicloxacillin granules49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Amoxicillin
Pellets 7.0
'
L30D-55/NE 30D coated Dicloxacillin
Eudragit 7.0
Pellets
AQOAT coated Amoxicillin Pellets 7.9
AQOAT coated Dicloxacillin Pellets7.9
Eudragit FS 30D coated Amoxicillin
Pellets
7.6
Eudragit FS 30D coated Dicloxacillin
Pellets
7.6
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Tota I 100
~ Blend the Amoxicillin/Dicloxacillin granules, Avicel PH-200, Amoxicillin
coated pellets, Dicloxacillin coated pellets and colloidal silicon dioxide
for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 500 mg total dose
tablet.
In one embodiment, Amoxicillin will be dosed in an alternate pulse to
dicloxacillin. This will alternate the exposure to the bacteria in such a way
as to
make both antibiotics more effective than if they were co-administered, and
thereby
competing with each other for sites on the bacterial cell wall receptors, or
sites within
the bacterial cells.
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In addition, even when Amoxicillin and dicloxacillin are not delivered in
alternate pulses, the dosage forms as hereinabove described provide for
improved
treatment of infection.
Example 54
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Metronidazole pellets provided in Table 87.
Table 87 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV
Purified Water
Total 100
Removed during processing
Preparation Procedure for Metronidazole Pellets
~ Blend metronidazole, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
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Metronidazole Delayed Enteric-Release Pellets Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole
pellets
is provided below in Table 88.
Table 88 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
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Preparation of an AQOAT AS-HF/Eudragit~ FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion
applied to the Opadry coated metronidazole pellets is provided below in Table
89.
Table 89 AQOAT AS-HFI Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudragit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
'Removed during processing
Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aaueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add sodium lauryl sulfate into the triethyl citrate
dispersion with stirring.
~ Slowly add the AQOAT AS-HF powder to the dispersion above
and stir for a minimum of 30 minutes.
~ Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF
dispersion and continue to stir for a minimum of 1 hour.
~ Slowly add the talc to the coating dispersion and continue to stir
for at least 2 hours.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
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Coating Conditions for the Application of Opadry and AQOAT/Eudraait FS30D
Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T~~ Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat metronidazole pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1TM Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated metronidazole pellets with the AQOATAS-
HF/Eudragit FS30D coating dispersion such that you apply 32% coat
weight gain to the pellets. Dry the coated pellets in the fluid bed for 20
minutes at 50°C.
iso
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Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Cefuroxime axetil pellets provided in Table 90.
Table 90 Composition of Cefuroxime axetil Pellets
Component Percentage (%)
Cefuroxime axetil 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
*Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets
~ Blend Cefuroxime axetil, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
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Cefuroxime axetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit~ L 30 D-55/Eudraait NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Cefuroxime axetil pellets is provided below
in Table
91
Table 91 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraait~ L 30D-55/Eudraait NE 30D Aaueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
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~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55lEudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating
dispersion such that you apply 20% coat weight gain to the pellets.
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Cefuroxime axetil Colonic-Release Pellets Formulation and Preparation
Procedure
Preparation of an Eudragit~ FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Cefuroxime axetil pellets is provided below in Table 92.
Table 92 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraait~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the taIc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
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Coating Conditions for the Application of Eudraait FS30D Aaueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
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Metronidazole and Cefuroxime axetil Tablets
Preparation of Metronidazole Granulation for tableting
Table 93 Composition of Metronidazole Granulation (Immediate Release)
Component Percentage (%)
Metronidazole 42.5
Lactose monohydrate, spray dried 36.5
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
'~Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Metronidazole, lactose, and Avicel~ PH 101 using a high shear
mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
is~
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Tableting of the Metronidazole and Cefuroxime axetil
Table 94 Composition of Metronidazole and Cefuroxime axetil Tablets
Component - Percentage (%)
Metronidazole granules 45.0
Avicel PH 200 7.6
Eudragit L30D-55/NE 30D coated Cefuroxime
axetil Pellets 8.2
AQOAT/Eudragit FS 30D coated
Metronidazole
Pellets 27.8
Eudragit FS 30D coated Cefuroxime axetil
Pellets g,g
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Metronidazole granules, Avicel PH-200, Metronidazole
coated pellets, Cefuroxime axetil coated pellets and colloidal silicon
dioxide for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 500 mg total dose
tablet.
The present invention is particularly advantageous in that there is provided
an
antibiotic product which provides an improvement over twice a day
administration of
the antibiotic and an improvement over a once a day administration of the
antibiotic.
Numerous modification and variations of the present invention are possible in
light of
the above teachings and therefore, within the scope of the appended claims the
invention may be practiced otherwise than as particularly described.
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Example 55
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 95.
Table 95 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water
Total 100
'Removed during processing
Precaration Procedure for Metronidazole Pellets
~ Blend metronidazole, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
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Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ L 30 D-55/Eudragit NE 30D Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Metronidazole pellets is provided below in
Table 96.
Table 96 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20_.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraait~ L 30D-55/Eudragit NE 30D Aqueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion
and stir for at least 10 minutes.
~ Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudraait L30D-55/Eudraait NE
_30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
~ Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D
film coating dispersion such that you apply 20% coat weight gain to the
pellets.
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Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole
pellets is provided below in Table 97.
Table 97 Opadry Clear Apueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for O~adry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
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Preparation of an AQOAT AS-HF/Eudragit~ FS30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion
applied to the Opadry coated metronidazole pellets is provided below in Table
98.
Table 98 AQ~AT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing
Preparation Procedure for AQOAT AS-HFl Eudragit FS30D Aqueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add sodium lauryl sulfate into the triethyl citrate
dispersion with stirring.
~ Slowly add the AQOAT AS-HF powder to the dispersion above
and stir for a minimum of 30 minutes.
~ Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF
dispersion and continue to stir for a minimum of 1 hour.
~ Slowly add the talc to the coating dispersion and continue to stir
for at least 2 hours.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D
Aqueous Coating Dispersions
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The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"~ Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat metronidazole pellets with Opadry coating solution such that you
apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1T"~ Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated metronidazole pellets with the AQOATAS-
HF/Eudragit FS30D coating dispersion such that you apply 32% coat
weight gain to the pellets. Dry the coated pellets in the fluid bed for 20
minutes at 50°C.
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Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraait~ FS 30D Aaueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 99.
Table 99 Eudragit~ FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit~ FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the talc/TEC dispersion
with stirring.
Continue to stir the coating dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
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Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Cefuroxime axetil pellets provided in Table 100.
Table 100 Composition of Cefuroxime axetil Pellets
Component Percentage (%)
Cefuroxime axetil 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets
~ Blend Cefuroxime axetil, Avicel~ PH 101, and Methocel using a
Robot Coupe high shear granulator.
~ Add the purified water slowly into the powder blend under
continuous mixing.
~ Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mm.
~ Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
~ Dry the spheronized pellets at 50°C until moisture level is < 3%.
~ Pellets between 16 and 30 Mesh were collected for further
processing.
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Cefuroxime axetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit~ L 30 D-55/Eudragit NE 30D Agueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous
coating dispersion applied to the Cefuroxime axetil pellets is provided below
in Table
101.
Table 101 Eudragit~ L 30 D-551Eudragit NE 30D Aqueous Coating
Dispersion
Component Percentage (%)
Eudragit~ L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit~ L 30D-55/Eudragit NE 30D Agueous
Dispersion
~ Heat purified water to 75-80°C and then add triethyl citrate (TEC)
and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
~ The TEC/Imwitor 900 dispersion is then stirred until the temperature is
less than 35°C.
~ Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex
dispersion and stir for at least 30 minutes.
~ Add Eudragit NE 30D to the Eudragit L30DlTEC/lmwitor 900 dispersion
and stir for at least 10 minutes.
16~
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Screen the dispersion through a No. 60 mesh sieve prior to coating.
~ Continue to stir the dispersion until the coating process is complete.
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Coating Conditions for the Application of Eudraqit L30D-55/Eudraait NE
30DAaueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit~ L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature45 C
Outlet Air Temperature32 to 35 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE 30D film
coating
dispersion such that you apply 20% coat weight gain to the pellets.
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Cefuroxime axetil Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Cefuroxime
axetil
pellets is provided below in Table 102.
Table 102 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Ohadry Clear Aaueous Solution
~ Charge the purified water into a container
~ Slowly add the Opadry Clear YS-1-7006 to the water with
continuous mixing.
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Preparation of an Eudragit~ FS 30DlEudragit L 30D-55 Aaueous Coating
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating
dispersion applied to the Opadry coated Cefuroxime axetil pellets is provided
below
in Table 103.
Table 103 Eudragit FS 30DIEudragit L 30D-55 Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing
Preparation Procedure for Eudraait FS 30D/Eudraait L 30D-55 Aaueous Dispersion
~ Disperse triethyl citrate in purified water with stirring.
~ Slowly add talc into the triethyl citrate dispersion with stirring.
~ Slowly add the Eudragit L 30D-55 to the dispersion above and
stir for a minimum of 10 minutes.
~ Slowly add the Eudragit FS 30D dispersion to the Eudragit L
30D-55 dispersion and continue to stir for a minimum of 1 hour.
~ Screen the dispersion through a No. 60 mesh sieve.
~ Continue to stir the screened coating dispersion throughout the
coating process.
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Coating Conditions for the Application of Opadry and Eudraait FS 30D/ Eudraait
L
30D-55 Aaueous Coating Dispersions
The following coating parameters were used for coating with the Opadry
solution film
coating.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 350 gram
Inlet Air Temperature60 C
Outlet Air Temperature40 C
Atomization Air
Pressure 1.6 Bar
~ Coat Cefuroxime axetil pellets with Opadry coating solution such that
you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.0 mm
Material Charge 300 gram
Inlet Air Temperature50 C
Outlet Air Temperature30 C
Atomization Air
Pressure 1.6 Bar
~ Coat Opadry coated Cefuroxime axetil pellets with the Eudragit FS30D/
Eudragit L 30D-55 coating dispersion such that you apply 32% coat
weight gain to the pellets.
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Cefuroxime axetil Colonic-Release Pellet Formulation and Preparation
Procedure
Preaaration of an Eudragit~ FS 30D Aaueous CoatincLDispersion
Dispersion Formulation
The composition of the aqueous Eudragit~ FS 30D dispersion applied to the
Cefuroxime axetil pellets is provided below in Table 104.
Table 104 Eudragit~ FS 30D Aqueous Coating Dispersion
Component ~ Pe
r
centage (%)
Eudragit~ FS 30D _
_
54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
"Kemoved during processing
Preparation Procedure for an Eudraait~ FS 30D Aaueous Dispersion
~ Disperse triethyl citrate (TEC) in the purified water.
~ Add the talc in the triethyl citrate dispersion.
~ Homogenize the dispersion using a homogenizer.
~ Add slowly the Eudragit~ FS 30D dispersion to the taIc/TEC dispersion
with stirring.
~ Continue to stir the coating dispersion until the coating process is
complete.
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Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the
Eudragit~
FS 30 D aqueous film coating.
Coating Equipment STREA 1T"~ Table Top Laboratory Fluid
Bed Coater
Spray nozzle diameter1.2 mm
Material Charge 300 gram
Inlet Air Temperature38 C
Outlet Air Temperature22 C
Atomization Air
Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30%
coat
weight gain to the pellets.
ms
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Metronidazole and Cefuroxime axetil Tablets
Preparation of Metronidazole and Cefuroxime axetil Granulation for tableting
Table 105 Composition of Metronidazole and Cefuroxime axetil Granulation
. (Immediate Release)
Component Percentage (%)
Metronidazole Trihydrate powder 13.3
Cefuroxime axetil 9.0
Lactose monohydrate, spray dried 56.7
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a
2.9% w/w aqueous solution during wet massing.
~ Blend Metronidazole, Cefuroxime axetil, lactose, and Avicel~ PH 101
using a high shear mixer.
~ Add the hydroxypropyl methylcellulose binder solution slowly into the
powder blend under continuous mixing.
~ Dry the granulation at 60°C using a fluid bed dryer until the exhaust
temperature reaches 40°C.
~ Granules between 20 and 40 Mesh are collected for further processing.
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TabletincLof the Metronidazole and Cefuroxime axetil
Table 106 Composition of Metronidazole and Cefuroxime axetil Tablets
Component Percentage (%)
Metronidazole/Cefuroxime axetil granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole
Pellets 8.4
Eudragit L30D-55/NE 30D coated Cefuroxime
axetil Pellets 5.6
AQOAT/ Eudragit FS 30D coated Metronidazole
Pellets 9.5
Eudragit FS 30D / L30D coated Cefuroxime
axetil Pellets 6.3
Eudragit FS 30D coated Metronidazole Pellets
9.1
Eudragit FS 30D coated Cefuroxime axetil
Pellets 6.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
~ Blend the Metronidazole/Cefuroxime axetil granules, Avicel PH-200,
Metronidazole coated pellets, Cefuroxime axetil coated pellets and
colloidal silicon dioxide for 15 minutes in a tumble blender.
~ Add the magnesium stearate to the blender, and blend for 5 minutes.
~ Compress the blend on a rotary tablet press.
~ The fill weight should be adjusted to achieve a 625 mg total dose
tablet.
In one embodiment, cephalosporin will be dosed in an alternate pulse to
Metronidazole. This will alternate the exposure to the bacteria in such a way
as to
make both antibiotics more effective than if they were co-administered, and
thereby
competing with each other for sites on the bacterial cell wall receptors, or
sites within
the bacterial cells.
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In addition, even when cephalosporin and Metronidazole are not delivered in
alternate pulses, the dosage forms as hereinabove described provide for
improved
treatment of infection.
Numerous modifications and variations of the present invention are possible
in light of the above teachings; therefore, within the scope of the appended
claims,
the invention may be practiced otherwise than as particularly described.
i7a
