Note: Descriptions are shown in the official language in which they were submitted.
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ORALLY ADMINISTERED CONTROLLED DELIVERY
SYSTEM FOR ONCE DAILY ADMINISTRATION OF CIPROFLOXACIN
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition in the form
of tablets or capsules which provides a combination of spatial and temporal
control of drug delivery, specifically for the drug ciprofloxacin, to a
patient for
effective therapeutic results. The pharmaceutical composition comprises
ciprofloxacin, a gas generating component, a swelling agent, and at least one
of either a viscolyzing agent and a gelling agent. The swelling agent belongs
to
a class of highly absorbent compounds commonly referred to as superdisinte-
grants. This class of compounds includes, for example, cross-linked polyvinyl
pyrrolidone and cross-linked sodium carboxymethylcellulose. The viscolyzing
agent is a highly viscous material which upon contact with gastric fluid
entraps
the gas produced by the gas generating component. The viscolyzing agent
comprises, for example, a carbohydrate gum, e.g., xanthan gum or a cellulose
ether, e.g., hydroxypropyl methylcellulose (methocel). The gelling agent is
preferably a cross-linkable gelling agent, such as a water soluble salt of one
or
more polyuronic acids, e.g., sodium alginate.
The improved controlled drug delivery system of the present invention is
designed to deliver effectively ciprofloxacin to a patient over a specific
time
period (temporal control) and from a particular portion of the patient's
gastrointestinal tract (spatial control). The improved controlled drug
delivery
system avoids dose dumping and results in the most therapeutic administration
of ciprofloxacin to a person.
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CONFIRMATION COPY
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It is well known to those skilled in the art that for ailments requiring
multiple doses of a particular drug, the blood levels of a drug need to be
maintained above its minimum effective level and below its minimum toxic level
in order to obtain the desired therapeutic effects, to avoid undesired toxic
effects,
and to minimize side effects. When the blood levels of a drug are in this
range,
the drug is eliminated from the body at a particular rate. A controlled drug
delivery system is usually designed to deliver the drug at this particular
rate; safe
and effective blood levels are maintained for a period as long as the system
continues to deliver the drug at this rate. Controlled drug delivery usually
results
in substantially constant blood levels of the active ingredient as compared to
the
uncontrolled fluctuations observed when multiple doses of quick releasing
conventional dosage forms are administered to a patient. Controlled drug
delivery results in optimum therapy, and not only reduces the frequency of
dosing, but may also reduce the severity and frequency of side effects.
The above basic concepts of controlled drug delivery are well known to
those skilled in the art. Considerable efforts have been made in the last
decades
to develop new pharmaceutically viable and therapeutically effective
controlled
drug delivery systems. Attention has been focused particularly on orally
administered controlled drug delivery systems because of the ease of
administration via the oral route as well as the ease and economy of
manufacture of oral dosage forms such as tablets and capsules. A number of
different oral controlled drug delivery systems based on different release
mechanisms have been developed. These oral controlled drug delivery systems
are based on different modes of operation and have been variously named, for
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example, as dissolution controlled systems, diffusion controlled systems, ion-
exchange resins, osmotically controlled systems, erodible matrix systems, pH-
independent formulations, swelling controlled systems, and the like.
An orally administered controlled drug delivery system encounters a wide
range of highly variable conditions, such as pH, agitation intensity, and
composition of the gastrointestinal fluids as it passes down the
gastrointestinal
tract. Ideally, an oral controlled drug delivery system will deliver the drug
at a
constant and reproducible rate in spite of the varying conditions.
Considerable
efforts have therefore been made to design oral controlled drug delivery
systems
that overcome these drawbacks and deliver the drug at a constant rate as it
passes down the gastrointestinal tract.
It is well known to those skilled in the art that a drug may not be absorbed
uniformly over the length of the gastrointestinal tract, and that drug
absorption
from the colon is usually erratic and inefficient. Also, certain drugs are
absorbed
only from the stomach or the upper parts of the small intestine. Furthermore,
an
important factor which may adversely affect the performance of an oral
controlled drug delivery system is that the dosage form may be rapidly
transported from more absorptive upper regions of the intestine to lower
regions
where the drug is less well absorbed. Therefore, in instances where the drug
is
not absorbed uniformly over the gastrointestinal tract, the rate of drug
absorption
may not be constant in spite of the drug delivery system delivering the drug
at
a constant rate into the gastrointestinal fluids. More particularly, in
instances
where a drug has a clear cut "absorption window," i.e., the drug is absorbed
only
from specific regions of the stomach or upper parts of the small intestine, it
may
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not be completely absorbed when administered in the form of a typical oral
controlled drug delivery system. It is apparent that for a drug having such an
"absorption window," an effective oral controlled drug delivery system should
be
designed not only to deliver the drug at a controlled rate, but also to retain
the
drug in the upper parts of the gastrointestinal tract for a long period of
time.
U.S. Patent No. 5,651,985, assigned to Bayer AG, discloses a
composition comprising ' a pharmacologically active compound, a
pharmaceutically acceptable auxiliary, polyvinylpyrrolidone, and a methacrylic
acid polymer having an acidic number between 100 and 1200 mg of KOH/g of
polymer solid substance. Optionally, the composition also comprises a gas
forming additive. The composition absorbs many times its weight of acidic
water
and forms a highly swollen gel of high mechanical and dimensional stability.
The
gel forming agent should be sufficient so that after administration it can
swell up
to a size which prevents passage through the pylorous for a relatively long
time.
r
At least 30% by weight and up to 90% by weight of the composition comprises
the polymers, and thus dosage forms containing a high dose medicament would
be large and inconvenient for oral administration.
Generally, in the field of controlled drug delivery systems, it is known that
in order to make a particular drug available as a once-daily tablet or
capsule, it
is necessary to experiment and invent with the particular drug together with
specific excipients. Thus, what particular excipients and in what particular
relative amounts may work for a particular active ingredient or drug, to make
it
available on a once-daily basis, will likely not work for another drug.
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Nishioka et al. (JP 06024959) is a Japanese patent publication wherein
an attempt is made to cause the release of ciprofloxacin over a longer period
of
time by causing the tablet containing ciprofloxacin to remain suspended in the
stomach. The release period obtained by the Nishioka tablet is so slow that
only
46% of the Nishioka tablet is dissolved after 24 hours (see plot). The
practical
and significant effect of this slow dissolution is that the Nishioka
formulation
would not be effective as a "once daily" ciprofloxacin formulation.
Accordingly, none of the oral controlled drug delivery systems heretofore
described is completely satisfactory for the purpose of providing a once daily
formulation for the controlled release of ciprofloxacin.
OBJECTS OF THE PRESENT INVENTION
It is an object of the present invention to provide a pharmaceutical
composition in the form of tablets or capsules which constitutes a once daily
formulation for the controlled release of ciprofloxacin that:
a. generates and entraps a gas in a hydrated matrix upon contact
with an aqueous medium or gastric fluids, and which retains a
substantially monolithic form in the stomach,
b. provides increased gastric residence and thereby a longer period
of residence of the drug delivery system in the gastrointestinal
tract,
c. delivers the drug at a controlled rate such that the drug is delivered
over a period of time which is the same as or less than the period
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of residence of the delivery system in the absorptive regions of the
gastrointestinal tract, and
d. provides, as compared to other oral controlled drug delivery
systems, increased absorption of a drug that is absorbed largely
from the upper parts of the gastrointestinal tract.
It is also an object of the present invention to provide a once daily
formulation for the controlled release of ciprofloxacin that maintains its
physical
integrity, i.e., remains intact or substantially gains a monolithic form when
contacted with an aqueous medium, even when the quantity of medicaments is
large, and wherein the proportion of polymers is small compared to other
components of the system. It is a further object of the present invention to
provide a once daily formulation for the controlled release of ciprofloxacin
that
incorporates a high dose medicament without the loss of any of its desirable
attributes, as listed above, such that the system is of an acceptable size for
oral
administration.
SUMMARY OF THE INVENTION
The present invention provides a novel pharmaceutical composition in the
form of tablets or capsules which composition constitutes an orally
administered
once daily formulation for the controlled release of ciprofloxacin. The pharma-
ceutical composition comprises ciprofloxacin, a gas generating component, a
swelling agent (e.g., cross-linked polyvinylpyrrolidone or cross-linked sodium
carboxymethylcellulose), at least one of either a viscolyzing agent (e.g., a
carbohydrate gum such as xanthan gum or a cellulose ether such as hydroxy-
propyl methylcellulose), and a gelling agent (e.g., sodium alginate).
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Preferably, the inventive oral controlled drug delivery system which is a
pharmaceutical composition in the form of tablets or capsules comprises a
pharmaceutically effective amount of ciprofloxacin, about 0.1 % to about 8% by
weight of at least one of a viscolyzing agent and a gelling agent, about 5% to
about 15% by weight of the gas generating component, and about 3% to about
15% by weight of the swelling agent.
More preferably, the amount of at least one of the viscolyzing agent and
the gelling agent ranges from about 0.2% to about 5% and the amount of the
swelling agent ranges from about 3% to about 15%.
Even more preferably, the present invention is related to a once-daily
tablet formulation for oral administration in humans for the controlled
release of
ciprofloxacin comprising a pharmaceutically effective amount of ciprofloxacin,
about 0.2% to about 0.5% sodium alginate, about 0.5 to about 2.0% xanthan
gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about
20% cross-linked polyvinylpyrrolidone, said percentages being w/w of the
composition, wherein the weight ratio of sodium alginate to xanthan gum is
between about 1:1 to about 1:10.
The swelling agents used herein (cross-linked polyvinylpyrrolidone or
cross-linked sodium carboxymethylcellulose) belong to a class of compounds
known as super-disintegrants which usually function to promote disintegration
of a tablet by absorbing large amounts of water and thereby swelling. This
expansion, as well as hydrostatic pressure, cause the tablet to burst. In a
tablet
which also comprises a gas generating component (which may actually be a gas
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generating couple), one would expect the tablet to disintegrate instantly upon
contact with aqueous fluid, if not blow apart. Remarkably, it has been found
that
in the presence of an instantly acting viscolyzing agent and/or a gelling
agent,
the generated gas is entrapped and the super-disintegrant acts as a swelling
agent which swells to, preferably, at least twice its original volume. Thus,
the
combination of the gas generating component, the swelling agent which is
actually a super-disintegrant, and the viscolyzing agent or a gelling agent
permit
the formulation to act as a controlled drug delivery system. Additionally,
with the
passage of time, the gelling agent and/or the viscolyzing agent produces a
cross-linked three-dimensional molecular network resulting in a hydrodynam-
ically balanced system that is retained in the stomach and releases the drug
over
a sustained period of time.
Surprisingly, it has been found that a tablet or capsule formed from the
formulation of the present invention is retained for longer periods of time in
the
stomach (spatial control) than previously known hydrophilic matrix tablets,
floating capsules and bioadhesive tablets when these systems are administered
with food. The formulation of the present invention results in release of the
drug
into the more absorptive regions of the gastrointestinal tract, i.e., into the
stomach and the small intestine rather than into the large intestine where
drug
absorption is poor or erratic. Thus, one may expect that if the drug is
released
at a constant and controlled rate, it will also be absorbed at a more or less
constant rate.
- Even more surprisingly, it has been found that even for a drug that is
absorbed only from the upper gastrointestinal tract (i.e., from the stomach
down
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to the jejunum), such as ciprofloxacin, the present formulation provides the
desired absorption at a rate such that effective plasma levels are maintained
for
a prolonged duration and the formulation is especially suitable for once-daily
administration (temporal control). Moreover, the formulation provides
increased
absorption of the drug as compared to other oral controlled drug delivery
systems such as hydrophilic matrix tablets and floating capsules. This is
achieved by adjusting the time period of release for the drug so that it is
about
the same as or less than the retention time of the tablets at the site of
absorption. Thus, the tablet or capsule is not transported past the
"absorption
window" prior to releasing all of the drug, and maximum bioavailability is
attained.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph illustrating mean serum concentration vs. time for the
drug ciprofloxacin free base and ciprofloxacin HCI when incorporated in the
oral
controlled drug delivery system as compared to the presently marketed CiproTM
(Bayer Corp.) immediate release tablets.
Figs. 2 and 3 are graphs illustrating mean plasma concentration vs. time
for ciprofloxacin free base when incorporated in the oral controlled drug
delivery
system of the present invention as compared to CiproT"~ immediate release
tablets under fed and fasting conditions.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the formulation of the present inven-
tion includes ciprofloxacin, a swelling agent, and at least one of either a
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viscolyzing agent and a gelling agent. Together these components form a
hydrated gel matrix. The formulation further comprises a gas generating
component such that a gas (generally COZ but in some cases S02) is generated
in a controlled manner and is entrapped in the hydrated gel matrix. The
swelling
agent which belongs to the class of compounds known as superdisintegrants,
absorbs large amounts of fluid and causes the matrix to swell significantly.
The
gas generated by the gas generating component also causes matrix expansion.
However, in the present invention, swelling of the matrix is controlled by the
viscolyzing agent and/or the gelling agent, which acts both as a swelling and
a
drug release controlling agent.
The characteristics of the hydrated gel matrix can be modified by altering
the ratios and amounts of the swelling agent, the viscolyzing agent and/or the
gelling agent, and the gas generating component without loss of physical
integrity of the hydrated gel system. The composition can thus be designed to
obtain the optimal rate of release of the ciprofloxacin. It has also been
found
that such a composition when administered with food is retained for longer
periods in the stomach, and thereby in the gastrointestinal tract without loss
of
its physical integrity.
The generated gas influences the drug delivery from the tablets or
capsules in ways that are currently not well understood. For example, factors
that may influence drug delivery include:
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a. the presence of entrapped gas within the matrix can affect the
diffusion path length of the drug and thus exerts a release-
controlling effect;
b. the presence of entrapped gas within the matrix can affect the rate
of surface erosion of the hydrated gel matrix and thus exerts both
a hydrodynamic and a release controlling effect;
c. the expanding pressure and the presence of the gas affects the
internal structure of the hydrated gel and thus exerts both a
hydrodynamic and a release controlling effect; and,
d. the presence of entrapped gas and its expanding pressure affects
the influx of the acidic gastric fluid through the pores of the matrix
and thus exerts a release-controlling effect.
It should be realized that gas generated in a small volume within the
matrix can exert a high pressure. If this exceeds the capillary pressure due
to
the surface tension of the aqueous fluid, then it will cause the aqueous fluid
in
a pore to be pushed by the gas allowing the gas to expand until the internal
gas
pressure equals the capillary pressure. This phenomenon thus would affect the
rate of hydration of the matrix and have a role in determining the rate of
release
of the drug. In systems which cross-link, it will also have an influence on
the
developing gel structurization.
The various components of the novel formulation will now be described
in more detail.
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DRUG
According to the present invention, the pharmaceutical composition is in
the form of tablets or capsules that provide a controlled rate of delivery
(i.e.,
temporal control, specifically) of ciprofloxacin. The present invention is
partic-
ularly suitable for controlled rate of delivery of a drug such as
ciprofloxacin that
does not show uniform dissolution and absorption characteristics throughout
the
length of the gastrointestinal tract.
The novel pharmaceutical composition is most suited for controlled
delivery of drugs that are absorbed only from the upper parts of the gastro-
intestinal tract with a specific absorption window (i.e., spatial control),
i.e.,
ciprofloxacin (which is absorbed only from the region extending from the
stomach to the jejunum). The pharmaceutical composition is particularly
suitable
for ciprofloxacin because the absorption of the drug is dependent on its
solubility
characteristics. Ciprofloxacin dissolves at lower pH values and therefore the
"absorption window" is predominantly in the stomach or upper parts of the
small
intestine. In the case of drugs such as ciprofloxacin, the tablet is not
transported
past the "absorption window" prior to releasing all the drug so that maximum
bioavailability can be attained.
Ciprofloxacin itself or its pharmaceutically acceptable salt or ester may be
used in the present invention. The amount of ciprofloxacin to be used in the
composition is that which is typically administered for a given period of
time.
According to the present invention, the pharmaceutical composition can
incorporate a high dose medicament. Accordingly, the amount of ciprofloxacin
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to be used in the present invention typically ranges from about 0.5 mg up to
about 1200 mg.
GAS GENERATING COMPONENT
The gas generating component comprises a substance known to produce
gas upon contact with gastric fluid. Examples of the gas generating component
that may be used in the present invention include carbonates, such as calcium
carbonate, potassium carbonate or sodium carbonate, and bicarbonates such
as sodium hydrogen carbonate.
The gas generating component interacts with an acid source triggered by
contact with water or simply with gastric fluid to generate carbon dioxide
that
gets entrapped within the hydrated gel matrix of the swelling composition. The
gas generating component such as carbonates and bicarbonates may be
present in amounts from about 5% to about 15%, by weight of the composition.
These salts can be used alone or in combination with an acid source as
a couple. The acid source may be one or more of an edible organic acid, a salt
of an edible organic acid, or mixtures thereof. Examples of organic acids that
may be used as the acid source in the present invention include, for example:
citric acid or its salts such as sodium citrate or calcium citrate; malic
acid, tartaric
acid, succinic acid, fumaric acid, malefic acid, or their salts; ascorbic acid
or its
salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine,
taurine,
glutamic acid, and the like. The organic acid salts that may be used as the
acid
source in the present invention include, for example, a mono-alkali salt of an
organic acid having more than one carboxylic acid functional group, a bialkali
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metal salt of an organic acid having more than two carboxylic acid functional
groups, and the like. The acid source may be present in an amount from about
0.5% to 15% by weight, preferably from about 0.5% to about 10% by weight, and
more preferably from about 0.5 % to about 5% by weight, of the total weight of
the composition.
SWELLING AGENT
According to the present invention, the pharmaceutical composition
comprises a swelling agent which is capable of swelling to greater than its
original volume when coming into contact with an aqueous fluid, such a
gastrointestinal fluid. The preferred swelling agent is cross-linked polyvinyl-
pyrrolidone; other swelling agents include cross-linked carboxymethylcellulose
sodium and the like. These compounds belong to the class of compounds
known as super-disintegrants. The swelling agent, which normally swells to
several times its original volume in water, exhibits a controlled swelling in
the
presence of the viscolyzing and/or gelling agent. The swelling agent may be
present in an amount from about 3% to about 15% by weight of the total weight
of the composition. More preferably, the swelling agent may be present in an
amount from about 5% to about 15% by weight of the total weight of the
composition.
VISCOLYZING AGENT AND GELLING AGENT
According to the present invention, the pharmaceutical composition
comprises a viscolyzing agent which, upon contact with gastrointestinal fluid,
instantaneously viscolyzes to trap the gas generated by the gas generating
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component. Preferably, the viscolyzing agent comprises of a carbohydrate gum,
such as xanthan gum. Other examples of carbohydrate gums include tragacanth
gum, gum karaya, guar gum, acacia, and the like. Cellulose ethers of moderate
to high viscosity, like hydroxypropyl methylcellulose, can also be used. In
the
present invention, it has been found that xanthan gum helps in maintaining
tablet
integrity when stirred in an aqueous medium, and in sustaining the release of
the
drug.
According to the present invention, the pharmaceutical composition
comprises either said viscolyzing agent or a gelling agent .or both. The
gelling
agent is preferably sodium alginate. The gelling agent cross-links with time
to
form a stable structure which entraps the generated gas. Thus, with the
passage of time, the gelling agent results in a hydrodynamically balanced
system whereby the matrix is retained in the stomach for an extended period of
time. Simultaneously, the viscolyzing agent and the gelling agent provide a
tortuous diffusion pathway for the drug, thereby ,resulting in controlled drug
release.
Preferably, the viscolyzing agent and/or the gelling agent are present in
an amount from about 0.1 % to about 8% by weight of the total weight of the
composition. More preferably, the viscolyzing agent and/or the gelling agent
are
present in an amount from about 0.2% to about 5% by weight of the total weight
of the composition.
The successful use of even low amounts of a viscolyzing agent and/or
gelling agent such as xanthan gum in providing tablet integrity is indeed
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surprising in view of the fact that the pharmaceutical composition of the
present
invention comprises a gas generating component and a swelling agent which is
most frequently employed as a disintegrant. Those skilled in the art can well
recognize that both components can result in rapid disintegration of tablets.
Tablets containing hydroxypropylcellulose in amounts approximately the same
as the amounts of carbohydrate gum in the present invention disintegrate in 10
to 15 minutes when stirred in an acidic medium. Such disintegration can result
in a dose dumping effect, i.e., rapid delivery of a large quantity of drug
from the
system, and is undesirable particularly because controlled drug delivery
systems
contain several times the amount of drug in a conventional formulation.
Granules formed as a result of the disintegration are also emptied from the
stomach in a shorter time than intact tablets. The present invention avoids
such
disintegration with the use of small quantities of a viscolyzing agent, such
as a
heteropolysaccharide gum, so that tablets or capsules containing a high dose
medicament are of an acceptable size to be taken orally.
In preferred embodiments of the present invention, the viscolyzing agent
is xanthan gum. Xanthan gum, also known as corn sugar gum, is a high
molecular weight (ca. 2 x 106) biosynthetic polysaccharide gum produced by a
pure-culture aerobic fermentation of a carbohydrate with Xanthomonas
campestris. It is extraordinarily enzymatically resistant.
In preferred embodiments of the present invention, the xanthan gum has
a particle size such that at least 50% by weight passes through a sieve with
44
~m mesh aperture (Sieve No. 325, ASTM). In more preferred embodiments, the
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xanthan gum has a particle size such that all of it passes through a 44 ~m
mesh
aperture (Sieve No. 325, ASTM).
Preferably, the viscolyzing agent is present in an amount from about 0.1
to about 8%, by weight of the total weight of the composition. More
preferably,
the viscolyzing agent is present in an amount from about 0.2% to about 5%, by
weight of the total weight of the composition.
OTHER EXCIPIENTS
The pharmaceutical composition may also contain other conventional
pharmaceutical excipients, for example, water soluble diluents such as
lactose,
dextrose, mannitol, sorbitol, and the like; water insoluble diluents such as
starch,
microcrystalline cellulose, powdered cellulose, and the like; or lubricants
such as
talc, stearic acid or its salt, magnesium stearate, and the like.
PROCESS FOR PREPARATION
According to the present invention, the pharmaceutical composition is
prepared by mixing the drug with the gas generating component, the swelling
agent, and one or both of the viscolyzing agent and the gelling agent, plus
other
excipients and lubricants. The blend is directly compressed into tablets or
may
be filled into capsules. Alternatively, the pharmaceutical composition is
prepared
by mixing the foregoing ingredients with only one-half of the lubricants. The
mixture is roll compacted and then sieved to obtain granules. The granules are
then mixed with the remaining lubricants, and filled into capsules or
compressed
into tablets.
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The following table sets forth the various particle size ranges for the cipro-
floxacin base (determined using a Malvern Master Sizer) used in the examples
described below:
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r- z
0
M
O
O M M
OE of
~z M
m
z
V o 0
Q tn N
7C N
1~ ~. Z
O O O L
O N
a
_
U t
_
o ~E ~~.~ c
'cc
H E ~ o
0
pp o 0
N 'Q
G7
N ~ M
W as ~. ~i ~. 3
N -
_ ai
LIJ M ~ et L
J cE M~ O
of ~. ~i ~.
H
ca
N ~ d' d
O
N
~
01 3. N
Q.
7
N
r M M
_
N
~. M
ca
~
L
Z
t ~N
W W s
~
ca
ca
n~
~~ ~
c
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COATING
According to the present invention, when the pharmaceutical composition
is in the form of tablets, it may be coated with a thin layer of a rapidly
dissolving
water soluble pharmaceutical excipient. A coating of a water soluble excipient
results in faster hydration and gas formation than a coating of water soluble
polymer and is the preferred coating.
Examples of water soluble pharmaceutical excipients include film formers
like cellulose ether polymers, or soluble pharmaceutical diluents like
lactose,
sucrose, dextrose, mannitol, xylitol, and the like. In a preferred embodiment
of
the present invention, the water soluble excipient used as a coating is
lactose.
The tablets may be coated to a weight build-up of about 1 % to about 4%,
preferably, about 1 % to about 2%. The coating also helps in masking any
bitter
taste associated with the drug.
The present invention is illustrated by, but is by no means limited to, the
following examples:
EXAMPLE 1
This example illustrates the present invention when the active ingredient
is ciprofloxacin hydrochloride. Ciprofloxacin is an example of a drug which is
absorbed only from the upper part of the intestine. The pharmaceutical
composition is given in Table 1.
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T~RI F 1
Ingredient Weight
(mgltablet)% w/w
Ciprofloxacin hydrochloride monohydrate598.47 55.16
Xanthan Gum (Keltrol TF) 20.00 1.84
Sodium alginate (Keltone LVCR) 15.00 1.38
Cross-linked carboxymethylcellulose110.00 10.14
(Ac-Di-
Sol)
Sodium bicarbonate 230.00 21.20
Microcrystalline cellulose (Avicel 16.53 1.52
PH 101 )
Sodium Chloride 25.0 2.30
Citric Acid 20.0 1.84
Cross-linked polyacrylic acid (Carbopol10.0 0.93
971 P)
Talc 10.00 0.93
Magnesium Stearate 20.00 1.84
Aerosil 10.00 0.93
Total 1085.00 100%
Ciprofloxacin, xanthan gum, sodium alginate, cross-linked carboxymethyl-
cellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride,
citric
acid, and half of the lubricants were mixed together and sieved through a
sieve
(British Standard Sieve (BSS) No. 44). The blend was compacted on a roll-
compactor and the compact sieved through a sieve (BSS No. 22) to obtain
granules. The granules were mixed with the remaining lubricants and Carbopol
and then compressed into tablets. The tablets were spray coated with an
aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc, and
1.587% w/w titanium dioxide to a weight build up of 1 % to 1.5%.
The tablets were tested for dissolution in 0.1 N HCI using USP Apparatus
1 with basket speed at 100 rpm. The dissolution results are given in Table 2.
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TABLE 2
Time (hrs)Cumulative Percent Release
1 21.16
2 33.22
4 58.72
6 74.6
8 85.83
93.58
EXAMPLE 2
5
This example illustrates the present invention when the active ingredient
is ciprofloxacin base. The pharmaceutical composition is given in Table 3.
TABLE 3
Ingredient Weight % wlw of % w/w
(mg/tablet) tablet of drug
Ciprofloxacin base 1000.00 71.43 100.0
Xanthan Gum (Keltrol TF) 15.00 1.07 1.5
Sodium alginate (Keltone LVCR) 10.00 0.71 1.0
Cross-linked polyvinylpyrrolidone150.00 10.71 15.0
(Kollidon CL-M)
Sodium bicarbonate 200.00 14.28 20.0
Magnesium Stearate 15.00 1.07 1.5
Talc 10.00 0.71 10.0
Total 1400.00 100 --
Ciprofloxacin was sifted through British Standard Sieve (BSS) No. 22.
Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half the
quantities of lubricants, namely, magnesium stearate and talc, were sifted
through a sieve (BSS No. 44). All the above mentioned sifted ingredients were
blended uniformly, compacted on a roll-compactor and the compacts sifted
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through a sieve (BSS No. 18) to obtain granules. Remaining magnesium
stearate and talc were sifted through a sieve (BSS No. 60) and blended with
above granules and limited proportion of granule fines (finer than BSS No. 60)
and then compressed into tablets. The tablets were optionally spray coated
with
an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc
and 1.587% w/w titanium dioxide to a weight build up of 1 %, to 1.5%.
The dissolution results are given in Table 4.
TABLE 4
Time (hrs)Cumulative Percent
Release
1 24.9
2 37.8
4 60.5
6 80.6 -
8 85.4
98.8
EXAMPLE 3
This example illustrates the present invention when the active ingredient
is ciprofloxacin hydrochloride. The pharmaceutical composition is given in
Table
5.
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TABLE 5
Ingredient Weight % wlw
(mg/tablet)
Ciprofloxacin hydrochloride monohydrate600.00 61.54
Xanthan Gum (Keltrol TF) 10.00 1.02
Sodium alginate (Keltone LVCR) 25.00 2.57
Cross-linked carboxymethylcellulose 60.00 6.16
(Ac-Di-Sol)
Sodium bicarbonate 250.00 25.64
Microcrystalline cellulose (Avicel 15.00 1.54
PH 101 )
Talc . 5.00 0.52
Magnesium Stearate 10.00 1.02
Total 975.00 100%
The tablets were prepared as described in Example 1 except that Ac-Di-
Sol was incorporated extragranularly. Tablets were tested for dissolution as
described in Example 1. The dissolution results are given in Table 6.
TABLE 6
Time (hrs)Cumulative Percent Release
1 28.16
2 38.32
4 52.37
6 64.03
8 74.23
82.80
EXAMPLE 4
10 Gastric Retention and Bioavailability Studies
This example demonstrates that tablets prepared according to the
present invention are retained for extended periods in the stomach.
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The bioadhesive tablet was prepared as a bilayer tablet. The drug layer
composition is given in Table 7, and the bioadhesive layer composition is
given
in Table 8.
TABLE 7
Ingredient . Weight
(mgltablet)
Ciprofloxacin hydrochloride monohydrate599.99
Hydroxypropylcellulose-L 20.00
Disodium hydrogen phosphate 25.00
Citric Acid 25.00
Talc 7.00
Magnesium Stearate 15.00
Aerosil 200 10.00
Total 701.99
TABLE 8
Ingredient Weight
(mg/tablet)
Hydroxypropyl methylcellulose (Methocel215.00
K4M)
Cross-linked polyacrylic acid (Carbopol75.00
934 P)
Dicalcium phosphate 145.00
Sodium benzoate 8.00
Talc 2.00
Aerosil-200 2.50
Sunset Yellow 2.50
Total 450.00
The tablets were prepared by conventional steps of mixing, roll compac-
tion, sieving, blending with the lubricants and compression into bi-layered
tablets. 70 mg of barium sulphate was incorporated into the bioadhesive layer
to function as x-ray contrast medium. Gastric retention studies of the bio-
adhesive bi-layered tablets were done on healthy male volunteers who were
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given two tablets following a standard breakfast. X-ray images were recorded
periodically. The bioadhesive tablets were retained in the stomach for 2.5 to
3.5
h rs.
Hydrophilic matrix tablets with the composition given in Table 9 were also
prepared.
TABLE 9
Ingredient Weight
(mg/tablet)
Ciprofloxacin hydrochloride monohydrate599.99
Hydroxypropyl methylcellulose (Methocel20.00
K4M)
Hydroxypropylcellulose-L 40.00
Citric Acid 25.00
Disodium hydrogen phosphate 25.00
Talc 10.00
Magnesium Stearate 10.00
Total ~ 729.99
70mg of barium sulfate was also incorporated into the above composition.
The tablets were prepared by conventional steps of mixing, roll compaction,
sieving, blending with the lubricants and compression into tablets.
Floating capsules with the composition given in Table 10 were also
prepared.
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TABLE 10
Ingredient Weight
(mg/capsule)
Ciprofloxacin hydrochloride monohydrate5gg.gg
Hydroxypropyl methylcellulose 30.00
(Methocel K4M)
Hydroxypropylcellulose-L 30.00
Citric Acid 5.00
Disodium hydrogen phosphate 5.00 '
Talc 4.00
Magnesium Stearate 6.00
Total 679.99
50 mg of barium sulphate was incorporated into the above composition.
Gastric retention studies were done on healthy male volunteers who were given
two tablets/capsules after a standard breakfast. X-ray images were recorded
periodically. The hydrophilic matrix tablets were retained for 2 to 2.5 hrs,
and the
floating capsules for 3.5 to 4.5 hrs.
Gastric retention studies were also done on the ciprofloxacin base
formulation of a similar composition as given in Example 2. The volunteers
were
given two tablets after a standard breakfast. Magnetic resonance imaging
confirmed that the tablets according to the present invention were retained in
the
stomach for a period of 5 to 7 hrs.
In another experiment, a randomized, three-treatment, three period,
cross-over pilot bioavailability study was conducted for formulation A (two
ciprofloxacin hydrochloride 500 mg tablets, for once-daily administration,
prepared according to Example 1 ), formulation B (ciprofloxacin free base 1000
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mg tablets, for once-daily administration, prepared according to Example 2),
and
reference formulation R (CiproT"" (Bayer Corp.) 500 mg immediate release
tablets
given twice daily). The tablets were administered 30 minutes after a standard
breakfast. The mean serum concentration-time profile is given in Figure 1.
Figure 1 is based on the following data listed in Table 11, below.
TABLE 11
Mean Concentrations e /mL
m
Time (Hr) A B R
0 0.0000 0.0000 0.0000
0.5 * * 0.30000
1 0.0489 0.3720 1.8379
1.5 * * 2.0779
2 0.1557 0.9940 1.8546
2.5 * * 1.6348
3 1.1806 1.5004 1.3731
4 2.7070 2.1164 1.0868
5 2.8478 1.8898 0.7638
6 1.7944 1.3594 0.5404
8 1.2467 0.9494 0.3579
0.9367 0.7855 0.2323
12 0.6503 0.8714 0.1687
12.5 * * 0.1594
13 * * 0.3916
13.5 * * 0.8982
14 0.4171 0.6831 1.0993
14.5 * * 1.1432
* * 1.3889
16 0.2753 0.4826 1.1187
17 * * 0.9377
18 0.1901 0.3812 0.7633
* * 0.4864
22 * * 0.3766
24 0.1039 0.1778 0.2825
A: 500 mg X 2 OD Fed (FDA Meal)
B: 1000 mg OD, Fed (FDA Meal)
R: 500 mg b.l.d. Fed (FDA Meal)
10 *For OD formulation these sampling points were not included
Both the once-daily formulations (A and B) gave an extent of absorption
comparable to the immediate release tablets (R). Thus, it can be inferred that
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the time period of release of drug into gastric fluid was adjusted such that
it was
about the same as or less than the retention time of the tablets at the site
of
absorption. Furthermore, formulation B gave a serum concentration time profile
that would be desirable for a once-daily formulation in that the peak serum
concentration was comparable to that for the immediate release drug, and the
effective serum concentrations of the drug were maintained for longer periods.
EXAMPLE 5
In some respects, formulation B of the prior Example did not give as good
results as the twice-daily CiproT"" 500 mg tablets. For example, the Area
Under
the Curve above the Minimum Inhibitory Concentration (AUC above MIC) for
formulation B was less than that of conventional CiproT"" tablets.
An improved once-daily 1,000 mg ciprofloxacin free base formulation (the
"OD" formulation) was developed, the composition of which is given in Table
12.
In the OD formulation, the amount of gelling agent (sodium alginate) is about
one-half that of formulation B (0.49% vs. 1.0%).
TABLE 12
Ingredients Weight % w/w of the
(mg/tablet) drug
Ciprofloxacin base 1000.0 69.9
Sodium alginate 5.0 0.34
Xanthan gum 15.0 1.03
Sodium bicarbonate 200.0 13.74
Cross-Linked polyvinyl pyrrolidone
(Kollidon CL-M) 176.8 12.15
Magnesium stearate 33.0 2.26
Talc 10.0 0.68
Total 1440 100
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Tablets were prepared from the components in Table 12 and tested for
dissolution as described earlier. Remarkably, it was observed that the in
vitro
dissolution profile of the OD formulation (Table 13) was much faster releasing
than formulation B. Thus, more than 80% of the drug in the OD tablets was
released within 4 hours as compared to 8 hours for formulation B. Compare
Table 12 with Table 13.
TABLE 13
Time (hrs.) Cumulative percent Release
1 35.49
2 53.61
4 82.33
6 98.72
The mean stomach retention of the OD tablets was studied by magnetic
resonance imaging and was found to be 5.33 hours which correlated well with
the 6 hour dissolution profile of these tablets.
In order to compare the pharmacokinetic and pharmacodynamic para-
meters of this once daily formulation, a randomized, three period, balanced
crossover bioavailability study was conducted in 12 healthy, adult male human
subjects, between 18-45 years of age where one dose of ciprofloxacin 1000 mg
OD tablets was administered 30 minutes after a standard high fat breakfast.
The
immediate release CiproT"" tablets were tested under both fed and fasted
conditions.
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Under fed conditions, two oral doses of 500 mg immediate release
CiproT"" tablets were given. The first oral dose was given within 30 minutes
of
a high fat breakfast and the second dose was given 12 hours later after a high
fat meal (dinner).
Under fasted conditions, two oral doses of 500 mg tablets of the CiproT"'
immediate release tablets were administered. The first oral dose was given
after
an overnight fast, and the second oral dose was given 12 hours later but four
hours after a light meal.
The results of the study are shown in Figs. 2 and 3, where Fig. 2 shows
the plasma concentration over time of the OD tablets (fed) vs. CiproTM (fed),
and
Fig. 3 shows the plasma concentration of the OD tablets (fed) vs. CiproT""
(fasted). Figures 2 and 3 are based on the following data listed in Table 14
and
Table 15, respectively, below.
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TABLE 14
Mean Concentra tions me /mL
Time (Hr) A C
0 0.0000 0.0000
0.5 0.2190
1 1.0964 0.3430
1.5 1.9702
2 2.0397 0.9751
2.5 1.8232
3 1.5617 1.6335
4 1.2265 2.6216
1.0123 2.9162
6 0.7777 2.0336
8 0.5291 1.4256
0.3527 1.3841
12 0.2608 0.9790
12.5 0.3159
13 0.4176
13.5 0.8401
14 1.9238 0.5942
14.5 1.8384
1.6543
16 1.2336 0.4393
17 0.9689
18 0.8258 0.3357
0.5962
22 0.4366
24 0.3653 ~ 0.1843
A: 500 mg b.l.d. Fed (FDA Meal)
C: 1000 mg OD Fed (FDA Meal)
*For OD formulation these sampling points were not included
5
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TABLE 15
Mean Concentrations
me /mL
Time (Hr) B C
0 0.0000 0.0000
0.5 1.3580
1 2.4747 0.3430
1.5 2.7413
2 2.3684 0.9751
2.5 2.0204
3 1.5997 1.6335
4 1.1985 2.6216
0.9429 2.9162
6 0.7298 2.0336
8 0.5172 1.4256
0.3575 1.3841
12 0.2709 0.9790
12.5 0.9855
13 2.5113
13.5 2.7718
14 2.4376 0.5942
14.5 1.9856
1.7173
16 1.1702 0.4393
17 0.8631
18 0.7360 0.3357
0.5095
22 0.4207
24 0.3431 0.1843
B: 500 mg b.l.d. Fasting
C: 1000 mg OD Fed (FDA Meal)
*For OD formulation these sampling points were not included
5
The OD formulation gave a plasma concentration time profile desirable
for once daily dosage form in that the peak plasma concentration (Cmax) was
comparable to that for the immediate release drug indicating a similar rate of
absorption of the drug. The total bioavailability of the drug AUC~o~~ (Area
Under
10 the Curve) was also comparable to that of immediate release tablets
indicating
that all of the drug is released from the formulation during its residence
time in
the stomach. See Table 16.
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TABLE 16
Study Cmax (Ng/ml) AUC ~~~
(Ng.h/ml)
Ciprofloxacin 3.04 24.81
1000 mg. OD (Fed)
CiproT"" 3.17 26.28
500 mg Bid (Fasted)
CiproT"" 2.66 22.39
500 Mg Bid (Fed)
Table 17 gives the AUC above MIC at the three levels of 0.1 pg/ml, 0.25
Ng/ml and 0.5 Ng/ml for ciprofloxacin OD 1000 mg vs. CiproT"" 500 mg bid.
These values for ciprofloxacin OD were better than those for CiproT""
immediate
release tablets administered twice daily under fed conditions, indicating
better
therapeutic efficacy of the OD formulation when both immediate and controlled
dosage forms were administered after food. The therapeutic efficacy of the OD
tablets under fed condition was comparable to the therapeutic efficacy of the
CiproT"" immediate release tablets administered under fasting conditions.
Based on the above results seen in Figures 1, 2, and 3, it is anticipated
that a sustained release solid dosage form of ciprofloxacin would have to
provide
pharmacokinetic performance as measured by mean serum concentration, area
under the serum/plasma concentration-time curve above minimum inhibitory
concentrations and durations above minimum inhibitory serum/plasma
concentrations of at least 70% as compared to immediate release divided dose
treatment. While the above results have been specifically identified for 1,000
mg
tablets, it is anticipated that 100-1,000 mg tablets of ciprofloxacin, orally
administered to humans under fed conditions, would provide a medicament
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serum/plasma concentration - time curve with an area under the curve (time
zero to infinity), ranging from 3.5 to about 30 p,g-hours/ml. Similarly, it is
anticipated that the 100 mg-1,000 mg tablets would provide a mean peak
serum/plasma concentration ranging from about 0.5 to about 4 ~g/ml. Further,
it is anticipated that the 100 mg-1,000 mg tablets would provide a medicament
serum/plasma concentration - time curve with an area under the, curve (above
a minimum inhibitory concentration of 0.1 ~g/ml), ranging from about 3 to
about
26 ~.g-hours/ml. It is also anticipated that the 100 mg-1,000 mg tablets would
provide a medicament serum/plasma concentration - time curve with an area
under the curve (above a minimum inhibitory concentration of 0.25 ~g/ml),
ranging from about 2 to about 22 ~g-hours/ml. Finally, it is anticipated that
they
100 mg-1,000 mg tablets would provide a medicament serum/plasma concentra-
tion - time curve with an area under the curve (above a minimum inhibitory
concentration of 0.5 ~m/ml), ranging from about 1 to about 18 ~,g-hours/ml.
TABLE 17
AUC above MIC
Treatment 0.1 Ng/ml.h 0.25 Ng/ml.h0.5 Ng/ml.h
Ciprofloxacin base 20.7 4.4 17.4 4.3 13.2 4:1
1000 mg, OD (Fed)
CiproT"" 21.53.7 18.03.8 13.44.0
2 x 500 mg bid (Fasted)
CiproT"" 17.683.9 14.23.9 9.73.4
2 x 500 mg bid (Fed)
Thus, a minor change in the percentage of hydrophilic polymer (sodium
alginate) from 0.71 % w/w of the composition to 0.34% w/w of the composition
resulted in a dramatic and unexpected improvement in the pharmacodynamic
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and pharmacokinetic parameters, which are important measures of therapeutic
efficacy.
EXAMPLE 6
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 18
Ingredient Weight
(mg/tablet)% w/w
Ciprofloxacin 1012.10 68.53
Xanthan Gum 45.0 3.05
Sodium Bicarbonate 200 13.54
Crospovidone 176.82 11.97
Magnesium Stearate 33 2.23
Talc 10 0.68
Total 1476.92 100
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 19.
TABLE 19
Time (hrs) Cumulative Percent Release
1 34
2 51.4
4 69.0
6 94.8
8 100.5
EXAMPLE 7
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 20
Ingredient Weight
(mgltablet)% w/w
Ciprofloxacin 1012.10 69.47
Sodium Alginate 25 1.72
Sodium Bicarbonate 200 13.73
Crospovidone 176.82 12.14
Magnesium Stearate 33 2.27
Talc 10 0.69
Total 1456.92 100.02
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 21.
TABLE 21
Time (hrs.) Cumulative Percent Release
1 34.6
2 52
3 68.4
4 79.5
6 92.4
8 95.7
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EXAMPLE 8
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 22
Ingredient Weight
(mg/tablet)% w/w
Ciprofloxacin 1012.10 69
Sodium Alginate 5.0 0.34
Sodium Bicarbonate 200 13.63
Crospovidone 176.82 12.05
Magnesium Stearate 33 2.25
Talc 10 0.68
Methocel K15M 30 2.04
Total 1466.92 99.99
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 23.
TABLE 23
Time (hrs.) Cumulative Percent Release
1 43.6
2 57.6
3 74.4
4 87.0
6 97.5
8 100.2
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EXAMPLE 9
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 24
Ingredient Weight
(mg/tablet)% wlw
Ciprofloxacin 1015.18 75.15
Sodium Alginate 5.0 0.37
Xanthan Gum 15 1.11
Sodium Bicarbonate 200 14.8
Crospovidone 72.75 5.39
Magnesium Stearate 33 2.44
Talc 10 0.74
Total 1350.93 100
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 25.
TABLE 25
Time (hrs.) Cumulative Percent Release
1 39.2
2 54.2
3 72.39
4 84.9
6 100.29
EXAMPLE 10
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 26
Ingredient Weight
(mgltablet)% wlw
Ciprofloxacin 1015.18 67.35
Sodium Alginate 5.0 0.33
Xanthan Gum 15 1.0
Crospovidone 176.82 11.73
Magnesium Stearate 33 2.19
Talc 10 0.66
Sodium Carbonate 252.32 16.74
Total 1507.32 100
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 27.
TABLE 27
Time (hrs.) Cumulative Percent Release
1 31.34
2 59.86
3 75.3
4 81.69
6 90.39
8 91.5
EXAMPLE 11
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 28
Ingredient Weight
(mg/tablet)% w/w
Ciprofloxacin 1015.18 69.66
Sodium Alginate 7.28 0.5
Xanthan Gum 15 1.03
Sodium Bicarbonate 200 13.72
Crospovidone 176.82 12.13
Magnesium Stearate 33 2.26
Talc 10 0.69
Total 1457.28 99.99
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 29.
TABLE 29
Time (hrs.) Cumulative Percent Release
1 40.06
2 59.26
3 86.19
4 96.39
6 100.2
EXAMPLE 12
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 30
Ingredient Weight ~ w/w
m /tablet
Ciprofloxacin 1015.18 70.43
Sodium Alginate 5.0 0.35
Xanthan Gum 1.46 0.1
Sodium Bicarbonate 200 13.87
Crospovidone 176.82 12.27
Magnesium Stearate 33 2.29
Talc 10 0.69
Total 1441.46 100
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 31.
TABLE 31
Time (hrs.) Cumulative Percent Release
1 33.34
2 58.94
3 76.11
4 83.91
6 95.7
EXAMPLE 13
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 32
Ingredient Weight
(mgltablet)% w/w
Ciprofloxacin 1015.18 69.44
Sodium Alginate 5.0 0.34
Xanthan Gum 21.83 1.5
Sodium Bicarbonate 200 13.68
Crospovidone 176.82 12.1
Magnesium Stearate 33 2.26
Talc 10 0.68
Total 1461.83 100
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 33.
TABLE 33
Time (hrs.) Cumulative Percent Release
1 44.2
2 61.86
3 87.9
4 98.7
6 106.95
EXAMPLE 14
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
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TABLE 34
Ingredient Weight
(mgltablet)% w/w
Ciprofloxacin 1016.19 72.51
Sodium Alginate 5.0 0.36
Xanthan Gum 15 1.07
Sodium Bicarbonate 145.5 10.38
Crospovidone 176.82 12.61
Magnesium Stearate 33 2.35
Talc 10 0.71
Total 1401.51 99.99
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 35.
TABLE 35
Time (hrs.) Cumulative Percent Release
1 44.46
2 56.8
3 65.91
4 74.19
6 89.31
8 98.49
Table 36 below summarizes Examples 5-14 above with respect to their
ingredients and includes the dissolution profile of each formulation.
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Do
d:Op~ r-M ~t
~ O M CO M ~ ~ O ~ ~ O
- M
N c O N O N ~ ~ O f~M O
I' ~ ~
O
M ~ tf~M ~ Cfl ~ N OpO 1~
O ~ p N M ~. ~ ~ I~00O
CD ~ ~ ~ ~ O a0O ~
M InI~ I' ~ d'~
N ~t~ M N 00 ~ M O r-O f'
O O O N M N M 00CflM In
f~ ~- ~ ~ M tnI'a0O)
COM M N ~ CflCflO O
N
CflO tn~ !~ O O N ~ M
O ~ O N M O O O CflCflO
Cfl ~ ~ N ~ ~tu70OO
N
ca
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EXAMPLE 15
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 37
Ingredient ' Weight
(mg/tablet)% w/w
Ciprofloxacin 1015.18 67.98
Sodium Alginate 5.0 0.003
Xanthan Gum 15.0 0.01
Crospovidone 176.82 11.84
Mag. Stearate 33.0 2.21
Talc 10.0 0.67
Calcium Carbonate 238.27 15.96
Total 1493.27 98.673
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 38.
TABLE 38
Time (hrs.) Cumulative Percent Release
1 44.4
2 62.4
3 73.11
4 78.0
6 84.09
8 87.0
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EXAMPLE 16
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 39
Ingredient Weight
(mg/tablet)% w/w
Ciprofloxacin 1015.18 69.32
Sodium Alginate 14.55 0.009
Xanthan Gum 15.0 0.01
Sod. Bicarbonate 200.0 13.66
Crospovidone 176.82 12.07
Magnesium Stearate 33.0 2.25
Talc 10.0 0.68
TOTAL 1464.55 97.32
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 40.
TABLE 40
Time (hrs.) Cumulative Percent Release
1 37.9
2 45.06
3 65.91
4 71.1
6 78.81
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EXAMPLE 17
This example illustrates the present invention when the active ingredient
is ciprofloxacin base:
TABLE 41
Ingredient Weight
(mg/tablet) % w/w
Ciprofloxacin 1015.18 67.11
Sodium Alginate 5.0 0.003
Xanthan Gum 72.75 4.81
Sodium Bicarbonate 200.0 13.22
Crospovidone 176.82 11.69
Magnesium Stearate 33.0 2.18
Talc 10.0 0.006
TOTAL 1512.75 99.019
The tablets were prepared as described in Example 2. The tablets were
tested for dissolution as described in Example 1. The dissolution results are
given in Table 42.
TABLE 42
Time (hrs.) Cumulative Percent Release
1 32.26
2 47.2
3 63.3
4 74.01
6 94.2
Other than the above experiments, the following formulations were made
into tablets as described above. Dissolution and floating characteristics
testing
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was also done for the following formulations. One or the other, i.e., the
dissolution profile or floating characteristics, were found to be
unsatisfactory in
comparison to the above examples, for tablets according to the following
formulations:
TABLE 43
Ingredient Example 18 Example 19
Ciprofloxacin 1015.18 1015.18
Sodium Alginate 0 5.0
Xanthan Gum 15.0 0
Sodium Bicarbonate 200.0 200.0
Crospovidone 176.82 176.82
Magnesium Stearate 33.0 33.0
Talc 10.0 10.0
TOTAL 1450.00 1440.0
DISSOLUTION
Time (hrs.) Cumulative Percent
Release
1 68.8 52.5
2 93.2 68.94
3 104.1 90.39
4 - 100.8
6 - 104.79
g _ _
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TABLE 44
Ingredients Example Example Example Example Example
20 21 22 23 24
Ciprofloxacin 1016.19 1016.19 1012.1 1016.19 1012.1
Sodium Alginate5.0 5.0 5.0 5.0 5.0
Sodium 200.0 200.0 200.0 200.0 200.0
Bicarbonate
Crospovidone 176.82 176.82 176.82 176.82 176.82
Magnesium 33.0 33.0 33.0 33.0 33.0
Stearate
Talc 10.0 10.0 10.0 10.0 10.0
Methocel K15M 15.0 - - - -
Gellan Gum - 15.0 30.0 - -
(Gelrite)
Carrageenan - - - 15.0 45.0
TOTAL 1456.01 1456.01 1466.92 1456.01 1481.92
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 48.66 50.74 49.6 72.46 88.8
2 63.54 62.86 58.2 81.54 93.2
3 80.31 74.19 67.2 87.09 97.8
4 89.49 80.79 74.4 92.1 99.0
6 100.11 91.71 88.2 96.45 100.2
8 101.7 99.99 95.1 97.11 101.1
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TABLE 45
Ingredients Example Example Example Example Example Example
25 26 27 28 29 30
Ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1
Xanthan Gum 15.0 15.0 15.0 15.0 15.0 15.0
Sodium 200.0 200.0 200.0 200.0 200.0 200.0
Bicarbonate
Crospovidone 176.82 176.82 176.82 176.82 176.82 176.82
Magnesium 33.0 33.0 33.0 33.0 33.0 33.0
Stearate
Talc 10.0 10.0 10.0 10.0 10.0 10.0
Carbopol 971 5.0 10.0 - - - -
P
Methyl Cellulose- - 5.0 20.0 -
Eudragit EPO - - - - 5.0 30.0
TOTAL 1455.0 1446.92 1455.0 1456.92 1455.0 1466.92
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 45.2 56.8 74.26 68.2 94.26 101.4
2 59.34 67.0 87.06 83.0 94.94 -
3 71.79 76.8 95.61 92.4 97.89 -
4 80.91 84.9 97.71 95.4 98.79 -
6 92.01 95.1 99.21 99.0 - -
8 93.0 97.5 100.59 100.8 - -
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TABLE 46
Ingredient Example Example Example Example Example Example
31 32 33 34 35 36
Ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1
Sodium Alginate5.0 5.0 5.0 5.0 5.0 5.0
Xanthan Gum 15.0 15.0 15.0 15.0 15.0 15.0
Sodium 200.0 200.0 200.0 200.0 200.0 200.0
Bicarbonate
Magnesium 33.0 33.0 33.0 33.0 33.0 33.0
Stearate
Talc 10.0 10.0 10.0 10.0 10.0 10.0
Ac-di-sol 176.82 100.0 - - - -
Sodium Starch - - 176.82 125.0 - -
glycolate
MCC (Avicel - - - - 176.82 125.0
pH
101 )
TOTAL 1455.0 1375.1 1455.0 1400.1 1455.0 1400.1
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 42.86 47.6 57.46 53.8 67.4 62.6
2 51.4 55.8 65.6 62.4 79.26 74.4
3 60.21 62.4 72.81 70.8 86.7 84.9
4 66.81 67.5 77.19 75.6 91.5 88.2
6 81.09 76.2 84.69 82.4 95.49 94.8
8 87.6 83.1 92.31 88.2 98.79 97.2
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TABLE 47
Ingredient Example Example Example
37 38 39
Ciprofloxacin 1015.18 1015.18 1015.18
Sodium Alginate 5.0 5.0 5.0
Xanthan Gum 15.0 15.0 15.0
Sodium Bicarbonate 200.0 200.0 200.0
Crospovidone 0 261.9 363.75
Magnesium Stearate 33.0 33.0 33.0
Talc 10.0 10:0 10.0
TOTAL 1278.18 1540.08 1641.93
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 66.66 49.2 57.26
2 79.8 75.66 77.74
3 91.2 96.99 106.2
4 94.71 100.71 -
6 97.59 - -
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TABLE 48
Ingredients Example Example Example
40 41 42
Ciprofloxacin 1016.19 1016.19 1016.19
Sodium Alginate 5.0 5.0 5.0
Sodium Bicarbonate 200.0 200.0 200.0
Crospovidone 176.82 176.82 176.82
Magnesium Stearate 33.0 33.0 33.0
Talc 10.0 10.0 10.0
Methocel K15M 15.0 - -
Gellan gum (Gelrite)- 15.0 -
Carrageenan - - 15.0
TOTAL 1456.01 1456.01 1456.01
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 48.66 50.74 72.46
2 63.54 62.86 81.54
3 80.31 74.19 87.09
4 89.49 80.79 92.1
6 100.11 91.71 96.45
8 101.7 99.99 97.11
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TABLE 49
Ingredients Example Example Example
43 44 45
Ciprofloxacin 1015.18 1015.18 1015.18
Xanthan Gum 15.0 15.0 15.0
Sodium Bicarbonate ~ 200.0 200.0 200.0
Crospovidone 176.82 176.82 176.82
Magnesium Stearate 33.0 33.0 33.0
Talc 10.0 10.0 10.0
Carbopol 971 P 5.0 - -
Methyl Cellulose - 5.0 -
Eudragit EPO - - 5.0
TOTAL 1455.01 1455.01 1455.01
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 45.2 74.26 94.26
2 59.34 87.06 94.94
3 71.79 95.61 97.89
4 80.91 97.71 98.79
6 92.01 99.21 -
8 93.0 100.59 -
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TABLE 50
Ingredients Example Example Example
46 47 48
Ciprofloxacin 1015.18 1015.18 1015.18
Sodium Alginate 5.0 5.0 5.0
Xanthan Gum 15.0 15.0 15.0
Sodium Bicarbonate 200.0 200.0 200.0
Magnesium Stearate 33.0 33.0 33.0
Talc 10.0 10.0 10.0
Ac-di-sol 176.82 - -
Sodium Starch glycolate- 176.82 -
MCC (Avicel pH 101 - 176.82 -
)
TOTAL 1455.0 1455.0 1455.0
DISSOLUTION
Time (hrs.) Cumulative
Percent
Release
1 42.86 57.46 67.4
2 51.4 65.6 79.26
3 60.21 72.81 86.7
4 66.81 77.19 91.5
6 81.09 84.69 95.49
8 87.6 92.31 98.79
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TABLE 51
Ingredients Example 49
Ciprofloxacin 1015.18
Sodium Alginate 5.0
Xanthan Gum 15.0
Crospovidone 176.82
Magnesium Stearate 33.0
Talc 10.0
Potassium Bicarbonate 238.34
TOTAL 1493.34
DISSOLUTION
Time (hrs.) Cumulative Percent
Release
1 69.06
2 77.74
3 85.2
4 87.0
6 87.0
8 98.1
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TABLE 52
Ingredient Example 50 Example 51
Ciprofloxacin 1015.18 1015.18
Sod. Alginate 0 1.46
Xanthan Gum 15.0 15.0
Sodium Bicarbonate 200.0 200.0
Crospovidone 176.82 176.82
Magnesium Stearate 33.0 33.0
Talc 10.0 10.0
TOTAL 1450.00 1451.46
DISSOLUTION
Time (hrs.) Cumulative
Percent Release
1 68.8 51.46
2 93.2 65.34
3 104.1 84.39
4 - 92.79
6 - 97.41
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TABLE 53
Ingredient Example
52
Ciprofloxacin 1015.18
Sodium Alginate 5.0
Sodium Bicarbonate 200.0
Crospovidone 176.82
Magnesium Stearate 33.0
Talc 10.0
TOTAL 1440.0
DISSOLUTION
Time (hrs.) Cumulative Release
Percent
1 52.5
2 68.94
3 90.39
4 100.8
6 104.79
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TABLE 54
Ingredient Example Example 54 Example Example 56
53 55
Ciprofloxacin 1015.18 1016.19 1015.18 1015.18
Sodium Alginate 5.0 5.0 5.0 5.0
Xanthan Gum 15.0 15.0 15.0 15.0
Sodium Bicarbonate0 72.75 291.0 436.5
Crospovidone 176.82 176.82 176.82 176.82
Magnesium Stearate33.0 ~ 33.0 33.0 33.0
Talc 10.0 10.0 10.0 10.0
TOTAL 1255.0 1328.76 1546.0 1691.5
DISSOLUTION
Time (hrs) % released
1 73.06 50.86 49.0 42.46
2 73.7 63.6 72.14 74.66
3 - 73.89 96.3 96.6
4 94.8 83.7 103.8 104.1
6 87.9 93.51 - -
8 - 98.19 - -
While the invention has been described by reference to specific
examples, this was for purposes of illustration only. Numerous alternative
embodiments will be apparent to those skilled in the art and are considered to
be within the scope of the invention.
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