Note: Descriptions are shown in the official language in which they were submitted.
CA 02612994 2007-12-05
The present invention provides a composition comprising a cefditoren, or a
salt, derivative,
prodrug, or other form thereof, for example, cefditoren pivoxil, useful in the
treatment and
prevention of infections and related conditions. The invention provides a
composition which
comprises nanoparticulate particles comprising the cefditoren, or a salt,
derivative, prodrug, or
other form thereof and at least one surface stabilizer. The nanoparticulate
par6cies have an
effective average particle size of less than about 2000 nm. The invention
provides also a
composition that delivers a cefditoren, or a salt, derivative, prodrug, or
other form thereof, or
nanoparticies comprising the same, in a pulsatile or continuous manner.
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Nanoparticulate and
Controlled Release Compositions Comprising Cefditoren
FIELD OF INVENTION
The present invention relates to compositions and methods for the prevention
and
treatment of infections and related conditions. In particular, the present
invention relates
to a composition comprising a cefditoren, or a salt, derivative, prodrug, or
other form
thereof, for example cefditoren pivoxil, and methods for making and using such
a
composition. In an embodiment of the invention, the composition is in
nanoparticulate
form and comprises also at least one surface stabilizer. The present invention
relates also
to novel dosage forms for the controlled delivery of cefditoren, or a salt,
derivative,
prodrug, or other form thereof, for example cefditoren pivoxil.
BACKGROUND OF THE INVENTION
Cefditoren pivoxil, chemically known as (-)-(6R,7R)-2,2-
dimethylpropionyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamido]-
3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-
ene-2-
carboxylate, is an orally deliverable, third-generation cephalosporin. The
empirical
formula is C25H28N607S3 and the molecular weight is 620.73.
The chemical structure of cefditoren pivoxil is shown below:
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....... .............. .._.. ._~.__.~
C~~~c3cc~~~~-f~
Go
1.1010CH3
N
I
N *,. . .
CO-NH~~i 1ICH3
H~~ ~ H H
cefditorsn pivodl
Cefditoren pivoxil is a semi-synthetic cephalosporin antibiotic for oral
administration. It is a prodrug which is hydrolyzed by gastro-intestinal
esterases in the
stomach and small intestine during absorption to form active cefditoren.
Cefditoren is
distributed in the circulating blood. The amorphous form of cefditoren pivoxil
developed
for clinical use is a light yellow powder. It is freely soluble in dilute
hydrochloric acid
and soluble at levels equal to 6.06 mg/mL in ethanol and <0.1 mg/mL in water.
Cefditoren pivoxil may be administered as part of a dosage form marketed by
TAP Pharmaceuticals Inc. under the registered trademark name SPECTRACEF .
SPECTRACEF tablets contain 200 mg of cefditoren as cefditoren pivoxil and
inactive
ingredients such as croscarmellose sodium, sodium caseinate (a milk protein),
D-
mannitol, magnesium stearate, sodium tripolyphosphate, hydroxypropyl
methylcellulose,
and hydroxypropyl cellulose. The tablet coating contains hydroxypropyl
methylcellulose,
titanium dioxide, polyethylene glycol, and carnauba wax. Tablets are printed
with ink
containing FD&C Blue No. 1, D&C Red No. 27, shellac, and propylene glycol.
Cefditoren pivoxil is indicated for the treatment of mild to moderate
infections in
humans caused by susceptible strains of certain microorganisms in conditions
such as
acute bacteiial exacerbation of chronic bronchitis caused by Haemophilus
influenzae
(including (beta)-lactamase-producing strains), Haemophilus parainfluenzae
(including
(beta)-lactamase-producing strains), Streptococcus pneumoniae (penicillin-
susceptible
strains only), or Moraxella catarrhalis (including (beta)-lactamase-producing
strains);
community-acquired pneumonia caused by Haemophilus influenzae (including
(beta)-
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lactamase-producing strains), Haemophilus parainfluenzae (including (beta)-
lactamase-
producing strains), Streptococcus pneumoniae (penicillin-susceptible strains
only), or
Moraxella catarrhalis (including (beta)-lactamase-producing strains);
pharyngitis/tonsillitis caused by Streptococcus pyogenes; and uncomplicated
skin and
skin-structure infections caused by Staphylococcus aureus (including (beta)-
lactamase-
producing strains) or Streptococcus pyogenes .
Cephalosporin compounds and their use have been described, for example, in
U.S.
Patent No. 4,839,350 for "Cephalosporin Compounds and the Production Thereof,"
U.S.
Patent No. 4,918,068 for "Cephem Compounds," and U.S. Patent No. 5,958,915 for
"Antibacterial Composition for Oral Administration" which patents are hereby
incorporated by reference. .
Cefditoren exhibits poor bioavailability when taken orally and, as such,
cefditoren
pivoxil is generally prescribed to be taken with food to enhance absorption.
Additionally,
conventional cefditoren pivoxil tablets must generally be administered three
times a day
for the treatment of bacterial infections. The present invention addresses
such problems
by providing nanoparticulate compositions containing cefditoren, or a salt,
derivative,
prodrug, or other form thereof, for example cefditoren pivoxil, which overcome
the poor
bioavailability of cefditoren and eliminate the requirement to take the
product with food.
The present invention also provides a controlled release composition
comprising
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
picoxil, which eliminates the need to take cefditoren more than once a day,
thereby
increasing patient convenience and compliance.
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SUMMARY OF THE INVENTION
The present invention relates to a nanoparticulate composition comprising: (A)
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
pivoxil; and (B) at least one surface stabilizer. The composition may
optionally comprise
also a pharmaceutically acceptable carrier and any desired excipients. The
surface
stabilizer can be adsorbed on or associated with the surface of the
nanoparticulate
particles. The nanoparticulate particles have an effective average particle
size of less than
about 2,000 nm. A preferred dosage form of the invention is a solid dosage
form,
although any pharmaceutically acceptable dosage form can be utilized.
A preferred dosage form of the invention is a solid dosage form, although any
pharmaceutically-acceptable dosage form may be utilized.
One embodiment of the invention encompasses a nanoparticulate composition
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
for example
cefditoren pivoxil, wherein the pharmacokinetic profile of the cefditoren, or
a salt,
derivative, prodrug, or other form thereof, following administration of the
composition to
a subject, is not affected by the fed or fasted state of the subject.
In yet another embodiment, the invention encompasses a nanoparticulate
composition comprising cefditoren, or a salt, derivative, prodrug, or other
form thereof,
for example cefditoren pivoxil; wherein administration of the composition to a
subject in
a fasted state is bioequivalent to administration of the composition to a
subject in a fed
state.
Another embodiment of the invention is directed to a nanoparticulate
composition
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
for example
cefditoren pivoxil, and comprising also one or more additional compounds
useful in the
prevention and treatment of infections and other related conditions.
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This invention further provides a method of making the inventive
nanoparticulate
composition. Such a method comprises contacting nanoparticulate particles
comprising
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
pivoxil, with at least one surface stabilizer for a period of time and under
conditions
sufficient to provide a stabilized nanoparticulate composition comprising
cefditoren, or a
salt, derivative, prodrug, or other form thereof, for example cefditoren
pivoxil.
The present invention is also directed to methods of treatment including but
not
limited to, the prevention and treatment of infections and other related
disease states using
the novel nanoparticulate compositions disclosed herein. Such methods comprise
administering to a subject a therapeutically effective amount of such a
composition.
Other methods of treatment using the nanoparticulate compositions of the
invention are
known to those of skill in the art.
The present invention finther relates to a controlled release composition
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
for example
cefditoren pivoxil, which in operation produces a plasma profile substantially
similar to
the plasma profile produced by the administration of two or more IR dosage
form of
cefditoren, or a salt, derivative, prodrug, or other form thereof, given
sequentially.
Cefditoren, or a salt, derivative, prodrug, or other form thereof, may be
contained in
nanoparticulate particles which comprise also at least one surface stabilizer.
Conventional frequent dosage regimes in which an immediate release (IR) dosage
form is administered at periodic intervals typically give rise to a pulsatile
plasma profile.
In this case, a peak in the concentration of cefditoren, or a salt,
derivative, prodrug, or
other form thereof, is observed after administration of each IR dose with
troughs (regions
of low concentration of ceditoren, or the salt, derivative, prodrug, or other
form thereof)
developing between consecutive administration time points. Such dosage regimes
(and
their resultant pulsatile plasma profiles) have particular pharmacological and
therapeutic
effects associated with them. For example, the wash out period provided by the
fall off of
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the plasma concentration of the active between peaks has been thought to be a
contributing factor in reducing or preventing patient tolerance to cefditoren,
or the salt,
derivative, prodrug, or other form thereof.
The present invention fiuther relates to a controlled release composition
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
for example
cefditoren pivoxil, which in operation produces a plasma profile that
eliminates the
"peaks" and "troughs" produced by the administration of two or more IR dosage
forms of
the drug given sequentially if such a profile is beneficial. This type of
profile can be
obtained using a controlled release mechanism that allows for continuous
delivery. The
cefditoren, or a salt, derivative, prodrug, or other form thereof may be
contained in
nanoparticulate particles which comprise also at least one surface stabilizer.
Multiparticulate modified controlled release compositions similar to those
disclosed herein are disclosed and claimed in the United States Patent Nos.
6,228,398 and
6,730,325 to Devane et al; both of which are incorporated by reference herein.
All of the
relevant prior art in this field may also be found therein.
It is a further object of the invention to provide a controlled release
composition
which in operation delivers cefditoren, or a salt, derivative, prodrug, or
other form
thereof, for example cefditoren pivoxil, or nanoparticles containing the same,
in a
pulsatile manner or a continuous manner.
Another object of the invention is to provide a controlled release composition
which substantially mimics the pharmacological and therapeutic effects
produced by the
administration of two or more IR dosage forms given sequentially.
Another object of the invention is to provide a controlled release composition
which substantially reduces or eliminates the development of patient tolerance
to
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
pivoxil.
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Another object of the invention is to provide a controlled release composition
which releases an active ingredient therein in a bimodal manner. This may be
accomplished, for example, in a composition in which a fnst portion of the
active
ingredient of the composition is released immediately upon administration and
a second
portion of the active ingredient is released rapidly after an initial delay
period.
Another object of the invention is to fonnulate the dosage forms of
cefditoren, or
a salt, derivative, prodrug, or other form thereof, for example cefditoren
pivoxil, as an
erodable formulation, a diffusion controlled formulation, or an osmotic
controlled
formulation.
Another object of the invention is to provide a controlled release composition
capable of releasing cefditoren, or a salt, derivative, prodrug, or other form
thereof, for
example cefditoren pivoxil, or nanoparticles containing the same, in a bimodal
or multi-
modal manner in which a first portion of the cefditoren, or a salt,
derivative, prodrug, or
other form thereof, or nanoparticles containing the same, is released either
immediately or
after a delay time to provide a pulse of release and one or more additional
portions of the
cefditoren, or a salt, derivative, prodrug, or other form thereof, or
nanoparticles
containing the same, is released, after a respective lag time, to provide
additional pulses
of release during a period of up to twenty-four hours.
Another object of the invention is to provide solid oral dosage forms
comprising a
controlled release composition comprising cefditoren, or a salt, derivative,
prodrug, or
other form thereof, for example cefditoren pivoxil. The cefditoren, or a salt,
derivative,
prodrug, or other form thereof, may be contained in nanoparticulate particles
which
comprise also at least one surface stabilizer.
Other objects of the invention include provision of a once daily dosage form
of
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
pivoxil, which, in operation, produces a plasma profile substantially similar
to the plasma
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profile produced by the administration of two inunediate release dosage forms
thereof
given sequentially and a method for prevention and treatment of infections or
related
conditions based on the administration of such a dosage form. Cefditoren, or a
salt,
derivative, prodrug, or other form thereof, for example cefditoren pivoxil,
may be
contained in nanoparticulate particles which comprise also at least one
surface stabilizer.
The above objects are realized by a controlled release composition having a
first
component comprising a first population of cefditoren, or a salt, derivative,
prodrug, or
other fonn thereof, for example cefditoren pivoxil, or nanoparticules
containing the same,
and a second component or formulation comprising a second population of a
cefditoren,
or a salt, derivative, prodrug, or other form thereof, for example cefditoren
pivoxil, or
nanoparticulates containing the same. The ingredient-containing particles of
the second
component further comprises a modified release constituent comprising a
release coating
or release matrix material, or both. Following oral delivery, the composition
in operation
delivers the cefditoren, or a salt, derivative, prodrug, or other form
thereof, or
nanoparticulates containing the same, in a pulsatile or continuous manner.
The present invention utilizes controlled release delivery of cefditoren, or a
salt,
derivative, prodrug, or other form thereof, for example cefditoren pivoxil, or
nanoparticulates containing the same, from a solid oral dosage formulation, to
allow
dosage less frequently than before, and preferably once-a-day administration,
increasing
patient convenience and compliance. The mechanism of controlled release would
preferably utilize, but not be limited to, erodable formulations, diffusion
controlled
formulations and osmotic controlled formulations. A portion of the total dose
may be
released immediately to allow for rapid onset of effect. The invention is
useful in
improving patient compliance and, therefore, therapeutic outcome for all
treatments
requiring a cefditoren, or a salt, derivative, prodrug, or other form thereof,
including but
not limited to, the prevention and treatment of infective conditions. This
approach can
replace conventional cefditoren tablets and solutions, which are administered
multiple
times daily as adjunctive therapy in the prevention and treatment of infective
symptoms.
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The present invention also relates to a controlled modified release
composition for
the controlled release of cefditoren, or a salt, derivative, prodrug, or other
form thereof,
for example cefditoren pivoxil, or nanoparticles containing the same. In
particular, the
present invention relates to a controlled release composition that in
operation delivers
cefditoren, or a salt, derivative, prodrug, or other form thereof, for example
cefditoren
pivoxil, or nanoparticles containing the same, in a pulsatile or continuous
manner,
preferably during a period of up to twenty-four hours.
The present invention further relates to solid oral dosage forms containing a
controlled release composition.
Preferred controlled release formulations are erodable fonnulations, diffusion
controlled formulations and osmotic controlled formulations. According to the
invention,
a portion of the total dose may be released immediately to allow for rapid
onset of effect,
with the remaining portion of the total dose released over an extended time
period. The
invention is useful in improving compliance and, therefore, therapeutic
outcome for all
treatments requiring a cefditoren, or a salt, derivative, prodrug, or other
fonn thereof
including but not limited to, prevention and treatment of infective
conditions.
The present invention relates also to multiparticulate compositions of the
type
described above in which the nanoparticulate particles themselves form the
particles of
the multiparticulate.
Both the foregoing general description and the following detailed description
are
exemplary and explanatory and are intended to provide further explanation of
the
invention as claimed. Other objects, advantages, and novel features will be
readily
apparent to those skilled in the art from the following detailed description
of the
invention.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention is described herein using several defmitions, as set
forth
below and throughout the application.
As used herein, "about" will be understood by persons of ordinary skill in the
art
and will vary to some extent on the context in which it is used. If there are
uses of the
term which are not clear to persons of ordinary skill in the art given the
context in which
it is used, "about" will mean up to plus or minus 10% of the particular term.
As used herein, the phrase "therapeutically effective amount" shall mean the
dosage that provides the specific pharmacological response for which the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, is administered in a
significant number of
subjects in need of the relevant treatment. It is emphasized that a
therapeutically effective
amount of cefditoren, or a salt, derivative, prodrug, or other form thereof,
that is
administered to a particular subject in a particular instance will not always
be effective in
treating the conditions described herein, even though such dosage is deemed to
be a
therapeutically effective amount by those of skill in the art.
The term "prodrug" as used herein when referring to a prodrug of cefditoren
refers
to a compound which, following administration to a subject, is metabolized to
form active
cefitoren.
The term "particulate" as used herein refers to a state of matter which is
characterized by the presence of discrete particles, pellets, beads or
granules irrespective
of their size, shape or morphology.
The term "multiparticulate" as used herein means a plurality of discrete, or
aggregated, particles, pellets, beads, granules or mixture thereof
irrespective of their size,
shape or morphology. A composition comprising a multiparticulate is described
herein as
a "multiparticulate composition".
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The term "nanoparticulate" refers to a multiparticulate in which the
"effective
average particle size" (see below) of the particles therein is less than about
2000 nm (2
microns) in diameter. A composition comprising a nanoparticulate is described
herein as
a "nanoparticulate composition".
The phrase "effective average particle size" as used herein to describe a
multiparticulate (e.g., a nanoparticulate) means that at least 50% of the
particles therein
are of a specified size. Accordingly, "effective average particle size of less
than about
2000 nm in diameter" means that at least 50% of the particles therein are less
than about
2000 nm in diameter.
"D50" refers to the particle size below which 50% of the particles in a
multiparticulate fall. Similarly, "D90" is the particle size below which 90%
of the
particles in a multiparticulate fall.
As used herein with reference to stable particles, "stable" connotes, but is
not
limited to one or more of the following parameters: (1) the particles do not
appreciably
flocculate or agglomerate due to interparticle attractive forces or otherwise
significantly
increase in particle size over time; (2) the physical structure of the
particles is not altered
over time, such as by conversion from an amorphous phase to a crystalline
phase; (3) the
particles are chemically stable; and/or (4) where the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, has not been subject to a heating step at or
above the
melting point of the particles in the preparation of the nanoparticles of the
present
invention.
The phrase "poorly water soluble drug" refers to a drug that has a solubility
in
water of less than about 30 mg/ml, less than about 20 mg/ml, less than about
10 mg/ml, or
less than about I mg/ml.
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The term "modified release" as used herein includes a release which is not
inunediate and includes controlled release, extended release, sustained
release and
delayed release.
The term "time delay" as used herein refers to the period of time between the
administration of a dosage form comprising the composition of the invention
and the
release of the active ingredient from a particular component thereof.
The term "lag time" as used herein refers to the time between the release of
the
active ingredient from one component of the composition and the release of the
active
ingredient from another component of the composition.
The term "erodable" as used herein refers to formulations which may be worn
away, diminished, or deteriorated by the action of substances within the body.
The term "diffusion controlled" as used herein refers to formulations which
may
spread as the result of their spontaneous movement, for example, from a region
of higher
to one of lower concentration.
The tenn "osmotic controlled" as used herein refers to formulations which may
spread as the result of their movement through a semi-permeable membrane into
a
solution of higher concentration that tends to equalize the concentrations of
the
formulation on the two sides of the membrane.
I. Nanoparticulate Compositions Comprising a Cefditoren, or a Salt,
Derivative, Prodrug, or Other Form Thereof
The present invention provides a nanoparticulate composition comprising
particles
which comprise: (A) cefditoren, or a salt, derivative, prodrug, or other form
thereof, for
example cefditoren pivoxil; and (B) at least one surface stabilizer.
Nanoparticualte
compositions were first described in U.S. Patent No. 5,145,684.
Nanoparticulate active
agent compositions are described also in, for example, U.S. Patent Nos.
5,298,262;
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5,302,401; 5,318,767; 5,326,552; 5,328,404; 5,336,507; 5,340,564; 5,346,702;
5,349,957;
5,352,459; 5,399,363; 5,494,683; 5,401,492; 5,429,824; 5,447,710; 5,451,393;
5,466,440;
5,470,583; 5,472,683; 5,500,204; 5,518,738; 5,521,218; 5,525,328; 5,543,133;
5,552,160;
5,565,188; 5,569,448; 5,571,536; 5,573,749; 5,573,750; 5,573,783; 5,580,579;
5,585,108;
5,587,143; 5,591,456; 5,593,657; 5,622,938; 5,628,981; 5,643,552; 5,718,388;
5,718,919;
5,747,001; 5,834,025; 6,045,829; 6,068,858; 6,153,225; 6,165,506; 6,221,400;
6,264,922;
6,267,989; 6,270,806; 6,316,029; 6,375,986; 6,428,814; 6,431,478; 6,432,381;
6,582,285;
6,592,903; 6,656,504; 6,742,734; 6;745,962; 6,811,767; 6,908,626; 6,969,529;
6,976,647;
and 6,991,191; and U.S. Patent Publication Nos. 20020012675; 20050276974;
20050238725;20050233001;20050147664;20050063913;20050042177;20050031691;
200500I9412;20050004049;20040258758;20040258757;20040229038;20040208833;
20040195413;20040156895;20040156872;20040141925;20040115134;20040105889;
20040105778;20040101566;20040057905;20040033267;20040033202;20040018242;
20040015134;20030232796;20030215502;20030185869;20030181411;20030137067;
20030108616;20030095928;20030087308;20030023203;20020179758;20020012675;
and 20010053664. Amorphous small particle compositions are described, for
example, in
U.S. Patent Nos. 4,783,484; 4,826,689; 4,997,454; 5,741,522; 5,776,496.
As stated above, the effective average particle size of the particles in the
nanoparticulate composition of the present invention is less than about 2000
nm (i.e., 2
microns) in diameter. In embodiments of the present invention, the effective
average
particle size may be, for example, less than about 1900 nm, less than about
1800 nm, less
than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less
than about
1400 nm, less than about 1300 nm, less than about 1200 nm, less than about
1100 nm,
less than about 1000 nm, less than about 900 nm, less than about 800 nm, less
than about
700 nm, less than about 600 nm, less than about 500 nm, less than about 400
nm, less
than about 300 nm, less than about 250 nm, less than about 200 nm, less than
about 150
nm, less than about 100 nm, less than about 75 mn, or less than about 50 nm in
diameter,
as measured by light-scattering methods, microscopy, or other appropriate
methods.
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The nanoparticulate particles may exist in a crystalline phase, an amorphous
phase, a semi-crystalline phase, a semi amorphous phase, or a mixture thereof.
In addition to allowing for a smaller solid dosage fonm size, the
nanoparticulate
composition of the present invention exhibits increased bioavailability, and
requires
smaller doses of the cefditoren, or a salt, derivative, prodrug, or other form
thereof, as
compared to prior conventional, non-nanoparticulate compositions which
comprise a
cefditoren, or a salt, derivative, prodrug, or other form thereof. In one
embodiment of the
invention, the cefditoren, or a salt, derivative, prodrug, or other fonm
thereof, when
administered in the nanoparticulate composition of the present invention, has
a
bioavailabifity that is about 50% greater than the cefditoren, or a salt,
derivative, prodrug,
or other form thereof, when administered in a conventional dosage form. In
other
embodiments, the cefditoren, or a salt, derivative, prodrug, or other form
thereof, when
administered in the nanoparticulate composition of the present invention, has
a
bioavailability that is about 40% greater, about 30% greater, about 20% or
about 10%
greater than the cefditoren, or a salt, derivative, prodrug, or other form
thereof, when
administered in a conventional dosage form.
The nanoparticulate composition preferably also has a desirable
pharmacokinetic
profile as measured following the initial dosage thereof to a manunalian
subject. The
desirable pharmacokinetic profile of the composition includes, but is not
limited to: (1) a
C. for cefditoren, 9r a salt, derivative, prodrug, or other form thereof, when
assayed in
the plasma of a mammalian subject following administration, that is preferably
greater
than the C. for the same cefditoren, or a salt, derivative, prodrug, or other
form thereof,
delivered at the same dosage by a non-nanoparticulate composition; and/or (2)
an AUC
for cefditoren, or a salt, derivative, prodrug, or other form thereof, when
assayed in the
plasma of a mammalian subject following administration, that is preferably
greater than
the AUC for the same cefditoren, or a salt, derivative, prodrug, or other form
thereof,
delivered at the same dosage by a non-nanoparticulate composition; and/or (3)
a TmeX for
cefditoren, or a salt, derivative, prodrug, or other form thereof, when
assayed in the
plasma of a mammalian subject following administration, that is preferably
less than the
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Tm.,, for the same cefditoren, or a salt, derivative, prodrug, or other form
thereof,
delivered at the same dosage by a non-nanoparticulate composition.
In an embodiment of the present invention, a nanoparticulate composition of
the
present invention exhibits, for example, a T. for cefditoren, or a salt,
derivative,
prodrug, or other form thereof, contained therein which is not greater than
about 90% of
the T,,,.., for the same cefditoren, or a salt, derivative, prodrug, or other
form thereof,
delivered at the same dosage by a non-nanoparticulate composition. In other
embodiments of the present invention, the nanoparticulate composition of the
present
invention may exhibit, for example, a Tma,, for cefditoren, or a salt,
derivative, prodrug, or
other form thereof, contained therein which is not greater than about 80%, not
greater
than about 70%, not greater than about 60%, not greater than about 50%, not
greater than
about 30%, not greater than about 25%, not greater than about 20%, not greater
than
about 15%, not greater than about 10%, or not greater than about 5% of the
Tmax for the
same cefditoren, or a salt, derivative, prodrug, or other form thereof,
delivered at the same
dosage by a non-nanoparticulate composition. In one embodiment of the
invention,
the T,,f187C of cefditoren, or a salt, derivative, prodrug, or other form
thereof, when
assayed in the plasma of the mammalian subject, is less than about 6 to about
8
hours after administration. In other embodiments of the invention, the T,,,ax
of
cefditoren, or a salt, derivative, prodrug, or other form thereof, is less
than about 6
hours, less than about 5 hours, less than about 4 hours, less than about 3
hours, less
than about 2 hours, less than about I hour, or less than about 30 minutes
after
administration.
In an embodiment of the present invention, a nanoparticulate composition of
the
present invention exhibits, for example, a Cmax for cefditoren, or a salt,
derivative,
prodrug, or other fonn thereof, contained therein which is at least about 50%
of the C,,,,,,
for the same cefditoren, or a salt, derivative, prodrug, or other fonn
thereof, delivered at
the same dosage by a non-nanoparticulate composition. In other embodiments of
the
present invention, the nanoparticulate composition of the present invention
may exhibit,
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for example, a Cm.., for cefditoren, or a salt, derivative, prodrug, or other
form thereof,
contained therein which is at least about 100%, at least about 200%, at least
about 300%,
at least about 400%, at least about 500%, at least about 600%, at least about
700%, at
least about 800%, at least about 900%, at least about 1000%, at least about I
100%, at
least about 1200%, at least about 1300%, at least about 1400%, at least about
1500%, at
least about 1600%, at least about 1700%, at least about 1800%, or at least
about 1900%
greater than the Cm.,, for the same cefditoren, or a salt, derivative,
prodrug, or other form
thereof, delivered at the same dosage by a non-nanoparticulate composition.
In an embodiment of the present invention, a nanoparticulate composition of
the
present invention exhibits, for example,. an AUC for cefditoren, or a salt,
derivative,
prodrug, or other form thereof, contained therein which is at least about 25%
greater than
the AUC for the same cefditoren, or a salt, derivative, prodrug, or other form
thereof,
delivered at the same dosage by a non-nanoparticulate composition. In other
embodiments of the present invention, the nanoparticulate composition of the
present
invention may exhibit, for example, an AUC for cefditoren, or a salt,
derivative, prodrug,
or other form thereof, contained therein which is at least about 50%, at least
about 75%,
at least about 100%, at least about 125%, at least about 150%, at least about
175%, at
least about 200%, at least about 225%, at least about 250%, at least about
275%, at least
about 300%, at least about 350%, at least about 400%, at least about 450%, at
least about
500%, at least about 550%, at least about 600%, at least about 750%, at least
about 700%,
at least about 750%, at least about 800%, at least about 850%, at least about
900%, at
least about 950%, at least about 1000%, at least about 1050%, at least about
1100%, at
least about 1150%, or at least about 1200% greater than the AUC for the same
cefditoren,
or a salt, derivative, prodrug, or other form thereof, delivered at the same
dosage by a
non-nanoparticulate composition.
The invention encompasses a nanoparticulate composition wherein the
pharmacokinetic profile of cefditoren, or a salt, derivative, prodrug, or
other form thereof,
following administration is not substantially affected by the fed or fasted
state of a subject
ingesting the composition. This means that there is no substantial difference
in the
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quantity of cefditoren, or a salt, derivative, prodrug, or other form thereof,
absorbed or the
rate of absorption when the nanoparticulate composition is administered in the
fed versus
the fasted state. In conventional cefditoren formulations, i.e., SPECTRAFEC ,
the
absorption of cefditoran is increased when administered with food. This
difference in
absorption observed with conventional cefditoran formulations is undesirable.
The
composition of the invention overcomes this problem.
Benefits of a dosage form which substantially eliminates the effect of food
include
an increase in subject convenience, thereby increasing subject compliance, as
the subject
does not need to ensure that they are taking a dose either with or without
food. This is
significant as, with poor subject compliance, an increase in the medical
condition for
which the cefditoren, or a salt, derivative, prodrug, or other form thereof,
is being
prescribed may be observed.
The invention encompasses also a nanoparticulate composition comprising the
cefditoren, or a salt, derivative, prodrug, or other form thereof, in which
administration of
the composition to a subject in a fasted state is bioequivalent to
administration of the
composition to a subject in a fed state.
The difference in absorption of the composition of the invention, when
administered in the fed versus the fasted state, preferably is less than about
60%, less than
about 55%, less than about 50%, less than about 45%, less than about 40%, less
than
about 35%, less than about 30%, less than about 25%, less than about 20%, less
than
about 15%, less than about 10%, less than about 5%, or less than about 3%.
In one embodiment of the invention, the invention encompasses a composition
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
wherein the
administration of the composition to a subject in a fasted state is
bioequivalent to
administration of the composition to a subject in a fed state, in particular
as defined by
C. and AUC guidelines given by the U.S. Food and Drug Administration and the
corresponding European regulatory agency (EMEA). Under U.S. FDA guidelines,
two
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products or methods are bioequivalent if the 90% Confidence Intervals (CI) for
AUC and
Cm.,, are between 0.80 to 1.25 (Tmax measurements are not relevant to
bioequivalence for
regulatory purposes). To show bioequivalency between two compounds or
administration conditions pursuant to Europe's EMEA guidelines, the 90% Cl for
AUC
must be between 0.80 to 1.25 and the 90% CI for C. must between 0.70 to 1.43.
The nanoparticulate composition of the invention is proposed to have an
unexpectedly dramatic dissolution profile. Rapid dissolution of cefditoren, or
a salt,
derivative, prodrug, or other fonn thereof, is preferable, as faster
dissolution generally
leads to faster onset of action and greater bioavailability. To improve the
dissolution
profile and bioavailability of the cefditoren, or a salt, derivative, prodrug,
or other fonm
thereof, it would be useful to increase the drug's dissolution so that it
could attain a level
close to 100%.
The compositions of the invention preferably have a dissolution profile in
which
within about 5 minutes at least about 20% of the composition is dissolved. In
other
embodiments of the invention, at least about 30% or at least about 40% of the
composition is dissolved within about 5 minutes. In yet other embodiments of
the
invention, preferably at least about 40%, at least about 50%, at least about
60%, at least
about 70%, or at least about 80% of the composition is dissolved within about
10
minutes. Finally, in another embodiment of the invention, preferably at least
about 70%,
at least about 80%, at least about 90%, or at least about 100% of the
composition is
dissolved within about 20 minutes.
Dissolution is preferably measured in a medium which is discriminating. Such a
dissolution medium will produce two very different dissolution curves for two
products
having very different dissolution profiles in gastric juices; f.e., the
dissolution medium is
predictive of in vivo dissolution of a composition. An exemplary dissolution
medium is
an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M.
Detennination of the amount dissolved can be carried out by spectrophotometry.
The
rotating blade method (European Pharmacopoeia) can be used to measure
dissolution.
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An additional feature of the nanoparticulate composition of the invention is
that
particles thereof redisperse so that the particles have an effective average
particle size of
less than about 2000 nm in diameter. This is significant because, if the
particles did not
redisperse so that they have an effective average particle size of less than
about 2000 nm
in diameter, the composition may lose the benefits afforded by formulating the
cefditoren,
or a salt, derivative, prodrug, or other form thereof, therein into a
nanoparticulate form.
This is because nanoparticulate compositions benefit from the small size of
the particles
comprising the cefditoren, or a salt, derivative, prodrug, or other form
thereof. If the
particles do not redisperse into small particle sizes upon administration,
then "clumps" or
agglomerated particles are formed, owing to the extremely high surface free
energy of the
nanoparticulate system and the thermodynamic driving force to achieve an
overall
reduction in free energy. With the fonmation of such agglomerated particles,
the
bioavailability of the dosage form may fall well below that observed with the
liquid
dispersion form of the nanoparticulate composition.
In other embodiments of the invention, the redispersed particles of the
invention
(redispersed in water, a biorelevant media, or any other suitable liquid
media) have an
effective average particle size of less than about less than about 1900 nm,
less than about
1800 nm, less than about 1700 nm, less than about 1600 nm, less than about
1500 nm,
less than about 1400 nm, less than about 1300 nm, less than about 1200 nm,
less than
about 1100 nm, less than about 1000 nm, less than about 900 nm, less than
about 800 nm,
less than about 700 nm, less than about 600 nm, less than about 500 nm, less
than about
400 nm, less than about 300 nm, less than about 250 nm, less than about 200
nm, less
than about 150 nm, less than about 100 nm, less than about 75 nm, or less than
about 50
nm in diameter, as measured by light-scattering methods, microscopy, or other
appropriate methods. Such methods suitable for measuring effective average
particle
size are known to a person of ordinary skill in the art.
Redispersibility can be tested using any suitable means known in the art. See
e.g.,
the example sections of U.S. Patent No. 6,375,986 for "Solid Dose
Nanoparticulate
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Compositions Comprising a Synergistic Combination of a Polymeric Surface
Stabilizer
and Dioctyl Sodium Sulfosuccinate."
The nanoparticulate composition of the present invention exhibits dramatic
redispersion of the particles upon administration to a mammal, such as a human
or
animal, as demonstrated by reconstitution/redispersion in a biorelevant
aqueous media,
such that the effective average particle size of the redispersed particles is
less than about
2000 nm. Such biorelevant aqueous media can be any aqueous media that exlubits
the
desired ionic strength and pH, which form the basis for the biorelevance of
the media.
The desired pH and ionic strength are those that are representative of
physiological
conditions found in the human body. Such biorelevant aqueous media can be, for
example, aqueous electrolyte solutions or aqueous solutions of any salt, acid,
or base, or a
combination thereof, which exhibit the desired pH and ionic strength.
Biorelevant pH is well known in the art. For example, in the stomach, the pH
ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
In the small
intestine the pH can range from 4 to 6, and in the colon it can range from 6
to 8.
Biorelevant ionic strength is also well known in the art. Fasted state gastric
fluid has an
ionic strength of about 0.1 M while fasted state intestinal fluid has an ionic
strength of
about 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the
Stomach and
Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997). It is
believed that the pH and ionic strength of the test solution is more critical
than the
specific chemical content. Accordingly, appropriate pH and ionic strength
values can be
obtained through numerous combinations of strong acids, strong bases, salts,
single or
multiple conjugate acid-base.pairs (i.e., weak acids and corresponding salts
of that acid),
monoprotic and polyprotic electrolytes, etc.
Representative electrolyte solutions can be, but are not limited to, HCI
solutions,
ranging in concentration from about 0.001 to about 0.1 N, and NaCI solutions,
ranging in
concentration from about 0.001 to about 0.1 M, and mixtures thereof. For
example,
electrolyte solutions can be, but are not limited to, about 0.1 N HCI or less,
about 0.01 N
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HC1 or less, about 0.001 N HCl or less, about 0.1 M NaCI or less, about 0.01 M
NaCI or
less, about 0.001 M NaCI or less, and mixtures thereof. Of these electrolyte
solutions,
0.01 M HCI and/or 0.1 M NaCI, are most representative of fasted human
physiological
conditions, owing to the pH and ionic strength conditions of the proximal
gastrointestinal
tract.
Electrolyte concentrations of 0.001 N HCI, 0.01 N HCI, and 0.1 N HC1
correspond
to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 N HC1 solution simulates
typical
acidic conditions found in the stomach. A solution of 0.1 M NaC1 provides a
reasonable
approximation of the ionic strength conditions found throughout the body,
including the
gastrointestinal fluids, although concentrations higher than 0.1 M may be
employed to
simulate fed conditions within the human GI tract.
Exemplary solutions of salts, acids, bases or combinations thereof, which
exhibit
the desired pH and ionic strength, include but are not limited to phosphoric
acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic
acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic
acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and
citric
acid/citrate salts + sodium, potassium and calcium salts of chloride.
As stated above, the composition comprises also at least one surface
stabilizer.
The surface stabilizer can be adsorbed on or associated with the surface of
the cefditoren,
or a salt, derivative, prodrug, or other form thereof. Preferably, the surface
stabilizer
adheres on, or associates with, the surface of the particles, but does not
react chemically
with the particles or with other surface stabilizer molecules. Individually
adsorbed
molecules of the surface stabilizer are essentially free of intermolecular
cross-linkages.
The relative amounts of the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, and surface stabilizer present in the composition of the present
invention can vary
widely. The optional amount of the individual components can depend, upon,
among
other things, the particular drug selected, the hydrophilic-lipophilic balance
(HLB),
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melting point, and the surface tension of water solutions of the stabilizer.
The
concentration of the cefditoren, or a salt, derivative, prodrug, or other form
thereof, can
vary from about 99.5% to about 0.001 %, from about 95% to about 0.1 %, or from
about
90% to about 0.5%, by weight, based on the total combined weight of the
cefditoren, or
salt, derivative, prodrug, or other form thereof, and surface stabilizer(s),
not including
other excipients. The concentration of the surface stabilizer(s) can vary from
about 0.5%
to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about
99.5%,
by weight, based on the total combined dry weight of the cefditoren, or salt,
derivative,
prodrug, or other form thereof, and surface stabilizer(s), not including other
excipients.
The choice of a surface stabilizer(s) for the cefditoren, or salt, derivative,
prodrug,
or other form ihereof, is non-trivial and required extensive experimentation
to realize a
desirable formulation. Accordingly, the present invention is directed to the
surprising
discovery that nanoparticulate compositions comprising cefditoren, or a salt,
derivative,
prodrug, or other form thereof, can be made.
Combinations of more than one surface stabilizer can be used in the invention.
Useful surface stabilizers which can be employed in the invention include, but
are not
limited to, known organic and inorganic pharmaceutical excipients. Such
excipients
include various polymers, low molecular weight oligomers, natural products,
and
surfactants. Surface stabilizers include nonionic, anionic, cationic, ionic,
and zwitterionic
surfactants.
Representative examples of surface stabilizers include hydroxypropyl
methylcellulose (now known as hypromellose), hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin,
casein,
lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic
acid,
benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl
alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers
(e.g.,
macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives,
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available
Tweens such
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as e.g., Tween 20 and Tween 80 (ICI Speciality Chemicals)); polyethylene
glycols
(e.g., Carbowaxs 3550 and 934 (Union Carbide)), polyoxyethylene stearates,
colloidal
silicon dioxide, phosphates, carboxymethylcellulose calcium,
carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate,
noncrystalline
cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol
(PVA), 4-
(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and fonmaldehyde
(also
known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68
and F108 ,
which are block copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g.,
Tetronic 908 , also known as Poloxamine 908 , which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and ethylene
oxide to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508
(T-
1508) (BASF Wyandotte Corporation), Tritons X-200 , which is an alkyl aryl
polyether
sulfonate (Rohm and Haas); Crodestas F-110 , which is a mixture of sucrose
stearate and
sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known
as Olin-
IOG or Surfactant 10-G (Olin Chemicals, Stamford, CT); Crodestas SL-40
(Croda,
Inc.); and SA9OHCO, which is C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2
(Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl P-D-glucopyranoside;
n-
decyl (3-D-maltopyranoside; n-dodecyl (3-D-glucopyranoside; n-dodecyl (3-D-
maltoside;
heptanoyl-N-methylglucamide; n-heptyl-(i-D-glucopyranoside; n-heptyl (3-D-
thioglucoside; n-hexyl (3-D-glucopyranoside; nonanoyl-N-methylglucamide; n-
noyl (3-D-
glucopyranoside; octanoyl-N-methylglucamide; n-octyl-(3-D-glucopyranoside;
octyl P-D-
thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol
derivative,
PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone
and
vinyl acetate, and the like.
Examples of useful cationic surface stabilizers include, but are not limited
to,
polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids,
and
nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-
methylpyridinium,
anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide
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bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
Other useful cationic stabilizers include, but are not limited to, cationic
lipids,
sulfonium, phosphonium, and quarternary ammonium compounds, such as
stearyltrimethylanunonium chloride, benzyl-di(2-chloroethyl)ethylammonium
bromide,
coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl
ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride or bromide, C12_1 sdimethyl hydroxyethyl
ammonium
chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or
bromide,
myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide,
N-alkyl
(C12_1$)dimethylbenzyl ammonium chloride, N-alkyl (C,~1$)dimethyl-benzyl
ammonium
chloride, N-tetradecylidmethylbenzyl anunonium chloride monohydrate, dimethyl
didecyl
ammonium chloride, N-alkyl and (C12_14) dimethyl 1-napthylmethyl ammonium
chloride,
trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl-
dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium
salt,
dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
N-
tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C,2_14)
dimethyl 1-
naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride,
dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride,
alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide,
C12,
C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides,
alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride,
decyltrimethylammonium bromide, dodecyltriethylammonium bromide,
tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT
336T"'), POLYQUAT lOT"', tetrabutylammonium bromide, benzyl trimethylammonium
bromide, choline esters (such as choline esters of fatty acids), benzalkonium
chloride,
stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-
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stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts
of
quaternized polyoxyethylalkylamines, MIRAPOLT"' and ALKAQUATT"' (Alkaril
Chemical Company), alkyl pyridinium salts; amines, such as alkylamines,
dialkylamines,
alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and
vinyl
pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate,
alkylpyridinium
salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts;
protonated
quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and
cationic guar.
Such exemplary cationic surface stabilizers and other useful cationic surface
stabilizers are described in J. Cross and E. Singer, Cationic Surfactants:
Analytical and
Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor),
Cationic
Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond,
Cationic
Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
Nonpolymeric surface stabilizers are any nonpolymeric compound, such
benzalkonium chloride, a carbonium compound, a phosphonium compound, an
oxonium
compound, a halonium compound, a cationic organometallic compound, a
quartemary
phosphorous compound, a pyridinium compound, an anilinium compound, an
anunonium
compound, a hydroxylammonium compound, a primary ammonium compound, a
secondary ammonium compound, a tertiary ammonium compound, and quarternary
ammonium compounds of the formula NRiR2R3R4(+). For compounds of the formula
NRIR2R3R4(+):
(i) none of RI-R4 are CH3;
(ii) one of RI-Rd is CH3;
(iii) three of RI-R4 are CH3;
(iv) all of Rl-R4 are CH3;
(v) two of R, -R4 are CH3, one of R, -R4 is C6I-I5CH2, and one of R, -R4 is an
alkyl chain of seven carbon atoms or less;
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(vi) two of RI-R4 are CH3, one of RI-R4 is C6H5CH2, and one of RI-R4 is an
alkyl chain of nineteen carbon atoms or more;
(vii) two of RI-R4 are CH3 and one of RI-R-0 is the group C6H5(CH2),,, where
n>1;
(viii) two of RI-R4 are CH3, one of RI-R4 is C6HSCH2, and one of RI-R4
comprises at least one heteroatom;
(ix) two of RI-R4 are CH3, one of Rl-R4 is C6HSCH2i and one of RI-R4
comprises at least one halogen;
(x) two of RI-R4 are CH3, one of RI-R4 is C6H5CH2, and one of RI-R4
comprises at least one cyclic fragment;
(xi) two af RI-RA are CH3 and one of Ri-R4 is a phenyl ring; or
(xii) two of R, -R4 are CH3 and two of Rl-R4 are purely aliphatic fragments.
Such compounds include, but are not limited to, behenalkonium chloride,
benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride,
lauralkonium
chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride,
cethylamine
hydrofluoride, chlorallylmethenamine chloride (Quatennium-15),
distearyldimonium
chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium
chloride(Quaternium-
14), Quatennium-22, Quaternium-26, Quaternium-18 hectorite,
dimethylaminoethylchloride hydrochloride, cysteine hydrochloride,
diethanolammonium
POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether
phosphate,
tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium
chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride,
laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine
hydrochloride,
pyridoxine HCI, iofetamine hydrochloride, meglumine hydrochloride,
methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride,
polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite,
stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride,
tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
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The surface stabilizers are commercially available and/or can be prepared by
techniques known in the art. Most of these surface stabilizers are known
pharmaceutical
excipients and are described in detail in the Handbook ofPharmaceutical
Excipients,
published jointly by the American Pharmaceutical Association and The
Pharmaceutical
Society of Great Britain (The Pharmaceutical Press, 2000), specifically
incorporated by
reference.
The compositions of the invention can comprise, in addition to the cefditoren,
or
salt, derivative, prodrug, or other form thereof, one or more compounds useful
in treating
infective conditions, or other concurrent condition. The composition may also
be
administered in conjunction with such a compound. These other active compounds
preferably include those useful for treatment of bodily conditions such as
headaches,
fevers, soreness, and other like conditions that are generally occasioned with
the onset of
infection. Such active compounds should be present-in a manner, as determined
by one
skilled in the art, such that they do not interfere with the therapeutic
effect of cefditoren,
or a salt, derivative, prodrug, or other form thereof.
The composition of the present invention may comprise also one or more binding
agents, filling agents, diluents, lubricating agents, emulsifying and
suspending agents,
sweeteners, flavoringagents, preservatives, buffers, wetting agents,
disintegrants,
effervescent agents, perfuming agents, and other excipients. Such excipients
are known
in the art. In addition, prevention of the growth of microorganisms can be
ensured by the
addition of various antibacterial and antifungal agents, such as parabens,
chlorobutanol,
phenol, sorbic acid, and the like. For use in injectable formulations, the
composition may
comprise also isotonic agents, such as sugars, sodium chloride, and the like
and agents for
use in delaying the absorprion of the injectable pharmaceutical form, such as
aluminum
monostearate and gelatin.
Examples of filling agents are lactose monohydrate, lactose anhydrous, and
various starches; examples of binding agents are various celluloses and cross-
linked
polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel PH101 and
Avicel
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PH102, microcrystalline cellulose, and silicified microcrystalline cellulose
(ProSolv
SMCCTM).
Suitable lubricants, including agents that act on the flowability of the
powder to be
compressed, are colloidal silicon dioxide, such as Aerosil 200, talc, stearic
acid,
magnesium stearate, calcium stearate, and silica gel.
Examples of sweeteners are any natural or artificial sweetener, such as
sucrose,
xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of
flavoring
agents are Magnasweet (trademark of MAFCO), bubble gum flavor, and fruit
flavors,
and the like.
Examples of preservatives are potassium sorbate, methylparaben, propylparaben,
benzoic acid and its salts, other esters of parahydroxybenzoic acid such as
butylparaben,
alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or
quarternary compounds such as benzalkonium chloride.
Suitable diluents include pharmaceutically acceptable inert fillers, such as
mierocrystalline cellulose, lactose, dibasic calcium phosphate, saccharides,
and/or
mixtures of any of the foregoing. Examples of diluents include
microcrystalline
cellulose, such as Avicel PH 101 and Avicel PH 102; lactose such as lactose
monohydrate, lactose anhydrous, and Pharrnatose DCL21; dibasic calcium
phosphate
such as Emcompress ; mannitol; starch; sorbitol; sucrose; and glucose.
Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn
starch, potato starch, maize starch, and modified starches, croscarmellose
sodium, cross-
povidone, sodium starch glycolate, and mixtures thereof.
Examples of effervescent agents are effervescent couples such as an organic
acid
and a carbonate or bicarbonate. Suitable organic acids include, for example,
citric,
tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides
and acid salts.
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Suitable carbonates and bicarbonates include, for example, sodium carbonate,
sodium
bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate,
sodium
glycine carbonate, L-lysine carbonate, and arginine carbonate. Altematively,
only the
sodium bicarbonate component of the effervescent couple may be present.
The composition of the present invention may comprise also a carrier,
adjuvant, or
a vehicle (hereafter, collectively, "carriers").
The nanoparticulate compositions can be made using, for example, milling,
homogenization, precipitation, freezing, or template emulsion techniques.
Exemplary
methods of making nanoparticulate compositions are described in the '684
patent.
Methods of making nanoparticulate compositions are described also in U.S.
Patent Nos.
5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133;
5,534,270;
5,510,118; and 5,470,583.
In one method, particles comprising cefditoren, or a salt, derivative,
prodrug, or
other form thereof, are dispersed in a liquid dispersion medium in which the
cefditoren, or
salt, derivative, prodrug, or other form thereof, is poorly soluble.
Mechanical means are
then used in the presence of grinding media to reduce the particle size to the
desired
effective average particle size. The dispersion medium can be, for example,
water,
safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG),
hexane, or glycol.
A prefen-ed dispersion medium is water. The particles can be reduced in size
in the
presence of at least one surface stabilizer. The particles comprising the
cefditoren, or salt,
derivative, prodrug, or other form thereof, can be contacted with one or more
surface
stabilizers after attrition. Other compounds, such as a diluent, can be added
to the
composition during the size reduction process. Dispersions can be manufactured
continuously or in a batch mode. One skilled in the art would understand that
it may be
the case that, following milling, not all particles may be reduced to the
desired size. In
such an event, the particles of the desired size may be separated and used in
the practice
of the present invention.
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Another method of forming the desired nanoparticulate composition is by
microprecipitation. This is a method of preparing stable dispersions of poorly
soluble
cefditoren, or a salt, derivative, prodrug, or other form thereof, in the
presence of surface
stabilizer(s) and one or more colloid stability-enhancing surface active
agents free of any
trace toxic solvents or solubilized heavy metal impurities. Such a method
comprises, for
example: (1) dissolving cefditoren, or a salt, derivative, prodrug, or other
form thereof, in
a suitable solvent; (2) adding the formulation from step (1) to a solution
comprising at
least one surface stabilizer, and (3) precipitating the formulation from step
(2) using an
appropriate non-solvent. The method can be followed by removal of any formed
salt, if
present, by dialysis or diafiltration and concentration of the dispersion by
conventional
means.
A nanoparticulate composition may be formed also by homogenization.
Exemplary homogenization methods are described in U.S. Patent No. 5,510,118,
for
"Process of Preparing Therapeutic Compositions Containing Nanoparticles." Such
a
method comprises dispersing particles comprising cefditoren, or a salt,
derivative,
prodrug, or other form thereof, in a liquid dispersion medium, followed by
subjecting the
dispersion to homogenization to reduce the particle size to the desired
effective average
particle size. The particles can be reduced in size in the presence of at
least one surface
stabilizer. The particles can be contacted with one or more surface
stabilizers either
before or after attrition. Other compounds, such as a diluent, can be added to
the
composition before, during, or after the size reduction process. Dispersions
can be
manufactured continuously or in a batch mode.
Another method of forming the desired nanoparticulate composition is by spray
freezing into liquid (SFL). This technology comprises injecting an organic or
organoaqueous solution of the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, and surface stabilizer(s) into a cryogenic liquid, such as liquid
nitrogen. The
droplets of the drug-containing solution freeze at a rate sufficient to
minimize
crystallization and particle growth, thus formulating nano-structured
particles.
Depending on the choice of solvent system and processing conditions, the
particles can
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have varying particle morphology. In the isolation step, the nitrogen and
solvent are
removed under conditions that avoid agglomeration or ripening of the
particles.
As a complementary technology to SFL, ultra rapid freezing (URF) may also be
used to create equivalent nanostructured particles with greatly enhanced
surface area.
URF comprises taking a water-miscible, anhydrous, organic, or organoaqueous
solution
of cefditoren, or a salt, derivative, prodrug, or other form thereof, and
surface stabilizer(s)
and applying it onto a cryogenic substrate. The solvent is then removed by
means such as
lyophilization or atmospheric freeze-drying with the resulting nanostructured
particles
remaining.
Another method of forming the desired nanoparticulate composition is by
template emulsion. Template emulsion creates nano-structured particles with
controlled
particle size distribution and rapid dissolution performance. The method
comprises
preparing an oil-in-water emulsion and then swelling it with a non-aqueous
solution
comprising cefditoren, or a salt, derivative, prodrug, or other form thereof,
and surface
stabilizer(s). The size distribution of the particles is a direct result of
the size of the
emulsion droplets prior to loading of tlie emulsion with the drug. The
particle size can be
controlled and optimized in this process. Furthermore, through selected use of
solvents
and stabilizers, emulsion stability is achieved with no or suppressed Ostwald
ripening.
Subsequently, the solvent and water are removed, and the stabilized nano-
structured
particles are recovered. Various particle morphologies can be achieved by
appropriate
control of processing conditions.
The invention provides a method comprising the administration of an effective
amount of a nanoparticulate composition comprising cefditoren, or a salt,
derivative,
prodrug, or other form thereof.
The composition of the present invention can be formulated for administration
parentally (e.g., intravenous, intramuscular, or subcutaneous), orally (e.g.,
in solid, liquid,
or aerosol form, vaginal), nasally, rectally, ocularly, locally (e.g., in
powder, ointment, or
drop form), buccally, intracisternally, intraperitoneally, or topically, and
the like.
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The nanoparticulate composition can be utilized in solid or liquid dosage
formulations, such as liquid dispersions, gels, aerosols, ointments, creams,
controlled
release formulations, fast melt formulations, lyophilized formulations,
tablets, capsules,
delayed release formulations, extended release formulations, pulsatile release
formulations, mixed immediate release and controlled release formulations,
etc.
Compositions suitable for parenteral injection may comprise physiologically
acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions
or
emulsions, and sterile powders for reconstitution into sterile injectable
solutions or
dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents,
solvents,
or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-
glycol,
glycerol, and the like), suitable mixtures thereof, vegetable oils (such as
olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can be
maintained, for
example, by the use of a coating such as lecithin, by the maintenance of the
required
particle size in the case of dispersions, and by the use of surfactants.
Solid dosage forms for oral administration include, but are not limited to,
tablets,
capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage
form can be,
for example, a fast melt dosage form, controlled release dosage form,
lyophilized dosage
form, delayed release dosage form, extended release dosage form, pulsatile
release dosage
form, mixed immediate release and controlled release dosage form, or a
combination
thereof. A solid dose tablet formulation is preferred. In such solid dosage
forms, the
active agent is admixed with at least one of the following: (a) one or more
inert
excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b)
fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic
acid; (c)
binders, such as carboxymethylcellulose, alignates, gelatin,
polyvinylpyrrolidone,
sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating
agents, such as
agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain
complex
silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g)
absorption
accelerators, such as quaternary ammonium compounds; (h) wetting agents, such
as cetyl
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alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and
bentonite; and (j)
lubricants, such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols,
sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills,
the dosage
forms may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, solutions, suspensions, syrups, and elixirs. In addition to the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, the liquid dosage forms may
comprise
inert diluents commonly used in the art, such as water or other solvents,
solubilizing
agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl
alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol,
1,3-
butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut
oil, corn germ
oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl
alcohol,
polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these
substances, and the
like.
One of ordinary skill will appreciate that a therapeutically effective amount
of
cefditoren, or a salt, derivative, prodrug, or other form thereof, can be
detennined
empirically. Actual dosage levels of the cefditoren, or salt, derivative,
prodrug, or other
form thereof, in the nanoparticulate compositions of the invention may be
varied to obtain
an amount of the drug that is effective to obtain a desired therapeutic
response for a
particular composition and method of administration. The selected dosage level
therefore
depends upon the desired therapeutic effect, the route of administration, the
potency of
the administered cefditoren, or a salt, derivative, prodrug, or other form
thereof, the
desired duration of treatment, and other factors.
Dosage unit compositions may contain such amounts of cefditoren, or salt,
derivative, prodrug, or other form thereof, or such submultiples thereof as
may be used to
make up the daily dose. It will be understood, however, that the specific dose
level for
any particular patient will depend upon a variety of factors: the type and
degree of the
cellular or physiological response to be achieved; activity of the specific
agent or
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composition employed; the specific agents or composition employed; the age,
body
weight, general health, sex, and diet of the patient; the time of
administration, route of
administration, and rate of excretion of the cefditoren, or a salt,
derivative, prodrug, or
other form thereof; the duration of the treatment; active compound used in
combination or
coincidental with cefditoren, or a salt, derivative, prodrug, or other form
thereof; and like
factors well known in the medical arts.
U. Controlled Release Compositions Comprising Cefditoren, or a Salt,
Derivative, Prodrug, or Other Form Thereof
As used in the present application, the term "active agent" may refer to:
cefditoren, or a salt, derivative, prodrug, or other form thereof;
nanoparticles comprising
cefditoren, or a salt, derivative, prodrug, or other form thereof; or any
other compound
that has a pharmaceutical affect.
The effectiveness of pharmaceutical compounds in the prevention and treatment
of disease states depends on a variety of factors including the rate and
duration of
delivery of the compound from the dosage form to the patient. The combination
of
delivery rate and duration exhibited by a given dosage form in a patient can
be described
as its in vivo release profile and, depending on the pharmaceutical compound
administered, will be associated with a concentration and duration of the
pharmaceutical
compound in the blood plasma, referred to as a plasma profile. As
pharmaceutical
compounds vary in their pharmacokinetic properties such as bioavailability,
and rates of
absorption and elimination, the release profile and the resultant plasma
profile become
important elements to consider in designing effective therapies.
The release profiles of dosage forms may exhibit different rates and durations
of
release and may be continuous or pulsatile. Continuous release profiles
include release
profiles in which a quantity of one or more pharmaceutical compounds is
released
continuously throughout the dosing interval at either a constant or variable
rate. Pulsatile
release profiles include release profiles in which at least two discrete
quantities of one or
more pharmaceutical compounds are released at different rates and/or over
different time
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frames. For any given pharmaceutical compound or combination of such
compounds, the
release profile for a given dosage form gives rise to an associated plasma
profile in a
patient. When two or more components of a dosage fonn have different release
profiles,
the release profile of the dosage form as a whole is a combination of the
individual
release profiles and may be described generally as "multimodal." The release
profile of a
two-component dosage fonm in which each component has a different release
profile may
described as "bimodal," and the release profile of a three-component dosage
form in
which each component has a different release profile may described as
"trimodal."
Similar to the variables applicable to the release profile, the associated
plasma
profile in a patient may exhibit constant or variable blood plasma
concentration levels of
the pharmaceutical compounds over the duration of action and may be continuous
or
pulsatile. Continuous plasma profiles include plasma profiles of all rates and
duration
which exhibit a single plasma concentration maximum. Pulsatile plasma profiles
include
plasma profiles in which at least two higher blood plasma concentration levels
of
pharmaceutical compound are separated by a lower blood plasma concentration
level and
may be described generally as "multimodal." Pulsatile plasma profiles
exhibiting two
peaks may be described as "bimodal" and plasma profiles exhibiting three peaks
may be
described as "trimodal." Depending on, at least in part, the pharmacokinetics
of the
pharmaceutical compounds included in the dosage form as well as the release
profiles of
the individual components of the dosage form, a multimodal release profile may
result in
either a continuous or a pulsatile plasma profile upon administration to a
patient.
In one embodiment, the present invention provides a multiparticulate modified
release composition which delivers cefditoren, or a salt, derivative, prodrug,
or other form
thereof, for example cefditoren pivoxil, or nanoparticles containing the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, in a pulsatile manner. The
nanoparticles
are of the type described above and comprise also at least one surface
stabilizer.
In still another embodiment, the present invention provides a multiparticulate
modified release composition which delivers the cefditoren, or a salt,
derivative, prodrug,
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or other form thereof, for example cefditoren pivoxil, or nanoparticles
containing the
cefditoren, or a salt, derivative, prodrug, or other form thereof, in a
continuous manner.
The nanoparticles are of the type described above and comprise also at least
one surface
stabilizer.
In yet another embodiment, the present invention provides a multiparticulate
modified release composition in which a first portion of the cefditoren, or a
salt,
derivative, prodrug, or other form thereof, for example cefditoren pivoxil, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, is released immediately upon administration and one or more
subsequent portions
of the cefditoren, or a salt, derivative, prodrug, or other form thereof, for
example
cefditoren pivoxil, or nanoparticles containing the cefditoren, or a
salt,.derivative,
prodrug, or other fonn thereof, are released after an initial time delay.
In yet another embodiment, the present invention provides solid oral dosage
forms
for once-daily or twice-daily administration comprising the multiparticulate
modified
release composition of the present invention.
In still another embodiment, the present invention provides a method for the
prevention and/or treatment of infections and other related diseases
comprising the
administration of a composition of the present invention.
In an embodiment, the present invention provides a multiparticulate modified
release composition in which the particles forming the multiparticulate are
nanoparticulate particles of the type described above. The nanoparticulate
particles may,
as desired, contain a modified release coating and/or a modified release
matrix material.
In an embodiment, the cefditoren, or a salt, derivative, prodrug, or other
form
thereof used in the compositions described herein is cefditoren pivoxil.
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According to one aspect of the present invention, there is provided a
pharmaceutical composition having a first component comprising active
ingredient-
containing particles, and at least one subsequent component comprising active
ingredient-
containing particles, each subsequent component having a rate and/or duration
of release
different from the first component wherein at least one of said components
comprises
particles containing cefditoren, or a salt, derivative, prodrug, or other form
thereof, for
example cefditoren pivoxil. In an embodiment of the invention, the cefditoren,
or a salt,
derivative, prodrug, or other form thereof-containing particles that form the
multiparticulate may themselves contain nanoparticulate particles of the type
described
above which comprise the cefditoren, or a salt, derivative, prodrug, or other
form thereof
and also at least one surface stabilizer. In another embodiment of the
invention,
nanoparticulate particles of the type described above which comprise the
cefditoren, or a
salt, derivative, prodrug, or other forni thereof and also at least one
surface stabilizer
themselves are the drug-containing particles of the multiparticulate. The drug-
containing
particles may be coated with a modified release coating. Alternatively or
additionally, the
drug-containing particles may comprise a modified release matrix material.
Following
oral delivery, the composition delivers the cefditoren, or a salt, derivative,
prodrug, or
other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, in a pulsatile manner. In one embodiment, the
first
component provides an immediate release of the cefditoren, or a salt,
derivative, prodrug,
or other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, and the one or more subsequent components
provide a
modified release of the cefditoren, or a salt, derivative, prodrug, or other
form thereof, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof. In such embodiments, the immediate release component serves to hasten
the
onset of action by minimizing the time from administration to a
therapeutically effective
plasma concentration level, and the one or more subsequent components serve to
minimize the variation in plasma concentration levels and/or maintain a
therapeutically
effective plasma concentration throughout the dosing interval.
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The modified release coating andlor the modified release matrix material cause
a
lag time between the release of the active ingredient from the first
population of active
ingredient-containing particles and the release of the active ingredient from
subsequent
populations of active ingredient-containing particles. Where more than one
population of
active ingredient-containing particles provide a modified release, the
modified release
coating and/or the modified release matrix material causes a lag time between
the release
of the active ingredient from the different populations of active ingredient-
containing
particles. The duration of these lag times may be varied by altering the
composition
andlor the amount of the modified release coating and/or altering the
composition and/or
amount of modified release matrix material utilized. Thus, the duration of the
lag time can
be designed to mimic a desired plasma profile.
Because the plasma profile produced by the modified release composition upon
administration is substantially similar to the plasma profile produced by the
administration of two or more IR dosage forms given sequentially, the modified
release
composition of the present invention is particularly useful for administering
a cefditoren,
or a salt, derivative, prodrug, or other fon.n thereof.
According to another aspect of the present invention, the composition can be
designed to produce a plasma profile that minimizes or eliminates the
variations in
plasma concentration levels associated with the administration of two or more
IR dosage
forms given sequentially. In such embodiments, the composition may be provided
with
an inunediate release component to hasten the onset of action by minimizing
the time
from administration to a therapeutically effective plasma concentration level,
and at least
one modified release component to maintain a therapeutically effective plasma
concentration level throughout the dosing interval.
The active ingredients in each component may be the same or different. For
example, the composition may comprise components comprising only the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, or nanoparticles containing
the cefditoren,
or a salt, derivative, prodrug, or other form thereof, as the active
ingredient.
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Alternatively, the composition may comprise a first component comprising the
cefditoren,
or a salt, derivative, prodrug, or other form thereof, or nanoparticles
containing the
cefditoren, or a salt, derivative, prodrug, or other forrn thereof, and at
least one
subsequent component comprising an active ingredient other than the
cefditoren, or a salt,
derivative, prodrug, or other form thereof, or nanoparticles containing the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, suitable for co-
administration with the
cefditoren, or a salt, derivative, prodrug, or other form thereof, or a first
component
containing an active ingredient other than the cefditoren, or a salt,
derivative, prodrug, or
other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, and at least one subsequent component
comprising the
cefditoren, or a salt, derivative, prodrug, or other form thereof, or
nanoparticles
containing the cefditoren, or a salt, derivative, prodrug, or other form
thereof. Indeed,
two or more active ingredients may be incorporated into the same component
when the
active ingredients are compatible with each other. An active ingredient
present in one
component of the composition may be accompanied by, for example, an enhancer
compound or a sensitizer compound in another component of the composition, in
order to
modify the bioavailability or therapeutic effect thereof.
As used herein, the term "enhancer" refers to a compound which is capable of
enhancing the absorption and/or bioavailability of an active ingredient by
promoting net
transport across the GIT in an animal, such as a human. Enhancers include but
are not
limited to medium chain fatty acids; salts, esters, ethers and derivatives
thereof, including
glycerides and triglycerides; non-ionic surfactants such as those that can be
prepared by
reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or
a sorbitan or
glycerol fatty acid ester, cytochrome P450 inhibitors, P-glycoprotein
inhibitors and the
like; and mixtures of two or more of these agents.
In those embodiments in which more than one drug-containing component is
present, the proportion of cefditoren, or a salt, derivative, prodrug, or
other form thereof
contained in each component may be the same or different depending on the
desired
dosing regime. The cefditoren, or a salt, derivative, prodrug, or other form
thereof present
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in the first component and in subsequent components may be any amount
sufficient to
produce a therapeutically effective plasma concentration level. The
cefditoren, or a salt,
derivative, prodrug, or other form thereof, when applicable, may be present
either in the
form of one substantially optically pure stereoisomer or as a mixture, racemic
or
otherwise, of two or more stereoisomers. The cefditoren, or a salt,
derivative, prodrug, or
other form thereof is preferably present in the composition in an amount of
from about
0.1 to about 500 mg, preferably in the amount of from about I to about 100 mg.
The
cefditoren, or a salt, derivative, prodrug, or other form thereof is
preferably present in the
first component in an amount of from about 0.5 to about 60 mg; more preferably
the
cefditoren, or a salt, derivative, prodrug, or other fonn thereof, is present
in the first
component in an amount of from about 2.5 to about 30 mg. The cefditoren, or a
salt,
derivative, prodrug, or other fonn thereof is present in subsequent components
in an
amount within similar ranges to those described for the first component.
The time release characteristics for the delivery of the cefditoren, or a
salt,
derivative, prodrug, or other form thereof from each of the components may be
varied by
modifying the composition of each component, including modifying any of the
excipients
and/or coatings which may be present. In particular, the release of the
cefditoren, or a salt,
derivative, prodrug, or other form thereof, or nanoparticles containing the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, may be controlled by
changing the
composition and/or the amount of the modified release coating on the
particles, if such a
coating is present. If more than one modified release component is present,
the modified
release coating for each of these components may be the same or different.
Similarly,
when modified release is facilitated by the inclusion of a modified release
matrix
material, release of the active ingredient may be controlled by the choice and
amount of
modified release matrix material utilized. The modified release coating may be
present, in
each component, in any amount that is sufficient to yield the desired delay
time for each
particular component. The modified release coating may be preset, in each
component, in
any amount that is sufficient to yield the desired time lag between
components.
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The lag time and/or time delay for the release of the cefditoren, or a salt,
derivative, prodrug, or other form thereof from each component may also be
varied by
modifying the composition of each of the components, including modifying any
excipients and coatings which may be present. For example, the first component
may be
an immediate release component wherein the cefditoren, or a salt, derivative,
prodrug, or
other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, is released immediately upon administration.
Alternatively, the first component may be, for example, a time-delayed
immediate release
component in which the cefditoren, or a salt, derivative, prodrug, or other
fonn thereof, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, is released substantially in its entirety immediately after a time
delay. The second
and subsequent component may be, for example, a time-delayed immediate release
component as just descnbed or, alternatively, a time-delayed sustained release
or
extended release component in which the cefditoren, or a salt, derivative,
prodrug, or
other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other fonn thereof, is released in a controlled fashion over an
extended period
of time.
As will be appreciated by those skilled in the art, the exact nature of the
plasma
concentration curve will be influenced by the combination of all of these
factors just
described. In particular, the lag time between the delivery (and thus also the
onset of
action) of the cefditoren, or a salt, derivative, prodrug, or other form
thereof, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, in each component may be controlled by varying the composition and
coating (if
present) of each of the components. Thus by variation of the composition of
each
component (including the amount and nature of the active ingredient(s)) and by
variation
of the lag time, numerous release and plasma profiles may be obtained.
Depending on the
duration of the lag time between the release of the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, or nanoparticles containing the cefditoren, or
a salt,
derivative, prodrug, or other form thereof, from each component and the nature
of the
release of the cefditoren, or a salt, derivative, prodrug, or other form
thereof, or
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nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, from each component (i.e. immediate release, sustained release etc.),
the plasma
profile may be continuous (i.e., having a single maximum) or pulsatile in
which the peaks
in the plasma profile may be well separated and clearly defined (e.g. when the
lag time is
long) or superimposed to a degree (e.g. when the lag time is short).
The plasma profile produced from the administration of a single dosage unit
comprising the composition of the present invention is advantageous when it is
desirable
to deliver two or more pulses of active ingredient without the need for
administration of
two or more dosage units.
Any coating material which modifies the release of the cefditoren, or a salt,
derivative, prodrug, or other form thereof in the desired manner may be used.
In
particular, coating materials suitable for use in the practice of the present
invention
include but are not limited to polymer coating materials, such as cellulose
acetate
phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose
phthalate,
polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those
sold under
the trademark Eudragit RS and RL, poly acrylic acid and poly acrylate and
methacrylate
copolymers such as those sold under the trademark Eudragit S and L, polyvinyl
acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate,
shellac;
hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium
alginate,
sodium carmell.ose, calcium carnaellose, sodium carboxymethyl starch,
polyvinyl alcohol,
hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose based
cross-linked
polymers--in which the degree of crosslinking is low so as to facilitate
adsorption of
water and expansion of the polymer matrix, hydoxypropyl cellulose,
hydroxypropyl
methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline
cellulose,
chitin, aminoacryl-methacrylate copolymer (Eudragit RS-PM, Rohm & Haas),
pullulan,
collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable
hydrophilic polymers) poly(hydroxyalkyl methacrylate) (mol. wt. -5k-5,000k),
polyvinylpyrrolidone (mol. wt. -IOk-360k), anionic and cationic hydrogels,
polyvinyl
alcohol having a low acetate residual, a swellable mixture of agar and
carboxymethyl
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cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or
isobutylene, pectin (mol. wt. -30k-300k), polysaccharides such as agar,
acacia, karaya,
tragacanth, algins and guar, polyacrylamides, Polyox polyethylene oxides (mol.
wt.
-100k-5,000k), AquaKeep acrylate polymers, diesters of polyglucan,
crosslinked
polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate
(e.g.
Explotae; Edward Mandell C. Ltd.); hydrophilic polymers such as
polysaccharides,
methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl
methyl
cellulose, hydroxypropyl celhtlose, hydroxyethyl cellulose, nitro cellulose,
carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g. Polyox ,
Union
Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose
acetate, cellulose
butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin,
pullulan, polyvinyl
pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters,
polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or
methacrylic acid
(e.g. Eudragit , Rohm and Haas), other acrylic acid derivatives, sorbitan
esters, natural
gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium,
potassium
alginates, propylene glycol alginate, agar, and gums such as arabic, karaya,
locust bean,
tragacanth, carra.geens, guar, xanthan, scleroglucan and mixtures and blends
thereof. As
will be appreciated by the person skilled in the art, excipients such as
plasticisers,
lubricants, solvents and the like may be added to the coating. Suitable
plasticisers include
for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl
tartrate;
diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate;
glycerin; propylene
glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl
monoglyceride;
polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols,
glycerol, acetate
esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,
dihexyl phthalate,
butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl
azelate,
epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-
octyl phthalate, di-i-
octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl
phthalate, tri-2-
ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-
2-ethylhexyl
azelate, dibutyl sebacate.
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When the modified release component comprises a modified release matrix
material, any suitable modified release matrix material or suitable
combination of
modified release matrix materials may be used. Such materials are known to
those skilled
in the art. The term "modified release matrix material" as used herein
includes
hydrophilic polymers, hydrophobic polymers and mixtures thereof which are
capable of
modifying the release of a cefditoren, or a salt, derivative, prodrug, or
other form thereof
dispersed therein in vitro or in vivo. Modified release matrix materials
suitable for the
practice of the present invention include but are not limited to
microcrystalline cellulose,
sodium carboxymethylcellulose, hydoxyalkylcelluloses such as
hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide,
alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene
glycol,
polyvinylpyrrolidone, cellulose acteate, cellulose acetate butyrate, cellulose
acteate
phthalate, cellulose acteate trimellitate, polyvinylacetate phthalate,
polyalkylmethacrylates, polyvinyl acetate and mixture thereof.
A modified release composition according to the present invention may be
incorporated into any suitable dosage form which facilitates release of the
active
ingredient in a pulsatile manner. In one embodiment, the dosage form comprises
a blend
of different populations of active ingredient-containing particles which make
up the
immediate release and the modified release components, the blend being filled
into
suitable capsules, such as hard or soft gelatin capsules. Alternatively, the
different
individual populations of active ingredient-containing particles may be
compressed
(optionally with additional excipients) into mini-tablets which may be
subsequently filled
into capsules in the appropriate proportions. Another suitable dosage form is
that of a
multilayer tablet. In this instance the first component of the modified
release composition
may be compressed into one layer, with the second component being subsequently
added
as a second layer of the multilayer tablet. The populations of the particles
making up the
composition of the invention may further be included in rapidly dissolving
dosage forms
such as an effervescent dosage form or a fast-melt dosage form.
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In one embodiment, the composition comprises at least two components
containing cefditoren, or a salt, derivative, prodrug, or other form thereof:
a fnst
component and one or more subsequent components. In such embodiment, the fnst
component of the composition may exhibit a variety of release profiles
including profiles
in which substantially all of the cefditoren; or a salt, derivative, prodrug,
or other form
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
fonn thereof, contained in the first component is released rapidly upon
administration of
the dosage form, released rapidly but after a time delay (delayed release), or
released
slowly over time. In one such embodiment, the cefditoren, or a salt,
derivative, prodrug,
or other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, contained in the first component is released
rapidly upon
administration to a patient. As used herein, "released rapidly" includes
release profiles in
which at least about 80% of the active ingredient of a component is released
within about
an hour after administration, the terni "delayed release" includes release
profiles in which
the active ingredient of a component is released (rapidly or slowly) after a
time delay, and
the terms "controlled release" and "extended release" include release profiles
in which at
least about 80% of the active ingredient contained in a component is released
slowly.
The second component of such embodiment may also exhibit a variety of release
profiles including an immediate release profile, a delayed release profile or
a controlled
release profile. In one such embodiment, the second component exhibits a
delayed
release profile in which the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, is released after a time delay.
The plasma profile produced by the administration of dosage forms of the
present
invention which comprise an immediate release component comprising the
cefditoren, or
a salt, derivative, prodrug, or other form thereof, or nanoparticles
containing the
cefditoren, or a salt, derivative, prodrug, or other form thereof, and at
least one modified
release component comprising the cefditoren, or a salt, derivative, prodrug,
or other form
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
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form thereof, can be substantially similar to the plasma profile produced by
the
administration of two or more IR dosage fon-ns given sequentially, or to the
plasma
profile produced by the administration of separate IR and modified release
dosage forms.
Accordingly, the dosage forms of the present invention can be particularly
useful for
administering cefditoren, or a salt, derivative, prodrug, or other form
thereof where the
maintenance of phanmacokinetic parameters may be desired but is problematic.
In one embodiment, the composition and the solid oral dosage forms containing
the composition release the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, such that substantially all of the cefditoren, or a salt,
derivative, prodrug, or
other fonn thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, contained in the first component is released
prior to
release of the cefditoren, or a salt, derivative, prodrug, or other form
thereof, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, from the at least one subsequent component. When the first component
comprises
an IR component, for example, it is preferable that release of the cefditoren,
or a salt,
derivative, prodrug, or other fonn thereof, or nanoparticles containing the
cefditoren, or a
salt, derivative, prodrug, or other form thereof, from the at least one
subsequent
component is delayed until substantially all the cefditoren, or a salt,
derivative, prodrug,
or other form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, in the IR component has been released. Release
of the
cefditoren, or a salt, derivative, prodrug, or other form thereof, or
nanoparticles
containing the cefditoren, or a salt, derivative, prodrug, or other form
thereof, from the at
least one subsequent component may be delayed as detailed above by the use of
a
modified release coatings and/or a modified release matrix material.
When it is desirable to minimize patient tolerance by providing a dosage
regime
which facilitates wash-out of a first dose of the cefditoren, or a salt,
derivative, prodrug,
or other form thereof from a patient's system, release of the cefditoren, or a
salt,
derivative, prodrug, or other form thereof, or nanoparticles containing the
cefditoren, or a
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salt, derivative, prodrug, or other form thereof, from subsequent components
may be
delayed until substantially all of the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative, prodrug, or
other form thereof, contained in the first component has been released, and
further
delayed until at least a portion the cefditoren, or a salt, derivative,
prodrug, or other form
thereof released from the first component has been cleared from the patient's
system. In
one embodiment, release of the cefditoren, or a salt, derivative, prodiug, or
other form
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, from subsequent components of the composition is substantially,
if not
completely, delayed for a period of at least about two hours after
administration of the
composition. In another embodiment, the release of cefditoren, or a salt,
derivative,
prodrug, or other form thereof, or nanoparticles containing the cefditoren, or
a salt,
derivative, prodrug, or other form thereof, from subsequent components of the
composition is substantially, if not completely, delayed for a period of at
least about four
hours after administration of the composition.
As described hereinbelow, the present invention also includes various types of
modified release systems by which the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, or nanoparticles containing the cefditoren, or a salt,
derivative, prodrug, or
other form thereof, may be delivered in either a pulsatile or continuous
manner. These
systems include but are not limited to: films with the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, or nanoparticles containing the cefditoren, or
a salt,
derivative, prodrug, or other form thereof, in a polymer matrix (monolithic
devices);
systems in which the cefditoren, or a salt, derivative, prodrug, or other form
thereof, or
nanoparticles containing the cefditoren, or a salt, derivative, prodrug, or
other form
thereof, is contained by a polymer (reservoir devices); polymeric colloidal
particles or
microencapsulates (microparticles, microspheres or nanoparticles) in the form
of reservoir
and matrix devices; systems in which the cefditoren, or a salt, derivative,
prodrug, or
other fornn thereof, or nanoparticles containing the cefditoren, or a salt,
derivative,
prodrug, or other form thereof, is contained by a polymer which contains a
hydrophilic
and/or leachable additive e.g., a second polymer, surfactant or plasticizer,
etc. to give a
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porous device, or a device in which cefditoren, or a salt, derivative,
prodrug, or other
fornn thereof release may be osmotically controlled (both reservoir and matrix
devices);
enteric coatings (ionizable and dissolve at a suitable pH); (soluble) polymers
with
(covalently) attached pendant cefditoren molecules, or a salt, derivative,
prodrug, or other
form thereof; and devices where release rate is controlled dynamically: e.g.,
the osmotic
pump=
The delivery mechanism of the present invention can control the rate of
release of
cefditoren, or a salt, derivative, prodrug, or other form thereof, or
nanoparticles
containing the cefditoren, or a salt, derivative, prodrug, or other form
thereo~ VNlule
some mechanisms will release cefditoren, or a salt, derivative, prodrug, or
other fornn
thereof, or nanoparticles containing the cefditoren, or a salt, derivative,
prodrug, or other
form thereof, at a constant rate, others will vary as a function of time
depending on
factors such as changing concentration gradients or additive leaching leading
to porosity,
etc.
Polymers used in sustained release coatings are necessarily biocompatible, and
ideally biodegradable. Examples of both naturally occurring polymers such as
Aquacoat (FMC Corporation, Food & Pharmaceutical Products Division,
Philadelphia,
USA) (ethylcellulose mechanically spheronised to sub-micron sized, aqueous
based,
pseudo-latex dispersions), and also synthetic polymers such as the Eudragit
(R6hm
Pharma, Weiterstadt.) range of poly(acrylate, methacrylate) copolymers are
known in the
art.
Reservoir Devices
A typical approach to modified release is to encapsulate or contain the drug
entirely (e.g., as a core), within a polymer film or coat (i.e., microcapsules
or spray/pan
coated cores).
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The various factors that can affect the diffusion process may readily be
applied to
reservoir devices (e.g., the effects of additives, polymer functionality (and,
hence, sink-
solution pH) porosity, film casting conditions, etc.) and, hence, the choice
of polymer
must be an important consideration in the development of reservoir devices.
Modeling
the release characteristics of reservoir devices (and monolithic devices) in
which the
transport of the cefditoren, or a salt, derivative, prodrug, or other form
thereof is by a
solution-diffusion mechanism therefore typically involves a solution to Fick's
second law
(unsteady-state conditions; concentration dependent flux) for the relevant
bouridary
conditions. When the device contains dissolved active agent, the rate of
release decreases
exponentially with time as the concentration (activity) of the agent (i.e.,
the driving force
for release) within the device decreases (i.e., first order release). If,
however, the active
agent is in a saturated suspension, then the driving force for release is kept
constant until
the device is no longer saturated. Alternatively the release-rate kinetics may
be
desorption controlled, and a function of the square root of time.
Transport properties of coated tablets, may be enhanced compared to free-
polymer films, due to the enclosed nature of the tablet core (permeant) which
may enable
the internal build-up of an osmotic pressure which will then act to force the
pertneant out
of the tablet.
The effect of de-ionized water on salt containing tablets coated in
poly(ethylene
glycol) (PEG)-containing silicone elastomer, and also the effects of water on
free fihns
has been investigated. The release of salt from the tablets was found to be a
mixture of
diffusion through water filled pores, formed by hydration of the coating, and
osmotic
pumping. KCl transport through films containing just 10% PEG was negligible,
despite
extensive swelling observed in similar free films, indicating that porosity
was necessary
for the release of the KCI which then occurred by trans-pore diffusion. Coated
salt
tablets, shaped as disks, were found to swell in de-ionized water and change
shape to an
oblate spheroid as a result of the build-up of internal hydrostatic pressure:
the change in
shape providing a means to measure the force generated. As might be expected,
the
osmotic force decreased with increasing levels of PEG content. The lower PEG
levels
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allowed water to be imbibed through the hydrated polymer, while the porosity
resulting
from the coating dissolving at higher levels of PEG content (20 to 40%) allow
the
pressure to be relieved by the flow of KC1.
Methods and equations have been developed, which by monitoring
(independently) the release of two different salts (e.g., KCl and NaCI)
allowed the
calculation of the relative magnitudes that both osmotic pumping and trans-
pore diffusion
contributed to the release of salt from the tablet. At low PEG levels, osmotic
flow was
increased to a greater extent than was trans-pore diffusion due to the
generation of only a
low pore number density: at a loading of 20%, both mechanisms contributed
approximately equally to the release. The build-up of hydrostatic pressure,
however,
decreased the osmotic inflow, and osmotic pumping. At higher loadings of PEG,
the
hydrated film was more porous and less resistant to outflow of salt. Hence,
although the
osmotic pumping increased (compared to the lower loading), trans-pore
diffusion was the
dominant release mechanism. An osmotic release mechanism has also been
reported for
microcapsules containing a water soluble core.
Monolithic Devices (Matrix Devices)
Monolithic (matrix) devices may be used for controlling the release of a drug.
This is possibly because they are relatively easy to fabricate compared to
reservoir
devices, and the danger of an accidental high dosage that could result from
the rupture of
the membrane of a reservoir device is not present. In such a device, the
active agent is
present as a dispersion within the polymer matrix, and they are typically
fonned by the
compression of a polymer/drug mixture or by dissolution or melting. The dosage
release
properties of monolithic devices may be dependent upon the solubility of the
drug in the
polymer matrix or, in the case of porous matrixes, the solubility in the sink
solution
within the particle's pore network, and also the tortuosity of the network (to
a greater
extent than the permeability of the film), dependent on whether the drug is
dispersed in
the polymer or dissolved in the polymer. For low loadings of drug (0 to 5%
W/V), the
drug will be released by a solution-diffusion mechanism (in the absence of
pores). At
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higher loadings (5 to 10% W/V), the release mechanism will be complicated by
the
presence of cavities formed near the surface of the device as the drug is
lost: such
cavities fill with fluid from the environment increasing the rate of release
of the drug.
It is common to add a plasticizer (e.g., a poly(ethylene glycol)), a
surfactant, or
adjuvant (i.e., an ingredient which increases effectiveness), to matrix
devices (and
reservoir devices) as a means to enhance the permeability (although, in
contrast,
plasticizers may be fugitive, and siniply serve to aid film formation and,
hence, decrease
permeability - a property normally more desirable in polymer paint coatings).
It was
noted that the leaching of PEG increased the permeability of (ethyl cellulose)
fihns
linearly as a function of PEG loading by increasing the porosity, however, the
films
retained their barrier properties, not permitting the transport of
electrolyte. It was
deduced that the enhancement of their permeability was as a result of the
effective
decrease in thickness caused by the PEG leaching. This was evidenced from
plots of the
cumulative permeant flux per unit area as a function of time and fihn
reciprocal thickness
at a PEG loading of 50% W/W: plots showing a linear relationship between the
rate of
permeation and reciprocal fihn thickness, as expected for a (Fickian) solution-
diffusion
type transport mechanism in a homogeneous membrane. Extrapolation of the
linear
regions of the graphs to the time axis gave positive intercepts on the time
axis: the
magnitude of which decreased towards zero with decreasing film thickness.
These
changing lag times were attributed to the occurrence of two diffusional flows
during the
early stages of the experiment (the flow of the drug and also the flow of the
PEG), and
also to the more usual lag time during which the concentration of penmeant in
the fihn is
building-up. Caffeine, when used as a permeant, showed negative lag times. No
explanation of this was forthcoming, but it was noted that caffeine exhibited
a low
partition coefficient in the system, and that this was also a feature of
aniline permeation
through polyethylene fihns which showed a similar negative time lag.
The effects of added surfactants on (hydrophobic) matrix devices has been
investigated. It was thought that surfactant may increase the release rate of
a drug by
three possible mechanisms: (i) increased solubilization, (ii) improved
'wettability to the
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dissolution media, and (iii) pore formation as a result of surfactant
leaching. For the
system studied (Eudragit RL 100 and RS 100 plasticised by sorbitol,
flurbiprofen as the
drug, and a range of surfactants) it was concluded that improved wetting of
the tablet led
to only a partial improvement in drug release (implying that the release was
diffusion,
rather than dissolution, controlled), although the effect was greater for
Eudragit RS than
Eudragit RL, while the greatest influence on release was by those surfactants
that were
more soluble due to the formation of disruptions in the matrix allowing the
dissolution
medium access to within the matrix. This is of obvious relevance to a study of
latex fihns
which might be suitable for pharmaceutical coatings, due to the ease with
which a
polymer latex may be prepared with surfactant as opposed to surfactant-free.
Differences
were found between the two polymers with only the Eudragit RS showing
interactions
between the anionic/cationic surfactant and drug. This was ascribed to the
differing levels
of quaternary ammonium ions on the polymer.
Composite devices consisting of a polymer/drug matrix coated in a polymer
containing no drug also exist. Such a device was constructed from aqueous
Eudragit
lattices, and was found to provide a continuous release by diffusion of the
drug from the
core through the shell. Similarly, a polymer core containing the drug has been
produced
and coated with a shell that was eroded by gastric fluid. The rate of release
of the drug
was found to be relatively linear (a function of the rate limiting diffusion
process through
the shell) and inversely proportional to the shell thickness, whereas the
release from the
core alone was found to decrease with time.
Microspheres
Methods for the preparation of hollow microspheres have been described.
Hollow nvcrospheres were formed by preparing a solution of
ethanol/dichloromethane
containing the drug and polymer. On pouring into water, an emulsion is formed
containing the dispersed polymer/drug/solvent particles, by a coacervation-
type process
from which the ethanol rapidly diffused precipitating polymer at the surface
of the
droplet to give a hard-shelled particle enclosing the drug dissolved in the
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dichloromethane. A gas phase of dichloromethane was then generated within the
particle
which, after diffusing through the shell, was observed to bubble to the
surface of the
aqueous phase. The hollow sphere, at reduced pressure, then filled with water
which
could be removed by a period of drying. No drug was found in the water. Highly
porous
matrix-type microspheres have also been described. The matrix-type
microspheres were
prepared by dissolving the drug and polymer in ethanol. On addition to water,
the ethanol
diffused from the emulsion droplets to leave a highly porous particle. A
suggested use of
the microspheres was as floating drug delivery devices for use in the stomach.
Pendent devices
A means of attaching a range of drugs such as analgesics and antidepressants,
etc., by means of an ester linkage to poly(acrylate) ester latex particles
prepared by
aqueous emulsion polymerization has been developed. These lattices, when
passed
through an ion exchange resin such that the polymer end groups were converted
to their
strong acid form, could self-catalyze the release of the drug by hydrolysis of
the ester
link.
Drugs have been attached to polymers, and also monomers have been synthesized
with a pendentdrug attached. Dosage fonms have been prepared in which the drug
is
bound to a biocompatible polymer by a labile chemical bond e.g.,
polyanhydrides
prepared from a substituted anhydride (itself prepared by reacting an acid
chloride with
the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid)
were used
to form a matrix with a second polymer (Eudragit RL) which released the drug
on
hydrolysis in gastric fluid. The use of polymeric Schiff bases suitable for
use as carriers
of pharmaceutical amines has also been described.
Enteric films
Enteric coatings consist of pH sensitive polymers. Typically the polymers are
carboxylated and interact very little with water at low pH, while at high pH
the polymers
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ionize causing swelling or dissolving of the polymer. Coatings can therefore
be designed
to remain intact in the acidic environment of the stomach, protecting either
the drug from
this environment or the stomach from the drug, but to dissolve in the more
alkaline
environment of the intestine.
Osmotically controlled devices
The osmotic pump is similar to a reservoir device but contains an osmotic
agent
(e.g., the active agent in salt form) which acts to imbibe water from the
surrounding
medium via a semi-permeable membrane. Such a device, called an elementary
osmotic
pump, has been described. Pressure is generated within the device which forces
the active
agent out of the device via an orifice of a size designed to minimize solute
diffusion,
while preventing the build-up of a hydrostatic pressure head which can have
the effect of
decreasing the osmotic pressure and changing the dimensions of the device.
While the
internal volume of the device remains constant, and there is an excess of
solid or
saturated solution in the device, then the release rate remains constant
delivering a
volume equal to the volume of solvent uptake.
Electrically stimulated release devices
Monolithic devices have been prepared using polyelectrolyte gels which swell
when, for example, an external electrical stimulus is applied causing a change
in pH. The
release may be modulated by changes in the applied current to produce a
constant or
pulsatile release profile.
Hydrogels
In addition to their use in drug matrices, hydrogels fmd use in a number of
biomedical applications such as, for example, soft contact lenses, and various
soft
implants, and the like.
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Methods of Using Modified Release Compositions Comprising Cefditoren, or a
Salt,
Derivative, Prodrug, or Other Form Thereof
According to another aspect of the present invention, there is provided a
method
for treating a patient suffering from an infection or a related condition
comprising the
step of administering a therapeutically effective amount of the composition of
the present
invention in solid oral dosage form. Advantages of the method of the present
invention
include a reduction in the dosing frequency required by conventional multiple
IR dosage
regimes while still maintaining the benefits derived from a pulsatile plasma
profile or
eliminating or minimizing the variations in plasma concentration levels. This
reduced
dosing frequency is advantageous in terrns of patient compliance and the
reduction in
dosage frequency made possible by the method of the present invention would
contribute
to controlling health care costs by reducing the amount of time spent by
health care
workers on the administration of cefditoren, or a salt, derivative, prodrug,
or other form
thereofs.
In the following examples, all percentages are weight by weight unless
otherwise
stated. The term "purified water" as used throughout the Examples refers to
water that has
been purified by passing it through a water filtration system. It is to be
understood that the
examples are for illustrative purposes only, and should not be interpreted as
restricting the
spirit and breadth of the invention as defmed by the scope of the claims that
follow.
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Examples
Examples 1 to 4 provide exemplary cefditoren tablet fonnulations. These
examples are not intended to limit the claims in any respect, but rather to
provide
exemplary tablet formulations of cefditoren which can be utilized in the
methods of the
invention. Such exemplary tablets can also comprise a coating agent.
Example 1
Exemplary Nanoparticulate
Cefditoren Tablet Formulation #1
Component g/Kg
Cefditoren about 50 to about 500
Hypromellose, USP about 10 to about 70
Docusate Sodium, USP about I to about 10
Sucrose, NF about 100 to about 500
Sodium Lauryl Sulfate, NF about 1 to about 40
Lactose Monohydrate, NF about 50 to about 400
Silicified Microcrystalline Cellulose about 50 to about 300
Crospovidone, NF about 20 to about 300
Magnesium Stearate, NF about 0.5 to about 5
Example 2
Exemplary Nanoparticulate
Cefditoren Tablet Formulation #2
Component Component
Cefditoren about 100 to about 300
Hypromellose, USP about 30 to about 50
Docusate Sodium, USP about 0.5 to about 10
Sucrose, NF about 100 to about 300
Sodium Lauryl Sulfate, NF about I to about 30
Lactose Monohydrate, NF about 100 to about 300
Silicified Microcrystalline Cellulose about 50 to about 200
Crospovidone, NF about 50 to about 200
Magnesium Stearate, NF about 0.5 to about 5
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Example 3
Exemplary Nanoparticulate
Cefditoren Tablet Formulation #3
Component
Cefditoren about 200 to about 225
Hypromellose, USP about 42 to about 46
Docusate Sodium, USP about 2 to about 6
Sucrose, NF about 200 to about 225
Sodium Lauryl Sulfate, NF about 12 to about 18
Lactose Monohydrate, NF about 200 to about 205
Silicified Microcrystalline Cellulose about 130 to about 135
Crospovidone, NF about 112 to about 118
Magnesium Stearate, NF about 0.5 to about 3
Example 4
Exemplary Nanoparticulate
Cefditoren Tablet Formulation #4
Component gtKg
Cefditoren about 119 to about 224
Hypromellose, USP about 42 to about 46
Docusate Sodium, USP about 2 to about 6
Sucrose, NF about 119 to about 224
Sodium Lauryl Sulfate, NF about 12 to about 18
Lactose Monohydrate, NF about 119 to about 224
Silicified Microcrystalline Cellulose about 129 to about 134
Crospovidone, NF about 112 to about 118
Magnesium Stearate, NF about 0.5 to about 3
Example 5
Multiparticulate Modified Release Composition Containing Cefditoren
A multiparticulate modified release composition according to the present
invention comprising an immediate release component and a modified release
component
containing cefditoren is prepared as follows.
(a) Immediate Release Component.
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A solution of cefditoren is prepared according to any of the formulations
given in Table 1.
The methylphenidate solution is then coated onto nonpareil seeds to a level of
approximately 16.9% solids weight gain using, for example, a Glatt GPCG3
(Glatt,
Protech Ltd., Leicester, UK) fluid bed coating apparatus to form the IR
particles of the
immediate release component.
TABLE 5
Imnnediate release component solutions
Amount, % (w/w)
Ingredient (i) (ii)
Cefditoren 13.0 13.0
Polyethylene Glyco16000 0.5 0.5
Polyvinylpyrrolidone 3.5
Purified Water 83.5 86.5
(b) Modified Release Component
Cefditoren-containing delayed release particles are prepared by coating
inunediate
release particles prepared according to Example 1(a) above with a modified
release
coating solution as detailed in Table 2. The immediate release particles are
coated to
varying levels up to approximately to 30% weight gain using, for example, a
fluid bed
apparatus.
TABLE 6
Modified release component coating solutions
Amount, % (w/w)
Ingredient (i) (ii) (iii) (iv) (v) (vi) (vii) (viii)
Eudragit 49.7 42.0 47.1 53.2 40.6 - -- 25.0
RS 12.5
Eudragit -- -- - - - 54.35 46.5 --
S 12.5
Eudragit -- -- -- -- - -- 25.0
L 12.5
Polyvinyl- -- -- -- 0.35 0.3 -- --
pyrrolidone
Diethyl- 0.5 0.5 0.6 1.35 0.6 1.3 1.1 --
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phthalate
Triethyl- -- -- -- -- -- -- -- 1.25
citrate
Isopropyl 39.8 33.1 37.2 45.1 33.8 44.35 49.6 46.5
alcohol
Acetone 10.0 8.3 9.3 -- 8.4 -- -- --
Talc1 -- 16.0 5.9 -- 16.3 -- 2.8 2.25
l Talc is simultaneously applied during coating for formulations in
column (i), (iv) and (vi).
(c) Encapsulation of Immediate and Delayed Release Particles.
The immediate and delayed release particles prepared according to Example 1(a)
and (b) above are encapsulated in size 2 hard gelatin capsules to an overal120
mg dosage
strength using, for example, a Bosch GKF 4000S encapsulation apparatus. The
overall
dosage strength of 20 mg cefditoren was made up of 10 mg from the immediate
release
component and 10 mg from the modified release component.
EXAMPLE 6
Multiparticulate Modified Release Composition Containing Cefditoren
Multiparticulate modified release cefditoren compositions according to the
present
invention having an immediate release component and a modified release
component
having a modified release matrix material are prepared according to the
formulations
shown in Table 3(a) and (b).
TABLE 7 (a)
100 mg of IR component is encapsulated with 100 mg of modified
release (MR) component to give a 20 mg dosage strength product
% (w/w)
IR component
Cefditoren 10
Microcrytalline cellulose 40
Lactose 45
Povidone 5
MR component
Cefditoren 10
Microcrytalline cellulose 40
Eudragit RS 45
Povidone 5
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TABLE 7 (b)
50 mg of IR component is encapsulated with 50 mg of modified
release (MR) component to give a 20 mg dosage strength product.
% (w/w)
IR component
Cefditoren 20
Microcrystalline cellulose 50
Lactose 28
Povidone 2
MR component
Cefditoren 20
Microcrytalline cellulose 50
Eudragit S 28
Povidone 2
EXAMPLE 7
The purpose of this prophetic example is to describe how a nanoparticulate
ceftidoren composition could be prepared.
An aqueous dispersion of 5% (w/w) ceftidoren, combined with one or more
surface stabilizers, such as hydroxypropyl cellulose (HPC-SL) and
dioctylsulfosuccinate
(DOSS), could be milled in a 10 ml chamber of a NanoMill 0.01 (NanoMill
Systems,
King of Prussia, PA; see e.g., U.S. Patent No. 6,431,478), along with 500
micron
PolyMill attrition media (Dow Chemical Co.) (e.g., at an 89% media load). In
an
exemplary process, the mixture could be milled at a speed of 2500 rpms for 60
minutes.
Following milling, the particle size of the milled ceftidoren particles can be
measured, in deionized distilled water, using a Honba LA 910 particle size
analyzer. For
a successful composition, the initial mean and/or D50 milled ceftidoren
particle size is
expected to be less than 2000 nm.
It will be apparent to those skilled in the art that various modifications and
variations can be made in the methods and compositions of the present
inventions without
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departing from the spirit or scope of the invention. Thus, it is intended that
the present
invention cover the modification and variations of the invention provided they
come
within the scope of the appended claims and their equivalents.
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