Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITIONS COMPRISING A SODIUM SALT OF
CELECOXIB WITH IMPROVED DISSOLUTION
FIELD OF TBE INTENTION
15 The present invention relates to pharmaceutical compositions awl
methods for
preparing same.
BACKGROUND OF Tuite, INVENTION
Celecoxib (445-(4-methylpheny1)-3-(trifluoromethyl)-1H-pyrazol-1-
20 ylibenzenesulfonamide) is a substituted pyrazolylbenzenesulfonamide
represented by the
structure (I):
H01,4
40,
N
CF3
(I)
Celecoxib belongs to the general class of non-steroidal anti-inflammatory
drugs
(NSAIDs). Unlike traditional NSADDs, celecoxib is a selective inhibitor of
25 cyclooxygenase 31 (COX-2) that causes fewer side effects when
administered to a subject.
The synthesis and use of celecoxib are further described in U.S. Pat. Nos.
5,466,823,
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5,510,496, 5,563,165, 5,753,688, 5,760,068, 5,972,986, 6,156,781, and
6,579,895
Orally deliverable
liquid formulations of celecoxib are discussed in U.S. Patent Application
Publication No.
2002/0107250
Other COX-2 inhibitory drugs are related to celecoxib, which form part of a
larger
group of drugs, all of which are benzene sulfonamides. These include:
deracoxib, which is
4-(3-fluoro-4-methoxypheny1)-3-difluoromethy1-1H-pyrazol-1-ylibenzene
sulfonamide;
valdecoxib, which is 4-[5-methyl-3-phenyl isoxazol-4-yl]benzene sulfonamide;
rofecccdb,
which is 3-phenyl-44-(methylsblfonyl)pheny1]-5H-furan-2-one; and etoricmdb,
which is
5-chloro-3-(4-methylsulfonyl)pheny1-2-(2-methyl-5-pyridinyl)pyridine. These
drugs are
described in further detail in WO 01/78724 and WO 02/102376.
In its commercially available form, trademarked as CELEBREX, celecoxib is a
neutral molecule that is essentially insoluble in water. Celecoxib typically
exists as
needle-like crystals, which tend to aggregate into a mass. Aggregation occurs
even when
celecoxib is mixed with other substances, such that a non-uniform mixture is
obtained.
These properties are shared by other pyrazolylbenzenesulfonamides and present
significant
problems in preparing pharmaceutical formulations of the drugs, particularly
oral
formulations.
It would be advantageous to provide new forms of drugs that have low aqueous
dissolution which have improved properties, in particular as oral
formulations. In
particular, even where an active pharmaceutical ingredient (API) of low
aqueous solubility
is provided in a form which has improved aqueous solubility, there still
exists a problem
when dissolution of the API is required, for example after having been taken
as an oral
formulation where the API becomes diluted in the alimentary canal. (The terms
"API" and
"pharmaceutical" are used herein interchangeably.) In this situation, APIs
having low
aqueous solubility tend to come out of solution. When this happens, for
example by a
process of crystallization or precipitation, the bioavailability of the API is
significantly
decreased. It would therefore be desirable to improve the properties of
formulations
containing such APIs so as to increase the bioavailability of the API in an
orally-
administered form, thereby providing a more rapid onset to therapeutic effect.
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SUMMARY OF THE INVENTION
It has now been found that stable, crystalline salts and co-crystals of
celecoxib can
be synthesized. The celecoxib compositions of the present invention have a
greater
solubility, dissolution, total bioavailability (area under the curve or AUC),
lower Tmax, the
time to reach peak blood serum levels, and higher C,,,õõ the maximum blood
serum
concentration, than neutral celecoxib. The celecoxib compositions of the
present invention
also include compounds that are less hygroscopic and more stable. The
celecoxib salts of
the present invention when in crystalline form convert to either an amorphous
free form of
celecoxib upon neutralization of the salt, which subsequently converts to a
neutral
metastable crystalline form or directly to a neutral metastable crystalline
form. These
amorphous and metastable crystalline forms of neutral celecoxib are more
readily available
forms of the API than is presently-marketed neutral celecoxib. Neutral
crystalline
celecoxib is presently-marketed as CELEBREX, and is designated as "neutral" to
distinguish it from the ionized salt form of celecoxib. In addition,
acidification or
neutralization of a solution of the celecoxib salt in situ yields amorphous
celecoxib, which
subsequently converts to a metastable crystalline form or directly to a
neutral metastable
crystalline form of neutral celecoxib before finally converting into stable,
neutral
celecoxib.
An aspect of the present invention relates to methods of increasing
dissolution,
solubility, and or the time an API (either alone or as part of a
pharmaceutical composition),
can be maintained, upon dissolution, as a supersaturated solution, before
precipitating out
of solution. The increase in dissolution (or concentration as a function of
time) results in,
and thus can be represented by an increase in bioavailability, AUC, reduced
time to Tina, or
increased Cmax. The methods comprise the steps of making a salt or co-crystal
from an
API (e.g. free acid) and combining the salt or co-crystal with a precipitation
retardant and
optionally, a precipitation retardant enhancer (referred to as enhancer
hereafter). The term
"precipitation" refers to either a crystalline or amorphous solid form
separating or "coming
out of' the solution. The salt may be amorphous or crystalline, but is
preferably
crystalline. Normally the salt or co-crystal form used is in a crystalline
form that dissolves
and then recrystallizes and precipitates out of solution, which is why the
term
"crystallization" retardant may be used in place of "precipitation" for
greater specificity.
The term "crystallization" retardant can also be used to specify a salt or co-
crystal that was
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in amorphous form prior to dissolution, and precipitates out of solution in
crystalline form
after dissolution. Crystalline salts are superior to amorphous salts as the
initial compound,
with an amorphous salt being superior to a neutral amorphous or crystalline
form. Free
acid forms are not preferred initial compounds unless first solubilized in a
solubilizer
resulting in a liquid formulation comprising a precipitation retardant and
optional
enhancer. The precipitation retardant is often a surfactant, preferably a
surfactant with an
ether functional group, preferably a repeating ether group, e.g., an ether
group repeated at
least two or three times wherein the oxygen atoms are separated by 2 carbon
atoms.
Further preferred surfactants have an interfacial tension of less than 30
dynes per
centimeter when measured at a concentration of 0.1 percent w/w in water at 25
degrees C
and/or the surface tension of the precipitation retardant (e.g., poloxamers)
is less than 42
dynes/cm when measured as a concentration of 0.1 %w/w in water at 25 degrees
C. The
combination of salt or co-crystal, precipitation retardant and an optional
enhancer (or
precipitation retardant, an optional enhancer and some other form) preferably
prevents or
delays precipitation of a supersaturated solution by about 5, 10, 15, 20, 25,
30, 35, 40, 45,
50, 55, or 60 minutes or greater than 1 hour in an aqueous solution,
preferably water or
gastric fluid conditions such as the gastric fluids of an average human
stomach fasted for
12 hours or simulated gastric fluid (SGF). Preferably, the solution remains
supersaturated
for more than 15, 20, or 30 minutes to allow the composition to move out of
the stomach
and into an environment with a higher pH. The SGF may be diluted by 2, 3, 4,
5, 6, 7, 8,
9, or 10 fold to represent water intake. For example, the SGF may be diluted 5
fold to
represent a patient drinking a glass of water at the time a composition of the
present
invention is taken orally. The degree of increase in solubility, dissolution,
and/or
supersaturation may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80,
90, or 100%, or
by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175,
200, 250, 300, 350,
400, 500, 1000, 10,000, or 100,000 fold greater than neutral celecoxib (e.g.,
free acid) in
the same solution. The increase in dissolution may be further specified by the
time the
composition remains supersaturated.
The enhancer preferably comprises a cellulose ester such as
hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). Thus
according
to the methods of the present invention, supersaturated concentrations upon
which a drug
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may be maintained upon dissolution and/or the degree of dissolution of a drag
in gastric
fluid conditions (e.g., SGF) is enhanced.
Normally, the enhancer does not improve or only minimally improves (less
than/equal to 10%) the length of time the API can remain supersaturated
without the
additional presence of the precipitation retardant. The methods of the present
invention
are used to make a pharmaceutical drug formulation with greater solubility,
dissolution,
and bioavailability, AUC, reduced time to Tmax, the time to reach peak blood
serum levels,
and higher Cm,, the maximum blood serum concentration, when compared to the
neutral
form or salt alone. AUC is the area under the plot of plasma concentration of
drug (not
logarithm of the concentration) against time after drug administration. The
area is
conveniently determined by the "trapezoidal rule": the data points are
connected by
straight line segments, perpendiculars are erected from the abscissa to each
data point, and
the sum of the areas of the triangles and trapezoids so constructed is
computed. When the
last measured concentration (Cõ, at time tn) is not zero, the AUC from tn to
infinite time is
, 15 estimated by Cn/kei=
The AUC is of particular use in estimating bioavailability of drugs, and in
estimating total clearance of drugs (C1T). Following single intravenous doses,
AUG =
D/C1T, where D is the dose, for single compartment systems obeying first-order
elimination kinetics; alternatively, AUG = C0/k01, where kei is the drug
elimination rate
constant. With routes other than the intravenous, AUG = F = D/C1T, where F is
the absolute
bioavailability of the drug.
The invention further relates to wherein a precipitation retardant and an
optional
enhancer is combined with a pharmaceutical that is already in a salt or co-
crystal form.
The invention further relates to wherein a precipitation retardant and an
optional enhancer
is combined with a pharmaceutical that is a solvate, desolvate, hydrate,
dehydrate, or
anhydrous form of a salt or co-crystal form.
Accordingly, in a further aspect, the present invention provides a
pharmaceutical
composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a precipitation retardant; and
(c) an optional enhancer.
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In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably
in gastric
fluid conditions;
(b) a precipitation retardant having an interfacial tension of less than 10
dyne/cm or a surface tension of less then 42 dyne/cm; and
(c) an optional enhancer.
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a surfactant; and
(0) an optional enhancer.
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a poloxamer having an interfacial tension of less than 10 dyne/cm or
surface tension less then 42 dyne/cm; and
(c) an optional enhancer.
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably
in gastric
fluid conditions;
(b) a surfactant; and
(c) a cellulose ester.
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a surfactant having an interfacial tension of less than 10 dyne/cm or
surface
tension less then 42 dyne/cm; and
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(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a poloxamer; and
(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).
In a further aspect, the present invention provides a pharmaceutical
composition
comprising:
(a) an API having low aqueous solubility or dissolution, preferably in
gastric
fluid conditions;
(b) a poloxamer having an interfacial tension of less than 10 dyne/cm or
surface tension less then 42 dyne/cm; and
(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).
In a further aspect, the present invention provides a pharmaceutical
composition
comprising
(a) celecoxib;
(b) a poloxamer surfactant having an interfacial tension at a concentration
of
0.1% of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and
(c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC).
In a further aspect, the present invention provides a process for producing a
pharmaceutical composition for delivering a supersaturated concentration of a
drug having
low aqueous dissolution, preferably in gastric fluid conditions, which
comprises intimately
mixing together the components of the above aspects or elsewhere herein.
In a further aspect, the surfactant is at a concentration of less than 5 %, 4
%, 3 %, 2
%, 1 %, 0.9 %, 0.8 %, 0.7%, 0.6%, 0.5 %, 0.4%, 0.3 %, 0.2%, or 0.1 % or at a
concentration of 0.1 % (w/w) upon dissolving in the dissolution medium.
The present invention further provides a process for producing a
pharmaceutical
composition, which comprises:
(1) providing a plurality of containers;
(2) providing a plurality of excipient solutions;
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(3) providing a plurality of compound solutions, each having dissolved
therein
a pharmaceutical compound;
(4) dispensing into each container one of the excipient solutions with one
of the
compound solutions so as to form an intimate mixture, a property of each
mixture
being varied in different containers;
(5) incubating the mixture;
(6) determining onset of solid-state nucleation or precipitation;
(7) selecting a pharmaceutical compound/excipient combination whereby onset
of solid-state nucleation is retarded; and
(8) producing a pharmaceutical composition comprising the pharmaceutical
compound/excipient combination.
Applicants found that it is possible to screen mixtures containing a
pharmaceutical
compound and an excipient in a rapid and simple manner so as to identify which
properties of the pharmaceutical compound/excipient combination retard
(inhibit) solid-
state nucleation. The term "solid-state nucleation" is used herein to refer to
the initiation of
solidification, whether amorphous or crystalline, but may be specified as
being amorphous
or crystalline. In this way, those excipients or other properties of the
combination can be
chosen for the production of a pharmaceutical composition in which the API
remains in
solution for a sufficient time after administration to a subject. In this way,
pharmaceutical
compositions which attain at least a minimum bioavailability of the API may be
readily
produced based on a straightforward in vitro screen.
Various properties of a pharmaceutical composition may affect the onset of
solid-
state nucleation or precipitation of the API. Such properties include the
identity or
amount of the excipient and the identity or amount of the pharmaceutical
compound in the
composition. Other properties may include the amount of other diluents or
carriers such as
salts or buffering compounds. The pharmaceutical compound itself may be
screened in a
variety of different forms if it is capable of polymorphism. Additionally,
different salt,
solvate, hydrate, co-crystal and other forms of the API may be screened in
accordance
with the invention.
The invention is readily applicable to screening a large variety of different
excipients. Accordingly, in a preferred aspect, the present invention provides
a process for
producing a pharmaceutical composition, which comprises:
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(1) providing a plurality of containers;
(2) providing a plurality of excipient solutions;
(3) providing a plurality of compound solutions, each having dissolved
therein
a pharmaceutical compound;
(4) dispensing into each container one of the excipient solutions with one
of the
compound solutions so as to form an intimate mixture, the excipient being
varied in
different containers;
(5) incubating the mixture;
(6) determining onset of solid-state nucleation or precipitation;
(7) selecting an excipient which is found to retard onset of solid-state
nucleation or precipitation; and
(8) producing a pharmaceutical composition comprising the
pharmaceutical
compound and the selected excipient.
According to this embodiment, it is the excipient which is varied. Different
excipients may be used in different containers and may be present as a single
excipient or
in a combination of a plurality of excipients, for example, a binary, ternary,
tertiary or
higher order combination.
In a further aspect, the present invention provides a pharmaceutical
composition
obtained by processes according to the invention. The pharmaceutical
composition may
comprise a further excipient, diluent or carrier. In a preferred aspect, the
pharmaceutical
composition is formulated for oral administration.
The invention further provides a method for assessing excipient-mediated
retardation of solid-state nucleation or precipitation of a pharmaceutical
compound, which
method comprises:
(1) providing a plurality of containers;
(2) providing a plurality of excipient solutions;
(3) providing a plurality of compound solutions, each having dissolved
therein
a pharmaceutical compound;
(4) dispensing into each container one of the excipient solutions with one
of the
compound solutions so as to form an intimate mixture, a property of each
mixture
being varied in different containers;
(5) incubating the mixture;
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(6) determining onset of solid-state nucleation or precipitation; and
(7) ranking the property of the mixture according to time of onset of solid-
state
nucleation or precipitation.
In a further aspect the present invention provides a method for screening
excipients
that retard solid-state nucleation or precipitation of a pharmaceutical
compound, which
method comprises:
(1) providing a plurality of containers;
(2) providing a plurality of excipient solutions;
(3) providing a plurality of compound solutions, each having dissolved
therein
a pharmaceutical compound;
(4) dispensing into each container one of the excipient solutions with one
of the
compound solutions so as to form an intimate mixture, the excipient being
varied in
different containers;
(5) incubating the mixture;
(6) determining onset of solid-state nucleation or precipitation; and
(7) ranking the excipient according to time of onset of solid-state
nucleation or
precipitation.
Generally speaking, the active pharmaceutical ingredient (API) is typically
capable
of existing as a supersaturated solution, preferably in an aqueous-based
medium. The API
may be a free acid, free base, co-crystal or salt, or a solvate, hydrate or
dehydrate thereof.
The invention is particularly applicable to pharmaceutical compositions
comprising an API
which, when in contact with a body fluid such as gastric juices or intestinal
fluids, would
be likely to precipitate or crystallize from solution in a nucleation event.
Accordingly, the
invention is particularly applicable to pharmaceutical compounds which may
have
relatively low solubility, or dissolution, as defined herein, when in contact
with bodily
fluids but possibly relatively high solubility, or dissolution, in appropriate
in vitro
conditions.
According to the invention, the compound solution is a solution wherein the
compound is solubilized and may be a non-aqueous solution or an aqueous
solution with a
pH adjusted to accommodate the compound. For example, in order to achieve high
solubility of the compound, a free base-type compound would be dissolved in
aqueous
solution at acidic pH whereas a free acid-type compound would be dissolved in
an aqueous
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solution of lloasic pH. The compound solution may therefore be, and preferably
is, a
supersaturated solution when compared to water, gastric fluids or intestinal
fluids. It
would also be preferred for the excipient to be in a solution comprising
water, usually
deionised water, or another aqueous based solution. In one aspect, the mixture
simulates
gastric fluid (SGF) or intestinal fluids (SIF, 0.68% monobasic potassium
phosphate, 1%
pancreatin, and sodium hydroxide where the pH of the final solution is 7.5.)
and in this
aspect it is preferred that the excipient is added in a solution simulating
those body fluids.
Alternatively, further additives, usually in solution, may be added to form
the mixtures
creating an environment appropriate for the screening to be undertaken.
One advantage of the present invention is that the plurality of containers may
be
presented in a multiple well plate format or block and tube format such that
at least 24, 48,
96, 384, or 1536 samples are assayed in parallel. Multiple block and tubes or
multiwell
plates may be assayed such that at least 1000, 3000, 5000, 7000, 10000, 20000,
30000,
40000, 50000, 60000, 70000, 80000, 90000, or 100000 total samples are assayed.
This is
advantageous because the process may be operated in a semi-automated or
automated way
using existing multiple well plate format-based apparatus. At least the step
of dispensing
may be performed with automated liquid handling apparatus. Accordingly, it is
possible to
operate the process as a high throughput screen. Additionally, using a
multiple well plate
format, the scale of the screening is relatively low. For example, each sample
may contain
less than 100 mg, 50mg, 25mg, 10, mg, 5 mg, 750 micrograms, 500 micrograms,
250,
micrograms, 100 micrograms, 75 micrograms, 50 micrograms, 25 micrograms, 10
micrograms, 1 microgram, 750 ng, 500 ng, 250 ng, 100 ng, or less than 50 ng,
depending
on the API, sample size, etc. This, therefore, minimizes the amount of API
which is
needed to identify excipients or properties of the combination of
pharmaceutical
compound and excipient that retard onset of nucleation. In this way, improved
speed and
relatively low cost are advantages.
The intimate mixture formed in the process may be achieved by any conventional
method, including the use of a mixer during or after dispensing of the
solutions. Once the
mixture has been formed, it is generally advantageous to incubate the mixture
at a constant
temperature, such as approximately 37 degrees C, to simulate in vivo
conditions.
Measurement of onset of solid-state nucleation or precipitation may be
determined
for example, by measuring the light scattering of a mixture. This may be
achieved by any
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conventional light scattering measurement, such as the use of a nephelometer.
It is also
possible to include a further step in which the crystallinity of the products
of the solid-state
nucleation or precipitation is determined. This step is conveniently performed
before
selecting the pharmaceutical compound/excipient combination for use in the
pharmaceutical composition. Crystallinity may be determined, e.g., by
birefringence
screening.
Neither the light scattering measurement nor the birefringence screening are
invasive measurement techniques. Advantageously, a portion or all of the
sample solution
does not need to be transferred to a second container and the containers or
wells can be
sealed with a transparent seal to allow use of these techniques.
In its most general aspect, the present invention relates to a pharmaceutical
composition which includes an API having a low aqueous solubility or
dissolution (as
defined herein). Typically, low aqueous solubility in the present application
refers to a
compound having a solubility in water which is less than or equal to 10 mg/mL,
when
measured at 37 degrees C, and preferably less than or equal to 1 mg/mL. The
invention
relates more particularly to drugs which have a solubility of not greater than
0.1 mg/mL.
The invention further relates to compounds that cannot be maintained as a
supersaturated
solution in gastric or intestinal fluid or in SGF or SIF. Such drugs include
some
sulfonamide drugs, such as the benzene sulfonamides, particularly those
pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors.
Disclosed herein are stable crystalline metal salts of
pyrazolylbenzenesulfonamides such
as celecoxib. Such metal salts include alkali metal or alkaline earth metal
salts, preferably
sodium, potassium, lithium, calcium and magnesium salts.
It is preferred that the pharmaceutical composition is formulated for oral
administration. Drugs according to the invention may be prepared in a form
having
reduced time to onset of therapeutic effectiveness (the time when an effect
for which the
drug is administered can be identified or measured, e.g., the point in time
when a reduction
in fever or pain felt by a patient begins to occur) or increased
bioavailability. The
pharmaceutical compositions according to the invention are therefore
particularly suitable
for administration to human subjects.
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BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a reproduction of a differential scanning calorimetry (DSC)
thennogram of the sodium salt of celecoxib prepared by Example 1 between 50
degrees C
and 110 degrees C.
Fig. 2 shows a reproduction of a thermogravimetric analysis (TGA) thermogram
of
the sodium salt of celecoxib prepared by Example 1, which was conducted from
about 30
degrees C to about 160 degrees C.
Fig. 3 shows a reproduction of a PXRD diffractogram of the sodium salt of
celecoxib prepared by Example 1.
Figs. 4A and 4B show pharmacokinetics in male Sprague-Dawley rats after 5
mg/kg oral doses of the celecoxib crystal form used in the marketed
formulations and the
sodium salt of 445-(4-methylpheny1)-3-(trifluoromethyl)-1H-pyrazol-1-
ylThenzenesulfonamide, as obtained following the protocol described in Example
4.
Figs. 5A and 5B show the formulations and mean pharmacokinetic parameters (and
standard deviations thereof) of celecoxib in the plasma of male dogs following
a single
oral or single intravenous dose of celecoxib or celecoxib sodium salt.
Fig. 5C shows a linear dose response with a plot of AUC versus dose.
Fig. 6 shows the mean concentrations of celecoxib in plasma following the
administration of a single oral dose of celecoxib or celecoxib sodium or a
single
intravenous dose of celecoxib in male dogs.
Fig. 7 shows the effect of varying ratios of ethylene glycol to propylene
glycol
subunits in poloxamers on the concentration of celecoxib sodium salt in
solution.
Fig. 8 shows the effect of different celluloses on the dissolution of various
compositions comprising equal weights of cellulose (hydroxypropylcellulose
(HPC,
100,000 kDa), low-viscosity hydroxypropylmethylcellulose (low-density HPMC,
viscosity
80-120 cps), high-viscosity hydroxypropylmethylcellulose (high-density HPMC,
viscosity
15,000 cps), or microcrystalline cellulose (Avicel PH200)), in d-alpha-
tocopherol
polyethylene glycol-1000 succinate (vitamin E TPGS) and celecoxib sodium.
Fig. 9 shows the dissolution at 37 degrees C for compositions comprising
various
weight ratios of d-alpha-tocopherol polyethylene glycol-1000 succinate
(vitamin E TGPS),
hydroxypropylcellulose, and celecoxib sodium salt.
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Fig. 10 shows the dissolution profile of celecoxib sodium salt in simulated
gastric
fluid (SGF) from solid mixtures with excipients at room temperature. The
legend indicates
the excipient and the weight ratio of excipient to celecoxib sodium (if
unmarked, 1:1).
Excipients include polyvinylpyrrolidone (PVP), poloxamer 188 (P188), poloxamer
237
(P237), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E
TPGS), and
GelucireTM 50/13.
Fig. 11 shows the effect of Avicel microcrystalline cellulose and silica gel
on the
dissolution of mixtures of celecoxib sodium salt, d-alpha-tocopherol
polyethylene glycol-
1000 succinate (vit E TOPS), and hydroxypropylcellulose (HPC) mixtures in
simulated
gastric fluid (SGF) at 37 degrees C. The legend indicates the weight ratios of
the
components.
Fig. 12 shows the dissolution of celecoxib sodium salt in 5-times diluted
simulated
gastric fluid, with excipients including d-alpha-tocopherol polyethylene
glycol-1000
succinate (vitamin E TPGS), hydroxypropylcellulose (HPC), and poloxamer 237.
The
legend indicates the weight ratios of the components.
Figs. 13A and 13B show the PXRD diffractogram and Raman spectrum,
respectively, of the sodium salt of celecoxib prepared by the method of
Example 6.
Fig. 14 shows a differential scanning calorimetry (DSC) thermogram of
celecoxib
lithium salt MO-116-49B.
Fig. 15 shows a thermogravimetric analysis (TGA) thermogram of celecoxib
lithium salt MO-116-49B.
Fig. 16 shows the RAMAN spectrum of celecoxib lithium salt MO-116-49B.
Fig. 17 shows the PXRD diffractogram of celecoxib lithium salt MO-116-49B.
Fig. 18 shows a differential scanning calorimetry (DSC) thermogram of
celecoxib
potassium salt MO-116-49A.
Fig. 19 shows a thermogravimetric analysis (TGA) thermogram of celecoxib
potassium salt MO-116-49A.
Fig. 20 shows the RAMAN spectrum of celecoxib potassium salt MO-116-49A.
Fig. 21 shows the PXRD diffractogram of celecoxib potassium salt MO-116-49A.
Fig. 22 shows a thermogravimetric analysis (TGA) thermogram of celecoxib
potassium salt MO-116-55D.
Fig. 23 shows the RAMAN spectrum of celecoxib potassium salt MO-116-55D.
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Fig. 24 shows the PXRD diffractogram of celecoxib potassium salt MO-116-55D.
Fig. 25 shows a thermogravimetric analysis (TGA) thermogram of celecoxib
calcium salt MO-116-62A.
Fig. 26 shows the RAMAN spectrum of celecoxib calcium salt MO-116-62A.
Fig. 27 shows the PXRD diffractogram of celecoxib calcium salt MO-116-62A.
Fig. 28 shows the PXRD diffractogram of commercially-available celecoxib.
Fig. 29 shows the RAMAN spectrum of commercially-available celecoxib.
Fig. 30 shows crystal retardation time for celecoxib as a function of
excipient in
simulated gastric fluid (SGF).
Fig. 31A shows interfacial tension of selected PLURONIC excipients in water.
Fig. 31B shows that Pluronic concentrations greater than or equal to the CMC
are
preferred for effective precipitation inhibition.
Fig. 32 shows dissolution of celecoxib sodium hydrate from compositions
containing PLURONIC P123 and F127.
Fig. 33 shows dissolution of celecoxib sodium hydrate from PLURONIC P123,
F127 and F87, in the presence of HPC.
Fig. 34 shows dissolution of celecoxib sodium hydrate using PLURONIC F127,
HPC and a granulating fluid.
Fig. 35A shows dissolution of celecoxib sodium hydrate using PLURONIC F127
and HPC in a compact formulation.
Fig. 35B shows a dissolution profile of springs with and without parachutes.
Fig. 36 shows a flowchart outlining a process according to the invention.
Fig. 37 shows a platemap for an automated liquid dispenser.
Fig. 38 shows a trace of light scatter against time in an assay according to
the
invention.
Fig. 39 shows a thermogravimetric analysis (TGA) thermogram of a propylene
glycol solvate of a celecoxib sodium salt.
Figs. 40A-D show the PXRD diffractograms of a propylene glycol solvate of a
celecoxib sodium salt.
Fig. 41 shows a thermogravimetric analysis (TGA) thermogram of a propylene
glycol solvate of a celecoxib potassium salt.
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Fig. 42 shows the PXRD diffractogram of a propylene glycol solvate of a
celecoxib
potassium salt.
Fig. 43 shows a thermogravimetric analysis (TGA) thermogram of a propylene
glycol solvate of a celecoxib lithium salt.
Fig. 44 shows a thermogravimetric analysis (TGA) thermogram of the sodium salt
propylene glycol trihydrate of celecoxib prepared by Example 21.
Fig. 45 shows a PXRD diffractogram of the sodium salt propylene glycol
trihydrate
of celecoxib prepared by Example 21.
Fig. 46 shows a thermogravimetric analysis (TGA) thermogram of the sodium salt
propylene glycoltrihydrate of celecoxib prepared by Example 21.
Fig. 47 shows a PXRD diffractogram of the sodium salt propylene glycol
trihydrate
of celecoxib prepared by Example 21.
Fig. 48 shows a differential scanning calorimetry (DSC) thermogram of the
sodium
salt isopropyl alcohol solvate of celecoxib prepared by Example 22.
Fig. 49 shows a thermogravimetric analysis (TGA) thermogram of the sodium salt
isopropyl alcohol solvate of celecoxib prepared by Example 22, which was
conducted
from about 30 to about 160 degrees C.
Fig. 50 shows a PXRD diffractogram of the isopropyl alcohol solvate of
celecoxib
sodium salt prepared by Example 22.
Fig. 51 shows a PXRD diffractogram of the propylene glycol solvate of
celecoxib
lithium salt prepared by Example 20.
Fig. 52 shows a PXRD diffractogram of the celecoxib:nicotinamide co-crystals
prepared by Example 23.
Fig. 53 shows a PXRD diffractogram of the hydrate of celecoxib sodium salt
under
17 % RH prepared by Example 24.
Fig. 54 shows a PXRD diffractogram of the hydrate of celecoxib sodium salt
under
31 % RH prepared by Example 24.
Fig. 55 shows a PXRD diffractogram of the hydrate of celecoxib sodium salt
under
59 % RH prepared by Example 24.
Fig. 56 shows a PXRD diffractogram of the hydrate of celecoxib sodium salt
under
74 % RH prepared by Example 24.
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Fig. 57 shows a PXRD diffractogram of the hydrate of the propylene glycol
solvate
of celecoxib sodium salt under 17 % RH prepared by Example 24.
Fig. 58 shows a PXRD diffractogram of the hydrate of the propylene glycol
solvate
of celecoxib sodium salt under 31 % RH prepared by Example 24.
Fig. 59 shows a PXRD diffractogram of the hydrate of the propylene glycol
solvate
of celecoxib sodium salt under 59 % RH prepared by Example 24.
Fig. 60 shows a PXRD diffractogram of the hydrate of the propylene glycol
solvate
of celecoxib sodium salt under 74 % RH prepared by Example 24.
Fig. 61 shows PXRD diffractograms of multiple celecoxib sodium salt samples
with various hydration states prepared by Example 25.
Fig. 62 shows a PXRD diffractogram of celecoxib sodium salt prepared by
Example 2.
Fig. 63 shows a TGA thermogram of celecoxib potassium salt hydrate.
Fig. 64 shows a PXRD diffractogram of celecoxib potassium salt hydrate.
Fig. 65 shows a TGA thermogram of celecoxib sodium salt prepared with sodium
chloride.
Fig. 66 shows a PXRD diffractogram of celecoxib sodium salt prepared with
sodium chloride.
Fig. 67 shows a dissolution profile of celecoxib sodium salt hydrate.
Fig. 68 shows in vitro dissolution data of a controlled release formulation of
celecoxib.
Fig. 69 shows changes in the PXRD diffractogram of celecoxib sodium hydrate as
the ambient relative humidity is changed.
Fig. 70 shows changes in the PXRD diffractogram of celecoxib sodium propylene
glycol solvate as the ambient relative humidity is changed.
Fig. 71 shows dynamic vapor sorption data of celecoxib sodium hydrate.
Figs. 72A-B show dynamic vapor sorption data of celecoxib potassium salt and
PXRD data.
Fig. 73 shows dynamic vapor sorption data of celecoxib sodium propylene glycol
solvate.
Fig. 74 shows dynamic vapor sorption data of celecoxib sodium propylene glycol
solvate.
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Fig. 75 shows a comparison of PXRD diffractograms of celecoxib sodium
propylene glycol solvate.
Fig. 76 shows dynamic vapor sorption data of celecoxib potassium propylene
glycol solvate.
Fig. 77 shows a PXRD diffractogram of celecoxib potassium propylene glycol
solvate.
Fig. 78 shows dynamic vapor sorption data of celecoxib lithium propylene
glycol
solvate.
Fig. 79 shows a comparison of PXRD diffi-actograms of celecoxib lithium
propylene glycol solvate.
Fig. 80 shows dynamic vapor sorption data of a celecoxib:nicotinamide co-
crystal.
Fig. 81 shows a DSC thermogram of amorphous celecoxib potassium salt.
Fig. 82 shows a Raman spectrum of amorphous celecoxib potassium salt.
Fig. 83 shows a PXRD diffractogram of amorphous celecoxib potassium salt.
Fig. 84 shows a TGA thermogram of a celecoxib:18-crown-6 co-crystal.
Fig. 85 shows a DSC thermogram of a celecoxib:18-crown-6 co-crystal.
Fig. 86 shows a PXRD diffractogram of a celecoxib:18-crown-6 co-crystal.
Fig. 87 shows a TGA thermogram of celecoxib 15-crown-5 solvate.
Fig. 88 shows a DSC thermogram of celecoxib 15-crown-5 solvate.
Fig. 89 shows a PXRD diffractogram of celecoxib 15-crown-5 solvate.
Fig. 90 shows a TGA thermogram of celecoxib diglyme solvate.
Fig. 91 shows a DSC thermogram of celecoxib diglyme solvate.
Fig. 92 shows a PXRD diffractogram of celecoxib diglyme solvate.
Fig. 93 shows a TGA thermogram of a valdecoxib:18-crown-6 co-crystal.
Fig. 94 shows a PXRD diffractogram of a valdecoxib:18-crown-6 co-crystal.
Fig. 95 shows a single-crystal packing diagram for valdecoxib:18-crown-6 co-
crystal.
Fig. 96 shows a TGA thermogram of celecoxib NMP solvate.
Fig. 97 shows a Raman spectrum of celecoxib NMP solvate.
Fig. 98 shows a PXRD diffractogram of celecoxib NMP solvate.
Fig. 99 shows a packing diagram for celecoxib NMP solvate at 100 K.
Fig. 100 shows a packing diagram for celecoxib NMP solvate at 571 K.
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Fig. 101 shows a TGA thermogram of celecoxib sodium salt synthesized from 2-
propanol.
Fig. 102 shows a DSC thermogram of celecoxib sodium salt synthesized from 2-
propanol.
DETAILED DESCRIPTION OF THE INVENTION
In its most general aspect, the present invention relates to a pharmaceutical
composition
that includes an API having a low aqueous solubility, e.g., in gastric fluid
conditions.
Typically, low aqueous solubility in the present application refers to a
compound having a
solubility in water which is less than or equal to 10mg/mL, when measured at
37 degrees
C, and preferably less than or equal to 5mg/mL or lmg/mL. "Low aqueous
solubility" can
further be defined as less than or equal to 900, 800, 700, 600, 500, 400, 300,
200 150 100,
90, 80, 70, 60, 50, 40,30, 20 micrograms/mL, or further 10, 5 or 1
micrograms/mL, or
further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, 80, 70, 60, 50,
40, 30, 20, or
10 ng/mL, or less than 10 ng/mL when measured at 37 degrees C. Further aqueous
solubility can be measured in simulated gastric fluid (SGF) rather than water.
SGF (non-
diluted) of the present invention is made by combining 1 g/L Triton X-100 and
2 g/L NaC1
in water and adjusting the pH with 20mM HC1 to obtain a solution with a final
pH=1.7.
The pH of the solution may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7, 1.8, 1.9,
2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 6, 6.5, 7,
7.5, 8, 8.5, 9, 9.5, 10,
10.5, 11, 11.5, or 12.
APIs which have a solubility of not greater than 0.1 mg/mL, including some
sulfonamide drugs, such as the benzene sulfonamides, particularly those
pyrazolylbenzenesulfonamides discussed above, which include COX-2 inhibitors,
are
included in the present invention. Disclosed herein are stable crystalline
metal salts and
co-crystals of pyrazolylbenzenesulfonamides such as celecoxib. Such metal
salts include
alkali metal or alkaline earth metal salts, preferably sodium, potassium,
lithium, calcium
and magnesium salts.
In one aspect of the present invention, an API with low aqueous solubility is
formulated with a precipitation retardant and, optionally, with a
precipitation retardant
enhancer. The precipitation retardant used in the present invention can be
chosen from a
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wide range of surfactants (see e.g., Fig. 30). Embodiments include where the
surfactant is
non-ionic or wherein the surfactant is ionic. In embodiments of the present
invention, the
interfacial tension of the precipitation retardant (e.g., poloxamers) is less
than 10 dyne/cm
when measured as a concentration of 0.1 percent w/w in water as compared to
mineral oil
at 25 degrees C and/or the surface tension of the precipitation retardant
(e.g., poloxamers)
is less than 42 dyne/cm when measured as a concentration of 0.1%w/w in water.
In other ,
embodiments of the invention the interfacial tension is less than 15, 14, 13,
12, 11, 9, 8, 7,
or 6 dyne/cm or the surface tension is less than 45, 44, 43, 41, 40, 39, 38,
37, 36, or 35
dyne/cm. In other embodiments, the surfactant is a poloxamer. A poloxamer
comprises an
ethylene oxide-propylene oxide block copolymer, which preferably has the
structure
(PEG)-(PPG)-(PEG), where x, y and z are integers and x is usually equal to z.
Preferred
forms of poloxamers are those obtainable from BASF, as trademarked PLURONIC.
The
invention is not, however, limited to the PLURONIC series as similar
poloxamers
obtainable from other sources may be used. Examples of PLURONIC poloxamers
according to the invention include PLURONIC L122, PLURONIC P123, PLURONIC
F127 (Poloxamer 407), PLURONIC L72, PLURONIC P105, PLURONIC LP2,
PLURONIC P104, PLURONIC F108 (Poloxamer 338), PLURONIC P103, PLURONIC
L44 (Polaxamer 124), PLURONIC F68 (Poloxamer 188), and PLURONIC F87
(Poloxamer 237). A specific poloxamer and its corresponding PLURONIC, i.e.,
the
generic and tradename, may be used interchangeably throughout.
In one embodiment, the invention provides a pharmaceutical composition
comprising:
(a) an API; and
(b) a polyether block copolymer comprising an A-type linear polymeric segment
joined
at one end to a B-type linear polymeric segment, wherein the A-type segment is
of
relatively hydrophilic character, the repeating units of which contribute an
average
Hansch-Leo fragmental constant of about -0.4 or less and have molecular weight
contributions between about 30 and about 500, wherein the B-type segment is of
relatively hydrophobic character, the repeating units of which contribute an
average
Hansch-Leo fragmental constant of about -0.4 or more and have molecular weight
contributions between about 30 and about 500, wherein at least about 80% of
the
linkages joining the repeating units for each of the polymeric segments
comprise an
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ether linkage. In a preferred first embodiment, the polyether block copolymer
is
selected from the group consisting of polymers of formulas:
A-B-A', A-B, B-A-B', or L(R1)(R2)(R3)(R4)
(i) (ii) (iii) (iv)
wherein A and A' are A-type linear polymeric segments, B and B' are B-type
linear
polymeric segments, and RI, R2, R3 and R4 are either block copolymers of
formulas (i),
(ii) or (iii) or hydrogen and L is a linking group, with the proviso that no
more than two
of Rl, R2, R3 or R4 are hydrogen.
In another embodiment, the composition includes micelles of the block
copolymer or
forms micelles of the block copolymers during the course of administration or
subsequent
thereto. Preferably, at least about 0.1 % of the API is incorporated in the
micelles, more
preferably, at least about 1 % of the API, yet more preferably, at least about
5 % of the
API.
In another embodiment, the hydrophobic percentage of the copolymer of the
composition is at least about 50 % more preferably, at least about 60 %, yet
more
preferably 70 %.
In another embodiment, the hydrophobic weight of the copolymer is at least
about 900,
more preferably, at least about 1700, yet more preferably at least about 2000,
still more
.. preferably at least about 2300.
In other embodiments, the hydrophobic weight is at least about 2000 and the
hydrophobic percentage is at least about 20 %, preferably 35 %; or the
hydrophobic weight
is at least about 2300 and the hydrophobic percentage is at least about 20 %,
preferably 35
%.
The optional third component of the pharmaceutical composition according to
the
present invention comprises a precipitation retardant enhancer. An enhancer is
a
compound capable of increasing the effectiveness of the precipitation
retardant in
inhibiting, preventing or at least reducing the extent of precipitation of a
drug of low
aqueous solubility, usually when diluted such as following oral
administration. In one
.. embodiment the enhancer does not act as a precipitation retardant alone. In
another
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embodiment the enhancer has no effect or a negative effect in an in vitro
precipitation
assay, but increases the effectiveness of the precipitation retardant in an in
vivo or in vitro
dissolution assay. Cellulose esters, such as hydroxypropyl cellulose, are
particularly
useful enhancers according to the present invention. Cellulose esters vary in
the chain
length of their cellulosic backbone and consequently, vary in their
viscosities as measured
for example at a 2% by weight concentration in water at 20 degrees C. Lower
viscosities
are normally preferred to higher viscosities in the present invention. In
embodiments of
the present invention the cellulose ester, such as HPC, has a viscosity, 2% in
water, of
about 100 to about 100,000 cP or about 1000 to about 15,000 cP. In other
embodiments
the viscosity is less than 1,500,000, 1,000,000, 500,000, 100,000, 75,000,
50,000, 35,000,
25,000, 20,000, 17,500, 15,000, 12,500. 11,000, 10,500, 9,000, 8,000, 7,000,
6,000, 5,000,
4,000, 3,000, 2,000, 1,000, 750, 500, or 250 cP, or has a viscosity in a range
selected from
any two preceding integers.
Enhancers are also useful in delaying the Tmax and/or increasing the amount of
time
the API concentration is above 1/2 Tmax, thus acting to smooth out a curve of
blood serum
concentration vs. time. Preferred enhancers increase the amount of time the
API
concentration is above V2 Tn. by 25%, 50%, 75%, 100%, three fold or more than
three
fold. In a preferred embodiment, the composition has both a reduced time to
Tmax and
remains at Y2 Tmax longer than the free acid or in the same composition except
the salt or
co-crystal is replaced by the free acid.
The ratio of component a:b:c (API: precipitation retardant;enhancer) as
exemplified
herein is approximately 1:1:1 (+/- 0.2 for the precipitation retardant and
enhancer).
However, the ratio can be adjusted to suit the application. For example, the
amount of
precipitation retardant or enhancer may need to be decreased, and even
decreased below
the optimum concentration in order to decrease the amount of excipients in the
administered form of the composition, such as a tablet or capsule. In one
embodiment the
unit dosage form comprises an amount of precipitation retardant (surfactant)
that is at or
above an amount needed for the retardant to reach its critical micelle
concentration (CMC)
in H20 or SGF. It is noted the poloxamers may not form true micells but do
form
analogous structures which are considered micelles for the purpose of the
present
invention.
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The composition may further comprise a pharmaceutically-acceptable diluent,
excipient or carrier and such additional components are discussed in further
detail below.
One such additional component comprises a granulating fluid-like liquid, such
as
poloxamer 124, PEG 200 or PEG 400, that forms an intimate contact between the
API,
precipitation retardant and optional enhancer by binding or partially
dissolving them.
Preferably the composition remains in a solid, semi-solid or paste, although
an
embodiment is drawn to wherein the composition is at least 25%, 50%, 75% or
nearly or
fully dissolved. Any pharmaceutically acceptable liquid may be used as long as
it does not
cause conversion of the salt or co-crystal form to the free form in the solid
state. Some
non-limiting examples include methanol, ethanol, isopropanol, higher alcohols,
propylene
glycol, ethyl caprylate, propylene glycol laurate, PEG, diethyl glycol
monoethyl ether
(DGME), tetraethylene glycol dimethyl ether, triethylene glycol monoethyl
ether, and
polysorbate 80. The presence of the granulating fluid-like liquid increases
the dissolution
of the API, possibly by delaying the contact between the API and the
dissolution medium
until the surfactant dissolves to a significant extent, thus delaying
precipitation. The use of
a granulating fluid-like liquid is particularly useful when the API and
precipitation
retardant are solids.
As an alternative embodiment to increase supersaturation of the API, the
pharmaceutical composition is in the form of a compact whereby, during the
process of
producing the pharmaceutical composition, the components are compacted
together.
Compaction may perform a similar role to that performed by the granulating
fluid.
Retarded dissolution or a smoothing out of the curve of blood serum
concentration vs. time
may be limited, if required, by using a disintegrant in the compact.
In a further embodiment the API and precipitation retardant (and optional
enhancer), forms a paste or non-aqueous solution when mixed. An adherent mass
of
components may be produced if a paste is used, which is thought to delay
dissolution of
the API by allowing the surfactant to dissolve first. This is thought to
promote
supersaturation of the API.
Normally the compounds of the present invention are intimately associated as a
pharmaceutical composition. An "intimate association" in the present context
includes, for
example, the pharmaceutical admixed with the precipitation retardant, the
pharmaceutical
embedded or incorporated in the retardant, the compound forming a coating on
particles of
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the pharmaceutical or vice versa, and a substantially homogeneous dispersion
of the
pharmaceutical throughout the compounds.
Where the pharmaceutical composition includes a COX-2 inhibitor, a method of
treating a subject is provided in a further aspect of the invention, in which
the subject may
be suffering from pain, inflammation, cancer or pre-cancer such as intestinal
or colonic
polyps. The method comprises administering to the subject a pharmaceutical
composition
as described herein.
It is preferred that the pharmaceutical composition is formulated for oral
administration. Drugs according to the invention may be prepared in a form
having a
decreased time to onset of therapeutic effectiveness and an increased
bioavailability. The
pharmaceutical compositions according to the invention are particularly
suitable for
administration to human subjects.
The methods and compositions of the present invention relate to improving
solubility, dissolution and bioavailability of pharmaceuticals. The present
invention
further relates to improving the performance of pharmaceutical compounds that
initially
dissolve but then precipitate or recrystallize in gastric fluid conditions.
Further embodiments relate to pharmaceuticals with an aminosulfonyl functional
group. The term "aminosulfonyl functional group" herein refers to a functional
group
having the following structure (II):
0% sss-
R¨NH/
0 (II)
Wherein the wavy line represents a bond by which the functional group is
attached to the
rest of the drug molecule; and R is hydrogen or a substituent that preserves
ability of
polyethylene glycol or a polyethylene glycol degradation product to react with
the amino
group adjacent to R to form an addition compound. Illustrative examples of
such
substituents include partially unsaturated hereocyclyl, hereoaryl,
cycloalkenyl, aryl,
alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl,
phenyl, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl,
hydroxyl,
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alkoxyalkyloxyalkyl, haloalkylsulfonyloxy, carboxyalkoxyalkyl,
cycloalkylalkyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, heterocyclyl, cycloalkenyl, aralkyl,
heterocyclylalkyl, heteroarylcarbonyl, alkylthioalkyl, arylcarbonyl,
aralkylcarbonyl,
aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-
arylaminocarbonyl, N-
alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-
aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-Narylamino, aminoalkyl,
alkylaminoalkyl,
N-arylaminoalkyl, N-aralkylamincoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-
arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsufinyl,
alkylsufonyl, etc.
Non-limiting illustrative examples of amino sulfonyl-comprising drugs include
ABT-751 of Eisai (N-(2-(4-hydroxyphenyl)amino)-3-pyridy1)4-
methoxybenzenesulfonamide); alpiropride; amosulalol; amprenavir; amsacrine;
argatroban; asulacrine; azosemide; BAY-38-4766 of Bayer (N44-[[[5-
(dimethylamino)-1-
naphthalenyl]sulfonyliamino]phenyl]-3-hyrdroxy-2,2-dimethylpropanamide);
bendroflumethiazide; BMS-193884 of Bristol Myers Squibb (N-(3,4-dimethy1-5-
isoxazoly1)-41-(2-oxazoly1)41,11-biphenyl]-2-sulfonamide); bosentan; bumetide;
celecoxib; chlorthalidone; delavirdine; deracoxib dofetilide; domitroban;
dorzolamide;
dronedarone; E-7070 of Eisai (N-(3-chloro-1H-indo1-7-y1)-1, 4-benzene-
disulfonamide);
EF-7412 of Schwartz Pharma (N-344-14-(tetrahydro-1,3-dioxo-1H-pynolo[1,2-
c]imidazol-2(3H)-yl)butyl]-1-piperazinyl]phenyl]ethanesulfonamide);
fenquizone;
furosemide; glibenclamide; gliclazide; glimepiride; glipentide; glipizide;
gliquidone;
glisolamide; GW-8510 of Glaxo SmithKline (44[6,7-dihydro-7-oxo-8H-pyrrolo[2,3-
g]benzothiazol-8-ylidene)methyl]amino]-N-2-pyridinylbenzenesulfonamide); GYK1-
16638 of Ivax (N4442-[[2-(2,6-dimethoxylphenoxy)-1-
methlethyl]methylaminoiethyl]phenyl] methanesulfonamide); HMR-1098 of Aventis
(5-
chloro-2-methoxy-N-[244-methoxy-
3 [Emethylamino)thioxomethyl]aminoisulfonyliphenyl]ethylThenzamide);
hydrochlorothiazide; ibutilide; indapamide; IS-741 of Ishihara (N-[2-
[(ethylsufonyl)
amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanecarboxamide); JTE-522 of
Japan
Tobacco (4-(4-cyclohexy1-2-methy1-5-oxazoly1)-2-fluorobenzenesulfonamide); KCB-
328
of Chugai (N-[3-amino-442-[[2-3,4-dimethoxyphenyl)ethyl]methylamino]
ethoxylphenylimethanesulfonamide); KT2-962 of Kotobuki (314-[{(4-chlorophenyl)
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sulfonyl]amino]buty1]-6-(1-methylethyl)-1-azulene sulfonic acid);
levosulpiride; LY-
295501 (N-[[(3,4-dichlorophyenyl)amino]carbonyl]-2,3-dihydro-5-
benzofuransulfonamide) and LY-404187 (N-2-(4-(4-cyanophenyl)phenyl)propy1-2-
propanesulfonamide) of Eli Lilly; metolazone; naratriptan; nimesulide; NS-49
of Nippon
((R)-N-[3 -(2-amino-1 -hydroxyethyl)-4-flourophenyl]methanesulfonamide); ONO-
8711 of
Ono ((5Z)-6-[(2R,3S)-3-[[[(4-chloro-2-
methylphenyl)sulfonyl]amino]methyl]bicyclo[2.2.2]oct-2-y1]-5-hexenoic acid);
piretanide;
PNU-103657of Pharmacia (145-methanesulfonamidoindo1-2-ylcarbony1]-4-(N-methyl-
N-
(3-(2-methylpropy1)-2-pyridinyl)amino)piperidine); polythiazide; ramatroban;
RO-61-
1790 of Hoffmann LaRoche (N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-
tetrazol-5-y1)-4-pyridiny1]-4-pyrimidiny1]-5-methyl-2-pyridinesulfonamide);
RPR-130737
(4-hydroxy-3-[2-oxo-3(S)45-(3-pyridy1)thiophen-2-ylsulfonamido]pyrro1idin,1-
ylmethyl]benzamide) and RPR-208707 of Aventis; S-18886 (34(644-
chlorophenylsulfonylamino)-2-methy1-5,6,7,8-tetrahydronaphth]-1-yl)propionic
acid) and
S-32080 (346-(4-chlorophenylsulfonylamido)-2-propy1-3-(3pyridyl-methyl)-
5,6,7,8-
tetrahydronaphthalen-l-yl]propionic acid) of Server; S-36496 of Kaken (2-
sulfonyl4N-(4-
chlorophenyl)sulfonylamino-butyl-N-[(4-cyclobutylthiazol-2-yl)ethenylphenyl-3-
yl-
methylflaminobenzoic acid); sampatrilat;SB-203208 of Glaxo Smith Kline (L-
phenylalanine, b-methyl-,(4aR,6S,7R,7aS)-4-(aminocarbony1)-7-[[[[[(2S,3S)-2-
amino-3-
methyl-1-oxopentyl]amino]sulfonyl]acetyl]amino]-7-carboxy-2,4a,5,6,7,7a-
hexahydro-2-
methyl-1H-cyclopenta[c]pyridine-6y1 ester, (bS)-); SE-170 of DuPont (2-(5-
amidino-1H-
indo1-3-y1)N42'-(aminosulfony1)-3-bromo(1,1'bipheny1)-4-yl]acetamide);
sivelestat; SJA-
,
6017 of Senju (N-(4-flourophenylsulfony1)-L-valyl-L-leucinal); SM-19712 of
Sumitomo
(4-chloro-N-[[(4-cyano-3-methyl-1-pheny1-1H-pyrazol-5-y1) amino]
carbonylThenzenesulfonamide); sonepiprazole; sotalol; sulfadiazine;
sulfaguanole;
sulfasalazine; sulpride; sulprostone; sumatriptan; T-614 of Toyama (N-[3-
(formylamino)-
4-oxo-6-phenoxy-4H-1-benzopyran-7-y1]-methanesulfonamide); T-138067 (2,3,4,5,6-
pentafluoro-N-(3-flouro-4-methoxyphenyl)benzenesulfonamide) and T-900607
(2,3,4,5,6-
pentafluoro-N-3-ureido-4-methoxyphenyl)benzenesulfonamide) of Tularik; TAK-661
of
Takeda (2,2-dimethy1-3-[[7-(1-methylethyl)[1,2,4]triazolo[1,5-b]pyridazin-6-
yl]oxy]-1-
propanesulfonamide); tamsulosin; tezosentan; tipranavir; tirofiban;
torasemide;
trichloromethiazide; tripamide; valdecoxib; veralipride; xipamide; Z-335 of
Zeria (2-[2-(4-
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chlorophenylsulfonylaminomethyl)indan-5-yliacetic acid); zafirlukast;
zonisamide; and
salts thereof.
In a preferred embodiment, the aminosulfonyl-comprising drug is a selective
COX-
2 inhibitory drug of low water solubility. Suitable selective COX-2 inhibitory
drugs are
.. compounds having the formula (III):
R1
R4 ,/
(X)n
1
0\\
R3
R2
0 (III)
wherein:
A is a substituent selected from partially unsaturated or unsaturated
heterocyclic
and partially unsaturated or unsaturated carbocyclic rings, preferably a
heterocyclic group
.. selected from pyrazolyl, furanoyl, isoxazolyl, pyridinyl, cyclopentenonyl
and
pyridazinonyl groups;
X is 0, S or CH2;
n is 0 or 1;
.. R1 is at least one subsituent selected from heterocyclyl, cycloalkyl,
cycloalkenyl and aryl,
and is optionally substituted at a substitutable position with one or more
radicals selected
from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl,
haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsufinyl,
halo, alkoxy
and alkylthio;
.. R2 is NH2 group;
R3 is one or more radicals selected from hydrido, halo, alkyl, alkenyl,
alkynyl, oxo, cyano,
carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl,
cycloalkyl, aryl,
haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclyalkyl, acyl,
alkylthioalkyl,
hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl,
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arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-
arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl,
carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-
arylamino,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-
aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio,
aralkylthio,
alkylsulfinyl, alkylsulfonyl, amino sulfonyl, alkylaminosulfonyl, N-
arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R3 being optionally substituted
at a
substitutable position with one or more radicals selected from alkyl,
haloalkyl, cyano,
carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino,
arylamino, nitro, alkoxyalkyl, alkylsufinyl, halo, alkoxy and alkylthio; and
R4 is selected from hydrido and halo.
Particularly suitable selective COX-2 inhibitory drugs are compounds having
the
= formula (IV):
0
S \
NH2-
X
R4 (IV)
where R4 is hydrogen or a Ci4 alkyl or alkoxy group, X is N or CR5 where R5 is
hydrogen
or halogen, and Y and Z are independently carbon or nitrogen atoms defining
adjacent
atoms of a five-to-six-membered ring that is unsubstituted or substituted at
one or more
positions with oxo, halo, methyl, or halomethyl groups. Preferred such five-to
six-
membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and
pyridine
rings substituted at no more than one position.
Illustratively, compositions of the invention are suitable for celecoxib,
deracoxib,
valdecoxib and JTE-522, more particularly celecoxib, paracoxib and valdecoxib.
Other
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examples of suitable compositions include Acetazolamide CAS Registry Number:
59-66-
5, Acetohexamide CAS Registry Number: 968-81-0, Alpiropride CAS Registry
Number:
81982-32-3, Althiazide CAS Registry Number: 5588-16-9, Ambuside CAS Registry
Number: 3754-19-6,Amidephrine CAS Registry Number: 3354-67-4, Amosulalol CAS
Registry Number: 85320-68-9, Amsacrine CAS Registry Number: 51264-14-3,
Argatroban CAS Registry Number: 74863-84-6, Azosemide CAS Registry Number:
27589-33-9, Bendroflumethiazide CAS Registry Number: 73-48-3, Benzthiazide CAS
Registry Number: 91-33-8, Benzylhydrochlorothiazide CAS Registry Number: 1824-
50-
6, p-(Benzylsulfonamido)benzoic Acid CAS Registry Number: 536-95-8, Bosentan
CAS Registry Number: 147536-97-8, Brinzolamide CAS Registry Number: 138890-62-
7
Bumetanide CAS Registry Number: 28395-03-1, Butazolamide CAS Registry Number:
16790-49-1, Buthiazide CAS Registry Number: 2043-38-1, Carbutamide CAS
Registry
Number: 339-43-5, Celecoxib CAS Registry Number: 169590-42-5,
Chloraminophenamide CAS Registry Number: 121-30-2, Chlorothiazide CAS Registry
Number: 58-94-6,Chlorpropamide CAS Registry Number: 94-20-2, Chlorthalidone
CAS
Registry Number: 77-36-1, Clofenamide CAS Registry Number: 671-95-4, Clopamide
CAS Registry Number: 636-54-4, Clorexolone CAS Registry Number: 2127-01-7,
Cyclopenthiazide CAS Registry Number: 742-20-1, Cyclothiazide CAS Registry
Number:
2259-96-3, Daltroban CAS Registry Number: 79094-20-5, Delavirdine CAS Registry
Number: 136817-59-9, Diazoxide CAS Registry Number: 364-98-7, Dichlorphenamide
CAS Registry Number: 120-97-8, Disulfamide CAS Registry Number: 671-88-5,
Dofetilide CAS Registry Number: 115256-11-6, Domitroban CAS Registry Number:
112966-96-8, Dorzolamide CAS Registry Number: 120279-96-1, Ethiazide CAS
Registry
Number: 1824-58-4, Ethoxzolamide CAS Registry Number: 452-35-7, Fenquizone CAS
Registry Number: 20287-37-0, Flumethiazide CAS Registry Number: 148-56-1, N2_
Formylsulfisomidine CAS Registry Number: 795-13-1, Furosemide CAS Registry
Number: 54-31-9, Glibomuride CAS Registry Number: 26944-48-9, Gliclazide CAS
Registry Number: 21187-98-4, Glimepiride CAS Registry Number: 93479-97-1,
Glipizide CAS Registry Number: 29094-61-9, Gliquidone CAS Registry Number:
33342-
05-1, Glisoxepid CAS Registry Number: 25046-79-1, N4-Beta-D-
Glucosylsulfanilamide
CAS Registry Number: 53274-53-6, Glyburide CAS Registry Number: 10238-21-8,
Glybuthiazol(e) CAS Registry Number: 535-65-9, Glybuzole CAS Registry Number:
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-30-
1492-02-0, Glyhexamide CAS Registry Number: 451-71-8, Glymidine CAS Registry
Number: 339-44-6, Glypinamide CAS Registry Number: 1228-19-9,
Hydrochlorothiazide
CAS Registry Number: 58-93-5, Hydroflumethiazide CAS Registry Number: 135-09-
1,
Ibutilide CAS Registry Number: 122647-31-8, Indapamide CAS Registry Number:
26807-65-8, Mafenide CAS Registry Number: 138-39-6, Mefruside CAS Registry
Number: 7195-27-9, Methazolamide CAS Registry Number: 554-57-4,
Methyclothiazide CAS Registry Number: 135-07-9, Metolazone CAS Registry
Number:
17560-51-9, Naratriptan CAS Registry Number: 121679-13-8, Nimesulide CAS
Registry
Number: 51803-78-2, Noprylsulfamide CAS Registry Number: 576-97-6,
Paraflutizide
CAS Registry Number: 1580-83-2, Phenbutamide CAS Registry Number: 3149-00-6,
Phenosulfazole CAS Registry Number: 515-54-8, Phthalylsulfacetamide CAS
Registry
Number: 131-69-1, Phthalylsulfathiazole CAS Registry Number: 85-73-4,
Sulfacetamide
CAS Registry Number: 144-80-9, Sulfachlorpyridazine CAS Registry Number: 80-32-
0,
Sulfachrysoidine CAS Registry Number: 485-41-6, Sulfacytine CAS Registry
Number:
17784-12-2, Sulfadiazine CAS Registry Number: 68-35-9, Sulfadicramide CAS
Registry
Number: 115-68-4, Sulfadimethoxine CAS Registry Number: 122-11-2, Sulfadoxine
CAS Registry Number: 2447-57-6, Piretanide CAS Registry Number: 55837-27-9,
Polythiazide CAS Registry Number: 346-18-9, Quinethazone CAS Registry Number:
73-
49-4 Ramatroban CAS Registry Number: 116649-85-5, Salazosulfadimidine CAS
Registry Number: 2315-08-4, Sampatrilat CAS Registry Number: 129981-36-8,
Sematilide CAS Registry Number: 101526-83-4, Sivelestat CAS Registry Number:
127373-66-4, Sotalol CAS Registry Number: 3930-20-9, Soterenol CAS Registry
Number: 13642-52-9, Succinylsulfathiazole CAS Registry Number: 116-43-8,
Suclofenide CAS Registry Number: 30279-49-3, Sulfabenzamide CAS Registry
Number:
127-71-9, Sulfaethidole CAS Registry Number: 94-19-9, Sulfaguanole CAS
Registry
Number: 27031-08-9, Sulfalene CAS Registry Number: 152-47-6, Sulfaloxic Acid
CAS
Registry Number: 14376-16-0, Sulfamerazine CAS Registry Number: 127-79-7,
Sulfameter CAS Registry Number: 651-06-9, Sulfamethazine CAS Registry Number:
57-
68-1, Sulfamethizole CAS Registry Number: 144-82-1, Sulfamethomidine CAS
Registry
Number: 3772-76-7, Sulfamethoxazole CAS Registry Number: 723-46-6,
Sulfamethoxypyridazine CAS Registry Number: 80-35-3, Sulfametrole CAS Registry
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- 31 -
Number: 32909-92-5, Sulfamidochrysoidine CAS Registry Number: 103-12-8,
Sulfamoxole CAS Registry Number: 729-99-7, Sulfanilamide
CAS Registry Number: 63-74-1, 4-Sulfanilamidosalicylic Acid CAS Registry
Number:
6202-21-7, N4-Sulfanilylsulfanilamide CAS Registry Number: 547-52-4,
Sulfanilylurea
CAS Registry Number: 547-44-4, N-Sulfanily1-3,4-xylamide CAS Registry Number:
120-34-3, Sulfaperine CAS Registry Number: 599-88-2, Sulfaphenazole CAS
Registry
Number: 526-08-9, Sulfaproxyline CAS Registry Number: 116-42-7, Sulfapyrazine
CAS
Registry Number: 116-44-9, Sulfapyridine CAS Registry Number: 144-83-2,
Sulfarside
CAS Registry Number: 1134-98-1, Sulfasalazine, CAS Registry Number: 599-79-1,
Sulfasomizole CAS Registry Number: 632-00-8, Sulfasymazine CAS Registry
Number:
1984-94-7, Sulfathiazole CAS Registry Number: 72-14-0, Sulfathiourea CAS
Registry
Number: 515-49-1, Sulfisomidine CAS Registry Number: 515-64-0, Sulfisoxazole
CAS
Registry Number: 127-69-5, Sulpiride CAS Registry Number: 15676-16-1,
Sulprostone
CAS Registry Number: 60325-46-4, Sulthiame CAS Registry Number: 61-56-3,
Sumatriptan CAS Registry Number: 103628-46-2, Tamsulosin CAS Registry Number:
106133-20-4, Taurolidine CAS Registry Number: 19388-87-5, Teclothiazide CAS
Registry Number: 4267-05-4, Tevenele CAS Registry Number: 4302-95-8, Tirofiban
CAS Registry Number: 144494-65-5,
Tolazamide CAS Registry Number: 1156-19-0, Tolbutamide CAS Registry Number: 64-
77-7, Tolcyclamide CAS Registry Number: 664-95-9, Torsemide CAS Registry
Number:
56211-40-6, Trichlormethiazide CAS Registry Number: 133-67-5, Tripamide CAS
Registry Number: 73803-48-2, Veralipride CAS Registry Number: 66644-81-3,
Xipamide CAS Registry Number: 14293-44-8, Zafirlukast CAS Registry Number:
107753-78-6, Zonisamide CAS Registry Number: 68291-97-4.
In a particularly preferred embodiment, the pharmaceutical compositions of the
present invention comprise a salt of celecoxib, (e.g., sodium, lithium,
potassium,
magnesium, or calcium salt). The salt may be significantly more soluble in
water than
presently-marketed neutral celecoxib. Due to the high pKa of celecoxib
(approximately
11), salts only form under strongly basic conditions. Typically, more than
about one
equivalent of a base is required to convert celecoxib to its salt form. A
suitable aqueous
solution for converting celecoxib to a salt has a pH of about 11.0 or greater,
about 11.5 or
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greater, about 12 or greater, or about 13 or greater. Typically, the pH of
such a solution is
about 12 to about 13. Although celecoxib is a preferred embodiment, the
invention
includes other pharmaceutical drugs with a plc greater than 9, 9.5, 10, 10.5,
11, 11.5, 12,
12.5, or 13. The drug may normally be in a neutral form or a salt form may
already exist.
Salts of the pharmaceutical, such as celecoxib, are formed by reaction of the
pharmaceutical with an acceptable base. Acceptable bases include, but are not
limited to,
metal hydroxides and alkoxides. Metals include alkali metals (sodium,
potassium, lithium,
cesium), alkaline earth metals (magnesium, calcium), zinc, aluminum, and
bismuth.
Alkoxides include methoxide, ethoxide, n-propoxide, isopropoxide and t-
butoxide.
Additional bases include arginine, procaine, and other molecules having amino
or
guanidinium moieties with sufficiently high plc's (e.g., pKa's greater than
about 11, pKa's
greater than about 11.5, or pKa's greater than about 12), along with compounds
having a
carbon-alkali metal bond (e.g., t-butyl lithium). Sodium hydroxide and sodium
ethoxide
are preferred bases. The amount of base used to form a salt is typically about
one or more,
about two or more, about three or more, about four or more, about five or
more, or about
ten or more equivalents relative to the pharmaceutical. Preferably, about
three to about
five equivalents of one or more bases are reacted with the pharmaceutical to
form a salt.
A pharmaceutical salt can be transformed into a second pharmaceutical salt by
transmetallation or another process that replaces the cation of the first
pharmaceutical salt.
In one example, a sodium salt of the pharmaceutical is prepared and is
subsequently
reacted with a second salt such as an alkaline earth metal halide (e.g.,
MgBr2, MgCl2,
CaC12, CaBr2), an alkaline earth metal sulfate or nitrate (e.g., Mg(NO3)2,
Mg(SO4)2,
Ca(NO3)2, Ca(SO4)2), or an alkaline metal salt of an organic acid (e.g.
calcium formate,
magnesium formate, calcium acetate, magnesium acetate, calcium propionate,
magnesium
propionate) to form an alkaline earth metal salt of the pharmaceutical.
In a preferred embodiment of the present invention, the pharmaceutical salts
are
substantially pure. A salt that is substantially pure can be greater than
about 80% pure,
greater than about 85% pure, greater than about 90% pure, greater than about
95% pure,
greater than about 98% pure, or greater than about 99% pure. Purity of a salt
can' be
measured with respect to the amount of salt (as opposed to unreacted neutral
pharmaceutical or base) or can be measured with respect to a specific
polymorph, co-
crystal, solvate, desolvate, hydrate, dehydrate, or anhydrous form of a salt.
=
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A pharmaceutical salt as described herein may be significantly more soluble in
water than the existing neutral form, such as the free acid alone or the
presently-marketed
neutral celecoxib (CELEBREX), and is typically at least about twice, at least
about three
times, at least about five times, at least about ten times, at least about
twenty times, at least
.. about fifty times, or at least about one hundred times more soluble in
water or SGF than
the neutral form. CELEBREX is marketed by Pfizer Inc. and G. D. Searle & Co.
(Pharmacia Corporation), and described on pages 2676-2680 and 2780-2784 of the
2002
edition of the Physicians Desk Reference (also referred to herein as presently-
marketed
celecoxib). The reference compounds to the present invention herein can refer
to the free
.. acid neutral celecoxib, either crystalline or amorphous, or CELEBREX. The
solubility
depends on whether the salt is tested alone, or as a formulation further
comprising the
precipitation retardants and enhancers of the invention.
After dissolution, typically in an aqueous or partially-aqueous solution
(e.g., where
one or more polar organic solvents are a co-solvent), the salt can be
neutralized by an acid
.. or by dissolved gases such as carbon dioxide. Typically, the pH of such a
solution is 11 or
less, 10 or less, or 9 or less. Neutralizing the salt results in precipitation
of an amorphous
or metastable crystalline form of neutral celecoxib. Typically, neutralizing a
pharmaceutical salt includes protonating the majority of negatively charged
anions. For
celecoxib, protonation results in the formation of amorphous and/or metastable
crystalline
.. celecoxib, which are "neutral" (i.e., predominantly uncharged). Preferably,
the neutral
pharmaceutical (including amorphous and/or metastable crystalline forms
thereof, such as
celecoxib) comprises 10% mol or less of charged molecules. For example, at
about pH 2
(e.g., about the pH of the stomach interior), solutions of the sodium salt of
celecoxib
precipitate immediately as an amorphous form of neutral celecoxib. The
amorphous form
.. converts to a neutral metastable crystalline form, which subsequently
becomes the stable,
needle-like, insoluble form of neutral celecoxib. For example, amorphous
neutral
celecoxib formed from the salts of the present invention, e.g., the sodium
salt of Example
1, converts to metastable crystalline neutral celecoxib over about 5 to about
10 minutes.
Amorphous neutral celecoxib can be characterized by a lack of regular crystal
structure,
.. while metastable crystalline neutral celecoxib can be distinguished from
typical crystalline
neutral celecoxib by the PXRD pattern of isolated material.
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Amorphous and metastable crystalline forms of neutral celecoxib are more
soluble
and likely more readily absorbed by a subject than stable crystalline forms of
neutral
celecoxib, because the energy required for a drug molecule to escape from a
stable crystal
is greater than the energy required for the same drug molecule to escape from
a non-
crystalline, amorphous form or a metastable crystalline form. However, the
instability of
neutral amorphous and neutral metastable crystalline forms makes them
difficult to
formulate as pharmaceutical compositions. As is described in U.S. Publication
No.
2002/0006951, without stabilization by .a crystallization inhibitor, such as a
polymer,
amorphous
neutral celecoxib converts back to a stable, insoluble crystalline form of
free neutral
celecoxib. These teachings are incomplete and fall far short of the present
invention
however, as we have surprisingly found that far superior formulations can be
made from
the combination of a salt or co-crystal, precipitation retardant, and an
optional enhancer.
Whereas others have focused on the initial solubilization of celecoxib, the
present
invention is equally concerned with dissolution and precipitation of the drug
(See e.g., WO
02/102376 and WO 01/78724). Moreover, until now, no one has disclosed a salt
of
celecoxib and the vital role it plays in dissolution and precipitation.
Further, no one has
taught the addition of an enhancer to a precipitation retardant.
Further aspects of the invention relate to liquid formulations of compounds of
the
present invention (e.g. celecoxib). In these aspects, the drug is solubilized
either directly
with the precipitation retardant or with a solubilizer or solvent. Preferred
solubilizers are
polyethylene oxides. More preferably, the polyethylene oxide is a surfactant.
Preferred
ethylene oxides comprise the functional group ¨ (C2H40),- where n Other
preferred
polyethylene oxides are poloxamers having the general formula
HO(C2H40)1(C3H60)b(C2H4O)aH where a where a 3, where a and b where
a and b where a and b where a and b 60.
An aminosulfonyl containing API (celecoxib) was crystallized with molecules
comprising at least two oxygen atoms (e.g., ether groups) to examine the
physical
interactions involved in precipitation retardation by the precipitation
retardant. From these
results, in one aspect of the present invention the precipitation retardant
compounds,
preferably surfactants, have the following physical properties or
characteristics: The
retardant molecule comprises at least one, preferably two, 10, 25, 40, 50, 60,
80, 100 or
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more functional interacting groups, wherein a functional interacting group
comprises two
oxygen atoms, with each of the two oxygen atoms interacting (e.g., hydrogen
bonding)
with the API. Preferably the two oxygen atoms interact with the aminosulfonyl
group of
the API. Preferably the aminosulfonyl group is -SO2NH2. The two interacting
oxygen
atoms are preferably separated by between about 3.6 angstroms to about 5.8
angstroms,
about 3.9 angstroms to about 5.5 angstroms, 4.3 to about 5.2 angstroms, 4.6 to
about 5.0
angstroms, or about 4.7 to about 4.9 angstroms. In one embodiment, the two
oxygen
atoms are separated by at least three atoms. In another embodiment, the two
oxygen atoms
are separated by 5 atoms. In one embodiment of a 5 atom separation, the two
oxygen
atoms are separated by 4 carbons and one oxygen atom. In a more specific 5
atom
separation embodiment, the order of the 5 atoms is -C-C-O-C-C-, whereby a
single unit of
the functional interacting group (including the two interacting oxygen atoms),
is -0-C-C-
0-C-C-0-.
Glycol ethers can also be used as solubilizers of neutral or other forms of
celecoxib
including those that conform with the formula:
R1-04(CH2),,O)ri-R2 (V)
Wherein R.1 and R2 are independently hydrogen or C1-6 alkyl, C1-6 alkenyl,
phenyl or
benzyl groups, but no more than one of Rl and R2 is hydrogen; m is an integer
of 2 to
about 5; and n is an integer of 1 to about 20. It is preferred that one of Rl
and R2 is a C14
alkyl group and the other is hydrogen or a C14 alkyl group; more preferably at
least one of
Rl and R2 is a methyl or ethyl group. It is preferred that m is 2. It is
preferred that n is an
integer of 1 to about 4, more preferably 2. Non-surfactant glycol ethers, or
more
specifically glycol ethers of formula (V) and above, can also be specifically
excluded from
the present invention. Preferably, the glycol ethers are surfactants.
Compositions of the present invention optionally comprise one or more
pharmaceutically acceptable co-solvents. Non-limiting examples of co-solvents
suitable
for use in compositions of the present invention include any glycol ether
listed above;
alcohols, for example ethanol and n-butanol; glycols not listed above; for
example
propylene glycol, 1,3-butanediol and polyethylene glycol such as PEG-400;
oleic and
linoleic acid triglycerides, for example soybean oil; caprylic/capric
triglycerides, for
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example MiglyolTM 812 of Huls; caprylic/capric mono- and diglycerides, for
example
CapmulTM MCM of Abitec; polyoxyethylene caprylic/capric glycerides such as
polyoxyethylene caprylic/capric mono- and diglycerides, for example LabrasolTM
of
Gattefosse; propylene glycol fatty acid esters, for example propylene glycol
laurate;
polyoxyethylene castor oil, for example CremophorTM EL of BASF;
polyoxyethylene
glyceryl trioleate, for example TagatTm TO of Goldsclunidt; and lower alkyl
esters of fatty
acids, for example ethyl butyrate, ethyl caprylate and ethyl oleate.
Celecoxib salts are preferred because they are stable, such that they can be
formulated as pharmaceutical compositions and stored before administration to
a subject.
Only after dissolution and subsequent neutralization do the celecoxib salts
precipitate as or
transform into substantially amorphous neutral and then substantially
metastable
crystalline neutral forms. Preferably, dissolution and neutralization of
celecoxib salts
occur in situ in the gastrointestinal tract of a subject (e.g., stomach,
duodenum, ileum),
such that a maximal amount of amorphous and/or metastable crystalline neutral
celecoxib
is present with a maximum amount of celecoxib in solution after administration
(e.g., in
vivo), rather than before administration.
The salts, hydrates, and solvates of the present invention are non-limiting
examples
of species which can be solubilized more effectively in water, SGF, and/or SIF
than their
respective free forms. For example, celecoxib sodium is more soluble in water
than
celecoxib free acid. A "spring" is defined as a high energy species that
drives
supersaturation of the API. Such a high energy species is less stable and,
therefore, more
soluble than an analogous relatively more stable form (e.g., free form,
polymorph, etc.).
The intrinsic solubility of a high energy species can be 1.5, 2, 3, 4, 5, 6,
7, 8, 9, 10, 25, 50,
75, 100 or more times greater than for an analogous more stable form. A spring
can be in
the form of, for example,, a free acid, a free base, a salt, a liquid, a
hydrate, a solvate, a co-
crystal, etc. In this example, the sodium salt acts as a "spring" to drive the
supersaturation
of the API. One embodiment of the present invention provides for an API in a
form with
improved aqueous solubility. Once dissolution takes place, inhibition of
precipitation
becomes important. The inhibition of precipitation acts as a "parachute" to
slow the rate
of API precipitating from solution. Another embodiment of the present
invention provides
for an API in a formulation which inhibits precipitation upon initial
dissolution. Both
aspects are of great importance in a pharmaceutical composition. The ability
of a
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pharmaceutical composition to solubilize an API and to maintain the API in
solution for a
duration long enough to cause the desired therapeutic effect is vital.
Dissolution Modulation:
In another aspect of the present invention, the dissolution profile of the API
is
modulated whereby the aqueous dissolution rate or the dissolution rate in
simulated gastric
fluid or in simulated intestinal fluid, or in a solvent or plurality of
solvents is increased.
Dissolution rate is the rate at which API solids dissolve in a dissolution
medium. For APIs
whose absorption rates are faster than the dissolution rates (e.g., steroids),
the rate-limiting
step in the absorption process is dissolution. Because of a limited residence
time at the
absorption site, APIs that are not dissolved before they are removed from the
intestinal
absorption site are considered useless. Therefore, the rate of dissolution has
a major
impact on the performance of APIs that are poorly soluble. Because of this
factor, the
dissolution rate of APIs in solid dosage forms is an important, routine,
quality control
parameter used in the API manufacturing process.
Dissolution rate = K S (Cs-C)
where K is the dissolution rate constant, S is the surface area, Cs is the
apparent solubility
(saturated concentration), and C is the concentration of API in the
dissolution media.
For rapid API absorption, Cs-C is approximately equal to C. The dissolution
rate of APIs
may be measured by conventional means known in the art.
The increase in the dissolution rate of a composition of the present
invention, as
compared to the neutral free form, may be specified, such as by 10, 20, 30,
40, 50, 60, 70,
80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75,
100, 125, 150,
175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than
the free form
in the same solution. Conditions under which the dissolution rate is measured
are
discussed above. The increase in dissolution may be further specified by the
time the
composition remains supersaturated.
Examples of above embodiments include: compositions with a dissolution rate,
at
37 degrees C and a pH of 7.0, that is increased at least 5 fold over the
neutral free form,
compositions with a dissolution rate in SGF that is increased at least 5 fold
over the neutral
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free form, compositions with a dissolution rate in SIF that is increased at
least 5 fold over
the neutral free form.
The present invention demonstrates that the length of time in which celecoxib
or
other APIs remain in solution can be increased to a surprising high degree by
using a salt
or co-crystal form with the presence of a precipitation retardant, normally a
surfactant
(e.g., poloxamer, TPGS, SDS, etc.) and an optional enhancer (e.g.,
hydroxypropyl
cellulose) as discussed herein. The presence of these agents allows the
formation of a
supersaturated solution of the API and a relatively high concentration of API
will remain
in solution for an extended period of time (as compared to the neutral free
acid). The
presence of these components does not preclude the presence of other further
agents,
including further surfactants such as, polyethylene glycol and polyoxyethylene
sorbitan
esters. The additional presence of other suitable surfactants is also not
precluded and these
are listed herein. Further additional agents which might slow the rate of
precipitation such
as polyvinylpyrrolidone are also not precluded. Neutral free celecoxib, for
example, has a
solubility in water of less than 1 microgram/mL and cannot be maintained as a
supersaturated solution for any appreciable time. The present invention has
drawn
compositions that can be maintained for a period of time (e.g., 15, 30, 45, 60
minutes and
longer) as supersaturated solutions at concentrations 2, 3, 5, 7, 10, 20, 30,
40, 50, 60, 70,
80, 90, or 100% greater, or solubilities increased by 3, 4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30,
40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or
100,000 fold
over the neutral free form in the same solution (e.g., water or SGF).
The amount of precipitation inhibitor or enhancer may each or together be less
than
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80,
or 90 percent w/w
of the formulated pharmaceutical. The percent w/w for either or both
precipitation
inhibitor and enhancer may also be in a range represented by any two integers
of 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, or 90.
Celecoxib salts of the present invention are typically stable (i.e., more than
90% of
the celecoxib salt does not change in composition or crystalline structure)
for at least about
one week, at least about one month, at least about two months, at least about
three months,
at least about six months, at least about nine months, at least about one
year, or at least
about two years at room temperature in the absence of moisture. Room
temperature
typically ranges from about 15 degrees C to about 30 degrees C. The absence of
moisture,
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as defined herein, refers to celecoxib salts not contacting quantities of
liquid, particularly
water or alcohols. For purposes of the present invention, gases such as water
vapor are not
considered to be moisture.
The compositions of the present invention, including the active pharmaceutical
ingredient (API) and formulations comprising the API, are suitably stable for
pharmaceutical use. Preferably, the API or formulations thereof of the present
invention
are stable such that when stored at 30 degrees C for 2 years, less than 0.2%
of any one
degradant is formed. The term degradant refers herein to product(s) of a
single type of
chemical reaction. For example, if a hydrolysis event occurs that cleaves a
molecule into
two products, for the purpose of the present invention, it would be considered
a single
degradant. More preferably, when stored at 40 degrees C for 2 years, less than
0.2% of
any one degradant is formed. Alternatively, when stored at 30 degrees C for 3
months,
less than 0.2% or 0.15%, or 0.1% of any one degradant is formed, or when
stored at 40
degrees C for 3 months, less than 0.2% or 0.15%, or 0.1% of any one degradant
is formed.
Further alternatively, when stored at 60 degrees C for 4 weeks, less than 0.2%
or 0.15%, or
0.1% of any one degradant is formed. The relative humidity (RH) may be
specified as
ambient (RH), 75% (RH), or as any single integer between 1 to 99% (RH).
Bioavailability Modulation:
The methods of the present invention are used to make a pharmaceutical API
formulation with greater solubility, dissolution, bioavailability, AUC,
reduced time to
Tmax, the average time from administration to reach peak blood serum levels,
higher Cmax,,
the average maximum blood serum concentration of API following administration,
and
longer T112 , the average terminal half-life of API blood serum concentration
following
Tmaõ, when compared to the neutral free form.
AUC is the area under the curve of plasma concentration of API (not logarithm
of
the concentration) against time after API administration. The area is
conveniently
determined by the "trapezoidal rule": The data points are connected by
straight line
segments, perpendiculars are erected from the abscissa to each data point, and
the sum of
the areas of the triangles and trapezoids so constructed is computed. When the
last
measured concentration (Cs, at time ts) is not zero, the AUC from ts to
infinite time is
estimated by Cs/kei.
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The AUC is of particular use in estimating bioavailability of APIs, and in
estimating total clearance of APIs (C1T). Following single intravenous doses,
AUC =
D/C1T, for single compartment systems obeying first-order elimination kinetics
Alternatively, AUG = Co/kei. With routes other than the intravenous, AUC = F =
D/C1T,
where F is the absolute bioavailability of the API.
Thus, in a further aspect, the present invention provides a process for
modulating
the bioavailability of an API when administered in its normal and effective
dose range,
whereby the AUG is increased, the time to Tmax is reduced, or C. is increased,
which
process comprises:
(1) forming a salt or co-crystal of an API;
(2) combining the salt or co-crystal with a precipitation
retardant, and
optionally, further with an enhancer.
Examples of the above embodiments include: compositions with a time to Tmax
that
is reduced by at least 10% as compared to the neutral free form, compositions
with a time
to T. that is reduced by at least 20% over the free form, compositions with a
time to T.
that is reduced by at least 40% over the free form, compositions with a time
to Tmax that is
reduced by at least 50% over the free form, compositions with a Tmax that is
reduced by at
least 60% over the free form, compositions with a Tmax that is reduced by at
least 70% over
the free form, compositions with a Tmaõ that is reduced by at least 80% over
the free form,
compositions with a Cmax that is increased by at least 20% over the free form,
compositions
with a Cmax that is increased by at least 30% over the free form, compositions
with a Cmax
that is increased by at least 40% over the free form, compositions with a C.
that is
increased by at least 50% over the free form, compositions with a Cmax that is
increased by
at least 60% over the free form, compositions with a Cmaõ that is increased by
at least 70%
over the free form, compositions with a C. that is increased by at least 80%
over the free
form, compositions with an AUG that is increased by at least 10% over the free
form,
compositions with an AUG that is increased by at least 20% over the free form,
compositions with an AUG that is increased by at least 30% over the free form,
compositions with an AUG that is increased by at least 40% over the free form,
compositions with an AUG that is increased by at least 50% over the free form,
compositions with an AUG that is increased by at least 60% over the free form,
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compositions with an AUC that is increased by at least 70% over the free form,
or
compositions with an AUC that is increased by at least 80% over the free form.
The uptake of a drug by a subject can also be assessed in terms of maximum
blood
serum concentration and time to reach maximum blood serum concentration.
Pharmaceutical compositions with a more rapid onset to therapeutic effect
typically reach a
higher maximum blood serum concentration (Cmax) a shorter time after oral
administration
(Tinax). Preferably, compositions, preferably including salts, of the present
invention have
a higher Cmax and/or a shorter T.,õ than presently-marketed celecoxib. The
Trna, for the
compositions of the present invention occurs within about 60 minutes, 55
minutes, 50
minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20
minutes, 15
minutes, 10 minutes, or within about 5 minutes of administration (e.g., oral
administration). Even more preferably, the therapeutic effects of compositions
of the
present invention begin to occur within about 60 minutes, 55 minutes, 50
minutes, 45
minutes, 40 minutes, 35 minutes, 30 minutes, within about 25 minutes, within
about 20
minutes, within about 15 minutes, within about 10 minutes, or within about 5
minutes of
administration (e.g., oral administration). In US Pat. No. 6,579,895, Karim et
al. report
about a 2.5-fold increase in Cmax over that of presently-marketed celecoxib
(CELEBREX)
by the suspension of neutral free form celecoxib particles in an aqueous
liquid. The
present invention produces an increase in Cmax of about four-fold over that of
the
presently-marketed drug. In addition, the present invention yields an increase
in the AUC
of at least about two-fold over that of presently-marketed celecoxib.
Compositions of the present invention have a bioavailability greater than
neutral
celecoxib and currently-marketed CELEBREX. In several embodiments, the
compositions
of the present invention have a bioavailability of at least 50%, 60%, 65%,
70%, 75%, 80%,
85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% greater than
that of
neutral celecoxib and currently-marketed CELEBREX.
Administration of the present invention to a subject may result in effective
pain
relief. The desired therapeutic effect calls for inter alia an appropriate
blood serum
concentration of the API. Effective blood serum concentrations of celecoxib
can range
based on many factors (e.g., age, weight, etc.) but generally are about 10
ng/mL to about
500 ng/mL, or about 25 ng/mL to 400 ng/mL, or about 50 ng/mL to about 300
ng/mL.
Specifically, about 250 ng/mL is often suitable for effective pain relief. In
general, an
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effective dosage of celecoxib will be found in the range of about 1 mg/kg to
about 6 mg/kg
body weight. For an average 75 kg subject, this range equates to a celecoxib
dose of about
75 mg to about 450 mg. This is particularly in view of the extensive binding
of celecoxib
to plasma albinum which was known to occur following oral administration
(Davies et al.,
Clin. Pharmacokinet 38:225-242, 2000 and US Pat No. 6,579,895).
Thus, one could not have predicted that a particular blood
serum concentration would produce analgesia.
An "effective pain-relieving concentration" or "effective pain-relieving blood
serum concentration" as used herein is intended to mean a blood serum level in
a patient
which when tested in a standardized test involving patient scoring of the
severity of pain,
achieves a mean score indicating pain relief. In one such test as described
herein below,
patients score pain on a scale of from 0 (no reduction in severity of pain) to
4 (complete
relief of pain) and a mean score equal to or greater than a given value is
deemed to
constitute effective pain-relief. A mean score of 0.5 or greater and, more
preferably, 1.0 or
greater in such a test, as exemplified herein, is deemed to constitute
effective pain relief.
The skilled artisan will appreciate, however, that other approaches can be
used to assess
the severity of pain and relief from such pain.
Thus, one aspect of the present invention involves a therapeutic method for
analgesia in which a composition comprising a celecoxib salt or co-crystal is
administered
orally to a subject, in a formulation that provides detectable pain relief not
later than about
minutes after oral administration. By "detectable pain relief', it is meant
that the
fonnulation produces effective pain relief that is measurable by a standard
method such as
that described above. For example, a formulation, which achieves a mean score
of 0.5 or
greater and, more preferably, 1.0 or greater on a scale of from 0 to 4 in a
testing system as
25 described above, is deemed to provide detectable pain relief. The
invention is not limited
to use of any particular type of formulation, so long as it exhibits the
pharmacokinetic
profile defined herein. Examples of suitable formulation types are described
below.
Protocols for conducting human phannacokinetic studies are well known in the
art
and any standard protocol can be used to determine whether a particular
celecoxib
30 formulation satisfies the phannacokinetic criteria set out herein. An
example of a suitable
protocol is described below.
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An advantage of the present invention is that relief of pain, even intense
pain as can
occur, for example, following oral, general or orthopedic surgery, is achieved
significantly
faster, i.e., in a significantly shorter time after administration, than is
achievable with
standard formulations of celecoxib.
Any standard pharmacokinetic protocol can be used to determine blood serum
concentration profile in humans following oral administration of a celecoxib
formulation,
and thereby establish whether that formulation meets the pharmacokinetic
criteria set out
herein.
Illustratively, a randomized single-dose crossover study can be performed
using a
group of healthy adult human subjects. The number of subjects is sufficient to
provide
adequate control of variation in a statistical analysis, and is typically
about 10 or greater,
although for certain purposes a smaller group can suffice. Each subject
receives, by oral
administration at time zero, a single dose (e.g., 200 mg) of a test
formulation of celecoxib,
normally at around 8 am following an overnight fast. The subject continues to
fast and
remains in an upright position for about 4 hours after administration of the
celecoxib
formulation. Blood samples are collected from each subject before
administration (e.g., 15
minutes prior to administration) and at several intervals after
administration. For the
present purpose it is preferred to take several samples within the first hour,
and to sample
less frequently thereafter. Illustratively, blood samples can be collected 15,
30, 45, 60 and
90 minutes after administration, then every hour from 2 to 10 hours after
administration.
Optionally additional blood samples can be taken later, for example 12 and 24
hours after
administration. If the same subjects are to be used for study of a second test
formulation, a
period of at least 7 days is allowed to elapse before administration of the
second
formulation. Plasma is separated from the blood samples by centrifugation and
the
separated plasma is analyzed for celecoxib by a validated high performance
liquid
chromatography (HPLC) procedure with a lower limit of detection of 10 ng/mL
(see for
example, Paulson et al., Drug Metab. Dispos. 27:1133-1142, 1999; Paulson et
al., Drug
Metab. Dispos. 28:308-314, 2000; Davies et al). Blood serum concentrations of
celecoxib
referenced herein are intended to mean total celecoxib concentrations
including both free
and bound celecoxib as determined upon extraction from the plasma sample and
HPLC
detection according to methods known in the art such as those identified
above.Ailments
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treatable with celecoxib and salts thereof of the present invention are
discussed below.
Treatment of chronic pain is a preferred embodiment of the present invention.
Dose Response Modulation:
In a further aspect the present invention provides a process for improving the
dose
response of an API by making a composition of the present invention.
Dose response is the quantitative relationship between the magnitude of
response
and the dose inducing the response and may be measured by conventional means
known in
the art. The curve relating effect (dependent variable) to dose (independent
variable) for
an API-cell system is the "dose-response curve". Typically, the dose-response
curve is the
measured response to an API plotted against the dose of the API (mg/kg) given.
The dose
response curve can also be a curve of AUC against the dose of the API given.
The dose-response curve for presently-marketed celecoxib is nonlinear.
Preferably,
the dose-response curve for celecoxib salt and co-crystal compositions of the
present
invention is linear or contains a larger linear region than presently-marketed
celecoxib.
Also, the absorption or uptake of presently-marketed celecoxib depends in part
on food
effects, such that uptake of celecoxib increases when taken with food,
especially fatty
food. Preferably, uptake of celecoxib salts of the present invention exhibits
a decreased
dependence on food, such that the difference in uptake of celecoxib salts when
taken with
food and when not taken with food is less than the difference in uptake of
presently-
marketed celecoxib.
Decreasing Hygroscopicity:
In a still further aspect the present invention provides for APIs with
decreased
hygroscopicity and a method for decreasing the hygroscopicity of an API by
making the
same. An aspect of the present invention provides a pharmaceutical composition
of an
API that is less hygroscopic than amorphous or crystalline free form.
Hygroscopicity can
be assessed by dynamic vapor sorption analysis, in which 5-50 mg of the
compound is
suspended from a Calm microbalance. The compound being analyzed should be
placed in
a non-hygroscopic pan and its weight should be measured relative to an empty
pan
composed of identical material and having nearly identical size, shape, and
weight.
Ideally, platinum pans should be used. The pans should be suspended in a
chamber
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through which a gas, such as air or nitrogen, having a controlled and known
percent
relative humidity (% RH) is flowed until eqilibrium criteria are met. Typical
equilibrium
criteria include weight changes of less than 0.01 % change over 3 minutes at
constant
humidity and temperature. The relative humidity should be measured for samples
dried
under dry nitrogen to constant weight (<0.01 % change in 3 minutes) at 40
degrees C
unless doing so would de-solvate or otherwise convert the material to an
amorphous
compound. In one aspect, the hygroscopicity of a dried compound can be
assessed by
increasing the RH from 5 to 95 % in increments of 5 % RH and then decreasing
the RH
from 95 to 5 % in 5 % increments to generate a moisture sorption isotherm. The
sample
weight should be allowed to equilibrate between each change in % RH. If the
compound
deliquesces or becomes amorphous above 75 % RH but below 95 % RH, the
experiment
should be repeated with a fresh sample and the relative humidity range for the
cycling
should be narrowed to 5-75 % RH or 10-75 % RH instead of 5-95 % RH. If the
sample
cannot be dried prior to testing due to lack of form stability, than the
sample should be
studied using two complete humidity cycles of either 10-75 % RH or 5-95 % RH,
and the
results of the second cycle should be used if there is significant weight loss
at the end of
the first cycle.
Hygroscopicity can be defined using various parameters. For purposes of the
present invention, a non-hygroscopic molecule should not gain or lose more
than 1.0 %, or
more preferably, 0.5 % weight at 25 degrees C when cycled between 10 and 75 %
RH
(relative humidity at 25 degrees C). The non-hygroscopic molecule more
preferably
should not gain or lose more than 1.0%, or more preferably, 0.5 % weight when
cycled
between 5 and 95 %RH at 25 degrees C, or 0.25 % of its weight between 10 and
75 % RH.
Most preferably, a non-hygroscopic molecule will not gain or lose more than
0.25 % of its
weight when cycled between 5 and 95 % RH.
Alternatively, for purposes of the present invention, hygroscopicity can be
defined
using the parameters of Callaghan et al., Equilibrium Moisture Content of
Pharmaceutical
Excipients, in API Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). Callaghan et
al. classified
the degree of hygroscopicity into four classes.
Class 1: Non-hygroscopic Essentially no moisture increases occur at
relative
humidities below 90 %.
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Class 2: Slightly hygroscopic Essentially no moisture increases occur at
relative
humidities below 80 %.
Class 3: Moderately hygroscopic Moisture content does not increase more than 5
%
after storage for 1 week at relative humidities below
60%.
Class 4: Very hygroscopic Moisture content increase may occur at
relative
humidities as low as 40 to 50 %.
Alternatively, for purposes of the present invention, hygroscopicity can be
defined
using the parameters of the European Pharmacopoeia Technical Guide (1999, p.
86) which
has defined hygroscopicity, based on the static method, after storage at 25
degrees C for 24
h at 80 % RH:
Slightly hygroscopic: Increase in mass is less than 2 % m/m and equal to or
greater
than 0.2 % m/m.
Hygroscopic: Increase in mass is less than 15 % m/m and equal to or greater
than
0.2 % m/m.
Very Hygroscopic: Increase in mass is equal to or greater than 15 % m/m.
Deliquescent: Sufficient water is absorbed to form a liquid.
Compositions of the present invention can be set forth as being in Class 1,
Class 2,
or Class 3, or as being Slightly hygroscopic, Hygroscopic, or Very
Hygroscopic.
Compositions of the present invention can also be set forth based on their
ability to reduce
hygroscopicity. Thus, preferred compositions of the present invention are less
hygroscopic
than the neutral free form. Further included in the present invention are
compositions that
do not gain or lose more than 1.0 % weight at 25 degrees C when cycled between
10 and
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75 % RH, wherein the reference compound gains or loses more than 1.0 % weight
under
the same conditions. Further included in the present invention are
compositions that do
not gain or lose more than 0.5 % weight at 25 degrees C when cycled between 10
and 75
% RH, wherein the reference compound gains or loses more than 0.5 % or more
than 1.0
% weight under the same conditions. Further included in the present invention
are
compositions that do not gain or lose more than 1.0 % weight at 25 degrees C
when cycled
between 5 and 95 % RH, wherein the reference compound gains or loses more than
1.0 %
weight under the same conditions. Further included in the present invention
are
compositions that do not gain or lose more than 0.5% weight at 25 degrees C
when cycled
between 5 and 95 % RH, wherein the reference compound gains or loses more than
0.5 %
or more than 1.0 % weight under the same conditions. Further included in the
present
invention are compositions that do not gain or lose more than 0.25 % weight at
25 degrees
C when cycled between 5 and 95 % RH, wherein the reference compound gains or
loses
more than 0.5 % or more than 1.0 % weight under the same conditions.
Further included in the present invention are compositions that have a
hygroscopicity (according to Callaghan et al.) that is at least one class
lower than the
reference compound or at least two classes lower than the reference compound.
Included
are a Class 1 composition of a Class 2 reference compound, a Class 2
composition of a
Class 3 reference compound, a Class 3 composition of a Class 4 reference
compound, a
Class 1 composition of a Class 3 reference compound, a Class 1 composition of
a Class 4
reference compound, or a Class 2 composition of a Class 4 reference compound.
Further included in the present invention are compositions that have a
hygroscopicity (according to the European Pharmacopoeia Technical Guide) that
is at least
one class lower than the reference compound or at least two classes lower than
the
reference compound. Non-limiting examples include a Slightly hygroscopic
composition
of a Hygroscopic reference compound, a Hygroscopic composition of a Very
Hygroscopic
reference compound, a Very Hygroscopic composition of a Deliquescent reference
compound, a Slightly hygroscopic composition of a Very Hygroscopic reference
compound, a Slightly hygroscopic composition of a Deliquescent reference
compound, a
Hygroscopic composition of a Deliquescent reference compound.
In another aspect of the present invention, a correlation exists between in
vivo
dissolution and in vitro dissolution. For example, dissolution of celecoxib
sodium hydrate
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formulations in SGF at 37 degrees C is comparable to the pharmacokinetic data
obtained
in dogs in Example 7. For instance, the magnitude of Cmax in the
pharmacokinetic study
correlates with the Cma,, obtained with in vitro studies completed with
PLURONIC F127
and HPC at equal weight ratios to celecoxib free acid. Other pharrnacokinetic
parameters
.. such as, for example, Tmax and AUC, can also be closely related between
both types of
experiments.
Celecoxib salts can be characterized by differential scanning calorimetry
(DSC).
The sodium salt of celecoxib prepared in Example 1 is characterized by at
least 3
overlapping endothermic transitions between 50 degrees C and 110 degrees C
(Fig. 1).
.. Conditions for DSC can be found in the Exemplification.
Celecoxib salts can be characterized by thermogravimetric analysis (TGA). The
sodium salt product prepared by Example 1 was characterized by TGA, and was
determined to have about 3 loosely bound equivalents of water that evaporated
between
about 30 degrees C and about 40 degrees C, one more tightly bound equivalent
of water
.. that evaporated between about 40 degrees C and about 100 degrees C, and one
very tightly
bound equivalent of water that evaporated between about 140 degrees C and
about 160
degrees C (Fig. 2). As described herein however, the sodium salt can exist at
different
states of hydration depending on the humidity, temperature, and other
conditions.
Conditions for TGA can be found in the Exemplification section.
Celecoxib salts of the present invention can also be characterized by powder X-
ray
diffraction (PXRD). The sodium salt of celecoxib prepared by Example 1 had an
intense
reflection or peak at a 2-theta angle of 6.36 degrees, and other reflections
or peaks at 7.01,
16.72, and 20.93 degrees (Fig. 3). Conditions for PXRD can be found in the
Exemplification.
In one embodiment of the present invention, a solid form of celecoxib shows a
characteristic absence of a Raman scattering peak at 906 cm -I (e.g., salts,
solvates, etc.).
The Raman scattering spectrum of celecoxib free acid comprises a peak at this
position.
Celecoxib salts may comprise solvate molecules and can occur in a variety of
solvation states, also known as solvates. Thus, celecoxib salts can exist as
crystalline
.. polymorphs. Polymorphs are different crystalline forms of the same drug
substance, and
in the present use of the term include solvates and hydrates. For example,
different
polymorphs of a celecoxib salt can be obtained by varying the method of
preparation
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(compare Examples). Crystalline polymorphs typically have different
solubilities, such
that a more thermodynamically stable polymorph is less soluble than a less
thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ
in
properties such as shelf-life, bioavailability, morphology, vapor pressure,
density, color,
and compressibility.
Suitable solvate molecules include water, alcohols, other polar organic
solvents,
and combinations thereof. Alcohols include methanol, ethanol, n-propanol,
isopropanol,
n-butanol, isobutanol, propylene glycol and t-butanol. Propylene glycol
solvates are
particularly preferred because they are more stable and less hygroscopic than
other forms.
Alcohols also include polymerized alcohols such as polyalkylene glycols (e.g.,
polyethylene glycol, polypropylene glycol). In an embodiment, water is the
solvent. In
embodiments of the invention, a celecoxib salt contains about 0.0%, less than
0.5%, 0.5,
less than 1.0%, 1.0, less than 1.5%, 1.5, less than 2.0%, 2.0, 2.5, 3.0, 3.5,
4.0, 4.5, 5.0, 5.5
or about 6.0 equivalents, or about 1.0 to about 6.0, 2.0 to about 5.0, 3.0 to
about 6.0, 3.0 to
about 5.0, 1.0 to about 4.0, 2.0 to about 4.0, 1.0 to about 3.0, 2.0 to about
3.0, 0.0 to about
3.0, 0.5 to about 3.0, 0.0 to about 2.0, 0.5 to about 2.0, 0.0 to about 1.5,
0.5 to about 1.5,
1.0 to about 1.5, or 0.5 to about 1.0 equivalents of water per equivalent of
salt. The
amount of water equivalents in the above hydrates is primarily affected by the
experimental conditions (e.g., temperature). Solvate molecules can be removed
from a
crystalline salt, such that the salt is either a partial or complete
desolvate. If the solvate
molecule is water (forming a hydrate), then a desolvated salt is said to be a
dehydrate. A
salt with all water removed is anhydrous. Solvate molecules can be removed
from a salt
by methods such as heating, treating under vacuum or reduced pressure, blowing
dry air
over a salt, or a combination thereof. Following desolvation, there are
typically about one
to about five equivalents, about one to about four equivalents, about one to
about three
equivalents, or about one to about two equivalents of solvent per equivalent
of salt in a
crystal.
Pharmaceuticals including celecoxib, can co-crystallize with one or more other
substances. The term "co-crystal" as used herein means a crystalline material
comprised
of two or more unique solids at room temperature, each containing distinctive
physical
characteristics, such as structure, melting point and heats of fusion.
Solvates of API
compounds that do not further comprise a co-crystal forming compound are not
co-crystals
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according to the present invention. The co-crystals may however, include one
or more
solvent molecules in the crystalline lattice. That is, solvates of co-
crystals, or a co-crystal
further comprising a solvent or compound that is a liquid at room temperature,
is included
in the present invention, but crystalline material comprised of only one solid
and one or
more liquids (at room temperature) are not included by the term "co-crystal".
The co-
crystals may include a co-crystal former and a salt of an API, but the API and
the co-
crystal former of the present invention are constructed or bonded together
through
hydrogen bonds. Other modes of molecular recognition may also be present
including, H-
stacking, guest-host complexation and van der Waals interactions. Of the
interactions
listed above, hydrogen-bonding is the dominant interaction in the formation of
the co-
crystal, whereby a non-covalent bond is formed between a hydrogen bond donor
of one of
the moieties and a hydrogen bond acceptor of the other. An alternative
embodiment
provides for a co-crystal wherein the co-crystal former is a second API. In
another
embodiment, the co-crystal former is not an API.
In several embodiments of the present invention, the composition is a co-
crystal.
In other embodiments the co-crystal formers are selected from one or two (for
ternary co-
crystals) of the following: saccharin, nicotinamide, pyridoxine (4-pyridoxic
acid),
acesulfame, glycine, arginine, asparagine, cysteine, glutamine, histidine,
isoleucine, lysine,
methionine, phenylalanine, proline, threonine, tyrosine, valine, aspartic
acid, glutamic
acid, tryptophan, adenine, acetohydroxamic acid, alanine, allopurinaol, 4-
aminobenzoic
acid, cyclamic acid, 4-ethoxyphenyl urea, 4-aminopyridine, leucine, nicotinic
acid, senile,
tris, vitamin k5, xylito, succinic acid, tartaric acid, pyridoxamine, ascorbic
acid,
hydroquinone, salicylic acid, benzoic acid, caffeine, benzenesulfonic acid, 4-
chlorobenzene-sulfonic acid, citric acid, fumaric acid, gluconic acid,
glutaric acid, glycolic
acid, hippuric acid, maleic acid, malic acid, mandelic acid, malonic acid, 1,5-
napthalene-
disulfonic acid (armstrong's acid), clemizole, imidazole, glucosamine,
piperazine,
procaine, or urea.
In another embodiment of the present invention, a solid form of celecoxib can
give
rise to a distinct PXRD diffractogram. This can be caused by polymorphism, a
variable
hydrate, a different environmental condition, etc. In one embodiment, the
propylene glycol
solvate of celecoxib sodium salt can yield a PXRD pattern with theabsence or
presence of
a peak at 8.21 degrees 2-theta. In another embodiment, the propylene glycol
solvate of
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celecoxib sodium salt can yield a PXRD pattern with theabsence or presence of
a peak at
8.79 degrees 2-theta.
In another embodiment, a trihydrate of the propylene glycol solvate of
celecoxib
sodium salt is observed under 10 to 60 percent relative humidity (RH). In
another
embodiment, an anhydrous form of the propylene glycol solvate of celecoxib
sodium salt
is observed under 0 percent relative humidity (RH). In another embodiment, a
dihydrate
of the propylene glycol solvate of celecoxib sodium salt is observed under 40
to 60 percent
relative humidity (RH). In another embodiment, a monohydrate of the celecoxib
sodium
salt is observed under 10 to 20 percent relative humidity (RH). In another
embodiment, a
trihydrate of the celecoxib sodium salt is observed under 40 to 70 percent
relative humidity
(RH). In another embodiment, an anhydrous form of the propylene glycol solvate
of
celecoxib potassium salt is observed under 0 to 40 percent relative humidity
(RH).
Celecoxib salts may be prepared by contacting celecoxib with a solvent.
Suitable
solvents include water, alcohols, other polar organic solvents, and
combinations thereof.
Water and isopropanol are preferred solvents. Celecoxib is reacted with a
base, where
suitable bases are listed above, such that celecoxib forms a salt and
preferably dissolves.
Bases can be added to celecoxib with the solvent (i.e., dissolved in the
solvent), such that
celecoxib is solvated and deprotonated essentially simultaneously, or bases
can be added
after the celecoxib has been contacted with solvent (e.g., see Examples). In
the latter
scenario, bases can either be dissolved in a solvent, which can be either the
solvent already
contacting celecoxib or a different solvent, can be added as a neat solid or
liquid, or a
combination thereof. Sodium hydroxide and sodium ethoxide are preferred bases.
The
amount of base required is discussed above. The solvent can be evaporated to
obtain -
crystals of the celecoxib salt, or the celecoxib salt may precipitate and/or
crystallize
independent of evaporation. Crystals of a celecoxib salt can be filtered to
remove bulk
solvent. Methods of removing solvated solvent molecules are discussed above.
Excipients employed in pharmaceutical compositions of the present invention
can
be solids, semi-solids, liquids or combinations thereof. Preferably,
excipients are solids.
Compositions of the invention containing excipients can be prepared by any
known
technique of pharmacy that comprises admixing an excipient with a drug or
therapeutic
agent. A pharmaceutical composition of the invention contains a desired amount
of
celecoxib per dose unit and, if intended for oral administration, can be in
the form, for
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example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a
cachet, a
dispensable powder, granules, a suspension, an elixir, a dispersion, a liquid,
or any other
form reasonably adapted for such administration. If intended for parenteral
administration,
it can be in the form, for example, of a suspension or transdermal patch. If
intended for
rectal administration, it can be in the form, for example, of a suppository.
Presently
preferred are oral dosage forms that are discrete dose units each containing a
predetermined amount of the drug, such as tablets or capsules.
Non-limiting examples of excipients that can be used to prepare pharmaceutical
compositions of the invention follow.
Pharmaceutical compositions of the invention optionally comprise one or more
pharmaceutically acceptable carriers or diluents as excipients. Suitable
carriers or diluents
illustratively include, but are not limited to, either individually or in
combination, lactose,
including anhydrous lactose and lactose monohydrate; starches, including
directly
compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTm);
mannitol;
sorbitol; xylitol; dextrose (e.g., Cereloselm 2000) and dextrose monohydrate;
dibasic
calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar;
monobasic
calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium
lactate
trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses
including
microcrystalline cellulose, food grade sources of alpha- and amorphous
cellulose (e.g.,
Rexcell), powdered cellulose, and hydroxyproPylmethylcellulose (HPMC); calcium
carbonate; glycine; bentonite; block co-polymers; polyvinylpyrrolidone; and
the like.
Such carriers or diluents, if present, constitute in total about 5 % to about
99 %, preferably
about 10 % to about 85 %, and more preferably about 20 % to about 80 %, of the
total
weight of the composition. The carrier, carriers, diluent, or diluents
selected preferably
exhibit suitable flow properties and, where tablets are desired,
compressibility.
Lactose, mannitol, dibasic sodium phosphate, and microcrystalline cellulose
(e.g.,
AvicelTM PH (of FMC)), either individually or in combination, are preferred
diluents.
These diluents are chemically compatible with celecoxib. The use of
extragranular
microcrystalline cellulose (that is, microcrystalline cellulose added to a
granulated
composition) can be used to improve hardness (for tablets) and/or
disintegration time.
Lactose, especially lactose monohydrate, is particularly preferred. Lactose
typically
provides compositions having suitable release rates of celecoxib, stability,
pre-
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compression flowability, and/or drying properties at a relatively low diluent
cost. It
provides a high density substrate that aids densificafion during granulation
(where wet
granulation is employed) and therefore improves blend flow properties and
tablet
properties.
Pharmaceutical compositions of the invention optionally comprise one or more
pharmaceutically acceptable disintegrants as excipients, particularly for
tablet
formulations. Suitable disintegrants include, but are not limited to, either
individually or
in combination, starches, including sodium starch glycolate (e.g., ExplotabTM
of PenWest)
and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and
Chemical
Company, NationalTM 1550, and ColocornTM 1500), clays (e.g., VeegumTM HV of
R.T.
Vanderbilt), celluloses such as purified cellulose, microcrystalline
cellulose,
methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose,
croscarmellose sodium (e.g., AcDiSolTM of FMC), alginates, crospovidone, and
gums
such as agar, guar, locust bean, karaya, pectin and tragacanth gums.
Disintegrants may be added at any suitable step during the preparation of the
composition, particularly prior to granulation or during a lubrication step
prior to
compression. Such disintegrants, if present, constitute in total about 0.2 %
to about 30 %,
preferably about 0.2 % to about 10 %, and more preferably about 0.2 % to about
5 %, of
the total weight of the composition.
Croscarmellose sodium is a preferred disintegrant for tablet or capsule
disintegration, and, if present, preferably constitutes about 0.2 % to about
10 %, more
preferably about 0.2 % to about 7 %, and still more preferably about 0.2 % to
about 5 %,
of the total weight of the composition. Croscarmellose sodium confers superior
intragranular disintegration capabilities to granulated pharmaceutical
compositions of the
present invention.
Pharmaceutical compositions of the invention optionally comprise one or more
pharmaceutically acceptable binding agents or adhesives as excipients,
particularly for
tablet formulations. Such binding agents and adhesives preferably impart
sufficient
cohesion to the powder being tableted to allow for normal processing
operations such as
sizing, lubrication, compression and packaging, but still allow the tablet to
disintegrate and
the composition to be absorbed upon ingestion. Such binding agents may also
further
prevent or inhibit crystallization or recrystallization/precipitation of a
celecoxib salt of the
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present invention once the salt has been dissolved in a solution. Suitable
binding agents
and adhesives include, but are not limited to, either individually or in
combination, acacia;
tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to,
pregelatinized
starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but
not limited
to, methylcellulose and carmellose sodium (e.g., TyloseTm); alginic acid and
salts of
alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide
acids;
bentonites; povidone, for example povidone K-15, K-30 and K-29/32;
polymethacrylates;
HPMC; hydroxypropylcellulose (e.g., KlucelTM of Aqualon); and ethylcellulose
(e.g.,
EthocelTM of the Dow Chemical Company). Such binding agents and/or adhesives,
if
present, constitute in total about 0.5 % to about 25 %, preferably about 0.75
% to about 15
%, and more preferably about 1 % to about 10 %, of the total weight of the
pharmaceutical
composition.
Many of the binding agents are polymers comprising amide, ester, ether,
alcohol or
ketone groups and, as such, are preferably included in pharmaceutical
compositions of the
present invention. Polyvinylpyrrolidones such as povidone K-30 are especially
preferred.
Polymeric binding agents can have varying molecular weight, degrees of
crosslinking, and
grades of polymer. Polymeric binding agents can also be copolymers, such as
block co-
polymers that contain mixtures of ethylene oxide and propylene oxide units.
Variation in
these units' ratios in a given polymer affects properties and performance.
Examples of
block co-polymers with varying compositions of block units are Poloxamer 188
and
Poloxamer 237 (BASF Corporation).
Pharmaceutical compositions of the invention optionally comprise one or more
pharmaceutically acceptable wetting agents as excipients. Such wetting agents
are
preferably selected to maintain the celecoxib in close association with water,
a condition
that is believed to improve bioavailability of the composition. Such wetting
agents can
also be useful in solubilizing or increasing the solubility of metal salts of
celecoxib.
Non-limiting examples of surfactants that can be used as wetting agents (not
necessarily as the precipitation retardant) in pharmaceutical compositions of
the invention
include quaternary ammonium compounds, for example benzalkonium chloride,
benzethonium chloride and cetylpyridinium chloride, dioctyl sodium
sulfosuccinate,
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and
octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block
copolymers),
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polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene
(8)
caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse),
polyoxyethylene
(35) castor oil and polyoxyethylene (40) hydrogenated castor oil;
polyoxyethylene alkyl
ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene
fatty acid
esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan
esters, for
example polysorbate 20 and polysorbate 80 (e.g., TweenTm 80 of ICI), propylene
glycol
fatty acid esters, for example propylene glycol laurate (e.g., LauroglycolTM
of Gattefosse),
sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid,
sodium oleate
and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl
mono stearate,
sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate,
sorbitan
monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such
wetting
agents, if present, constitute in total about 0.25 % to about 15 %, preferably
about 0.4 % to
about 10 %, and more preferably about 0.5 % to about 5 %, of the total weight
of the
pharmaceutical composition.
Wetting agents that are anionic surfactants are preferred. Sodium lauryl
sulfate is a
particularly preferred wetting agent. Sodium lauryl sulfate, if present,
constitutes about
0.25 % to about 7 %, more preferably about 0.4 % to about 4 %, and still more
preferably
about 0.5 % to about 2 %, of the total weight of the pharmaceutical
composition.
Pharmaceutical compositions of the invention optionally comprise one or more
pharmaceutically acceptable lubricants (including anti-adherents and/or
glidants) as
excipients. Suitable lubricants include, but are not limited to, either
individually or in
combination, glyceryl behapate (e.g., CompritolTM 888 of Gattefosse); stearic
acid and
salts thereof, including magnesium, calcium and sodium stearates; hydrogenated
vegetable
oils (e.g., SterotexTM of Abitec); colloidal silica; talc; waxes; boric acid;
sodium benzoate;
sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,
CarbowaxTM
4000 and CarbowaxTM 6000 of the Dow Chemical Company); sodium oleate; sodium
lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present,
constitute in total
about 0. 1 % to about 10 %, preferably about 0.2 % to about 8 %, and more
preferably
about 0.25 % to about 5 %, of the total weight of the pharmaceutical
composition.
Magnesium stearate is a preferred lubricant used, for example, to reduce
friction
between the equipment and granulated mixture during compression of tablet
formulations.
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Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL-
leucine,
sodium lauryl sulfate and metallic stearates. Talc is a preferred anti-
adherent or glidant
used, for example, to reduce formulation sticking to equipment surfaces and
also to reduce
static in the blend. Talc, if present, constitutes about 0.1 % to about 10 %,
more preferably
about 0.25 % to about 5 %, and still more preferably about 0.5 % to about 2 %,
of the total
weight of the pharmaceutical composition.
Glidants can be used to promote powder flow of a solid formulation. Suitable
glidants include, but are not limited to, colloidal silicon dioxide, starch,
talc, tribasic
calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal
silicon
dioxide is particularly preferred. Other excipients such as colorants, flavors
and
sweeteners are known in the pharmaceutical arts and can be used in
pharmaceutical
compositions of the present invention. Tablets can be coated, for example with
an enteric
coating, or uncoated. Compositions of the invention can further comprise, for
example,
buffering agents.
Optionally, one or more effervescent agents can be used as disintegrants
and/or to
enhance organoleptic properties of pharmaceutical compositions of the
invention. When
present in pharmaceutical compositions of the invention to promote dosage form
disintegration, one or more effervescent agents are preferably present in a
total amount of
about 30 % to about 75 %, and preferably about 45 % to about 70 %, for example
about 60
%, by weight of the pharmaceutical composition.
According to a particularly preferred embodiment of the invention, an
effervescent
agent, present in a solid dosage form in an amount less than that effective to
promote
disintegration of the dosage form, provides improved dispersion of the
celecoxib in an
aqueous medium. Without being bound by theory, it is believed that the
effervescent agent
is effective to accelerate dispersion of celecoxib from the dosage form in the
gastrointestinal tract, thereby further enhancing absorption and rapid onset
of therapeutic
effect. When present in a pharmaceutical composition of the invention to
promote
intragastrointestinal dispersion but not to enhance disintegration, an
effervescent agent is
preferably present in an amount of about 1 % to about 20 %, more preferably
about 2.5 %
to about 15 %, and still more preferably about 5 % to about 10 % by weight of
the
pharmaceutical composition.
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An "effervescent agent" herein is an agent comprising one or more compounds
which, acting together or individually, evolve a gas on contact with water.
The gas
evolved is generally oxygen or, most commonly, carbon dioxide. Preferred
effervescent
agents comprise an acid and a base that react in the presence of water to
generate carbon
dioxide gas. Preferably, the base comprises an alkali metal or alkaline earth
metal
carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.
Non-limiting examples of suitable bases as components of effervescent agents
useful
in the invention include carbonate salts (e.g., calcium carbonate),
bicarbonate salts (e.g.,
sodium bicarbonate), sesquicarbonate salts, and mixtures thereof. Calcium
carbonate is a
preferred base.
Non-limiting examples of suitable acids as components of effervescent agents
and/or
solid organic acids useful in the invention include citric acid, tartaric acid
(as D-, L-, or
D/L-tartaric acid), malic acid, maleic acid, fumaric acid, adipic acid,
succinic acid, acid
anhydrides of such acids, acid salts of such acids, and mixtures thereof.
Citric acid is a
preferred acid.
In a preferred embodiment of the invention, where the effervescent agent
comprises
an acid and a base, the weight ratio of the acid to the base is about 1:100 to
about 100:1,
more preferably about 1:50 to about 50:1, and still more preferably about 1:10
to about
10:1. In a further preferred embodiment of the invention, where the
effervescent agent
comprises an acid and a base, the ratio of the acid to the base is
approximately
stoichiometric.
Excipients which solubilize metal salts of celecoxib typically have both
hydrophilic
and hydrophobic regions, or are preferably amphiphilic or have amphiphilic
regions. One
type of amphiphilic or partially-amphiphilic excipient comprises an
amphiphilic polymer
or is an amphiphilic polymer. A specific amphiphilic polymer is a polyalkylene
glycol,
which is commonly comprised of ethylene glycol and/or propylene glycol
subunits. Such
polyalkylene glycols can be esterified at their termini by a carboxylic acid,
ester, acid
anhyride or other suitable moiety. Examples of such excipients include
poloxamers
(symmetric block copolymers of ethylene glycol and propylene glycol; e.g.,
poloxamer
237), polyalkyene glycolated esters of tocopherol (including esters formed
from a di- or
multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol-
1000
succinate), and macrogolglycerides (formed by alcoholysis of an oil and
esterification of a
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polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides and
mono- and
di-esters; e.g., stearoyl macrogo1-32 glycerides). Such pharmaceutical
compositions are
advantageously administered orally.
Pharmaceutical compositions of the present invention can comprise about 10 %
to
about 50 %, about 25 % to about 50 %, about 30 % to about 45 %, or about 30 %
to about
35 % by weight of a metal salt of celecoxib; about 10 % to about 50 %, about
25 % to
about 50 %, about 30 % to about 45 %, or about 30 % to about 35 % by weight of
an
excipient which inhibits precipitation; and about 5 % to about 50 %, about 10
% to about
40 %, about 15 % to about 35 %, or about 30 % to about 35 % by weight of a
binding
agent. In one example, the weight ratio of the metal salt of celecoxib to the
excipient
which inhibits precipitation to binding agent is about 1 to 1 to 1.
The resulting formulations described above are both physically and chemically
stable. The present invention can be prepared in solid dosage form well in
advance (e.g.,
months) of oral administration without the risk of premature neutralization or
precipitation
of the API_ Liquid suspensions of celecoxib particles can suffer from a
tendency of the
particles to agglomerate and/or increase in size by crystal growth after only
several
minutes of standing. This crystal growth can significantly reduce the
bioavailability and
therapeutic effect of the drug.
Solid dosage forms of the invention can be prepared by any suitable process,
and
are not limited to processes described herein. An illustrative process
comprises (i) a step
of blending a celecoxib salt of the invention with one or more excipients to
form a blend,
and (ii) a step of tableting or encapsulating the blend to form tablets or
capsules,
respectively.
In a preferred process, solid dosage forms are prepared by a process
comprising (a)
a step of blending the celecoxib salt to form a blend, (b) a step of
granulating the blend to
form a granulate, and (c) a step of tableting or encapsulating the blend to
form tablets or
capsules respectively. Step (b) can be accomplished by any dry or wet
granulation
technique known in the art. A celecoxib salt is advantageously granulated to
form
particles of about 10 micrometer to about 1000 micrometer, about 25 micrometer
to about
500 micrometer, or about 50 micrometer to about 300 micrometer. More
specifically,
particles of about 100 micrometers in diameter are well suited to yield the
desired
therapeutic effect. One or more diluents, one or more disintegrants and one or
more
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binding agents may be added, for example in the blending step, a wetting agent
can
optionally be added, for example in the granulating step, and one or more
disintegrants
may be added after granulating but before tableting or encapsulating. A
lubricant may be
added before tableting. Blending and granulating can be performed
independently under
low or high shear. A process is preferably selected that forms a granulate
that is uniform
in drug content, that readily disintegrates, that flows with sufficient ease
so that weight
variation can be reliably controlled during capsule filling or tableting, and
that is dense
enough in bulk so that a batch can be processed in the selected equipment and
individual
doses fit into the specified capsules or tablet dies.
In an alternative embodiment, solid dosage forms are prepared by a process
that
includes a spray drying step, wherein a celecoxib salt is suspended with one
or more
excipients in one or more sprayable liquids, preferably a non-protic (e.g.,
non-aqueous or
non-alcoholic) sprayable liquid, and then is rapidly spray dried over a
current of warm air.
A granulate or spray dried powder resulting from any of the above illustrative
processes can be compressed or molded to prepare tablets or encapsulated to
prepare
capsules. Conventional tableting and encapsulation techniques known in the art
can be
employed. Where coated tablets are desired, conventional coating techniques
are suitable.
Excipients for tablet compositions of the invention are preferably selected to
provide a disintegration time of less than about 30 minutes, preferably about
25 minutes or
less, more preferably about 20 minutes or less, and still more preferably
about 15 minutes
or less, in a standard disintegration assay.
Celecoxib dosage forms of the invention preferably comprise celecoxib in a
daily
dosage amount of about 10 mg to about 1000 mg, more preferably about 50 mg to
about
100 mg, about 100 mg to about 150 mg, 150 mg to about 200 mg, 200 mg to about
250
mg, 250 mg to about 300 mg, 300 mg to about 350 mg, 350 mg to about 400 mg,
400 mg
to about 450 mg 450 mg to about 500 mg, 500 mg to about 550 mg, 550 mg to
about 600
mg, 600 mg to about 700 mg, and 700 mg to about 800 mg.
Pharmaceutical compositions of the invention comprise one or more orally
deliverable dose units. Each dose unit comprises celecoxib in a
therapeutically effective
amount that is preferably those listed. The term "dose unit" herein means a
portion of a
pharmaceutical composition that contains an amount of a therapeutic or
prophylactic
agent, in the present case celecoxib, suitable for a single oral
administration to provide a
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therapeutic effect. Typically one dose unit, or a small plurality (up to about
4) of dose
units, in a single administration provides a dose comprising a sufficient
amount of the
agent to result in the desired effect. Administration of such doses can be
repeated as
required, typically at a dosage frequency of 1, 2, 3, or 4 times per day.
It will be understood that a therapeutically effective amount of celecoxib for
a
subject is dependent inter alia on the body weight of the subject. A "subject"
to which a
celecoxib salt or a pharmaceutical composition thereof can be administered
includes a
human subject of either sex and of any age, and also includes any nonhuman
animal,
particularly a warm-blooded animal, more particularly a domestic or companion
animal,
illustratively a cat, dog or horse. When the subject is a child or a small
animal (e.g., a
dog), for example, an amount of celecoxib (measured as the neutral form of
celecoxib, that
is, not including counterions in a salt or water in a hydrate) relatively low
in the preferred
range of about 10 mg to about 1000 mg is likely to provide blood serum
concentrations
consistent with therapeutic effectiveness. Where the subject is an adult human
or a large
animal (e.g., a horse), achievement of such blood serum concentrations of
celecoxib is
likely to require dose units containing a relatively greater amount of
celecoxib.
Typical dose units in a pharmaceutical composition of the invention contain
about
10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 mg of
celecoxib.
For an adult human, a therapeutically effective amount of celecoxib per dose
unit in a
composition of the present invention is typically about 50 mg to about 400 mg.
Especially
preferred amounts of celecoxib per dose unit are about 100 mg to about 200 mg,
for
example about 100 mg or about 200 mg. Other doses that are not in current use
for
CELEBREX may become preferred, if the bioavailability is changed with a novel
formulation. For instance, 300 mg may become a preferred dose for certain
indications.
A dose unit containing a particular amount of celecoxib can be selected to
accommodate any desired frequency of administration used to achieve a desired
daily
dosage. The daily dosage and frequency of administration, and therefore the
selection of
appropriate dose unit, depends on a variety of factors, including the age,
weight, sex and
medical condition of the subject, and the nature and severity of the condition
or disorder,
and thus may vary widely.
For pain management, pharmaceutical compositions of the present invention can
be
used to provide a daily dosage of celecoxib of about 50 mg to about 1000 mg,
preferably
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about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg,
and still
more preferably about 175 mg to about 400 mg, for example about 200 mg. A
daily dose
of celecoxib of about 0.7 to about 13 mg/kg body weight, preferably about 1.3
to about 8
mg/kg body weight, more preferably about 2 to about 6.7 mg/kg body weight, and
still
more preferably about 2.3 to about 5.3 mg/kg body weight, for example about
2.7 mg/kg
body weight, is generally appropriate when administered in a pharmaceutical
composition
of the invention. The daily dose can be administered in one to about four
doses per day.
Administration at a rate of one 50 mg dose unit four times a day, one 100 mg
dose unit or
two 50 mg dose units twice a day, or one 200 mg dose unit, two 100 mg dose
units or four
50 mg dose units once a day is preferred.
The term "oral administration" herein includes any form of delivery of a
therapeutic agent or a composition thereof to a subject wherein the agent or
composition is
placed in the mouth of the subject, whether or not the agent or composition is
immediately
swallowed, although each are embodiments of the invention. Thus, "oral
administration"
includes buccal and sublingual as well as esophageal administration.
Absorption of the
agent can occur in any part or parts of the gastrointestinal tract including
the mouth,
esophagus, stomach, duodenum, ileum and colon. The term "orally deliverable"
herein
means suitable for oral administration.
In a particular embodiment of the present invention, multiple pellets can be
incorporated into the formulation, each with a distinct coating thickness.
This will allow
each pellet to dissolve at an exclusive, predetermined time interval following
administration. The result is an increased duration of the desired therapeutic
effect. Such a
controlled-release (CR) formulation can reduce the frequency at which a
pharmaceutical
must be administered to a patient, thereby decreasing the total amount of drug
intake.
Improvements such as reduced side effects, reduced drug accumulation, and
reduced
fluctuations in blood serum level are some advantages of controlled-release
formulations.
A further embodiment allows the formulation to include more than one
therapeutic agent.
Pellets of two or more APIs can be incorporated, each with distinct coating
thicknesses,
thereby resulting in binary, tertiary, or higher order pharmaceuticals (Chemg-
ju Kim,
Controlled Release Dosage Form Design).
An important aspect of the administration of drugs in conventional forms is
the
fluctuation between high and low blood serum concentration of the drug in the
period
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between the administration of two successive doses. In fact, if the drug is
too rapidly
absorbed, excessive plasma levels may be attained, leading to undesirable and
even toxic
side effects. On the other hand, drugs possessing a short half-life are
eliminated too rapidly
and require therefore frequent administrations. In both cases the patient must
be careful
because particular attention and constancy in the administration is required
during therapy
and such conditions cannot always be easily obtained. Many efforts have been
made to
formulate pharmaceutical preparations able to protract in time the activity of
the drug in
the body at optimum plasma levels, reducing the number of administrations and
thus
improving the response of the patient to the treatment.
The preparation of pharmaceutical compositions intended to supply a gradual
and
controlled release in time of the active ingredient is well known in the
pharmaceutical
technology field. Systems are known comprising tablets, capsules,
microcapsules,
microspheres and formulations in general, in which the active ingredient is
released
gradually by various means including the following. Particles containing the
API can be
coated with individual specific external coatings so that the release of
active medicament
from the inner core is separated by sequential intervals. The number of
defined pulses of
drug released by a formulation can range from about 1 to about 10, or more
specifically
from about 1 to about 5. When applicable, a drug-free lag time can be
instituted before the
release of first dosage of the active medicament. This drug-free lag time is
accomplished
by delaying the first pulse-release.
The dosage forms of the present invention may optionally be coated with one or
more materials suitable for the regulation of release or for the protection of
the
formulation. In one embodiment, coatings are provided to permit either pH-
dependent or
pH-independent release, e.g., when exposed to gastrointestinal fluid. A pH-
dependent
coating serves to release the API in desired areas of the gastro-intestinal
(GI) tract, e.g., the
stomach or small intestine, such that an absorption profile is provided which
is capable of
providing at least about eight hours and preferably about twelve hours to up
to about
twenty-four hours of analgesia to a patient. When a p11-independent coating is
desired, the
coating is designed to achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract. It is also possible to formulate
compositions which
release a portion of the dose in one desired area of the GI tract, e.g., the
stomach, and
release the remainder of the dose in another area of the GI tract, e.g., the
small intestine.
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Formulations according to the invention that utilize pH-dependent coatings to
obtain formulations may also impart a repeat-action effect whereby unprotected
drug is
coated over the enteric coat and is released in the stomach, while the
remainder, being
protected by the enteric coating, is released further down the
gastrointestinal tract.
Coatings which are pH-dependent may be used in accordance with the present
invention
include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate
phthalate (PVAP),
hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers,
zein, and
the like.
In certain preferred embodiments, the substrate (e.g., tablet core bead,
matrix
particle) containing the API is coated with a hydrophobic material selected
from (i) an
alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The
coating may be
applied in the form of an organic or aqueous solution or dispersion. The
coating may be
applied to obtain a weight gain from about 2 to about 25% of the substrate in
order to
obtain a desired sustained release profile. Coatings derived from aqueous
dispersions are
described in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493, and are hereby
incorporated
by reference in their entirety. Other examples of sustained release
formulations and
coatings which may be used in accordance with the present invention include
U.S. Pat.
Nos. 5,324,351, 5,356,467, and 5,472,712, also hereby incorporated by
reference in their
entirety.
Cellulosic materials and polymers, including alkylcelluloses, provide
hydrophobic
materials well suited for coating the beads according to the invention. Simply
by way of
example, one preferred alkylcellulosic polymer is ethylcellulose, although the
artisan will
appreciate that other cellulose and/or alkylcellulose polymers may be readily
employed,
singly or in any combination, as all or part of a hydrophobic coating
according to the
invention.
One commercially-available aqueous dispersion of ethylcellulose is Aquacoat
(FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat is prepared by dissolving
the
ethylcellulose in a water-immiscible organic solvent and then emulsifying the
same in
water in the presence of a surfactant and a stabilizer. After homogenization
to generate
submicron droplets, the organic solvent is evaporated under vacuum to form a
pseudolatex.
The plasticizer is not incorporated in the pseudolatex during the
manufacturing phase.
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Thus, prior to using the same as a coating, it is necessary to intimately mix
the Aquacoat
with a suitable plasticizer prior to use.
Another aqueous dispersion of ethylcellulose is commercially available as
Surelease (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared
by
incorporating plasticizer into the dispersion during the manufacturing
process. A hot melt
of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is
prepared as a
homogeneous mixture, which is then diluted with an alkaline solution to obtain
an aqueous
dispersion which can be applied directly onto substrates.
In other preferred embodiments of the present invention, the hydrophobic
material
comprising the controlled release coating is a pharmaceutically acceptable
acrylic polymer,
including but not limited to acrylic acid and methacrylic acid copolymers,
methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,
poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide
copolymer,
poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)
copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid
anhydride),
and glycidyl methacrylate co-polymers.
In certain preferred embodiments, the acrylic polymer is comprised of one or
more
ammonio methacrylate copolymers. Ammonio methacrylate copolymers arc well
known in
the art, and are described in NF XVII as fully polymerized copolymers of
acrylic and
methacrylic acid esters with a low content of quaternary ammonium groups.
In order to obtain a desirable dissolution profile, it may be necessary to
incorporate
two or more ammonio methacrylate copolymers having differing physical
properties, such
as different molar ratios of the quaternary ammonium groups to the neutral
(meth)acrylic
esters.
Certain methacrylic acid ester-type polymers are useful for preparing pH-
dependent coatings which may be used in accordance with the present invention.
For
example, there are a family of copolymers synthesized from diethylaminoethyl
methacrylate and other neutral methacrylic esters, also known as methacrylic
acid
copolymer or polymeric methacrylates, commercially available as Eudragit from
Rohm
Tech, Inc. There are several different types of Eudragit . For example,
Eudragit E is an
example of a methacrylic acid copolymer which swells and dissolves in acidic
media.
Eudragit L is a methacrylic acid copolymer which does not swell at about pH
<5.7 and is
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soluble at about pH >6. Eudragit S does not swell at about pH <6.5 and is
soluble at
about pH >7. Eudragit RL and Eudragit RS are water swellable, and the amount
of
water absorbed by these polymers is pH-dependent, however, dosage forms coated
with
Eudragit RL and RS are pH-independent.
In certain preferred embodiments, the acrylic coating comprises a mixture of
two
acrylic resin lacquers commercially available from Rohm Pharma under the
Tradenames
Eudragit RL3OD and Eudragit RS30D, respectively. Eudragit RL3OD and
Eudragit
RS3OD are copolymers of acrylic and methacrylic esters with a low content of
quaternary
ammonium groups, the molar ratio of ammonium groups to the remaining neutral
(meth)acrylic esters being 1:20 in Eudragit RL3OD and 1:40 in Eudragit
RS30D. The
mean molecular weight is about 150,000. The code designations RL (high
permeability)
and RS (low permeability) refer to the permeability properties of these
agents. Eudragit
RL/RS mixtures are insoluble in water and in digestive fluids. However,
coatings formed
from the same are swellable and permeable in aqueous solutions and digestive
fluids.
The Eudragit RL/RS dispersions of the present invention may be mixed together
in any desired ratio in order to ultimately obtain a sustained release
formulation having a
desirable dissolution profile. Desirable sustained release formulations may be
obtained, for
instance, from a retardant coating derived from 100% Eudragit RL, 50%
Eudragit RL
and 50% Eudragit RS, and 10% Eudragit RL:Eudragit0 90% RS. Of course, one
skilled in the art will recognize that other acrylic polymers may also be
used, such as, for
example, Eudragit L.
In embodiments of the present invention where the coating comprises an aqueous
dispersion of a hydrophobic material, the inclusion of an effective amount of
a plasticizer
in the aqueous dispersion of hydrophobic material will further improve the
physical
properties of the sustained release coating. For example, because
ethylcellulose has a
relatively high glass transition temperature and does not form flexible films
under normal
coating conditions, it is preferable to incorporate a plasticizer into an
ethylcellulose coating
containing sustained release coating before using the same as a coating
material.
Generally, the amount of plasticizer included in a coating solution is based
on the
concentration of the film-former, e.g., most often from about 1 to about 50
percent by
weight of the film-former. Concentration of the plasticizer, however, can only
be properly
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determined after careful experimentation with the particular coating solution
and method
of application.
Examples of suitable plasticizers for ethylcellulose include water insoluble
plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate,
tributyl citrate, and
triacetin, although it is possible that other water-insoluble plasticizers
(such as acetylated
monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl
citrate is an
especially preferred plasticizer for the aqueous dispersions of ethyl
cellulose of the present
invention.
Examples of suitable plasticizers for the acrylic polymers of the present
invention
to include, but are not limited to citric acid esters such as triethyl
citrate, tributyl citrate,
dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which
have proved
to be suitable for enhancing the elasticity of the films formed from acrylic
films such as
Eudragit RL/RS lacquer solutions include polyethylene glycols, propylene
glycol,
diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an
especially preferred
plasticizer for the aqueous dispersions of ethyl cellulose of the present
invention.
It has further been found that the addition of a small amount of talc reduces
the
tendency of the aqueous dispersion to stick during processing, and acts as a
polishing
agent.
When a hydrophobic material is used to coat inert pharmaceutical beads, a
plurality
of the resultant solid controlled release beads may thereafter be placed in a
gelatin capsule
in an amount sufficient to provide an effective controlled release dose when
ingested and
contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
The controlled release bead formulations of the present invention slowly
release the
therapeutically active agent, e.g., when ingested and exposed to gastric
fluids, and then to
intestinal fluids. The controlled release profile of the formulations of the
invention can be
altered, for example, by varying the amount of overcoating with the
hydrophobic material,
altering the manner in which the plasticizer is added to the hydrophobic
material, by
varying the amount of plasticizer relative to hydrophobic material, by the
inclusion of
additional ingredients or excipients, by altering the method of manufacture,
etc. The
dissolution profile of the ultimate product may also be modified, for example,
by
increasing or decreasing the thickness of the retardant coating.
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Spheroids or beads coated with a therapeutically active agent are prepared,
e.g., by
dissolving the therapeutically active agent in water and then spraying the
solution onto a
substrate, for example, using a Wuster insert. Optionally, additional
ingredients are also
added prior to coating the beads in order to assist the binding of the API to
the beads,
and/or to color the solution, etc. For example, a product which includes
hydroxypropylmethylcellulose, etc. with or without colorant (e.g., Opadry ,
commercially
available from Colorcon, Inc.) may be added to the solution and the solution
mixed (e.g.,
for about 1 hour) prior to application of the same onto the beads. The
resultant coated
substrate, in this example beads, may then be optionally overcoated with a
barrier agent, to
separate the therapeutically active agent from the hydrophobic controlled
release coating.
An example of a suitable barrier agent is one which comprises
hydroxypropylmethylcellulose. However, any film-former known in the art may be
used. It
is preferred that the barrier agent does not affect the dissolution rate of
the final product.
The beads may then be overcoated with an aqueous dispersion of the hydrophobic
material. The aqueous dispersion of hydrophobic material preferably further
includes an
effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous
dispersions of
ethylcellulose, such as Aquacoat or Surelease , may be used. If Surelease is
used, it is
not necessary to separately add a plasticizer. Alternatively, pre-formulated
aqueous
dispersions of acrylic polymers such as Eudragit can be used.
The coating solutions of the present invention preferably contain, in addition
to the
film-former, plasticizer, and solvent system (i.e., water), a colorant to
provide elegance and
product distinction. Color may be added to the solution of the therapeutically
active agent
instead, or in addition to the aqueous dispersion of hydrophobic material. For
example,
color may be added to Aquacoat via the use of alcohol or propylene glycol
based color
dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by
adding
color with shear to water soluble polymer solution and then using low shear to
the
plasticized Aquacoat . Alternatively, any suitable method of providing color
to the
formulations of the present invention may be used. Suitable ingredients for
providing color
to the formulation when an aqueous dispersion of an acrylic polymer is used
include
titanium dioxide and color pigments, such as iron oxide pigments. The
incorporation of
pigments, may, however, increase the retard effect of the coating.
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Plasticized hydrophobic material may be applied onto the substrate comprising
the
therapeutically active agent by spraying using any suitable spray equipment
known in the
art. In a preferred method, a Wurster fluidized-bed system is used in which an
air jet,
injected from underneath, fluidizes the core material and effects drying while
the acrylic
polymer coating is sprayed on. A sufficient amount of the hydrophobic material
to obtain a
predetermined controlled release of said therapeutically active agent when the
coated
substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably
applied, taking
into account the physical characteristics of the therapeutically active agent,
the manner of
incorporation of the plasticizer, etc. After coating with the hydrophobic
material, a further
overcoat of a film-former, such as Opadry , is optionally applied to the
beads. This
overcoat is provided, if at all, in order to substantially reduce
agglomeration of the beads.
The release of the therapeutically active agent from the controlled release
formulation of the present invention can be further influenced, i.e., adjusted
to a desired
rate, by the addition of one or more release-modifying agents, or by providing
one or more
passageways through the coating. The ratio of hydrophobic material to water
soluble
material is determined by, among other factors, the release rate required and
the solubility
characteristics of the materials selected.
The release-modifying agents which function as pore-formers may be organic or
inorganic, and include materials that can be dissolved, extracted or leached
from the
coating in the environment of use. The pore-formers may comprise one or more
hydrophilic materials such as hydroxypropylmethylcellulose.
The sustained release coatings of the present invention can also include
erosion-
promoting agents such as starch and gums.
The sustained release coatings of the present invention can also include
materials useful
for making microporous lamina in the environment of use, such as
polycarbonates
comprised of linear polyesters of carbonic acid in which carbonate groups
reoccur in the
polymer chain. The release-modifying agent may also comprise a semi-permeable
polymer.
In certain preferred embodiments, the release-modifying agent is selected from
hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of
the
foregoing.
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The sustained release coatings of the present invention may also include an
exit
means comprising at least one passageway, orifice, or the like. The passageway
may be
formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770;
3,916,889;
4,063,064; and 4,088,864 . The
passageway can have any shape such as round, triangular, square, elliptical,
irregular, etc.
The present invention may include dual-release compositions whereby a
celecoxib
salt is formulated so as to contain both a fast acting component and a
sustained release
component of drug delivery. This formulation allows for both relatively fast
and
prolonged therapeutic effects while minimizing administration frequency. Dual-
release
compositions are further described in WO 01/45706 Al.
A variety of known controlled- or extended-release dosage forms, formulations,
and devices can be adapted for use with the celecoxib salts and compositions
of the
invention. Examples include, but are not limited to, those described in U.S.
Pat. Nos.:
3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
5,591,767;
5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl.
These dosage forms can be used to provide slow or
controlled-release of one or more active ingredients using, for example,
hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable
membranes,
osmotic systems (such as OROS (Alza Corporation, Mountain View, Calif. USA)),
multilayer coatings, microparticles, liposomes, or microspheres or a
combination thereof to
provide the desired release profile in varying proportions. Additionally, ion
exchange
materials can be used to prepare immobilized, adsorbed salt forms of celecoxib
and thus
effect controlled delivery of the drug. Examples of specific anion exchangers
include, but
are not limited to, Duolite A568 and Duolite AP143 (Rohm & Haas, Spring
House,
PA. USA).
One embodiment of the invention encompasses a unit dosage form which
comprises a pharmaceutically acceptable salt of celecoxib (e.g., a sodium,
potassium, or
lithium salt), or a polymorph, solvate, hydrate, dehydrate, co-crystal,
anhydrous, or
amorphous form thereof, and one or more pharmaceutically acceptable excipients
or
diluents, wherein the pharmaceutical composition or dosage form is formulated
for
controlled-release. Specific dosage forms utilize an osmotic drug delivery
system.
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A particular and well-known osmotic drug delivery system is referred to as
OROS (Alza Corporation, Mountain View, Calif. USA). This technology can
readily be
adapted for the delivery of compounds and compositions of the invention.
Various aspects
of the technology are disclosed in U.S. Pat. Nos. 6,375,978 Bl; 6,368,626 Bl;
6,342,249
Bl; 6,333,050B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and
6,132,420. Specific adaptations of
OROS that can be used to administer compounds and compositions of the
invention
include, but are not limited to, the OROS Push-Pull, Delayed Push-PullTm,
Multi-
Layer Push-PullTm, and Push-Stick rm Systems, all of which are well known.
See, e.g.,
http://www.alza.com. Additional OROS systems that can be used for the
controlled oral
delivery of compounds and compositions of the invention include OROS -CT and L-
OROS . Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
Conventional OROS oral dosage forms are made by compressing a drug powder
(e.g., celecoxib salt) into a hard tablet, coating the tablet with cellulose
derivatives to form
a semi-permeable membrane, and then drilling an orifice in the coating (e.g.,
with a laser).
Kim, Chemg-ju, Controlled Release Dosage Form Design, 231-238 (Technomic
Publishing, Lancaster, Pa.: 2000). The advantage of such dosage forms is that
the delivery
rate of the drug is not influenced by physiological or experimental
conditions. Even a drug
with a pH-dependent solubility can be delivered at a constant rate regardless
of the pH of
the delivery medium. But because these advantages are provided by a build-up
of osmotic
pressure within the dosage form after administration, conventional OROS drug
delivery
systems cannot be used to effectively deliver drugs with low water solubility.
Because
celecoxib salts and complexes of this invention (e.g., celecoxib sodium) are
far more
soluble in water than celecoxib itself, they are well suited for osmotic-based
delivery to
patients. This invention does, however, encompass the incorporation of
celecoxib, and
non-salt isomers and isomeric mixtures thereof, into OROS dosage forms.
A specific dosage form of the invention comprises: a wall defining a cavity,
the
wall having an exit orifice formed or formable therein and at least a portion
of the wall
being semipermeable; an expandable layer located within the cavity remote from
the exit
orifice and in fluid communication with the semipermeable portion of the wall;
a dry or
substantially dry state drug layer located within the cavity adjacent to the
exit orifice and
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in direct or indirect contacting relationship with the expandable layer; and a
flow-
promoting layer interposed between the inner surface of the wall and at least
the external
surface of the drug layer located within the cavity, wherein the drug layer
comprises a salt
of celecoxib, or a polymorph, solvate, hydrate, dehydrate, co-crystal,
anhydrous, or
amorphous form thereof. See U.S. Pat No. 6,368,626..
Another specific dosage form of the invention comprises: a wall defining a
cavity,
the wall having an exit orifice formed or formable therein and at least a
portion of the wall
being semipermeable; an expandable layer located within the cavity remote from
the exit
orifice and in fluid communication with the semipermeable portion of the wall;
a drug
layer located within the cavity adjacent the exit orifice and in direct or
indirect contacting
relationship with the expandable layer; the drug layer comprising a liquid,
active agent
formulation absorbed in porous particles, the porous particles being adapted
to resist
compaction forces sufficient to form a compacted drug layer without
significant exudation
of the liquid, active agent formulation, the dosage form optionally having a
placebo layer
between the exit orifice and the drug layer, wherein the active agent
formulation comprises
a salt of celecoxib, or a polymorph, solvate, hydrate, dehydrate, co-crystal,
anhydrous, or
amorphous form thereof. See U.S. Pat. No. 6,342,249
Celecoxib compositions useful in methods of the present invention can be used
in
combination therapies with opioids and other analgesics. The compound to be
administered in combination with a celecoxib composition useful in methods of
the
invention can be formulated separately from said composition or co-formulated
with said
.composition. Where a celecoxib composition is co-formulated With a second
drag, for
example an opioid drug, the second drug can be formulated in immediate-
release, rapid
onset, sustained-release or dual-release form. In a specific embodiment of the
present
invention, celecoxib can be combined with an anti-platelet drag for example,
but not
limited to, tirofiban, aspirin, dipyridamole, anagrelide, epoprostenol,
eptifibatide,
clopidogrel, cilostazol, abciximab, or ticlopidine.
In another embodiment of the present invention, a formulation comprises a
celecoxib salt (e.g., celecoxib sodium salt) and the free acid form. This
combination
allows for both a fast onset and a delayed response following administration
to a subject.
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In another embodiment, the combination of a celecoxib salt and the free acid
also
comprises any one, any two, any three, any four, or any five or more
excipients listed
herein (e.g., precipitation retardants, enhancers, etc.).
Pharmaceutical compositions of the invention are useful in treatment and
.. prevention of a very wide range of disorders mediated by COX-2, including
but not
restricted to disorders characterized by inflammation, pain and/or fever. Such
pharmaceutical compositions are especially useful as anti-inflammatory agents,
such as in
treatment of arthritis, with the additional benefit of having significantly
less harmful side
effects than compositions of conventional non-steroidal anti-inflammatory
drugs
.. (NSAIDs) that lack selectivity for COX-2 over COX-1. In particular,
pharmaceutical
compositions of the invention have reduced the potential for gastrointestinal
toxicity and
gastrointestinal irritation including upper gastrointestinal ulceration and
bleeding, reduced
potential for renal side effects such as reduction in renal function leading
to fluid retention
and exacerbation of hypertension, reduced effect on bleeding times including
inhibition of
.. platelet function, and possibly a lessened ability to induce asthma attacks
in aspirin-
sensitive asthmatic subjects, by comparison with compositions of conventional
NSAIDs.
Thus compositions of the invention are particularly useful as an alternative
to conventional
NSAIDs where such NSAIDs are contraindicated, for example in subjects with
peptic
ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or
with a recurrent
.. history of gastrointestinal lesions; gastrointestinal bleeding, coagulation
disorders
including anemia such as hypoprothrombinemia, hemophilia or other bleeding
problems,
kidney disease, or in subjects prior to surgery or subjects taking
anticoagulants.
Contemplated pharmaceutical compositions are useful to treat a variety of
arthritic
disorders, including but not limited to rheumatoid arthritis,
spondyloarthropathies, gouty
.. arthritis, osteoarthritis, systemic lupus erythematosus and juvenile
arthritis.
Such pharmaceutical compositions are useful in treatment of asthma,
bronchitis,
menstrual cramps, preterm labor, tendonitis, bursitis, allergic neuritis,
cytomegalovirus
infectivity, apoptosis including HIV-induced apoptosis, lumbago, liver disease
including
hepatitis, skin-related conditions such as psoriasis, eczema, acne, burns,
dermatitis and
.. ultraviolet radiation damage including sunburn, and post-operative
inflammation including
that following ophthalmic surgery such as cataract surgery or refractive
surgery.
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Pharmaceutical compositions of the present invention are useful to treat
gastrointestinal conditions such as, but not limited to, inflammatory bowel
disease, Crohn's
disease, gastritis, irritable bowel syndrome and ulcerative colitis.
Such pharmaceutical compositions are useful in treating inflammation in such
diseases as migraine headaches, periarteritis nodosa, thyroiditis, aplastic
anemia,
Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular
junction
disease including myasthenia gravis, white matter disease including multiple
sclerosis,
sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,
nephritis,
hypersensitivity, swelling occurring after injury including brain edema,
myocardial
ischemia, and the like.
In addition, these pharmaceutical compositions are useful in treatment of
ophthalmic
diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular
photophobia, and of
acute injury to the eye tissue.
Also, such pharmaceutical compositions are useful in treatment of pulmonary
inflammation, such as that associated with viral infections and cystic
fibrosis, and in bone
resorption such as that associated with osteoporosis.
The pharmaceutical compositions are useful for treatment of certain central
nervous
system disorders, such as cortical dementias including Alzheimer's disease,
neurodegeneration, and central nervous system damage resulting from stroke,
ischemia
and trauma. The term "treatment" in the present context includes partial or
total inhibition
of dementias, including Alzheimer's disease, vascular dementia, multi-infarct
dementia,
pre-senile dementia, alcoholic dementia and senile dementia.
Such pharmaceutical compositions are useful in treatment of allergic rhinitis,
respiratory distress syndrome, endotoxin shock syndrome and liver disease.
Further, pharmaceutical compositions of the present invention are useful in
treatment of pain, including but not limited to postoperative pain, dental
pain, muscular
pain, and pain resulting from cancer. For example, such compositions are
useful for relief
of pain, fever and inflammation in a variety of conditions including rheumatic
fever,
influenza and other viral infections including common cold, low back and neck
pain,
dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia,
synovitis,
arthritis, including rheumatoid arthritis, degenerative joint diseases
(osteoarthritis), gout
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and ankylosing spondylitis, bursitis, bums, and trauma following surgical and
dental
procedures.
The present invention is further directed to a therapeutic method of treating
a
condition or disorder where treatment with a COX-2 inhibitory drug is
indicated, the
method comprising oral administration of a pharmaceutical composition of the
invention to
a subject in need thereof. The dosage regimen to prevent, give relief from, or
ameliorate
the condition or disorder preferably corresponds to once-a-day or twice-a-day
treatment,
but can be modified in accordance with a variety of factors. These include the
type, age,
weight, sex, diet and medical condition of the subject and the nature and
severity of the
disorder. Thus, the dosage regimen actually employed can vary widely and can
therefore
deviate from the preferred dosage regimens set forth above. The present
pharmaceutical
compositions can be used in combination with other therapies or therapeutic
agents,
including but not limited to, therapies with opioids and other analgesics,
including narcotic
analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic
(i.e. non-
addictive) analgesics, monoamine uptake inhibitors, adenosine regulating
agents,
cannabinoid derivatives, GABA active agents, norexin neuropeptide modulators,
Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel
blockers,
among others. Preferred combination therapies comprise use of a composition of
the
invention with one or more compounds selected from aceclofenac, acemetacin, e-
acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide,
acetylsalicylic acid
(aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine,
alminoprofen,
aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amfenac,
aminochlorthenoxazin,
3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine,
amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine,
antipyrine,
antipyrine salicylate, antrafenine, apazone, bendazac, benorylate,
benoxaprofen,
benzpiperylon, benzydamine, benzylmorphine, bermoprofen, bezitramide, alpha-
bisabolol,
bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin,
bucetin,
bucloxic acid, bucolome, bufexamac, bumadizon, buprenorphine, butacetin,
butibufen,
butophanol, calcium acetylsalicylate, carbamazepine, carbiphene, carprofen,
carsalam,
chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin,
ciramadol,
clidanac, clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine
methyl
bromide, codeine phosphate, codeine sulfate, cropropamide, crotethamide,
desomorphine,
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dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium,
difenamizole,
difenpiramide, diflunisal, dihydrocodeine, dihydrocodeinone enol acetate,
dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol,
dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone,
ditazol,
droxicam, emorfazone, enfenamic acid, epirizole, eptazocine, etersalate,
ethenzamide,
ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmonthine, etodolac,
etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid,
fendosal, fenoprofen,
fentanyl, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid,
flunoxapr6fen,
fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine,
glucametacin, glycol salicylate, guaiazulene, hydrocodone, hydromorphone,
hydrox-ypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate,
indomethacin,
indoprofen, isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam;
ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine,
levorphanol, lofentanil,
lonazolac, lomoxicam, loxoprofen, lysine acetylsalicylate, magnesium
acetylsalicylate,
meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine,
metazocine,
methadone hydrochloride, methotrimeprazine, metiazinic acid, metofoline,
metopon,
modafinil, mofebutazone, mofezolac, morazone, morphine, morphine
hydrochloride,
morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-
naphthyl
salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic
acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone,
normorphine,
norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone,
oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsahnide,
pentazocine,
perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride,
phenocoll, phenoperidine, phenopyrazone, phenyl acetylsalicylate,
phenylbutazone, phenyl
salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone,
piprofen,
pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine,
promedol,
propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protizinic
acid,
ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin,
salicylamide,
salicylamide o-acetic acid, salicylsulfuric acid, salsalte, salverine,
simetride, sodium
salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase,
suprofen, suxibuzone,
talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine,
thiazolinobutazone, tiaprofenic
acid, tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, topiramate,
tramadol,
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tropesin, viminol, xenbucin, ximoprofen, zaltoprofen and zomepirac (see The
Merck
Index, 12th Edition, Therapeutic Category and Biological Activity Index, ed.
S. Budavari
(1996), pp. Ther-2 to Ther-3 and Ther-12 (Analgesic (D)ental), Analgesic
(Narcotic),
Analgesic (Non-narcotic), Anti-inflammatory (Non-steroidal)).
Pharmaceutical compositions of the present invention are useful for treating
and
preventing inflammation-related cardiovascular disorders, including vascular
diseases,
coronary artery disease, aneurysm, vascular rejection, arteriosclerosis,
atherosclerosis
including cardiac transplant atherosclerosis, myocardial infarction, embolism,
stroke,
thrombosis including venous thrombosis, angina including unstable angina,
coronary
plaque inflammation, bacterial-induced inflammation including Chlamydia-
induced
inflammation, viral induced inflammation, and inflammation associated with
surgical
procedures such as vascular grafting including coronary artery bypass surgery,
revascularization procedures including angioplasty, stent placement,
endarterectomy, or
other invasive procedures involving arteries, veins and capillaries.
These pharmaceutical compositions are also useful in treatment of angiogenesis-
related disorders in a subject, for example to inhibit tumor angiogenesis.
Such
pharmaceutical compositions are useful in treatment of neoplasia, including
metastasis;
ophthalmological conditions such as corneal graft rejection, ocular
neovascularization,
retinal neovascularization including neovascularization following injury or
infection,
diabetic retinopathy, macular degeneration, retrolental fibroplasia and
neovascular
glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-
malignant,
conditions such as hemangiomas, including infantile hemaginomas, angiofibroma
of the
nasopharynx and avascular necrosis of bone; and disorders of the female
reproductive
system such as endometriosis.
Moreover, pharmaceutical compositions of the present invention are useful in
prevention and treatment of benign and malignant tumors and neoplasia
including cancer,
such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived
neoplasia
(epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma,
gastrointestinal
cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel
cancer, stomach
cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian
cancer,
cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell
and basal
cell cancers, prostate cancer, renal cell carcinoma, and other known cancers
that effect
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epithelial cells throughout the body. Neoplasias for which compositions of the
invention
are contemplated to be particularly useful are gastrointestinal cancer,
Barrett's esophagus,
liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate
cancer, cervical
cancer, lung cancer, breast cancer and skin cancer. Such pharmaceutical
compositions can
also be used to treat fibrosis that occurs with radiation therapy. These
pharmaceutical
compositions can be used to treat subjects having adenomatous polyps,
including those
with familial adenomatous polyposis (FAP). Additionally, pharmaceutical
compositions
of the present invention can be used to prevent polyps from forming in
subjects at risk of
FAP.
Also, the pharmaceutical compositions inhibit prostanoid-induced smooth muscle
contraction by inhibiting synthesis of contractile pro stanoids and hence can
be of use in
treatment of dysmenorrhea, premature labor, asthma and eosinophil-related
disorders.
They also can be of use for decreasing bone loss particularly in
postmenopausal women
(i.e., treatment of osteoporosis), and for treatment of glaucoma.
Preferred uses for pharmaceutical compositions of the invention are for
treatment of
rheumatoid arthritis and osteoarthritis, for pain management generally
(particularly post-
oral surgery pain, post-general surgery pain, post-orthopedic surgery pain,
and acute flares
of osteoarthritis), for treatment of Alzheimer's disease, and for colon cancer
chemoprevention. A particular preferred use is for rapid pain management, such
as when a
celecoxib salt or a pharmaceutical composition thereof is effective in
treating pain within
about 30 minutes or less.
Besides being useful for human treatment, pharmaceutical compositions of the
invention are useful for veterinary treatment of companion animals, exotic
animals, farm
animals, and the like, particularly mammals. More particularly, pharmaceutical
compositions of the invention are useful for treatment of COX-2 mediated
disorders in
horses, dogs, and cats.
EXEMPLIFICATION
Below are standard procedures for acquiring Raman, PXRD, DSC and TGA data
herein.
These procedures will be followed for each respective method of analysis
herein unless
otherwise indicated.
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Procedure for Raman Acquisition
Acquisition
The sample was either left in the glass vial in which it was processed or an
aliquot of the
sample was transferred to a glass slide. The glass vial or slide was
positioned in the sample
chamber. The measurement was made using an AlmegaTM Dispersive Raman (AlmegaTM
Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495)
system fitted with a 785 nm laser source. The sample was manually brought into
focus
using the microscope portion of the apparatus with a 10x power objective
(unless
otherwise noted), thus directing the laser onto the surface of the sample. The
spectrum was
acquired using the parameters outlined in Table 1. (Exposure times and number
of
exposures may vary; changes to parameters will be indicated for each
acquisition.) Unless
otherwise noted, all Raman scattering peaks are +/- 5 cm-1.
Table 1. Raman Spectral acquisition parameters
Parameter Setting Used
Exposure time (s) 2.0
Number of exposures 10
Laser source wavelength (nm) 785
Laser power (%) 100
Aperture shape pin hole
Aperture size (um) 100
Spectral range (cm-1) 104-3428
Grating position Single
Temperature at acquisition 24.0
(degrees C)
Procedure for Powder X-Ray Diffraction (PXRD)
All powder x-ray diffraction patterns were obtained using the D/Max Rapid X-
ray
Diffractometer (D/Max Rapid, Contact Rigaku/MSC, 9009 New Trails Drive, The
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Woodlands, TX, USA 77381-5209) equipped with a copper source (Cu/Ku. 1.5406
angstroms), manual x-y stage, and 0.3 mm collimator (unless otherwise
indicated). The
sample was loaded into a 0.3 mm boron rich glass capillary tube (e.g., Charles
Supper
Company, 15 Tech Circle, Natick, MA 01760-1024) by sectioning off one end of
the tube
and tapping the open, sectioned end into a bed of the powdered sample or into
the
sediment of a slurried precipitate. Note, precipitate can be amorphous or
crystalline. The
loaded capillary was mounted in a holder that was secured into the x-y stage.
A
diffractogram was acquired (e.g., Control software: RINT Rapid Control
Software,
Rigaku Rapid/XRD, version 1Ø0, 1999 Rigaku Co.) under ambient conditions
at a
power setting of 46 kV at 40 mA in reflection mode, while oscillating about
the omega-
axis from 0 - 5 degrees at 1 degree/s and spinning about the phi-axis at 2
degrees/s. The
exposure time was 15 minutes unless otherwise specified. The diffractogram
obtained was
integrated over 2-theta from 2-60 degrees and chi (1 segment) from 0-360
degrees at a
step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display
software
(Analysis software: RINT Rapid display software, version 1.18, Rigaku/MSC.)
provided
by Rigaku with the instrument. The dark counts value was set to 8 as per the
system
calibration (System set-up and calibration by Rigaku); normalization was set
to average;
the omega offset was set to 180'; and no chi or phi offsets were used for the
integration.
The analysis software JADE XRD Pattern Processing, versions 5.0 and 6.0 (81995-
2002,
Materials Data, Inc.) was also used.
The relative intensity of peaks in a diffractogram is not necessarily a
limitation of
the PXRD pattern because peak intensity can vary from sample to sample, e.g.,
due to
crystalline impurities. Further, the angles of each peak can vary by about +/-
0.1 degrees,
preferably +/-0.05. The entire pattern or most of the pattern peaks may also
shift by about
+/- 0.1 degree due to differences in calibration, settings, and other
variations from
instrument to instrument and from operator to operator. The above limitations
result in a
PXRD error of +/- 0.2 degrees 2-theta for each diffraction peak.
Procedure for Differential Scanning Calorimetry (DSC)
An aliquot of the sample was weighed into an aluminum sample pan. (e.g., Pan
part
# 900786.091; lid part #900779.901; TA Instruments, 109 Lukens Drive, New
Castle, DE
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19720) The sample pan was sealed either by crimping for dry samples or press
fitting for
wet samples (e.g., hydrated or solvated samples). The sample pan was loaded
into the
apparatus (DSC: Q1000 Differential Scanning Calorimeter, TA Instruments, 109
Lukens
Drive, New Castle, DE 19720), which is equipped with an autosampler, and a
thermogram was obtained by individually heating the sample (e.g., Control
software:
Advantage for QW- Series, version 1Ø0.78, Thermal Advantage Release 2.0, C
2001 TA
instruments ¨ Water LLC) at a rate of 10 degrees C /min from Trnin (typically
20 degrees
C) to Tmax (typically 300 degrees C) (Heating rate and temperature range may
vary,
changes to these parameters will be indicated for each sample) using an empty
aluminum
pan as a reference. Dry nitrogen (e.g., Compressed nitrogen, grade 4.8, BOC
Gases, 575
Mountain Avenue, Murray Hill, NJ 07974-2082) was used as a sample purge gas
and was
set at a flow rate of 50 mL/min. Thermal transitions were viewed and analyzed
using the
analysis software (Analysis Software:
Universal Analysis 2000 for Windows
95/95/2000/NT, version 3.1E; Build 3.1Ø40, C 1991 - 2001TA instruments ¨
Water
LLC) provided with the instrument.
Procedure for Thermogravimetric Analysis (TGA)
An aliquot of the sample was transferred into a platinum sample pan. (Pan part
#
952019.906; TA Instruments, 109 Lukens Drive, New Castle, DE 19720) The pan
was
placed on the loading platform and was then automatically loaded into the
apparatus
(TGA: Q500 Thermogravimetric Analyzer, TA Instruments, 109 Lukens Drive, New
Castle, DE 19720) using the control software (Control software: Advantage for
QW-
Series, version 1Ø0.78, Thermal Advantage Release 2.0, C 2001 TA instruments
¨ Water
LLC). Thermograms were obtained by individually heating the sample at 10
degrees C
/min from 25 degrees C to 300 degrees C (Heating rate and temperature range
may vary,
changes in parameters will be indicated for each sample) under flowing dry
nitrogen (e.g.,
Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Murray Hill,
NJ
07974-2082), with a sample purge flow rate of 60 mL/min and a balance purge
flow rate of
40 mL/min. Thermal transitions (e.g. weight changes) were viewed and analyzed
using the
analysis software (Analysis Software:
Universal Analysis 2000 for Windows
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95/95/2000/NT, version 3.1E; Build 3.1Ø40, 1991 - 2001TA instruments
¨Water LLC)
provided with the instrument.
Example 1
Celecoxib Sodium Salt from Aqueous Solution
To 77.3 mg of commercially-available celecoxib was added 1.0 mL distilled
water,
followed by 0.220 mL of 1 M NaOH. The mixture was heated with stirring to 60
degrees
C, whereupon an additional 1.0 mL distilled water was added. Solid NaOH (22
mg) was
added, and the solid NaOH and celecoxib dissolved. The mixture was heated
again at 60
degrees C to evaporate water. About 15 mL reagent-grade ethanol was added,
while the
mixture was stirred and heated at 60 degrees C with air blowing over the
solution. Heating
continued until the solution was dry. The resulting material was analyzed by
differential
scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder x-ray
diffraction (PXRD), the results of which are seen in Figs. 1-3. The product
was found to
contain about 4.1 equivalents of water per equivalent of salt, although most
of all of the
water could be contained in the NaOH that co-precipitated with the salt.
For the DSC analysis, the purge gas used was dry nitrogen, the reference
material
was an empty aluminum pan that was crimped, and the sample purge was 50
mL/minute.
DSC analysis of the sample was performed by placing 2.594 mg of sample in an
aluminum
pan with a crimped pan closure. The starting temperature was 20 degrees C with
a heating
rate of 10 degrees C/minute, and the ending temperature was 200 degrees C. A
reproduction of the resulting DSC analysis is shown in Fig. 1. The transitions
observed
include a melt/dehydration process between about 40 and about 70 degrees C,
another
transition between about 70 and about 100 degrees C possibly resulting from a
recrystallization/precipitation event and a second melt/dehydration transition
between
about 100 and about 110 degrees C.
TGA of the sample was performed by placing 2.460 mg of sample in a platinum
pan. The starting temperature was 20 degrees C with a heating rate of 10
degrees
C/minute, and the ending temperature was 300 degrees C. A reproduction of the
resulting
TGA analysis is shown in Fig. 2. The TGA shows a mass loss of about 12.5
percent
between about 30 and about 50 degrees C, attributed to the loss of about 2.8
equivalents of
water. A second mass loss of about 2.5 percent between about 71 and 85 degrees
C,
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attributed to the loss of about 0.5 equivalents of water. Finally, a mass loss
of about 4.0
percent between about 148 and 1700C attributed to either the loss of about 1
equivalent of
water or some decomposition of the drug compound. The hydration state of the
salt can
vary depending on the humidity, temperature and other conditions, as discussed
in
Examples 24, 25, and 30.
A reproduction of the PXRD pattern for the compound prepared above is shown in
Fig. 3. In the diffractogram of Fig. 3, the background has been removed. The
PXRD
pattern has characteristic peaks that can be used to characterize the salt
comprising any
one, or any combination of any two, any three, any four, or any five peaks or
any other
combination of peaks at a 2-theta angle of Fig. 3 including for example, the
peaks at 2.87,
6.36, 7.01, 16.72, and 20.83 degrees 2-theta.
Example 2
Celecoxib Sodium Salt from 2-propanol Solution
To 126.3 mg of celecoxib was added a 1.0 mL aliquot of isopropanol, and the
mixture was heated to dissolve the celecoxib. Sodium ethoxide was added as a
solution
(21%) in ethanol (0.124 mL solution, 3.31 x 104 mol sodium ethoxide). An
additional 1.0
mL of isopropanol was added. The mixture was stirred to obtain a slurry of
white
crystalline solids that appeared as fine birefringent needles by polarized
light microscopy.
The slurry was filtered by suction filtration and rinsed with 2 mL of
isopropanol.
The solid was allowed to air dry before being gently ground to a powder. The
product was
analyzed by PXRD, DSC, and TGA as in Example 1, but a 0.5 mm capillary was
used to
hold the sample in the PXRD experiment. The compound lost 17.37 % weight
between
room temperature and 120 degrees C (See Fig. 101). The DSC thermogram shows a
broad
endothermic region, which is consistent with a loss of volatile components
with increasing
temperature (See Fig. 102). The endotherm peaks at 66 degrees C. The PXRD
pattern
peaks that can be used to characterize the salt include any one or combination
comprising
any two, any three, any four, any five, any six, any seven, any eight, any
nine, any ten, any
eleven, any twelve, or all thirteen 2-theta angles of 4.09, 4.99, 6.51, 7.07,
9.99, 11.59,
16.53 , 17.69 , 18.47 , 19.13 , 20.11 , 20.95 , 22.67 degrees, or any one or
combination of 2,
3, 4, 5, 6, 7, 8,9, 10, 11, 12, or 13 peaks of Fig. 62.
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Example 3
Celecoxib Sodium Salt from Aqueous Solution
Synthesis I: To a vial was added 29.64 mg celecoxib and 3.00 mL of 1 M sodium
hydroxide. The celecoxib dissolved. After a time, celecoxib sodium salt
precipitated from
solution.
Synthesis 2: To a vial was added 7.10 mg celecoxib and 3.00 mL of 1 M sodium
hydroxide. The celecoxib dissolved. Overnight, celecoxib sodium salt
precipitated and
formed white, needle-like crystals.
Synthesis 3: To a vial was added 17.6 mg celecoxib and 10 mL of 1 M sodium
hydroxide.
The celecoxib dissolved. The vial was placed in a beaker wrapped in aluminum
foil and
filled with a large tissue for insulation. The beaker was left and celecoxib
sodium salt
crystals formed within about 12-36 hours.
Analysis: The product solids from syntheses 1 and 2 were combined and analyzed
by
PXRD, DSC, and TGA as in example 1, but a 0.5 mm capillary was used to hold
the
sample in the PXRD experiment. The product salt was found to contain about 4
equivalents of water per equivalent of salt, although as stated herein the
hydration state of
the salt can vary depending on humidity, temperature, and other conditions.
TGA showed
a weight loss of 14.9 percent as the temperature was increased from room
temperature to
100 degrees C at 10 degrees C/min. DSC analysis showed a large endothermic
transition
at 74 +/- 1.0 degrees C and a second broad and noisy endothermic transition at
about 130
+/- 5.0 degrees C. The PXRD pattern has peaks that can be used to characterize
the salt by
including any one or a combination comprising any two, any three, any four,
any five, or
all six 2-theta angle peaks of 3.6, 8.9, 9.6, 10.8, 11.4, and 20.0 degrees.
Example 4
Pharmacokinetic Studies in Rats
The sodium salt form (from Example 6) was compared with CELEBREX powder
in terms of absorption in rats (Figs. 4A and 4B).
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Pharmacokinetics in male Sprague-Dawley rats after 5 mg/kg oral doses of the
celecoxib crystal form used in the marketed formulations and the sodium salt
form are
shown in Fig. 4A and 4B. Solids were placed in size 9 gelatin capsules
(Totrac) and
dosed via gavage needle, followed by oral gavage of 1 mL water. CELEBREX
granulation was transferred from commercial 200 mg capsules. The sodium salt
was
blended with polyvinylpyrrolidone (e.g. PovidoneK30) in a 1:4 mixture. The
plots are
averages of plasma levels at each of the time points from plasma of 5 rats.
The pharmacokinetics at 5 mg/kg doses of the celecoxib sodium salt demonstrate
a
faster peak level of the drug in plasma. Early timepoints show higher levels
of celecoxib
in plasma from the sodium salt relative to CELEBREX (in particular, see Fig.
4A).
Example 5
Solubility of Celecoxib Sodium Salt in the Presence of Polyvinylpyrrolidone
Water was added to a 1:4 mixture of celecoxib sodium salt and
polyvinylpyrrolidone (PVP) to obtain a clear solution. The solution was stable
for at least
15 minutes, after which time, crystals of neutral celecoxib began to form.
Crystalline neutral celecoxib did not dissolve when added to aqueous
polyvinylpyrrolidone or when water was added to a dry blend of neutral
crystalline
celecoxib and polyvinylpyrrolidone.
Example 6
Preparation of Celecoxib Sodium Salt
= The free acid of celecoxib (5.027 g; 13.16 mmol) was suspended in a 1 M
aqueous
solution of NaOH (13.18 mL; 13.18 mmol). The suspension was gently heated at
60
degrees C for 1 minute to dissolve the remaining solid. The mixture was
allowed to cool
to room temperature, which yielded no solid. Further cooling in an ice bath
for 1 hour
yielded crystallization of the product. The resulting suspension was filtered
and allowed to
air dry.
Characterization of the product has been achieved via TGA, DSC, PXRD, and
Raman spectroscopy. The TGA shows a weight loss of 6.67 wt % from 25 degrees C
to
105 degrees C. This weight loss indicates some level of hydration or residual
water. The
DSC shows a large endotherm centered at 100 degrees C. The PXRD pattern has
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characteristic peaks as shown in Fig. 13A. An intense peak can be seen at
19.85 with other
peaks at 2-theta angles including but not limited to, 3.57, 10.69, 13.69,
20.43, 21.53 and
22.39 degrees. The crystal can be characterized by any one, any two, any
three, any four,
any five, or all six of the peaks above, or any one or combination of any
number of 2-theta
angles of Fig. 13A. Results of Raman spectroscopy can be seen in Fig. 13B.
Raman shift
(cm-1) peaks occur at positions including, but not limited to, any one, any
two, any three,
any four, all five of 1617, 1446, 1374, 975 and 800 cm-1, or any combinations
of 2, 3, 4, 5
or more peaks of Fig. 13B.
Example 7
Administration of Celecoxib Compositions to Dogs
The celecoxib salt of Example 6 was administered to dogs and compared to
administration of commercially available celecoxib. Six male beagle dogs aged
2-4 years
old and weighing 8-12 kg were food-deprived overnight, but were given water.
Each of
the dogs was administered 3 test doses as described below and allowed a one
week
washout period between doses. The test doses included: (1) commercially
available
celecoxib in the form of CELEBREX at 1 milligram per kilogram (mpk) combined
with
PEG 400:water (70:30) which was administered intravenously, (2) an oral dose
of
commercially available celecoxib in the form of CELEBREX at 5 mpk adfdsted for
each
dog's weight in size 4 gelatin capsules, and (3) an oral dose of the sodium
salt of the
present invention as prepared according to Example 6 at 5 mpk adjusted for
each dog's
weight in size 4 gelatin capsules. Details regarding formulations of the
intravenous and
oral doses can be found in Fig. 5A. Blood samples of approximately 2 mL in
sodium
heparin were obtained by jugular venipuncture at 0.25, 0.5, 1, 3, 4, 6, 8, 12,
and 24 hours
post-dose. Additional samples were obtained predose and at 0.08 hr for the IV
study.
Blood samples were immediately placed on ice and centrifuged within 30 minutes
of
collection. Plasma samples (-1.0 mL) were harvested and stored in 4 aliquots
of 0.25 mL
at -20 degrees C. Plasma samples were analyzed for celecoxib using an LC-MS/MS
assay
with a lower limit of quantitation of 5 ng/mL. Pharmacokinetic profiles of
celecoxib in
plasma were analyzed using the PhAST software Program (Version 2.3, Pheonix
Life
Sciences, Inc.). The absolute bioavailability (F) is reported for oral doses
relative to the IV
dose.
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Fig. 5B shows the mean pharmacokinetic parameters (and standard deviations
thereof) of celecoxib in the plasma of male dogs following a single oral or
single
intravenous dose of celecoxib or celecoxib sodium salt. The maximum blood
serum
concentration and bioavailability of orally-administered celecoxib sodium salt
was about
three- and two-fold greater, respectively, than a roughly equal dose of orally-
administered
celecoxib, and the maximum blood serum concentration of celecoxib sodium was
reached
40% faster than for celecoxib. Figure 6 shows the dissolution of celecoxib in
the plasma
of male dogs following a single oral or single intravenous dose of celecoxib
or celecoxib
sodium salt.
All novel combinations of form and formulation performed significantly better
than
the commercial product, Celebrex. The supporting data for this conclusion are
detailed in
Fig. 5B and are summarized as follows: (1) The formulations were fully
bioavailable
versus only 40 percent bioavailable for Celebrex; (2) The formulations had
pharmacokinetics that were linear with dose, as shown in Fig. 5C, which was
not the case
with Celebrex; and (3) A half dose of the formulations (i.e., 2.5mg/kg)
exhibited a mean
celecoxib plasma level that was 5-fold greater that a full dose of Celebrex
(5mg/kg) in the
first 15 minutes post dosing. The last observation, illustrated in Figure 5B,
indicates an
improved rate of therapeutic onset for the formulations of the present
invention.
Fig. 5B shows mean pharmacokinetic parameters of celecoxib in plasma following
administration of IV and oral doses. Definitions of the parameters are as
follows: (a)
Cmax: peak concentration; observed value; (b) Tmax: Time to Cmax; observed
value; (c)
AUC(I): The area under the plasma concentration versus time curve from time
zero to
infinity; (d) t%: Terminal phase half-life; (e) F: Relative oral
bioavailability; and (f) CL/F:
Plasma clearance of the absorbed fraction. The number of beagles used per
formulation
are identified by the superscript next to the formulation name, where (i) a
refers to n = 6;
(ii) b refers to n = 3; and (iii) c refers to n = 2.
Example 8
Celecoxib Lithium Salt Preparation Method: MO-116-49B
To celecoxib (101.4 mg; 0.2656 mmol) was added an aqueous solution of LiOH
(0.35 M; 1.05 mL; 0.37 mmol). The mixture was gently heated during dissolution
with
occasional swirling until the solid dissolved. The water was evaporated with
flowing
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nitrogen gas to yield a white crystalline solid. Characterization of the
product mixture
was achieved via DSC (Fig. 14), TGA (Fig. 15), Raman spectroscopy (Fig. 16)
and PXRD
(Fig. 17) and showed the presence of celecoxib Li salt. Further purification
of the drug to
remove the excess base can be achieved via recrystallization.
Results of the DSC thermogram (Fig. 14) show an endotherm at 111.84 degrees C
and a second endotherm at 237.11 degrees C. Results of the TGA (Fig. 15)
demonstrated a
14% weight loss between about 25 degrees C and 190 degrees C. Results of Raman
spectroscopy show multiple spectral peaks that can be used to characterize the
salt. These
include any one, any two, any three, any four, any five, any six, any seven,
any eight, any
nine, any ten, or any other combination of peaks of Fig. 16, e.g., 1617, 1597,
1450, 1374,
1115, 1063, 976, 801, 741 and 634 cm-I. The PXRD pattern has characteristic
peaks as
shown in Fig. 17. PXRD peaks that can be useci to characterize the salt
include any one, or
combination of any two, any three, any four, any five, any six, any seven, any
eight, any
nine, any ten, any eleven, or any other combination of 2-theta angles from
Fig. 17, e.g.,
4.14, 9.04, 10.705, 12.47, 15.08, 15.75, 18.71, 19.64, 20.52, 21.55 and 23.00
degrees. A
0.8 mm collimator was used during acquisition of the diffractogram.
Example 9
Celecoxib Potassium Salt: Preparation Method MO-116-49A
To celecoxib (100.7 mg; 0.2637 mmol) was added an aqueous solution of KOH
(0.35 M; 1.15 ml; 0.40 mmol). The mixture was gently heated during dissolution
with
occasional swirling until the solid dissolved. The water was subsequently
evaporated with
flowing nitrogen gas to yield a white crystalline solid. Characterization of
the resulting
mixture was performed via DSC (Fig. 18,) TGA (Fig. 19), Raman spectroscopy
(Fig. 20)
and PXRD (Fig. 21) and verified the presence of celecoxib K salt. Further
purification of
the drug to remove the excess base could be achieved via recrystallization.
The results of the DSC analysis are depicted in the graph of Fig. 18 and show
that
the mixture has an endotherm at 87.4 degrees C. The results of the TGA are
depicted in
Fig. 19 and show a 5.8 wt % loss between 25 and 200 degrees C. A shoulder in
the data is
seen at 80 degrees C. The Raman spectrum is depicted in Fig. 20 and show
characteristic
Raman shift (cm-I) peaks at positions including, but not limited to any one or
combination
of any two, any three, any four, or all five of the peaks: 1618, 1448, 1374,
976, and 801
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-
cm', or any combinations of 1, 2, 3, 4, 5, or more peaks of Fig. 20. The PXRD
pattern has
characteristic peaks as shown in Fig. 21. Peaks can be seen at 2-theta angles
including, but
not limited to, 4.03, 9.11, 12.23, 15.35, 18.87, 19.79, 20.97, and 22.81
degrees. The
crystal can be characterized by any one or combination of any two, any three,
any four,
any five, any six, any seven, or all eight of the above angles or any one or
any number
combination of 2-theta angles of Fig. 21. A 0.8 mm collimator was used during
acquisition of the diffractogram.
Example 10
Celecoxib Potassium Salt: Preparation Method MO-116-55D
A suspension of celecoxib (100.2 mg; 0.2627 mmol) in toluene (2.2 mL) and
methanol (0.1 mL) was gently warmed to yield a solution. To the solution was
added 3M
aqueous KOH (0.090 ml; 0.027 mmol). After the resulting phase separation, the
aqueous
phase was removed and dried by flowing nitrogen gas. The resulting crystalline
solid was
characterized via TGA (Fig. 22), Raman spectroscopy (Fig. 23), and PXRD (Fig.
24).
The TGA sample was heated at 10 degrees C/min to 90 degrees C, held for 10
minutes, ramped 10 degrees C/min to 300 degrees C, and held for 10 minutes
with 40
mL/min nitrogen purge gas. The results are depicted in Fig. 22 and show a
weight loss of
about 4.9 wt % from 25 degrees C to 200 degrees C and 2.9 wt % at a shoulder
from about
70 degrees C to 200 degrees C. This weight loss may indicate some level of
solvation or
residual solvent. The Raman spectrum of the solid is depicted in Fig. 23 and
shows
characteristic Raman shift (cm-1) peaks at positions including, but not
limited to any one or
a combination of any two, any three, any four, any five, any six, any seven,
any eight, any
nine, any ten, or all eleven of the peaks 1616, 1446, 1374, 1233, 1197, 1109,
1061, 973,
799, 740, or 633 cm-1, or any one or combinations of 2, 3,4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14
or more peaks of Fig. 23. The PXRD pattern is depicted in Fig. 24 and shows
characteristic peaks at 2-theta angles of 3.93, 10.83, 12.11, 15.07, 17.79,
18.57, 19.95,
24.77, and 26.97 degrees. Any one, any two, any three, any four, any five, any
six, any
seven, any eight, any nine, or more of these peaks or those listed in Fig. 24
may be used to
characterize celecoxib potassium salt.
Example 11
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Celecoxib Calcium Salt: Preparation Method MO-116-62A
To celecoxib (100 mg; 0.262 mmol) was added a solution of 1 M NaOH in
methanol (0.29 mL; 0.29 mmol). The mixture was gently warmed with occasional
swirling until all the solids were dissolved resulting in a colorless
solution. To the solution
was added a 3 M CaC12 solution in methanol (0.131 mL; 0.393 mmol). A solid
formed
within minutes. The precipitate was filtered and the powder was dried
overnight with
flowing nitrogen gas. Characterization of the product mixture was achieved via
TGA (Fig.
25), Raman spectroscopy (Fig. 26), and PXRD (Fig. 27) and showed the presence
of
celecoxib Ca salt and NaCl.
Results of the TGA (Fig. 25) show a total loss of 4.2 wt % between 25 and 200
degrees C. The Raman spectrum shows characteristic Raman shift (cm-1) peaks at
positions including, but not limited to, any one, any two, any three, any
four, any five, any
six, or all seven of the peaks 1617, 1598, 1450, 1377, 973, 801, 642, or any
combinations
of 2, 3, 4, 5, 6, 7 or more peaks of Fig. 26. The PXRD pattern shows 2-theta
angles at
3.91, 7.82, 9.27, 11.66, 20.56, and 23.08 degrees. Any one or a combination of
2, 3, 4, 5,
or more of the preceding peaks can be used to characterize the salt, as well
as, any 1, 2, 3,
4, 5, 6, or more peaks of Fig. 27. The peaks at 27.35 and 31.67 degrees 2-
theta are due to
NaCl.
Example 12
Comparative Analysis of Neutral Celecoxib
To aid in the analysis of some of the data retrieved, commercially available
celecoxib was subjected to the same analytical techniques of powder X-ray
diffraction
(PXRD) and Raman spectroscopy. The results were used as a comparison for the
salts of
the present invention.
Comparison Data: Celecoxib (PXRD)
A small amount of commercially available celecoxib was placed in a 0.3 mm
glass
PXRD tube. The tube was placed in Rigaku D/Max Rapid PXRD set to Cu; 46 kV/40
mA;
Collimator: 0.5 mm; Omega-axis oscillation, Pos(deg) 0-5, speed 1; Phi-axis
spin, Pos
360, Speed 2; Collection time was 15 minutes. The results are depicted in Fig.
28.
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Some of the peaks of the free acid may also be found in the compositions of
the
present invention. As a further means of characterizing the compositions of
the present
invention, the peaks characteristic of the free acid, as shown in Fig. 28, may
also be
specifically excluded from compositions of the present invention.
Comparison Data: Celecoxib (Raman)
A small quantity of commercially available celecoxib was placed on a glass
slide and
mounted in the Thermo Nicolet Almega Dispersive Raman spectrometer. The sample
capture was set to 6 background scans and 12 sample collection scans. The
results are
depicted in Fig. 29. An important feature in the Raman spectrum of celecoxib
free acid is
a peak near 906 cm-1. This peak is not found in the Raman spectra of the
sodium,
potassium, lithium, and calcium salts of the present invention.
Example 13
Solid-state Formulations of Celecoxib Sodium Salt Hydrate
Solid-state formulations based on selected PLURONIC excipients in combination
with
hydroxypropylcellulose (HPC) and the crystalline celecoxib sodium hydrate
salt, prepared
using traditional mortar and pestle technique, showed enhanced dissolution of
the
celecoxib salt in simulated gastric fluid.
This example demonstrates that related solid-state formulations enhance the
dissolution
and retard the precipitation of celecoxib salts as compared to the celecoxib
neutral free
acid compound. The processes used to identify and test the preferred
excipients in these
examples are two-fold: (1) A "precipitation retardation assay" was used to
identify
excipients that supersaturate celecoxib in solution; and (2) In-vitro
dissolution studies were
performed on selected excipients to verify the "precipitation retardation
assay" results.
Example 14
Precipitation Retardation Assay
Precipitation Retardation Assay - Method
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1. 58 excipients according to Table 2 were prepared at a concentration of 1.8
mg/mL
(0.18 % by weight) in simulated gastric fluid (SGF) having 200 mM hydrochloric
acid and dispensed in quadruplicate in 96-well plates at a volume of 150
microliters. SGF without excipients was used as a negative control. The
composition of SGF was 2 g/L sodium chloride, 1 g/L Triton X-100, and 200 mM
HC1 in deionized water.
Table 2.
Excipients used in Precipitation Retardation Assay
Polyethyleneglycol Monooleate
Alkamus 719 (Mapeg 400-M0) PLURONIC P123
Alkamus EL 620 Polyethyleneglycol 300 PLURONIC P85
Alkamus EL 719 PLURONIC 17R2 Poloxamer 188
Benzyl Alcohol PLURONIC F108 Poloxamer 338
Cremophor EL PLURONIC F127 Polypropyl 52
Cremophor RH40 PLURONIC F38 Polysorbate 40
Crillet 1 HP PLURONIC F68 Polysorbate 80
Crovol A-70 PLURONIC F77 Propylene Glycol
Ethosperse G-26 PLURONIC F87 Polyvinylpyrrolidone 10K
Ethylene Glycol PLURONIC F88 Polyvinylpyrrolidone 360K
Glycerin PLURONIC F98 Polyvinylpyrrolidone 55K
HEC 250K 2-Ethoxyethanol Saccharin
Hydroxypropylcellulose (HPC)PLURONIC L31 Sodium lauryl sulphate
Isopropanolamine PLURONIC L43 Tagat 02
Myrj 52 PLURONIC L44 Transcutol P
Polyethyleneglycol 1000 PLURONIC L92 Triacetin
Polyethyleneglycol 200 PLURONIC P103 Triethanol amine
Polyethyleneglycol 400 PLURONIC P104 Vitamin E TPGS
Polyethyleneglycol 600 PLURONIC P105 Vitamin E TPGS & HPC
2. The 96-well plates were sealed, and incubated to a temperature of 40
degrees C for
20 minutes. After incubation, the plate seals were removed.
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3. Celecoxib, pre-dissolved in potassium hydroxide at 5.5 mg/mL, was dispensed
in
15 microliter aliquots to each well and immediately mixed to give a final
celecoxib
concentration of 0.5 mg/mL per well. The final excipient concentration was 1.8
mg/mL. The assay plate was sealed using an optically clear seal.
4. A nephelometer (Nephelostar Galaxy, BMG Technologies, Durham, NC), with a
chamber preheated to 37 degrees C, was used to analyze the ability of the
excipients to retard the crystallization/precipitation of supersaturated
celecoxib via
light scatter measurements.
Precipitation Reiardation Assay - Results:
Fig. 30 shows precipitation retardation time for celecoxib as a function of
excipient
in simulated gastric fluid (SGF). Final concentration of celecoxib was 0.5
mg/mL. Black
bars indicate precipitation retardation time that may be greater than 60 min.
Excipients
listed in Table 8, but excluded from Fig. 30 did not show any appreciable
precipitation
retardation time (i.e., greater than 1.5 minutes). Nineteen of 58 excipients
were found to
retard recrystallization/precipitation of celecoxib.
The presence of six PLURONIC (poloxamer) excipients among successful
precipitation retardants prompted further study of these compounds. PLURONICs
are
ethylene oxide - propylene oxide block copolymers, whose properties can be
significantly
altered (e.g., melting point, cloud point, molecular weight, HLB number,
critical micelle
concentration, surface tension, interfacial tension, etc.) by adjusting the
ratio of copolymer
blocks. Further examination of these properties showed that the surface
tension of these
copolymers at a 0.1 % concentration in water correlates with the ability to
retard the
crystallization/precipitation of celecoxib. PLURONIC excipients having low
interfacial
tension (i.e., less than about 10 dyne/cm) or having a surface tension less
then about 42
dyne/cm were more effective at keeping celecoxib in solution than PLURONIC
excipients
having high interfacial tension or surface tension. This observation is
illustrated in Fig.
31A, along with interfacial data for PLURONICs that were not tested.
Fig. 31A shows interfacial tension values of selected PLURONIC excipients in
water. PLURONIC excipients having low interfacial tension correlated with
excipients
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that retarded crystallization/precipitation of celecoxib in simulated gastric
fluid. An
interfacial tension threshold for precipitation retardation was loosely
defined as less than
about 9 or 10 dyne/cm. The excipient concentration in the assay was 0.18 %;
celecoxib
concentration was 0.5 mg/mL. Interfacial data obtained from BASF at 0.1 %
concentration in water versus mineral oil at 25 degrees C. (PLURONIC is a
trademark of
BASF). It is important to emphasize that the Pluronics were used at a 1.8
mg/mL
concentration in this assay. It is suggested that a higher interfacial and
surface tension
threshold will correlate with the ability to prevent celecoxib precipitation
when the
Pluronics are used at a higher concentration.
The precipitation retardation data obtained using the Pluronic excipients was
further correlated to critical micelle concentration (CMC) values as a
function of
temperature. In this analysis, the dependence of CMC values as a function of
propylene
oxide content (i.e., PPO units) at both 25 and 37 degrees is illustrated in
Fig. 31B, where
the concentration values of the Pluronic excipients used in the screen are
overlayed for
comparison. As shown in Fig. 31, effective retardants at 37 degrees C had a
propylene
oxide content greater than 40 PPO because the retardants were used at a
concentration
higher than the CMC value. At 25 degrees C, the number of effective retardants
became
smaller because the use level of the Pluronic compounds fell below the CMC
value at this
temperature. A concentration of Pluronic excipients greater than the CMC is
thus
preferred for preventing immediate precipitation of celecoxib. The reported
CMC data
was obtained from V.M. Nace, in Nonionic Surfactants (V.M. Nace, Ed.), Marcel
Dekker,
New York, 1996, pp78-80.
Example 15
In Vitro Dissolution Studies of PLURONIC Excipients
In Vitro Dissolution Studies of PLURONIC Excipients - Method
1. Celecoxib Preparation
a. Fresh celecoxib sodium salt hydrate was prepared and analyzed to be
approximately 90 percent free acid vs. sodium content.
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b. The celecoxib salt was ground using mortar and pestle until fine powder
was formed. The fine powder was sieved using a 105 micrometer pore size
mesh and stored in a 20 mL scintillation vial at room temperature.
2. Formulation Preparation
a. Fresh PLURONIC excipient was dispensed into a mortar. If initially a
solid
at room temperature, the PLURONIC was ground until a smooth powder
was formed.
b. If hydroxypropylcellulose (HPC) was to be added, it was dispensed after
the PLURONIC excipient. The HPC was combined with the PLURONIC
and the two were ground together using a pestle and mixed with a spatula
for 1 minute.
c. 105 micrometer sieved celecoxib salt was added to mortar and the mixture
was ground and mixed for several minutes.
d. If needed, a liquid excipient such as Poloxamer 124, PEG 200, or PEG 400
was added to the mortar as a granulating fluid-like liquid to form an
intimate contact between drug and excipient. The mixture was ground and
mixed until a uniform consistency was observed in the solid-state mixture.
3. Dissolution Assay
a. A water bath was set up at 37 degrees C.
b. Simulated gastric fluid in the fasted state (SGF) was prepared at pH 1.7
and
diluted by a factor of five with deionized water. The final pH was
approximately 2.4. The simulated gastric fluid was diluted by a factor of
five to simulate the effect of drinking a glass of water with the medication.
The SGF was pre-heated to 37 degrees C.
c. The formulation was placed in a 20 mL scintillation vial.
d. A 10 mm x 3 mm stir bar was added.
e. Diluted SGF was added to the formulation. The volume added was set to
satisfy a 2 mg/mL dose of celecoxib free acid.
f. The vial was placed in the water bath and allowed to stir.
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g. At each time point, 0.9 mL of solution was extracted and filtered through a
0.2 micrometer polyvinylflouridine filter. The first 2/3 of filtrate was
discarded as waste and the last 1/3 was collected into an eppendorf tube.
0.1 mL of the collected filtrate was immediately transferred to an
autosampler vial and diluted by a factor of ten with 0.9 mL of methanol.
The autosampler vials were crimp sealed and submitted for content analysis
using high performance liquid chromatography with ultraviolet detection.
In Vitro Dissolution Studies of PLURONIC Excipients - Results:
1. Dissolution of two PLURONIC excipients that had low interfacial tension:
PLURONIC P123 and F127. PLURONIC P123 was a paste at room temperature,
and resulted in a sticky formulation of celecoxib salt. PLURONIC F127 was a
solid at room temperature and formed a flowable powder solid-state mixture
with
the celecoxib salt. The dissolution results for these mixtures at equal weight
concentrations of excipient to celecoxib free acid content are shown in Fig.
32.
(Weight ratios for the dissolution studies were based on the molar mass of
celecoxib free acid.) PLURONIC P123 gave enhanced dissolution of celecoxib
salt, while PLURONIC F127 did not. The poor performance of PLURONIC F127
in enhancing celecoxib dissolution was due to the slow dissolution of the
excipient.
In contrast, PLURONIC P123 was intimately bound with the celecoxib salt in a
"sticky" waxy mass, which delayed the dissolution of celecoxib. This allowed
the
excipient to dissolve to a greater extent prior to the full dissolution of the
celecoxib
salt form.
2. Dissolution of celecoxib sodium hydrate was performed in the presence of
HPC
using PLURONIC P123, PLURONIC F127, and PLURONIC F87. PLURONIC
F87 has a high interfacial tension value. Equal weight concentrations of
PLURONIC and HPC to celecoxib free acid content were used in the formulations.
The PLURONIC P123 formulation was sticky due to the pasty nature of the
excipient. The PLURONIC F127 and F87 formulation were flowable since these
excipients are solids at room temperature. Dissolution data for these
formulations
are shown in Fig. 33. The data showed that addition of HPC in the PLURONIC
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P123 formulation produced a widening of the dissolution profile. In the
PLURONIC F127 formulation, HPC enhanced the initial dissolution component of
the profile (i.e. < 10 minutes). In contrast, no dissolution profile was
observed in
the PLURONIC F87 formulation. Since PLURONIC F87 has a high interfacial
tension (17.4 dyne/cm), the resulting data supports the correlation of
precipitation
retardants with interfacial tension. Since the PLURONIC P123 formulation
(i.e.,
sticky) showed a dissolution profile that was enhanced to a greater extent
than the
PLURONIC F127 formulation (i.e., loose powder) in terms of time to
recrystallization/precipitation, it was hypothesized that the addition of an
excipient
that physically binds the components of the PLURONIC F127 formulation will
result in further dissolution enhancement.
3. Dissolution of celecoxib sodium /hydrate using PLURONIC F127 and HPC was
performed using a granulated fluid-like liquid to bind the solid-state
mixture.
Three granulating fluid-like liquids were chosen: PEG 200, PEG 400, and
Poloxamer 124. Equal weight ratios of celecoxib free acid content, PLURONIC
F127, and HPC were formulated with 40-45% celecoxib free acid weight of
granulating fluid. The effect of these formulations on dissolution is shown in
Fig.
34. The granulating fluid-like liquids increased the dissolution of celecoxib,
possibly by delaying the contact between the celecoxib salt and the
dissolution
media until PLURONIC F127 had been dissolved to a significant extent.
Dissolution of celecoxib sodium hydrate was then measured from a compacted
formulation
containing PLURONIC F127 and HPC excipients. Formulations containing equal
weight
ratios of celecoxib free acid content, PLURONIC F127, and HPC were mixed and
compacted into 6 mm discs at 4900 psi. Dissolution results, shown in Fig. 35A,
indicated
enhanced dissolution with onset retarded by approximately 15-20 minutes. The
compaction process produced a similar effect on dissolution to that observed
by the
addition of a granulating fluid (see Fig. 34) with the addition of a delayed
release
mechanism. The delayed release characteristic of the profile can be modulated
by
selecting HPC or HPMC with varying grades of viscosity and the addition of
disintegrants
into the compact. Compacts are attractive formulations due to their lower
production cost
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and fewer processing steps. Fig. 31B shows the concentration of PLURONIC
excipients
as a function of polypropylene oxide (PPO) units. This figure shows that
PLURONIC
concentrations greater than the CMC are preferred for effectively inhibiting
precipitation.
The data collected thus far, assumped that both initial solubilization and
precipitation inhibition were needed to achieve enhanced dissolution of
celecoxib. To
confirm this assumption, free acid celecoxib was tested in the selected
precipitation
inhibition excipients: Pluronic F127 and HPC. As shown in Fig. 35B, the
dissolution of
celecoxib did not show a supersaturation component. The small but measurable
increased
dissolution over the commercial formulation (i.e., Celebrex) reflects the
enhanced
thermodynamic solubility of the celecoxib free form in the excipient solution.
These data
highlight the importance of a novel form to serve as a "spring" and provide a
good driving
force for supersaturation to occur. In the precipitation inhibition screen the
driving force
was pre-solubilized celecoxib freeacid in 1 M potassium hydroxide.
Fig. 35B shows the dose of celecoxib free acid in the dissolution medium was 2
mg/ml. The parachute component was comprised of a surfactant, Pluronic F127,
and an
enhancer, 100,000 MW hydroxypropylcellulose (HPC) at equal mass ratios of
celecoxib
free acid. "Springs" refer to celecoxib free acid dissolved in either 2:1
PEG400:DI Water
or Transcutol P. "No spring" refers to neat celecoxib free acid. DI =
deionized,
Transcutol P = diethylene glycol monoethyl ether. Dissolution was performed at
37
degrees C.
To test if the "parachute" concept (i.e., surfactant or surfactant plus
enhancer)
enhances the dissolution of these springs, we decided to co-formulate several
species with
Pluronic F127 and HPC. The dissolution data obtained with these "springs",
Fig. 35B,
strongly suggest a "parachute" (surfactant or surfactant plus enhancer) is
needed for any
appreciable dissolution. Addition of "parachutes", such as of Pluronic F127
and HPC,
enabled the dissolution.
Dissolution was performed on a selection of celecoxib "springs" to generalize
the
concept that the "parachutes" function independently of "spring" type. In
these
experiments, it was assumed that the selected "springs" were "strong enough"
to drive the
compound of interest into solution. Once in solution, the "spring" component
is
theoretically exhausted and the "parachute" component takes an active role in
retarding
precipitation. The following celecoxib "springs" were compared: (i) freeacid;
(ii) sodium
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hydrate; (iii) sodium propylene glycol solvate; (iv) n-methyl pyrolidone (NMP)
solvate;
and (v) celecoxib:nicotinamide co-crystal. The parachute(s) used in the
comparison was a
combination surfactant and enhancer, Pluronic F127 and HPC, at same celecoxib
free acid
mass concentrations. A granulating agent such as Pluronic L44 or PEG400 was
added to
some of the samples for the purpose of determining its effect on the
dissolution profile.
The results shown in Fig. 35C confirm that the "parachute" maintained
supersaturated
levels of celecoxib when a spring was used. The free acid sample, which
represents a
spring with zero strength, showed concentration levels that were below those
concentrations obtained for the other springs.
Fig. 35C shows spring enhanced celecoxib dissolution in presence of parachute.
The dose of celecoxib free acid in the dissolution media was 2 mg/ml. The
implied
parachute in all samples was the combined surfactant and enhancer, Pluronic
F127 and
100,000 MW HPC, at equal mass ratios of celecoxib free acid. PG = propylene
glycol,
NMP = n-methyl pyrolidone, PEG400 = polyethylene glycol with an average
molecular
weight of 400 Da. Dissolution was performed at 37 degrees C.
Example 16
General Method of Precipitation Retardation Assay
The methods described above are specific examples of general methods of the
present
invention aimed at identifying excipients that retard the nucleation of solid-
state API, their
derivatives, and other non-pharmaceutical compounds of marketable interest
from a
solution supersaturated with API. The method is outlined in Fig. 36 and is
described as
follows:
1. Excipients are dissolved to a desired concentration in de-ionized (DI)
water or other
media (i.e., simulated gastric or intestinal fluids).
2. API is
dissolved in a suitable solvent in which it has high solubility (i.e., acidic
pH
environment for free base type API; and basic pH environment for free acid
type
API).
3. The excipient solutions are dispensed into an assay plate (i.e., 96-well
or 384-well
optically clear plate) either manually or using automated liquid handling
equipment.
The excipients can be added as single, binary, ternary, or higher order
excipient
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combinations into each well. An example of a liquid handling instrument is the
Tecan Genesis (Tecan U.S. Inc, Research Triangle Park, NC).
4. The API solution is dispensed into the assay plate. The API solution can
be
dispensed one well at a time, by rows, or columns using the Tecan Genesis
instrument or simultaneously into all wells using the Tecan Genmate
instrument.
The volume of API solution added is restricted to a small size to avoid
causing any
shifts in the properties of the excipient solution.
5. The solutions are mixed to uniformly distribute the API throughout the
excipient
solution. The plate is sealed and incubated at a desired temperature.
6. Onset of solid-state nucleation is determined using an instrument capable
of
measuring scattered light. Examples of scattered light measurement capable
instruments are the NepheloStar nephelometer (BMG Technologies, Durham, NC)
and the SPECTRAmax PLUS plate reader (Molecular Devices Corp, Sunnyvale,
CA). Temperature is maintained at a constant pre-defined set point by the
incubation features of the instruments.
7. Birefringence screening, PXRD, etc. may be performed to determine if
precipitated
API is amorphous or crystalline. If the API is crystalline, crystal habit and
particle
size can be recorded.
8. The data are analyzed and the excipients are ranked according to their
respective
retardation times.
Informatics may be used to correlate successful excipients that retard
nucleation with
physical property information.
Example 17
Illustration of Resulting Precipitation Retardation Data
Goal: Identify excipients that retard the solid-state nucleation of Compound A
in Fluid F at
a temperature of 37 degrees C.
Method:
1. 24 excipient solutions were prepared at a concentration of 16 mg/rnL in de-
ionized
water.
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2. Fluid F was prepared in de-ionized H20 by mixing ingredients at twice the
desired
final concentration.
3. API solution was prepared at a concentration of 5.5 mg/mL in Fluid C.
4. The Tecan Genesis instrument was used to dispense a combination of 75
microliters Fluid F, 18.75 microliters excipient solution, and 56.25
microliters de-
ionized H20 into each well of a 96-well plate. The final concentration of
excipient
in each well was 2 mg/mL in Fluid F. The total fluid volume per well was 150
microliters. Four replicate wells were used for each single excipient
solution. An
example of the layout is shown in Fig. 37.
5. The plate was sealed using a transparent seal and incubated at 40 degrees C
for 20
minutes.
6. The seal was removed and 15 microliters of API solution was dispensed
simultaneously into all 96-wells. The final concentration of API in each well
was
0.5mg/mL. (Note: The time dependence for solid-state nucleation began as soon
as
the API solution was added.)
7. The well contents were mixed and sealed using the transparent seal.
8. The plate was placed on the Nephelostar instrument to collect light scatter
data
over a 1 hour time period. The Nephelostar incubated the plate at 37 degrees C
as
specified in the goal of the assay.
9. At the end of the assay, the data were analyzed using Microsoft Excel and
retardation times were calculated. An example of collected light scatter data
is
shown in Fig. 38. Onset of solid-state nucleation is defined as the time when
the
light scatter signal increases above the baseline signal. The threshold limit
for the
increase of the light scatter signal used to define a
precipitation/crystallization
event is usually set at three times the standard deviation of the baseline
signal to
take into account background noise. The threshold can be set however, to a
different value depending on the sensitivity of the assay and the desired
limit of
precipitation/crystallization.
10. The retardation times (if any) for the excipient solutions were ranked.
Figure 30
shows a graphical representation of the ranking.
Non-limiting examples of alternatives to this general method include:
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1. Retardation time can be measured as a function of excipient concentration.
2. Retardation time can be measured as a function of API salt or co-crystal
concentration.
3. API can be concentrated in a non-aqueous medium prior to assay.
4. Temperature can be varied and controlled according to a desired
specification.
Example 18
Propylene Glycol Solvate of Celecoxib Sodium Salt
A propylene glycol solvate of the sodium salt of celecoxib was prepared. To a
solution of celecoxib (312 mg; 0.818 mmol) in diethyl ether (6 mL) was added
propylene
glycol (0.127 mL, 1.73 mmol). To the clear solution was added sodium ethoxide
in
ethanol (21%, 0.275 mL, 0.817 mmol). After 1 minute, crystals began to form.
After 5
minutes, the solid had completely crystallized. The solid was collected by
filtration and
was washed with additional diethyl ether (10 mL). The off-white solid was then
air-dried
and collected. The crystalline salt form was identified as a 1:1 solvate of
propylene glycol.
The solid was characterized by TGA and PXRD. The results are depicted in Fig.
39 and
40A.
Fig. 39 shows the results of TGA. A weight loss of about 15.6% was observed
between
about 65 and 200 degrees C which represents 1 molar equivalent of propylene
glycol to
celecoxib Na salt. Fig. 40A shows the results of PXRD. Peaks, in 2-theta
angles, that can
be used to characterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10 of the
following: 3.77, 7.57, 8.21, 11.33, 14.23, 16.13, 18.69, 20.65, 22.69 and
24.77 degrees or
any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks of
Fig. 40A. The
TGA thermogram or PXRD diffractogram data may be used alone or in any
combination
to characterize the solvate. A 0.8 mm collimator was used during acquisition
of the
diffractogram.
Several closely related, yet distinguishable, PXRD diffractograms have been
obtained by performing the above synthesis several times. Figs. 40B, 40C, and
40D are
additional diffractograms of the propylene glycol solvate of celecoxib sodium
salt. A
comparison of these diffractograms yields a number of noticeable differences.
For
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example, the peak at 8.21 degrees 2-theta in Fig. 40A is not present in Figs.
40B or 40C.
Another peak at 8.79 degrees 2-theta, present in Figs. 40B and 40D, is not
found in Figs.
40A or 40C. Other distinctions can also be found between the four diffi-
actograms. Such
distinctions in otherwise similar diffractograms suggest the existence of
polymorphism or
perhaps a variable hydrate.
Example 19
Propylene Glycol Solvate of Celecoxib Potassium Salt
A propylene glycol solvate of the potassium salt of celecoxib was prepared. To
a
solution of celecoxib (253 mg, 0.664 mmol) in diethyl ether (6 mL) was added
propylene
glycol (0.075 mL, 1.02 mmol). To the clear solution was added potassium t-
butoxide in
tetrahydrofuran (TBF) (1 M, 0.66 mL, 0.66 mmol). Crystals immediately began to
form.
After 5 minutes, the solid had completely crystallized. The solid was
collected by
filtration and was washed with additional diethyl ether (10 mL). The white
solid was then
air-dried and collected. The crystalline salt form was found to be a 1:1
propylene glycol
solvate of celecoxib K salt. The solid was characterized by TGA and PXRD. The
results
are depicted in Fig. 41 and 42.
Fig. 41 shows the results of TGA. A weight loss of about 14.94% was observed
between
about 65 and about 250 degrees C which is consistent with 1 molar equivalent
of
propylene glycol to celecoxib K. Fig. 42 shows the results of PXRD. Peaks, in
2-theta
angles, that can be used to characterize the solvate include any 1, 2, 3, 4,
5, 6, 7, 8 , 9, or
10 of the following: 3.75, 7.47, 11.33, 14.89, 15.65, 18.31, 20.49, 21.73,
22.51, and 24.97
degrees or any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more peaks of Fig.
42.
Example 20
Propylene Glycol Solvate of Celecoxib Lithium Salt
A propylene glycol solvate of the lithium salt of celecoxib was prepared. To a
solution of celecoxib (264 mg, 0.693 mmol) in diethyl ether Et20 (8 mL) was
added
propylene glycol (0.075 mL, 1.02 mmol). To the clear solution was added t-
butyl lithium
in pentane (1.7 M, 0.40 mL, 0.68 mmol). A brown solid formed immediately but
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dissolved within one minute which subsequently yielded a white fluffy solid.
The white
solid crystallized completely after 10 minutes. The solid was collected by
filtration and
was washed with additional diethyl ether (10 mL). The white solid was then air-
dried and
collected. The crystalline salt form was found to be a 1:1 propylene glycol
solvate of
celecoxib Li. The solid was characterized by TGA and PXRD.
The results of TGA are depicted in Fig. 43 and show a weight loss of about
16.3 %
between 50 degrees C and 210 degrees C which is consistent with 1 molar
equivalent of
propylene glycol to celecoxib Li. The results of PXRD are shown in Fig. 51.
Characteristic peaks of 2-theta angles that can be used to characterize the
salt include any
one, or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 3.79,
7.51, 8.19, 9.83,
11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01, or 25.09 degrees or any one
or any
combination of peaks of Fig. 51.
Example 21
Propylene Glycol Solvate of Celecoxib Sodium Trihydrate
Preparation:
Celecoxib Na propylene glycol trihydrate was formed by allowing the celecoxib
sodium salt propylene glycol solvate to sit at 60 % RH and 20 degrees C for 3
days.
(Note: Formation of the trihydrate at 75 % and 40 degrees C occurs as well).
The
trihydrate begins to form somewhere between 31 and 40 % RH at room
temperature.
The solid was characterized by TGA and PXRD, which are shown in Fig. 44 and
45, respectively. Fig. 44 shows the results of the TGA where 9.64 % weight
loss was
observed between room temperature and 60 degrees C and 13.6 % weight loss was
observed between 60 degrees C and 175 degrees C. The PXRD pattern has
characteristic
peaks at 2-theta angles shown in Fig. 45. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
or more peaks
can be used to characterize the trihydrate, including for example, peaks at
3.47, 6.97,
10.37, 13.97, 16.41, 19.45, 21.29, 22.69, 23.87, and 25.75 degrees.
The trihydrate can also be formed by crystallization of celecoxib Na propylene
glycol solvate in the presence of H20. To a solution of celecoxib (136.2 mg;
0.357 mmol)
in diethyl ether (6.0 mL), water (0.025 mL; 1.39 mmol), and propylene glycol
(0.030 mL;
0.408 mmol) was added sodium ethoxide in ethanol (21 wt. %; 0.135 mL; 0.362
mmol). A
solid formed within one minute and was isolated via filtration. The solid was
then washed
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with additional diethyl ether (2.0 mL) and allowed to air dry. This procedure
gives
essentially the same PXRD pattern but there is a slight excess of water, which
is probably
surface water.
The solid was characterized by TGA and PXRD, which are shown in Fig. 46 and
47, respectively. Fig. 46 shows the results of TGA where 10.92% weight loss
was
observed between room temperature and 50 degrees C and 12.95% weight loss was
observed between 50 degrees C and 195 degrees C. The PXRD pattern has
characteristic
peaks at 2-theta angles shown in Fig. 47. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, or more
peaks can be used to characterize the trihydrate, including for example, peaks
at 3.43, 6.95,
10.25, 13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21, 22.61, and 25.71
degrees. A 0.8
mm collimator was used during acquisition of the diffractogram.
Example 22
Isopropyl Alcohol Solvate of Celecoxib Sodium Salt
To a solution of celecoxib (204.2 mg; 0.5354 mmol) in diethyl ether (6.0 mL)
was
added isopropanol (0.070 mL). To the colorless solution was added a solution
of sodium
methoxide (0.5 M; 2.52 mL; 6.75 mmol) in methanol followed by hexanes (3.0
mL). The
volatiles were reduced under flowing nitrogen gas. A white solid formed and
was
collected via filtration. After drying, the solid was found to be an
isopropanol solvate
(1.5:1 isopropanol:celecoxib) via TGA and PXRD.
The results of DSC, TGA and PXRD analysis are shown in Figs. 48-50. Fig. 48
shows the results of DSC analysis where an endotherm was observed at 67.69
degrees C.
The results of TGA, as shown in Fig. 49, revealed a weight loss of about 18.23
% from
about room temperature to about 120 degrees C which represents a 1.5 molar
equivalent of
isopropanol to celecoxib Na. The PXRD pattern has characteristic peaks at 2-
theta angles
shown in Fig. 50. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more peaks
can be used to
characterize the solvate, including for example, peaks at 3.43, 7.03, 10.13,
11.75, 14.11,
16.61, 17.61, 18.49, 19.51, 20.97, 22.33, 22.81, and 25.93 degrees 2-theta.
Example 23
1:1 Celecoxib:Nicotinamide Co-crystals
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Celecoxib (100 mg, 0.26 mmol) and nicotinamide (32.0 mg, 0.26 mmol) were each
dissolved in acetone (2 mL). The two solutions were mixed and the resulting
mixture was
allowed to evaporate slowly overnight. The precipitated solid was collected
and
characterized. Detailed characterization of the co-crystal was performed using
DSC, TGA
and PXRD. The results of DSC showed two phase transitions at 117.2 and 118.8
degrees
C and a sharp endotherm at 129.7 degrees C. The results of TGA showed
decomposition
beginning at about 150 degrees C. The results of PXRD are shown in Fig. 52.
Characteristic peaks that can be used to characterize the co-crystal include
any one, or any
combination of any 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, of the peaks
at 3.77, 7.56,
9.63, 14.76, 16.01, 17.78, 18.68, 19.31, 20.435, 21.19, 22.10, 23.80, 24.70,
25.295, and
26.73 degrees 2-theta, or any combination of peaks in Fig. 52.
Example 24
Hydrates of Celecoxib Sodium Salt and Celecoxib Sodium Propylene Glycol
Solvate
Celecoxib sodium is a variable hydrate. To analyze the affect of hydration on
crystal
structure, celecoxib sodium salt and celecoxib sodium salt propylene glycol
solvate were
analyzed by PXRD under 17 percent, 31 percent, 59 percent and 74 percent
constant
relative humidity (RH) at room temperature. An analysis of celecoxib sodium
hydrate and
celecoxib sodium propylene glycol solvate was performed by incubating the
samples at the
above relative humidity levels at room temperature for 48 hours. The following
table lists
PXRD 2-theta angle (degrees) peaks at the different relative humidities.
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Table 3- Celecoxib Sodium Salt and Celecoxib Sodium Propylene Glycol Solvate
PXRD
Data
Celecoxib Celecoxib
Sodium Sodium
Propylene
Glycol
17% 31% 59% 74% 17% 31% 59%
74%
3.51 3.51 3.49 3.59 3.79 3.82 3.47 3.47
3.99 3.95 3.95 4.61 7.65 7.61 6.97 6.97
8.87 8.91 4.61 5.35 8.75 8.69 10.29 10.29
9.51 10.71 5.35 8.91 11.45 11.44 11.91 11.85
10.75 11.59 7.83 9.51 12.19 12.19 13.03 12.97
11.59 11.97 8.91 10.71 16.47 15.29 13.95 13.97
13.39 13.31 9.19 11.29 18.43 15.88 16.41 16.41 _
18.47 14.45 11.65 12.99 19.21 16.43 17.39 17.39 _
19.09 18.49 12.21 13.85 20.91 17.19
17.79 17.79
20.17 19.07 12.97 14.43 22.13 18.45
18.23 18.23
21.55 20.13 13.87 14.83 22.95 19.17
19.45 19.45
21.91 20.47 14.79 16.07 20.84 20.59 20.63
31.67 21.53 16.05 16.75 22.09 21.27 21.27
21.85 17.47 17.13 22.95 22.67 22.63
22.77 18.43 17.97 23.99 23.91 23.91
31.69 18.89 18.39 25.47 24.37 24.35
19.57 18.71 31.05 25.71 25.71
20.13 19.63 29.09 27.83
20.43 19.89 31.33 29.11
21.57 20.43 31.83 31.31
22.41 21.55 32.79 31.87
24.53 22.39 33.55 32.83
25.37 23.43 33.59
25.75 24.55
27.23 25.35
27.69 25.71
29.49 27.17
30.11 27.69
31.70 28.19
35.23 29.49
37.95 29.99
32.29
37.87
The composition can be characterized by any one or combination of any 2, 3, 4,
5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, or more
peaks listed in Table 3 or any one or combination of any 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more
peaks of any
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one of Figs. 53-60. Fig. 53-56 are PXRD diffractograms of celecoxib sodium
hydrates at
17 percent, 31 percent, 59 percent, and 74 percent RH, respectively. Fig. 57-
60 are PXRD
diffractograms of celecoxib sodium propylene glycol hydrates at 17 percent, 31
percent, 59
percent, and 74 percent RH, respectively.
PXRD analysis of celecoxib sodium hydrate shows that crystal packing changes
as
water is absorbed. (See Figure 69 and dynamic moisture sorption data in
Example 30.)
PXRD analysis of celecoxib sodium propylene glycol solvate indicates the
presence of two
unique crystal forms when exposed to varying amounts of humidity. (See Figure
70 and
dynamic moisture sorption data in Example 30.) Form I is present at 31 percent
RH and
below, while Form II is present at 59 percent RH and above.
Example 25
Various Hydrates of Celecoxib Sodium Salt
Multiple celecoxib sodium salt samples, all form Ml, varying in hydration
(believed to range from about 0.5-4 equivalents of H20 per equivalent of
celecoxib) were
assayed by PXRD. The PXRD patterns were then grouped based on shared peaks.
Several
groups were identified with four shown in Fig. 61. Group D is consistent with
a mixture of
amorphous and crystalline celecoxib sodium. Table 4 lists PXRD peaks
characteristic in
common to groups A, B, and C and peaks that are specific to each group.
Table 4- Celecoxib Sodium Salt Hydrate PXRD Data
Peaks common to all Peaks for form Peaks for form Peaks for form
Variants of fonn M1 M1 A M1 B M1 C
_
3.7 0.3 9.5 0.2 9.5 0.2 12.1 0.2
8.9 0.2 11.3 0.2 11.4 0.2 14.7 0.2
10.7 0.2 17.2 0.2 13.3 0.2
20 0.2 14.4 0.2
21.8 0.3
Example 26
Hydrate of Celecoxib Potassium Salt
A celecoxib potassium salt hydrate was prepared. To a solution of celecoxib
(233.4 mg; 0.6120 mmol) in a methanolic potassium hydroxide solution (1.008 M;
0.606
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0.611 mL; ) was added wet methanol (methanol 1.0 mL; water 0.100 mL). The
solution
was then reduced nearly to dryness (0.5 mL) via evaporation with flowing
nitrogen gas.
To the residual solution was added diethyl ether (6.0 mL) and the mixture was
stirred.
Within one minute, crystals started forming and the solid was completely
crystallized
.. within 10 minutes. The solid was then filtered and allowed to air dry. The
solid was
characterized via TGA and PXRD.
The results of TGA and PXRD are shown in Fig. 63 and 64. Fig. 63 shows the
results of TGA where an 8.36 % weight loss was observed between room
temperature and
140 degrees C. The PXRD pattern has characteristic peaks at 2-theta angles
shown in Fig.
.. 64. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks can be used to
characterize the celecoxib
potassium hydrate, including for example, peaks at 3.69, 8.99, 10.65, 11.11,
13.35, 20.05,
21.45, 22.39, 24.77, and 26.71 degrees 2-theta.
Example'27
.. Preparation of Celecoxib Sodium Salt Using Sodium Chloride
To a solution of celecoxib (1.787 g; 4.686 mmol) in 1 M sodium hydroxide (5.0
mL; 5.0 mmol) was added a solution of 1 M sodium chloride (5 mL). The mixture
was
stirred and cooled to give slow crystallization of celecoxib sodium salt. The
solid was
collected via filtration and was washed with additional 1 M sodium chloride
(10 mL). The
.. solid was allowed to dry under flowing nitrogen gas.
The results of TGA and PXRD are shown in Fig. 65 and 66. Fig. 65 shows the
results of TGA where an 8.98 percent weight loss was observed between room
temperature
and 140 degrees C including a 4.06 percent weight loss between about 50
degrees C and
140 degrees C. The PXRD pattern has characteristic peaks at 2-theta angles
shown in Fig.
.. 66. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can be used to
characterize the
celecoxib sodium salt, including for example, peaks at 3.65, 8.95, 9.61,
10.77, 11.43,
14.01, 17.19, 18.33, 19.47, 19.99, 20.61, 21.71, 22.57, and 25.81 degrees 2-
theta.
Example 28
.. In Vitro Dissolution Study of Incubated Celecoxib Sodium Hydrate Salt
Formulations
In-vitro dissolution was performed on celecoxib formulations pre and post
incubation at 40 degrees C for 18 weeks. The composition of the test
formulations was: (i)
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celecoxib sodium hydrate salt, hydroxypropylcellulose (HPC), and poloxamer
407; (ii)
celecoxib sodium hydrate salt, hydroxypropylcellulose (HPC), poloxamer 407,
and PEG
400; and (iii) celecoxib sodium propylene glycol solvate,
hydroxypropylcellulose (HPC),
and poloxamer 407. Dissolution was performed using 5 times diluted simulated
gastric
fluid (0.3 mM Triton X-100) at 37 degrees C in 20 mL scintillation vials with
a magnetic
stirrer.
As illustrated in Figure 67, the dissolution profiles for formulations (ii)
and (iii)
post 40 degrees C incubation displayed small losses in peak dissolution
magnitudes versus
the fresh formulations. This loss, however, should not impact the in-vivo
bioavailability
and dose-response properties of celecoxib, as was observed in the dog
pharmacokinetics
section, where it was shown that in-vitro dissolution profiles of varying peak
magnitude
correlate with dog pharmacokinetic profiles (i.e., the in-vivo ¨ in-vitro
correlation). In
contrast to the dissolution behavior of formulations (ii) and (iii),
formulation (i) exhibited
improved dissolution which may result from slight melting of Pluronic F127 at
40 C.
Melted Pluronic F127 may provide a benefit to dissolution similar to that
provided by
Pluronic L44 and PEG400.
Example 29
Controlled Release Formulation of Celecoxib Sodium Propylene Glycol Solvate
A membrane coated system was selected to achieve controlled release of
celecoxib.
The membrane, an erodible polymer with low water permeability, controlled the
release of
celecoxib through an erosion process. The membrane is used to facilitate
erosion of the
coating in water without permitting the water to enter the interior of the
pellet. The rate of
celecoxib release was controlled by applying the polymer at increasing
membrane
thicknesses to sub-populations of pellets within the final formulation dose.
Pellets with a
thin polymer coat release celecoxib more quickly than pellets that have a
thicker polymer
coat. Modulation of the coating thickness across many pellets results in a
distribution of
drug release profiles. Factors that affect the rate of polymer erosion include
polymer type,
plasticizer content, temperature, solvent, curing, and coat thickness. The
formulation used
in this example was comprised of celecoxib sodium propylene glycol solvate,
Pluronic
F127, and hydroxypropylcelluse (100,000 MW) at equal weight equivalents of
celecoxib
free acid. The formulation was supplemented with magnesium stearate at a
concentration
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of 0.05 weight percent to aid in the compression and ejection of pellets. This
formulation
comprised 30.4 weight percent celecoxib free acid.
Pellets were compressed at 10.3 MPa into 2 mm diameter pellets of
cylindrical shape. The cylindrical pellets had an average height of 1 mm and
average
weight of 3.8 mg. Polymer coatings (e.g., cellulose acetate phthalate (CAP),
polyvinyl
acetate crotonic acid copolymer) were applied using a spray coater. The values
of coating
thicknesses ranged from 15 to 70 micrometers
The application of the polymer coat was designed to delay the release of
celecoxib
and prevent its rapid conversion to the free acid form prior to absorption. To
elucidate
how the coating affects delayed release and dissolution during a transit
through the
stomach, an assay was developed that employed both SGF and SIF. This assay was
a two
step process where, dissolution was performed in SGF in the first step, and
the SGF
medium was replaced with SIF medium to complete the dissolution assay in the
second
step. Two assumptions were made: (1) the typical transit time in the stomach
for small
food particles is 30 minutes; and (2) solubilized celecoxib is quickly
absorbed thus
justifying complete exchange of SGF having solubilized celecoxib with SIF.
In vitro dissolution was tested in both simulated gastric and intestinal
fluids in the
fasted state. As a specific example, dissolution was performed in simulated
gastric fluid
on celecoxib sodium propylene glycol pellets coated with cellulose acetate
phthalate
containing 10 percent by weight triethyl citrate plasticizer (approximately 64
,m coating
thickness). After about 30 minutes, the dissolution media was transferred to
simulated
intestinal fluid. The dissolution profile showed no celecoxib release in the
first 30 minutes
which is consistent with the behavior of enteric coatings in low pH solutions.
Once in the
simulated intestinal fluid, the coating began to erode and celecoxib sodium
was released.
A maximum concentration of 0.64 mg/ml was obtained after about 90 minutes in
the assay
(See Figure 68). This example demonstrates that controlled release can be
achieved by
applying varying coating thicknesses with discrete populations of pellets in a
drug capsule.
The controlled release of celecoxib can be achieved through a combination of
coated
formulation pellets and/or a combination of formulation powder with coated
formulation
pellets.
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Example 30
Dynamic Moisture Sorption Analysis of Celecoxib Salts, Hydrates, Solvates, and
Co-
Crystals
Moisture sorption analysis was performed using the DVS-1 apparatus (Surface
Measurement Systems, Monarch Beach, CA) with a Calm D-200 microbalance (Thermo
Calm, Madison, WI). Each sample was placed in a clean glass crucible and
equilibrated in
the apparatus at a specified relative humidity (RH) level. Initial
equilibration was
performed in the DVS apparatus, unless otherwise specified. After initial
equilibration,
RH was varied and change in mass was recorded over time as an indication of
moisture
sorption. RH was controlled by varying flow rates of dry and water saturated
nitrogen
streams at 25 degrees C; the total combined flow rate of both streams was kept
constant at
200 standard cubic meters per minute. A full humidity cycle typically refers
to a ramp
from 0 to 95 percent RH and back down 0 percent RH, unless otherwise
specified. Mass
equilibration at each humidity level was obtained when the change in mass per
time value
(i.e., dm/dt) was less than 2 micrograms/min. After the assay, change in mass,
due to
water sorption, was mathematically converted to water molar equivalents per
dry
compound molar equivalent. Form analysis was performed at the end of the assay
on
select samples using powder x-ray diffraction pattern (PXRD; D/Max Rapid,
Rigaku,
Danvers, MA). Samples were packed into 3 mm diameter borosilicate capillary
tubes for
the analysis.
Celecoxib Sodium Hydrate
Celecoxib sodium hydrate (dry mass: 9.2593 mg, dry molecular weight: 404.36,
temperature: 25.4 degrees C) was initially equilibrated at 20 percent RH at 25
degrees C.
RH was ramped up from 20 percent to 95 percent RH, and then ramped down to 0
percent
RH. Two complete humidity cycles were performed as illustrated in Figure 71.
The
moisture sorption isotherms for both cycles overlapped indicating a lack of
irreversible
form changes. In the transition from 0 to 10 percent RH the compound adsorbed
1 water
molar equivalent per dry compound. Water sorption increased steadily from 20
to 40
percent RH until approximately 3 water equivalents were obtained at 40 percent
RH. The
trihydrate was kinetically stable in the 40 to 70 percent RH range. At RH
values greater
than 70 %, water sorption continued to rise until deliquescence occurred at 95
percent RH.
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Key observations in this assay were the formation of forms consistent with a
tri-hydrate
designation in the 40 to 70 percent RH range and a monohydrate designation in
the 10 to
20 percent RH range.
Celecoxib Potassium
Celecoxib potassium (dry mass: 15.8563 mg, dry molecular weight: 419.48,
temperature: 25.5 degrees C) was initially equilibrated at 0 percent RH at 25
degrees C.
RH was then ramped from 0 to 95 percent RH in a two cycle experiment, as
illustrated in
Fig. 72A. Water sorption was strongly dependent on RH with immediate
adsorption
occurring at very low RH levels, and deliquescence occurring at 95 percent RH.
The
analysis was characterized by very low hysteresis and large amounts of water
uptake. A
PXRD pattern taken at the end of the assay, Fig. 72B, showed the compound to
be in the
crystalline state. Small changes in form are apparent, as compared to the pre-
incubation
PXRD, indicating some crystal rearrangement (i.e., polymorphism) associated
with
moisture sorption. The pre-incubation PXRD is representative of celecoxib
potassium that
had been equilibrated at room temperature and ambient humidity.
Celecoxib Sodium Propylene Glycol Solvate
Celecoxib sodium propylene glycol solvate (dry mass: 19.4851 mg, dry molecular
weight: 480.45, temperature: 25.8 degrees C) was initially equilibrated at 0
percent RH at
degrees C. RH was ramped from 0 to 75 percent RH in a three cycle experiment
as
illustrated in Figure 73. No change in mass was observed from 0 to 34 percent
RH,
indicating the presence of a stable anhydrous form over this range. At 40
percent RH, the
compound gained one water molar equivalent and monotonically keeps increasing
in water
25 content up to 75 percent RH.
The desorption cycle was characterized by significant hysteresis which is
consistent with hydration processes. During water desorption water was shed
very slowly
until a dihydrate was formed below 40 percent RH. The dihydrate was stable
from 33 to
17 percent RH. Upon further drying to 0 percent RH, the sample continued to
lose water
before equilibrating at a weight lower than the original dry weight (i.e., 0
percent RH in
Cycle 1 Sorp). The additional loss of mass suggests propylene glycol was
released during
the RH transitions. Assuming that the compound was dry (i.e., without water)
at 0 percent
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RH, the calculated propylene glycol loss was 0.16 equivalents. Two additional
humidity
cycles were run to verify these observations. The additional cycles showed
similar trends
to the first cycle, but on a lower y-axis scale due to the propylene glycol
mass loss.
Furthermore, additional mass loss was observed at the end of each cycle. The
total
calculated propylene glycol loss at the end of the second and third cycles was
0.25 and
0.32 mass equivalents of propylene glycol respectively.
A second dynamic moisture sorption analysis was completed with celecoxib
sodium propylene glycol solvate. In this trial, the sample was incubated at 55
percent RH
at room temperature for 72 hours in a salt bath solution. In the moisture
sorption analysis,
the sample was removed from the 55 percent RH chamber and equilibrated at 20
percent
RH at 25 degrees C in the dynamic moisture sorption instrument. RH was then
ramped
from 20 to 60 percent RH and down to 0 percent RH in the first cycle. As shown
in Fig.
74, a stable trihydrate was observed from 10 to 60 percent RH. At 0 percent
RH, the water
molecules were shed to yield an anhydrous form.
In the second humidity cycle, water began to adsorb at RH values greater than
20
percent. At 40 percent RH, 2 water equivalents had been absorbed which is
consistent
with a dihydrate form designation. This dihydrate was stable from 40 to 60
percent RH.
At greater RH, water content exponentially increased and deliquescence was
observed at
95 percent RH. The desorption cycle was characterized by significant
hysteresis below 70
percent RH. Between 30 and 10 percent RH the dihydrate form was reestablished.
Upon
further drying to 0 percent RH the sample equilibrated at a weight lower the
than original
dry weight of the compound. Assuming that the sample was completely dry, the
calculated propylene glycol loss was estimated to be 0.16 molar equivalents.
A third humidity assay was begun, but was stopped shortly thereafter at 30
percent
RH prior to equilibration. As shown in Figure 75, a PXRD pattern taken at this
time
showed form conversion, with respect to the starting material, suggesting that
water
sorption involves rearrangement of the crystal structure.
The primary difference observed in this study, with respect to the first
celecoxib
sodium propylene glycol solvate analysis, was the presence of a stable
trihydrate form in
10 to 60 percent RH region following equilibration at 55 percent RH for 72
hours.
Because the observations made in the second humidity cycle were remarkably
consistent
with those made in the prior assay, assay reproducibility was confirmed. These
findings
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suggests that the dihydrate form was kinetically stable for extended time
periods of time
(i.e., hours) before converting to a thermodynamically stable trihydrate form.
Celecoxib Potassium Propylene Glycol Solvate
Celecoxib potassium propylene glycol solvate (dry mass: 17.2584 mg, dry
molecular weight: 496.57, temperature 25.1 degrees C) was initially
equilibrated in 0
percent RH at 25 degrees C. RH was ramped from 0 to 95 percent RH in a one
cycle
experiment as illustrated in Fig. 76. No change in mass was observed from 0 to
43 percent
RH, indicating the presence of a stable anhydrous form over this range. Above
43 percent
RH, water sorption increased exponentially with increasing percent RH until.
Deliquescence was observed at 95 percent RH.
The desorption cycle was characterized by negative hysteresis consistent with
that
observed for the sodium propylene glycol solvate form. At 30 percent RH the
sample
equilibrated at a mass below that of the initial dry mass of the sample. This
mass loss,
attributed to removal of propylene glycol, was calculated to be 0.27
equivalents at 0
percent RH. A PXRD pattern (see Fig. 77) taken at the end of the assay showed
the
sample had converted to an amorphous form.
Celecoxib Lithium Propylene Glycol Solvate
Celecoxib lithium propylene glycol solvate (dry mass: 5.5916 mg, dry molecular
weight: 387.32, temperature: 25.5 degrees C) was initially equilibrated at 20
percent RH at
degrees C. RH was ramped up from 20 to 95 percent RH and back down to 0
percent
RH. Two complete humidity cycles were performed as illustrated in Fig. 78. In
the initial
20 to 50 percent RH transition the data shows 1 molar water equivalent was
desorbed,
25 assuming PG was not lost at this stage. Above 60 percent RH water
sorption increased
exponentially with increasing percent RH before deliquescence occurred at 95
percent RH.
In the desorption cycles, a lower dry weight was consistently obtained after
equilibration in 0% RH. The decreasing dry weight obtained at 0 percent RH was
consistent with the properties of other propylene glycol forms and suggests
loss of
propylene glycol during the RH ramp cycles. The calculated propylene glycol
loss was
0.11 molar equivalents. A PXRD pattern, Fig. 79, taken at the end of the assay
showed a
change in crystalline form during the assay.
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Celecoxib:Nicotinamide Co-Crystal
Celecoxib:Nicotinamide co-crystal (dry mass: 3.129 mg, dry molecular weight:
1044.8, temperature: 25.3 degrees C) was initially equilibrated at 0 percent
RH at 25
degrees C. RH was ramped from 0 to 95 percent RH in a two cycle experiment, as
illustrated in Fig. 80. The co-crystal was not hygroscopic below 70 percent
RH. The
small amount of water content observed in the figure is attributed to surface
adsorption.
Above 70 percent RH, water content increased gradually and reached a peak
concentration
of 2 water molecules per mole of co-crystal at 95 percent RH. The desorption
cycle was
characterized by minimal hysteresis..
Example 31
Amorphous Celecoxib Potassium Salt: Preparation Method MO-116-55B
To celecoxib (105.3 mg; 0.2761 mmol) was added aqueous 3M KOH (0.090 ml;
0.27 mmol) to give a suspension. The suspension was gently warmed and to it
was added
methanol (0.3 mL) which yielded a colorless solution. The solution was cooled
to room
temperature and the volatiles were subsequently evaporated with flowing
nitrogen gas.
The resulting amorphous solid was characterized via DSC, Raman spectroscopy,
and
PXRD.
The DSC is depicted in Fig. 81. The Raman spectrum is depicted in Fig. 82 and
shows
characteristic Raman shift peaks (cm') at positions including, but not limited
to any one or
a combination of any two, any three, any four, any five, any six, any seven,
any eight, any
nine, any ten, or all eleven of the peaks 1616, 1450, 1376, 1236, 1198, 1112,
1063, 976,
800, 742, or 634 cm-1, or any one or combinations of 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14
or more peaks of Fig. 82. The PXRD pattern is depicted in Fig. 83 for which
one peak is
observed at 3.87 degrees 2-theta.
Example 32
Crystallization of Celecoxib and Valdecoxib with Various Ethers
Celecoxib:18-crown-6 Co-crystal
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To solid 18-crown-6 (118.1 mg; 0,447 mmol) was added a solution of celecoxib
(157.8 mg; 0.4138 mmol) in diethyl ether (10.0 mL). The opaque solid dissolved
immediately and a white solid subsequently began to crystallize very rapidly.
The solid
was collected via filtration and was washed with additional diethyl ether (5
mL).
The solid was allowed to air dry and was characterized via TGA, DSC, and PXRD.
Unit cell determination by single crystal X-Ray diffraction is consistent with
a 2:1 adduct
(celecoxib:18-crown-6). The co-crystal has a higher melting point (189 degrees
C) than
celecoxib (156-159 degrees C).
Fig. 84 shows the TGA thermogram of the celecoxib:18-crown-6 co-crystal.
Results of the TGA analysis show an approximate 25 percent weight loss between
about
125 degrees C and 220 degrees C. Fig. 85 shows the DSC thermogram of the
celecoxib:18-crown-6 co-crystal. Results of the DSC analysis shows an
endotherm at
189.6 degrees C. Fig. 86 shows the PXRD diffractogram of the celecoxib:18-
crown-6 co-
crystal. Peaks can be seen at 2-theta angles including, but not limited to,
8.73, 11.89,
13.13, 16.37, 17.75, 18.45, 20.75, 22.37, and 23.11 degrees. The crystal can
be
characterized by any one or combination of any two, any three, any four, any
five, any six,
any seven, any eight, or all nine of the above angles or any one or any
combination of 2-
theta angles of Fig. 86.
Celecoxib 15-crown-5 Solvate
To a solution of celecoxib (165.2 mg; 0.4332 mmol) in diethyl ether (5.0 mL)
was
added a solution of 15-crown-5 (0.095 mL; 0.48 mmol) in diethyl ether (1.0
mL). The
volatiles were allowed to evaporate slowly yielding an oil. The oil was then
recrystallized
from ethanol (5 mL). The recrystallization also yielded an oil that
crystallized after 1 week
without agitation. The solid was found to be a 15-crown-5 solvate of
celecoxib.
The solid was characterized via TGA, DSC, and PXRD. The TGA data shows a
loss of 34.67 weight percent which is consistent with 1 molar equivalent of 15-
crown-5 per
mole of celecoxib (See Figure 87). DSC shows a melting point at 91.2 degrees C
which is
significantly lower than that of the 18-crown-6 analogue (189 degrees C) and
free
celecoxib (156-159 degrees C). The DSC thermogram is shown in Fig. 88. Fig. 89
shows
the PXRD diffractogram of the celecoxib 15-crown-5 solvate. Peaks can be seen
at 2-theta
angles including, but not limited to, 7.67, 13.57, 14.61, 20.61, 21.69, 23.07,
and 24.81
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degrees. The crystal can be characterized by any one or a combination of any
two, any
three, any four, any five, any six, or all seven of the above angles or any
one or any
combination of 2-theta angles of Fig. 89.
Celecoxib Diglyme Solvate
To a solution of celecoxib (129.3 mg; 0.3390mmo1) in diethyl ether (5.0 mL)
was
added a solution of diglyme (0.100 mL; 0.698mmo1) in diethyl ether (3.0 mL).
The
volatiles were allowed to evaporate slowly yielding a white solid. The solid
continued to
crystallize as the solvent was reduced (2 mL) and subsequently cooled. The
white powder
was collected via filtration and air-dried. The solid was found to be a
diglyme solvate of
celecoxib.
The solid was characterized via TGA, DSC, and PXRD. The TGA data shows a
loss of 24.85 weight percent which is consistent with 1 molar equivalent of
diglyme per
mole of celecoxib (See Figure 90). The melting point of the solvate is shown
to be 98.2
degrees C by DSC, which is significantly lower than celecoxib (156-159 degrees
C). ).
The DSC thermogram is shown in Fig. 91. Fig. 92 shows the PXRD diffractogram
of the
celecoxib diglyme solvate. Peaks can be seen at 2-theta angles including, but
not limited
to, 6.71, 10.77, 16.15, 20.53, 21.05, 21.81, and 22.69 degrees. The crystal
can be
characterized by any one or a combination of any two, any three, any four, any
five, any
six, or all seven of the above angles or any one or any combination of 2-theta
angles of
Fig. 92.
Valdecoxib:18-crown-6 Co-Crystal
To a solution of valdecoxib (33.3 mg; 0.107 mmol) in tetrahydrofuran (2.0 mL)
is
added a solution of 18-Crown-6 (30.2 mg; 0.114 mmol) in tetrahydrofuran (2.0
mL). The
solution was stirred and was allowed to slowly evaporate. After evaporation to
dryness,
the residual solid was a white crystalline material. A single crystal was
removed for single
crystal X-ray diffraction and was found to be a 2:1 adduct with two
independent
supramolecular complexes in the asymmetric unit. TGA analysis of the
valdecoxib:18-
crown-6 co-crystal is shown in Fig. 93. Fig. 94 shows the PXRD diffractogram
of the
valdecoxib:18-crown-6 co-crystal. Peaks can be seen at 2-theta angles
including, but not
limited to, 11.31, 13.23, 16.01, 17.69, 18.19, 21.11, 21.59, 22.51, 23.23, and
24.03
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degrees. The crystal can be characterized by any one or a combination of any
two, any
three, any four, any five, any six, any seven, any eight, any nine, or all ten
of the above
angles or any one or any combination of 2-theta angles of Fig. 94. Fig. 95
shows the
single crystal structure of the valdecoxib:18-crown-6 co-crystal.
Single-crystal x-ray data for the valdecoxib:18-crown-6 co-crystal 2:1 are as
follows:
Empirical formula C44 H52 N4 012 S2
Formula weight 893.02
Temperature 100(2) K
Wavelength 0.71073 angstroms
Unit cell dimensions a = 10.1721(11) angstroms alpha = 83.127(2) deg.
b = 13.7178(15) angstroms beta = 73.362(2) deg.
c = 16.7202(18) angstroms gamma = 89.017(2)
deg.
Volume 2219.0(4) A3
Z, Calculated density 2, 1.337 Mg/m3
Absorption coefficient 0.187 mnil
F(000) 944
Reflections collected! unique 13432! 9849 [R(int) = 0.0330]
Refinement method Full-matrix least-squares on F2
Data! restraints / parameters 9849 / 0! 559
Goodness-of-fit on F2 0.995
Final R indices [I>2sigma(I)] R1 = 0.0594, wR2 = 0.1345
R indices (all data) R1 = 0.1097, wR2 = 0.1573
The above co-crystals and solvates exemplify the importance of the ether-
sulfonamide interaction. This ether-sulfonamide interaction is highly
favorable and plays
an important role in the formulations of the present invention.
Example 33
Celecoxib NMP Solvate
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To solid celecoxib (127 mg; 0.333 mmol) was added N-methyl-2-pyrrolidone (0.75
mL) to give a white suspension. The mixture was heated to 75 degrees C and
held at this
temperature for 3 minutes at which point the solid dissolved to give a
colorless solution.
The solution was cooled to room temperature and then cooled to 5 degrees C for
three
days. After three days, colorless hexagonal crystals had formed. The mother
liquor was
decanted and the solid was suspended in pentane (2 mL) and filtered. The solid
was air
dried and collected. The solid was found to be a 1:1 N-methyl-2-pyrrolidone
(NMP)
solvate of celecoxib.
The solid was characterized by TGA, Raman spectroscopy, and PXRD. TGA data
show
an initial loss of 7.40 % weight loss between room temperature and 60 degrees
C which is
attributed to residual solvent (See Fig. 96). Between about 95 degrees C and
about 165
degrees C, the solvate loses 19.39 percent weight. This loss represents 1:1
molar
equivalent of NMP to celecoxib. The residual solvent can be removed to give
the pure
solvate. Raman scattering peaks were found at, for example, 1615, 1451, 1375,
1159, 973,
799, 741, and 626 cm-1. Any one, any two, any three, any four, any five, any
six, any
seven, or all eight of the above or any one or a combination of peaks in Fig.
97 can be used
to characterize the crystal. Fig. 98 shows the PXRD diffractogram of the
celecoxib:NMP
solvate. Peaks can be seen at 2-theta angles including, but not limited to,
8.19, 12.69,
15.01, 15.65, 16.37, 17.89, 19.37, 21.05 and 23.01 degrees. The crystal can be
characterized by any one or a combination of any two, any three, any four, any
five, any
six, any seven, any eight, or all nine of the above angles or any one or any
combination of
2-theta angles of Fig. 98.
Single-crystal x-ray data for the celecoxib:NMP co-crystal at 100 K is as
follows:
Empirical formula C22 1123 F3 N4 03 S
Formula weight 480.50
Temperature 100(2) K
Wavelength 0.71073 angstroms
Crystal system Monoclinic
Space group P2(1)/n
Unit cell dimensions a = 21.1232(14) angstroms alpha= 90 .
b = 9.2669(6) angstroms beta=
102.5320(10) .
c = 23.8250(16) angstroms gamma = 90 .
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Volume 4552.5(5) A3
8
Density (calculated) 1.402 Mg/m3
Absorption coefficient 0.199 mm-1
F(000) 2000
Crystal size 0.20 x 0.15 x 0.10 mm3
Theta range for data collection 1.17 to 28.33 .
Index ranges -26<=h<=28, -11<=k<=12, -3 1<=1<=25
Reflections collected 27520
Independent reflections 10573 [R(int) = 0.0366]
Completeness to theta = 28.33 93.0 %
Absorption correction None
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 10573 / 0 / 729
Goodness-of-fit on F2 1.026
Final R indices [I>2sigma(I)] R1 = 0.0580, wR2 = 0.1386
R indices (all data) R1 = 0.0873, wR2 = 0.1547
Largest cliff. peak and hole 0.694 and -0.655 e.A-3
Fig. 99 shows a packing diagram for the celecoxib:NMP solvate at 100 K.
Single-crystal x-ray data for the celecoxib:NMP co-crystal at 571 K is as
follows:
Empirical formula C22 H23 F3 N4 03 S
Formula weight 480.50
Temperature 571(2) K
Wavelength 0.71073 angstroms
Crystal system Monoclinic
Space group P2(1)/c
Unit cell dimensions a = 12.0017(10) angstroms alpha= 90 .
b = 9.0910(7) angstroms beta=
101.338(2) .
c = 21.9595(18) angstroms gamma = 90 .
Volume 2349.2(3) A3
4
Density (calculated) 1.359 Mg/m3
Absorption coefficient 0.192 mm-1
F(000) 1000
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Crystal size 0.20 x 0.15 x 0.15 mm3
Theta range for data collection 1.73 to 28.33 .
Index ranges -14<=h<=15, -12<=k<=11, -29<=1<=24
Reflections collected 14668
Independent reflections 5509 [R(int) = 0.0226]
Completeness to theta = 28.33 94.2 %
Absorption correction None
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 5509 / 0 / 328
Goodness-of-fit on F2 1.041
Final R indices [I>2sigma(I)] R1 = 0.0597, wR2 = 0.1698
R indices (all data) R1 = 0.0950, wR2 = 0.1958
Largest cliff. peak and hole 0.455 and -0.217 e.A-3
Fig. 100 shows a packing diagram for the celecoxib:NMP solvate at 571 K.
Example 34
Dissolution of Celecoxib Sodium Formulations with Potential Precipitation
Inhibitors
The dissolution profile in SGF of solid mixtures of celecoxib sodium with
excipients was studied at room temperature. Those mixtures that provided
concentrations
greater than 0.10 mg/mL at any time point studied are included in Figure 10.
Poloxamer 237, vitamin E TPGS (TPGS), and Gelucire 50/13 were all effective at
providing elevated concentrations for some period of time. PVP and poloxamer
188 were
less effective, but maintained measurable concentrations for at least some
period. The
TPGS solutions appeared mostly clear, and were clear after filtration. The
Poloxamer 237
samples appeared milky, even after filtration.
Since the mixtures with poloxamer 237 and 188 led to widely different
solubility
profiles, other poloxamers were studied as well, and the relationship between
poloxamer
structure and dissolution profile was evaluated (see Fig. 7). The weight ratio
of drug to
poloxamer is 1:1 for all profiles shown on the plot. Poloxamers 237 and 407
have a clear
enhancement effect relative to poloxamers 188 and 338.
Poloxamers are block copolymers of polyethyleneglycol (PEG) and
polypropyleneglycol (PPG). Fig. 7 also shows the block composition for each
poloxamer
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studied. The solubility is enhanced by poloxamers containing a high
composition of the
PPG block.
Fig. 8 shows the effects of celluloses on dissolution of 1:1 TPGS:celecoxib
sodium
at room temperature. The effect of excipient loading and ratio on the
dissolution profile
was tested and found to have a profound impact on the dissolution profile (see
Fig. 9). Fig.
shows a dissolution profile of celecoxib sodium in SGF from solid mixtures
with
excipients at room temperature. Fig. 11 shows the effect of Avicel and silica
gel on the
dissolution of celecoxib sodium, TPGS, HPC formulations in SGF at 37 degrees
C. Fig. 12
shows the dissolution of celecoxib sodium salt in several formulations at 37
degrees C in 5
10 times diluted SGF.
It is noted that as used in the Figures, the terms "TPI336" and "TPI-336"
refer to celecoxib
or a salt of celecoxib depending upon the context.
