U.S. patent application number 10/601092 was filed with the patent office on 2005-02-03 for pharmaceutical compositions with improved dissolution.
Invention is credited to Almarsson, Orn, Chen, Hongming, Guzman, Hector, Oliveira, Mark, Peterson, Matthew, Remenar, Julius, Tawa, Mark.
Application Number | 20050025791 10/601092 |
Document ID | / |
Family ID | 30004092 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050025791 |
Kind Code |
A1 |
Remenar, Julius ; et
al. |
February 3, 2005 |
Pharmaceutical compositions with improved dissolution
Abstract
The invention relates to methods of screening mixtures
containing a pharmaceutical compound and an excipient to identify
properties of the pharmaceutical compound/excipient combination
that retard solid-state nucleation. The invention further relates
to increasing the solubility, dissolution and bioavailability of a
drug with low solubility in gastric fluids conditions by combining
the drug with a recrystallization/precipit- ation retardant and an
optional enhancer.
Inventors: |
Remenar, Julius;
(Framingham, MA) ; Peterson, Matthew; (Framingham,
MA) ; Almarsson, Orn; (Shrewsbury, MA) ;
Guzman, Hector; (Jamaica Plain, MA) ; Chen,
Hongming; (Acton, MA) ; Tawa, Mark; (West
Roxbury, MA) ; Oliveira, Mark; (Framingham,
MA) |
Correspondence
Address: |
Transform Pharmaceuticals, Inc.
29 Hartwell Avenue
Lexington
MA
02421-3102
US
|
Family ID: |
30004092 |
Appl. No.: |
10/601092 |
Filed: |
June 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60390881 |
Jun 21, 2002 |
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60426275 |
Nov 14, 2002 |
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60427086 |
Nov 15, 2002 |
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60429515 |
Nov 26, 2002 |
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60437516 |
Dec 30, 2002 |
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60456027 |
Mar 18, 2003 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61K 31/18 20130101; A61P 29/00 20180101; A61K 31/635 20130101;
C07D 231/12 20130101; A61K 31/415 20130101; A61K 47/10 20130101;
A61K 9/145 20130101; A61K 9/146 20130101; A61K 31/365 20130101;
A61K 47/32 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 009/00 |
Claims
1. A process for producing a pharmaceutical composition, which
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 at least 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; (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.
2. A process according to claim 1, wherein the property varied in
step (4) comprises identity or amount of the excipient or the
pharmaceutical compound.
3. A process according to claim 1, wherein each solution comprises
an aqueous solution.
4. A process according to claim 3, wherein the mixture simulates
gastric juices or intestinal fluids.
5. A process according to claim 1, wherein the compound solution is
supersaturated.
6. A process according to claim 1, wherein the plurality of
containers are presented in a multiple well plate format.
7. A process according to claim 1, wherein at least the step of
dispensing is performed with automated liquid handling
apparatus.
8. A process according to claim 1, wherein the intimate mixture is
formed using a mixer.
9. A process according to claim 1, wherein the step of incubating
the mixture is preformed at constant temperature.
10. A process according to claim 9, wherein the temperature is
approximately 37.degree. C.
11. A process according to claim 1, wherein the onset of
solid-state nucleation is determined by measuring the light
scattering of the mixture.
12. A process according to claim 11, wherein the light scattering
is measured using a nephelometer.
13. A process according to claim 1, which further comprises a step
of determining the crystallinity of the product of solid-state
nucleation before selecting the pharmaceutical compound/excipient
combination.
14. A process according to claim 13, wherein the crystallinity is
determined by birefringence screening.
15. A pharmaceutical composition obtained by a process according to
claim 1.
16. A process for producing a pharmaceutical composition, which
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; (7) selecting an excipient which is found
to retard onset of solid-state nucleation; and (8) producing a
pharmaceutical composition comprising the pharmaceutical compound
and the selected excipient.
17. A pharmaceutical composition obtained by a process according to
claim 16.
18. A method for assessing excipient-mediated retardation of
solid-state nucleation 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; (6) determining
onset of solid-state nucleation; and (7) ranking the property of
the mixture according to time of onset of solid-state
nucleation.
19. A method for screening excipients that retard solid-state
nucleation 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; and (7) ranking the excipient according to time of
onset of solid-state nucleation.
20. A pharmaceutical composition comprising: (a) a salt form of a
drug having low solubility in gastric fluid conditions; (b) a
recrystallization/precipitation retardant; and (c) a an optional
enhancer; wherein the composition retards
recrystallization/precipitation of the drug for at least 5 minutes
in gastric fluid conditions.
21. The pharmaceutical composition according to claim 20, wherein
the recrystallization/precipitation retardant is a surfactant.
22. The pharmaceutical composition according to claim 21, wherein
the surfactant has an interfacial tension of less than 10 dyne/cm
or a surface tension of less then 42 dyne/cm.
23. The pharmaceutical composition according to claim 22, wherein
the surfactant is a poloxamer.
24. The pharmaceutical composition according to claim 23, wherein
the poloxamer has an interfacial tension of less than 10 dyne/cm or
surface tension less then 42 dyne/cm.
25. The pharmaceutical composition according to claim 21, wherein
the composition comprises an enhancer.
26. The pharmaceutical composition according to claim 22, wherein
the composition comprises a cellulose ester as an enhancer.
27. The pharmaceutical composition according to claim 23, wherein
the composition comprises HPC or HPMC as an enhancer.
28. The pharmaceutical composition according to claim 24, wherein
the composition comprises HPC as an enhancer.
29. The composition according to claim 26, wherein
recrystallization/preci- pitation is retarded for at least 10
minutes.
30. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 15
minutes.
31. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 20
minutes.
32. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 25
minutes.
33. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 30
minutes.
34. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 35
minutes.
35. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 40
minutes.
36. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 45
minutes.
37. The composition according to claim 29, wherein
recrystallization/preci- pitation is retarded for at least 60
minutes.
38. The pharmaceutical composition according to claim 20, wherein
the drug comprises a sulfonamide drug.
39. The pharmaceutical composition according to claim 38, wherein
the sulfonamide drug is a benzene sulfonamide.
40. The pharmaceutical composition according to claim 39, wherein
the benzene sulfonamide comprises celecoxib, deracoxib, valdecoxib,
rofecoxib or eturicoxib.
41. The pharmaceutical composition according to claim 39, wherein
the benzene sulfonamide is in the form of an alkali metal or
alkaline earth metal salt.
42. The pharmaceutical composition according to claim 20, wherein
the aqueous solubility of the drug is not more than 0.1 mg/ml when
measured at 37.degree. C.
43. The pharmaceutical composition according to claim 20, wherein
the aqueous solubility of the drug is not more than 10 mg/ml when
measured at 37.degree. C.
44. A process for producing a pharmaceutical composition for
delivering a supersaturated concentration of a drug having low
aqueous solubility, which process comprises intimately mixing
together components (a) (b) and (c) of claim 20.
45. The process according to claim 44, wherein the drug comprises a
sulfonamide drug.
46. A process according to claim 45, wherein the sulfonamide drug
is a benzene sulfonamide.
47. The process according to claim 46, wherein wherein the benzene
sulfonamide comprises celecoxib, deracoxib, valdecoxib, rofecoxib
or eturicoxib.
48. A process according to claim 47, wherein the benzene
sulfonamide is in the form of an alkali metal or alkaline earth
metal salt.
49. The process according to claim 44, wherein the aqueous
solubility of the drug is not more than 0.1 mg/ml when measured at
37.degree. C.
50. The process according to claim 44, wherein the aqueous
solubility of the drug is not more than 10 mg/ml when measured at
37.degree. C.
51. The pharmaceutical composition according to claim 20, wherein
the salt is an alkali metal or alkaline earth metal salt.
52. The pharmaceutical composition according to claim 52, wherein
the metal is sodium, potassium, lithium, calcium or magnesium.
53. The pharmaceutical composition according to claim 52, wherein
the salt is crystalline.
54. The pharmaceutical composition according to claim 20, wherein:
(a) the bioavailability of the composition orally administered is
at least 70%; (b) the bioavailability of the composition orally
administered is as least 80%; (c) the bioavailability of the
composition orally administered is as least 85%; (d) the
bioavailability of the composition orally administered is as least
90%; (e) the bioavailability of the composition orally administered
is as least 95%; (f) the Cmax is at least 2 fold greater than a
neutral form in vivo or in an in vitro dissolution assay; (g) the
Cmax is at least 3 fold greater than a neutral form in vivo or in
an in vitro dissolution assay; (h) the Cmax is at least 4 fold
greater than a neutral form in vivo or in an in vitro dissolution
assay; (i) the Cmax is at least 5 fold greater than a neutral form
in vivo or in an in vitro dissolution assay; (j) the Cmax is at
least 10 fold greater than a neutral form in vivo or in an in vitro
dissolution assay; the Cmax is at least 2 fold greater than a
neutral form in vivo or in an in vitro dissolution assay; (k) the
Cmax is at least 25 fold greater than a neutral form in vivo or in
an in vitro dissolution assay; (l) the Cmax is at least 50 fold
greater than a neutral form in vivo or in an in vitro dissolution
assay; (m)the Cmax is at least 100 fold greater than a neutral form
in vivo or in an in vitro dissolution assay; (n) the Cmax is at
least 250 fold greater than a neutral form in vivo or in an in
vitro dissolution assay; (o) the Cmax is at least 500 fold greater
than a neutral form in vivo or in an in vitro dissolution assay;
(p) the Cmax is at least 750 fold greater than a neutral form in
vivo or in an in vitro dissolution assay; (q) the Cmax is at least
1000 fold greater than a neutral form in vivo or in an in vitro
dissolution assay; (r) the bioavailability of the composition is at
least 50% greater than a neutral form; (s) the bioavailability of
the composition is at least 75% greater than a neutral form; (t)
the bioavailability of the composition is at least 2 fold that of a
neutral form; (u) the bioavailability of the composition is at
least 3 fold that of a neutral form; (v) the bioavailability of the
composition is at least 4 fold that of a neutral form; (w) the
bioavailability of the composition is at least 5 fold that of a
neutral form; or (x) the bioavailability of the composition is at
least 10 fold that of a neutral form.
Description
RELATED APPLICATIONS
[0001] This application has been converted from U.S. Provisional
Application No. 60/390,881, filed on Jun. 21, 2002 which is hereby
incorporated by reference for all purposes. This application also
claims priority to U.S. Provisional Application No. 60/426,275,
filed on Nov. 14, 2002; U.S. Provisional Application No. 60/427,086
filed on Nov. 15, 2002; U.S. Provisional Application No. 60/429,515
filed on Nov. 26, 2002; U.S. Provisional Application No. 60/437,516
filed on Dec. 30, 2002; and U.S. Provisional Application No.
60/456,027 filed on Mar. 18, 2003 which are hereby incorporated by
reference for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical compositions
and methods for preparing same.
BACKGROUND OF THE INVENTION
[0003] Celecoxib
(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide) is a substituted pyrazolylbenzenesulfonamide
represented by the structure: 1
[0004] Celecoxib belongs to the general class of non-steroidal
anti-inflammatory drugs (NSAIDs). Unlike traditional NSAIDs,
celecoxib is a selective inhibitor of cyclooxygenase II (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, 5,510,496, 5,563,165, 5,753,688, 5,760,068,
5,972,986, and 6,156,781, the contents of which are incorporated by
reference in their entirety. Orally deliverable liquid formulations
of celecoxib are discussed in U.S. Patent Application Publication
No. 2002/0107250 in the name of Hariharan, et al., the contents of
which are incorporated herein by reference in their entirety. 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-methoxyphe-
nyl)-3-difluoromethyl-1H-pyrazol-1-yl]benzene sulfonamide;
valdecoxib, which is 4-[5-methyl-3-phenyl isoxazol-4-yl]benzene
sulfonamide; rofecoxib, which is
3-phenyl-4-[-(methylsulfonyl)phenyl]-5H-furan-2-one; and
etoricoxib, which is
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl--
5-pyridinyl)pyridine. These drugs are described in further detail
in WO01/78724 and WO02/102376.
[0005] In its commercially available form as CELEBREX.TM.,
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.
[0006] 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 drug is required,
for example after having been taken as an oral formulation where
the drug becomes diluted in the alimentary canal. 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 to provide a more rapid onset to therapeutic effect.
SUMMARY OF THE INVENTION
[0007] It has now been found that a stable, crystalline salts and
co-crystal 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 T.sub.max, the time to reach peak blood serum levels, and
higher C.sub.max,, 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.TM., 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.
[0008] An aspect of the present invention relates to methods of
increasing dissolution, solubility, and or the time a
pharmaceutical (the terms pharmaceutical and drug are used herein
interchangeably), 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 Tmax or increased Cmax. The
methods comprise the steps of making a salt or co-crystal of a free
acid api and combining the salt or co-crystal with a
recrystallization or precipitation retardant and optionally, a
recrystallization/precipitation retardant enhancer (referred to as
enhancer hereafter). The salt may be amorphous or crystalline, but
is preferably crystalline. Normally the salt or co-crystal form
used is in a crystalline form which dissolves and then
recrystallizes and precipitates out of solution, which is why the
term "re"crystallization retardant is used. It is noted however,
that one could begin with an amorphous form of the salt so the term
is used when beginning with either a crystalline or amorphous form.
The term "recrystallization" can also be interchanged with the term
"precipitation" which refers to either a crystalline or amorphous
solid form separating or "coming out of" the solution. 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 recrystallization/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
atom is separated by 2 carbon atoms. Further preferred surfactants
have an interfacial tension of less than 10 dynes per centimeter
when measured at a concentration of 0.1% w/w in water as compared
to mineral oil at 25.degree. C. and/or the surface tension of the
recrystallization retardant (e.g., poloxamers) is less than 42
dynes/cm when measured as a concentration of 0.1% w/w in water at
25.degree. C. The combination of salt or co-crystal,
recrystallization/precipitation retardant and an optional enhancer
(or recrystallization/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 remain
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, 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 remain supersaturated.
[0009] The enhancer preferably comprises a cellulose ester such as
hydroxypropylcellulose (HPC) or hydroxyproplymethylcellulose
(HPMC). Thus according to the methods of the present invention,
supersaturated concentrations upon which a drug may be maintained
upon dissolution and/or the degree of dissolution of a drug in
gastric fluid conditions (e.g., SGF) is enhanced.
[0010] Normally, the enhancer does not improve the length of time
the api can remain supersaturated without the additional pressure
of the recrystallization/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 T.sub.max, the time to reach
peak blood serum levels, and higher C.sub.max, 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
(C.sub.n, at time t.sub.n) is not zero, the AUC from t.sub.n to
infinite time is estimated by C.sub.n/k.sub.el.
[0011] The AUC is of particular use in estimating bioavailability
of drugs, and in estimating total clearance of drugs (Cl.sub.T).
Following single intravenous doses, AUC=D/Cl.sub.T, for single
compartment systems obeying first-order elimination kinetics;
alternatively, AUC=C.sub.0/k.sub.e1. With routes other than the
intravenous, for such systems, AUC=F.multidot.D/Cl.sub.T, where F
is the availability of the drug.
[0012] The invention further relates to wherein a
recrystallization/precip- itation 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
recrystallization/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.
[0013] Accordingly, in a further aspect, the present invention
provides a pharmaceutical composition comprising:
[0014] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0015] (b) a recrystallization/precipitation retardant; and
[0016] (c) a an optional enhancer.
[0017] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0018] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0019] (b) a recrystallization/precipitation retardant having an
interfacial tension of less than 10 dyne/cm or a surface tension of
less then 42 dyne/cm; and
[0020] (c) a an optional enhancer.
[0021] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0022] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0023] (b) a surfactant; and
[0024] (c) a an optional enhancer.
[0025] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0026] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0027] (b) a poloxamer having an interfacial tension of less than
10 dyne/cm or surface tension less then 42 dyne/cm; and
[0028] (c) a an optional enhancer.
[0029] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0030] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0031] (b) a surfactant; and
[0032] (c) a cellulose ester.
[0033] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0034] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0035] (b) a surfactant having an interfacial tension of less than
10 dyne/cm or surface tension less then 42 dyne/cm; and
[0036] (c) hydroxyproply cellulose or hydroxyproply
methylcellulose.
[0037] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0038] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0039] (b) a poloxamer; and
[0040] (c) hydroxyproply cellulose or hydroxyproply
methylcellulose.
[0041] In a further aspect, the present invention provides a
pharmaceutical composition comprising:
[0042] (a) an api having low aqueous solubility or dissolution,
preferably in gastric fluid conditions;
[0043] (b) a poloxamer having an interfacial tension of less than
10 dyne/cm or surface tension less then 42 dyne/cm; and
[0044] (c) hydroxyproply cellulose or hydroxyproply
methylcellulose.
[0045] In a further aspect, the present invention provides a
pharmaceutical composition comprising
[0046] (a) celecoxib;
[0047] (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
[0048] (c) a recrystallization/precipitation retardant comprising a
hydroxypropyl cellulose or hydroxyproply methylcellulose.
[0049] 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 process
comprises intimately mixing together the components of the above
aspects or elsewhere herein.
[0050] 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).
[0051] The present invention further provides a process for
producing a pharmaceutical composition, which comprises:
[0052] (1) providing a plurality of containers;
[0053] (2) providing a plurality of excipient solutions;
[0054] (3) providing a plurality of compound solutions, each having
dissolved therein a pharmaceutical compound;
[0055] (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;
[0056] (5) incubating the mixture;
[0057] (6) determining onset of solid-state nucleation or
precipitation;
[0058] (7) selecting a pharmaceutical compound/excipient
combination whereby onset of solid-state nucleation is retarded;
and
[0059] (8) producing a pharmaceutical composition comprising the
pharmaceutical compound/excipient combination.
[0060] 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 which is used herein to refer to the
initiation of solidification, whether 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
screening.
[0061] Various properties of a pharmaceutical composition may
affect the onset of solid-state nucleation or precipitation of the
api (pharmaceutical compound). 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.
[0062] 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:
[0063] (1) providing a plurality of containers;
[0064] (2) providing a plurality of excipient solutions;
[0065] (3) providing a plurality of compound solutions, each having
dissolved therein a pharmaceutical compound;
[0066] (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;
[0067] (5) incubating the mixture;
[0068] (6) determining onset of solid-state nucleation or
precipitation;
[0069] (7) selecting an excipient which is found to retard onset of
solid-state nucleation or precipitation; and
[0070] (8) producing a pharmaceutical composition comprising the
pharmaceutical compound and the selected excipient.
[0071] 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.
[0072] 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.
[0073] The invention further provides a method for assessing
excipient-mediated retardation of solid-state nucleation or
precipitation of a pharmaceutical compound, which method
comprises:
[0074] (1) providing a plurality of containers;
[0075] (2) providing a plurality of excipient solutions;
[0076] (3) providing a plurality of compound solutions, each having
dissolved therein a pharmaceutical compound;
[0077] (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;
[0078] (5) incubating the mixture;
[0079] (6) determining onset of solid-state nucleation or
precipitation; and
[0080] (7) ranking the property of the mixture according to time of
onset of solid-state nucleation or precipitation.
[0081] 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:
[0082] (1) providing a plurality of containers;
[0083] (2) providing a plurality of excipient solutions;
[0084] (3) providing a plurality of compound solutions, each having
dissolved therein a pharmaceutical compound;
[0085] (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;
[0086] (5) incubating the mixture;
[0087] (6) determining onset of solid-state nucleation or
precipitation; and
[0088] (7) ranking the excipient according to time of onset of
solid-state nucleation or precipitation.
[0089] Generally speaking, the pharmaceutical compound of the
invention is an active pharmaceutical ingredient (API) 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 such pharmaceutical
compositions 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, as defined
herein, when in contact with bodily fluids but possibly relatively
high solubility in appropriate in vitro conditions.
[0090] 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 solution of basic 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 formed in a solution comprising water, usually deionised water,
or another aqueous based solution. In one aspect, the mixture
simulates gastric juices (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.
[0091] 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 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, 50 mg, 25
mg, 10, mg, 5 mg, 750 ug, 500 ug, 250, ug, 100 ug, 75 ug, 50 ug, 25
ug, 10 ug, 1 ug, 750 ng, 500 ng, 250 ng, 100 ng, or less than 50
ng, depending on the api, sample size, etc. This therefore
minimises the amount of active pharmaceutical ingredient material
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.
[0092] 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.degree. C., to
simulate in vivo conditions.
[0093] Measurement of onset of solid-state nucleation or
precipitation may be determined by measuring light scattering of a
mixture. This may be achieved by any 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.
[0094] 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.
[0095] In its most general aspect, the present invention relates to
a pharmaceutical composition which includes an api having a low
aqueous solubility (or a solubility as disclosed 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.degree. 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.
[0096] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0097] FIG. 1 shows a differential scanning calorimetry trace of
the sodium salt of celecoxib prepared by Example 1 between
50.degree. C. and 110.degree. C.
[0098] FIG. 2 shows a thermogravimetric analysis of the sodium salt
of celecoxib prepared by Example 1, which was conducted from about
30.degree. C. to about 160.degree. C.
[0099] FIG. 3 shows a powder x-ray diffraction plot of the sodium
salt of celecoxib prepared by Example 1.
[0100] 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
4-[5-(4-methylphenyl)-3-(tri-
fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, as obtained
following the protocol described in Example 4.
[0101] FIG. 5 shows the mean pharmacokinetic parameters (and
standard deviations therefor) of celecoxib in the plasma of male
dogs following a single oral or single intravenous dose of
celecoxib or celecoxib sodium. The maximum serum concentration and
bioavailability of orally-administered celecoxib sodium was about
three- and two-fold greater, respectively, than a roughly equal
dose of orally-administered celecoxib, and the maximum serum
concentration of celecoxib sodium was reached 40% faster than for
celecoxib.
[0102] 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.
[0103] FIG. 7 shows the effect of varying ratios of ethylene glycol
to propylene glycol subunits in poloxamers on the concentration of
celecoxib sodium in solution.
[0104] FIG. 8 shows the effect of different celluloses on the
dissolution of various composition comprising equal weights of
cellulose (hydroxypropylcellulose (HPC, 100,000 kDa), low-viscosity
hydroxypropylmethylcellulose (ld HPMC, viscocity was 80-120 cps),
high-viscosity hydroxypropylmethylcellulose (hd HPMC, viscosity was
15,000 cps), microcrystalline cellulose (Avicel PH200)),
d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E
TGPS), and celecoxib sodium.
[0105] FIG. 9 shows the dissolution at 37.degree. C. for
compositions comprising various weight ratios of d-alpha-tocopherol
polyethylene glycol-1000 succinate (vitamin E TGPS),
hydroxypropylcellulose and celecoxib sodium.
[0106] FIG. 10 shows the dissolution profile of celecoxib sodium 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 (vit E TGPS), and Gelucire.TM. 50/13.
[0107] FIG. 11 shows the effect of Avicel microcrystalline
cellulose and silica gel on the dissolution of mixtures of
celecoxib sodium, d-alpha-tocopherol polyethylene glycol-1000
succinate (vit E TGPS), and hydroxypropylcellulose (HPC) mixtures
in simulated gastric fluid (SGF) at 37.degree. C. The legend
indicates the weight ratios of the components.
[0108] FIG. 12 shows the dissolution of celecoxib sodium (TPI336Na)
in 5-times diluted simulated gastric fluid, with excipients
including d-alpha-tocopherol polyethylene glycol-1000 succinate
(vitamin E TGPS), hydroxypropylcellulose (HPC), and poloxamer 237.
the legend indicates the weight ratios of the components.
[0109] FIGS. 13A and 13B shows the particle-induced x-ray
diffraction (PXRD) and raman spectra, respectively, of the sodium
salt of celecoxib prepared by the method of Example 6.
[0110] FIG. 14 shows a differential scanning calorimetry analysis
of celecoxib lithium salt MO-116-49B.
[0111] FIG. 15 shows a thermogravimetric analysis of celecoxib
lithium salt MO-116-49B.
[0112] FIG. 16 shows the RAMAN spectrum of celecoxib lithium salt
MO-116-49B.
[0113] FIG. 17 shows the PXRD spectrum of celecoxib lithium salt
MO-116-49B.
[0114] FIG. 18 shows a differential scanring calorimetry analysis
of celecoxib potassium salt MO-116-49A.
[0115] FIG. 19 shows a thermogravimetric analysis of celecoxib
potassium salt MO-116-49A.
[0116] FIG. 20 shows the RAMAN spectrum of celecoxib potassium salt
MO-116-49A.
[0117] FIG. 21 shows the PXRD spectrum of celecoxib potassium salt
MO-116-49A.
[0118] FIG. 22 shows a thermogravimetric analysis of celecoxib
potassium salt MO-116-55D.
[0119] FIG. 23 shows the RAMAN spectrum of celecoxib potassium salt
MO-116-55D.
[0120] FIG. 24 shows the PXRD spectrum of celecoxib potassium salt
MO-116-55D.
[0121] FIG. 25 shows a thermogravimetric analysis of celecoxib
calcium salt MO-116-62A.
[0122] FIG. 26 shows the RAMAN spectrum of celecoxib calcium salt
MO-116-62A.
[0123] FIG. 27 shows the PXRD spectrum of celecoxib calcium salt
MO-116-62A.
[0124] FIG. 28 shows the PXRD spectrum of commercially-available
celecoxib.
[0125] FIG. 29 shows the RAMAN spectrum of commercially-available
celecoxib.
[0126] FIG. 30 shows crystal retardation time for celecoxib as a
function of excipient in simulated gastric fluid (SGF).
[0127] FIG. 31 shows interfacial tension of selected PLURONIC
excipients in water.
[0128] FIG. 32 shows dissolution of celecoxib sodium hydrate from
compositions containing PLURONIC P123 and F127.
[0129] FIG. 33 shows dissolution of celecoxib sodium hydrate from
PLURONIC P123, F127 and F87, in the presence of HPC.
[0130] FIG. 34 shows dissolution of celecoxib sodium hydrate using
PLURONIC F1 27, HPC and a granulating fluid.
[0131] FIG. 35 shows dissolution of celecoxib sodium hydrate using
PLURONIC F127 and HPC in a compact formulation.
[0132] FIG. 36 shows a flowchart outlining a process according to
the invention.
[0133] FIG. 37 shows a platemap for an automated liquid
dispenser.
[0134] FIG. 38 shows a trace of light scatter against time in an
assay according to the invention.
[0135] FIG. 39 shows a thermogravimetric analysis of a propylene
glycol solvate of a celecoxib sodium salt.
[0136] FIG. 40 shows the PXRD spectrum of a propylene glycol
solvate of a celecoxib sodium salt.
[0137] FIG. 41 shows a thermogravimetric analysis a propylene
glycol solvate of a celecoxib potassium salt.
[0138] FIG. 42 shows the PXRD spectrum of a propylene glycol
solvate of a celecoxib potassium salt.
[0139] FIG. 43 shows a thermogravimetric analysis of a propylene
glycol solvate of a celecoxib lithium salt.
[0140] FIG. 44 shows a thermogravimetric analysis of the sodium
salt propylene glycol trihydrate of celecoxib prepared by Example
21.
[0141] FIG. 45 shows a powder X-ray diffraction plot of the sodium
salt propylene glycol trihydrate of celecoxib prepared by Example
21a.
[0142] FIG. 46 shows a thermogravimetric analysis of the sodium
salt propylene glycoltrihydrate of celecoxib prepared by Example
21b.
[0143] FIG. 47 shows a powder X-ray diffraction plot of the sodium
salt propylene glycol trihydrate of celecoxib prepared by Example
21b.
[0144] FIG. 48 show a DSC trace of the sodium salt isopropyl
alcohol solvate of celecoxib prepared by Example 22.
[0145] FIG. 49 shows a thermogravimetric analysis of the sodium
salt isopropyl alcohol solvate of celecoxib prepared by Example 22,
which was conducted from about 30.degree. to about 160.degree.
C.
[0146] FIG. 50 shows a powder X-ray diffraction plot of the sodium
salt of isopropyl alcohol solvate of celecoxib prepared by Example
22.
DETAILED DESCRIPTION OF THE INVENTION
[0147] 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 10 mg/ml, when measured at 37.degree. C., and preferably less
than or equal to 5 mg/ml or 1 mg/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.degree. 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 NaCl in water and adjusting the pH with 20 mM to obtain a
solution with a final pH=1.7.
[0148] The pH 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
include 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 pyrazolylbenzenesulfona- mides such as celecoxib.
Such metal salts include alkali metal or alkaline earth metal
salts, preferably sodium, potassium, lithium, calcium and magnesium
salts.
[0149] The precipitation retardant used in the present invention
can be chosen from a 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 recrystallization/precipitation
retardant (e.g., poloxamers) is less than 10 dyne/cm when measured
as a concentration of 0.1% w/w in water as compared to mineral oil
at 25.degree. C. and/or the surface tension of the
recrystallization/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 dyenes/cm or
the surface tension is less than 45, 44, 43, 41, 40, 39, 38, 37,
36, or 35 dynes/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).sub.x-(PPG).sub.y-(PEG).sub.z, where x, y and z are integers
and x is usually equal to z. A preferred form of poloxamer are
those obtainable from BASF designated "PLURONIC".RTM.. 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 PLUROIC, i.e., the generic
and tradename, may be used interchangeably throughout.
[0150] The optional third component of the pharmaceutical
composition according to the present invention comprises a
recrystallization/precipit- ation retardant enhancer. An enhancer
is a compound capable of increasing the effectiveness of the
recrystallization/precipitation retardant in inhibiting, preventing
or at least reducing the extent of crystallization or precipitation
of the drug of low aqueous solubility, usually when diluted such as
following oral administration. In one embodiment the enhancer does
not act as a recrystallization/precipitation retardant alone. In
another embodiment the enhancer has no affect or a negative affect
in an in vitro recrystallization/precipitation assay, but increases
the effectiveness of the recrystallization/precipitation retardant
in an in vitro or in situ dissolution assay. Cellulose esters, such
as hydroxypropyl cellulose are particularly useful enhancer
according to the present invention. Cellulose esters vary in the
chain length of their cellulosic backbone and consequently, in
their viscosity 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.
[0151] 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 the curve. Preferred enhancers
increase the amount of time the api concentration is above 1/2 Tmax
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 1/2 Tmax longer than the free acid or in the
same composition except the salt or co-crystal is replaced by the
free acid.
[0152] The ratio of component a:b:c (api:
recrystallization/precipitation retardant;enhancer) as exemplified
herein is approximately 1:1:1 (+/-0.2 for the
recrystallization/precipitation retardant and enhancer). However,
the ratio can be adjusted to suit the application. For example, the
amount of recrystallization/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 sufactant that is at or above an amount
needed for the retardant to reach its critical micell concentration
(CMC) in 100 ml in 500 ml H.sub.2O or SGF, or H.sub.2O or SGF or in
1L H.sub.2O or SGF. It is noted the poloxamers may not form true
micells but do form analogous structures which are considered
micells for the purpose of the present invention.
[0153] 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, recrystallization/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 granulated 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
recrystallization/precipitation. The use of a granulating
fluid-like liquid is particularly useful when the api and
recrystallization/precipitation retardant are solids.
[0154] 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 may be
limited, if required, by using a disintegrant in the compact.
[0155] In a further embodiment the api and
crystallization/precipitation retardant (and optional enhancer),
when mixed forms a paste or non-aqueous solution. 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 dissolution of the
api.
[0156] Normally the compound(s)s and the api of the present
invention are in intimately associated as a pharmaceutical
composition. An "intimate association" in the present context
includes, for example, the pharmaceutical admixed with the
recrystallization/precipitation retardant inhibitor, the
pharmaceutical embedded or incorporated in the retardant, the
compound forming a coating on particles of the pharmaceutical or
vice versa, and a substantially homogeneous dispersion of the
pharmaceutical throughout the compound(s).
[0157] 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.
[0158] It is preferred that the pharmaceutical composition is
formulated for oral administration. Drugs according to the
invention may be prepared in a form having an increased time to
onset of therapeutic effectiveness and likely having increased
bioavailability. The pharmaceutical compositions according to the
invention are therefore particularly suitable for administration to
human subjects.
[0159] 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 are free acids in
their neutral state or that initially dissolve but then
recrystallize in gastric fluid conditions. Further embodiments
relate to pharmaceuticals with an aminosulfonyl functional
group.
[0160] The term "aminosulfonly functional group" herein refers to a
functional group having the following structure: 2
[0161] 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,
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,
alkylsufmyl, alkylsulfonyl, etc.
[0162] Non-limiting illustrative examples of
aminosulfonyl-comprising drugs include ABT-751 of Eisai
(N-(2-(4-hydroxyphenyl)amino)-3-pyridyl)4--
methoxybenzenesulfonamide); alpiropride; amosulalol; amprenavir;
ainsacrine; argatroban; asulacrine; azosemide; BAY-38-4766 of Bayer
(N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-3-hydrox-
y-2,2-dimethylpropanamide); bendroflumethiazide; BMS-193884 of
Bristol Myers Squibb
(N-(3,4-dimethyl-5-isoxazolyl)-4.sup.1-(2-oxazolyl)-[1,1.sup-
.1-biphenyl]-2-sulfonamide); bosentan; bumetide; celecoxib;
chlorthalidone; delavirdine; deracoxib dofetilide; domitroban;
dorzolamide; dronedarone; E-7070 of Eisai
(N-(3-chloro-1H-indol-7-yl)-1,4- -benzene-disulfonamide); EF-7412
of Schwartz Pharma
(N-3-[4-[4-(tetrahydro-1,3-dioxo-1H-pyrrolo[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
(4-[[6,7-dihydro-7-oxo-8H-pyrrolo[2,3-g]benzothiazol-8-ylidene)methyl]ami-
no]-N-2-pyridinylbenzenesulfonamide); GYKI-16638 of Ivax
(N-[4-[2-[[2-(2,6-dimethoxylphenoxy)-1-methlethyl]methylamino]ethyl]pheny-
l]methanesulfonamide); HMR-1098 of Aventis
(5-chloro-2-methoxy-N-[2-[4-met-
hoxy-3[[[(methylamino)thioxomethyl]amino]sulfonyl]phenyl]ethyl]benzamide);
hydrochlorothiazide; ibutilide; indapamide; IS-741 of Ishihara
(N-[2-[(ethylsufonyl)
amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanec- arboxamide);
JTE-522 of Japan Tobacco (4-(4-cyclohexyl-2-methyl-5-oxazolyl-
)-2-fluorobenzenesulfonamide); KCB-328 of Chugai
(N-[3-amino-4-[2-[[2-3,4--
dimethoxyphenyl)ethyl]methylamino]ethoxy]phenyl]methanesulfonamide);
KT2-962 of Kotobuki
(3-[4-[[(4-chlorophenyl)sulfonyl]amino]butyl]-6-(1-me-
thylethyl)-1-azulene sulfonic acid); levosulpiride; LY-295501
(N-[[(3,4-dichlorophyenyl)amino]carbonyl]-2,3-dihydro-5-benzofuransulfona-
mide) and LY-404187
(N-2-(4-(4-cyanophenyl)phenyl)propyl-2-propanesulfonam- ide) 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]a-
mino]methyl]bicyclo[2.2.2]oct-2-yl]-5-hexenoic acid); piretanide;
PNU-103657of Pharmacia
(1-[5-methanesulfonamidoindol-2-ylcarbonyl]-4-(N-m-
ethyl-N-(3-(2-methylpropyl)-2-pyridinyl)amino)piperidine);
polythiazide; ramatroban; RO-61-1790 of Hoffmann LaRoche
(N-[6-(2-hydroxyethoxy)-5-(2-m-
ethoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-methy-
l-2-pyridinesulfonamide); RPR-130737
(4-hydroxy-3-[2-oxo-3(S)-[5-(3-pyridy-
l)thiophen-2-ylsulfonamido]pyrrolidin-1-ylmethyl]benzamide) and
RPR-208707 of Aventis; S-18886
(3-[(6-(4-chlorophenylsulfonylamino)-2-methyl-5,6,7,8-
-tetrahydronaphth]-1-yl)propionic acid) and S-32080
(3-[6-(4-chlorophenylsulfonylamido)-2-propyl-3-(3pyridyl-methyl)-5,6,7,8--
tetrahydronaphthalen-1-yl]propionic acid) of Server; S-36496 of
Kaken
(2-sulfonyl-[N-(4-chlorophenyl)sulfonylamino-butyl-N-[(4-cyclobutylthiazo-
l-2-yl)ethenylphenyl-3-yl-methyl]]aminobenzoic acid);
sampatrilat;SB-203208 of Glaxo Smith Kline (L-phenylalanine,
b-methyl-,(4aR,6S,7R,7aS)-4-(aminocarbonyl)-7-[[[[[(2S,3S)-2-amino-3-meth-
yl-1-oxopentyl]amino]sulfonyl]acetyl]amino]-7-carboxy-2,4a,5,6,7,7a-hexahy-
dro-2-methyl-1H-cyclopenta[c]pyridine-6yl ester, (bS)-); SE-170 of
DuPont
(2-(5-amidino-1H-indol-3-yl)N-[2'-(aminosulfonyl)-3-bromo(1,1'biphenyl)-4-
-yl]acetamide); sivelestat; SJA-6017 of Senju
(N-(4-flourophenylsulfonyl)-- L-valyl-L-leucinal); SM-19712 of
Sumitomo (4-chloro-N-[[(4-cyano-3-methyl--
1-phenyl-1H-pyrazol-5-yl) amino]carbonyl]benzenesulfonamide);
sonepiprazole; sotalol; sulfadiazine; sulfaguanole; sulfasalazine;
sulpride; sulprostone; sumatriptan; T-614 of Toyama
(N-[3-(formylaiino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonam-
ide); T-138067
(2,3,4,5,6-pentafluoro-N-(3-flouro-4-methoxyphenyl)benzenes-
ulfonamide) and T-900607
(2,3,4,5,6-pentafluoro-N-3-ureido-4-methoxyphenyl-
)benzenesulfonamide) of Tularik; TAK-661 of Takeda
(2,2-dimethyl-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-chlorophenylsulfonylaminomethyl)indan-5-yl]acetic acid);
zafirlukast; zonisamide; and salts thereof.
[0163] 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 (IV): 3
[0164] wherein:
[0165] A is a substituent selected from partially unsaturated or
unsaturated heterocyclyl and partially unsaturated or unsaturated
carbocyclic rings, preferably a heterocyclyl group selected from
pyrazolyl, furanoyl, isoxazolyl, pyridinyl, cyclopentenonyl and
pyridazinonyl groups;
[0166] X is O, S or CH.sub.2;
[0167] n is 0 or 1;
[0168] R.sup.1 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;
[0169] R.sup.2 is NH.sub.2 group;
[0170] R.sup.3 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, 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,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R.sup.3 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
[0171] R.sup.4 is selected from hydrido and halo.
[0172] Particularly suitable selective COX-2 inhibitory drugs are
compounds having the formula (V): 4
[0173] where R.sup.4 is hydrogen or a C.sub.1-4 alkyl or alkoxy
group, X is N or CR.sup.5 where R.sup.5 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.
[0174] Illustratively, compositions of the invention are suitable
for celecoxib, deracoxib, valdecoxib and JTE-522, more particularly
celecoxib, paracoxib and valdecoxib. Other 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-(Benzylsulfona- mido)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, N.sup.2-Formylsulfisomidine CAS Registry Number:
795-13-1, Furosemide CAS Registry Number: 54-31-9, Glibornuride 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,
N.sup.4-.quadrature.-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: 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 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,
N.sup.4-Sulfanilylsulfanilamide CAS Registry Number: 547-52-4,
Sulfanilylurea CAS Registry Number: 547-44-4,
N-Sulfanilyl-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, Tainsulosin CAS Registry Number: 106133-20-4,
Taurolidine CAS Registry Number: 19388-87-5, Teclothiazide CAS
Registry Number: 4267-05-4, Tevenel.RTM. 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.
[0175] In a particularly preferred embodiment, the pharmaceutical
compositions of the present invention comprise a salt of celecoxib,
(e.g., sodium, lithium, potassium or calcium salt). The salt may be
significantly more soluble in water than presently-marketed neutral
celecoxib. Due to the high pK.sub.a 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 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 pKa 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.
[0176] 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 pK.sub.a=s (e.g., pK.sub.a=s
greater than about 11, pK.sub.a=s greater than about 11.5, or
pK.sub.a=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.
[0177] 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 pharmaceutical is prepared and is
subsequently reacted with a second salt such as an alkaline earth
metal halide (e.g., MgBr.sub.2, MgCl.sub.2, CaCl.sub.2,
CaBr.sub.2), an alkaline earth metal sulfate or nitrate (e.g.,
Mg(NO.sub.3).sub.2, Mg(SO.sub.4).sub.2, Ca(NO.sub.3).sub.2,
Ca(SO.sub.4).sub.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.
[0178] 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.
[0179] A pharmaceutical salt as described herein may be
significantly more soluble in water than the existing neutral form,
such as the presently-marketed neutral celecoxib, 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 one at least about hundred times
more or soluble in water or SGF than the neutral form, such as
celecoxib marketed by Pfizer Inc. and G. D. Searle & Co.
(Pharmacia Corporation), and described at pages 2676-2680 and
2780-2784 of the 2002 edition of the Physicians Desk Reference
(also referred to herein as presently-marketed celecoxib). The
solubility depends on whether the salt is tested alone, or as a
formulation further comprising the recrystallization/precipitation
retardants and enhancers of the invention.
[0180] 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 converts to the same more
rapidly. Amorphous neutral celecoxib can be characterized by a lack
of a regular crystal structure, while metastable crystalline
neutral celecoxib can be distinguished from typical crystalline
neutral celecoxib by the PXRD pattern of isolated material.
[0181] 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, the teachings of
which are incorporated herein by reference in their entirety,
without stabilization by a crystallization inhibitor, such as a
polymer, amorphous and metastable crystalline neutral celecoxib
convert 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,
recrystallization/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 recrystallization/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 recrystallization/precipitation. No one has further
taught the addition of an enhancer to a
recrystallization/precipitation retardant.
[0182] 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
--(C.sub.2H.sub.4O).sub.n-- where n.gtoreq.2. Other preferred
polyethylene oxides are poloxamers having the general formula
HO(C.sub.2H.sub.4O)a(C.sub.3H.sub.6O)b(C.sub.2H.sub.4O)aH where
a.gtoreq.2, where a.gtoreq.3, where a.gtoreq.2 and b.gtoreq.30,
where a.gtoreq.2 and b.gtoreq.4, where a.gtoreq.2 and b.gtoreq.50,
where a.gtoreq.2 and b.gtoreq.60.
[0183] 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
recrystallization 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 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 --SO.sub.2NH.sub.2. 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 --O--C--C--O--C--C--O--.
[0184] Glycol ethers can also be used as solubilizers of neutral or
other forms of celecoxib include those that conform with the
formula:
R.sup.1--O--((CH.sub.2).sub.mO).sub.n--R.sup.2 (VII)
[0185] Wherein R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, phenyl or benzyl groups, but no
more than one of R.sup.1 and R.sup.2 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 R.sup.1 and R.sup.2 is a C.sub.1-4 alkyl
group and the other is hydrogen or a C.sub.1-4 alkyl group; more
preferably at least one of R.sup.1 and R.sup.2 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. Glycol ethers,
including those of the above formula, can also be specifically
excluded from the present invention. Preferably, the glycol ethers
are surfactants.
[0186] 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
[0187] 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 after administration
(e.g., in vivo), rather than before administration.
[0188] Dissolution Modulation:
[0189] 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 or decreased. Dissolution rate is the rate at
which api solids dissolve in a dissolution media. For apis whose
absorption rates are faster than the dissolution rates (e.g.,
steroids), the rate-limiting step in the absorption process is
often the dissolution rate. Because of a limited residence time at
the absorption site, apis that are not dissolved before they are
removed from 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 (C.sub.s-C)
[0190] where K is dissolution rate constant, S is the surface area,
C.sub.s is the apparent solubility, and C is the concentration of
api in the dissolution media. For rapid api absorption, C.sub.s-C
is approximately equal to C.sub.s
[0191] The dissolution rate of apis may be measured by conventional
means known in the art.
[0192] 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 is the same
as discussed above The increase in dissolution may be further
specified by the time the composition remains supersaturated.
[0193] Examples of above embodiments includes: 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 free form, compositions with a dissolution rate in
SIF that is increased at least 5 fold over the neutral free
form.
[0194] The present invention demonstrates that the length of time
in which celecoxib or other apis remains in solution can be
increased to a surprising high degree by using a salt or co-crystal
form with the presence of a recrystallization/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 high concentration of
api will remain in solution for an extended period of time. The
presence of these components does not preclude the presence of
other further agents, including further surfactants such as,
polyethyl 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 is drawn
compositions that can be maintained for a period of time (e.g., 15,
30, 45, 60, mins and longer) as supersaturated solutions at
concentrations 2, 3, 5, 7, 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 the solubility of the neutral free form
in the same solution (e.g., water or SGF).
[0195] The amount of recrystallization/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% w/w
(recrystallization/precipitation inhibitor or
enhancer/pharmaceutical). The % w/w for either or both
recrystallization/precipitation inhibitor or 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.
[0196] 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.degree. C. to about 30.degree. C.
The absence of moisture, 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.
[0197] 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 deg. 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 deg. C. for 2
years, less than 0.2% of any one degradant is formed.
Alternatively, when stored at 30 deg. 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 deg. 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 deg. 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%
[0198] Bioavailability Modulation:
[0199] The methods of the present invention are used to make a
pharmaceutical api formulation with greater solubility,
dissolution, and bioavailability, AUC, reduced time to T.sub.max,
the time to reach peak blood serum levels, and higher C.sub.max,,
the maximum blood serum concentration, when compared to the neutral
free form.
[0200] AUC is the area under the plot 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
(C.sub.n, at time t.sub.n) is not zero, the AUC from t.sub.n to
infinite time is estimated by C.sub.n/k.sub.el.
[0201] The AUC is of particular use in estimating bioavailability
of apis, and in estimating total clearance of apis (Cl.sub.T).
Following single intravenous doses, AUC=D/Cl.sub.T, for single
compartment systems obeying first-order elimination kinetics;
alternatively, AUC=C.sub.0/k.sub.el. With routes other than the
intravenous, for such systems, AUC=F.multidot.D/Cl.sub.T, where F
is the availability of the api.
[0202] 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
AUC is increased, the time to T.sub.max is reduced, or C.sub.max is
increased, which process comprises:
[0203] (1) forming a salt or co-crystal of an api;
[0204] (2) combining the salt or co-crystal with a precipitation
retardant, and optionally, further with an enhancer.
[0205] Examples of the above embodiments includes: compositions
with a time to T.sub.max that is reduced by at least 10% as
compared to the neutral free form, compositions with a time to
T.sub.max that is reduced by at least 20% over the free form,
compositions with a time to T.sub.max that is reduced by at least
40% over the free form, compositions with a time to T.sub.max that
is reduced by at least 50% over the free form, compositions with a
T.sub.max that is reduced by at least 60% over the free form,
compositions with a T.sub.max that is reduced by at least 70% over
the free form, compositions with a T.sub.max that is reduced by at
least 80% over the free form, compositions with a C.sub.max that is
increased by at least 20% over the free form, compositions with a
C.sub.max that is increased by at least 30% over the free form,
compositions with a C.sub.max that is increased by at least 40%
over the free form, compositions with a C.sub.max that is increased
by at least 50% over the free form, compositions with a C.sub.max
that is increased by at least 60% over the free form, compositions
with a C.sub.max that is increased by at least 70% over the free
form, compositions with a C.sub.max that is increased by at least
80% over the free form, compositions with an AUC that is increased
by at least 10% over the free form, compositions with an AUC that
is increased by at least 20% over the free form, compositions with
an AUC that is increased by at least 30% over the free form,
compositions with an AUC that is increased by at least 40% over the
free form, compositions with an AUC that is increased by at least
50% over the free form, compositions with an AUC that is increased
by at least 60% over the free form, 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.
[0206] 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 (C.sub.max) a shorter time after
oral administration (T.sub.max). Preferably, compositions,
preferably including salts, of the present invention have a higher
C.sub.max and/or a shorter T.sub.max than presently-marketed
celecoxib. The Tmax for the compositions of the present invention
may 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).
[0207] Compositions of the present invention have a bioavailability
greater than the neutral celecoxib and currently marketed
CELEBREX.TM.. In other 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%.
[0208] Ailments treatable with celecoxib and salts thereof of the
present invention are discussed below. Treatment of both and
chronic pain is a preferred embodiment of the present
invention.
[0209] Dose Response Modulation:
[0210] 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.
[0211] 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 (as the dependent variable) to dose (as the 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.
[0212] The dose-response curve for presently-marketed celecoxib is
nonlinear. Preferably, the dose-response curve for celecoxib salts
and co-crystal composition of the present invention are 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.
[0213] Decreasing Hygroscopicity:
[0214] 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.
[0215] 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 Cahn 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 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.degree. 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 between 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.
[0216] 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 25degrees 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 more than 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.
[0217] 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.
1 Class 1: Essentially no moisture increases degrees
Non-hygroscopic occur at relative humidities below 90%. Class 2:
Essentially no moisture increases degrees Slightly hygroscopic
occur at relative humidities below 80%. Class 3: Moisture content
does not increase more than Moderately hygroscopic 5% after storage
for 1 week at relative humidities below 60%. Class 4: Moisture
content increase may degrees occur Very hygroscopic at relative
humidities as low as 40 to 50%.
[0218] 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
hygrospocity, based on the static method, after storage at
25.degree. C. for 24 h at 80 percent RH:
[0219] Slightly hygroscopic: Increase in mass is less than 2
percent m/m and equal to or greater than 0.2 percent m/m.
[0220] Hygroscopic: Increase in mass is less than 15 percent m/m
and equal to or greater than 0.2 percent m/m.
[0221] Very Hygroscopic: Increase in mass is equal to or greater
than 15 percent m/m.
[0222] Deliquescent: Sufficient water is absorbed to form a
liquid.
[0223] 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. Composition of the
present invention can also be set forth based on their ability to
reduce hygroscopicity. Thus, preferred composition of the present
invention are less hygroscopic than the neutral free form. Further
included in the present invention are composition that do not gain
or lose more than 1.0% weight at 25 degrees C. when cycled between
10 and 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 composition 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 composition 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 composition 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 composition 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.
[0224] Further included in the present invention are composition
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.
[0225] Further included in the present invention are composition
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.
[0226] A celecoxib salt 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.degree. C. and 110.degree. C. (FIG. 1).
Conditions for DSC can be found in Example 1.
[0227] Celecoxib salts can be characterized by thermogravimetric
analysis (TGA). The sodium salt product prepared by Example 1 was
characterized by TGA, and had about 3 loosely bound equivalents of
water that evaporated between about 30.degree. C. and about
40.degree. C., one more tightly bound equivalent of water that
evaporated between about 40.degree. C. and about 100.degree. C.,
and one very tightly bound equivalent of water that evaporated
between about 140.degree. C. and about 160.degree. 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 Example
section.
[0228] 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 6.40.degree., and other reflections or
peaks at 7.01.degree., 16.73.degree., and 20.93.degree. (FIG. 3).
Conditions for PXKD can be found in Example 1.
[0229] 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 (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.
[0230] 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 embodiments, water is the solvent. In
embodiments of the invention, a celecoxib salt contains about 0.0%,
less than 0.5%, 0.5, 1, less than 1%, 1.5, less than 1.5%, 2, less
than 2%, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or about 6 equivalents, or
about 1 to about 6, 2 to about 5, 3 to about 6, 3 to about 5, 1 to
about 4, 2 to about 4, 1 to about 3, 2 to about 3, 0 to about 3,
0.5 to about 3, 0 to about 2, 0.5 to about 2, 0 to about 1.5, 0.5
to about 1.5, 1 to about 1.5, or 0.5 to about 1 equivalents of
water per equivalent of salt. 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.
[0231] 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 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 in the present invention. The co-crystals may also be a
co-crystal between 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,
.PI.-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.
[0232] In embodiments of the present invention, the pharmaceutical
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, serine, 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, malic acid, mandelic acid, malonic,
1,5-napthalene-disulfonic acid (armstrong's acid), clemizole,
imidazole, glucosamine, piperazine, procaine, or urea.
[0233] 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.
[0234] 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 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.
[0235] Non-limiting examples follow of excipients that can be used
to prepare pharmaceutical compositions of the invention.
[0236] Pharmaceutical compositions of the invention optionally
comprise one or more further 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., Celutab.TM. and Emdex.TM.); mannitol;
sorbitol; xylitol; dextrose (e.g., Cerelose.TM. 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., RexcelJ), 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.
[0237] Lactose, mannitol, dibasic sodium phosphate, and
microcrystalline cellulose particularly Avicel PH microcrystalline
cellulose such as Avicel PH 101), 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-compression flowability, and/or drying properties at
a relatively low diluent cost. It provides a high density substrate
that aids densification during granulation (where wet granulation
is employed) and therefore improves blend flow properties and
tablet properties.
[0238] 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., Explotab.TM. of PenWest) and pregelatinized corn starches
(e.g., National.TM. 1551 of National Starch and Chemical Company,
National.TM. 1550, and Colocorn.TM. 1500), clays (e.g., Veegum.TM.
HV of R. T. Vanderbilt), celluloses such as purified cellulose,
microcrystalline cellulose, methylcellulose, carboxymethylcellulose
and sodium carboxymethylcellulose, croscarmellose sodium (e.g.,
Ac-Di-Sol.TM. of FMC), alginates, crospovidone, and gums such as
agar, guar, locust bean, karaya, pectin and tragacanth gums.
[0239] 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.
[0240] 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.
[0241] 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 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., National.TM. 1511 and National.TM.
1500); celluloses such as, but not limited to, methylcellulose and
carmellose sodium (e.g., Tylose.TM.); 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., Klucel.TM. of Aqualon); and
ethylcellulose (e.g., Ethocel.TM. 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.
[0242] 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).
[0243] 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.
[0244] Non-limiting examples of surfactants that can be used as
wetting agents (not necessarily as the
recrystallization/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), polyoxyethylene fatty acid
glycerides and oils, for example polyoxyethylene (8)
caprylic/capric mono- and diglycerides (e.g., Labrasol.TM. 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., Tween.TM. 80 of ICI), propylene glycol fatty
acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. 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 monostearate, 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.
[0245] 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.
[0246] 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., Compritol.TM. 888 of
Gattefosse); stearic acid and salts thereof, including magnesium,
calcium and sodium stearates; hydrogenated vegetable oils (e.g.,
Sterotex.TM. of Abitec); colloidal silica; talc; waxes; boric acid;
sodium benzoate; sodium acetate; sodium fumarate; sodium chloride;
DL-leucine; PEG (e.g., Carbowax.TM. 4000 and Carbowax.TM. 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.
[0247] Magnesium stearate is a preferred lubricant used, for
example, to reduce friction between the equipment and granulated
mixture during compression of tablet formulations.
[0248] 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.
[0249] 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
art 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.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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.
[0256] 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 polyalkylene glycol to produce a mixture of
mono-, di- and tri-glycerides and mono- and di-esters; e.g.,
stearoyl macrogol-32 glycerides). Such pharmaceutical compositions
are advantageously administered orally.
[0257] 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 a an
excipient which inhibits crystallization; 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 crystallization to binding agent is about 1 to 1 to 1.
[0258] Solid dosage forms of the invention can be prepared by any
suitable process, not limited to processes described herein.
[0259] 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.
[0260] 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 1 micrometer to about 100 micrometer, about 5
micrometer to about 50 micrometer, or about 10 micrometer to about
25 micrometer. One or more diluents, one or more disintegrants and
one or more 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.
[0261] 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.
[0262] 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.
[0263] 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.
[0264] 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 to about 700, and 700 to about 800
mg.
[0265] 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 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.
[0266] 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.
[0267] 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.TM. may become preferred, if the bioavailability is
changed with a novel formulation. For instance, 300 mg may become a
preferred dose for certain indications.
[0268] 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.
[0269] 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 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.
[0270] 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.
[0271] 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 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.
[0272] 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.
[0273] 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
ophthahnic surgery such as cataract surgery or refractive
surgery.
[0274] 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.
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] Such pharmaceutical compositions are useful in treatment of
allergic rhinitis, respiratory distress syndrome, endotoxin shock
syndrome and liver disease.
[0280] 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 and ankylosing
spondylitis, bursitis, bums, and trauma following surgical and
dental procedures.
[0281] 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, 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, ethylmorphine, etodolac, etofenamate,
etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone,
flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene,
hydrocodone, hydromorphone, hydroxypethidine, 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, 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)).
[0282] 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.
[0283] 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.
[0284] 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
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.
[0285] Also, the pharmaceutical compositions inhibit
prostanoid-induced smooth muscle contraction by inhibiting
synthesis of contractile prostanoids 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.
[0286] 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.
[0287] 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
[0288] Below are standard procedures for acquiring Raman, XRD, DSC
and TGA data herein. These procedures will be followed for each
respective method of analysis herein unless otherwise
indicated.
[0289] Procedure for Raman Acquisition, Filtering and Binning
[0290] Acquisition
[0291] 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 Almega.TM. Dispersive
Raman (Almega.TM. Dispersive Raman, Thermo-Nicolet, 5225 Verona
Road, Madison, Wis. 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 10.times. 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.)
[0292] Filtering and Binning
[0293] Each spectrum in a set was filtered using a matched filter
of feature size 25 to remove background signals, including glass
contributions and sample fluorescence. This is particularly
important as large background signal or fluorescence limit the
ability to accurately pick and assign peak positions in the
subsequent steps of the binning process. Filtered spectra were
binned using the peak pick and bin algorithm with the parameters
given in Table 2. The sorted cluster diagrams for each sample set
and the corresponding cluster assignments for each spectral file
were used to identify groups of samples with similar spectra, which
was used to identify samples for secondary analyses.
2TABLE 1 Raman Spectral acquisition parameters Parameter Setting
Used Exposure time (s) 2.0 Number of exposures 10 Laser source
wavelength 785 (nm) Laser power (%) 100 Aperture shape pin hole
Aperture size (um) 100 Spectral range 104-3428 Grating position
Single Temperature at acquisition 24.0 (.degree. C.)
[0294]
3TABLE 2 Raman Filtering and Binning Parameters Setting Parameter
Used Filtering Parameters Filter type Matched Filter size 25 QC
Parameters Peak Height Threshold 1000 Region for noise test 0-10000
(cm.sup.-1) RMS noise threshold 10000 Automatically eliminate Yes
failed spectra Region of Interest Include (cm.sup.-1) 104-3428
Exclude region I (cm.sup.-1) Exclude region II (cm.sup.-1) Exclude
region III (cm.sup.-1) Exclude region IV (cm.sup.-1) Peak Pick
Parameters Peak Pick Sensitivity Variable Peak Pick Threshold 100
Peak Comparison Parameters Peak Window (cm.sup.-1) 2 Analysis
Parameters Number of clusters Variable
[0295] Procedure for X-Ray Powder Diffraction
[0296] All x-ray powder diffraction patterns were obtained using
the D/Max Rapid X-ray Diffractometer (D/Max Rapid, Contact
Rigaku/MSC, 9009 New Trails Drive, The Woodlands, Tex., USA
77381-5209) equipped with a copper source (Cu/K.sub..alpha.
1.5406), manual x-y stage, and 0.3 mm collimator. The sample was
loaded into a 0.3 mm boron rich glass capillary tube (e.g., Charles
Supper Company, 15 Tech Circle, Natick Mass. 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 1.0.0, .COPYRGT. 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.degree.; and no chi or phi offsets were used for the
integration. The analysis software JADE XRD Pattern Processing,
versions 5.0 and 6.0 ((.sup.81995-2002, Materials Data, Inc. was
also used.
[0297] 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 operator to operator.
[0298] Procedure for Differential Thermal Analysis (DSC)
[0299] 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, Del. 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 in to the apparatus (DSC: Q1000 Differential
Scanning Calorimeter, TA Instruments, 109 Lukens Drive, New Castle,
Del. 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 1.0.0.78,
Thermal Advantage Release 2.0, .COPYRGT. 2001 TA instruments--Water
LLC) at a rate of 10.degree. C./min from T.sub.min (typically
20.degree. C.) to T.sub.max (typically 300.degree. 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, N.J. 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 3.1.0.40, .COPYRGT. 1991-2001TA
instruments--Water LLC) provided with the instrument. Procedure for
Thermogravimetric Analysis (TGA)
[0300] An aliquot of the sample was transferred into a platinum
sample pan. (Pan part #952019.906; TA Instruments, 109 Lukens
Drive, New Castle, Del. 19720) The pan was placed on the loading
platform and was then automatically loaded in to the apparatus
(TGA: Q500 Thermogravimetric Analyzer, TA Instruments, 109 Lukens
Drive, New Castle, Del. 19720) using the control software (Control
software: Advantage for QW-Series, version 1.0.0.78, Thermal
Advantage Release 2.0, .COPYRGT. 2001 TA instruments--Water LLC).
Thermograms were obtained by individually heating the sample at
10.degree. C./min from 25.degree. C. to 300.degree. 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, N.J. 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 95/95/2000/NT, version 3.1E; Build 3.1.0.40, .COPYRGT.
1991-2001TA instruments--Water LLC) provided with the
instrument.
EXAMPLE 1
[0301] Celecoxib Sodium Salt from Aqueous Solution
[0302] To 77.3 mg of commercially-available celecoxib was added 1.0
mL distilled water, followed by 0.220 mL of 1 M NaOH (VWR). The
mixture was heated with stirring to 60.degree. 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.degree. C. to evaporate water. About 15 mL
reagent-grade ethanol was added, while the mixture was stirred and
heated at 60.degree. C. with air blowing over the solution. Heating
continued until the solution was dry. The resulting material was
analyzed by powder x-ray diffraction (PXRD), differential scanning
calorimetry (DSC), and thermogravimetric analysis (TGA), 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.
[0303] 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.degree. C.
with a heating rate of 10.degree. C./minute, and the ending
temperature was 200.degree. C. The resulting DSC analysis is shown
in FIG. 1. The transitions observed include a melt/dehydration
process between about 40 and about 70 C, another transition between
about 70 and about 100 C possibly resulting from a
recrystallization/precipitation event and a second melt/dehydration
transition between about 100 and about 110 C.
[0304] For all of the TGA experiments, the purge gas used was dry
nitrogen, the balance purge was 40 mL/minute N.sub.2, and the
sample purge was 60 mL/minute N.sub.2. TGA of the sample was
performed by placing 2.460 mg of sample in a platinum pan. The
starting temperature was 20.degree. C. with a heating rate of
10.degree. C./minute, and the ending temperature was 300.degree. C.
The resulting TGA analysis is shown in FIG. 2. The TGA shows a mass
loss of about 12.5% between about 30 and about 50.degree. C.,
attributed to the loss of about 2.8 water molecules. A second mass
loss of about 2.0% between about 71 and 85.degree. C., attributed
to the loss of about 0.5 water molecules. Finally, a mass loss of
about 4.0% between about 148 and 170.degree. C. attributed to
either the loss of about 1 water molecule or some decomposition of
the drug compound. The hydration state of the salt can vary
depending on the humidity, temperature and other conditions.
[0305] 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 or any four peaks or any other combination of
peaks at a 2-theta angle of FIG. 3 including for example, the peaks
at 6.40.degree., 7.01.degree., 16.73.degree., and
20.93.degree..
EXAMPLE 2
[0306] Celecoxib Sodium Salt from 2-propanol Solution
[0307] To 126.3 mg of celecoxib (Fako Hazlari) 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.times.10.sup.-4 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.
[0308] 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 17.35%
weight between room temperature and 120.degree. C. The DSC trace
shows a broad endothermic region, which is consistent with a loss
of volatile components with increasing temperature. The endotherm
peaks at 66.degree. 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.degree., 4.99.degree., 6.51.degree., 7.07.degree.,
9.99.degree., 11.59.degree., 16.53.degree., 17.69.degree.,
18.47.degree., 19.13.degree., 20.11.degree., 20.95.degree.,
22.67.degree., or any one or combination of 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, or 13 peaks of FIG. 62.
EXAMPLE 3
[0309] Celecoxib Sodium Salt from Aqueous Solution
[0310] Synthesis 1: To a vial was added 29.64 mg celecoxib and 3.00
mL of 1 N sodium hydroxide. The celecoxib dissolved immediately.
After a time, the celecoxib precipitated from solution.
[0311] Synthesis 2: To a vial was added 7.10 mg celecoxib and 3.00
mL of 1 N sodium hydroxide. The celecoxib dissolved. Overnight, the
celecoxib precipitated and formed white, needle-like crystals.
[0312] Synthesis 3: To a vial was added 17.6 mg celecoxib and 10 mL
of 1 N 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 crystals formed
within about 12-36 hours.
[0313] 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% as the temperature was increased from room
temperature to 100.degree. C. at 10.degree. C./min. DSC analysis
showed a large endothermic transition at 74+/-1.0.degree. C. and a
second broad and noisy endothermic transition at about
130+/-5.0.degree. C. The PXRD pattern has peaks that can be used to
characterize the salt include any one or combination comprising any
two, any three, any four, any five, or all six 2-theta angle peaks
of 3.6.degree., 8.9.degree., 9.6.degree., 10.8.degree.,
11.4.degree., and 20.0.degree..
EXAMPLE 4
[0314] Pharmacokinetic Studies in Rats
[0315] The sodium salt form (from Example 6) was compared with
CELEBREX powder in terms of absorption in rats (FIGS. 4A and
4B).
[0316] 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 FIGS. 4A and 4B.
Solids were placed in size 9 gelatin capsules (Torpac) and dosed
via gavage needle, followed by oral gavage of 1 mL water.
CELEBREX.RTM. granulation was transferred from commercial 200 mg
capsules. The sodium salt was blended with Povidone K30 (4:1 weight
ratio to the sodium salt of celecoxib). The plots are averages of
plasma levels at each of the time points from plasma of 5 rats.
[0317] The pharmacokinetics at 5 mg/kg doses of celecoxib or 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.RTM. (in
particular, see FIG. 4A).
EXAMPLE 5
[0318] Solubility of Celecoxib Sodium in the Presence of
Polyvinylpyrrolidone
[0319] Water was added to a 1:4 mixture of celecoxib sodium 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.
[0320] 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
[0321] Preparation of Celecoxib Sodium
[0322] The free acid of Celecoxib (5.027 g) was suspended in an
aqueous solution of NaOH (13.181 mL, 1 M). The suspension was
gently heated at 60.degree. C. for 1 minute to dissolve the
remaining solid. The mixture was allowed to cool to room
temperature, which yielded no precipitation. Further cooling in an
ice bath for 1 hour gives precipitation of the product. The
resulting solution was filtered and allowed to air dry.
[0323] Characterization of the product has been achieved via TGA,
DSC, PXRD, Raman spectroscopy, microscopy, and .sup.1H NMR
spectroscopy. NMR acquisitions were performed on a Varian 300 MHz
Spectrometer in (methyl sulfoxide)-d.sup.6.
[0324] The PXRD pattern has 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. 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 2-theta angles of
FIG. 13A.
[0325] Results of Raman spectroscopy can be seen in FIG. 13B. Raman
shift (cm.sup.-1) peaks occur at positions including, but not
limited to, any one, any two, any three, any four, all five of
1617.11, 1446.20, 1373.73, 975.02 and 800.15, or any combinations
2, 3, 4, 5 or more peaks of FIG. 13B.
EXAMPLE 7
[0326] Administration of Celecoxib Compositions to Dogs
[0327] 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 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 were: (1) commercially
available celecoxib in the form of CELEBREX.RTM. at 1 milligrams
per kilograms (mpk) combined with 70/30 PEG400/water which was
administered IV, (2) oral dose of commercially available celecoxib
in the form of CELEBREX.RTM. at 5 mpk adjusted for each dog's
weight in size 4 gelatin capsules, and (3) oral dose of the sodium
salt of the instant invention as prepared according to Example 6 at
5 mpk adjusted for each dog's weight in size 4 gelatin capsules.
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 min of collection at 3200 g at 4
degrees C. nominal for 10 minutes. Plasma samples (.about.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 a 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 biovavailability (F) is reported for oral doses
relative to the IV dose.
[0328] FIG. 5 shows the mean pharmacokinetic parameters (and
standard deviations therefore) of celecoxib in the plasma of male
dogs following a single oral or single intravenous dose of
celecoxib or celecoxib sodium. The maximum serum concentration and
bioavailability of orally-administered celecoxib sodium was about
three- and two-fold greater, respectively, than a roughly equal
dose of orally-administered celecoxib, and the maximum serum
concentration of celecoxib sodium was reached 40% faster than for
celecoxib.
EXAMPLE 8
[0329] Celecoxib-Lithium Salt Preparation Method: MO-116-49B
[0330] To 100 mg of commercially available Celecoxib was added 0.3
5M LiOH(aq) (Lithium Hydroxide Monohydrate--Aldrich Cat#25,427-4,
Lot 00331K1) solution with a Lithium:celecoxib ratio of 1.53:1 in a
vial with a Teflon coated silicon rubber septum cap. The mixture
was gently heated during dissolution with occasional swirling until
all solids dissolved. Flowing dry nitrogen was blown over the
solution for 2 days through stainless steel needles inserted into
the septum cap until the solution was dry. Characterization of the
product was achieved via DSC (FIG. 14), TGA (FIG. 15), Raman
spectroscopy (FIG. 16) and PXRD (FIG. 17).
[0331] Celecoxib-Lithium Salt Data (DSC)
[0332] 1.56 mg of collected sample was placed into an aluminum DSC
pan with cover. During heating, 50 ml/min nitrogen purge gas was
used. Results of the DSC thermogram (FIG. 14) show amelting point
at 111.84 degrees C. and a second endotherm, less sharp at 237.11
degrees C.
[0333] Celecoxib-Lithium Salt Data (TGA)
[0334] 8.2290 mg of collected sample was placed into a platinum TGA
pan. Results of the TGA (FIG. 15) demonstrated about a 14% weight
loss between about 25 degrees C. and 190 degrees C.
[0335] Celecoxib-Lithium Salt (MO-116-49A) Data (Raman)
[0336] A small quantity of collected sample was placed on a glass
slide and mounted in the Thermo Nicolet Almega Dispersive Raman.
The sample capture was set to 6 background scans and 12 sample
collection scans. The parameters used for this analysis were:
4 DATA COLLECTION INFORMATION SPECTROMETER DESCRIPTION Exposure
time: 2.00 sec Spectrometer: Visible Raman Microscope Number of
exposures: 12 Laser: 785 nm Number of background Laser power level:
100% exposures: 6 Laser polarization: Parallel Grating: 360
lines/mm Spectrograph aperture: 100 .mu.m slit Sample position:
Microscope Camera temperature: -50 C. CCD rows binned: 89-150 CCD
binning: On chip RIM position: Mirror Polarization analyzer: Out
Illuminators: Of
[0337] 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 and any other combination of peaks of
FIG. 16, e.g., 1617.10, 1596.95, 1449.56, 1374.03, 1115.24,
1062.85, 976.50, 800.67, 740.91 and 633.94.
[0338] Celecoxib-Lithium Salt Data (PXRD)
[0339] A small amount of collected sample was placed in a 0.3 mm
glass PXRD tube. The tube was placed into a Rigaku D/Max Rapid PXRD
and set to: Cu; 46 kV/40 mA; Collimeter:0.3; Omega-axis
oscillation, Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed
2; Collection time was equal to 15 minutes. The PXRD pattern has
characteristic peaks as shown in FIG. 17. PXRD peaks that can be
used 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 or any other combination of peaks from
FIG. 17, e.g., 4.18, 9.04, 10.705, 12.47, 15.75, 18.71, 19.64,
20.52, 21.55 and 23.0.
EXAMPLE 9
[0340] Celecoxib-Potassium Salt: Preparation Method MO-116-49A
[0341] 100 mg of Celecoxib (Fako Ilaclari A.S.) was dissolved in a
0.35M KOH(aq) solution (Potassium Hydroxide--Spectrum, Cat#P0180,
Lot#PN0690) with a Potassium:Celecoxib ratio of 1.40:1 in a vial
with a Teflon coated silicon rubber septum cap. The resulting
solution was gently warmed during dissolution with occasional
swirling until all solids dissolved. After all solids were
dissolved, the solution was dried by flowing dry nitrogen over the
solution for 2 days through stainless steel needles inserted into
the septum cap. Analysis of the resulting product was performed.
Characterization of the product was achieved via DSC (FIG. 18,) TGA
(FIG. 19), Raman spectroscopy (FIG. 20) and PXRD (FIG. 21).
[0342] Celecoxib-Potassium Salt (MO-116-49A) Data (DSC)
[0343] 1.119 mg of collected sample was placed into an aluminum DSC
pan with cover. The results are depicted in the graph of FIG. 18
and show a melting point endotherm at 87.39 degrees C.
[0344] Celecoxib-Potassium Salt (MO-116-49A) Data (TGA)
[0345] 5.9890 mg of collected sample was placed into a platinum TGA
pan. The pan was placed in TA Instruments Q500 TGA and heated
10.degree. C./min to 90.degree. C., held for 10 minutes, ramped
10.degree. C./min to 300.degree. C., and held for 10 minutes with
40 ml/min nitrogen purge gas. The results are depicted in FIG. 19
and show a 5.778% weight loss between 25 and 200 degrees C. A
shoulder in the data is seen at 80 degrees C. Weight loss before
this point is due to unbound water. The weight loss between 80 and
200 degrees C. is due to more closely bound water, and represents
0.64 equivalents of water.
[0346] Celecoxib-Potassium Salt (MO-116-49A) Data (Raman)
[0347] A small quantity of collected sample was placed on a glass
slide and mounted in the Thermo Nicolet Almega Dispersive Raman.
The sample capture was set to 6 background scans and 12 sample
collections. The parameters used for this analysis were:
5 DATA COLLECTION INFORMATION SPECTROMETER DESCRIPTION Exposure
time: 2.00 sec Spectrometer: Visible Raman Microscope Number of
exposures: 12 Laser: 785 nm Number of background Laser power level:
100% exposures: 6 Laser polarization: Parallel Grating: 360
lines/mm Spectrograph aperture: 100 .mu.m slit Sample position:
Microscope Camera temperature: -50 C. CCD rows binned: 89-150 CCD
binning: On chip RIM position: Mirror Polarization analyzer: Out
Illuminators: Of
[0348] The results are depicted in FIG. 20 and show characteristic
Raman shift (cm.sup.-1) peaks at positions including, but not
limited to any one or combination of any two, any three, any four,
any five or all six of the peaks: 1617.66, 1448.22, 1374.09,
976.28, 801.60, or any combinations of 2, 3, 4, 5, 6 or more peaks
of FIG. 20.
[0349] Celecoxib-Potassium Salt (MO-116-49A) Data (PXRD)
[0350] A small amount of collected sample 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; Collimeter:0.3; Omega-axis oscillation,
Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection
time was equal to 15 minutes. 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, 12.23, 15.35, and 19.79. The
crystal can be characterized by any one or combination of any two,
any three, or all four, of the above angles or any one or any
number combination of 2-theta angles of FIG. 21.
EXAMPLE 10
[0351] Celecoxib-Potassium Salt: Preparation Method MO-116-55D
[0352] An alternative method of preparing a celecoxib-potassium
salt of the instant invention was performed. 100 mg of celecoxib
(commercially available) was dissolved in 2.2 mL toluene and 0.1 mL
methanol in a vial with a TEFLON.RTM. coated silicon rubber septum
cap. The solution was warmed gently during dissolution with
occasional swirling until all solids were dissolved. 1.03
equivalents of KOH (Potassium Hydroxide--Spectrum, Cat#P0180,
Lot#PN0690) using a 3M KOH(aq) solution were added to the solution.
After the resulting phase separation, the bottom phase was removed
and was dried by flowing dry nitrogen over the solution for 1 day
through stainless steel needles inserted into the septum cap.
[0353] Analysis was performed. Characterization of the product was
achieved via TGA (FIG. 22), Raman spectroscopy (FIG. 23) and PXRD
(FIG. 24).
[0354] Celecoxib-Potassium Salt (MO-116-55D) Data (TGA)
[0355] 5.4470 mg of collected sample was placed into a platinum TGA
pan. The pan was placed in TA Instruments Q500 TGA and heated
10.degree. C./min to 90.degree. C., held for 10 minutes, ramped
10.degree. C./min to 300.degree. 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 about 2.9 wt % at a shoulder from about 70 degrees
C. to 200 degrees C. Initial weight loss before the shoulder is
most likely to the evaporation of methanol. The weight loss after
the shoulder is most likely due to excess water.
[0356] Celecoxib-Potassium Salt (MO-116-55D) Data (Raman)
[0357] A small quantity of collected sample was placed on a glass
slide and mounted in the Thermo Nicolet Almega Dispersive Raman.
The sample capture was set to 6 background scans and 12 sample
collection scans. The parameters of the spectrometer were as
follows:
6 DATA COLLECTION INFORMATION SPECTROMETER DESCRIPTION Exposure
time: 2.00 sec Spectrometer: Visible Raman Microscope Number of
exposures: 12 Laser: 785 nm Number of background Laser power level:
100% exposures: 6 Laser polarization: Parallel Grating: 360
lines/mm Spectrograph aperture: 100 .mu.m slit Sample position:
Microscope Camera temperature: -50 C. CCD rows binned: 89-150 CCD
binning: On chip RIM position: Mirror Polarization analyzer: Out
Illuminators: Of
[0358] The results are depicted in FIG. 23 and show characteristic
Raman shift (cm.sup.-1) peaks at positions including, but not
limited to any one or combination of any two, any three, any four,
any five or any six, any seven, any eight, any nine, any ten, or
all eleven of the peaks 1615.51, 1446.09, 1374.28, 1232.91,
1197.04, 1108.99, 1060.94, 973.01, 798.86, 739.82, 633.37 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.
[0359] Celecoxib-Potassium Salt (MO-116-55D) Data (PXRD)
[0360] A small amount of collected sample was placed in a 0.3 mm
glass PXRD tube. The tube was placed into a Rigaku D/Max Rapid PXRD
set to Cu; 46 kV/40 mA; Collimeter:0.3; Omega-axis oscillation,
Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection
time was equal to 15 minutes. The results are depicted in FIG.
24.
EXAMPLE 11
[0361] Celecoxib-Calcium Salt: Preparation Method MO-116-62A
[0362] 100 mg of celecoxib (commercially available) was dissolved
in a 1M NaOH methanol solution at a 1:1 ratio of NaOH:Celecoxib in
a vial and heated gently with occasional swirling until all solids
were dissolved. 3M CaCl.sub.2 in methanol was added to achieve a
ratio of 1.5:1 Ca.sup.2+ to Celecoxib. The precipitate was filtered
with a centrifuge tube filter (Corning Inc. Costar (0.22 micron)
#8169) in an Eppendorf Centrifuge (5415D) set at 12000 rpm for 5
minutes. The upper section of the Eppendorf tube containing the
solids was placed into a vial with a rubber septum cap. The powder
was dried overnight by flowing dry nitrogen into the vial through
stainless steel needles inserted in the septum cap.
[0363] Analysis was performed. Characterization of the product was
achieved via TGA (FIG. 25), Raman spectroscopy (FIG. 26) and PXRD
(FIG. 27).
[0364] Celecoxib-Calcium Salt (MO-116-62A) Data (TGA)
[0365] 3.4140 mg of collected sample was placed into a platinum TGA
pan. The pan was placed in TA Instruments Q500 TGA and heated
10.degree. C./min to 90.degree. C., held for 10 minutes, ramped
10.degree. C./min to 300.degree. C., and held for 10 minutes with
40 ml/min nitrogen purge gas. Results (FIG. 25) show a weight loss
of about 4.2% between 25 and 200 degrees C. and about 3.2% between
70 and 200 degrees C. Initial weight loss below 70 degrees C. is
due to unbound solvent. The shoulder seen after 70 degrees C. is
due to the loss of more closely bound methanol and represents 0.45
equivalents of methanol.
[0366] Celecoxib-Calcium Salt (MO-116-62A) Data (Raman)
[0367] A small quantity of collected sample was placed on a glass
slide and mounted in the Thermo Nicolet Almega Dispersive Raman.
The sample capture was set to 6 background scans and 12 sample
collection scans.
7 DATA COLLECTION INFORMATION SPECTROMETER DESCRIPTION Exposure
time: 2.00 sec Spectrometer: Visible Raman Microscope Number of
exposures: 12 Laser: 785 nm Number of background Laser power level:
100% exposures: 6 Laser polarization: Parallel Grating: 360
lines/mm Spectrograph aperture: 100 .mu.m slit Sample position:
Microscope Camera temperature: -50 C. CCD rows binned: 89-150 CCD
binning: On chip RIM position: Mirror Polarization analyzer: Out
Illuminators: Of
[0368] Characteristic raman shift (cm.sup.-1) peaks were observed
at positions including, but not limited to, any one, any two, any
three, any four, any five, and six or all seven of the peaks
16.16.99, 1598.42, 1450.05, 1376.57, 973.10, 800.62, 642.20, or any
combinations of 2, 3, 4, 5, 6, 7 or more peaks of FIG. 26.
[0369] Celecoxib-Calcium Salt (MO-116-62A) Data (PXRD)
[0370] A small amount of collected sample was placed into a 0.3 mm
glass PXRD tube. The tube was placed in Rigaku D/Max Rapid PXRD set
to Cu; 46 kV/40 mA; Collimeter:0.3; Omega-axis oscillation,
Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed 2; Collection
time was equal to 15 minutes. An intense peak was observed at
2-theta angle of 31.67 and lesser peaks at 7.82, 9.27, 20.56, and
27.35. Any one or combination of 2, 3, 4, or 5 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.
EXAMPLE 12
[0371] Comparative Analysis of Neutral Celecoxib
[0372] To aid in the analysis of some of the data retrieved,
commercially available celecoxib was subjected to the same
analytical techniques of particle-induced X-ray diffraction (PXRD)
and Raman spectroscopy. The results were used as a comparison for
the salts of the instant invention.
[0373] Comparison Data: Celecoxib (PXRD)
[0374] 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; Collimeter:0.3; Omega-axis
oscillation, Pos(deg) 0-5, speed 1; Phi-axis spin, Pos 360, Speed
2; Collection time was equal to 15 minutes. The results are
depicted in FIG. 28.
[0375] 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.
[0376] Comparison Data: Celecoxib (Raman)
[0377] A small quantity of commercially available celecoxib was
placed on a glass slide and mounted in the Thermo Nicolet Almega
Dispersive Raman. The sample capture was set to 6 background scans
and 12 sample collection. The parameters were as follows:
8 DATA COLLECTION INFORMATION SPECTROMETER DESCRIPTION Exposure
time: 2.00 sec Spectrometer: Visible Raman Microscope Number of
exposures: 12 Laser: 785 nm Number of background Laser power level:
100% exposures: 6 Laser polarization: Parallel Grating: 360
lines/mm Spectrograph aperture: 100 .mu.m slit Sample position:
Microscope Camera temperature: -50 C. CCD rows binned: 89-150 CCD
binning: On chip RIM position: Mirror Polarization analyzer: Out
Illuminators: Of
[0378] The results are depicted in FIG. 29.
EXAMPLE 13
[0379] Solid-state formulations based on selected PLURONIC
excipients in combination with hydroxypropylcellulose (BPC) 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.
[0380] This example demonstrates that related solid-state
formulations enhance the dissolution and retard the
recrystallization/precipitation of celecoxib salts as compared to
the celecoxib freeacid compound. The processes used to identify and
test the preferred excipients in these examples are two-fold: (1) A
"Crystal 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
"Crystal Retardation Assay" results.
EXAMPLE 14
[0381] Crystal Retardation Assay
[0382] Crystal Retardation Assay--Method
[0383] 1. 58 excipients according to Table 1 were prepared at a
concentration of2 mg/ml (0.2% by weight) in simulated gastric fluid
having 200 mM hydrochloric acid and dispensed in quadruplicate in
96-well plates at a volume of 150 ul. Two controls were used: (a)
Simulated gastric fluid lacking excipients; and (b) Simulated
gastric fluid containing 2 mg/ml Vitamin E TPGS and 2 mg/ml HPC.
The latter control was chosen because of prior indication that this
excipient combination provides enhanced dissolution of celecoxib
sodium hydrate. Simulated gastric fluid was prepared by adding 2
g/L sodium chloride and 1 g/L Triton X-100 to DI H20. 200 mM
hydrochloric acid was added to adjust and buffer the pH.
9TABLE 1 Excipients use in Recrystallization/precip- itation
Retardation Assay 2 Ethoxyethanol Polyethyleneglycol PLURONIC P123
Monooleate (Mapeg 400-MO) Alkamus 719 Alkamus EL 620
Polyethyleneglycol PLURONIC P85 300 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 Saccharin Hydroxypropylcellulose
PLURONIC L31 Sodium lauryl sulphate (HPC) 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
[0384] 2. The 96-well plates were sealed, and incubated to a
temperature of 40.degree. C. for 20 minutes. After incubation, the
plate seals were removed.
[0385] 3. Celecoxib, pre-dissolved in potassium hydroxide to a
concentration of 5.5 mg/ml, was dispensed in 15 ul aliquots into
each well and immediately mixed. This gave a final celecoxib
concentration of 0.5 ml/ml in each well. The final excipient
concentration was 1.8 mg/ml.
[0386] 4. A nephelometer (Nephelostar Galaxy, BMG Technologies,
Durham, N.C.), with a chamber preheated to 37.degree. C., was used
to analyze the ability of the excipients to retard the
crystallization of supersaturated celecoxib. The assay plate
containing celecoxib and excipients was sealed using an optically
clear seal and placed into the nephelometer instrument. The
nephelometer recorded changes in solution turbidity over a 1 hour
time period. Solutions that showed signs of increasing turbidity
over a baseline indicated that celecoxib had precipitated out
solution.
[0387] Crystal retardation Assay--Results:
[0388] FIG. 30 shows crystal 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
crystal retardation time that may be greater than 60 min.
Excipients listed in Table I, but excluded from FIG. 30 did not
show any appreciable crystal retardation time (i.e., greater than
1.5 min). Nineteen of 58 excipients were found to retard
recrystallization/precipitation of celecoxib. Interestingly, in
contrast to the dissolution assay, Vitamin E TPGS alone had a
longer retardation time than in combination with HPC alone did not
show any retardation time.
[0389] Importantly, formulations that increase the solubility of a
drug will not necessarily increase the dissolution. For example,
according to PCT application WO 01/78724, the solubility of
celecoxib freeacid in Transcutol P is 350 mg/g. It was found that
in contrast to enhancing solubility, Transcutol P does not enhance
dissolution of the free acid. Transcutol P does extend the time to
Tmax and increases the time the concentration of celecoxib is above
1/2 Tmax when used in combination with a
recrystallization/precipitation retardant and enhancer. It was
further found that dissolution of a salt form is far superior to
the dissolution of composition comprising the free acid.
[0390] The presence of six PLURONIC (poloxamer) excipients among
successful crystal retardants prompted further study of these
compounds. PLURONICs are ethylene oxide--propylene oxide block
copolymers, whose properties can be significantly altered (i.e.,
melting point, cloud point, molecular weight, HLB number, 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 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. 31, along with interfacial data for PLURONICs
that were not tested. Based on this correlation, the
supersaturation properties of these additional PLURONICs also
correlate with interfacial tension.
[0391] FIG. 31 shows interfacial tension of selected PLURONIC
excipients in water. PLURONIC excipients having low interfacial
tension correlate with excipients that retard crystallization of
celecoxib in simulated gastric fluid. An interfacial tension
threshold for crystal retardation was loosely defined as less than
about 9 or 10 dyne/cm. 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.degree. C. (PLURONIC is a trademark of BASF).
EXAMPLE 15
[0392] In Vitro Dissolution Studies of PLURONIC Excipients
[0393] In Vitro Dissolution Studies of PLURONIC
Excipients--Method
[0394] 1. Celecoxib Preparation
[0395] a. Fresh celecoxib sodium salt hydrate was prepared and
analyzed to be approximately 90% freeacid vs. sodium content.
[0396] b. The celecoxib salt was ground using mortar and pestle
until fine powder was formed. The fine powder was sieved using a
105 um pore size mesh and stored in a 20 ml scintillation vial at
room temperature.
[0397] 2. Formulation Preparation
[0398] 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.
[0399] b. If BPC 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.
[0400] c. 105 um sieved celecoxib salt was added to mortar and the
mixture was ground and mixed for several minutes.
[0401] 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.
[0402] 3. Dissolution Assay
[0403] a. A water bath was set up at 37.degree. C.
[0404] b. Simulated gastric fluid in the fasted state (SGF) was
prepared at pH 1.7 and diluted five times with deionized water. The
final pH was approximately 2.4. The simulated gastric fluid was
diluted five times to simulate the effect of drinking a glass of
water with the medication. The SGF was pre-heated to 37.degree.
C.
[0405] c. The formulation was placed in a 20 ml scintillation
vial.
[0406] d. A 10 mm.times.3 mm stir bar was added.
[0407] e. Diluted SGF was added to the formulation. The volume
added was set to satisfy a 2 mg/ml dose of celecoxib free acid.
[0408] f. The vial was placed in the water bath and allowed to
stir.
[0409] g. At each time point, 0.9 ml of solution was extracted and
filtered through a 0.2 um 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 ten
times with 0.9 ml of methanol. The autosampler vials were crimp
sealed and submitted for content analysis using high performance
liquid chromatography with ultra-violet detection.
[0410] In Vitro Dissolution Studies of PLURONIC
Excipients--Results:
[0411] 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 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 result for these mixtures at equal weight
concentrations of excipient to celecoxib freeacid content are shown
in FIG. 32. 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.
[0412] 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 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 87 has
a high interfacial tension (17.4 dyne/cm), the resulting data
supports the correlation of crystal 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.
[0413] 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 freeacid 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.
[0414] 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 freeacid content, PLURONIC F127, and HPC were mixed and
compacted into 6 mm discs at 4900 psi. Dissolution results, shown
in FIG. 35, 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 controlled
release mechanism. The controlled 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 and fewer processing steps.
EXAMPLE 16
[0415] General Method of Crystal Retardation Assay
[0416] 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:
[0417] 1. Excipients are dissolved to a desired concentration in
de-ionized (DI) water or other media (i.e., simulated gastric or
intestinal fluids).
[0418] 2. API is dissolved in a suitable solvent in which it has
high solubility (i.e., acidic pH environment for freebase type API;
and basic pH environment for freeacid type API).
[0419] 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-excipient combinations into each well. An example of a
liquid handling instrument is the Tecan Genesis (Tecan U.S. Inc,
Research Triangle Park, N.C.).
[0420] 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.
[0421] 5. The solutions are mixed to uniformly distribute the API
throughout the excipient solution. The plate is sealed and
incubated at a desired temperature.
[0422] 6. Onset of solid-state nucleation is determined using an
instrument capable of measuring light scatter. Examples of light
scatter measurement capable instruments are the NepheloStar
nephelometer (BMG Technologies, Durham, N.C.) and the SPECTRAmax
PLUS plate reader (Molecular Devices Corp, Sunnyvale, Calif.).
Temperature is maintained at a constant pre-defined set point by
the incubation features of the light scatter instruments.
[0423] 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.
[0424] 8. The data is analyzed and the excipients are ranked
according to their respective retardation times.
[0425] 9. Informatics may be used to correlate successful
excipients that retard nucleation with physical property
information.
[0426] Typical Information Obtained from the Methods:
[0427] 1. Solid-state retardation time as a function of
excipient
[0428] 2. Qualitative measure of crystallization kinetics as a
function of excipient
[0429] 3. API final solid-state form analysis (i.e., amorphous,
crystalline, habit) in excipient solutions
EXAMPLE 17
[0430] Illustration of Resulting Data
[0431] Goal: Identify excipients that retard the solid-state
nucleation of Compound A in Fluid F at a temperature of 37.degree.
C.
[0432] Method:
[0433] 1. 24 excipient solutions were prepared at a concentration
of 16 mg/ml in DI water.
[0434] 2. Fluid F was prepared in DI H20 by mixing ingredients at
twice the desired final concentration.
[0435] 3. API solution was prepared at a concentration of 5.5 mg/ml
in Fluid C.
[0436] 4. The Tecan Genesis instrument was used to dispense a
combination of 75 ul Fluid F, 18.75 ul excipient solution, and
56.25 ul DI 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 ul. 4 replicates wells were
used for each single excipient solution. An example of the layout
is shown in FIG. 37.
[0437] 5. The plate was sealed using a transparent seal (Part No.
6575; Corning Incorporated, Corning, N.Y.) and incubated at
40.degree. C. for 20 minutes.
[0438] 6. The seal was removed and 15 ul of API solution was
dispensed simultaneously into all 96-wells. The final concentration
of API in each well was 0.5 mg/ml. (Note: The time dependence for
solid-state nucleation began as soon as the API solution was
added.)
[0439] 7. The well contents were mixed and sealed using the
transparent seal (Part No. 6575; Corning Incorporated, Corning,
N.Y.).
[0440] 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.degree. C. as specified in
the goal of the assay.
[0441] 9. At the end of the assay, the data was 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.
[0442] 10. The retardation times (in any) for the excipient
solutions were ranked. FIG. 30 shows a graphical representation of
the ranking.
[0443] Non-limiting examples of alternatives to this general method
include:
[0444] 1. Retardation time can be measured as a function of
excipient concentration.
[0445] 2. Retardation time can be measured as a function of API
salt or co-crystal concentration.
[0446] 3. API can be concentrated in a non-aqueous medium prior to
assay.
[0447] 4. Temperature can be varied and controlled according to a
desired specification.
[0448] 5. Instead of mixing the compound solution with the
excipient solution, the test excipient can be mixed with the api in
the compound solution prior to combining with the aqueous/SGF/SIF
or other test solution (which is the excipient solution minus the
excipient).
[0449] FIG. 39 shows the results of TGA. A weight loss of about
15.6% was observed between about 65.degree. and 200.degree. C. FIG.
40 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, 16.15,
18.69, 20.63, 22.69 and 24.77 or any one or any combination of 1,
2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks of FIG. 40. The other
peaks of the graphs may also be used alone or in any combination to
characterize the salt.
EXAMPLE 18
[0450] Propylene Glycol Solvate of Celecoxib Sodium Salt
[0451] A propylene glycol solvates of the sodium salt of celecoxib
was prepared. To a solution of celecoxib (312 mg; 0.818 mmol) in
Et.sub.2O (6 mL) was added propylene glycol (0.127 ml, 1.73 mmol).
To the clear solution was added NaOEt in EtOH (21%, 0.275 .mu.L,
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 Et.sub.2O (10 mL). The
off-white solid was then air-dried and collected. This was a 1:1
solvate. The solid was characterized by TGA and PXRD. The results
are depicted in FIGS. 39 and 40.
EXAMPLE 19
[0452] A propylene glycol solvate of the potassium salt of
celecoxib was prepared. To a solution of celecoxib (253 mg, 0.664
mmol) in Et.sub.2O (6 mL) was added propylene glycol (0.075 ml,
1.02 mmol). To the clear solution was added KOtBu in THF (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 Et.sub.2O (10 mL). The
white solid was then air-dried and collected. This solid was a 1:1
solvate. The solid was characterized by TGA and PXRD. The results
are depicted in FIGS. 41 and 42.
[0453] FIG. 41 shows the results of TGA. A weight loss of about
14.94% was observed between about 65.degree. and about 250.degree.
C. FIG. 42 shows the results of PXRD. Peaks; in 2-theta angles,
that can be used to characterize te solvate include any 1, 2, 3, 4,
5, 6, 7, 8 , 9 or 10 of the following: 3.75, 7.47, 11.33, 14.93,
15.65, 18.31, 20.47, 21.71, and 24.67 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
[0454] A propylene glycol solvate of lithium salt of celecoxib was
prepared. To a solution of celecoxib (264 mg, 0.693 mmol) in
Et.sub.2O (8 mL) was added propylene glycol (0.075 ml, 1.02 mmol).
To the clear solution was added tBu-Li in pentane (1.7 M, 0.40 mL,
0.68 mmol). A brown solid formed immediately but dissolved within
one minute yielding white solid. The white solid crystallized
completely after 10 minutes. The solid was collected by filtration
and was washed with Et.sub.2O (10 mL). The white solid was then
air-dried and collected. The solid was a 1:1 solvate. The solid was
characterized by TGA and PXRD. The results of TGA are depicted in
FIG. 42 and show a weight loss of about 16.3% between 50.degree. C.
and 210.degree. C. 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, 25.09 or any one or any
combination of peaks of FIG. 51.
EXAMPLE 21
[0455] Celecoxib Na Propylene Glycol Trihydrate
[0456] Preparation:
[0457] a.) Celecoxib Na propylene glycol was formed by allowing the
celecoxib sodium salt propylene glycol solvate to sit at 60% RH and
20.degree. C. for 3 days. (Note: formation of the trihydrate at 75%
and 40.degree. C. as well). The trihydrate starts forming somewhere
between 31 and 40% RH at room temperature.
[0458] The results of TGA and PXRD are shown in FIG. 44. FIG. 44
shows the results of TGA where an about 9.64% weight loss was
observed between room temperature and 60.degree. C. and an about
13.6% weight loss was observed between abuot 60.degree. C. and
175.degree. C.
[0459] The PXRD pattern has characteristic peaks at 2-theta angles
shown in FIG. 45. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, or more peaks can
be used to characterize the solvate, 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.
[0460] b.) The trihydrate can also be formed by crystallization of
Celecoxib Na propylene glycol in the presence of H.sub.2O. To a
solution of Celecoxib (136.2 mg; 0.357 mmol) in Et.sub.2O (6.0 mL),
H.sub.2O (0.025 mL; 1.39 mmol), and propylene glycol (0.030 ml;
0.408 mmol) was added NaOEt in EtOH (21 wt. %; 0.135 mL; 0.362
mmol). A solid formed within one minute and was isolated via
filtration. The solid was then washed with additional Et.sub.2O
(2.0 mL) and allowed to air dry. This procedure gives essentially
the same PXRD pattern but there is a slight excess of H.sub.2O,
which is probably surface water.
[0461] The results of TGA and PXRD are shown in FIG. 46. FIG. 46
shows the results of TGA where an about 10.92% weight loss was
observed between room temperature and 50.degree. C. and an about
12.95% weight loss was observed between about 50.degree. C. and
195.degree. C.
[0462] The PXRD pattern has characteristic peaks at 2-theta angles
shown in FIG. 47. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, or more peaks can
be used to characterize the solvate, including for example, peaks
at 3.43, 6.95, 10.25, 13.95, 16.39, 19.43, 21.21, 22.61 and
25.71.
EXAMPLE 22
[0463] Celecoxib Na iPrOH
[0464] To a solution of Celecoxib (204.2 mg; 0.5354 mmol) in
Et.sub.2O (6.0 mL) was added iPrOH (0.070 mL). To the colorless
solution was added a solution of NaOMe (0.5 M; 2.52 mL; 6.75 mmol)
in MeOH followed by hexanes (3.0 mL). The volatiles were reduced
under flowing N.sub.2 gas. A white solid formed and was collected
via filtration. After drying, the solid was found to be a 1.5 iPrOH
solvate via TGA.
[0465] The results of DSC, TGA and PXRD analysis are shown in FIGS.
48-50. FIG. 48 shows the results of DSC analysis where a peak
endotherm was observed at 67.69.degree. 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.degree. C.
[0466] The PXRD pattern has characteristic peaks at 2-theta angles
shown in FIG. 50. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 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.
EXAMPLE 23
[0467] 1:1 Celecoxib: Nicotinamide Co-crystals.
[0468] 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 & PXRD. The results of DSC showed
decomposition beginning at .about.150.degree. C. The results of TGA
showed two phase transitions at 117.2 and 118.8.degree. C. and a
sharp endotherm at 129.7.degree. C. The results of PXRD is 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 or 15 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, or any one or any combination of any 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more peaks of
FIG. 52.
EXAMPLE 24
[0469] As discussed above, the celecoxib sodium is a variable
hydrate. To analyze the affect of hydration on crystal structure,
the celecoxib sodium salt and celecoxib sodium salt propylene
glycol solvate were analyzed by PXRD under 17%, 31%, 59% and 74%
constant relative humidity at room temperature. The following table
lists PXRD 2-theta angle peaks at the different relative
humidities.
10TABLE X Celecoxib Sodium Celecoxib Propylene Sodium Glyclol 17%
31% 59% 74% 17% 31% 59% 74% 3.51 3.51 3.49 3.59 3.79 3.82 3.49 3.47
3.99 3.95 3.95 4.61 7.65 7.61 3.95 6.97 8.87 8.91 4.61 5.23 8.75
8.69 4.61 10.21 9.51 9.51 5.35 8.91 11.45 11.44 5.35 11.85 10.75
11.59 7.79 9.51 12.19 12.19 9.21 12.97 11.59 11.97 8.09 10.77 16.47
15.29 10.77 13.97 13.45 13.31 8.93 11.29 18.43 15.88 11.62 16.41
18.47 14.45 9.21 12.99 19.21 16.43 13.89 17.39 19.09 18.49 10.79
13.85 20.91 17.19 14.82 18.23 20.17 19.05 11.63 14.43 22.13 18.45
16.05 18.87 21.55 20.13 12.97 14.83 22.95 19.17 17.47 19.45 21.91
20.47 13.89 16.07 20.84 18.43 20.63 31.67 21.53 14.59 16.75 22.09
20.43 21.27 22.75 14.83 17.13 22.95 21.55 22.63 22.71 16.05 17.97
23.99 22.41 23.91 31.69 17.47 18.39 25.47 25.35 24.35 18.43 18.71
31.05 35.23 25.73 18.91 19.63 37.93 27.83 19.57 19.89 29.11 20.09
20.43 31.31 20.43 21.55 31.87 21.55 22.39 32.83 22.41 23.43 33.59
24.95 24.55 25.35 25.35 25.75 25.71 27.25 27.17 34.19 27.69 35.23
28.19 37.93 29.49 29.99 32.29 37.87
[0470] 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 X 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 one of FIGS.
53-60.
EXAMPLE 25
[0471] Multiple celecoxib sodium salt samples, all form M1, varying
in hydration (believed to range from about 0.5-4 equivalents of
H.sub.2O per equivalent of celecoxib) was assayed by PXRD. The PXRD
patterns were then grouped based on shared peaks. Several groups
were identified with four of the these groups shown in FIG. 61.
Group D is consistent with a mixture of amorphous and crystalline
celecoxib sodium. Table Y lists PXRD peaks characteristic in common
to groups A, B, and C and peaks that are specific to each
group.
11TABLE Y Peaks common to all Peaks for form Peaks for form Peaks
for form Variants of form M1 M1_A M1_B M1_C 3.7 .+-. 0.3.degree.
9.5 .+-. 0.2.degree. 9.5 .+-. 0.2.degree. 12.1 .+-. 0.2.degree. 8.9
.+-. 0.2.degree. 11.3 .+-. 0.2.degree. 11.4 .+-. 0.2.degree. 14.7
.+-. 0.2.degree. 10.7 .+-. 0.2.degree. 17.2 .+-. 0.2.degree. 13.3
.+-. 0.2.degree. 20 .+-. 0.2.degree. 14.4 .+-. 0.2.degree. 21.8
.+-. 0.3.degree.
[0472] It is noted that as used herein, the term "TPI-336" refers
to celecoxib or a celecoxib salt depending on the context.
* * * * *