MEDICAMENT THAT IS INTENDED FOR ORAL ADMINISTRATION,
COMPRISING A CYCLOOXYGENASE-2 INHIBITOR, AND
PREPARATION METHOD THEREOF
The present invention relates to a medicament that is
intended for oral administration, which comprises a
cyclooxygenase-2 inhibitor and which has an improved'
bioavailability, and to a process for preparing this
medicament.
In a known manner, many active principles used in
medicaments that are administered orally, such as antiinflammatories,
have the drawback of being formed from
solid particles that are not very soluble in aqueous
media, which adversely affects the oral bioavailability
of these medicaments.
On that subject, mention may especially be made of the
active principles having a therapeutic and/or
prophylactic anti-inflammatory effect belonging to the
family of cyclooxygenase-2 inhibitors including, in a
nonlimiting manner, a large number of substituted
pyrazolyl benzenesulfonamides, such as celecoxib and
deracoxib (see Patent document US-A-5 466 823),
substituted isoxazolyl benzenesulfonamides, such as
valdecoxib (see document US-A-5 633 272), (methylsulfonyl)
phenyl furanones, such as rofecoxib (see
documents US-A-5 Al A 995 and US-A-5 981 576),
substituted pyridines, such as etoricoxib (see document
US-A-5 8 61 419) , 2-(3,5-difluorophenyl)-3-[ 4-(methylsulfonyl)
phenyl]-2-cyclopentene-l-one (see document EPA-
863 134), benzopyranes (see document US-A-6 034 256),
substituted pyridazinones (see document WO-A-00/24719)
and imidazoles such as cimicoxib (see document
EP-B-1 122 243) .
Document EP-B-1 122 243 presents, on page 11, a
medicament that is intended for oral administration,
for example in the form of a tablet, which comprises in
its core a cyclooxygenase-2 inhibitor of imidazole type
mixed with an inert diluent, a binder and a lubricant,
and an outer film provided to delay the disintegration
and absorption of the medicament until the gastrointestinal
area of the body. This outer film may be
based on sugar, gelatin, hydroxypropyl cellulose or an
acrylic resin.
Given that the absorption of these active principles in
the digestive tract is limited, the therapeutic dose to
be administered must be increased to overcome this
drawback. This is the reason why recently it has been
sought to improve the bioavailability of these
inhibitors for one and the same administration dose.
One of the simplest ways of improving the bioavailability
is to increase the solubility of the
active principle. This parameter may be modified in
various ways, by addition of solubilizing agents,
surfactants, cyclodextrin, hydrophilic polymers, or
else by modifying the structure of the inhibitor
particles and by using solid dispersion techniques.
Document WO-A-03/030876 presents a medicament that is
intended for oral administration in the form of a
tablet that disintegrates in the mouth, which comprises
an aqueous dispersion of valdecoxib grains by way of
cyclooxygenase-2 inhibitor, these grains being mixed
with one or more excipients such as saccharides which
are present in the majority in the medicament, to
obtain a liquid that is dried by spray drying.
A major drawback of these orally administered
medicaments that comprise a cyclooxygenase-2 inhibitor
lies especially in their bioavailability that is
relatively unsatisfactory and varies from one
individual to another.
One object of the present invention is to overcome this
drawback, and this object is achieved as the Applicant
has just surprisingly discovered that spraying inert
solid particles based on at least one excipient with a
solution or suspension of micronized grains of a cyclooxygenase-
2 specific inhibitor in at least one
hydrophilic polymer makes it possible to obtain a
medicament that is intended for oral administration and
that has an improved bioavailability, in comparison
with that of medicaments of the prior art, that
incorporate a cyclooxygenase-2 inhibitor, such as
cimicoxib, this medicament according to the invention
comprising an agglomerate of said solid particles that
are agglomerated by the product of spraying this
solution or suspension.
According to the invention, this cyclooxygenase-2
specific inhibitor is composed of at least one compound
as described in the aforementioned Patent document
EP-B-1 122 243 and preferably corresponding to the
formula {1} below, or else to that of a salt or solvate
of this compound:
where:
one of the components X and Y represents N and the
other represents C;
Ri represents a hydrogen, methyl, halogen, cyano,
nitro, -CHO, -COCH3 or -COOR,, group;
R2 represents an aryl or heteroaryl group
optionally substituted by one or more groups chosen
independently from halogen, Ci-e alkyl, Cj-a haloalkyl.
FUOCVe alkyl, R4SC0-8 alkyl, cyano, nitro, -NR4R6,
-NR4SO2R5, -SOR5, -SO2R5- -S02NR4R6, or -CONR„R6 groups;
R3 represents a Ci_8 alkyl, Ci-8 haloalkyl or -NR4R6
group;
R4 represents a hydrogen, Ci_e alkyl or C0-9 alkyl
aryl group (where the aryl group may optionally be
substituted by one or more groups chosen from Ci-a
alkyl, halogen, Ci-3 haloalkyl, cyano, nitro, R7OC0-8
alkyl, R7SC0-8 alkyl, -NR7R8, -NR7COR5, -COR7 or -COOR7
groups);
R5 represents a Ci-s alkyl or Ci-8 haloalkyl group;
Re represents a hydrogen, Ci-8 alkyl, aryl Ci-e
alkyl (where the aryl group may optionally be
substituted by one or more groups chosen from Ci-8
alkyl, halogen, Ci-8 haloalkyl, cyano, nitro, R7OC0-a
alkyl, R7SC0-8 alkyl, -NR7Ra, -NR7COR5/ -COR7 or -COOR7
groups), -CORg or -COORg group;
R7 represents a hydrogen, Ci-s alkyl or benzyl
group;
Ra represents a Ci-a alkyl or Ci-e haloalkyl group;
the aryl group in the definitions above represents
a phenyl or naphthyl group; and
the heteroaryl group in the definitions above
represents a pyridine, pyrazine, pyrimidine or
pyridazine group, which may optionally be fused to a
benzene ring.
Even more preferably, by way of cyclooxygenase-2
inhibitor, at least one imidazole, such as cimicoxib,
is used that corresponds in a known manner to the
formula (II) below:
- sr-
According to one advantageous feature of the invention,
said solid particles of excipient(s) are soluble or
dlspersible in an aqueous medium. Generally, these
particles of excipient(s) are hydrophilic, possibly
being of crystalline or amorphous structure.
Preferably, by way of excipient(s), water-soluble or
water-dispersible particles are used which are chosen
from the group consisting of sugars, preferably lactose
or saccharose, starch hydrolysates such as maltodextrin,
microcrystalline cellulose, sorbitols and
mixtures of several of these compounds.
Even more preferably, said solid particles comprise, in
addition, at least one acid that is mixed with said
excipient(s), such as, preferably, citric acid, or else
tartaric acid or fumaric acid, which makes it possible
to increase the solubility of said inhibitor in the
body.
According to one main feature of the invention, said
agglomerate is capable of being obtained by wet
granulation in a device, such as a fluidized air bed.
Preferably, said agglomerate according to the invention
specifically comprises the product of spraying said
solid particles with a solution of said inhibitor in
said hydrophilic polymer(s). Indeed, the Applicant has
been able to prove that, unexpectedly, dissolving said
inhibitor in this or these polymer or polymers gives
the medicament according to the invention a
bioavailability that is further improved in comparison
with that given by suspending the same inhibitor in the
same hydrophilic polymer(s).
These micronized grains of said inhibitor are
preferably such that around 90% of them have a largest
dimension in cross section which is less than 20 um.
?
- Jer-
Preferably, said or at least one of said hydrophilic
polymer(s) is chosen from the group consisting of
polyvinylpyrrolidones, polyethylene glycols or
macrogols, polyvinyl alcohols, cellulose polymers such
as hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, hydroxymethyl cellulose and carboxymethyl
cellulose, methacrylic copolymers, starch, dextrins,
gelatin and blends of several of these polymers.
Even more preferably, said or at least one of said
hydrophilic polymer(s) is chosen from the group
consisting of polyvinylpyrrolidones and polyethylene
glycols or macrogols.
Even more preferably still, at least one polyethylene
glycol or macrogol is used having a weight-average
molecular weight MH ranging from 190 to 9000 g/mol and,
even more preferably, ranging from 250 to 600 g/mol and
advantageously from 285 to 420 g/mol.
According to one particularly advantageous embodiment
of the invention, as hydrophilic polymers, a blend of
said polyethylene glycol or macrogol and a
polyvinylpyrrolidone having a weight-average molecular
weight Mw ranging from 2000 to 1 000 000 g/mol,
preferably ranging from 5000 to 55 000 g/mol, is used.
According to another advantageous feature of the
invention, said product of spraying the solution or
suspension of said inhibitor in said polymer(s)
comprises, in addition, at least one amphoteric, ionic
(i.e. anionic or cationic) or nonionic surfactant.
As a surfactant that can be used, mention may, for
example, be made nonlimitingly of:
sodium lauryl sulfate;
polyethoxylated sorbitan esters, or
polysorbates; and
poloxamers.
- *--
It is also possible to use mixtures of several of these
surfactants. Preferably, sodium lauryl sulfate is used
as the surfactant.
According to another advantageous feature of the
invention, said agglomerate comprises said inhibitor
according to a weight fraction ranging from 1% to 20%
and, preferably, ranging from 3% to 10%.
Advantageously, said agglomerate comprises said
excipient(s) according to a weight fraction ranging
from 10% to 80% and, preferably, ranging from 30% to
75%.
Also advantageously, said agglomerate comprises said
hydrophilic polymer(s) according to a weight fraction
ranging from 3% to 30% and, preferably, ranging from
12% to 25%.
Also advantageously, the weight fraction of said
surfactant(s) in said agglomerate varies from 0.1% to
6%.
According to another feature of the invention, said
medicament may optionally comprise at least one outer
layer covering said particle agglomerate and comprising
compatible additives chosen from the group consisting
of disintegrating agents, fillers, pigments,
flavorings, surfactants, humectants, lubricants and
mixtures of several of these additives.
The medicament according to the invention may comprise
said outer layer(s) according to a weight fraction
ranging from 0% to 80% and, preferably, ranging from
10% to 50%.
Advantageously, the medicament according to the present
invention is composed of a solid dosage in granule or
?
- -&--
tablet form, preferably obtained by compressing said
particle agglomerate that optionally compresses said
outer layer(s), or else in a solid form which contains
said agglomerate in powdered form, which is packaged in
an immediate container, such as a capsule, a gelatin
capsule, a sachet or a vial.
Tests have shown that the medicaments according to the
invention, in the form of a tablet containing 30 mg of
cimicoxib, are at least 90% dissolved after 30 minutes
in a medium based on around 0. IN HC1 (+ 0.15% sodium
lauryl sulfate).
Other tests have shown that the medicaments according
to the invention, in the form of a tablet containing
10 mg or even 5 mg of cimicoxib, are at least 65%
dissolved after 15 minutes in a medium based on
0.IN HC1.
A process for preparing a medicament according to the
invention, as defined previously, comprises the
following successive steps:
{i) preparing a sprayable liquid based on
micronized grains of said specific (cf. formula {I)
above) cyclooxygenase-2 inhibitor, especially an
imidazole such as cimicoxib, which are in solution or
in suspension in at least one hydrophilic polymer;
(ii) spraying said liquid, in a granulator, onto
inert solid particles based on at least one excipient
designed to be compatible with said inhibitor, to
obtain, by wet granulation, a particle agglomerate
comprising the product of spraying the solution or
suspension of said grains;
(iii) optionally compressing the particle
agglomerate obtained in (ii); and
(iv) optionally covering the agglomerate obtained
in (ii) or in (iii) with at least one outer layer
comprising compatible additives chosen from the group
consisting of disintegrating agents, fillers, pigments,
flavorings, surfactants, humectants, lubricants and
mixtures of several of these additives.
According to one preferred feature of the invention,
said granulator used in step (ii) is of the fluidized
air bed type.
According to one embodiment of the invention, in order
to implement this wet granulation a fluidized air bed
granulator is used operating at a relative pressure
approximately ranging from 1 bar to 1.5 bar, with a hot
air inlet temperature in this granulator ranging from
40 to 75°C and a temperature of the solid particles
ranging from 30 to 50°C.
Preferably, the step (i) is specifically implemented by
completely dissolving said inhibitor in said
hydrophilic polymer{s) , to obtain an improved
bioavailability for the medicament according to the
invention.
It should be noted that the medicaments according to
the invention can be used for therapeutic and/or
prophylactic treatment of diverse inflammations of a
human or animal body, or for any other dysfunction of
this body that is caused by cyclooxygenase-2.
The aforementioned features of the present invention,
and also others, will be better understood when reading
the following description of several embodiments of the
invention, given by way of illustration and being
nonlimiting.
CONTROL EXAMPLE
A "control" medicament that did not conform to the
invention was prepared comprising a tablet of
conventional formula composed of:
w
- 13- -
a core based on a mixture of solid particles of
cimicoxib and lactose;
a granulation liquid containing purified water
and a surfactant based on a polysorbate according to a
weight fraction of 0.40%, to agglomerate said
particles; and
an outer layer formed from a mixture of a
disintegrating agent, a flavoring and a lubricant
composed of magnesium stearate.
More specifically, the formulation of this "control"
medicament was the following, per 100 g:
Active principle: cimicoxib 8.0 g
Croscarmellose sodium 5.0 g
Pregelatinized starch 15.0 g
Polysorbate 0.40 g
Lactose monohydrate 68.10 g
Appetent 3.0 g
Magnesium stearate 0.5 g
This "control" particle agglomerate was prepared by wet
granulation in a high-shear granulator, and the
particle agglomerate obtained was converted to a
"control" tablet by the technique known to a person
skilled in the art.
This "control" tablet contained 30 mg of cimicoxib.
EXAMPLE 1 ACCORDING TO THE INVENTION
A first medicament according to the invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying a suspension
according to the invention, and which is, in addition,
provided with an outer layer.
I I .
- Mr -
This agglomerate was composed of a pharmaceutical
composition of the following formulation (as weight
fractions, outer layer excluded):
Substrate:
lactose particles 72.90%
Liquid to be sprayed in the
form of a suspension:
micronized grains of cimicoxib 8.74%
polyvinylpyrrolidone PVP "K25" 13.11%
polyethylene glycol PEG "400" 1.96%
sodium lauryl sulfate 3.28%
The outer layer covering the particle agglomerate had
the following formulation {in grams}:
Disintegrating agent "acdisol" 5 g
Flavoring 3 g
Lubricant (magnesium stearate) 0.5 g
As a first step, the sprayable liquid based on
cimicoxib was prepared as follows. Firstly, the
hydrophilic polymer PVP was dispersed with stirring.
When a clear solution was obtained, the other
hydrophilic polymer PEG was added. Added slowly to the
solution thus obtained was the micronized active
principle (cimicoxib) that was then mixed with stirring
for 30 minutes. Finally, the lauryl sulfate was added
with stirring for 3 minutes.
In a second step, the suspension of cimicoxib thus
obtained was sprayed in a fluidized air bed granulator
over the inert heated particles of the substrate
(composed of lactose), under the following conditions
established for a batch of 300 g:
Relative spraying pressure 1 bar
Hot air inlet temperature 60°C
Air outlet temperature 33°C
Particle temperature 34°C
Spraying duration 36 minutes.
- is- -
Next, the granule or particle agglomerate thus obtained
was converted to a tablet, by covering it with the
aforementioned outer layer, or else it was placed
inside a capsule, by using in either case the
techniques known to a person skilled in the art to
obtain a suitable dosage.
In order to convert each granule to a tablet and with
reference to a batch of 100 g, 91.5 g of the granule
obtained was mixed with 8.5 g of the outer layer
composition described above, using, for example, a
mixer of the planetary mixer type or a tumble mixer.
It should be noted that this tablet may be obtained
using a reciprocating or else rotary tableting machine.
EXAMPLE 2 ACCORDING TO THE INVENTION
A second medicament according to the invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying another
suspension according to the invention, and which is, in
addition, provided with an outer layer.
This agglomerate was composed of a pharmaceutical
composition of the following formulation (as weight
fractions, outer layer excluded):
Substrate:
lactose particles 61.97%
Liquid to be sprayed in the
form of a suspension:
micronized grains of cimicoxib 8.74%
polyvinylpyrrolidone PVP "K25" 21.86%
polyethylene glycol PEG "400" 1.97%
sodium lauryl sulfate 5.46%
- 4^- -
The outer layer covering the particle agglomerate had
the same formulation as in Example 1.
The sprayable liquid, the particle agglomerate
incorporating it and the tablet finally obtained from
this agglomerate were prepared using the process
described in Example 1, except for the hot air outlet
temperature which was between 33 and 38aC and the
particle temperature which was between 45 and 50°C.
By way of indication, the solubility SO of the
cimicoxib powder alone and the solubility 32 of the
particle agglomerate according to this second example
of the invention were measured by the HPLC (high
performance liquid chromatography) technique and in an
approximately 0.1N HC1 medium, with the following
results (solubilities in milligrams/liter}:
SO = 3.1 mg/1 and S2 = 26.8 mg/1.
This result shows that the particle agglomerate
according to this second example of the invention has a
greatly improved solubility in acid medium.
The tablet according to this second embodiment of the
invention contained 30 mg of cimicoxib.
EXAMPLE 3 ACCORDING TO THE INVENTION
A third medicament according to ;he invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying another
suspension according to the invention, and which is, in
addition, provided with an outer layer.
This agglomerate was composed of a pharmaceutical
composition of the following formulation (as weight
fractions, outer layer excluded):
- W -
Substrate:
lactose particles 53.02%
citric acid 16.39%
sodium lauryl sulfate 2.73%
Liquid to be sprayed in the
form of a suspension:
micronized grains of cimicoxib 8.74%
polyvinylpyrrolidone PVP "K25" 13.11%
polyethylene glycol PEG "400" 3.28%
sodium lauryl sulfate 2.73%
The outer layer covering the particle agglomerate had
the same formulation as in Example 1.
The sprayable liquid, the particle agglomerate
incorporating it and the tablet finally obtained from
this agglomerate were prepared by using the process
described in Example 1, except that:
citric acid and sodium lauryl sulfate (in the
same amount as in the sprayable liquid) were
incorporated into the preheated substrate; and
the hot air outlet temperature was between 33
and 38°C and the particle temperature was between 45
and 50°C.
The tablet according to this third embodiment of the
invention contained 30 mg of cimicoxib.
EXAMPLE 4 ACCORDING TO THE INVENTION
A fourth medicament according to the invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying another
suspension according to the invention, and which is, in
addition, provided with an outer layer.
it
- 1-5 -
This agglomerate was composed of a pharmaceutical
composition of the following formulation (as weight
fractions, outer layer excluded):
Substrate:
lactose particles 57.61%
citric acid 16.39%
sodium lauryl sulfate 2.73%
Liquid to be sprayed in the
form of a suspension:
micronized grains of cimicoxib 4.37%
polyvinylpyrrolidone PVP "K25" 13.11%
polyethylene glycol PEG MOO" 3.06%
sodium lauryl sulfate 2.73%
The outer layer covering the particle agglomerate had
the same formulation as in Example 1.
The sprayable liquid, the particle agglomerate
incorporating it and the tablet finally obtained from
this agglomerate were prepared by using the exact same
process as described in Example 3.
EXAMPLE 5 ACCORDING TO THE INVENTION
A fifth medicament according to the invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying a solution
according to the invention, but which was free of an
outer layer, contrary to the Examples 1 to 4.
This agglomerate was composed of a pharmaceutical
composition of the following formulation (in weight
fractions}:
Substrate:
lactose particles 59.80%
Microcrystalline cellulose 6.65%
0
- *e- -
Liquid to be sprayed in the
form of a solution:
micronized grains of cimicoxib 3.30%
polyethylene glycol PEG "400" 30.25%
As a first step, the liquid to be sprayed was prepared
as follows. Added slowly to a solution of PEG "400"
were the micronized grains of the active principle
(cimicoxib) , that were then mixed with stirring for 20
minutes. A solution of cimicoxib in this PEG was
obtained.
As a second step, the solution thus obtained was
sprayed in a fluidized air bed granulator, onto the
heated inert substrate particles {composed of lactose
with the addition of microcrystalline cellulose), under
the following conditions established for a batch of
200 g:
Relative spraying pressure 1.5 bar
Hot air inlet temperature 70 °C
Air outlet temperature 33°C
Particle temperature 34 to 45°C
Spraying duration 17 minutes
By way of indication, the solubility S5 of this
particle agglomerate according to this fifth example of
the invention was compared to the solubility SO of the
cimicoxib powder alone by the HPLC technique and in an
approximately 0.IN HC1 medium, with the following
results (milligrams/liter):
SO = 3.1 mg/1 and S5 - 23.9 mg/1.
This result shows that the granule or particle
agglomerate according to this fifth example of the
invention has a greatly improved solubility in acid
medium.
I *
- &- -
This granule was then packaged directly inside a
gelatin capsule.
EXAMPLE 6 ACCORDING TO THE INVENTION
A sixth medicament according to the invention was
prepared based on a particle agglomerate which
comprised a substrate, based on solid particles
agglomerated by the product of spraying a solution
according to the invention, but which was free of an
outer layer, contrary to the Examples 1 to 4.
This agglomerate was composed of a pharmaceutical
composition of the following formulation (in weight
fractions):
Substrate:
lactose particles 62.55%
Microcrystalline cellulose 6.95%
Liquid to be sprayed in the
form of a solution:
micronized grains of cimicoxib 3.00%
polyethylene glycol PEG 'MOO" 27.50%
This particle agglomerate was obtained by implementing
the exact same process described above in Example 5.
This granule was then packaged directly inside a
gelatin capsule.
MEASUREMENTS OF THE BIOAVAILABILITY OF THE "CONTROL"
MEDICAMENT AND OF SEVERAL MEDICAMENTS ACCORDING TO THE
INVENTION
Administered orally to four dogs (two males and two
females), all of the "Beagle" breed, were: the
"control" tablet, the second and third tablets
according to the invention and the gelatin capsule
according to the fifth example of the invention,
11
- J * -
respectively obtained in the Examples "control", 2, 3
and 5 above. Each dog thus received the same dose of
30 mg of cimicoxib during the ingestion of these four
types of formulations, while spacing each
administration over a minimum time interval of 6 days.
Blood samples relating to each tablet or gelatin
capsule administered to each of the four dogs were
collected, at various times following each
administration of these pharmaceutical forms, in order
to carry out an analysis of the bioavailability of
these products in terms of concentration Cmax (plasma
level of cimicoxib, in ug/ml) and of the area under the
curve (AUC in ug.h/ml, calculated over 10 hours). These
collection times (expressed in hours) were the
following:
0; 0.25 h; 0.5 h; 0.75 h; 1 h; 1.5 h; 2 h; 3 h;
4 h; 5 h; 6 h; 8 h; 10 h; 24 h; 32 h; 48 h.
Table 1 below gives the average results obtained for
the "control" tablet, the second and third tablets
according to the invention and the gelatin capsule
according to the fifth example of the invention
administered to all four dogs.
Table 1:
Tablets tested
"Control" tablet
Second tablet of the
invention
Third tablet of the
invention
Gelatin capsule
according to the
fifth example of the
invention
Tmax (h)
2.13
2.76
2.00
1.33
t-max
(ug/ml)
0.2825
0.62 7 9
0.6215
1.648
"AUC" (pg.h/ml,
over 10 h)
1.341
2. 606
2.355
5.938
20
- ir9- -
This table shows that the medicaments according to the
invention have an assimilation in the body (i.e. a
bioavailability) that is greatly improved relative to
that of the "control" tablet, as is shown by the higher
values of the concentration Cmax and of the "AUC" area.
This table also shows that spraying a cyclooxygenase-2
inhibitor specifically in the form of a solution (i.e.
dissolved in the hydrophilic polymer(s)) on the solid
particles of the inert substrate further improves the
bioavailability of the medicaments according to the
invention by oral means.

CLAIMS
1. A medicament that is intended for oral
administration and that has an improved bioavailability,
said medicament comprising an agglomerate
based on inert solid particles that are based on at
least one excipient, said agglomerate comprising a
cyclooxygenase-2 inhibitor and at least one hydrophilic
polymer, characterized in that said agglomerate
comprises the product of spraying said particles with a
solution or suspension of micronized grains of said
inhibitor in said polymer(s) in order to agglomerate
said particles, and in that said inhibitor is composed
of at least one compound of formula {1} below cr else a
salt or solvate of this compound:
where:
one of the components X and Y represents tJ and the
other represents C;
Ri represents a hydrogen, methyl, halogen, cyano,
nitro, -CHO, -COCH3 or -COOR4 group;
R2 represents an aryl or heteroaryl group
optionally substituted by one or more groups chosen
independently from halogen, Ci-8 alkyl, Ci-e h^loalkyl,
R4OC0-8 alkyl, R4SC0-8 alkyl, cyano, nitro, -NR4Re,
-NR4SO2R5, -SOR5, -SO2R5, -SO2NR4R6, or -CONR^Rs groups;
R3 represents a C^s alkyl, Ci-e haloalkyl or -NR4R6
group;
R4 represents a hydrogen, Ci-a alkyl or Cos alkyl
aryl group (where the aryl group may optionally be
substituted by one or more groups chosen from Ci_8
alkyl, halogen, C! e haloalkyl, cyano, nit ro, R7OC0-s
alkyl, R7SC0-e alkyl, -NR7RB, -NR7COR5, -COR7 or -COOR7
groups);
R5 represents a Ci-a alkyl or Ci_s haloalkyl group;
R6 represents a hydrogen, Ci-e alkyl, aryl Ci_B
alkyl (where the aryl group may optionally be
substituted by one or more groups chosen from Ci_e
alkyl, halogen, Ci-a haloalkyl, cyano, nitro, R7OC0-8
alkyl, R7SC0-e alkyl, -NR7R8, -NR7COR5, -COR7 or -COOR7
groups), -CORa or -COOR8 group;
R7 represents a hydrogen, Ci_8 alkyl or benzyl
group;
Rs represents a Ci-a alkyl or Ci-e haloalkyl group;
the aryl group in the definitions above represents
a phenyl or naphthyl group; and
the heteroaryl group in the definitions above
represents a pyridine, pyrazine, pyrimidine or
pyridazine group, which may optionally be fused to a
benzene ring.
2. The medicament as claimed in claim 1,
characterized in that said inhibitor is composed of at
least one imidazole, such as cimicoxib.
3. The medicament as claimed in claim 1 or 2,
characterized in that said agglomerate is capable of
being obtained by wet granulation in a device, such as
a fluidized air bed.
4. The medicament as claimed in one of the preceding
claims, characterized in that said agglomerate
comprises the product of spraying a solution of said
inhibitor in said polymer(s).
5. The medicament as claimed in one of the preceding
claims, characterized in that said particles of
excipient(s) are soluble or dispersible in an aqueous
medium.
6. The medicament as claimed in one of the preceding
claims, characterized in that said agglomerate
comprises said inhibitor according to a weight fraction
ranging from 1% to 20%.
7. The medicament as claimed in claim 6,
characterized in that said agglomerate comprises said
inhibitor according to a weight fraction ranging from
3% to 10%.
8. The medicament as claimed in claim 6 or 7,
characterized in that said agglomerate comprises said
excipient(s) according to a weight fraction ranging
from 10% to 80%.
9. The medicament as claimed in claim 8,
characterized in that said agglomerate comprises said
excipient(s) according to a weight fraction ranging
from 30% to 75%.
10. The medicament as claimed in one of claims 6 to 9,
characterized in that said agglomerate comprises said
hydrophilic polymer{s) according to a weight fraction
ranging from 3% to 30%.
11. The medicament as claimed in claim 10,
characterized in that said agglomerate comprises said
hydrophilic polymerfs) according to a weight fraction
ranging from 12% to 25%.
12. The medicament as claimed in one of the preceding
claims, characterized in that said or at least one of
said hydrophilic polymer(s) is chosen from the group
consisting of polyvinylpyrrolidones, polyethylene
glycols or macrogols, polyvinyl alcohols, cellulose
polymers such as hydroxypropylmethyl cellulose,
hydroxypropyl cellulose and carboxymethyl cellulose,
methacrylic copolymers, starch, dextrins, gelatin and
blends of several of these polymers.
13. The medicament as claimed in claim 12,
characterized in that said or at least one of said
hydrophilic polymer(s) is chosen from the group
consisting of polyvinylpyrrolidones and polyethylene
glycols or macrogols.
14. The medicament as claimed in claim 13,
characterized in that said or at least one of said
polyethylene glycol (s) or macrogol(s) has a weightaverage
molecular weight Mw ranging from 190 to
9000 g/mol.
15. The medicament as claimed in claim 14,
characterized in that said or at least one of said
polyethylene glycol(s) or macrogol(s) has a weightaverage
molecular weight Mw ranging from 250 to
600 g/mol.
16. The medicament as claimed in one of claims 13 to
15, characterized in that said hydrophilic polymers
comprise a blend of said polyethylene glycol or
macrogol and a polyvinylpyrrolidone having a weightaverage
molecular weight MH ranging from 2000 to
1 000 000 g/mol.
17. The medicament as claimed in claim 16,
characterized in that said polyvinylpyrrolidone has a
weight-average molecular weight Mw ranging from 20 000
to 55 000 g/mol.
18. The medicament as claimed in one of the preceding
claims, characterized in that said product of spraying
the solution or suspension of said inhibitor in said
polymer(s) comprises, in addition, at least one
amphoteric, ionic or nonionic surfactant, the weight
fraction of said surfactant(s) in said agglomerate
ranging from 0.1% to 6%.
19. The medicament as claimed in claim 18,
characterized in that said surfactant is sodium lauryl
sulfate.
20. The medicament as claimed in one of the preceding
claims, characterized in that said excipient(s)
comprises or comprise water-soluble or waterdispersible
inert particles which are chosen from the
group consisting of sugars, preferably lactose or
saccharose, starch hydrolysates such as maltodextrin,
microcrystalline cellulose, sorbitols and mixtures of
several of these compounds.
21. The medicament as claimed in one of the preceding
claims, characterized in that said agglomerate
comprises, in addition, at least one acid that is mixed
with said particles of excipient(s), such as citric
acid, tartaric acid or fumaric acid.
22. The medicament as claimed in one of the preceding
claims, characterized in that it comprises at least one
outer layer covering said agglomerate and comprising
compatible additives chosen from the group consisting
of disintegrating agents, fillers, pigments,
flavorings, surfactants, humectants, lubricants and
mixtures of several of these additives.
23. The medicament as claimed in one of the preceding
claims, characterized in that it is composed of said
agglomerate of solid particles being in the form of a
powder packaged in an immediate container, or else in
the form of a tablet.
24. A process for preparing a medicament as claimed in
one of the preceding claims, characterized in that it
comprises the following successive steps:
(i) preparing a sprayable liquid based on
micronized grains of said cyclooxygenase-2 inhibitor,
especially an imidazole such as cimicoxib, which are in
solution or in suspension in at least one hydrophilic
polymer;
(ii) spraying said liquid, in a granulator, onto
inert solid particles based on at least one excipient
designed to be compatible with said inhibitor, to
obtain, by wet granulation, a particle agglomerate
comprising the product of spraying the solution or
suspension of said grains;
(iii) optionally compressing the particle
agglomerate obtained in (ii); and
(iv) optionally covering the agglomerate obtained
in (ii) or in (iii) with at least one outer layer
comprising compatible additives chosen from the group
consisting of disintegrating agents, fillers, pigments,
flavorings, surfactants, humectants, lubricants and
mixtures of several of these additives.
25. The process as claimed in claim 24, characterized
in that said granulator is of the fluidized air bed
type.
26. The process as claimed in claim 24 or 25,
characterized in that the hot air inlet temperature in
said granulator is between 40°C and 75°C.
27. The process as claimed in one of claims 24 to 26,
characterized in that the temperature of said solid
particles in said granulator is between 30°C and 50°C.
28. The process as claimed in one of claims 24 to 27,
characterized in that the step (i) is implemented by
completely dissolving said inhibitor in said
polymer(s).