SOLID PHARMACEUTICAL FIXED DOSE COMPOSITIONS COMPRISING IRBESARTAN AND
AMLODIPINE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FIELD OF THE INVENTION
the present invention is directed to solid stable pharmaceutical fixed dose
compositions comprising irbesartan, amlodipine besilate and pharmaceutically
acceptable excipients, to their preparation and to their therapeutic application.
BACKGROUND OF THE INVENTION.
Amlodipine is a calcium channel blocker developed for the treatment of
hypertension and other medical indications as disclosed in USP 4,572,909 and USP
4,879,303. Its chemical name is 3-ethyl-5-methyl-(+-)-2-[(2-aminoethoxy)methyl]-4-
(2-chorophenyl)-1,4,4-dmydro-6-memylpyridine-3,5-dicarboxylate.
Amlodipine is marketed as the monobenzenesulfonate salt, amlodipine besylate
under the trade name Norvasc® or Istin®. It is available as oral tablets in strengths of
2.5 mg, 5 mg and 10 mg. The inactive ingredients in the Norvasc® tablets include
microcrystalline cellulose, dibasic calcium, phosphate anhydrous, sodium starch
glycolate and magnesium stearate.
Amlodipine besylate is slightly soluble in water and has an absolute
bioavailability of 64-90%.
Irbesartan is described in Bernhart et al., U.S. Patent No. 5,270,317,
incorporated herein by reference.
Irbesartan, is a potent, long-acting angiotensin LT receptor antagonist which is
particularly useful in the treatment of cardiovascular ailments such as hypertension
and heart failure. Its chemical name is2-n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-
5-yl)biphenyM-yl)memyl]-2-imidazolin-5-one.
Irbesartan is marketed by under the trade name Aprovel® or Karvea®.
Irbesartan is insoluble in water. Irbesartan has a parabolic pH solubility profile
in aqueous medium with minimum, solubility between pH 2.0 and 6.0 and maximum
solubility in 0.1 N HC1 and pH 7.5 phosphate buffer.
It is often desirable to combine multiple active ingredients in a single
pharmaceutical composition. Inclusion of multiple ingredients in a single composition
generally reduces costs and provides the convenience of consuming a single
medication rather than multiple medications for treating individual symptoms.
However, a combination of active ingredients is not without drawbacks.
Certain physical properties of the drugs and specifically stability, present a
challenge in developing formulations suitable for preparing a tablet having reduced
levels of total impurities on long term stability.
Irbesartan is, for example, a fluffy material, with relatively low bulk and tap
densities. It is also a sticky and abrasive material.
These properties make it difficult to formulate an effective amount of the drug
into a small tablet with uniformity of weight, hardness, and other desirable tablet
properties. In addition, irbesartan has certain undesirable flow characteristics, for
example, is sticky and can adhere to surfaces such as tablet punch faces and dies,
causing problems in tableting, especially on a high speed tablet press.
The very low aqueous solubility of irbesartan also presents a challenge, since
only limited amounts of excipients may be adaed to facilitate wetting, disintegration,
and ultimately, rapid and complete drug release.
The addition of a second active ingredient such as amlodipine besilate, which is
also a fluffy material exhibiting poor flow and low aqueous solubility, can further
contribute to problems such as tableting or uniformity of dosage units.
In addition, the stability of a composition might be compromised due to
incompatibility of an active with an essential excipient or even between a second
active itself.
Concerning formulations containing Amlodipine besilate alone, WO
2006/059217 discloses that amlodipine is highly hygroscopic and absorbs moisture,
which leads to degradation. One of the major routes of degradation is via a catalytic
oxidative process, which is pH dependent. One of the major degradation products
known in the art is 3-emyl-5-memyl-2-[(2-arrimoemoxy)methyl]-4-(2-chlorophenyl)-
6- methylpyridine-3,5-dicarboxylate and called Impurity D.
WO2003/051364 discloses Amlodipine besilate tablets with improved stability
of the active ingredient and reduced in weight containing microcrystalline cellulose, a
lubricant and a disintegrating agent and the process for the preparation of said tablets.
WO2008/062435 discloses a stable solid dosage form of amlodipine besylate
comprising polyols and having reduced levels of total impurities on stability and
especially impurity D.
Concerning formulations containing Irbesartan, EP747050 from Sanofi discloses
pharmaceutical composition under tablets comprising Irbesartan alone or in
combination with a diuretic compound such as Hydrochlorothiazide (HCTZ) prepared
by a process comprising mixing an extragranular composition with granules
comprising either irbesartan alone or the two active principles in the presence of
lactose and an antiadherent such as silicon dioxide. No problem of stability is raised.
WO2005/070762 from Sepracor discloses oral formulation under capsules
comprising the combination of S-amlodipine and Irbesartan obtained by simple
mixing about 25wt% of the two active principles together in the presence of corn
starch and about 65wt% of lactose. No problem of stability is raised.
Thus, there is no known stable solid dosage form comprising the specific
combination of Irbesartan and Amlodipine besilate.
In addition to stability, when formulating solid fixed dose combination, the
objective is to provide a patient-convenient combination dosage form of active
ingredients that is bioequivalent to the corresponding free-combination of the same
active ingredients.
As used herein, "fixed-dose-combination or FDC" refers to a combination of
two drugs or active ingredients presented in a single dosage unit such as a tablet or
oral dosage form.
Further as used herein, "free- combination" refers to a combination of two drugs
or active ingredients dosed simultaneously but as two dosage units.
As a result of these complex biopharmaceutical properties, development of a
fixed-combination dosage form of irbesartan and amlodipine besilate that is
bioequivalent to a free-combination thereof is challenging.
Accordingly, a fixed-combination solid dosage formulation of Irbesartan and
amlodipine besilate that is stable and bioequivalent to the corresponding free-
combination would be desirable.
One other challenge faced is homogenity of Amlodipine in a lubricated blend as
the content of Amlodipine in the total tablet weight should be very low compared to
the high amount of irbesartan .
The object of the present invention is to alleviate at least partly the above
mentioned drawbacks.
SUMMARY OF THE INVENTION
This object is achieved with a stable solid oral pharmaceutical fixed dose
composition comprising irbesartan, amlodipine besilate and pharmaceutically
acceptable excipients, wherein irbesartan is physically separated from amlodipine
besilate.
This solid dosage form is particularly advantageous since amlodipine besilate
does not undergo degradation and this combination product shows reduced and
controlled impurities even lesser than with regards to individual reference products of
same dose when subjected to stress studies and in finished pack.
In addition, the dissolution profile of both irbesartan and amlodipine besilate is
not compromised by comparison to the dissolution profile of each active ingredient
alone.
In a preferred embodiment, irbesartan under the form of coated granules is
embedded in an extragranular matrix comprising amlodipine besilate.
Preferably the solid composition of the invention takes the form of a monolayer
tablet, preferably film coated
Preferably, the tablet is further package in suitable packing material such as
PVC, PVC / PVdC, PVC / PE / PVdC.
In a preferred embodiment of the composition according to invention, the
irbesartan represents between about 20% and about 70% by weight of the total
composition.
In a preferred embodiment of the composition according to invention the
amlodipine besilate represents between about 1% and about 20% by weight of the
total composition.
In a preferred embodiment of the composition according to invention the
pharmaceutically acceptable excipients are selected from the group consisting of
diluent, disintegrant, antiadherent, binder lubricant and mixture thereof.
Preferably said solid composition is free of lactose.
In a preferred embodiment of the composition according to invention the
amount of Irbesartan is comprised between 150mg and 300mg of the total weight of
the tablet, preferably 300mg or 150mg.
In a preferred embodiment of the composition according to invention the
amount of amlodipine besilate is comprised between 5mg and 10mg of the total
weight of the tablet, preferably 7mg or 14mg.
rn a preferred embodiment of the composition according to invention the solid
composition is under the form of a tablet wherein the total weight of the tablet is
between 400mg and 600mg, preferably 500mg.
In a preferred embodiment the composition has less than 1.50%(w/w) of total
impurities for Amlodipine and less than 0.50%(w/w) of total impurities for Irbesartan
after 6 months at 40°C/75%RH.
According to another object, the invention is related to a process for the
preparation of a stable oral pharmaceutical composition comprising irbesartan and
amlodipine besilate, wherein the process comprises the steps of:
i. granulating irbesartan and one or more pharmaceutically acceptable
excipients, with, aqueous solution containing a binder, to form granules,
ii. drying the granules;
iii. separately blending amlodipine besilate with pharmaceutically acceptable
excipients,
iv. mixing the irbesartan granules of step ii with the amlodipine besilate blend
of step iii);
v. lubricating the blend of step iv); optionally after a pre-lubricating step; and
vi. compressing the mixture into tablets.
Preferably, the group of pharmaceutically acceptable excipients used in step I
and iii) of the process is free of lactose.
In a preferred embodiment of the process further comprises the step of coating
the tablet and packaging in suitable packing material such as PVC, PVC / PVdC, PVC
/PE/PVdC.
Preferably the pre-lubricating step comprises the mixing of the blend of step (iv)
during 10 to 25mn, preferably 20mn before doing the lubricating step.
According to another object, the invention is related to the use of Irbesartan and
amlodipine besilate in the manufacture of a medicament for the treatment of
hypertension wherein said medicament is in the stable solid fixed dose composition as
described above
Preferably, the use referred to a second line treatment for hypertensive patients
not sufficiently controlled using amlodipine as Calcium Chanel Blockers (CCB)
monotherapy or irbesartan as angiotensin II receptor antagonist (ARB).
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the dissolution profile of Irbesartan in routine media i.e. 0.1 N HC1.
Fig 2 shows the dissolution profile of amlodipine in routine media i.e. 0.1 N
HC1.
DETAILED DESCRIPTION OF THE INVENTION.
Preferred Irbesartan and Amlodipine besilate compositions.
The two actives are present in a single unit dosage form, such as tablets or
pellets, wherein irbesartan is physically separated from amlodipine besilate.
Pharmaceutically acceptable additives suitable for use in the present invention
with arnlodipine besylate are selected from suitable diluents such as microcryastalline
cellulose, di calcium phosphate and suitable lubricants such as magnesium stearate.
Pharmaceutically acceptable additives suitable for use in the present invention
with Irbesartan are selected from suitable diluents such as Microcrystalline cellulose,
suitable glidants such as silicone dioxide, suitable lubricants such as magnessium
sterate, suitable binders such as hypromellose.
In the composition of the invention, Amlodipine portion composition is similar
to the reference composition of Amlodipine formulation Norvasc® and Irbesartan
portion is similar to the reference composition of Approvel® except without Lactose
monohydrate.
In a preferred embodiment, the composition is free of lactose as diluent. Indeed
the absence of this excipient allows achieving best results in term of global stability of
amlodipine besilate and specifically lowering the amount of impurity D.
In a preferred form of the tablet, irbesartan is present under the form of coated
granules embedded in an extragranular matrix comprising amlodipine besilate along
with excipients. Irbesartan is granuled with a binder such as HPMC for faciliting
granulation and amlodipine is added in the extragranular portion before compression
step.
In another preferred form, irbesartan and amlodipine are both separately
granulated using respective suitable binder before blending with lubricants and further
compression.
Thus the solid composition takes the form of a monolayer tablet, preferably film
coated.
In another preferred form, irbesartan granules and amlodipine granules along
with excipients are separated by an inert layer. Thus the solid composition takes the
form of a trilayer tablet, preferably film coated. In that embodiment the inert layer
preferably comprises suitable diluent.
The preferred form is a monolayer form wherein a physical barrier is placed
around the irbesartan active ingredient. The physical barrier serves to reduce or
eliminate the physical contact between irbesartan as the protected active ingredient
and amlodipine besilate, the other active ingredients of the combination.
Preferred compositions of the present invention contain one or more of the
following components in the indicated concentration range (% by weight): irbesartan,
50 to 70% most preferably, 60%, amlodipine besilate, 1 to 10%, most preferably 2 to
6%, diluent, 20 to 30%, most preferably about 25%, binder, 1 to 5%, most preferably
2 to 3%; disintegrant, 3 to 6%, most preferably about 5%; antiadherentor glidant, 0.25
to 5.0% most preferably 0.7 to 2%, lubricant, 0.5 to 1.5, most preferably about 1%.
The amount of each ingredient (active and additives) in the solid dosage
formulation of the invention may specifically vary within the following ranges.
Particle size distribution of Irbesartan is important because the fines of
Irbesartan granules help for uniformity of Amlodipine. The particle size distribution of
Irbesartan granules mainly depends on fluid uptake during granulation and kneading
time. The preferred size distribution of Irbesartan granules is in the range of 65 to 85%
passing through # 60 BSS, i.e. having a size or a diameter less than 250µm.
The final pH observed for the Irbesartan and Amlodipine formula composition
of the invention is around 6.0, where as pH of individual reference product was found
to be higher than 6,0 i.e. in between pH 6.0 to 7.0. The Amlodipine composition
favors pH above 6, but below pH 6.0 the degradation process of amlodipine
accelerates.
Hence in the present invention the selected compositions can attain pH 6 when
compressed into tablets.
The final primary packaging material used is blister packaging i.e. Opaque
Triplex (300rrricPVC/30micPE/90gsmPVdC), Opaque duplex (250micPVC and 60
mic PVdC) and Alu-Alu blister packs. These materials will avoid increasing
generation of Impurity-D in amlodipine thereby inhibiting direct exposure of sun light
on drug product.
The main impurity to be controlled in the composition of the invention is
Impurity D known in the art as 3-emyl-5-memyl-2-[(2-aminoethoxy)methyl]-4-(2-
clilorophenyl)-6-memylpyridine-3,5-dicarboxylate.
In the compositions according to the invention, less than 1.5 % (w/w) of total
impurities for Amlodipine is found after 6 months at 40°C/75%RH, but more than
1.6% of impurity is found when irbesartan and amlodipine are not physically
separated. In a preferred embodiment less than 1,0% and more preferably less than
0,5% (w/w) of total impurities for Amlodipine is found in the composition of the
invention after 6 months at 40°C/75%RH.
In addition less than l,5%(w/w) [actual 0.097 % w/w] of Impurity D for
Amlodipine is found after 6 months at 40°C/75%RH in the compositions according to
the invention, but more than 1,6% of impurity D is found when Irbesartan and
amlodipine are not physically separated. In a preferred embodiment less than 1,0%
and more preferably less that 0,15% (w/w) of impurity D for Amlodipine is found in
the composition of the invention after 6 months at 40°C/75%RH.
This shows that the specific compositions of the invention have a lowering
impact on the degradation profile of amlodipine besilate.
On the other side less than 0,5 % (w/w) of total impurities for irbesartan is found
after 6 months at 40°C/75%RH. This shows that the specific composition of the
invention have no impact on the degradation profile of Irbesartan. In addition, there is
no change in the physical properties of tablets such as color, shape, hardness, and
disintegration time.
Physical properties.
Stability performances.
The oral pharmaceutical compositions of the present invention were subjected to
accelerated stability studies at the following conditions; 40°C/ 75 % relative humidity
RH, 30°C / 75 % RH and 25°C/ 60 % RH. These were evaluated on the basis of assay,
in vitro dissolution, moisture content and related substances measured between initial
and 6-months time points for irbesartan as well as amlodipine besilate.
The results provide a significant decrease in the total impurity levels in
Amlodipine mainly Imp D when Irbesartan and Amlodipine both are physically
separated.
Specifically, it was found that impurity levels in the Amlodipine is quite low
and within the target limit in the formula where Irbesartan granulated and Amlodipine
was added in the extragranular portion. This composition shows impurity levels much
lower than that of reference products.
Dissolution performances.
The "dissolution performance" of a tablet containing the combination of
Irbesartan and amlodipine besilate is compared to the dissolution performance of each
reference product in multimedia dissolution conditions such as 0.1 N HC1, pH 4.5
Acetate buffer, pH 6.8 phosphate buffer and pH 7.5 phosphate buffer. The progress of
dissolution is monitored at various time points between initial point and 60 minutes.
The dissolution profiles refers to the weight % of irbesartan or amlodiopine
release, based on the total weight of irbesartan or amlodipine contained in the tablet,
which dissolves within 60 minutes under the different multimedia conditions (see fig 1
and 2 for routine media i.e. 0.1 N HC1).
The results show that the dissolution performances of the tablet containing the
combination of irbesartan and amlodipine besilate of the invention are equivalent to
the dissolution performances of the tablets containing each active ingredient irbesartan
or amlodipine alone.
Method of manufacture.
The process for the preparation of a stable oral pharmaceutical composition
comprising irbesartan and amlodipine besilate, comprises the following steps:
i. granulating irbesartan and one or more pharmaceutically acceptable
excipients with aqueous solution containing a binder to form granules,
Preferably acceptable excipients are selected from the group consisting of
microcrystalline cellulose, croscarmelose sodium. Preferably acceptable binder, are
selected from the group consisting of cellulose derivatives such as hydroxypropyl
methylcellulose.
ii. drying the granules;
iii. separately blending amlodipine besilate with pharmaceutically
acceptable-"excipients for better uniform distribution of Amlodipine. Preferably
acceptable excipients are selected from the group consisting of microcrystalline
cellulose, silicon dioxide.
iv. mixing the irbesartan granules of step i) with the amlodipine besilate
blend of step iii);
v. lubricating the blend of step iv); optionally after a pre-lubricating step;
and
vi. compressing the mixture into tablets.
In a preferred embodiment of the process, a pre-lubricating step is carried on
before step v) in order to achieve good homogenity for both Irbesartan and
Amlodipine. Preferably the pre-lubricating step comprises the mixing of the blend of
step (iv) during 10 to 25mn, preferably 20mn before doing the lubricating step.
indeed, since the Irbesartan is present in the intragramilar portion and
Amlodipine is mixed with other extragranular excipients like Microcrystalline
Cellulose and silicon dioxide, homogeneous distribution of Amlodipine in the final
blend is necessary.
Hence, proper mixing of intragramilar and extragranular material is important
stage to achieve homogeneity of Amlodipine in the final blend, which can be done
during prelubrication step by mixing Irbesartan granules with extragranular material
till the content uniformity for Amlodipine is achieved, between 90 to 110% of the
label claim with RSD (Relative standard deviation) less than 5%, which revealed the
uniform distribution of Amlodipine Besilate in the lubricated blend.
In a preferred embodiment, the group of pharmaceutically acceptable excipients
used in the process is free of lactose.
The process further comprises the step of coating the tablet and packaging
preferably in opaque triplex blister pack.
Efficacy performance.
An object of the invention is the use of the composition of the invention
containing Irbesartan and amlodipine besilate in the manufacture of a medicament for
the treatment of hypertension wherein said medicament is in stable solid fixed dose
compositions as described above.
In a preferred embodiment, the compositions of the invention are administered
to patient having a mild to moderate hypertension, as second line treatment for
hypertensive patients not sufficiently controlled on amlodipine (Calcium Chanel
Blockers CCB) or irbesartan (angiotensin II receptor antagonist ARB) monotherapy.
Phase HI, double-blind, randomized, placebo-controlled, 8-week partial factorial
was designed to evaluate the combinations of Irbesartan 150 mg / Amlodipine 5 mg
and Irbesartan 300 mg / Amlodipine 5 mg tablets versus Amlodipine 5 mg, Irbesartan
150 mg and 300 mg monotherapy, after 8 weeks of treatment in patients with"
uncomplicated primary essential hypertension.
This study afma to demonstrate that the antihypertensive efficacy of the fixed
dose composition Ibesartan and amlodipine 150/5mg or 300/5mg is superior to the
corresponding dose of monotherapy of amlodipine or irbesartan.
The invention has been described with reference to preferred embodiments.
However, many variations are possible within the scope of the invention.
Examples.
C1, C2, C3 represent comparative formulations. I1, I2,I3 represent formulations
of the invention wherein irbesartan is physically separated from amlodipine.
Aprovel® 300mg Karvea® 300mg represents formula C1 as reference product
for Irbesartan alone.
Istin 10mg or Norvasc® 10mg represents formula C2 as reference product for
Amlodipine besilate alone.
Example 1.
Preparation of composition C3 wherein Irbesartan and Amlodipine are both
granulated together.
This formula C3 may be prepared by any suitable granulation process known in
the art.
Example 2.
Preparation of composition of the invention I1 wherein Irbesartan is in the
Intragranular portion and Amlodipine is added in the extragranularly
Extragranulation process of manufacturing the combination of Irbesartan and
amlodipine besilate under tablet according to formula I1.
Step -1: Mix Irbesartan, Microcrystalline cellulose and Croscarmellose sodium
in raped mixer granulator.
Step-2: Granulate the dry mix of step 1 with aqueous solution of hypromellose.
Step- 3: Dry the wet granules and mill the dried granules through 1.00 to 2.00
mm screen.
Step- 4: Add extragranular material i.e. Amlodipine Besilate, Microcrystalline
Cellulose and Silicone dioxide and mix in a low shear blender.
Step- 5: Add Magnesium Stearate to step 4 material and mix in a low shear
blender.
Step- 6: Compress the lubricated blend using suitable toolings.
Step- 7: Finally coat the compressed tablets to achieve 2 - 4 % of weight gain.
Exemple 3.
Preparation of composition of the invention 12 wherein Irbesartan and
Amlodipine besilate are physically separated by both separate granulations.

Exemple 4.
Preparation of composition of the invention 13 under tri-layers tablet wherein
frbesartan layer and Amlodipine besilate layer are physically separated by an inert
layer.
Table 4
Example 5.
Stability studies
The oral pharmaceutical compositions of the present invention were subjected to
accelerated stability studies at the folio-wing conditions; 40°C/ 15 % relative humidity
RH, 30°C / 75 % RH and 25°C/ 60 % RH. These were evaluated on the basis of assay,
in vitro dissolution, moisture content and related substances measured between initial
and 6-months time points for irbesartan as well as amlodipine besilate.
This test is carried on under the following conditions.
The tablets were packed in to the opaque triplex - alu blister pack and such
blister were further packed in to the cartons, and cartons were charged on to the
stability as per ICH guidelines, and samples were taken out at each stability stage
interval and submitted for analysis.
The stability results at +40°C/75%RH are provided in table 5.
The formulation containing both Irbesartan and Amlodipine granulated together
shows higher level of imp D during stability studies at 40°C / 75 % RH at 2 months,
hence further stability study was discontinued.
From the above results, it may be concluded that there is an increase in the
total impurity levels in Amlodipine and mainly Imp D when Irbesartan and
Amlodipine are granulated together.
"When Irbesartan and Amlodipine both are physically separated it was found
that impurity levels in the Amlodipine is quite low.
Hence formula II where Irbesartan granulated and Amlodipine was added in
the extragranular portion shows the best results of impurity levels i.e. specifically
much lower than that of reference products (Istin 10 mg).
In the compositions according to the invention II, 12,13, less than 1.5% (w/w)
of total impurities for Amlodipine is found after 6 months at 40oC/75%RH, although
more than 1.6% of impurity is found when irbesartan and amlodipine are not
physically separated (C3). hi a preferred embodiment less than 1,0% and more
preferably less that 0,5% (w/w) of total impurities for Amlodipine is found in the
composition of the invention (II, 12,13) after 6 months at 40°C/75%RH.
In addition less than l,5%(w/w) of Impurity D for Amlodipine is found after 6
months at 40°C/75%RH in the compositions according to the invention (II, 12, 13),
although more than 1,6% of impurity D is found when irbesartan and amlodipine are
not physically separated (C3). In preferred embodiments, less than 1,0% and more
preferably less that 0,15% (w/w) of impurity D for Amlodipine is found in the
composition of the invention (II, 12,13) after 6 months at 40°C/75%RH.
In a more preferred embodiment less that 0,15% (w/w) of impurity D for
Amlodipine and less than 1,5 % (w/w) of total impurities for Amlodipine is found
after 6 months at 40°C/75%RH in the composition of the invention (II).
This shows that the specific compositions of the invention have a lowering
impact on the degradation profile of amlodipine besilate.
On the other side less than 0,5 % (w/w) of total impurities for irbesartan is found
after 6 months at 40°C/75%RH. This shows that the specific composition of the
invention have no impact on the degradation profile of Irbesartan.
Example 4
Bioequivalence Dissolution profiles.
The dissolution profiles of the products of the invention are compared to the
dissolution profiles of the references products. These studies are carried out per the
multimedia dissolution profile study conditions established as followed.
The dissolution profiles were carried out with avg tablet weight of 260 mg [for
150/5 mg & 150/10 mg] or 520 mg [for 300/5 & 300/10 mg strength] of Irbesartan
and Amlodipine FCT using USP apparatus n, placing a tablet in 900 ml of dissolution
media at 37°C and measuring the amount of Irbesartan or Amlodipine progressively
dissolved [using HPLC, wavelength 240 Dm] at different time points such as 10, 15,
30,45 & 60 mins till the extend of 90% drug dissolves was achieved.
The results as illustrated in figures 1 and 2 show that the dissolution
performances of the tablet containing the combination of irbesartan and amlodipine
besilate of the invention are equivalent to the dissolution performances of the tablets
containing each active ingredient irbesartan or amlodipine alone.
Example 5.
Clinical studies Phase JR.
The first study is conducted with the fixed combination of irbesartan and
amlodipine 150/5 and 300/5mg and with irbesartan 150 and 300 mg.
The combination therapy of irbesartan and amlodipine is expected to provide
enhanced efficacy in patients not adequately controlled by irbesartan monotherapy
alone.
The second study is conducted with the fixed combination of irbesartan and
amlodipine 150/5 and 150/10 mg and with amlodipine 5 and 10 mg.
The combination therapy of irbesartan and amlodipine is expected to provide
enhanced efficacy in patients not adequately controlled by irbesartan monotherapy
alone.
The results will demonstrate that the antihypertensive effect as assessed by
home blood pressure measurement (HBPM) of the fixed combination of irbesartan
and amlodipine 150/5 mg is superior to that of amlodipine 5 mg alone in hypertensive
patients insufficiently controlled by amlodipine 5 mg monotherapy.
244 patients are randomised in each clinical study. This will give 122 patients
randomised and 103 patients for evaluation in each treatment group.
- All the treatments were administrated orally, once daily in the morning. .
Efficacy criteria.
Home Blood pressure BP measurements is performed using for all patients
the same validated automatic non invasive BP monitor according to a standard
procedure: Twice a day for 7 days, 2 measurements in the morning and 2
measurements in the evening.
These HBPM periods are performed the week before V2, V3 and V4.
Office BP measurements are performed at each visit. All investigators are
using the same validated automatic non invasive BP monitor.
Primary efficacy criterion: Home SBP as primary criterion is based on the
measurements made by the patient for the last 7 days of each measurement period.
Morning and evening measurements of the first day of each measurement
period are discounted in this criterion as they are considered as a training.
The primary criterion is calculated based on the average of all available
measurements out of a maximum of 24 measurements (4 measurements per day for 6
days). This average is computed only if a minimum of 12 correct measurements are
recorded over the last 6 days of each period of measurement
From the first study, the results will demonstrate that the antihypertensive
efficacy of the fixed combination irfaesartan/am1odipine 300/5 mg is superior to that of
irbesartan 300 mg monotherapy in lowering Systolic Blood Pressure assessed by
home blood pressure measurement (HBPM) after 10 weeks of treatment (Wl 0).
From the second study, the results will demonstrate that the antihypertensive
effect as assessed by home blood pressure measurement (HBPM) of the fixed
combination of irbesartan and amlodipine 150/5 mg is superior to that of amlodipine 5
mg alone in hypertensive patients insufficiently controlled by amlodipine 5 mg
monotherapy.
CLAIMS
1) A stable solid oral pharmaceutical fixed dose composition comprising
irbesartan, amlodipine besilate and pharmaceutically acceptable excipients, wherein
irbesartan is physically separated from amlodipine besilate.
2) The composition according to claim 1 wherein irbesartan under the form of
coated granules is embedded in an extragranular matrix comprising amlodipine
besilate.
3) The composition according to any one of claims 1 to 2, wherein the solid
composition takes the form of a monolayer tablet, preferably film coated
4) The composition according to any one of claims 1 to 3 wherein the tablet is
further package in suitable packing material such as PVC, PVC / PVdC, PVC / PE /
PVdC.
5) The composition according to any one of claims 1 to 4 wherein the irbesartan
represents between about 20% and about 70% by weight of the total composition.
6) The composition according to any one of claims 1 to 5 wherein the amlodipine
besilate represents between about 1% and about 20% by weight of the total
composition.
7) The composition according to any one of claims 1 to 6 wherein the
pharmaceutically acceptable excipients are selected from the group consisting of
diluent, disintegrant, antiadherent, binder lubricant and mixture thereof.
8) The composition according to any one of claims 1 to 7 wherein said solid
composition is free of lactose.
9) The solid composition according to any one of claims 1 to 8 wherein the
amount of irbesartan is comprised between 150mg and 300mg of the total weight of
the tablet, preferably 300mg or 150mg.
10) The solid composition according to any one of claims 1 to 9 wherein the
amount of amlodipine besilate is comprised between 5mg and 10mg of the total
weight of the tablet, preferably 7mg or 14mg.
11) The solid composition according to any one of claims 1 to 10 under the form
of a tablet wherein the total weight of the tablet is between 400mg and 600mg,
preferably 500mg.
12) The composition according to any one of claims 1 to 11 having less than
1.50%(w/w) of total impurities for Amlodipine and less than 0.50%(w/w) of total
impurities for Irbesartan after 6 months at 40°C/75%RH.
13) A process for the preparation of a stable oral pharmaceutical composition
comprising irbesartan and amlodipine besilate, wherein the process comprises the
steps of:
i. granulating irbesartan and one or more pharmaceutically acceptable
excipients, with aqueous solution containing a binder, to form granules,
ii. drying the granules;
hi. separately blending amlodipine besilate with pharmaceutically acceptable
excipients,
iv. mixing the irbesartan granules of step ii with the amlodipine besilate blend
of step iii);
v. lubricating the blend of step iv); optionally after a pre-lubricating step; and
vi. compressing the mixture into tablets.
14) The process of claim 13 wherein the group of pharmaceutically acceptable
excipients used in step I and iii) of the process is free of lactose.
15) The process according to any one of claims 13 or 14 further comprising the
step of coating the tablet and packaging in suitable packing material such as PVC,
PVC / PVdC, PVC / PE / PVdC.
16) The process according to any one of claims 13 to 15 wherein the pre-
lubricating step comprise the mixing of the blend of step (iv) during 10 to 25mn,
preferably 20mn before doing the lubricating step.
17) Use of Irbesartan and amlodipine besilate in the manufacture of a medicament
for the treatment of hypertension wherein said medicament is in the stable solid fixed
dose composition according to anyone of claim 1 to 12.
18) Use according to claim 17 as second line treatment for hypertensive patients
not sufficiently controlled using amlodipine as Calcium Chanel Blockers (CCB)
monotherapy or irbesartan as angiotensin IE receptor antagonist (ARB).

The present invention is directed to solid stable pharmaceutical fixed dose compositions comprising irbesartan,
amlodipine besilate and pharmaceutically acceptable excipients, to their preparation and to their therapeutic application.