FIELD OF THE INVENTION
The present invention relates to single layer pharmaceutical compositions comprising
amlodipine and valsartan or their pharmaceutically acceptable salts, hydrates, solvates or
polymorphs or enantiomers and racemates thereof and a process of forming the same.
BACKGROUND OF THE INVENTION
Valsartan is an angiotensin II antagonist and is known to be effective in the treatment of
congestive heart failure and reducing blood pressure irrespective of age, sex or race and
is also well tolerated. It has also been approved to treat people after heart attacks.
U.S. patent No: 5,399,578 describes the preparation of valsartan and its pharmaceutically
acceptable salt.
US patent 4,879,303 and 4,572,909 describes the preparation of amlodipine and its
pharmaceutically acceptable salt. The compound amlodipine (3-ethyl 5-methyl 2-(2-
aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methylpyridine-3,5-
dicarboxylate) is a potent and long acting calcium channel blocker having utility as an
anti-ischaemic and anti-hypertensive agent.
U.S. patent nos: 6,294,197, 6,485,745 and 6,858,228 describe a solid oral dosage form of
valsartan and optionally hydrochlorothiazide (HCTZ) prepared by compression method
having more than 35% by weight based on total weight of the compressed solid oral
dosage form, of the active ingredient.
US 6,395,728 disclose combination of valsartan and amlodipine comprising from about
lOmg to about 200mg of valsartan and lmg to about 180mg amlodipine.
Combination of amlodipine and valsartan is marketed under the brand name Exforge®
available in four different strengths: 5mg/160mg; 10mg/160mg; 5mg/320mg and
10mg/320mg. It is used for the treatment of hypertension.
WO 2007/022113 relates to monolayer and bilayer solid dosage forms of a combination
of valsartan and amlodipine. This application discloses that for the 320mg/5mg fixed
dose combination of valsartan and amlodipine it was not possible to get a bioequivalent
product unless a bilayer tablet formulation was used.
As a person skilled in the art is aware, a bilayer tablet can exhibit certain disadvantages
from many processing related limitations. Specialized machines are required for
2

producing such tablets and the tablets are susceptible to bilayer separation. Moreover, the
process of making bilayered tablets is less economical.
In light of this it was highly desirable to prepare a single layer composition of the
combination product, which would also be bioequivalent to the bilayer tablet.
We have now surprisingly, found that it is possible to prepare a single layered
pharmaceutical composition comprising amlodipine and valsartan or their
pharmaceutically acceptable salts thereof, wherein the composition is bioequivalent to a
tablet combination dosage form of amlodipine and valsartan marketed under the trade
nameofExforge®.
SUMMARY OF THE INVENTION
The invention is to provide a single layer pharmaceutical composition
comprising active agent(s)
(a) amlodipine or a pharmaceutically acceptable salts thereof and
(b) valsartan or a pharmaceutically acceptable salts thereof
wherein: (i) the composition exhibits bioequivalence to the commercially available
bilayer tablet dosage form comprising amlodipine besylate and valsartan; when
administered to human subject, under the bioequivalence parameters of: (a) a 90%
Confidence Interval for AUC which is between 80% and 125%, and (b) a 90%
Confidence Interval for Cmax, which is between 80% and 125%.
Another aspect of the present invention is to provide a method of achieving
bioequivalence between a single layer pharmaceutical composition comprising active
agent(s)
(a) amlodipine or a pharmaceutically acceptable salts thereof and
(b) valsartan or a pharmaceutically acceptable salts thereof
wherein: (i) the composition exhibits bioequivalence to the commercially available
bilayer tablet dosage form comprising amlodipine besylate and valsartan; when
administered to human subject, under the bioequivalence parameters of: (a) a 90%
Confidence Interval for AUC which is between 80% and 125%, and (b) a 90%
Confidence Interval for Cmax, which is between 80% and 125%.
3

Another aspect of the present invention is to provide a method of achieving
bioequivalence between a single layer pharmaceutical composition comprising active
agent(s)
(a) amlodipine or a pharmaceutically acceptable salts thereof and
(b) valsartan or a pharmaceutically acceptable salts thereof
wherein: (i) the composition exhibits bioequivalence to the commercially available
bilayer tablet dosage form comprising amlodipine besylate and valsartan; when
administered to human subject, under the bioequivalence parameters of: (a) a 90%
Confidence Interval for AUC which is between 80% and 125%, and (b) a 90%
Confidence Interval for Cmax, which is between 80% and 125%, and iii) valsartan is
present in an amount greater than 250mg.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to single layer pharmaceutical compositions comprising
amlodipine and valsartan or their pharmaceutically acceptable salts, hydrates, solvates or
polymorphs or enantiomers and racemates thereof and a process of forming the same
which is bioequivalent to the commercially available bilayer tablet dosage form
comprising amlodipine besylate and valsartan.
The "commercially available bilayer tablet dosage form comprising amlodipine besylate
and valsartan" is Exforge . The bilayer tablet strengths are 10mg/320gm and 5mg/320mg
of amlodipine besylate and valsartan.
In the pharmaceutical composition according to the invention, the active agent(s)
comprises valsartan which includes its pharmaceutically acceptable salts, hydrates,
solvates or polymorphs or enantiomers and racemates thereof in amount of about 250mg
to about 640mg e.g. 320mg, and amlodipine which includes its pharmaceutically
acceptable salts, hydrates, solvates or polymorphs or enantiomers and racemates thereof.
Especially preferred is the besylate salt.
In an embodiment of the present invention the pharmaceutical composition comprises
active agent(s) in an amount less than about 35% by weight, based on the total weight of
the pharmaceutical composition.
4

In another embodiment of the present invention the pharmaceutical composition
comprises valsartan in an amount less than about 35% by weight, based on the total
weight of the pharmaceutical composition.
The determination of the dose of the active agent(s) necessary to achieve the desired
therapeutic effect is within the skill of those who practice in the art. The dose depends on
the warm-blooded animal species, the age and the individual condition and on the manner
of administration. In the normal case, an approximate daily dose in the case of oral
administration for a patient weighing approximately 75 kg for oral application is of about
10 mg to about 320mg, especially about 20 to about 120 mg, most preferably about 40
mg to about 80 mg for valsartan and about 1.0 mg to about 180 mg, preferably about 2.5
mg to about 50 mg, for the CCB, depending on the specific CCB. The exact dose of
active agent(s) and the particular formulation to be administered depends on a number of
factors, e.g. the condition to be treated, the desired duration of the treatment and the rate
of release of the active agent. For example, the amount of the active agent required and
the release rate thereof may be determined on the basis of known in vitro or in vivo
techniques, determining how long a particular active agent concentration in the blood
plasma remains at an acceptable level for a therapeutic effect.
The combination therapy with valsartan and a calcium channel blocker results in a more
effective antihypertensive therapy through improved efficacy as well as a greater
responder rate.
The active may further comprises another active agent selected from the group
comprising, but are not limited to, other calcium channel blocker (CCB), AT II
Antagonist, renin inhibitors an angiotensin converting enzyme (ACE) inhibitor, an
aldosterone synthase inhibitor an aldosterone antagonist, a dual angiotensin converting
enzyme/neutral endopetidase (ACE/NEP) inhibitor, an endothelin antagonist, alpha and
beta adrenergic blockers, HMG CoA reductase inhibitors and a diuretic or their
pharmaceutically acceptable salts, hydrates, solvates or polymorphs or enantiomers and
racemates thereof.
"Pharmaceutical composition" includes granules, pellets or those in unit dose forms such
as tablets, capsules and the like, and furthermore ampoules and the like; prepared by
methods well known to a person skilled in the art.. Thus, pharmaceutical preparations for
5

oral use can be obtained by combining the active agent(s) with solid carriers, if desired
granulating a mixture obtained, and processing the mixture or granules, if desired or
necessary, after addition of suitable or pharmaceutically acceptable excipients to give
tablets.
The term "single layer" as per the invention includes solid oral dosage forms wherein
both the actives are present together either as coated or uncoated dosage forms preferably
tablets. The coated or uncoated dosage forms can be prepared in various sizes and shapes
as appreciated by the person skilled in the art. The above dosage forms can also made as
mini tablets which can further be filled into capsule shells.
The term single layer specifically excludes solid oral dosage forms wherein both the
actives are present separately as bilayered tablets.
The pharmaceutically acceptable excipients or additives include but are not limited to
disintegrants, binders, lubricants, glidants, fillers, diluents and the like.
The amounts of additive employed will depend upon how much active agent is to be
used. One excipient can perform more than one function. The absolute amount of
additives and the amounts relative to other additives are also dependent on the desired
properties of the pharmaceutical composition and may also be chosen by the skilled
artisan by routine experimentation without undue burden.
Disintegrants, include but are not limited to, cross linked polyvinylpyrrolidone
(crospovidone, polyplasdone, kollidon XL); starches such as modified starches,
pregelatinized starch, maize starch, pregelatinized starch, dried starch and sodium starch
glycolate; gum such as alginic acid, sodium alginate, guar gum; croscarmellose sodium,
cellulose products such as microcrystalline cellulose and its salts, microfine cellulose,
low substituted hydroxypropylcellulose and mixtures thereof; ion exchange resins like
polacrilin potassium; most preferably crosslinked polyvinylpyrrolidone, crospovidone,
crosslinkedcarboxymethylcellulose.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn
starch; microcrystalline cellulose such as products known under the registered trade
marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium
6

carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid
glucose, dextrin, povidone, syrup, polyethylene oxide and mixtures thereof.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
One or more of these additives can be selected and used by the skilled artisan having
regard to the particular desired properties of the solid oral dosage form. The amount of
each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and
lubricant may vary within ranges conventional in the art.
The pharmaceutical composition of the invention, wherein the core can be formed by
various methods known in the art such as by dry granulation, wet granulation, direct
compression, extrusion spheronization, layering and the like;
The pharmaceutical composition of the invention can be prepared for oral administration
to mammals (warm-blooded animals), including man, comprising a therapeutically
effective amount of the pharmacologically active compound(s), alone or in combination
with one or more pharmaceutically acceptable carries, especially suitable for.
The invention provides in another of its aspects a process of making a pharmaceutical
composition as hereinabove described. Such pharmaceutical compositions may be
produced by working up components a) amlodipine b) valsartan and c) pharmaceutically
acceptable additive(s) defined hereinabove in appropriate amounts, to form unit dosage
forms.
In a preferred embodiment, there is provided a process of making a pharmaceutical
composition as hereinabove described comprising the steps of
i) blending the active agents with pharmaceutically acceptable additives,
ii) subjecting the blend to slugging/compaction to form a compacted mass
7

iii) sifting the compacted mass to form granules and
iv) compressing the granules to form the solid oral dosage form.
Compaction of the blend into compacted mass may be carried out using a slugging
technique or preferably, roller compaction. The milling of the granules may be carried
out according to conventional milling methods. The compression of the granulates to
tablet cores can be carried out in a conventional tabletting machine, eccentric tabletting
machine or a rotary compression machine.
The tablets may further be coated by using any of the conventional coating techniques,
such as pan or perforated pan, well known to the persons skilled in the art.
These coating layers comprise of one or more excipients selected from the group
comprising coating agents, opacifiers, taste-masking agents, colouring agents, antitacking
agents and the like.
Coating agents which are useful in the coating process, include, but are not limited to,
polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose,
hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses);
polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl
acetate (e.g. marketed under the brand name of Plasdone) and polymers based on
methacrylic acid such as those marketed under the brand name of Eudragit. These may be
applied from aqueous or non-aqueous systems or combinations of aqueous and non-
aqueous systems as appropriate. Additives can be included along with the film formers to
obtain satisfactory films. These additives can include plasticizers such as dibutyl
phthalate, triethyl citrate, polyethylene glycol and the like, antitacking agents such as talc,
stearic.acid, magnesium stearate and colloidal silicon dioxide and the like, surfactants
such as polysorbates and sodium lauryl sulphate and opacifying agents such as titanium
dioxide and the like. All these excipients can be used at levels well known to the persons
skilled in the art.
While the foregoing specification teaches the principles of the present invention, with
examples provided for the purpose of illustration, it will be understood that the practice
of the invention encompasses all of the casual variations, adaptations, modifications,
deletions or additions of procedures and protocols described herein, as come within the
scope of the following claims and its equivalents.
8

EXAMPLES:
Example 1 & 2: Amlodipine and Valsartan Tablets

Ingredient % w/w

Example 1:
10/320 Example 2:
5/320
Valsartan 30.42 30.42
Amlodipine besylate 1.32 0.66
Microcrystalline Cellulose 58.13 58.79
Crospovidone 5.71 5.71
Colloidal Silicone Dioxide 1.99 1.99
Magnesium Stearate NF 1.19 1.09
Croscarmellose Sodium USP 1.24 1.24
Film Coating Q.S. Q.S.
Brief Manufacturing Process
1. The sifted components except a part of microcrystalline cellulose, crosslinked
polyvinylpyrrolidone and colloidal silicon dioxide are blended in a suitable
blender.
2. Mixed Amlodipine with step 1 material geometrically and & sifted through
appropriate sieve
3. Sifted magnesium stearate through appropriate sieve and lubricated step 2
material.
4. The blended material is compacted to form slugs/compacts.
5. The compacted mass is milled and sieved again to form granules. The remaining
portion of the microcrystalline cellulose, crospovidone, colloidal silicon dioxide,
croscarmellose silicon dioxide are added and blended in a suitable blender.
6. The prepared granules are lubricated and compressed into the tablets.
7. The tablets are then coated using film coating composition.
Bioequivalence Study
The test composition was prepared according to example 1 and was evaluated against
Exforge® having lOmg amlodipine besylate and 320mg of Valsartan, by Novartis, as
reference.
9

An open label, balanced, randomized, two treatment, two sequence, two-period,
crossover oral bioequivalence study was carried out in 51 healthy human volunteers.
Each received single dose of 10 mg of amlodipine besylate and 320 mg of valsartan in
fasted state. 47 healthy volunteers received single dose of 10 mg of amlodipine besylate
and 320 mg of valsartan in fed state.
The study was monitored in terms of the AUC and Cmax achieved with the test product
and reference product. AUCs are areas under plasma concentration of valsartan - time
curves or amlodipine-time curves. Generally, the values for AUC represent a number of
values taken from all the subjects in a population and are, therefore, mean values
averaged over the entire population. Cmax, the observed maximum plasma concentration
of valsartan or amlodipine is likewise an average value. The ratios of the log transformed
mean values for Cmax and AUC for the test and reference product (T/R ratio) is a measure
of the bioequivalence between the test and reference product. Values between 80 and 125
% for these intervals indicate bioequivalence as recommended by the US FDA.
Bioequivalence data for composition containing amlodipine and valsartan against the
commercially available tablets "Exforge" is shown below in Tables 1,2,3 and 4.
Surprisingly, we have found that single layered pharmaceutical composition comprising
active agent(s) amlodipine besylate and valsartan exhibits bioequivalence to the
commercially available bilayere tablet, Exforge"; when administered to human subject,
under the bioequivalence parameters of: (a) a 90% Confidence Interval (CI) for AUC
which is between 80% and 125%, and (b) a 90% Confidence Interval for Cmax, which is
between 80% and 125%.
Table 1: Fed BE study data of Amlodipine against commercially available tablets Exforge ;
n = 47
PK Parameters Geometric Mean Plasma
Concentration Log Transformed T/R (%) of
Geometric Least Square Mean CI 90% on Log
Transformed data
r
max 5.5231 ng/ml 94.44 0.962-0.984
AUQo-t) 346.6522 ng.hr/ml 96.78 0.917-1.027
AUC(o-oo) 376.0003 ng.hr/ml 97.48 0.918-1.034
10

Table 2: Fed BE study data of Valsartan against commercially available tablets Exforge ;
n = 47

PK Parameters Geometric Mean Plasma
Concentration Log Transformed T/R (%) of
Geometric Least Square Mean CI 90% on Log
Transformed data
r
'-max 6173.4059 ng/ml 103.62 0.972-1.104
AUC(0-„ 49733.7888 ng.hr/ml 104.27 0.979-1.110
AUC(o.oo) 51727.6142ng.hr/ml
104.74 0.983-1.115
Table 3: Fasted BE study data of Amlodipine against commercially available tablets
"Exforge®" n = 51

PK Parameters Geometric Mean Plasma
Concentration Log Transformed T/R (%) of
Geometric Least Square
Mean CI 90% on Log
Transformed data
r
'-'max 5.3728 ng/ml 96.00 0.917-1.004
AUC(o-t) 315.1817ng.hr/ml
96.72 0.909-1.028
AUQo -co) 337.1193ng.hr/ml
96.63 0.910-1.025
Table 4: Fasted BE study data of Valsartan against commercially available tablets
"Exforge®" n = 51

PK Parameters Geometric Mean Plasma
Concentration Log Transformed T/R (%) of
Geometric Least Square Mean CI 90% on Log
Transformed data
c
'-'max 7027.7017 ng/ml 94.34 0.873-1.019
AUC(o-t) 45779.3115ng.hr/ml
91.59 0.856-0.979
AUQo CO) 46983.5253 ng.hr/ml 91.27 0.854-0.975
Cmax = Maximum plasma concentration
AUC(0.t)= Area under the plasma concentration time curve from time 0 to t
AUC (o-co) = Area under the plasma concentration time curve from time 0 to oo
11

WE CLAIM:
1. A single layer pharmaceutical composition comprising active agent(s)
(a) amlodipine or a pharmaceutically acceptable salt thereof and
(b) valsartan or a pharmaceutically acceptable salt thereof
wherein: (i) the composition exhibits bioequivalence to the commercially
available bilayer tablet dosage form comprising amlodipine besylate and
valsartan; when administered to human subject, under the bioequivalence
parameters of: (a) a 90% Confidence Interval for AUC which is between 80% and
125%, and (b) a 90% Confidence Interval for Cmax, which is between 80% and
125%.
2. A single layer pharmaceutical composition according to claim 1, wherein
valsartan is present in a unit dose in amount ranging from about 250mg to about
640mg.
3. A single layer pharmaceutical composition according to claim 1, wherein
valsartan is present in an amount less than 35% by weight, based on the total
weight of the pharmaceutical composition.
4. A single layer pharmaceutical composition according to claim 1, wherein the
active agent is present in an amount less than 35% by weight, based on the total
weight of the pharmaceutical composition.
5. A single layer pharmaceutical composition according to claim 1, further
comprises pharmaceutically acceptable additives selected from the group
comprising fillers or diluents, binders, lubricants, glidants and disintegrants.
6. A single layer pharmaceutical composition of claim 1, wherein the diluent is one
or more selected from the group comprising confectioner's sugar, compressible
sugar, dextrates, dextrin, dextrose, lactitol, fructose, mannitol, sucrose, starch,
lactose, dibasic or tribasic calcium phosphate, calcium carbonate, calcium
sulphate, xylitol, sorbitol, talc, micro-crystalline cellulose or mixtures thereof.
7. A single layer pharmaceutical composition claim 1, wherein the binder is one or
more selected from the group comprising methyl cellulose,
hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropyl
12

methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, microcrystalline
cellulose, potato starch, wheat starch, corn starch, pregelatinised maize starch,
polyvinylpyrrolidone, acacia, alginic acid, guar gum; liquid glucose, dextrin,
povidone, syrup, polyethylene oxide and mixtures thereof.
8. A single layer pharmaceutical composition of claim 1, wherein the lubricant is
one or more selected from the group comprising Mg, Al, Zn or Ca stearate,
polyethylene glycol, mineral oil, sodium stearyl fumarate, stearic acid,
hydrogenated vegetable oil, glyceryl behenate, talc and mixtures thereof.
9. A single layer pharmaceutical composition of claim 1, wherein the glidant is one
or more selected from the group comprising silicon dioxide, colloidal silica,
powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.
10. A single layer pharmaceutical composition of claim 1, wherein the disintegrant is
one or more selected from the group comprising cross linked
polyvinylpyrrolidone, maize starch, dried starch, pregelatinized starch, sodium
starch glycolate, alginic acid, sodium alginate, guar gum, croscarmellose sodium,
microcrystalline cellulose and its salts, microfine cellulose, low substituted
hydroxypropylcellulose, ion exchange resins and mixtures thereof.
11. A pharmaceutical composition described in claim 1, which is in the form of
tablets, capsules, granules, microparticles, minitablets and pellets.

12. A pharmaceutical composition of claim 10 is further coated.
Dated this 31st day of December 2007
13

A single layer pharmaceutical composition comprising active agent(s) amlodipine or
a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically
acceptable salt thereof wherein the composition exhibits bioequivalence to the
commercially available bilayer tablet dosage form comprising amlodipine besylate
and valsartan; when administered to human subject, under the bioequivalence
parameters of a 90% Confidence Interval for AUC which is between 80% and 125%, and a 90% Confidence Interval for Cmax, which is between 80% and 125%.