A STABLE PHARMACEUTICAL COMPOSITION OF AMLODIPINE AND
BENAZEPRIL OR SALTS THEREOF
Field of the Invention
The present invention relates to a stable pharmaceutical composition of
amiodipine and benazepril or salts thereof. In particular, the invention relates to a
stable pharmaceutical composition comprising at least one amiodipine
component and at least two benazepril components in which physical contact
between amiodipine and benazepril components is limited. The invention also
includes a process of preparing such compositions and method of treating
hypertension by administering the composition to a patient in need thereof.
Background of the Invention
Cardiovascular diseases are a group of disorders of the heart and blood vessels
and include coronary heart disease, cerebrovascular disease, peripheral arterial
disease, rheumatic heart disease, congenital heart disease, deep vein
thrombosis and pulmonary embolism. Heart attacks and strokes are usually
acute events and are mainly caused by a blockage that prevents blood from
flowing to the heart or brain.
A variety of therapeutic options are currently employed in the treatment of
cardiovascular diseases and conditions associated with cardiovascular diseases.
Combination therapy of an angiotensin converting enzyme inhibitors with a
calcium channel blocker can achieve synergistic results effective in treating a
variety of conditions including hypertension, congestive heart failure, angina,
myocardial infarction, atherosclerosis, diabetic nephropathy, and diabetic cardiac
myopathy, renal insufficiency, peripheral vascular disease, left ventricular
hypertrophy, cognitive dysfunction, stroke, and headache.
Numerous studies have been conducted to address the combination formulation
variables including combination therapy of ACE inhibitors and calcium channel
blockers, and attempts have been made to improve the combination therapy.
Benazepril is a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.
Chemically, Benazepril is 2-[(3S)-3-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2-yl]
amino}-2-oxo-2, 3, 4, 5-tetrahydro-1 H-1 -benzazepin-1 -yl] acetic acid, with the
following structure:
Amiodipine is a long-acting 1, 4-dihydropyridine calcium channel blocker,
chemically, Amiodipine, is 3-ethyl 5-methyl 2-[(2-aminoethoxy) methyl]-4-(2-
chlorophenyl)-6-methyl-1 , 4-dihydropyridine-3, 5-dicarboxylate, with the following
structure:
A combination of benazepril hydrochloride and amiodipine besylate is the drug of
choice for the treatment of cardiovascular diseases. A combination of benazepril
hydrochloride and amiodipine besylate is marketed by Novartis in the United
States in the form of oral capsules under trade name Lotrel®.
U.S. Patent No. 4,41 0,520 and 4,572,909 respectively discloses a benazepril,
benazeprilat and amiodipine, their salts along with pharmaceutical dosage forms,
dosage ranges and suitable routes of administration therewith, and uses.
U.S. Patent No. 4,879,303 discloses a besylate salt of amiodipine.
European Patent No. EP 2,574,85 B 1 discloses a combination of ACE-inhibiting
compounds and inotropic dihydropyridines and is used for lowering blood
pressure.
European Patent Application No. EP 3,342,64 A2 discloses composition of an
ACE inhibitor alone or in combination with a calcium channel blocker.
U.S. Patent No. 6,1 62,802 discloses a combination composition of benazepril
and amiodipine. The benazepril and the amiodipine are administered in a single
dosage form, such that the benazepril and amiodipine are completely physically
separated from each other.
U.S. Patent No. 8,1 58,146 discloses a combination formulation of benazepril and
amiodipine in which both benazepril and amiodipine are in complete physical
contact.
Benazepril and amiodipine are physically incompatible substances. Hence, if
incorporated into a single dosage form they must be kept physically separated.
This may be accomplished in any of the myriad ways known in the art, such as
bi-layered tablets, coated pellets of one agent incorporated into a tablet of the
other, separately coated pellets of each agent in a capsule or tablet, coated
pellets of one agent in capsule together with powder of the other agent, each
agent microencapsulated separately and then blended together for use in a tablet
or capsule, use of a dual or multiple compartment transdermal device, etc. Due
to the incompatibility, combination products of the two agents in an injectable
solution are not really acceptable. For convenience purposes, a coated
compressed tablet of benazepril together with amiodipine powder in a capsule
has been found to be the most desirable oral form.
It is evident from the prior art that stable formulations of benazepril and
amiodipine can be prepared by maintaining complete physical separation due to
possible incompatibility between both the actives. The prior also suggests a
method of preparing stable combination formulation of both the active in which
the actives are in complete physical contact. However, such formulation may not
substantiate the ultimate stability of the resulting formulation due to
incompatibility between the two actives.
Thus, there still exists a need to devise a novel and alternative formulation of
amiodipine and benazepril which could provide a viable alternative to the existing
formulations, without compromising on the stability over the storage period and
involve simple manufacturing process which is extendable for commercial
manufacturing.
The inventors of the present invention have devised a novel pharmaceutical
composition comprising at least one amiodipine component and at least two
benazepril components such that physical contact between amiodipine and
benazepril components is limited. Particularly, the inventors have found that
when physical contact between benazepril component and amiodipine
component is limited enough, the resulting composition can retain the desired
stability over the storage period.
The present invention relates to a novel and stabilized pharmaceutical
composition of benazepril and amiodipine and process of preparing such
compositions.
Summary of the Invention
In one general aspect, there is provided a stable pharmaceutical composition
comprising:
(a) at least one first benazepril component comprising benazepril or salts thereof;
(b) at least one second benazepril component comprising benazepril or salts
thereof; and
(c) at least one amiodipine component comprising amiodipine or salts thereof,
wherein the first benazepril component is substantially physically separated from
the amiodipine component and the second benazepril component is in physical
contact with the amiodipine component.
In another general aspect, the second benazepril component is in intimate
physical contact with the amiodipine components.
In another general aspect, the second benazepril component and amiodipine
components are physically inseparable.
In another general aspect, the second benazepril component and amiodipine
components are in the form of a blend, which comprises amiodipine, benazepril
or salts thereof and one or more pharmaceutical excipients.
In another general aspect, the second benazepril component is in limited or
enough physical contact with at least one amiodipine component such that the
composition exhibits desired stability over the storage period.
In another general aspect, first benazepril component is devoid of amiodipine.
In another general aspect, 50% of the total amount of benazepril in the
composition is present in the first components and remaining 50% of the
benazepril in the composition is present in the second components.
In another general aspect, the stable pharmaceutical composition of the present
invention retains at least 90% w/w of total potency of both amiodipine and
benazepril after storage at 40°C and 75% relative humidity for at least 3 months.
In another general aspect, the stable pharmaceutical composition of the present
invention comprises no more than 2.5% of (s,s)-diacid by weight relative to the
benazepril; and/or no more than 0.3% of impurity D by weight relative to the
amiodipine.
In another general aspect, there is provided a capsule comprising:
(a) one or more tablets comprising benazepril or its salt with one or more
pharmaceutical excipients; and
(b) a blend comprising benazepril, amiodipine or salts thereof and one or more
pharmaceutical excipients.
In another general aspect, there is provided a process for preparation of a stable
pharmaceutical composition comprising one or more amiodipine components and
at least two benazepril components, which process comprises of:
(a) providing at least one first benazepril component;
(b) providing at least one second benazepril component;
(c) providing at least one amiodipine component; and
(d) formulating the first and second benazepril components in a unit dosage form,
wherein the first benazepril component is substantially physically separated from
the amiodipine component and the second benazepril component is in physical
contact with the amiodipine component.
In another general aspect, there is provided a method of treating hypertension in
a patient which method comprising administering the pharmaceutical composition
as substantially described herein.
Detailed Description of the Invention
The stable pharmaceutical composition comprises at least one first benazepril
component; at least one second benazepril component; and at least one
amiodipine component, wherein the first benazepril component is substantially
physically separated from the amiodipine component and the second benazepril
component is in physical contact with the amiodipine component. The
combination composition is administered in the form of a single dosage form.
The term "amiodipine" as used throughout the specification refers to not only
amiodipine per se, but also its pharmaceutically acceptable salts, solvates,
hydrates, enantiomers and polymorphs. The preferred salt is amiodipine
besylate.
The term "benazepril" as used throughout the specification refers to not only
amiodipine per se, but also its pharmaceutically acceptable salts, solvates,
hydrates, enantiomers and polymorphs. The preferred salt is benazepril
hydrochloride.
The term "substantially physically separated from the amiodipine component" as
used throughout the specification refers to less than 10% w/w, preferably less
than 5% of amiodipine or salt thereof is in physical contact with second
benazepril component.
The term "physical contact" used throughout the specification refers to a physical
contact at an uncoated interface or physical contact throughout a blended
mixture of the two active ingredients. Particularly, the term "physical contact" is
used to refer an intimate physical contact between the two active ingredients.
The term "component" as used throughout the specification refers to one or more
tablets, mini-tablets, powder blend, granules, pellets, beads, solid particles,
layers coated on a surface or combination thereof.
In an embodiment, the composition comprises one or more tablets comprising
first part of benazepril or salt thereof along with one or more pharmaceutical
excipients and a powder blend comprising the second part of benazepril or salt
thereof, amiodipine or salt thereof and one or more pharmaceutical excipients.
The second part of benazepril and amiodipine in the blend are in physical contact
with each other.
The stable pharmaceutical composition of the present invention retains at least
90% w/w of total potency of both amiodipine and benazepril after storage at 40°C
and 75% relative humidity for at least 3 months. The composition comprises no
more than 2.5% of (s,s)-diacid (which is the main degradation product of
benazepril, also known as benazeprilat) by weight relative to the total amount of
benazepril; and/or no more than 0.3% of impurity D (which is the main
degradation product of amiodipine) by weight relative to the total amount of
amiodipine.
In an embodiment, the second benazepril component is in intimate physical
contact with the amiodipine components. In an alternate embodiment, the second
benazepril component and amiodipine components are physically inseparable.
In another embodiment, first benazepril component is devoid of amiodipine.
In a further embodiment, 50% of the total amount of benazepril in the
composition is present in the first components and remaining 50% of the
benazepril in the composition is present in the second components.
In an embodiment, the second benazepril component and amiodipine
components are in the form of a blend, which comprises amiodipine, benazepril
or salts thereof and one or more pharmaceutical excipients.
In a further embodiment, the composition comprises one or more tablets
comprising first part of benazepril or salt thereof, amiodipine or salt thereof along
with one or more pharmaceutical excipients and a powder blend comprising the
second part of benazepril or salt thereof and one or more pharmaceutical
excipients. The first part of benazepril and amiodipine in the blend are in physical
contact with each other.
The physical separation between the first component of benazepril and
amiodipine may be achieved by placing one or more protective coats over either
on the first benazepril component or on the part of the composition comprising
second benazepril part and amiodipine.
The stale pharmaceutical composition of the present invention is developed in
the form of single unit dosage form, such as capsules, multilayer tablets, bead,
beadlets, tablet in tablet, or inlay tablet.
In an embodiment, the first benazepril component is in the form of tablets and the
second benazepril component and amiodipine components are present in the
form of blend.
In one preferred embodiment, the stable unit dosage form comprises:
(a) a coated tablets comprising first part of benazepril and one or more
pharmaceutical excipients, and
(b) a blend comprising second part of benazepril or salt thereof, amiodipine or
salt thereof along with one or more pharmaceutical excipients, wherein the
coated tablet is substantially physically separated from the blend.
The dosages can be conveniently presented in unit dosage form and prepared by
suitable methods well known in the pharmaceutical arts.
In one embodiment, a process for the preparation of a stable pharmaceutical
composition of the present invention comprises steps of:
(a) providing at least one first benazepril component;
(b) providing at least one second benazepril component;
(c) providing at least one amlodipine component; and
(d) formulating the first and second benazepril components in a unit dosage form.
The stable composition of the present invention may include one or more
conventional excipients to enable formation of a present composition. The
pharmaceutical excipients includes, but not limited to one or more diluents,
binders, disintegrants, glidants, lubricants, plasticizer, opacifying agent, and
colorants.
Examples of suitable diluents include, but not limited to microcrystalline cellulose,
microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate,
calcium sulfate, sugar, dibasic calcium phosphate dihydrate, tribasic calcium
phosphate, mannitol, powdered cellulose and sorbitol.
Examples of suitable binders include, but not limited to carboxymethylcellulose
sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, methylcellulose, povidone, pregelatinized starch,
and starch.
Examples of suitable disintegrants include, but not limited to
carboxymethylcellulose calcium, croscarmellose sodium, crospovidone,
microcrystalline cellulose, polacrilin potassium, pregelatinized starch, sodium
starch glycolate, and starch.
Examples of suitable glidants include, but not limited to colloidal silicon dioxide,
magnesium trisilicate, powdered cellulose, starch and talc.
Examples of suitable lubricants include, but not limited to magnesium stearate,
calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated
castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium
lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
Examples of suitable plasticizers include, but not limited to such as glycerin and
sorbitol, and an opacifying agent or colorant.
In an embodiment, the stable combination composition of the present invention
one or more pharmaceutical excipients selected from the group consisting
of pregelatinized starch, lactose monohydrate, starch, crospovidone, and
microcrystalline cellulose, povidone, hydrogenated castor oil, mannitol, sodium
starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, crospovidone
magnesium stearate.
The present invention further provides a method of treating hypertension in a
patient which method comprising administering the pharmaceutical composition
as substantially described herein.
The present invention is further illustrated by the following examples which are
provided merely to be exemplary of the invention and do not limit the scope of
the invention. Certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Example : Capsule of amiodipine besylate and benazepril hydrochloride
Table 1
Total fill weight of capsule 212.10
Process:
(a) Process for Coated tablet preparation :
Half of the total quantity of benazepril hydrochloride, lactose monohydrate,
microcrystalline cellulose and pregelatinised starch were mixed with purified
water to form granulate. Granulate was dried in fluidized bed dryer at 60°C till the
desired LOD is achieved. To the dry granulate, crospovidone & colloidal silicon
dioxide was added followed by lubrication with magnesium stearate. The
lubricated granules were then compressed in to tablets. The tablets were then
coated using opadry as a coating material.
(b) Process for Powder blend preparation :
A blend of Amlodipine besylate, remaining half of the total quantity of benazepril
hydrochloride, microcrystalline cellulose, mannitol, sodium starch glycollate,
colloidal silicon dioxide and talc was mixed in a blender.
(c) Process for capsule filling :
The empty hard gelatin capsules were filled by using capsule filling machine by
placing the powder blend [prepared in step (b)] and coated tablet [prepared in
step (a)] in size ' 1 ' capsule shells.
Example 2: Stability Study of amiodipine besylate and benazepril
hydrochloride Capsule according to Example 1
Table 2
Not less than 80% of the
labeled amount of
Amiodipine free base is
dissolved in 30 minutes
Result of the stability study conducted on the capsule of Example 1 indicated that
amiodipine besylate and benazepril hydrochloride composition in accordance
with the present invention exhibits excellent storage stability over the storage
period.
Claims:
1. A stable pharmaceutical composition comprising:
(a) at least one first benazepril component comprising benazepril or salts
thereof;
(b) at least one second benazepril component comprising benazepril or
salts thereof; and
(c) at least one amiodipine component comprising amiodipine or salts
thereof,
wherein the first benazepril component is substantially physically
separated from the amiodipine component and the second benazepril
component is in physical contact with the amiodipine component.
2. The stable pharmaceutical composition of claim 1, wherein the second
benazepril component is in intimate physical contact with the amiodipine
components.
3. The stable pharmaceutical composition of claim 1 or 2, wherein the
second benazepril component and amiodipine components are physically
inseparable.
4. The stable pharmaceutical composition of claim 1, wherein the first
benazepril component comprises one or more protective coats over the
said component.
5. The stable pharmaceutical composition of claim 1, wherein the second
benazepril component and amiodipine components are in the form of a
blend, which comprises amiodipine, benazepril or salts thereof and one or
more pharmaceutical excipients.
6. The stable pharmaceutical composition of claim 5, wherein the blend of
second benazepril component and amlodipine component is coated with
one or more protective coats.
7. The stable pharmaceutical composition of claim 1, 2 or 3, wherein the
second benazepril component and amlodipine components are formulated
in the form of a tablet comprising benazepril and amlodipine or salts
thereof and one or more pharmaceutical excipients and the first benazepril
component is in the form of a blend.
8. The stable pharmaceutical composition of claim 1 or 4 , wherein the first
benazepril component is devoid of amlodipine.
9. The stable pharmaceutical composition of claim 1, wherein 50% of the
total amount of benazepril in the composition is present in the first
components and remaining 50% of the benazepril in the composition is
present in the second components.
10.The stable pharmaceutical composition of any of the preceding claims,
wherein the components are in the form of tablets, mini-tablets, powder
blend, granules, pellets, beads, solid particles, layers coated on a surface
or combination thereof.
11.The stable pharmaceutical composition of any of the preceding claims,
wherein the composition retains at least 90% w/w of total potency of both
amlodipine and benazepril after storage at 40°C and 75% relative humidity
for at least 3 months.
12.The stable pharmaceutical composition of any of the preceding claims,
wherein the composition comprises no more than 2.5% of (s,s)-diacid by
weight relative to the total amount of benazepril; and/or no more than
0.3% of impurity D by weight relative to the total amount of amlodipine.
13.A process for preparation of the stable pharmaceutical composition of any
of the preceding claims, which process comprises steps of:
(a) providing at least one first benazepril component;
(b) providing at least one second benazepril component;
(c) providing at least one amlodipine component; and
(d) formulating the first and second benazepril components in a unit
dosage form,
wherein the first benazepril component is substantially physically
separated from the amlodipine component and the second benazepril
component is in physical contact with the amlodipine component.
14. A capsule comprising:
(a) one or more tablets comprising benazepril or salts thereof with one or
more pharmaceutical excipients; and
(b) a blend comprising benazepril, amlodipine or salts thereof and one or
more pharmaceutical excipients.