"A STABILISED PHARMACEUTICAL COMPOSITION IN SOLID DOSAGE FORM"
The present invention relates to pharmaceutical compositions comprising
amlodipine maleate and to processes for making the same.
Calcium channel blockers are useful in treating a variety of cardiac conditions,
primarily angina and hypertension. EP 089 167 and corresponding US 4,572,909
disclose a class of substituted dihydropyridine derivatives as being useful calcium
channel blockers. These patents identify that one of the most preferred compounds is
2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-
methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now
commonly known as amlodipine, has the tbllowing formula:

Examples 8, 11, 12, and 22 of EP 089 167 show the synthesis of amlodipine in
the maleate salt form. While a variety of acid addition salts are taught to be suitable,
the maleate salt is identified as the most preferred acid addition salt.
Subsequently, EP 244 944 and corresponding US 4,879,303 were issued
directed to the besylate (or benzene sulfonate) salt of amlodipine. The besylate salt is
stated to provide certain advantages over the known salts including good formulating
properties. Indeed, amlodipine besylate, and not amlodipine maleate, has been
developed into a commercial prescription pharmaceutical by Pfizer and is sold in the
U.S. under the trade name NORVASC.
A review of the available portions of the NORVASC (amlodipine besylate)
New Drug Application (NDA) filed with the U.S. Food & Drug Administration by
Pfizer reveals that a switch was made during development from the original
amlodipine maleate to the amlodipine besylate. (See "Review of Original NDA" for
NDA# 19-787 of 10.10.1990, obtainable from FDA under Freedom of Information
Act ). The reasons for the switch were apparently tabletting and stability problems.
However, the precise stability and tabletting problems/issues/causes are not publicly
disclosed in the information available from the FDA. Interestingly, clinical studies in
the NDA include the use of the maleate salt form and the besylate salt form, the two
salt forms being therapeutically equivalent (bioequivalent). However, in these studies
amlodipine maleate was always used in a capsule or solution dosage form, not a tablet
dosage form.
The present invention relates to the discovery of stable amlodipine maleate
pharmaceutical compositions. A first aspect of the invention relates to a
pharmaceutical composition comprising an effective amount of amlodipine maleate
and at least one pharmaceutically acceptable excipient wherein the composition has a
pH within the range of 5.5 - 7.0. The composition is preferably a solid dosage form
such as a tablet or capsule. The invention also relates to methods of making such a
composition as well as to the use of such compositions in treating or preventing
angina or hypertension.
Another aspect of the invention relates to a process which comprises mixing
solid particles of amlodipine maleate having an average particle size of at least 20
microns with one or more pharmaceutically acceptable excipients to form a mixture.
Preferably the mixture has a pH of from 5 5 to 7.0. The mixture can be compressed
into tablets or filled into capsules to form a solid dosage form.
Stability is an important aspect of a pharmaceutical composition. The present
invention is based on the discovery that the prior art stability problems associated with
amlodipine maleate can be overcome primarily by controlling the pH of the
composition to be within the range of about 5.5 to 7.0, preferably of about 6.0-7.0.
Within this range the potential degradation reactions are minimized. In particular, the
formation of the following degradation product, referred to herein as amlodipine
aspartate, is diminished or prevented in this pH range.
Amlodipine Aspartate

Amlodipine aspartate is formed by a Michael addition reaction between
amlodipine and maleic acid. Because amlodipine and maleic acid are in intimate
contact with each other in the amlodipine maleate salt, the chances of the addition
reaction occurring increase with time; hence raising a stability issue. By controlling
the pH, the addition is significantly slowed or prevented altogether. Thus, it has now
been discovered that pH levels above 7.0 tend to encourage the degradation of
amlodipine maleate into amlodipine aspartate. Below a pH of about 5.5, other
degradation reactions tend to be encouraged, including the pyridine analogue of
amlodipine having the following structure:

Preferably the pH of the stabilized composition of our invention is in the range
of about 6.0 to 7.0 and more typically from about 6.1 or 6.2 to 6.8. For solid
compositions, the pH is determined by forming a slurry of the material with water
(demineralized water) and measuring the pH of the slurry, as is understood by workers
skilled in the art regarding the pH of a solid composition. The concentration of the
composition in the slurry is 20 wt%. The pH is measured by any standard technique.
The pharmaceutical compositions of the present invention comprise a
pharmaceutically effective amount of amlodipine maleate and at least one
pharmaceutically acceptable excipient. Preferably the stability of the composition is
such that after three months, more preferably after six months, in an environment
controlled room at 40°C/75% RH, it exhibits a loss of amlodipine (or, accordingly, an
increase in impurities content) of less than 10 %, preferably less than 5 %, and more
preferably less than 1%. Alternatively, the amlodipine maleate pharmaceutical
compositions of the present invention preferably exhibit a storage stability equivalent
to or superior to amlodipine besylate compositions. For example, the loss of
amlodipine during storage to degradation reactions is equivalent to (+/- 10%) or less
than the amlodipine loss in amlodipine besylate compositions, especially the
commercial product.
The form of the amlodipine maleate is not particularly limited and includes
anhydrates, solvates, hydrates and partial hydrates as well as crystalline and
amorphous forms. Further, the ratio of amlodipine to maleate can be varied and
specifically includes the more common and prior art form of 1:1 as well as a novel 2:1
form described commonly owned co-pending U.S. patent application serial No.
09/809,356, filed on March 16, 2001, and entitled "Amlodipine Hemimaleate," the
entire contents of which are incorporated herein by reference.
The amount of amlodipine is not particularly limited and includes any amount
that provides a pharmaceutical effect. In particular, amlodipine maleate can be used
to treat or prevent hypertension or angina by administering an effective amount to a
patient in need thereof. The specific form of angina is not particularly limited and
specifically includes chronic stable angina pectoris and vasospastic angina
(Prinzmetal's angina). The compound can be administered by any suitable route
including orally or parenterally depending on the dosage form. The "patients"
intended to be treated include human and non-human animals especially non-human
mammals. Generally the amount of amlodipine maleate in a unit dose is from 1 to
100 mg, more typically from 1 to 25 mg, and preferably about 1, 1.25, 2.5, 5 or 10 mg
(expressed in terms of the free base).
Amlodipine maleate can be made by any of the known techniques set forth in
the prior art, including those described in the above-mentioned patents EP 089 167
and US 4,572,909. It is desirable that the amlodipine maleate active be substantially
pure. For example, the content of impurities such as amlodipine aspartate, amlo-
pyridine, etc. that can be produced during the synthesis should be limited, preferably
to less than 2 wt %, although such purity is not required for the present invention. A
useful method to produce amlodipine maleate substantially free from amlodipine
aspartate is described in commonly owned co-pending U.S. patent application serial
No. 09/809,343, filed on March 16, 2001, and entitled "Process for Making
Amlodipine Maleate," the entire contents of which are incorporated by reference.
Similarly, a useful method for making amlodipine free base is described in commonly
owned co-pending U.S. patent application serial No. 09/809,351, filed on March'16,
2001, and entitled "Process For Making Amlodipine, Derivatives Thereof, and
Precursors Therefor," the entire contents of which are incorporated herein by
reference.
The pharmaceutical compositions of the present invention also contain at least
one excipient. An "excipient" as used herein means any pharmaceutical^ acceptable
inactive component of the composition. As is well known in the art, excipients
include diluents, binders, lubricants, disintegrants, colorants, preservatives, pH-
adjusters etc. The excipients are selected based on the desired physical aspects of the
final form: e.g., obtaining a tablet with desired hardness and friability, being rapidly
dispersible and easily swallowed, etc. The desired release rate of the active substance
from the composition after its ingestion also plays a role in the choice of excipients.
Preferred release rate is the rate comparable with commercially available amlodipine
besylate tablets.
Suitable excipients for use in this invention include:
- a diluent such as calcium hydrogen phosphate, lactose, mannitol etc.
- a binder such as microcrystalline cellulose or a modified cellulose, povidone
etc.
- a disintegrant such as sodium starch glycollate, crosspovidone
- a lubricant such as magnesium stearate, sodium stearyl fumarate, talc
- a colorant, taste masking agent etc..
The pH of the composition can be controlled or adjusted by the proper
selection of excipients. It should be borne in mind that amlodipine maleate is slightly
acidic. For example, amlodipine maleate has a pH of about 4.8 as a saturated aqueous
solution. Thus using excipients that are pH inert; i.e., they have little to no effect on
pH, generally results in a non-alkaline pharmaceutical composition because the
amlodipine maleate essentially acts as its own adjusting agent. An example of a pH-
inert excipient is microcrystalline cellulose. A composition comprising amlodipine
maleate and microcrystalline cellulose generally exhibits a pH of about 6. For
comparison, the corresponding amlodipine besylate composition generally has a pH of
about 7 and the corresponding amlodipine free base composition generally has a pH of
about 9. Commercially available tablets comprising amlodipine besylate and sold
under brand name Norvasc exhibit a pH typically between 7.05-7.35 (again measured
as a 20 wt% slurry).
Excipients having a pH effect can also be used. The pH of these excipients
must be taken into account in developing the pharmaceutical composition so that the
overall pH of the pharmaceutical composition falls within the range of about 5.5 to
7.0.
For example, the commercially available/pharmaceutically acceptable calcium
phosphates are generally alkaline; i.e. pH greater than 7 when measured as described
above in a 20% slurry. For instance, DI-TAB, a commercially available dibasic
calcium phosphate dihydrate, is reported as having a pH of about 7.4. Nonetheless
some forms and grades of calcium phosphate are acidic or neutral pH. This lower pH
can be due to the species of calcium phosphate as well as the treatment during
processing of the material, such as in removing impurities/washing. For example,
dibasic calcium phosphate anhydrate is generally considered to have a pH of about 7.3
whereas A-Tab ™ (Rhodia), also a dibasic calcium phosphate anhydrate, has a pH of
about 5.0. Further examples of commercially available non-alkaline calcium
phosphates include DiCAFOS A (Budenheim) having a pH of about 7 (10 % slurry)
and Fujicalin SG (Fuji) having a pH from 6.1-7.2 (5 % slurry). By using a non-
alkaline calcium phosphate as an excipient, a pharmaceutical composition meeting the
desired pH can be attained. Alternatively, a blend of calcium phosphates, some at pH
above 7 and some a pH below 7 can be used to achieve the desired pH of the
composition.
Instead of, or in addition to a non-alkaline calcium phosphate, other acidic
excipients can be used by themselves or to counter balance an alkaline excipient. An
example of such an acidic excipient is the disintegrant Explotab(TM) of Penwest,
which is a cross-linked, low substituted sodium starch glycollate. Further, pH
adjusting agents can also be used to attained the desired pH. These agents include
pharmaceutically acceptable acids such as maleic acid, citric acid or ascorbic acid (the
second two have utility also to act as antioxidants) and pharmaceutically acceptable
bases such as calcium oxide or magnesium oxide. Salts of weak acids and/or weak
bases are also suitable pH adjusters as they act as buffers imparting pH to lower or
higher values according to the chemical nature of their components.
The pharmaceutical compositions of the present invention are not particularly
limited in terms of form or route of administration. Oral dosage forms as well as
parenteral dosage forms are included. The composition can be in the form of a liquid,
solid, or suspension. Preferably, the pharmaceutical composition is a solid dosage
form such as a tablet, capsule or sachet intended for oral administration.
Preferred solid dosage forms contain as a major excipient microcrystalline
cellulose, a calcium phosphate, especially calcium hydrogenphosphate, or a
combination thereof. The sum of the other excipients, if any, is generally less than 25
wt%, more usually less than 10 wt% and in some cases less than 5 wt% of the total
pharmaceutical composition. Preferred other excipients are a disintegrant such as
sodium starch glycollate and/or a lubricant such as magnesium stearate and/or talc.
For example, a pharmaceutical composition comprising amlodipine maleate
and microcrystalline cellulose as the only excipient has been shown to provide good
stability against the formation of impurities.
The pharmaceutical compositions of the present invention can be made by
techniques generally known in the art. In general, the amlodipine maleate is mixed
with one or more excipients to form a blend. The mixing can be carried out wet or dry
(i.e. using or not using a solvent or a liquid diluent in the process) and can involve
granulating, slugging, or blending of powders. A dry process is however preferred.
The blend, after optional further processing, can be compressed into tablets or filled
into capsules such as gelatin capsules. Typically the amlodipine maleate to be mixed
is in the form of particles. The storage stability of the pharmaceutical composition of
the present invention is enhanced, in general, by using larger particle sizes. Preferably
the average particle size of the amlodipine maleate is at least 20 microns, more
preferably at least 100 microns, and in some embodiments at least 300 microns. If an
adjustment of the pH of the composition is needed, it preferably is adjusted before
processing into the final form such as a tablet or capsule.
For example, tablets made of the present invention can be prepared, e.g. by a
wst granulation of a mixture of amlodipine maleate and a solid carrier/diluent such as
calcium phosphate of the proper grade, with the aid of a granulating solvent such as
water or ethanol; drying the wet granulate; sieving the granulate; blending with
sodium starch glycollate and magnesium stearate and compressing the tablet mixture
For example, tablets made of the present invention can be prepared, e.g. by a
wet granulation of a mixture of amlodipine maleate and a solid carrier/diluent such as
calcium phosphate of the proper grade, with the aid of a granulating solvent such as
water or ethanol; drying the wet granulate; sieving the granulate; blending with
sodium starch glycollate and magnesium stearate and compressing the tablet mixture
into tablets. The control of pH and/or adjusting the pH value should be
advantageously included before blending with magnesium stearate. In this example
both the granulating step and the blending step are considered as "mixing" steps since
amlodipine maleate and an excipient are mixed.
Yet another suitable process comprises direct compression of the blend of
amlodipine maleate and excipient(s). In this process, the ingredients are blended
together to form a compressible blend composition that is subsequently compressed
into a tablet. A blend that comprises amlodipine maleate, microcrystalline cellulose
and/or calcium phosphate, and optionally sodium starch glycollate and/or magnesium
stearate may be useful in forming a tablet by direct compression. For example, a
blend comprising amlodipine maleate, calcium hydrogen phosphate , microcrystalline
cellulose and sodium starch glycollate having a pH of 5.5 to 7.0 can be blended
together, re-blended with magnesium stearate and pressurized to form a stable tablet.
The tablets of the present invention comprising amlodipine maleate,
microcrystalline cellulose, sodium starch glycollate and magnesium stearate,
optionally with addition of calcium hydrogenphosphate, does not suffer from the
problem of stickiness to the tablet punch as reported in prior art regarding other
amlodipine formulations (see the above cited EP 244 944). Accordingly, the
composition of the present invention may be produced in industrial scale without
technological problems.
Tablets may be covered with a suitable coating. For example, the coating can
be a moisture barrier to help with storage stability or a sustained or delayed release
coating composition as are well known in the art.
Alternative dosage forms are capsules, both soft and hard capsules. The
stabilized amlodipine maleate composition of the invention as described above is
filled into capsules by techniques known in the art, in amounts comprising the desired
therapeutical dose of amlodipine.
Suitable package material for packing the pharmaceutical dosage forms are
plastic or glass containers and blisters. Particularly blisters made from non-permeable
materials (high density polyethylene or aluminium) are advantageous as they may
contribute to decreasing the rate of formation of degradation impurities, namely the
amlo-pyridine impurity, during storage.
The pharmaceutical compositions of the present invention are used in treating
or preventing angina or hypertension, as previously defined, by administering an
effective amount of the pharmaceutical composition to a patient in need thereof.
Typically the pharmaceutical composition is a unit dose. Individual unit dose
compositions generally contain from 1 to 100 mg of amlodipine maleate, more usually
from 1 to 25 mg. Preferable are unit doses comprising amlodipine maleate in an
equivalent of 1.25, 2.5, 5 or 10 mg of amlodipine, such as tablets or capsules for oral
administration. The pharmaceutical composition is administered from 1 to 3 times
daily, preferably once a day. The above compositions are also useful in reducing heart
failure symptoms, improving systolic left ventricular function and increasing exercise
capacity in patients with ischaemic LVD and heart failure without current angina.
Amlodipine maleate compositions of our invention may be also used in
medical applications in combination with other antihypertensive and/or antianginal
agents, for instance with ACE- inhibitors such as benazepril. The combination may be
realized in a form of single combination preparation, e.g. a capsule containing
amlodipine maleate and benazepril hydrochloride, or by separate administration of
drugs containing the above agents. Similarly, amlodipine maleate may also be
combined with HMG-CoA reductase inhibitors, particularly statins such as lovastin,
simvastatin, atorvastatin, etc.
Accordingly, the present invention further provides a method for treating
and/or preventing any one or more of angina, hypertension and heart failure (the
Disorders) by administering a pharmaceutical composition of our invention
comprising an effective and/or prophylactic amount of amlodipine maleate to a
sufferer in need thereof.
The present invention also provides the use of the composition of the invention
in the manufacture of a medicament for treating and/or preventing any one or more of
the Disorders.
Particle size of the amlodipine maleate substance used for production of
batches A - F was measured by laser diffraction and it was proven that less than 90%
of particles is smaller than 204 microns and 50% of particles is smaller than 80
microns.
This amlodipine maleate was milled to a particle size of 10-20 microns and
used for producing batches (G) and (H). Alternately, another batch of amlodipine
maleate with particle sizes 90% less than 11 microns and 50% less than 6 microns was
used for producing batch (I).
c) Manufacturing procedures
Batches (A) - (F) and (I) have been manufactured as follows:
- The amlodipine maleate was sieved through a 500 µm screen.
- The other excipients have been sieved through a 850 µm screen.
- All excipients except magnesium stearate have been mixed in a free fall mixer for
15 minutes at about 25 rpm. Value of pH was checked at 20% aqueous slurry.
Magnesium stearate was added and the powder blend was mixed for another 5
minutes at about 25 rpm.
2.5 mg and / or 10 mg tablets have been compressed using a Korsch EK0 excenter
press.
Batches (G) and (H) have been manufactured as follows:
Amlodipine maleate was milled
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate have been mixed in a free fall mixer
for 15 minutes at about 25 rpm. Value of pH was checked at 20% aqueous slurry.
Magnesium stearate was added and the powder blend was mixed for another 5
minutes at about 25 rpm.
2.5 mg / 10 mg tablets have been compressed on Korsch EKO excenter press.

Manufacturing process
Amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate and talc have been mixed in
a free fall mixer for 15 minutes at about 25 rpm. Value of pH was checked at 20%
aqueous slurry.
Magnesium stearate and talc were added and the powder blend was
mixed for another 5 minutes at about 25 rpm.
2.5 mg and 10 mg tablets have been compressed using a Korsch EKO
excenter press.
Properties of tablet composition :
pH of 20% (w/V) slurry: - Batch (J) = 5.92
- Batch (K) = 5.96
EXAMPLE 3 Amlodipine maleate tablets comprising mannitol
Composition

Manufacturing procedure
Amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate and talc have been mixed in
a free fall mixer for 15 minutes at about 25 rpm. Value of pH was checked at 20%
aqueous slurry.
Magnesium stearate and talc were added and the powder blend was
mixed for another 5 minutes at about 25 rpm.
10 mg tablets have been compressed using a Korsch EK0 excenter
press.
Manufacturing process
The amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 nm screen.
Amlodipine maleate, magnesium oxide and about 30 % of the amount
of microcrystalline cellulose (MCC) were mixed in a free fall mixer for 10 minutes at
about 25 rpm.
The remaining amount of MCC, calcium hydrogenphopsphafe
anhydrous and sodium starch glycollate were added and the blend was mixed in a free
fall mixer for 15 minutes at about 25 rpm. Value of pH was checked at 20% aqueous
slurry.
Magnesium stearate was added and the powder blend was mixed for
another 5 minutes at about 25 rpm.
2.5 mg tablets and proportionately larger 10 mg tablets have been
compressed using a Korsch EK0 excenter press.
Example 5 Stability studies on amlodipine maleate tablets
Stability studies on batches produced in Examples 1-4 were performed in a
thermostated chamber adjusted to 40 +2 °C and 75+5 % of releative humidity in
various package materials ( HDPE bottles, PVC/PVDC/PE blisters ) or on an open
dish. Assay of the active substance and of the content of impurities was performed by
HPLC method, using reference materials of amlodipine maleate and major
degradation impurities :
amlodipine aspartate ( Z#204)
amlo-pyridine (Z#202)
Apart, two minor impurities Z#203 and Z#205 were detected and identified.
The content of other detected impurities/degradation products was calculated
by internal normalization.
In the following tables, the assay of the active substance is expressed in
miligrams, the content of impurities is expressed in per cent.
Stability studies performed in PVC/PE/PVDC blister at 40°C/75%RH

Stability studies performed open dish at 40°C/75%RH

Stability studies performed in HDPE container at 40°C/75%RH

Comparative stability studies performed at the composition with alkaline pH (open
dish, 40°C/75%RH

Stability studies performed at 40°C/75%RH, open dish (influence of particle size)

For a comparison of stability, increase in total impurities, identified and unidentified,
with regard to the t=0 months level, is considered:

Batch (CA) has been manufactured as follows:
The amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate have been mixed in a free
fall mixer for 15 minutes at about 25 rpm. pH value was checked in 20% aqueous
slurry.
Magnesium stearate was added and the powder blend was mixed for
another 5 minutes at about 25 rpm.
gelatine capsules have been filled with this powder blend
Batch (CB) has been manufactured as follows:
The amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate have been mixed in a free
fall mixer for 15 minutes at about 25 rpm. pH value was checked in 20% aqueous
slurry.
Magnesium stearate was added and the powder blend was mixed for
another 5 minutes at about 25 rpm.
HPMC capsules have been filled with this powder blend
Batch (CC) has been manufactured as follows:
The amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
All excipients except magnesium stearate have been mixed in a free
fall mixer for 15 minutes at about 25 rpm. pH value was checked in 20% aqueous
slurry.
Magnesium stearate was added and the powder blend was mixed for
another 5 minutes at about 25 rpm.
gelatine capsules have been filled with this powder blend
Batch (CX) has been manufactured as follows:
The amlodipine maleate was sieved through a 500 µm screen.
The other excipients have been sieved through a 850 µm screen.
Amlodipine maleate, magnesium oxide and about 30 % of the amount
of microcrystalline cellulose (MCC) were mixed in a free fall mixer for 10 minutes at
about 25 rpm.
The remaining amount of MCC, calcium hydrogenphosphate
anhydrous and sodium starch glycollate were added and the blend was mixed in a free
fall mixer for 15 minutes at about 25 rpm. pH value was checked in 20% aqueous
slurry.
Magnesium stearate was added and the powderblend was mixed for
another 5 minutes at about 25 rpm.
gelatine capsules have been filled with this powderblend, using an
automatic capsule filling machine.
Example 7 Stability studies on amlodipine maleate capsules
Stability studies on batches prepared in Example 6 were performed
essentially as described in Example 5.
Stability studies performed in PVC/PE/PVDC blister at 40 °C/75 % RH

Two one month stability studies performed in open dish

Stability studies performed in HDPE container

Stability studies on commercially available Amlor® (amlodipine besylate)
capsules
Stability studies performed in original blister

The invention having been described, it will be readily apparent to those
skilled in the art that further changes and modifications in actual implementation of
the concepts and embodiments described herein can easily be made or may be learned
by practice of the invention, without departing from the spirit and scope of the
invention as defined by the following claims
WE CLAIM:
1. A pharmaceutical composition comprising an effective amount of amlodipine
maleate and at least one pharmaceutically acceptable excipient wherein said composition
has a pH within the range of 6.0 - 7.0.
2. The composition as claimed in claim 1, wherein said composition is in solid
form.
3. The composition as claimed in claims 1 or 2, wherein said excipient is calcium
phosphate or microcrystalline cellulose.
4. The composition as claimed in claim 3, wherein said composition comprises
calcium phosphate and microcrystalline cellulose.
5. The composition as claimed in claim 3, wherein said excipient is calcium
hydrogen phosphate.
6. The composition as claimed in claim 3, wherein said excipient is microcrystalline
cellulose.
7. The composition as claimed in any of the preceding claims, comprising an acidic
pH adjusting agent.
8. The composition as claimed in any of the preceding claims, wherein said
composition is in the form of a tablet.
9. The composition as claimed in claim 8, which has an outer moisture and/or light
barrier layer surrounding said tablet.
10. The composition as claimed in any of the preceding claims 1-7, wherein said
composition is in the form of a capsule.
11. The composition as claimed in any of the preceding claims, wherein said amount
of amlodipine maleate corresponds to 1.0 to 25 mg of amlodipine free base.
12. The composition as claimed in claim 11, wherein said amount of amlodipine
maleate corresponds to 1.25, 2.5, 5 or 10 mg of amlodipine free base.
13. A process for making the composition as claimed in any of the claims 1-12, which
comprises mixing amlodipine maleate and at least one pharmaceutically acceptable
excipient to form a mixture, having a pH within the range of 6.0 to 7.0 respectively.
14. A process as claimed in claim 13, wherein the pH of the resulting mixture is
within the range of 6.0 to 7.0.
15. A process as claimed in claim 13 or 14, wherein the amlodipine maleate is mixed
as solid particles having an average particle size of at least 20 microns.
16. A process as claimed in claim 15, wherein the amlodipine maleate is mixed as
solid particles having an average particle size of at least 100 microns.
17. A process as claimed in any of the claims 13-16, wherein said mixing is carried
out by wet granulation.
18. A process as claimed in any of the claims 13-16, wherein said mixing is carried
out by a dry method.
19. A process as claimed in any of the claims 13-18, which comprises compressing
said mixture into a tablet.
20. A process as claimed in any of the claims 13 - 18, which comprises filling
capsules with said mixture to form a pharmaceutical dosage form.
21. A composition as claimed in any of the claims 1-12 for the manufacture of a
medicament for the treatment of angina, hypertension or heart failure.

An amlodipine maleate pharmaceutical composition is provided with good stability when formulated with a pH
within the range of 5.5 to 7, when measured as a 20 wt% aqueous slurry. The stability can also be aided by making the pharmaceutical
composition from amlodipine maleate particles having an average particle size of greater than 20 microns, preferably greater than
100 microns.