FIELD OF INVENTION:
The present invention relates to stable pharmaceutical compositions comprising ramipril or
pharmaceutically acceptable salts thereof, which are susceptible to degradation, and
processes for the preparation thereof.
BACKGROUND OF INVENTION:
ACE inhibitors, or inhibitors of Angiotensin Converting Enzymes, are drugs useful in the
treatment of cardiovascular disorders, especially hypertension. However, it has been widely
observed that ACE inhibitors are susceptible to breakdown, especially due to degradation
and/or cyclization between the time of manufacture and the time of desired usage.
Breakdown of ACE inhibitors has been found to occur both in solid and in liquid states. As
breakdown of ACE inhibitor increases, the concentration of available, functional ACE
inhibitor decreases.
Ramipril and other related ACE inhibitors like containing compositions suffer from the
drawback that they degrade readily in pharmaceutical dosage forms giving rise to a diketo
piperazine also known as DKP (the internal cyclization product) and a diacid (the ester
hydrolysis product).
Other examples of related ACE inhibitors include, quinapril, enalapril, spirapril, perindopril,
indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and
combinations thereof; which also degrade readily in dosage forms. It is believed that one or
more of these types of degradation including oxidation cause the discoloration in
pharmaceutical compositions containing ACE inhibitors.
The degradation products result in decreased drug effectiveness. Accordingly various
methods of improving the stability of certain ACE inhibitors have been tried.
U.S. Pat. No. 4,743,450 discloses that certain ACE inhibitors, and in particular, quinapril and
its acid addition salts can be stabilized by making solid compositions that include an alkali or
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alkaline earth metal carbonate, preferably magnesium carbonate, and a saccharide,
specifically a sugar, such as mannitol or lactose.
U.S. Pat. No. 4,793,998 discloses that certain ACE inhibitors, and in particular, quinapril and
its acid addition salts can be stabilized by making solid compositions that include ascorbic
acid, and optionally one or more acids selected from citric, fumaric and maleic acids.
U.S. Pat. No. 4,830,853 discloses that certain ACE inhibitors, and in particular, quinapril and
its acid addition salts can be stabilized by making solid compositions that include ascorbic
acid or a metal or ammonium ascorbate.
U.S. Pat. Nos. 5,151,433 and 5,442,008 relate to method for stabilization of ramipril which
comprises coating ramipril or its pharmaceutically acceptable salt, with a polymeric
protective film, or comprises mixing ramipril or its pharmaceutically acceptable salt with a
physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly
alkaline range is set up in a formulation in the presence of moisture, and ramipril which has
been stabilized by a polymeric protective film or by mixture with a buffer.
The patent teaches that decomposition of ramipril is favored by mechanical stress during
formulating the dosage form as well as with increasing temperature and moisture that the
formulation may be subjected to, during storage. The use of a protective coating of polymeric
film-formers around the ramipril counteracts the decomposition of ramipril due to
mechanical stress. The invention of this patent uses a layer or coating of a polymer having a
defined thickness to prevent damage to ramipril due to mechanical stress.
US Pat. Appln. 2005/0169981A1 relates to a solid pharmaceutical composition for oral
administration comprising ramipril and lactose monohydrate. It is disclosed that the use of
lactose monohydrate as a diluent provides a ramipril formulation with stability superior to
that achieved by using either anhydrous lactose or starch as diluent.
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WO 2005/067887A2 claims a stable tablet formulation comprising ramipril, calcium sulphate
dihydrate and sodium hydrogen carbonate optionally in combination with a disintegrant,
binder and lubricant and other excipients
US Pat. Appln 2005/202081A1 claims a stable pharmaceutical composition wherein a
compressed core is coated with an ACE inhibitor, such as ramipril. This process avoids
degradation of the ACE inhibitor to the diketopiperazine due to mechanical stress, and also
avoids direct contact of the auxiliaries used in the composition with the ACE inhibitor
thereby further preventing degradation.
US Pat. Appln 2003/0215526A1 claims a pharmaceutical composition comprising an ACE
inhibitor susceptible to degradation, mixed with a greater than stoichiometric amount of an
alkali or alkaline earth metal carbonate.
WO 2005/011737A3 relates to a pharmaceutical composition in combination, with at least
one stabilising agent comprising at least one carbonate salt of an amino acid optionally
together with one or more saccharides, whereby the stabilising agent can provide a protective
stabilising effect for the at least one therapeutic agent susceptible to degradation when
present in a pharmaceutical formulation.
US Pat. Appln 2006/0188568A1 relates to a stabilized pharmaceutical solid composition of
ACE inhibitor comprising an ACE inhibitor and a selective dosage formulation thereof
comprising of meglumine.
US Pat. Appln 2006/0134213Al claims a pharmaceutical composition comprising ramipril
coated by a blending agent, wherein the blending agent is selected from; glyceryl behenate,
glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol,
polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or
combinations thereof.
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US Pat. Appln 2006/0045911A1 claims a stable oral pharmaceutical formulation comprising
ramipril or its pharmaceutically acceptable salt and a stabilizing amount of an
ammoniomethacrylate copolymer.
US Pat. Appln 2006/0177498A1 relates to a solid pharmaceutical compositions comprising
ramipril with suitably low water content, and processes for preparing said compositions.
Although each of the above patents or patent applications represents an effort to overcome
the instability problems associated with pharmaceutical compositions containing an ACE
inhibitor, there still exists a need for improving the stability of such pharmaceutical
compositions.
SUMMARY OF THE INVENTION:
The invention provides stable pharmaceutical compositions comprising ramipril or
pharmaceutical acceptable salts thereof and stabilizer (s), which include magnesium salts.
Another embodiment of the present invention provides stable pharmaceutical compositions
comprising ramipril or pharmaceutical acceptable salts thereof and stabilizer (s), which
include magnesium salts along with lactic acid. Preferred magnesium salts include
magnesium carbonate, magnesium oxide and magnesium hydroxide.
Yet another embodiment of the present invention provides a stable pharmaceutical
composition comprising ramipril or pharmaceutical acceptable salts thereof wherein the
formation of an internal cyclization product, and/or ester hydrolysis product, and/or oxidation
product, has been reduced or eliminated and the weight percentages are based on the total
weight of the pharmaceutical composition.
Yet another embodiment of the present invention provides stable pharmaceutical
compositions comprising ramipril or pharmaceutical acceptable salts thereof wherein the
stabilizer consists essentially of magnesium oxide.
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Yet another embodiment the present invention provides for using packaging materials along
with a desiccant. Preferred packaging materials are containers including lid composed of
polyethylene and/or polypropylene and/or glass, and blisters or strips composed of
aluminium or high-density polyethylene. Preferred desiccants include Silica gel, Activated
alumina, Magnesium sulfate.
Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril-
diketopiperazine is less than about 0.1 %, of the total weight of ramipril during the first,
month when the pharmaceutical composition is stored at 40° C/75% RH.
Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril-
diacid is less than about 0.2 %, of the total weight of ramipril during the first, month when
the pharmaceutical composition is stored at 40° C/75% RH.
Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril-
diketopiperazine is less than about 0.3 %, of the total weight of ramipril during the third,
month when the pharmaceutical composition is stored at 40° C/75% RH.
Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril-
diacid is less than about 0.45 %, of the total weight of ramipril during the third, month when
the pharmaceutical composition is stored at 40° C/75% RH.
Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril-
diketopiperazine is less than about 0.15 %, of the total weight of ramipril during the third,
month when the pharmaceutical composition is stored at 25° C/60% RH.
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Yet another embodiment, the present invention provides a pharmaceutical composition
comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril-
diacid is less than about 0.25 %, of the total weight of ramipril during the third, month when
the pharmaceutical composition is stored at 25° C/60% RH.
DETAILED DESCRIPTION OF INVENTION:
It has been surprisingly found that ramipril or pharmaceutical acceptable salts thereof are
enabled to be stable in the presence of a stabilizing effective amount of magnesium salts and
lactic acid.
It has also been found that stable compositions comprising ramipril magnesium can be made
using ramipril or an acid addition salt thereof, by reacting the ramipril or acid addition salt
with an alkaline magnesium compound, so as to convert all or substantially all of the ramipril
or acid addition salt to ramipril magnesium.
The term "all or substantially all" means that the remaining quantity of ramipril or acid
addition salt thereof, if any, will be small enough that any degradation thereof will not be
significant to the stability of the final product. Hence "all or substantially all" will be
understood to mean that at least about 80% of the ramipril or addition salt thereof is
converted to ramipril magnesium, preferably at least 90%, more preferably at least 95%, and
most preferably 100% or virtually 100%.
A reaction to convert the ramipril or acid addition salt thereof to ramipril magnesium can be
accomplished simply by mixing the ramipril or acid addition salt together with the alkaline
magnesium compound in dry state or by reacting ramipril or acid addition salt and the
alkaline magnesium compound with the aid of solvent, which may be water or organic
solvent or a mixture of water and organic solvent, and then evaporating the solvent to obtain
a dry substance. The solvent will preferably be a water or mixture of water and organic
solvent. After the solvent is evaporated, the dried material obtained is further processed into a
dosage form, such as tablets or capsules.
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Additional stabilizers such as Lactic acid can be added to the dried material.
The term "stabilizing effective amount" used means any amount, which will effectively
retard or prevent degradation of the ramipril or pharmaceutically acceptable salts thereof.
The quantity of the stabilizer component to be used may lie between about 0.1% w/w and
50% w/w, preferably about 0.1% w/w to about 10% w/w. In general, any amount, which will
effectively retard or prevent degradation of the ramipril or pharmaceutically acceptable salts
thereof, can be used.
The solid dosage form may further comprise diluent and other formulating agents such as
binder, disintegrant, lubricant and glidant.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent. Particular
examples include lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch,
calcium hydrogen phosphate, mannitol and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, hydroxypropylcellulose or the like. Disintegrant may be, for example,
croscarmellose sodium, crosspovidone, sodium starch glycolate, bentonite, sodium alginate,
hydroxypropylmethylcellulose or the like.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, hydrogenated
vegetable oils, stearic acid, sodium stearyl fumarate, sodium benzoate or the like.
Glidants may be, for example, colloidal silicon dioxide (aerosil), talc or the like.
Any techniques for processing the products of the invention, which are appropriate, can be
employed.
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The invention is now described by following non-limiting illustrative examples:
EXAMPLE 1
Formula Quantity in Mg
A B C
Ramipril 1.25 1.25 1.25
Magnesium oxide 0.56 1.25 2.00
Water Q.S Q.S QS
Lactose monohydrate 59.98 59.29 60.35
Lactic acid 0.31 0.31 0.5
Pregelatinized starch 27 27 25
Sodium stearyl fumarate 0.9 0.9 0.9
Total weight 90 mg 90 mg 90 mg
BRIEF MANUFACTURING PROCEDURE:
1.Disperse magnesium oxide in water.
2. Add slowly weighed qty of Ramipril in step one.
3.Mix the resultant mixture of step 2 for 15 minutes.
4.Sift lactose monohydrate through a suitable mesh, and adsorb lactic acid on the lactose.
5.Granulate step 4 blend with step three dispersion.
6.Dry in Tray dryer at 40°C till a desired LOD is achieved.
7.Pass the dried granules through a suitable mesh.
8.Lubricate the granules with Pregelatinized starch and sodium stearyl fumarate.
9.Compress the lubricated blend into tablet or fill the blend into the empty hard gelatin
capsule.
EXAMPLE 2
Formula A B
Ramipril 1.25 1.25
Magnesium oxide 0.56 NA
Water Q.S Q.S
Lactose monohydrate 59.98 60.85
Lactic acid 0.31 NA
Pregelatinized starch 27 27
Sodium stearyl fumarate 0.9 0.9
Total weight 90 mg 90 mg
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BRIEF MANUFACTURING PROCEDURE: Same as Example 1 except no magnesium
oxide and lactic acid are added.
STABILITY PROFILE:
The degradation of ramipril or pharmaceutically acceptable salts thereof occur mainly via
two pathways: the hydrolysis to ramipril diacid (also known as impurity E) and the
cyclization to ramipril diketopiperazide (also known as impurity D).
Table 1, 2 and 3 show a comparative stability data between the formulation and packaging
materials.
Table I: Comparative stability profile of formulation containing MgO and Lactic acid and
formulation without MgO and Lactic acid
Formulation With MgO and Lactic Acid Without MgO and Lactic Acid
Ex 2A Ex 2B
1M HDPE HDPE
40° C / 75 % RH With Desiccant With Desiccant
Impurity D 0.054 5.539
Impurity E 0.096 0.283
Table II: Stability profile of Ex 1 at 40° C / 75 % RH for 3 months
Formulation with MgO and Lactic Acid
3M HDPE Blister (PVC/Aclar) in Alu Pouch
40° C / 75 % RH With Desiccant With Desiccant
Impurity D 0.210 0.146
Impurity E 0.309 0.389
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Table III: Stability profile of Ex 1 at 25° C / 60 % RH for 3 months
Formulation with MgO and Lactic Acid
3 Month HDPE Blister (PVC/Aclar) in Alu Pouch
25° C / 60 % RH With Desiccant With Desiccant
Impurity D 0.088 0.097
Impurity E 0.160 0.183
Thus presence of Magnesium salts and lactic acid provide stability to the composition. The
tables above further demonstrate that the effect of packaging with HDPE and Blister pack.
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WE CLAIM;
1. A pharmaceutical composition comprising ramipril or pharmaceutically acceptable
salts thereof and magnesium salts and lactic acid in a stabilizing effective amount to
prevent cyclization and hydrolysis of ramipril or other related ACE inhibitors.
2. A pharmaceutical composition of claim 1 wherein the magnesium salts is selected
from the group comprising magnesium carbonate, magnesium oxide and magnesium
hydroxide.
3. A pharmaceutical composition of claim 1 wherein the magnesium salt is magnesium
oxide.
4. A pharmaceutical composition in claim 1 wherein magnesium oxide is present in a
stabilizing effective amount ranges from about 0.1% w/w to about 50 % w/w to
prevent cyclization and hydrolysis of ramipril or other related ACE inhibitors.
5. A pharmaceutical composition in claim 1 wherein lactic acid is present in a
stabilizing effective amount from about 0.1% w/w to 10 % w/w to prevent cyclization
and hydrolysis of ramipril or other related ACE inhibitors.
6. A process for stabilizing ramipril pharmaceutically acceptable salts thereof against
cyclization, which comprises the step of contacting the drug with: (a) a stabilizing
effective amount magnesium oxide and/or, (b) stabilizing effective amount of lactic
acid.
7. A pharmaceutical composition of claim 1 comprising ramipril or pharmaceutically
acceptable salts thereof and magnesium oxide and lactic acid in a stabilizing effective
amount to prevent cyclization and hydrolysis of ramipril or other related ACE
inhibitors is packed using suitable packaging materials along with a desiccant.
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8. A pharmaceutical composition of claim 6 wherein the desiccants are selected from the
group comprising of Silica gel, Activated alumina, Magnesium sulfate, Calcium
hydride, Calcium sulfate, Molecular sieve, Sodium sulfate.
9. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less
than about 0.1 % of the total weight of ramipril during the first month when the
pharmaceutical composition is at 40°/75% RH.
10. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diacid is less than about
0.2 % of the total weight of ramipril during the first month when the pharmaceutical
composition is at 40°/75% RH.
11. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less
than about 0.3 % of the total weight of ramipril during the third month when the
pharmaceutical composition is at 40°/75% RH.
12. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diacid is less than about
0.45 % of the total weight of ramipril during the third month when the pharmaceutical
composition is at 40°/75% RH.
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13. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diketopiperazine is less
than about 0.15% of the total weight of ramipril during the third month when the
pharmaceutical composition is at 25°/60% RH.
14. A pharmaceutical composition comprising ramipril and magnesium oxide and lactic
acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril
wherein the rate of decomposition of the ramipril to ramipril-diacid is less than about
0.25 % of the total weight of ramipril during the third month when the pharmaceutical
composition is at 25°/60% RH.
Dated this 1st day of May 2007.

A pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and magnesium salts and lactic acid in a stabilizing effective amount to prevent cyclization and hydrolysis of ramipril or other related ACE inhibitors. A process for stabilizing ramipril pharmaceutically acceptable salts thereof against cyclization, which comprises the step of contacting the drug with: (a) a stabilizing effective amount magnesium oxide and/or, (b) stabilizing effective amount of lactic acid