FORM 2 THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)

1. TITLE OF THE INVENTION:
"A NOVEL PROCESS FOR PREPARATION OF FIXED DOSE COMBINATION OF DUAL RELEASE METOPROLOL SUCCINATE AND
RAMIPRIL"
2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:


TECHNICAL FIELD OF THE INVENTION:
The present invention relates to novel process for preparation of stable fixed dose combination of Metoprolol succinate and Ramipril, which provides dual release of both active ingrediants.
BACKGROUND AND PRIOR ART:
Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat a heart condition called angina. Its chemical name is (±) l-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). It reduces the oxygen demand to heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure.
EP 0293347 by Henry A. C and Christina E. E. describes Metoprolol succinate as new therapeutically active compound, and pharmaceutical preparation comprising it. The invention describes a core containing a therapeutically active compound, the core coated with a layer comprising an anionic polymer soluble, and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers.
i US Pat. No. 4871549 to Yoshio U et al., describes a time controlled explosion system comprising Metoprolol, a swelling agent such as a low substituted hydroxy propyl cellulose, sodium starch glycolate or carboxy methyl cellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.
EP1110542 by Mccall Troy W and Bachiwal Anand R describes once-a-day oral dosage form of Metoprolol to be released over a period of 24 hours in the gastrointestinal tract. The sustained release matrix comprised of heterosaccharide derivatives of xanthan gum.

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There have been controlled and sustained release metoprolol formulations already known which comprise of controlled release pellets, wherein each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be done. So, in accordance with the present investigation, an extended release pharmaceutical formulation is devised to release the drug for upto 24 hours in a suitable controlled manner.
i Ramipril is an ACE inhibitor, used to treat hypertension and congestive heart failure.
ACE inhibitors lower the production of angiotensin II, therefore relaxing arterial muscles
while at the same time enlarging the arteries, allowing the heart to pump blood more
easily, and thus increasing blood flow due to more blood being pumped into and through
larger passageways. Ramipril is a prodrug and is converted to the active metabolite
Ramiprilat, which has a long elimination half life, permitting once daily administration.
i
Approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with Ramipril 2.5 or 5mg/day, while comparative trials indicate that antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and Atenolol (J. E. Frampton, D.H. Peters, Ramipril: an updated review of its therapeutic use in essential hypertension and heart failure, Drugs, 1995 Mar, 49(3)pp 440-66) Ambulatory blood pressure monitoring has documented full 24-hour control.
In diabetic patients who have had a previous cardiovascular event or having one other cardiovascular risk factor, the MICRO-HOPE clinical trial showed that Ramipril lowers the combined risk of myocardial infarction, stroke and cardiovascular death by 25%. Ramipril has also been shown to reduce proteinuria in patients with diabetes. [S.A.Doggrell, Is Ramipril the pril for diabetes and kidney disease? Drugs Today (Bare) 2001 Miy,37(5), pp 321-331].
Experimental studies carried out with combination of Ramipril with Metoprolol showed the following:
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*

Results from the study examining the effects of combined Ramipril and Metoprolol treatment on the creatine kinase (CK) system and hemodynamic function in rats after infarction provided evidence of an interaction between normalization of energy metabolism and improvement in cardiac function due to a combination of ACE inhibition and beta blockade after myocardial infarction. (H.P. Theres, K.D. Wagner, D. Romberg, C.Feig, S.Strube, K.P. Leiterer, J. .Gunther, K.Stang, G. Baumann, I. Schimke, Combined treatment with Ramipril pnd metoprolol prevents changes in the creatine kinase isoenzyme system and improves hemodynamic function in rat hearts after myocardial infraction, Cardiovasc. Drugs. Ther., 2000 Dec, 14(6),pp597-606.
The effects of chronic treatment with the beta-adrenoceptor antagonist Metoprolol, the angiotensin converting enzyme inhibitor Ramipril, their combination, or placebo on action potential configuration 6 weeks after myocardial infarction in rats were studied. After infarction, the action potential amplitude was reduced and this phenomenon was partially reversed by Metoprolol and Ramipril treatment. Prolonged repolarisation after infarction was additionally delayed after Metoprolol treatment. Thus, Metoprolol extends the refractory period, which may counteract tachyarrhythmia. (K. Wagner, et al Effects of metoprolol and Ramipril on action potential after myocardial infraction A rats, Eur. J. Pharmacol., 2000 Feb 4 388(3), pp 263-6)
A study conducted in 17 sheep with coronary Iigation-induced anteroapical infarction, randomized to Ramipril or Ramipril and Metoprolol, showed that when added to ACE inhibition, beta-blockade improves EF and adjacent regional sympathetic innervation during postinfarction remodeling. (CM. Kramer, P.D. Nicol et al Beta- blockade improves adjacent regional sympathetic innervation during postinfection remodeling, Am. J. Physiol. 1999 Oct, 277(4 Pt 2), pp H1429-34.)

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In 10 insulin-dependent diabetic patients with early diabetic nephropathy who were receiving continuous therapy with Metoprolol and Bendroflumethiazide. a double-blind crossover study with four months addition of Ramipril 5 mg and placebo was conducted. UAE and fractional albumin excretion were significantly reduced after the four months of Ramipril administration. Renal plasma flow tended to increase and renal resistance was decreased. ACE activity was
suppressed in all patients. M.M. Pedersen, K.W. Hansen et al Effects of ACE inhibition supplementary to beta blockers and diuretics in early diabetic
nephropathy, Kidney Int,1992 Apr, 41(4), pp883-90).
EP0050800 patent discloses use of carboxyalkyl dipeptides, process for their production and pharmaceutical composition of hard gelatin capsules containing them.
EP0488059 disclose combination and composition of a ACE inhibitor including Ramipril
and a calcium antagonists for therapy of proteinuria.
i
EPl216,038 relates to the use of an inhibitor of the rennin - angiotensin system or optionally together with antihypertensive, a cholesterol lowering agent, a diuretic for a pharmaceutical combination for the prevention of cardiovascular event.
EPl212081 discloses the use of the RAS inhibitor particularly Ramipril or Ramiprilat, in pharmaceutical composition for the prevention of stork, diabetes and /or congestive heart failure.
EP0417473 discloses method for the treatment of cardiac and vascular hypertrophy and hyperplasia by administration of angiotensin converting enzyme inhibitors and its pharmaceutical compositions.
However, none of the above prior arts deal with combination of an anti-hypertensive such as a beta-selective (cardioselective) adrenoreceptor blocking agent and ACE inhibitor
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wherein the adrenoreceptor blocking agent is suitably formulated for extended release while the ACE inhibitor is incorporated suitably for immediate release.
Thus there exists a need to introduce stable, cost effective pharmaceutical compositions having a super additive effect in lowering blood pressure in hypertensive patients
comprising rapid effect of Ramipril by immediate release and an extended release of
i
Metoprplol for 24 hours release thereby providing dual effect to sustain the concentration of bothjactive ingredients in blood plasma.
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OBJECT OF THE INVENTION:
i
The main object of the present invention is to provide stable dual release pharmaceutical compositions used for treatment of hypertension, chronic stable angina and other related cardiovascular diseases comprising combination of therapeutically effective amount of a synthetijc beta-selective (cardioselective) adenoreceptor blocking agent Metoprolol succinate and ACE inhibitor such as Ramipril.
Another, object is to provide extended release of selective beta-adrenoreceptor blocker by
using monolithic matrix that is combination of hydrophobic (carbomer) and hydrophilic
(hydroxy propyl methyl cellulose) polymers, in an effective manner in extended release
i layer arid immediate release of ACE inhibitor, thus providing two drugs combination
therapy to have super additive effect in lowering blood pressure in hypertensive patients
with co-existing coronary artery disease or diabetes.
i
SUMMARY OF THE INVENTION:
i
The present invention discloses stable pharmaceutical compositions comprising of two active ingredients, formulated in a single dosage form providing different release profiles comprising dual release drug absorption system technology. The compositions involves use of disintegrants, which helps to immediate release of drug comprising ACE inhibitor and the use of monolithic matrix technique for extended release of an adrenergic blocking agent. The monolithic matrix comprises a combination of hydrophobic polymer
preferably carbomer and hydrophilic polymer preferably hydroxypropyl methyl cellulose,
i
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thereby facilitating extended release of adrenergic blocking agent, over a time period of up to 24 hours.
The stable solid pharmaceutical compositions for oral administration comprises a ACE inhibitors such as Ramipril and a synthetic adrenoreceptor blocking agent, such as Metoprolol succinate equivalent to Metoprolol tartarate; and pharmaceutically acceptable excipients. The amount of the said salts of Ramipril is in range of 2.5 tol5mg preferably 5mg and 2.5mg. The amount of Metoprolol succinate equivalent to Metoprolol tartarate is in the range of 12.5 mg to 200mg and preferably 50mg and 25mg. The compositions possess' super additive effect in lowering blood pressure in hypertensive patients.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention describes stable dual release pharmaceutical compositions for oral administration that comprises an ACE inhibitor such as Ramipril as an immediate release component and a synthetic beta-selective (cardioselective) adrenoreceptor blocking agent such as Metoprolol succinate incorporated in an extended release matrix using monolithic matrix technology, along with pharmaceutically acceptable excipients.
Monolithic matrix technique includes use of combination of hydrophobic such as
carbomer and hydrophilic polymers, thereby helps the extended release of drug over
specific period of time. The drug is dispersed in a mixture' of hydrophilic and
hydrophobic matrix resulting in the initial dissolution of matrix polymer and then
i
diffusion of the dissolved drug through the pores of the matrix before release.

The invention further describes a process for preparation of dual release pharmaceutical compositions comprising bilayered tablets or inlay tablets of two active ingredients such as Ramipril and Metoprolol succinate, formulated in a single dosage form providing differeni release profile using dual drug release absorption system. The invention describes Ramipril as immediate release and Metoprolol succinate equivalent to
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Metoprolol tartarate as an extended release component. The two drugs in combination therapy possess super additive effect in lowering blood pressure in hypertensive patients.
Monolithic matrix technique includes use of combination of hydrophobic preferably carbomer and hydrophilic polymers, thereby helps the extended release of drug over specific: period of time. The carbomer is included in an amount from about 4.54% to about ill 1.5%, by weight of the final product. The drug to carbomer ratio may be e.g.
from about 10:1 to about 1:12. More appropriately, the drug to carbomer ratio is from
i about 10:1.25 to about 1:12 by weight of final product. The preparation of the extended
release layer is accomplished by mixing of polymers and compression. Carbomers are
used both in granulation as well as mixing stages.
i
By extended release it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time e.g., providing a 24 hour dosage form.
In one embodiment, the solid oral dual release formulation of the present invention is prepared by a process comprising the following steps:
(i) Wet granulating metoprolol succinate equivalent to metoprolol tartarate
together with extended release polymers comprising carbomer and

hydroxypropyl methyl cellulose in amount from about 5% to 95% by weight
of the final product along with selected excipients, using non-aqueous wet

granulation process;
(ii) granulating Ramipril together with selective excipients by aqueous wet
granulation process;
lubricating the said granules or blend; and
compressing the said granules or blend into Bilayer tablets characterized by
the presence of the two drug substances in two different layers wherein one
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drug is given in conventional release and other as extended release using standard compression tooling known in art with or without coating.
i In another embodiment, the solid oral dual release formulation of the present invention is
prepared by a process comprising the following steps:,
(i) wet granulating metoprolol succinate equivalent to metoprolol tartarate
together with an extended release polymers comprising carbomer and
i
hydroxypropyl methyl cellulose in amount from about 5% to 95% by weight of the final product along with selected excipients, using non-aqueous wet
granulation process
i
(ii) wet granulating Ramipril together with selective excipients, using PH
modifier by aqueous wet granulation;
(iii) ] lubricating the said granules or blend and
(iv) compressing the said granules or blend into two different part of Inlay tablets
characterized by the presence of the two drug substances in two distinctly
separate parts in one layer wherein one drug is given in conventional release
and other drug as extended release using press coater CPC 20 (tab-in-tab)

compression machine and tooling known in art with or without coating.
The selective excipients as mentioned above are chosen among the group comprising of
binder, diluent & lubricant.
The dose range of Ramipril in the said composition is in the range of about 2mg to 1 Omg
and dose range for Metoprolol succinate equivalent to Metoprolol tartarate is in the range
of about 12.5mg to 200mg. Most preferred dose range of Ramipril in the said
composition is 2.5mg and 5mg for Metoprolol succinate equivalent to Metoprolol
tartarate is 50mg and 25mg.
The dua release pharmaceutical combination of the present invention drug absorption system comprising Ramipril and Metoprolol succinate equivalent to Metoprolol tartarate in association with pharmaceutically acceptable excipients selected from polymers, diluents, binders, flavors, preservatives, pH modifier, alkalizing agent, disintegrating
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agents, film formers, lubricants and/or glidants plasticizers either alone or in combination thereof.
The diluents are selected from microcrystalline cellulose, Avicei pH 112 and are used in the range of 2 to 95% of tablet weight.
The binders are selected from the group containing starch, polyvinylpyrrolidone, preferably polyvinylpyrrolidone. The polyvinylpyrrolidone is used in the range of 3 to 15%.
The disintegrants are selected from the group containing starch, derivative of starch, preferably starch 1500. The starch is used in the range of 2-25%.
The lubricant are selected from the group containing magnesium stearate used in the range of 0.25% to 5% and sodium stearyl fumarate is used in range of 0.5 to 2%
The glidants are selected from the group containing colloidal silicon dioxide and is used in the raige of 0.1 % to 0.5 %.
i The film formers are selected from group of polymers, which is used in the range of 0%
to 10%;; preferably, hydroxy propyl methyl cellulose which is used in the range of
0.45% to 3%.
The carbomer used in the extended release layer is carbopol 71G
Sodium bicarbonate is used as pH modifier in the immediate release. Solvent is selected
from group containing isopropyl alcohol is used in range of 0.5 to 2%.
i
i i
Colors are selected from the group consisting of quinoline yellow, in the range of 0.1 to 5%. j
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Other miscellaneous auxiliaries required for processing the product and maintaining stability can also be used.
The stable compositions of the invention are preferably in the dosage form of tablets and inlay or bilayered tablets. Preferably bilayer tablet may be film coated preferably with hydroxy propyl methyl cellulose, talc, titanium dioxide, polyethylene glycol 6000.
The pharmaceutical compositions of Ramipril and Metoprolol succinate according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets.
The compositions of Ramipril and Metoprolol succinate are physically and chemically stable oyer its shelf life period.
The invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the following examples and further can be modified and altered within the technical concept of the present invention.
Each example described below contains Metoprolol succinate equivalent to Metoprolol tartarate 50mg or 25mg and Ramipril 5mg or 2.5mg.
Example-1:
Metoprolol succinate granules: Contains 50mg metoprolol succinate equivalent to

metopro

ol tartarate along with the following excipients:

Sr.No

Ingredient

Qty % w/w of total weight

1

Metoprolol succinate

12.83%

Microcrystalline cellulose

25%

Hydroxypropylmethylcellulose K-15M

32.43%

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4 :
i i Carbpol 71G 21.62%
5 i
1 Polyvinylpyrrolidone 30 6.48%
6 Isopropyl alcohol q.s.
7 Mg. Stearate 1.62%
Prepara ion of metoprolol succinate granules:
Metoprolol succinate, Microcrystalline cellulose, Hydroxypropylmethylcellulose K 15M, Carbopl 71G were passed through mesh 40# for 10 min. Binder solution was prepared by dissolving Polyvinylpyrrolidone 30 in isopropyl alcohol. Granulated the above blend. The wet mass was passed through 8# & the dried granules were passed through 20#. These granules were lubricated with Hydroxypropylmethylcellulose K 15M which is passed through 40# mesh and then lubricated with Mg. Stearate which is passed through mesh 40# to obtain Metoprolol succinate extended release granules.
Granules containing 25mg metoprolol succinate equivalent of metoprolol tartarate are
similarly prepared
B) Ramipril granules: Contains 5mg of Ramipril along with the following excipients:

Sr. No.

Ingredient

Qty % w/w of total weight

1

Ramipril

2.19%

Hydroxypropylmethylcellulose E-5

0.21%

AvicelpH112

92.39%

Purified water

q.s.

Crosspovidon

2.60%

Colloidal silicon dioxide

0.87%

Sodium stearyl fumarate

0.87%

Quinoline yellow

0.87%

Preparation for Ramipril granules:
In luke warm water, under continuous mechanical stirring, hydroxypropylmethylcellulose E-5 was dispersed. To this solution added ramipril under continuous mechanical stirring. The solution thus obtained is homogenized for about 20 minutes at medium speed. Avicel
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112 were passed through mesh 40# and added to the bend. Granulated the above blend and the wet mass is dried in GPCG till IR moisture balance achieved. The dried granules were passed through 40#. These granules were lubricated with Colloidal silicon dioxide and Crosspovidone which were passed through #40 and quinoline yellow passed through #100 for 10 minutes and then with Sodium Stearly fumarate which is shift through #40 for 2 minutes to obtain ramipril immediate release granules.
The extended release metoprolol succinate tablets were fed in the press coater CPC 20 (tab-in-tab) machine and the extended release tablet surrounded by conventional release granules compressed into tablets. The dual release Inlay tablets were prepared using compression with suitable punch size.
Granules containing 2.5mg ramipril are similarly prepared
Tablets [containing 25 + 2.5 mg of metoprolol succinate extended release and Ramipril were similarly prepared.
Example-2:
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as

example

1.

B) Ramipril granules: Contains 5mg of Ramipril along with the following excipients:

Sr.N 0. Ingredient Qty % w/w of total weight
1 Ramipril 2.19%
2 Hydroxypropylmethylcellulose E-5 0.21%
3 Sodium bicarbonate 1.08%
4 AvicelpH112 92.39%
5 Purified water q.s.
6 Starch 1500 3.33%
7 1 i Colloidal silicon dioxide 0.87%
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8 Sodium stearyl fumarate 0.87%
9 Quinoline yellow 0.87%
Preparation for Ramipril granules:
Sodium bicarbonate was passed through mesh 40# and Ramipril through 60#. Binder solution was prepared by dissolving Sodium bicarbonate and HydroxypropylmethylceUulose E-5 in purified water and dispersed Ramipril into it and homogenized the solution. Avicel 112 were passed through mesh 40# and added to the blend and granulated the above blend. The wet mass is dried in GPCG till IR moisture balance achieved. The dried granules were passed through 30#. These granules were
lubricated with Colloidal silicon dioxide and starch 1500 which are passed through #40
i
and quinoline yellow passed through #100 for 10 minutes and then with Sodium stearyl fumarate which is shifted through #40 for 2 minutes to obtain Ramipril immediate release granules.
The extended release metoprolol succinate tablets were fed in the press coater CPC 20 (tab-in-tab) machine and the extended release tablet surrounded by conventional release granules compressed into tablets. The dual release Inlay tablets were prepared using compression with suitable punch size.
Granules containing 2.5mg ramipril are similarly prepared

Tablets

containing 25 + 2.5 mg of metoprolol succinate extended release and Ramipril

were similarly prepared.
ExampIe-3:
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as example 1.
B) Ramipril granules: Contains 5mg of Ramipril along with the following excipients:
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Sr. No. Ingredient Qty % w/w of total weight
1 1 Ramipril 2.17%
2
i Hydroxypropylmethylcellulose E-5 2.17%
3 Sodium bicarbonate 2.17% *
4 Avicel pH 112 58.19%
5 Purified water q.s.
6 : Starch 1500 7.19%
7 Colloidal silicon dioxide 0.87%
8 Sodium stearyl fumarate 0.87%
9 i
i Quinoline yellow 0.87%
Preparation for Ramipril granules:
Sodium bicarbonate was passed through mesh 40# and Ramipril through 60#. Binder
solution was prepared by dissolving Sodium bicarbonate and
Hydroxypropylmethylcellulose E-5 in purified water and dispersed Ramipril into it and
homogenized the solution. Avicel 112 were passed through mesh 40# and added to the
blend and granulated the above blend. The wet mass was dried in GPCG till IR moisture
balance achieved. The dried granules were passed through 30#. These granules were
i lubricated with Colloidal silicon dioxide and starch 1500 which are passed through #40
and quinoline yellow passed through #100 for 10 minutes and then with Sodium stearyl
fumarate which is shifted through #40 for 2 minutes to obtain immediate release granules
of Ramipril.
i For bilayered tablet, weighing 612mg (containing 370mg of extended release layer and
230mg of immediate release layer) 18 x 8mm in dimension were produced on tablets
pressed by two stage pressing procedure as described. The granules of extended release
layer are pressed first and immediate release layer is then added and the press is operated
again.
The coating solution to be coated on the tablets has the following composition:
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!

Isopropyl alcohol was taken in suitable container and dispersed hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes Then added titanium dioxide & talc again under stirring for approximately 10 minutes followed by the addition of purified water and polyethylene glycol 6000 under stirring for 10 minutes. The stirring was continued for 30 minutes and passed the suspension through a bolting cloth, and homogenized by passing through a homogenizer. This solution was used to coat tablet with conventional coater/auto-coater.
Dissolution profile: For 50+5mg

The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 50+5mg is as follows:
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The pharmaceutical composition of is physically and chemically stable over its shelf life

period, t he stability data for 25+2.5mg is as follows
Test Specification Hrs. Initial After 03 months
Appearar Lee Oval shaped, film
coated, bilayer tablet plain on both sides with yellow color on immediate release side and white to off white color on extended release side Complies Complies
i 1 17-19% 17-18%
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We claim,
1. Novel process for preparation of stable dual release fixed dose combination of
Ramipril and Metoprolol succinate comprising:
a) wet granulating metoprolol succinate equivalent to metoprolol tartarate together with extended release polymers comprising hydroxypropyl methyl cellulose and carbomer in amount from about 5% to 95% by weight of the final product along with selected pharmaceutical excipients, using non-aqueous wet granulation process to obtain extended release granules;
b) wet granulating Ramipril together with pharmaceutical excipients by aqueous wet granulation, to obtain immediate release granules;
c) lubricating the said granules or blend; and
d) compressing the said granules or blend into Bilayer tablets characterized by the presence of the two drug substances in two different layers wherein one drug is given in conventional release and other as extended release using standard compression tooling known in art.

2. The process as claimed in claim 1, wherein, the said blend or granules are compressed into two different part of Inlay tablets characterized by the presence of the two drug substances in two distinctly separate parts in one layer wherein one drug is given in conventional release and other drug as extended release using press coater CPC 20 (tab-in-tab) compression machine and tooling known in art.
3. Th; process as claimed in claim 1, wherein said carbomer used in the extended release layer is carbopol 71G.
4. The process as claimed in claim 1, wherein said ramipril granules optionally prepared using pH modifiers.
5. The process as claimed in claim 4, wherein said pH modifier is sodium bicarbonate.
6. The process as claimed in claim 1, wherein said tablets further comprising a film coating.
7. The process as claimed in claim 1, wherein said excipients are selected from selected from polymers, diluents, binders, flavors, preservatives, pH modifier,
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alkalizing agent, disintegrating agents, film formers, lubricants and/or glidants plasticizers either alone or in combination.
8. The process as claimed in claiml, wherein said diluents are selected from
microcrystalline cellulose, Avicel pH 112 and are used in the range of 2 to 95% of
i
tablet weight.
9. The process as claimed in claiml, wherein said binders are selected from the group
containing starch, polyvinylpyrrolidone, preferably polyvinylpyrrolidone used in
the range of 3 to 15%.
10. The process as claimed in claiml, wherein said disintegrants are selected from the
group containing starch, derivative of starch, preferably pregel strach used in the
range of 2-25%.
11. The process as claimed in claiml, wherein said lubricant are selected from the
group containing magnesium stearate used in the range of 0.25% to 5% and sodium
stearyl famarate is used in range of 0.5 to 2%
12. The process as claimed in claiml, wherein said glidants are selected from the group
containing colloidal silicon dioxide used in the range of 0.1 % to 0.5 %.
13. The process as claimed in claiml, wherein said film formers are selected from
group of polymers, which is used in the range of 0% to 10%; preferably hydroxy
i
propyl methyl cellulose which is used in the range of 0.45% to 3 %. Dated this 22nd day of May, 2009

Dr. Gopakumar G. Nair Agent for the Applicant
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