FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
"A novel process for preparation of fixed dose combination of dual release Metoprolol succinate and Losartan potassium"

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-4OO 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 stable dual release pharmaceutical compositions of angiotensin II receptor antagonist such as losartan potassium and a synthetic beta-selective (cardioselective) adrenoreceptor blocking agent such as metoprolol succinate in the form of an oral solid bilayered formulation and to a process for preparation thereof. The salt of metoprolol is provided with an extended release polymer base retardant coating and the potassium salt of losartan is provided as an immediate release component.
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. There have been controlled and sustained release metoprolol formulations already known which comprise of controlled release pellets, where 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.
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.
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
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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.
Angiotensin II is a potent vasoconstrictor. Its generation in the rennin angiotensin cascade results from the enzymatic action of rennin on ablood plasma a2-globuline, angiotensinogen, to produce agiotensin I. Angiotensin I is then converted to octapeptide hormone angiotensin II by angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II has been implicated as a causaitive agent in hypertension as it leads to vasoconstriction on binding with AT1 receptor angiotensin that inhibit the pharmacological action of angiotensin II, no matter the pathway of biosynthesis, are useful in the treatment of hypertension.
Losartan potassium represents the first antihypertensive in the class of AT1 receptor angiotensin which disclosed in the US patent 5,138,069 issued on August 11, 1992 and which is assigned to E.I. du pont de Nemours. Losartan potassium has been demonstrated to be a potent orally active angiotensin II antagonist, selective for AT1 receptor subtype, useful in the treatment of hypertension.
Losartan free acid is also known as 2-butyl-4-chloro-l-[[(2'-(lH-tetrazoI-5-yl)[l,r-biphenyl]-4-yl]methyI]-lH-imidazole-5-methanol, whose potassium salt has been shown to be useful in the treatment of hypertension.
Losartan potassium has been approved by the FDA for the treatment of hypertension. The product is marketed as coated tablets for oral administration under the name Cozaar(R), and in combination with hydrochlorothiazide as coated tablets for oral administration, under the trade mark of Hyzaar(R).
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Losartan may be prepared using the reactions and techniques described in U.S. Pat. No. 5,138,069, U.S. Pat. No. 5,130,439 and U.S. Pat No. 5,206,374, the disclosures of which are incorporated herein by reference.
The patent WO2007026261 relates, in general, to new formulations and dosage units containing losartan and/or its salts (e.g., losartan potassium) that are useful for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, and a process for making the same. The process generally includes mixing and blending losartan potassium and compacting the mixture to form an agglomerate; breaking apart the agglomerate in order to obtain a granulate; and tableting the granulate mixture into tablets. The process can further include coating the prepared tablets with a suitable coating material.
Object of the invention:
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 synthetic beta-selective (cardioselective) adenoreceptor blocking agent Metoprolol succinate and angiotensin II receptor antagonist such as losartan potassium.
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 layer and immediate release of angiotensin II receptor antagonist, thus providing two drugs combination therapy to have additive effect in lowering blood pressure in hypertensive patients.
Yet another object of the invention is to reduce the dose of one of the active ingredient by extending the drug release over a period of time.
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Summary of the invention:
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 .The compositions involves use of disintegrants, which helps to immediate release of drug comprising angiotensin II receptor antagonist 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 methylcellulose, 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 angiotensin II receptor antagonist such as losartan 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 losartan is in range the of 12.5 to 100 mg and preferably 25mg and 50mg. 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 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 angiotensin II receptor antagonist drug such as losartan 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.
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Monolithic matrix techmque 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 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 either inlay or tab-in-tab or bilayered tablets of two active ingredients such as Losartan potassium and Metoprolol succinate, formulated in a single dosage form providing different release profile using dual drug release absorption system. The invention describes immediate release Losartan potassium and Metoprolol succinate equivalent to Metoprolol tartarate as an extended release component. The two drugs in combination therapy possess additive effect in lowering blood pressure in hypertensive patients.
The either bilayered or tab-in-tab or inlay tablets of the present invention provide dual release rates of the individual components wherein, an accurate dose of individual active is delivered. The process involves reduced manufacturing steps and manufacturing time. This process provides a cost effective formulation as conventionally there is always loss of 20-25 % at coating stage.
The said pharmaceutical composition of metoprolol succinate and losartan potassium according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets.
The First embodiment of this pharmaceutically accepted solid oral dosage dual release formulation of the present invention, the said process comprises; (i) metoprolol succinate equivalent to metoprolol tartarate and an extended release polymers comprising 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) Losartan potassium together with selective excipients, in direct compression or grannulation process (iii) lubricating the said granules or blend and (iv) compressing the
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said granules or blend of into two layer tablets characterized by the presence of the one drug substances in two different layers wherein same drug is given in conventional as well as extended release using standard compression tooling known in art with or without coating.
The Second embodiment of this pharmaceutically accepted solid oral dosage dual release formulation of the present invention, the said process comprises; (i) metoprolol succinate equivalent to metoprolol tartarate and an extended release polymers comprising 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) Losartan potassium together with selective excipients, in wet granulation or geometrical mixing process (iii) lubricating the said granules or blend and (iv) compressing the said granules or blend of into two different part inlay tablets characterized by the presence of the one drug substances in two distinctly separate parts in one layer wherein same drug is given in conventional as well as extended release using press coater CPC 20 (tab-in-tab) compression machine and tooling known in art with or without coating.
The Third embodiment of this pharmaceutically accepted solid oral dosage dual release formulation of the present invention, the said process comprises; The manufacturing process comprises of the steps of: (i) preparation of inner tablet of metoprolol succinate equivalent to metoprolol tartarate and an extended release polymers comprising 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 and compressed into tablets; (ii) Losartan potassium together with selective excipients, was separately granulated in wet granulation or geometrical mixing process to form outer tablet;(iii) after which metoprolol succinate coated tablets are compressed within losartan granules or blend so as to form the core of Losartan potassium tablets by tablet-in-tablet technology with or without coating.
The carefully screened pharmaceutically acceptable excipients used are selected from diluents, binders, disintegrants, emulsifiers, lubricants, glidants, flavors, alkalizing
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agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof.
The said diluents are microcrystalline cellulose, Avicel pH 101, lactose monohydrate and are used in the range of 2 to 95% of tablet weight and dried maize starch in the range of
5-25%.
The said binders are selected from the group containing polyvinylpyrrolidone. The said Polyvinylpyrrolidone K 30 in the range of 3 to 15%.
Lubricants and glidants are selected from the group consisting of magnesium stearate, preferably in the range of 0.25% to 5.0%, purified talc is used in the range of 0.1% to 2%, and colloidal silicon dioxide is used in the range of 0.1 % to 0.5%.
Retarded polymers are selected from the group consisting of a carbomer or hydrophilic polymer, hydroxy propyl methyl cellulose, in the range of 0.45% to 5%.
Plasticizers are selected from the group consisting of polyethylene glycol with molecular weight 6000 in the range of 5%-15%.
The said disintegrants are selected from the group containing starch, derivative of starch, preferably sodium starch glycolate and crosscarmellose sodium. The said glycolate is used in the range of 1-6% and crosscarmellose sodium is used in the range 0.5 to 5%.
The said disintegrant are selected from the group containing crosscarmellose sodium. The said crosscarmellose sodium in the range of 0.5 to 5%.
Opacifier selected from group consisting of titanium dioxide is used in range of 0.1%
to2.7%.
Solvents selected from group containing isopropyl alcohol and methylene chloride is
used in range of 0.5 to 2%.
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Colors are selected from the group consisting of quinoline yellow, in the range of 0.1 to
5%.
Other miscellaneous auxiliaries required for processing the product and maintaining
stability.
The said stable composition may be in the dosage form of tablets. The said tablet may be
film coated.
The said tablet may be coated with hydroxy propyl methyl cellulose, talc, titanium
dioxide, polyethylene glycol 6000.
The said compositions of metoprolol succinate and losartan potassium are physically and
chemically stable over its shelf life period.
The following examples illustrate various aspects of the present invention: Example-1:
Metoprolol succinate granules: Contains 50mg metoprolol succinate equivalent to metoprolol tartarate along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Metoprolol succinate 19.42%
2 Microcrystalline cellulose 8.66%
3 Hydroxypropylmethylcellulose K-15M 49.38%
4 Carbpol 71G 8.97%
5 Polyvinylpyrrolidone 30 12.24%
6 Isopropyl alcohol q.s.
7 Mg. Stearate 1.02%
Preparation 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
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dissolving Polyvinylpyrrolidone 30 in isopropyl alcohol. Granulate 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
10#.
Granules containing 25mg metoprolol succinate equivalent of metoprolol tartarate are similarly prepared
B) Losartan potassium dry mix: Contains 50mg of Losartan potassium along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Losartan potassium 43.85%
■2 Dried maize starch 17.54%
3 Avicel pH 101 23.85%
4 Talc 0.96%
5 Colloidal silicon dioxide 1.35%
6 Sodium starch glycolate 9.65%
7 Mg. stearate 0.96%
8 Quinoline yellow 0.12%
Preparation of Losartan potassium dry mix:
Losartan potassium, dried maize starch, Avicel pH 101, talc, colloidal silicon dioxide and sodium starch glycolate were passed through 40#. Quinoline yellow was passed through 100#. The entire ingredients were geometrical mixed.
Dry mix containing 25mg Losartan potassium were similarly prepared
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For bilayered tablet, weighing 359mg (containing 245mg of extended release layer and 114mg of immediate release layer) 14 x 6mm in dimension were produced on tablets pressed by two stage pressing procedure as described. The granules of extended release layer are press 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:

Sr. No. Ingredient Qty % w/w of total weight
1 HPMC 5cps 0.98%
2 PEG 4000 0.21%
3 Titanium oxide 0.07%
4 Talc 0.014%
5 Methyl chloride q.s
6 Isopropyl alcohol q-s.
There is a 2.5% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide & talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 25 + 25 mg of metoprolol succinate extended release and losartan potassium 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.
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B) Losartan potassium dry mix: Contains 50mg of Losartan potassium along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
I Losartan potassium 10.86%
2 Dried maize starch 5.43%
3 Avicel pH 101 62.07%
4 Colloidal silicon dioxide 1.2%
5 Sodium starch glycolate 5.43%
6 Mg. stearate 0.98%
7 Quinoline yellow 0.32%
Preparation of Losartan potassium dry mix:
Losartan potassium, dried maize starch, Avicel pH 101, talc, colloidal silicon dioxide and sodium starch glycolate were passed through 40#. Quinoline yellow was passed through 100#. The entire ingredients were geometrical mixed.
Dry mix containing 25mg Losartan potassium were similarly prepared
For Inlay tablet, weighing 665mg (containing 205mg of extended release layer and 460mg of immediate release layer) 12mm in dimension were produced
The extended release 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 12 mm punch size.
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The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 HPMC 5cps 0.98%
2 PEG 4000 0.21%
3 Titanium oxide 0.07%
4 Methyl chloride q.s
5 Isopropyl alcohol q.s
There is a 3% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 25 + 25 mg of metoprolol succinate extended release and losartari potassium were similarly prepared.
Example -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. These granules pressed in core tablets in compression machine as known in art.
B) Losartan potassium: Contains 50mg of Losartan potassium along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Losartan potassium 10%
2 Lactose monohydrate 46.2%
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3 Pregel starch 3%
4 Avicel pH 101 12.34%
5 Colloidal silicon dioxide 0.5%
6 Sodium starch glycolate- 2.8%
7 Mg. stearate 0.8%
8 Quinoline yellow 0.36%
9 Water q.s.
Preparation of Losartan potassium granules:
Losartan potassium, pregel starch, Avicel pH 101, colloidal silicon dioxide, lactose monohydrate and sodium starch glycolate were passed through 40#. Quinoline yellow was passed through 100#. After aqueous granulation, dry the granules in fluid bed drier until LOD reaches to 2.3 % at 105°C. Passed dried granules from mesh 20# and then lubricate with Mg. stearate.
For tablet - in - tablet, weighing 704mg (containing 204mg of extended release layer and 500mg of immediate release layer) 12.8 mm in dimension were produced
The extended release tablets were fed in the press coater CPC 20 (tab-in-tab) machine and the extended release tablet covered by conventional release granules compressed into tablets. The dual release tablet - in - tablet were prepared using compression with 12.8 mm punch size.
The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 HPMC 5cps 0.98%
2 PEG 4000 0.21%
3 Titanium oxide 0.07%
4 Methyl chloride q.s
5 Isopropyl alcohol q.s
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There is a 3% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 25 + 25 mg of metoprolol succinate extended release and losartan potassium were similarly prepared.
Dissolution profile: For 50+50mg

Hrs. Results
Metoprolol
1 7.33-10.87%
4 32.62-35.55%
8 54.90-59.61%
20 87.56-97.02%
Losartan
1 89.96-97.56%
The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 50+50mg is as follows:

Test Specification Hrs. Initial After 03 months
Appearance Yellow coloured, circular, biconvex, tablet plain on both side Complies Complies
Dissolution 40±2°C & 75±5%Rh Metoprolol 1 7.33-10.87% 10.66-13.21%

4 32.62-35.55% 28.61-39.72%)

8 54.90-59.61% 46.34-63.84%

20 87.56-97.02% 81.42-93.45%

Losartan 1 89.96-97.56% 88.57-89.73%
Assay Metoprolol 97.44% 95.84%

Losartan
100.16% 96.4%
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Dissolution profile: For 25+25mg

Hrs. Results
Metoprolol
1 10.31-11.33%
4 34.21-35.66%
8 56.12-57.99%
20 86.75-102.91%
Losartan
1 95.80-103.77%
The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 25+25mg is as follows:

Test Specification Hrs. Initial After 03 months
Appearance Yellow coloured, circular, biconvex, tablet plain on both side Complies Complies
Dissolution 40±2°C & 75±5%Rh Metoprolol 1 .10.31-11.33% 11.59-13.56%

4 34.21-35.66% 34.68-37.89%

8 56.12-57.99% 55.98-61.75%

20 86.75-102.91% 91.33-97.71%

Losartan 1 95.80-103.77% 89.12-93.73%
Assay Metoprolol 97.94% 94.07%

Losartan
104.63% 102.90%
Example -4
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as example 1.
These granules pressed in core tablets in compression machine as known in art.
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B) Losartan potassium: Contains 50mg of Losartan potassium along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Losartan potassium 9.92%
2 Lactose monohydrate 31-05%
3 Crosscarmellose sodium 5.95%
4 Avicel pH 101 49.60%
5 Colloidal silicon dioxide 0.49%
6 Polyvinylpyrrolidone 30 2.98%
7 Mg. stearate 0.99%
8 Quinoline yellow 0.05%
9 Isopropyl acohol q.s.
Preparation of Losartan potassium granules:
Losartan potassium, Avicel pH 101, colloidal silicon dioxide, lactose monohydrate and crosscarmellose sodium were passed through 40#. Quinoline yellow was passed through 100#. Binder solution was prepared by dissolving Polyvinylpyrrolidone 30 in isopropyl alcohol. Granulate the above blend. The wet mass was passed through 8# & the dried granules were passed through 20#. These granules were lubricated with Mg. stearate.
For tablet - in - tablet, weighing 705mg (containing 201mg of extended release layer and 504mg of immediate release layer) 12.8 mm in dimension were produced
The extended release tablets were fed in the press coater CPC 20 (tab-in-tab) machine and the extended release tablet covered by conventional release granules compressed into tablets. The dual release tablet - in - tablet were prepared using compression with 12.8 mm punch size.
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The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 HPMC 5cps 0.98%
2 PEG 4000 0.21%
3 Titanium oxide 0.07%
4 Methyl chloride q.s
5 Isopropyl alcohol q.s
There is a 3% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 25 + 25 mg of metoprolol succinate extended release and losartan potassium were similarly prepared.
The dissolution profile of the extended release tablet - in - tablet is studied and shown as
follows:
Dissolution profile: For 50+50mg

Hrs. Results
Metoprolol
1 11.27-13.6%
4 35.66-38.73%
8 55.24-64.66%
20 87.76-97.93%
Losartan
1 94.42-103.25%
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The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 50+50mg is as follows:

Test Specification Hrs. Initial After 02 months
Appearance Yellow coloured, circular, biconvex, tablet plain on both side Complies Complies
Dissolution 40±2°C & 75±5%Rh Metoprolol 1 11.27-13.6% 9.03-13.01%

4 35.66-38.73% 32.10-38.75%

8 55.24-64.66% 55.77-60.75%

20 87.76-97.93% 88.51-94.62%

Losartan 1 94.42-103.25% 85.63-91.72%
Assay Metoprolol 98.22% 98.02%

Losartan
100.12% 99.92%
Dissolution profile: For 25+25rag

Hrs. Results
Metoprolol
1 10.46-14.02%
4 36.66-40.61%
8 60.26-63.13%
20 95.29-96.28%
Losartan
1 83.50-95.24%
The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 25+25mg is as follows:

Test Specification Hrs. Initial After 02 months
Appearance Yellow coloured, circular, biconvex, tablet plain on both side Complies Complies
Dissolution 40±2°C & 75±5%Rh Metoprolol 1 10.46-14.02% 11.08-12.98%

4 36.66-40.61% 35.93-38.40%

8 60.26-63.13% 59.62-60.18%

20 95.29-96.28% 92.46-97.18%

Losartan 1 83.50-95.24% 89.86-98.91%
Assay Metoprolol 102.77% 98.00%

Losartan
97.76% 98.45%
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We Claim,
1. A stable tablet - in - tablet pharmaceutical composition, prepared with dual release drug absorption system technology, comprising angiotensin II receptor antagonist such as losartan potassium and a beta-selective adrenoreceptor blocking agent, such as Metoprolol, wherein losartan is incorporated as an immediate release component and Metoprolol is incorporated as an extended release component comprising monolithic matrix technology; wherein, the said composition is prepared by a process comprising;
a. granulating metoprolol succinate with pharmaceutically acceptable
excipients by non-aqueous granulation process and blending the said
granules of metoprolol succinate with disintegrants, lubricants and
glidants;
b. granulating losartan potassium with pharrnaceutically acceptable
excipients by wet granulation process or geometrical mixing with
polyvinylpyrrolidone used as moisture barrier layer and blending the
granules or blend with disintegrants, lubricants and glidants and
c. compressing the said two blends (a) and (b) into an either bilayered or
inlay or tablet - in - tablet where each layer represents blend comprising a
single active ingredient with excipients and
d. coating the tablets.
2. Pharmaceutical compositions as claimed in claim 1, wherein the said losartan potassium in the range of 12.5 to lOOmg and preferably 25mg and 50mg.
3. Pharmaceutical compositions as claimed in claim 1, wherein the said Metoprolol salt is Metoprolol succinate in the range of 12.5 to 200mg equivalent to Metoprolol tartarate and preferably 50mg and 25mg.
4. Pharmaceutical compositions as claimed in claim 1, wherein Metoprolol succinate is incorporated as an extended release monolithic matrix comprising a polymer
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base retardant coating comprising a combination of hydrophobic polymer such as carbomer and a hydrophilic polymer such as hydroxypropyl methyl cellulose.
5. Pharmaceutical compositions as claimed in claim 1, wherein the pharmaceuticalIy acceptable excipients are selected from diluents, binders, disintegrants, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof.
6. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said diluents are selected from the group consisting of microcrystalline cellulose, maize starch or their modified forms used in the range of 5 to 95% of tablet weight.
7. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said binders are selected from the group containing maize starch, polyvinylpyrrolidone wherein preferred binder is polyvinylpyrrolidone used in the range of 3 to 15% and maize starch in the range of 2 tolO%.
8. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said disintegrants are selected from the group containing starch, derivative of starch and the preferred disintegrants are sodium starch glycolate used in the range of 1-6% and crosscarmellose sodium used in the range 1-6%.
9. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said lubricant and glidants are selected from the group containing magnesium stearate in the range of 0.25% to 5%, and colloidal silicon dioxide used in the range of 0.1% to 0.5%
10. Pharmaceutical compositions as claimed in claim 1 and 9, wherein the said film formers are selected from group of polymers such as carbomer used in the range of 5% to 10% and hydroxy propyl methyl cellulose used in the range of 0.45% to
1%.
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11. Stable pharmaceutical compositions as claimed in any of the preceding claims 1 to 10 and their process of preparation as described herein with reference to the foregoing examples 1-4.
Dated this the 24th day of June 2008
Dr. Gopakumar G. Nair Gopakumar Nair Associates
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