FORM 2
THE PATENTS ACT 1970 (39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
STABLE PHARMACEUTICAL COMPOSITION OF BETA ADRENORECEPTOR BLOCKER AND ANGIOTENSIN II ANTAGONIST
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING
ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE,
OFF S.V. ROAD, JOGESHWARI (WEST), MUMBAI - 400 102
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF INVENTION
The present invention relates to a dual release bilayer solid oral pharmaceutical tablet composition comprising of beta-blocker and angiotensin II antagonist. More particularly, the present invention relates to the dual release bilayer solid oral pharmaceutical composition comprising combination of extended release beta blocker such as metoprolol and instant release angiotensin II receptor antagonist such as telmisartan, wherein the two active ingredients are present in two separate layers in single solid dosage form. The present invention also provides method for preparing bilayer tablets.
BACKGROUND OF THE INVENTION
Telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and the other medical indication as disclosed in US5591762 (1997, Norbert H. et al). It is chemically described as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1-yl) methyl]-[1,l'-biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63, and its structural formula is

Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.
Telmisartan is generally manufactured and supplied in the free acid form. It is characterized by its very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7, as disclosed under US 20090227802 (2009, Friedl T. et al) patent application.

Metoprolol which has the following structural formula is disclosed in US 3998790 (1976, AB Hassle) and which can be used as β adrenoceptor antagonist.

Metoprolol succinate is a white crystalline powder. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl acetate, acetone, diethylether and heptane. Its chemical name is chemically described as (+/-)l-(isopropylamino)-3-(p-(2-methoxyethyl) phenoxy) -2 propanol succinate (2:1) (salt). Its empirical formula is (C15H25NO3)2.C4H6O4. Its molecular weight is 652.8 and its structural formula is

Metoprolol succinate is a β1 selective (cardioselective) adrenoreceptor-blocking agent, for oral administration, available as extended release tablet. Metoprolol succinate has apparently been formulated to provide controlled and predictable release of metoprolol for once daily administration as per disclosure under US20090068260 (2009, Gold T. et al)
Metoprolol is employed either as Metoprolol succinate or Metoprolol tartrate (i.e. 100 mg metoprolol tartrate corresponds to 95 mg metoprolol succinate) respectively as prolonged-release or conventional-release formulation. For Metoprolol Tartarate 25 mg is equivalent to

23.75 mg of Metoprolol succinate and for Metoprolol Tartarate 50 mg is equivalent to 47.5 mg of Metoprolol succinate.
US 4957745 (1990, Ulf E. J., et al) describe a controlled release metoprolol. After the initial forming of the beads containing metoprolol, the beads obtained are coated with the polymeric layer and finally filled into capsule or compressed tablets.
WO2008146178 (2008, Jain, G. et al) discloses a novel tablet dosage forms and methods of preparing these forms, which can be used for different classes of pharmaceutical active in gredients posing stability issues in a single unit system. The dosage form includes a first layer that includes a tablet of one or more active pharmaceutical ingredients, which is inlayed in the first layer along with other pharmaceutically acceptable excipients, and a second layer that includes one or more active pharmaceutical ingredients optionally with other pharmaceutically acceptable excipients.
WO2006102476 (2006, Basecomb N., et al) discloses combination comprising of beta-adrenergic receptor antagonists (beta blockers); with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAID), anabolic steroids, natural oils or fatty acids or any combination thereof.
US20060024365 (2006, Navin V., et al) discloses combination of high dose high solubility active ingredient, as modified release and low dose active ingredient as immediate release; comprising a dual retard technique to control the release of high dose, high solubility active ingredient.
WO2005011586 (2005, Sasmal B., et al) covers the combination of beta-adrenergic receptors, a diuretic agent, or both; a cholesterol-lowering agent; an inhibitor of the renin-angiotensin system; and aspirin.
EP1467712 (2002, Friedl, T., et al) discloses a bilayer pharmaceutical tablet comprising a first layer formulated for immediate release of the angiotensin II receptor antagonist telmisartan from a dissolving tablet matrix, which contains telmisartan in substantially

amorphous form, and a second layer formulated for immediate release of a diuretic like hydrochlorothiazide from a fast disintegrating tablet matrix.
WO2006119692 (2006, Liu Lisheng, et al) discloses a medicinal combination composition comprising of one or two antihypertensive medicines selected from calcium antagonist, a-receptor antagonist, p-receptor antagonist, renin-angiotensin system regulator, and diuretic, with calcium component selected from shell, fossil bone, calcium chloride, calcium carbonate, calcium phosphate, calcium citrate, calcium lactate, calcium gluconate, and calcium L-threonate, and pharmaceutically acceptable adjuvants.
CN101254182 (2008, Zhao Zhiquan) describes a conventional fixed dose pharmaceutical combination composition for treating high blood pressure comprising S-metoprolol and other angiotensin angiotensin II receptor blocker such as losartan, valsartan, irbesartan or Olmesartan by preparing the tablets by conventional technology. However, the preparation of tablets by bilayer tablet is not described under '182.
CN10124379 (2008, Chen Ruijing) discloses an antihypertensive sustained-release drug delivery system, containing selective β1 receptor blocker metoprolol and angiotensin II receptor antagonists. The cardiac selective Betal blocker metoprolol releases 25 percent to 45 percent in the first hour, 40 percent to 75 percent in the fourth hour, and above 75 percent in the eighth hour; while the angiotensin II receptor antagonist (saltans) releases above 75 percent after 45 min
CN101185624 (2007, Chen Ruijing) discloses a controlled-release medical composition comprising controlled-release delivery system containing metoprolol (its levo-isomer, dextro-isomer or racemate) or its pharmaceutically acceptable salt (such as tartrate, succinate, fumarate or maleate) as β1 receptor blocker, rapid-release delivery system as angiotensin II receptor antagonist, and controlled-release matrix. The delayed release part shows 1 Hr 25-45%, 4 Hrs 40 to 75 % & 8 Hrs over 75 %. The angiotensin II receptor antagonist is selected from irbesartan, olmesartan, candesartan, telmisartan, valsartan, eprosartan, losartan, or their esters and salts, whereas present invention shows better release pattern which facilitating extended release of adrenergic blocking agent, over a time period of up to 24 Hrs.

Thus, it appears that the combination therapy of Telmisartan with metoprolol shows therapeutic efficacy in treatment of hypertension. Both drug act by different mechanism and hence the combination have a synergistic effects on reducing the blood pressure.
Development of fixed dose combination (FDCs) using multi-layer tablets technology gaining importance in recent years as oral solid drug delivery system in pharmaceutical industries over traditional conventional or modified release tablets due to many advantages and being used in the treatment of a wide range of conditions and are particularly useful in the management of chronic conditions and applicable for broad range of compatible as well as incompatible drugs for both immediate as well as modified release dosage form. There are many reasons for choosing bilayer or multi-layer tabletting technology due to its different therapeutic and technical advantages as compared to problems encountered with conventional or monolithic matrix tablet. Layering in the tablet revealed better management on release profile, it is a possible alternative to conventional matrix tablets to avoid the initial burst release upon placement of controlled release formulation in release medium or dissolution medium. Multilayer tabletting able to provide multiple release kinetics of same or different drugs of same or different physicochemical properties by application of multiple layers in which each monolith was formulated in order to parcel out the delivery of drug dose by means of different release mechanisms.
Multi-layer tabletting reduce dosing frequency by providing immediate release and then sustaining drug release over the period of time more than 12 hrs and reducing tablet intake thereby improving patient compliance.
It is possible to avoid the incompatibility in between active-active, excipient-excipient and active-excipients by mean of physical separation and well known reaction called as Maillard reactions occurring during conventional tableting.
In present invention multilayered tablets provide dual release, in which one layer of bilayer tablet or outer layer provides the initial dose in the form of rapidly disintegrating in the

stomach & inner layer tablet is formulated with components that are insoluble in gastric media but release in the intestinal environment over the period of time.
Multilayering also provide maximum flexibility in drug release patterns, ease of manufacturing, increase in safety margin of high potency drug & reduction in health care cost, higher drug loading capacity & ability to release multiple APIs, reducing manufacturing activities, overall unique, cost effective & stable dosage form.
Also, the modes of action of telmisartan and metoprolol succinate are considered to co-operate favorably in the treatment of hypertension particularly in patient where the target blood pressure cannot be achieved with one of the medications only. On this ground, it is needed to develop an oral fixed dose combination dosage form which combines the features of pharmacological efficacy, adequate drug stability and robust method of manufacturing has to overcome a number of technical problems.
Hence, on this ground it indicates that there exists a scope to develop a new or modified stable, cost effective pharmaceutical combination composition comprising Telmisartan and Metoprolol having an effect in lowering blood pressure in hypertensive patients comprising dual effect thereby providing rapid & sustained effects for more than 20 hours release.
OBJECT OF THE INVENTION
An object of the present invention is to provide a dual release bilayer solid oral pharmaceutical combination composition comprising an effective amount of a beta-blocker and an effective amount of an angiotensin II receptor antagonist along with the use of pharmaceutically acceptable excipients.
Another objective of the present invention is to prepare a safe and novel pharmaceutical combination composition.
Yet another objective of the present invention is to provide a dual release bilayer solid pharmaceutical composition dosage form suitable for oral administration.

Yet another objective of the present invention is to provide a method of manufacturing a dual release bilayer solid oral combination of a beta blocker and an an angiotensin II receptor antagonist drug in their therapeutically effective amounts along with other pharmaceutically acceptable excipients.
Another object is to provide extended release of selective beta-adrenoreceptor blocker by using monolithic matrix that is hydrophilic polymer or hydrophobic polymer or combination thereof in intra and extra granular stages, in an effective manner in extended release layer, thus providing two drugs combination therapy to have additive effect in lowering blood pressure in hypertensive patients.
Further objective of the present invention is to provide a dual release bilayer solid oral fixed dose combination dosage form in the treatment of hypertension, particularly in-patient where the target blood pressure cannot be achieved with one of the medications only.
Another object of present invention is to describe a process for preparation of dual release pharmaceutical compositions comprising biiayered tablets of two active ingredients formulated in a single dosage form providing different release profile using dual drug release absorption system (Duredas Technology).
SUMMARY OF THE INVENTION
The present invention relates to an stable dual release bilayer solid oral pharmaceutical composition comprising a first layer of metoprolol succinate as a beta adrenoreceptor blocker, hydrophilic polymer, hydrophobic polymer or combination thereof, and pharmaceutically acceptable excipients and, a second layer comprising of Telmisartan as a angiotensin II antagonist along with pharmaceutically acceptable excipients.
Further, the present invention also relates to an process for preparation of stable
pharmaceutical composition wherein it
comprises-
a) granulation of metoprolol succinate with pharmaceutically acceptable excipients by

non-aqueous granulation and blending the said granules with hydrophobic & hydrophilic polymers & lubricants;
b) Dissolve sodium hydroxide pellets in Methanol under stirring to get clear alkaline
methanolic solution & add Telmisartan in said alkaline methanolic solution, granulating with
pharmaceutically acceptable excipients by wet granulation using water soluble diluents and
blending the said granules with disintegrants, binders and lubricants
c) compressing the said two blends (a) and (b) into a bilayer tablet wherein each layer represents blend comprising a single active ingredient with excipients and;
d) coating the said bilayer tablet.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stable bilayer pharmaceutical composition for oral administration comprising of two active ingredients, formulated in a single dosage form with different release profile i.e. this stable pharmaceutical composition comprises dual release drug absorption system technology. The invention provides a dual release composition which reduces the dose of one of the active ingredient by extending the drug release over a period of time. The invention further describes a process for preparation of dual release pharmaceutical compositions comprising bilayered tablets of two active ingredients formulated in a single dosage form providing different release profile using dual drug release absorption system (Duredas Technology). The monolithic matrix of first layer comprises of hydrophobic polymer preferably carbomer or high viscosity hydrophilic polymer preferably hydroxyl propyl methylcellulose, or combination of hydrophilic and hydrophobic polymers thereby facilitating extended release of adrenergic blocking agent, over a time period more than 12 hours.
Monolithic matrix technique includes use of hydrophilic polymer or hydrophobic polymer or combination of hydrophilic and hydrophobic thereby helps the extended release of drug over specific period of time. The drug is dispersed in hydrophilic or hydrophobic or 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.

A bilayer solid oral pharmaceutical composition of present invention, wherein a first layer comprises of a beta adrenoreceptor blocker such as Metoprolol Succinate, hydrophilic or hydrophilic polymer or a combination of hydrophilic and hydrophobic polymer for an extended release delivery of beta blocker and pharmaceutical acceptable excipients, and a second layer comprising at least one angiotensin II antagonist such as Telmisartan and an adequate pharmaceutical carrier for an immediate release of angiotensin II antagonist.
As described herein, "bilayer tablet" is a tablet which is made up of two or more parallel separate layers or discrete zones of granulation compressed together with the individual layers lying one on top of another.
In accordance with the present invention problem associated with the preparation of a fixed dose combination of drug Telmisartan and Metoprolol Succinate is handled by means of bilayer pharmaceutical tablet comprising a first layer of metoprolol succinate in extended release form and second layer of telmisartan in immediate release pharmaceutical form.
The beta-blocker used in the present invention is selected from the group comprising metoprolol, labetalol, atenolol, propranolol and its pharmaceutically acceptable salts, preferably Metoprolol. The amount of Metoprolol succinate is equivalent to Metoprolol tartrate and it is in the range of 12.5 mg to 200mg.
Further, the stable pharmaceutical composition of present invention wherein, Metoprolol succinate is incorporated as an extended release monolithic matrix comprising a polymer combination of hydrophobic polymer and a hydrophilic polymer e in intra & extra granular stages.
The angiotensin II antagonist used in the present invention is selected from the group comprising telmisartan, irbesartan, losartan, olmesartan or alike and its pharmaceutically acceptable salts, preferably Telmisartan. Telmisartan used is in the range of 20 to 80 mg preferably 20 mg & 40 mg.

The dual release drug absorption system of present invention comprising Telmisartan and Metoprolol succinate equivalent to Metoprolol tartrate further comprises combination with pharmaceutically acceptable excipients selected from diluents, binders, alkalizing agent, disintegrating agents, film formers, lubricants and plasticizers either alone or in combination thereof.
The binders used in the present invention may be one or more of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia, agar, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, sugar, dextrin, ethyl cellulose, glyceryl behenate, hydroxy propyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, polyethylene oxide, Sorbitol, Pregelatinised starch wherein preferred binder is polyvinyl pyrrolidone used in the range of 1 to 15%.
The disintegrants used in the present invention may be one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin, wherein preferred disintegrant is crospovidone used in the range of 1 to 6%.
The diluents used in the present invention may be one or more of lactose, starch, dibasic calcium phosphate dihydrate, mannitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, ethyl cellulose, sodium alginate, tragacanth, xylitol and microcrystalline cellulose.
The diluent used in the present invention is in the range of 10-50% preferably 15-35% in first layer, and 30-90%, preferably 60-80% in second layer.
The lubricants used in the present invention may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumarate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate in the range of 0.1 to 6%, preferably 0.5 to 5.0%

The plasticizers used in the present invention may be one or more of Polyethylene glycol, Triethyl citrate, Triacetin, diethyl phthalate, Acetyl Triethyl citrate, Dibutyl Sebacate, Dibutyl phthalate preferably polyethylene glycol.
The hydrophobic and hydrophilic polymers are used as release retardant material. The retardant materials can be used alone or in combination.
The hydrophobic polymers used in the present invention may be one or more of acrylic acid and methacrylic acid copolymers, methacrylates polymers, carbomer homopolymers USP/NF type A or B, Acrylic acid & polyacrylic acid or carboxyvinyl polymer and carbopols preferably carboxyvinyl polymer or carbopols used in the range of 10-60% preferably 15-40%;
The hydrophilic polymers used in the present invention may be one or more of Hydroxy propyl methyl celluloses (HPMC), hydroxy propyl ethyl celluloses (HPEC), hydroxy propyl celluloses (HPC), methyl celluloses (MC), ethyl celluloses (EC), sodium carboxyl methyl celluloses (Na CMC) or a mixture of different grades of HPMC form low viscosity to high viscosity grade from 5 cps to 75000 cps to 140000 cps such as HPMC E5, HPMC K15M, HPMC K4M, HPMC K100M, HPMC 100LV or ethyl cellulose preferably HPMC K15M in the range of 20-60%, preferably 15 to 40%.
The film formers used in present invention comprises of polymers like cellulosic derivatives with low viscosity polymers from synthetic and natural sources preferably low viscosity HPMC 5 cps in the range of 0.5 to 6%, preferably 1 to 5.0%.
The solvents used may be one or more of methanol, isopropyl alcohol, ethanol, or purified water. Telmisartan is dissolved in methanol with the help of one or more basic agents selected from the group comprising of an alkali metal hydroxide like sodium hydroxide.
Another aspect of present invention describes preparation of dual release bilayer tablet, in which extended release composition give 1 Hr (NMT 25 %), 4 Hrs (between 30 to 55 %), 8 Hrs (between 50 to 80 %) and 20 Hrs NLT 80 % release of metoprolol succinate i.e. facilitating extended release of adrenergic blocking agent, over a time period of up to 24 Hrs.

The process of preparation of dual release pharmaceutical composition comprises of granulating metoprolol succinate equivalent to metoprolol tartrate together with selected excipients by non-aqueous granulation process, blending the said granules of metoprolol succinate equivalent to metoprolol tartrate with lubricants and glidants; wherein carbomers & HPMC are used both in granulation and blending stage. Thus, the non-aqueous granulation of Metoprolol succinate prepared using extended release matrix comprising a hydrophobic polymer (carbomer) and hydrophilic polymer (hydroxypropyl methyl cellulose) along with selected excipients. More preferably, metoprolol and diluent sifted through (cosifting twice) with hydrophobic and hydrophilic polymers, dry mix in RMG and granulated using binder dissolved in solvent like isopropyl alcohol, sifted' dried, with moisture NMT 3% w/w. Dried granules of metoprolol succinate are sifted through 20#, and blended with extra granular part of hydrophobic and hydrophilic polymer followed by lubricants. This lubricated blend used for preparation of bilayer tablet as extended release layer part.
The granulation of Telmisartan composition comprises dissolving of Telmisartan in clear solution of solvent like methanol and basic agent, and adsorption of this solution on selected excipients by wet granulation process, blending the said granules of Telmisartan with disintegrant, binder and lubricants. More preferably, sodium hydroxide pellets dissolved in Methanol to get clear solution, Telmisartan dissolved in it and adsorb on diluents in RMG and dried with moisture NMT 2% w/w, dried granules sift through 20# using vibro sifter, and blended using combination of disintegrants and then with lubricants in octagonal blender. This lubricated blend used for preparation of bilayer tablet as immediate release layer part.
Compressing the said two lubricated blends into a bilayered tablet where each layer represents blend comprising a single active ingredient with excipients. Compression of blends into two layer tablets, characterized by the presence of the two drug substances in two parallel different layers. Compressed two-layer tablets coated with non-functional coating polymer by taking isopropyl alcohol in suitable stainless steel container and dissolving water soluble low viscosity polymer such as hydroxy propyl methyl cellulose with plasticizer such as Polyethylene Glycol 6000 under constant stirring for approximately 10 minutes and by finally by adding purified water under continue stirring for 30 minutes. This solution is used

to coat tablet in conventional coater / Autocoater. The film coating solution is used to coat
the core bilayer tablet in order to get the weight gain of 2 to 3%.
A stable pharmaceutical composition as per present invention wherein the compression force
applied during compression of first tablet layer is from 10 to 60 Newtons, preferably 20 to 40
Newtons, and final compression force of the first and second layer tablet compression is
from 80 to 200 Newtons.
The tablet according to present invention provides a largely pH independent dissolution of
poorly water soluble Telmisartan.
The amount of Metoprolol succinate equivalent to Metoprolol tartrate is in the range of 12.5
mg to 200mg. Further, in this developed composition the preparation of extended release
dose of metoprolol succinate & Telmisartan act differently.
A stable pharmaceutical composition as per present invention wherein the tablet packaging in
a moisture proof packing material like aluminum foil blister pack or polypropylene or HDPE
bottles or Alu-Alu blister pack.
The compositions possess dual release profile in lowering blood pressure in hypertensive
patients.
Further, the present combination composition invention relates to the treatment of
hypertension.
This combination of telmisartan with metoprolol is expected to show therapeutic efficacy in treatment of hypertension. Both drug act by different release rate and hence the combination is useful in reducing the blood pressure. The combination can be used for moderate to severe hypertension and act for more than 12 hours and hence combination will be pharmacologically complaint
Although the present invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Example 1:
A) Metoprolol succinate granules: Contains 23.75 mg metoprolol succinate equivalent of metoprolol tartrate 25 mg along with the following excipients.

Sr. No. Ingredients Quantity (Mg/Tablet)
1 Metoprolol succinate 23.75 mg
2 Hydroxy propyl Methyl Cellulose (K15 M) 40 mg
3 Carbomer 25 mg
4 Microcrystalline cellulose 40.34 mg
5 Povidone K30 15 mg
6 Isopropyl alcohol* q.s.
7 Hydroxy propyl Methyl Cellulose (K15 M) 40 mg
8 Carbomer 30 mg
9 Talc 2.15 mg
10 Magnesium stearate 3.76 mg
Total lav er weight 220 me
* Volatile component does not remain in final product
B) Telmisartan granules: Contains Telmisartan 40 mg along with following excipients

Sr. No. Ingredients Quantity (Mg / Tablet)
1 Telmisartan 40 mg
2 Mannitol 306.18 mg
3 Sodium Hydroxide 3.5 mg
4 Iron oxide yellow 3 mg
5 Methanol * 40 ml
6 Pregelatinised starch 20 mg
7 Crospovidone 10.5 mg
8 Talc 10 mg
9 Magnesium Stearate 6.82 mg
Total layer weight 400 mg
* Volatile component does not remain in final product C) Compression and film coating: Strength 25/40 mg

Sr. No. Ingredients Quantity

(Mg/Tablet)
1 Bilayer uncoated tablet 620 mg
2 Hydroxy propyl methyl cellulose (5 cps) 13.95 mg
3 Poly Ethylene Glycol 6000 1.55 mg
4 Isopropyl alcohol* 58.9 mg
5 Water* 235.6 mg
Film coated bilayer tablet weight 635.5 mg
* Component does not remain in final product
1) Metoprolol succinate layer weight: 220 mg
2) Telmisartan layer weight: 400 mg
3) Bilayer core tablet weight: 620 mg
4) Film coated tablet weight: 635.5 mg
5) % film coating 2.5 % & % solid content of film coating solution: 5 % w/w
Metoprolol Succinate
1) Sifted Metoprolol succinate and microcrystalline cellulose through 30 # twice.
2) Sifted HPMCK15M&Carbomer through 30 #.
3) Dry mixed step -1 & step - 2 ingredients in RMG for 10 mins
4) Dissolved povidone K30 in isopropyl alcohol to get clear solution.
5) Mixed step-3 dry mix with step -4 solution and granulation was done in RMG for
10 mins.
6) Dried granules of step 5 in FBP for two hrs (LOD NMT 3% w/w)
7) Sifted dried granules of Metoprolol succinate through 20 #
8) Sifted HPMC Kl 5 M and Carbomer through 20 # and blended with step - 7, dried granules for 10 mins.
9) Sifted magnesium stearare and talc through 60 # and lubrication was done for 10 mins.
Telmisartan Granulation
1) Dissolved sodium hydroxide pellets in methanol under continuous stirring to get clear solution.
2) Telmisartan was added to step 1 solution, brown color solution obtained.
3) Sifted Mannitol and iron oxide yellow through 60 # and dry mixed for 5 mins in
RMG at slow speed.

4) Step - 2 brown colour solution was added to dry mix of step -3 under high speed of chopper & impellor slowly and wet mixed for 5 mins.
5) Wet granules from RMG were removed and dried in FBP for 2 Hrs and checked for LOD NMT 2 % w/w.
6) Sifted dried granules of Telmisartan through 20 # using Vibro sifter.
7) Sifted Crospovidone and Pregelatinised starch through 40 # and prelubrication was done
for 10 mins in octagonal blender.
8) Sifted Magnesium stearate and talc through 60 # and lubrication was done for 10 mins in octagonal blender.
9) Packed lubricated blend in double polybag.
Compression:
Compression was performed using bilayer tablet compression machine by setting individual layer weight for respective strength.
Film Coating
1) Dissolved Low viscosity HPMC in mixture of IP A & water, and PEG 6000 was added as plasticizer and stirred for 30 mins.
2) Film coating was done on core of bilayer tablets.
Example 2:
A) Metoprolol succinate granules: Contains 47.5 mg metoprolol succinate equivalent of metoprolol tartrate 50 mg along with the following excipients

Sr. No. Ingredients Quantity (Mg/Tablet)
1 Metoprolol succinate 47.5 mg
2 Hydroxy propyl Methyl Cellulose (K15 M) 40 mg
3 Carbomer 15 mg
4 Microcrystalline cellulose 70.08 mg
5 Povidone K30 15 mg
6 Isopropyl alcohol* q.s.
7 Hydroxy Propyl Methyl Cellulose (K15 M) 40 mg
8 Carbomer 30 mg
9 Talc 4.77 mg
10 Magnesium stearate 2.65 mg

1 Total laver weieht 265 mg
* Volatile component does not remain in tinal product
B) Telmisartan granules: Contains Telmisartan 40 mg along with following excipients

Sr. No. Ingredients Quantity (Me / Tablet)
1 Telmisartan 40 mg
2 Mannitol 306.18 mg
3 Sodium Hydroxide 3.5 mg
4 Iron oxide yellow 3 mg
5 Methanol * 40 ml
6 Pregelatinised starch 20 mg
7 Crospovidone 10.5 mg
8 Talc 10 mg
9 Magnesium Stearate 6.82 mg
Total layer weight 400 mg
* Volatile component does not remain in tinal product
C) Compression and film coating:: Strength 50/40 mg

Sr. No. Ingredients Quantity (Mg/ Tablet)
1 Bilayer uncoated tablet 665 mg
2 HPMC E5 18.0 mg
3 PEG 6000 2.0 mg
4 Isopropyl alcohol* 228 mg
5 Water* 152 mg
Film coated bilayer tablet weight 685 mg
*Component does not remain in final product
1) Metoprolol S. layer weight: 265 mg
2) Telmisartan layer weight : 400 mg
3) Bilayer core tablet weight : 665 mg
4) Film coated tablet weight : 685 mg
5) % film coating 3.0 % & % solid content of film coating solution: 5 % w/w.
Metoprolol Succinate:
1) Sifted Metoprolol succinate and micro crystalline cellulose through 30 # twice.
2) Sifted HPMC K l5 M & Carbomer through 30 #.
3) Dry mixed step - 1 & step - 2 ingredients in RMG for 10 mins

4) Dissolved povidone K30 in isopropyl alcohol to get clear solution.
5) Mixed step-3 dry mix with step -4 solution and granulation was done in RMG for
10 mins.
6) Dried granules of step 5 in FBP for two hrs (LOD NMT 3% w/w)
7) Sifted dried granules of Metoprolol succinate through 20 #
8) Sifted HPMC K 15 M and Carbomer through 20 # and blend with step - 7 dried granules for 10 mins.
9) Sifted magnesium stearate and talc through 60 # and lubrication was done for 10 mins.
Telmisartan Granulation
1) Dissolved sodium hydroxide pellets in methanol under continuous stirring to get clear solution.
2) Telmisartan was added to step 1 solution ,brown color solution obtained.
3) Sifted Mannitol and iron oxide yellow through 60 # and dry mixed for 5 mins in RMG at slow speed.
4) Step - 2 brown colour solution was added to dry mix of step -3 under high speed of chopper & impellor slowly and wet mix for 5 mins.
5) Wet granules from RMG were removed and dried in FBP for 2 Hrs and check LOD NMT 2 % w/w.

6) Sifted dried granules of Telmisartan through 20 # using Vibro sifter.
7) Sifted Crospovidone and Pregelatinised starch through 40 # and prelubrication was done for 10 mins in octagonal blender.
8) Sifted Magnesium stearate and talc through 60 # and lubrication was done for 10 mins in octagonal blender.
9) Packed lubricated blend in double polybag.
Compression:
Compression was performed using bilayer tablet compression machine by setting individual layer weight for respective strength.

Film Coating
1) Dissolved Low viscosity HPMC in mixture of IP A & water, and PEG 6000 was added as plasticizer and stirred for 30 mins.
2) Film coating was done on core of bilayer tablets.
The said pharmaceutical compositions of Metoprolol Succinate & Telmisartan are physically and chemically stable over its shelf life period based on three months accelerated and controlled room temperature, and hence dissolution testing parameters of said dual release developed in-house which is as follows. Dissolution parameters: Dissolution medium: Phosphate buffer pH 7.5, apparatus: USP II (paddle), speed 100 rpm, time points 1, 4, 8, & 20 Hrs for Metoprolol succinate & lhr for telmisartan as dissolution time points. Following are the details stability data which is as follows: Bilayer tablet comprising Metoprolol succinate extended release and telmisartan immediate release Tablets strength 25/40 mg, each film coated bilayered tablet contains Metoprolol succinate USP 23.75 mg equivalent to Metoprolol tartrate USP 25 mg and Telmisartan IP 40 mg is stored at controlled room temperature condition (25 ± 2°C & 60 ± 5% RH) & at accelerated stability condition at (40 ± 20C & 75 ± 5% RH) based on three months following data is as follows.
Comparative stability data at controlled room temperature, for strength 25/40 mg at condition (25 ± 2°C & 60 ± 5% RID
1) Physical appearance of three batches for strength (25/40 mg)

Test Specification Batch no Initial At condition (25
± 2°C & 60 ±
5%RH)
After three
months At condition (40 ± 2°C & 75 ± 5% RH) After three months
Capsule shape, biconvex, film coated bilayer tablets having PTD/1632/06 (25+40) Complies Complies Complies

Appearance yellow colored Telmisartan layer & white colored Metoprolol succinate layer with plain surface on both sides PTD/1632/07 (25+40) Complies Complies Complies

PTD/1632/11 (25+40) Complies Complies Complies
2) Comparative initial dissolution profile data of three batches for strength (25/40 mg)

Dissolution Time in Hrs Limits Initial dissolution % release

Batch No. PTD/1632/06 Batch No. PTD/1632/07 Batch No. PTD/1632/11
Metoprolol Succinate 1st hr NMT 25 % 12 11 14

4th hrs 30% to 55 % 39 38 43

8th hrs 50 % to 80 % 66 64 70

20th hrs NLT 80 % 99 95 100
Telmisartan l Hr NLT 70 % 82 96 88
3) Comparative dissolution profile data after three months for strength (25/40 mg) at condition (25 2°C & 60 ± 5% RH) on three batches.

Dissolution Time in Hrs Limits After three months dissolution release at (25 ± 2°C & 60 ± 5% RH)

Batch No. PTD/1632/06 Batch No. PTD/1632/07 Batch No. PTD/1632/11
Metoprolol Succinate 1st hr NMT 25 % 14 16 14

4th hrs 30% to 55 % 43 40 43

8th hrs 50 % to 80 % 71 67 70

20th hrs NLT 80 % 100 86 100
Telmisartan l Hr NLT 70 % 87 100 88
4) Comparative dissolution profile for after three month's for strength (25/40 mg) at condition (40 ± 2°C & 75 ± 5% RH) on three batches.

Dissolution Time in Hrs Limits Initial % release of Metoprolol Succinate layer part

Batch No. PTD/1632/06 Batch No. PTD/1632/07 Batch No. PTD/1632/11
1st hr NMT 25 % 14 13 13

5) Comparative assay results initial & after three months for strength 25/40 mg

Batch No. Assay Limits for Metoprolol
Succinate (90% -100%) Assay Limits
for Telmisartan
(90% -100%) After three months (25 ± 2°C & 60 ± 5% RH) After three months (25 ± 2°C & 60 ± 5% RH) After three months (40±2°C & 75 ± 5% RH) After three months
(40 ± 2°C & 75 ± 5% RH)

Initial assay results

Metoprolol Succinate Telmisartan Metoprolol Succinate Telmisartan Metoprolol Succinate Telmisartan
PTD/1632/06 103.5 105 99.6 109.7 106.5 108.1
PTD/1632/07 102.7 105.3 105.7 . 106 108.5 107
PTD/1632/11 105.5 102.5 105.5 104.3 102.5 103.3
The sample comprising Metoprolol succinate extended release + Telmisartan immediate release Tablets strength (50+40) mg, each film coated bilayer tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg and Telmisartan EP 40 mg is stored at controlled room temperature at 25 ± 2°C & 60 ± 5% RH & at accelerated stability condition at (40 ± 2°C & 75 ± 5% RH) based on three months following data is as follows.
1) Comparative physical appearance of three batches for strength (50/40 mg)

Test Specification Batch no Initial At condition (25 ± 2°C & 60 ± 5% RH) After three months At condition (40 ± 2°C & 75 ± 5% RH) After three months
Appearance Round shape, biconvex, film coated bilayer tablets having yellow colored Telmisartan layer & white colored PTD/1631/04 (50+40) Complies Complies Complies

PTD/1631/05 (50+40) Complies Complies Complies

Metoprolol succinate layer with plain surface on both sides PTD/1631/06 (50+40) Complies Complies Complies
Comparative initial dissolution profile data of three batches for strength (50/40 me)

Dissolution Time in Hrs Limits Initial dissolution % release

Batch No. PTD/1631/04 Batch No. PTD/1631/05 Batch No. PTD/1631/06
Metoprolol Succinate 1st hr NMT 25 % 15 17 17

4th hrs 30% to 55 % 41 45 43

8th hrs 50 % to 80 % 66 69 68

20th hrs NLT 80 % 100 98 97
Telmisartan l Hr NLT 70 % 100 88 90
2) Comparative dissolution profile data after three months for strength (50/40 mg) at condition (25 ± 2°C & 60 ± 5% RH) on three batches.

Dissolution Time in Hrs Limits After three months dissolution release at (25 ± 2°C& 60 ± 5% RH)

Batch No. PTD/1631/04 Batch No. PTD/1631/05 Batch No. PTD/1631/06
Metoprolol Succinate 1st hr NMT 25 % 15 17 15

4th hrs 30% to 55 % 43 44 42

8th hrs 50 % to 80 % 68 68 68

20th hrs NLT 80 % 100 97 97
Telmisartan l Hr NLT 70 % 91 99 98
3) Comparative dissolution profile for after three month's for strength (50/40 mg) at condition (40 ± 2°C & 75 ± 5% RH) on three batches.

Dissolution Time in Hrs Limits Initial % release of Metoprolol Succinate layer part

Batch No. PTD/1631/04 Batch No. PTD/1631/05 Batch No. PTD/1631/06
Metoprolol Succinate 1st hr NMT 25 % 14 17 15

4th hrs 30% to 55 % 41 44 43

8th hrs 50 % to 80 % 66 69 68

20th hrs NLT 80 % 98 101 98
Telmisartan l Hr NLT 70 % 87 98 97
5) Comparative assay results initial & after three months for strength 50/40 mg

Batch No. Assay Limits for Metoprolol
Succinate (90% -100%) Assay Limits
for Telmisartan (90% -100%) After three months
(25 ± 2°C
& 60±5%
RH) After three months
(25 ± 2°C & 60 ± 5% RH) After three months
(40 ± 2°C
&75±5%
RH) After three months (40 ± 2°C &
75 ± 5% RH)

Initial assay results

Metoprolol Succinate Telmisartan Metoprolol Succinate Telmisartan Metoprolol Succinate Telmisartan
PTD/1631/04 108.8 101.5 104.0 102.5 103.4 103.3
PTD/1631/05 100.6 104.1 102.7 104.4 100.7 104.9
PTD/1631/06 108.8 104.1 104.0 104.2 103.4 104.9

We Claim:
1. A stable dual release bilayer solid oral pharmaceutical composition comprising
a first layer of metoprolol succinate as a beta adrenoreceptor blocker, hydrophilic polymer, hydrophobic polymer or combination thereof, and pharmaceutically acceptable excipients and;
a second layer comprising of Telmisartan as a angiotensin II antagonist along with pharmaceutically acceptable excipients.
2. A stable pharmaceutical composition as claimed in claim 1, wherein hydrophilic polymer, hydrophobic polymer or combination thereof used as release retardant for an extended release delivery.
3. A stable pharmaceutical composition as claimed in claim 1, wherein second layer acts as an immediate release of said angiotensin II antagonist.
4. A stable pharmaceutical composition as per claim 1, wherein the pharmaceutically acceptable excipients comprises of diluents, binders, disintegrants, lubricants, alkalizing agents, plasticizers, and film formers either alone or in combination thereof.
5. A stable pharmaceutical composition as per claim 4, wherein the said diluents comprises of one or more lactose, starch, dibasic calcium phosphate dihydrate, mannitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, ethyl cellulose, sodium alginate, tragacanth, xylitol and microcrystalline cellulose, preferably mannitol and microcrystalline cellulose.
6. A stable pharmaceutical composition as per claim 5, wherein the said diluent is in the range of 10-50% preferably 15-35% in first layer, and 30-90%, preferably 60-80% in second layer.
7. The stable pharmaceutical composition as per claim 4, wherein the said binders comprises of one or more of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia.

agar, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, sugar, dextrin, ethyl cellulose, glyceryl behenate, hydroxy propyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, polyethylene oxide, sorbitol, pregelatinised starch and polyvinylpyrrolidone, preferably polyvinyl pyrrolidone used in the range of 1 to 15%
8. A stable pharmaceutical composition as per claim 4, wherein the said disintegrants comprises of croscartnellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, microcrystalline cellulose, and potassium polacrilin, preferably crospovidone used in the range of 1 to 6%.
9. The stable pharmaceutical composition as per claim 4, wherein the said lubricants comprises of one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumarate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesiurn lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate in the range of 0.1% to 6%, preferably 0.5 to 5.0%

10. The stable pharmaceutical composition as per claim 4 wherein the said plasticizers comprises of one or more of polyethylene glycol, Triethyl citrate, Triacetin, diethyl phthalate, Acetyl Triethyl citrate, Dibutyl Sebacate, Dibutyl phthalate preferably polyethylene glycol.
11. The stable pharmaceutical composition as per claim 4, wherein alkalizing agents comprises of sodium hydroxide.
12. A stable pharmaceutical composition as per claim 4, wherein the said film formers comprises of polymers like cellulosic derivatives with low viscosity polymers from synthetic and natural sources preferably low viscosity HPMC 5 cps in the range of 0.5 to 6%, preferably 1 to 5.0%.

13. A stable pharmaceutical composition as per claim 1, wherein the hydrophobic polymers
comprises one or more of acrylic acid, methacrylic acid copolymers, methacrylates
polymers, carbomer homopolymers USP/NF type A or B, acrylic acid & polyacrylic acid,
carboxyvinyl polymer or carbopols, preferably carboxyvinyl polymer or carbopols used in
the range of 10-60% preferably 15-40%;
hydrophilic polymers comprises of one or more of Hydroxy propyl methyl celluloses (HPMC), hydroxy propyl ethyl celluloses (HPEC), hydroxy propyl celluloses (HPC), methyl celluloses (MC), ethyl celluloses (EC), sodium carboxyl methyl celluloses (Na CMC) or a mixture of different grades of HPMC from low viscosity to high viscosity grade from 5 cps to 75000 cps to 140000 cps such as HPMC E5, HPMC K15M, HPMC
K4M, HPMC K100M, HPMC 100LV and ethyl cellulose, preferably HPMC K15M in the range of 20-60%, preferably 15 to 40%.
14. Process for preparation for stable pharmaceutical composition as per claim 1, wherein
comprises-
a) granulation of metoprolol succinate with pharmaceutically acceptable excipients by
non-aqueous granulation and blending the said granules with hydrophobic & hydrophilic
polymers & lubricants;
b) adding Telmisartan in a alkaline methanolic solution of NaOH, granulating with
pharmaceutically acceptable excipients by wet granulation using water soluble diluents and
blending the said granules with disintegrants, binders and lubricants.
c) compressing the said two blends (a) and (b) into a bilayer tablet wherein each layer represents blend comprising a single active ingredient with excipients and;
d) coating the said bilayer tablet.
15. A stable pharmaceutical composition as per claim 1, wherein the compression force
applied during compression of first tablet layer is from 10 to 60 Newtons, preferably 20 to 40
Newtons and final compression force of the first and second layer tablet compression is from
80 to 200 Newtons.

16. The stable pharmaceutical composition substantially as herein described and illustrated with reference to accompanying examples.