FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Stable pharmaceutical compositions of Beta adrenoreceptor blocker and
Diuretic"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LIMITED
(b) NATIONALITY: an 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 particularly describes the invention and the manner in which it has to be performed.

Technical Field of the Invention:
The present invention relates to 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) adrenoreceptor blocking agent Metoprolol succinate in the form of an extended release formulation and a diuretic Chlorthalidone in the form of an immediate release formulation. Further the invention relates to process of preparation of the said compositions.
Background and prior art of the Invention:
Diuretics, sometimes commonly referred as "water pills" are drugs that increase the rate of urine flow. Diuretics cause sodium to be lost in the urine thus decreasing the volume of extra-cellular fluid, as sodium is the main determinant of water present in extra-cellular space. Diseases associated with excess fluid accumulation include congestive heart failure, pulmonary edema and liver cirrhosis to name a few. Ability of diuretics to reduce the blood pressure is known since decades. Initially the diuretic lowers the blood pressure by causing a decrease in the extra-cellular fluid volume and decreased cardiac output. The long-term effect is due to the reduction in the resistance of vessels to blood flow which results in lower blood pressure. Diuretic treatment converts the non-rennin dependent state in regulating blood pressure to a rennin dependent state. W0974932 has reported that about 40% of hypertensive patients are non responsive to angiotensin converting enzyme inhibitors (ACEI). But when a diuretic is given together with an ACEI the blood pressure of most hypertensive patients is effectively normalized.
Chlorthalidone is a sulfonamide diuretic and is commonly used in the initial treatment of high blood pressure. Sulfonamide diuretics are used in the treatment of conditions associated with excess fluid accumulation including congestive heart failure. Chlorthalidone is a monosulfamyl diuretic and is chemically described as 2-chloro-5 (1-hydroxy-3-oxo-l-isoindolinyl) benzenesulfonamide its empirical formula is C14H11C1N2O4S.
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Chlorthalidone is a well-known diuretic agent, which has been widely marketed since the early 1960's. Chlorthalidone is well absorbed and after oral administration, absorption produces peak plasma concentrations between 8 and 12 hours. Absolute bioavailability has been estimated to be approximately 64%.
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. It reduces the oxygen demand to heart, slowing the heart rate, reducing cardiac output when at rest and on exercise, reduces systolic blood pressure among other things. There have been many 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 up to 24 hours in a suitable controlled manner.
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.
Patent number ES8602633 (boehringer Ingelheim Ltd. US) discloses the process of solid state dispersion of Chlorthalidone in order to increase the dissolution rate of Chlorthalidone and thereby increasing its bioavailability.
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.
Korean Patent No. 9507207 to Park Sok- Ryon describes a drug composition for treatment of hypertension comprising a beta-blocking agent, an ACE inhibitor and a diuretic.
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However, none of the above patents deal with combination of anti-hypertensive and diuretic agents wherein one of the drugs namely the anti-hypertensive is suitably formulated for extended release while the diuretic agent is incorporated suitably for immediate release.
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) adrenoreceptor blocking agent Metoprolol succinate and a diuretic Chlorthalidone.
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 selective diuretic, thus providing two drug combination therapy to have additive effect in lowering blood pressure in hypertensive patients.
Yet another object is to reduce the dose of one of the active ingredient by extending the drug release over a period of time.
Summary of the Invention:
The present invention discloses stable dual release pharmaceutical compositions comprising of two active ingredients, formulated into a single dosage form providing different release profile. It involves use of combination of hydrophobic and hydrophilic polymers, which provides extended release of one active drug over specific period of time.
Particularly, the invention discloses novel stable pharmaceutical compositions of adrenergic blocking agent, preferably Metoprolol succinate, oral solid extended release pharmaceutical formulations, which release Metoprolol succinate equivalent to Metoprolol tartrate over a time period of up to 24 hours and a diuretic Chlorthalidone to
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treat various cardiovascular diseases. The amount of the said salts Chlorthalidone is in the range of 6.25 to l00mg equivalent to Chlorthalidone free base, preferably 5mg and 2.5mg. The amount of the said Metoprolol succinate equivalent to Metoprolol tartrate is in the range of 12.5 to 200mg preferably, 50mg and 25mg. The said compositions are preferably in the solid dosage forms, such as tablets, pills, granules, capsules or sachets, preferably tablets. The present invention further discloses different process for preparing said stable composition of Chlorthalidone with Metoprolol succinate.
Description of the Invention:
The present invention describes stable dual release pharmaceutical compositions used for treatment of hypertension, chronic stable angina and other related cardiovascular diseases comprising two active ingredients, which are formulated in a single dosage form providing different release profile.
Particularly, the invention describes pharmaceutical compositions for oral administration comprising combination of therapeutically effective amount of a synthetic beta-selective (cardioselective) adrenoreceptor blocking agent Metoprolol succinate in the form of an oral solid extended release pharmaceutical formulation and a diuretic Chlorthalidone along with pharmaceutically acceptable excipients. The said compositions are preferably in the solid dosage forms, such as tablets, pills, granules, capsules or sachets, preferably tablets.
According to one aspect of the present invention, the dose range of Chlorthalidone in the said composition is 6.25 tol00mg and dose range for Metoprolol succinate is 12.5 to 200mg. Most preferred dose of Chlorthalidone in the said composition is 6.25mg for Chlorthalidone and Metoprolol succinate equivalent to Metoprolol tartarte is 50mg.
The said composition comprises Chlorthalidone and Metoprolol succinate equivalent to Metoprolol tartrate in combination with pharmaceutically acceptable excipients selected from diluents, binders, flavors, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, lubricants and/or glidants.
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Further, the invention describes the process of preparation of the said dual release compositions comprising bilayered tablets of Metoprolol succinate equivalent to Metoprolol tartrate and Chlorthalidone. The bilayered tablets of the present invention provide dual release rates of the individual components within the single dosage form wherein, an accurate dose of individual active is delivered. The process involves use of combination of hydrophobic (carbomer) and hydrophilic (hydroxy propyl methyl cellulose) polymers, which provides extended release of drug over specific period of time. The process comprises of formulating in one of the compartment which is upper layer and which release the beta-selective adrenoreceptor blocking active agent Metoprolol succinate over a period of time, ensuring uniform and constant blood levels after absorption and lower layer and which is formulated for immediate release of the diuretic, Chlorothalidone. This process involves reduced manufacturing steps and manufacturing time and also provides a cost effective formulation.
Process I
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 are used both in granulation and blending stage; blending the Chlorthalidone with disintegrants, lubricants and glidants and compressing the said two blends into bilayered tablet where each layer repents blend comprising single active ingredient with excipients.
Process II
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, lubricants and glidants; wherein carbomers are used both in granulation and blending stage; granulating Chlorthalidone together with selected excipients by moist granulation process blending a said granules of Chlorthalidone with disintegrants, lubricants and glidants and compressing the said two
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blends into a bilayered tablet where each layer represents blend comprising a single active ingredient with excipients.
As per one embodiment (X) of the present invention, the said process comprises;
(i) Metoprolol succinate equivalent to Metoprolol tartrate and an extended release matrix
comprising a hydrophobic (carbomer) and hydrophilic (hydroxy propyl methyl cellulose)
polymers, in amount from about 40% to 60% by weight of the final product along with
selected excipients, using non-aqueous wet granulation process,
(ii)Wet granulation of Chlorthalidone together with selective excipients such as diluents
in the range of 5% to 95% and disintegrants in the range of 1% to 6.0%.
(iii)Compressing (i) and (ii) into two layer tablets characterized by the presence of the
two drug substances in two different layers.
As per another embodiment (Y) of the present invention, the said process comprises;
(i) Metoprolol succinate equivalent to Metoprolol tartrate and an extended release matrix
comprising a hydrophobic (carbomer) and hydrophilic (hydroxy propyl methyl cellulose)
polymers in an amount from about 40% to 60% by weight of the final product along with
selected excipients, using non-aqueous wet granulation process,
(ii) Chlorthalidone together with selective excipients, wherein amount of diluents is more
by 1% than the earlier embodiment (X) and amount of disintegrants is more by 4% than
the earlier embodiment (X), in the wet granulation process,
(iii) lubricating the said granules,
(iv) compressing the said granules into two layer tablets characterized by the presence of
the two drug substances in two different layers, using standard compression tooling
known in art.
As per the present invention, the carefully screened pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, emulsifiers, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof.
Diluents are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, maize starch or their modified forms and are used in the range of 5% to 95% of tablet weight.
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Binders are selected from the group consisting of maize starch, polyvinylpyrrolidone. The said polyvinylpyrrolidone is in the range of 3% to 15% and maize starch is in the range of 2%tol0%.
Disintegrants are selected from the group consisting of containing starch, derivative of starch, preferably sodium starch glycollate. The preferred disintegrant is sodium starch glycolate, used in the range of l%-6%.
Lubricants and glidants are selected from the group consisting of magnesium stearate, used in the range of 0.25% to 5.0% and colloidal silicon dioxide, used in the range of 0.1% to 0.5%.
Film formers are selected from the group consisting 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 1.0%.
Other miscellaneous auxiliaries required for processing the product and maintaining stability.
The dual release drug compositions as per the present invention delivers the drug in such a way that the drug level is maintained within the therapeutic window and effective and safe blood levels are maintained for a period as long as the system continues to deliver the drug at a particular rate. Controlled drug delivery usually results in substantially constant blood levels of the active ingredient as compared to fluctuations observed with immediate release dosage forms. Controlled drug therapy reduces the required frequency of administration, and single doses at periodic intervals are sufficient, resulting in improved patient compliance. Further, the bilayered technology provides adequate drug stability, optimum drug release of both active ingredients and pharmacological efficacy.
The stable pharmaceutical compositions of the present invention may be in the dosage form of tablets and bilayered tablets. The two active ingredients are provided in the two strengths of (50+12.5mg) and (25+6.25mg) respectively for Metoprolol succinate
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equivalent to Metoprolol tartrate and Chlorthalidone. Oval shaped punches are used for compression and the two layers are superimposed one on top of the other.
The release of the active ingredient in extended release layer from the pharmaceutical composition is extended about 6 to 24 hours after predetermined time delay and the release of the active ingredient in immediate layer from the pharmaceutical composition is between 30 to 60min after ingestion.
The present investigation 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 investigation includes the following examples and further can be modified and altered within the technical concept of the present investigation.
EXAMPLES
Each example described below contains Metoprolol succinate equivalent to Metoprolol tartrate.
Example -1
A) Metoprolol succinate granules: Contains 50mg Metoprolol succinate equivalent to Metoprolol tartrate along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Metoprolol succinate 19.4%
2 Microcrystalline cellulose 8.97%
3 Carbomer 8.98%
4 Hydroxy propyl methyl cellulose (K15M) 24.9%
5 Polyvinylpyrrolidone (K30) 12.24%
6 Isopropyl alcohol Qs
7 Hydroxy propyl methyl cellulose (K15M) 24.49%
8 Magnesium stearate 1.02%
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Preparation of Metoprolol succinate granules:
Metoprolol succinate, microcrystalline cellulose, carbomer, hydroxy propyl methyl cellulose were mixed geometrically after sifting through mesh 40. This blend was granulated with mixture of polyvinylpyrrolidone and isopropyl alcohol using nonaqueous wet granulation. Granules were milled through mesh 8. Granules are dried at 40-50°C Dried granules were sifted through mesh 20. It was then lubricated with magnesium stearate.
Metoprolol succinate granules: Contains 25mg Metoprolol succinate equivalent to Metoprolol tartrate along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Metoprolol succinate 12.9%
2 Microcrystalline cellulose 24.89%
3 Carbomer 21.6%
4 Hydroxy propyl methyl cellulose (K15M) 32.40%
5 Polyvinylpyrrolidone (K30) 6.80%
6 Isopropyl alcohol Qs
7 Magnesium stearate 1.62%
Granules containing 25mg Metoprolol succinate equivalent of Metoprolol tartrate are similarly prepared
B) Chlorthalidone granules: Contains 12.5mg of Chlorthalidone base along with the following excipients

Sr. No. Ingredient Qty % w/w of total weight
1 Chlorthalidone 11.47%
2 Lactose monohydrate 75.84%
3 Colloidal silicon dioxide 1.82%
4 Sodium starch glycolate 5.92%
5 Sodium lauryl sulphate 0.91%
6 Indigo blue (lake) 0.18%
7 Quinoline yellow (soluble) 0.18%
8 Maize starch 1.67%
9 Purified water Qs
10 Purified talc 0.76%
11 Magnesium stearate 1.37%
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Preparation of Chlorthalidone granules:
Chlorthalidone, lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, sodium lauryl sulphate were mixed geometrically after sifting through mesh 40 and indigo blue through 100 mesh and mix. Binding is carried out by starch paste wherein quinoline yellow was dissolved. The final blend is prepared by mixing the lubricants and glidants with above dried granules.
Chlorthalidone granules: Contains 6.25mg of Chlorthalidone base along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Chlorthalidone 6.3%
2 Lactose monohydrate 80.14%
3 Colloidal silicon dioxide 2%
4 Sodium starch glycolate 6%
5 Sodium lauryl sulphate 1%
6 Indigo blue (lake) 0.2%
7 Quinoline yellow (soluble) 0.2%
8 Maize starch 1.83%
9 Purified water Qs
10 Purified talc 0.83%
11 Magnesium stearate 1.5%
Granules containing 6.25mg Chlorthalidone are similarly prepared
For bilayered tablet, weighing 352mg (containing 242mg of extended release layer and 110mg of immediate release layer) 10mm in dimension were produced on tablets pressed by two stage pressing procedure as described. The granules of immediate release layer are press first and the extended release layer is then added and the press is operated again.
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Example - 2
A) Metoprolol succinate granules: Contains 50mg and 25mg of Metoprolol succinate equivalent to Metoprolol tartrate along with the excipients and formulated in the same manner as in Example 1.
B) Chlorthalidone granules: Contains 12.5mg of Chlorthalidone base along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Chlorthalidone 11.47%
2 Lactose monohydrate 75.84%
3 Colloidal silicon dioxide 1.82%
4 Sodium starch glycolate 5.92%
5 Sodium lauryl sulphate 0.91%
6 Indigo blue (lake) 0.18%
7 Quinoline yellow (soluble) 0.18%
8 Maize starch 1.67%
9 Purified water Qs
10 Purified talc 0.76%
11 Magnesium stearate 1.37%
Preparation of Chlorthalidone granules:
Chlorthalidone, lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, sodium lauryl sulphate were mixed geometrically after sifting through mesh 40 and indigo blue through 100 mesh and mix. Binding is carried out by starch paste wherein quinoline yellow was dissolved. The final blend is prepared by mixing the lubricants and glidants with above dried granules.
Chlorthalidone granules: Contains 6.25mg of Chlorthalidone base along with the following excipients.
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Sr.No. Ingredient Qty % w/w of total weight
1 Chlorthalidone 5.4%
2 Lactose monohydrate 84.11%
3 Colloidal silicon dioxide 1.6%
4 Sodium starch glycolate 4.96%
5 Sodium lauryl sulphate 0.8%
6 Indigo blue (lake) 0.16%
7 Quinoline yellow (soluble) 0.16%
8 Maize starch 1.46%
9 Purified water Qs
10 Purified talc 0.66%
11 Magnesium stearate 1.20%
Granules containing 6.25mg Chlorthalidone are similarly prepared.
For bilayered tablet, weighing 367.05mg (containing 242mg of extended release layer and 125.5mg of immediate release layer) 10mm in dimension were produced on tablets pressed by two stage pressing procedure as described. The granules of immediate release layer are compressed first and the extended release layer is then added and the press is operated again.
The pharmaceutical compositions of Chlorthalidone and Metoprolol succinate equivalent to Metoprolol tartrate as per the present invention are physically and chemically stable over its shelf life period. The stability study data is given below in Table 1 to Table 4.
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The sample comprising Metoprolol succinate extended release + Chlorthalidone Tablets (25+6.25) mg, each bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg (as extended release part) and Chlorthalidone 6.25mg is stored at: 25 ± 2°C & 60 ± 5% RH. Table 1 provides the stability study data.
Table 1

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
Appearance Green - white coloured, bilayered, oval shaped, biconvex, plain tablets IN/MCT(25+6. 25)01/05 Complies Complies
IN/MCT(25+6. 25)02/05 Complies Complies
IN/MCT(25+6.25)04C/05 Complies Complies
Dissolution Metoprolol Succinate 1Hr. :NMT25% 4Hrs: 25-40% <-50% 8Hrs: 45-60% <-75% 20Hrs.: NLT 80% IN/MCT(25+«. 25)01/05 12.08%-12..59% 36.91%-39.38% 55.08%-55.64 % 93.51%-96.96% 14.65%~14.89% 37.21%--37.47% 56.76%~58.77 % 89.16%-90.56-%
IN/MCT(25+6.25)02/05 11.62%-12.98% 36.85%-40.86% 61.26%-64.39 % 93.85%-98.10% 13.04%-14.59 % 36.61%~39.07% 58.84%~60.98 % 93.92%-94.63-%
IN/MCT(25+6.25)04C/05 14.19%-15.23% 36.58%-38.41% 58.70%-61.65% 93.76%-95..80% 12.11%--12.55% 33.36%--34.75% 55.36%~56.61 % 90.30%~92.91%
Chlorthalidone NLT 70% in 60 min IN/MCT(25+6. 25)01/05 92.27%-l 04.64% 97.40%-106.37%
IN/MCT(25-H5. 25)02/05 101..74%-108.04 101.57%-103.91%
IN/MCT(25+6. 25)04C/05 95.57%-104.79% 97.49%-103.51
Assay Metoprolol succinate: 90%-105% IN/MCT(25+6. 25)01/05 99.80% 98.41%
IN/MCT(25-^. 25)02/05 100.10% 100.25%
IN/MCT(25+6.25)04C/05 99.80% 97.81%
Chlorthalidone: 90%-105% IN/MCT(25+6.25)01/05 100.13% 100.13%
IN/MCT(25+6. 25)02/05 101..70% 99.46%
IN/MCT(25+6.25J04C/05 99.10% 100.28%
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The sample comprising Metoprolol succinate extended release + Chlorthalidone Tablets (25+6.25) mg, each bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg (as extended release part) and Chlorthalidone 6.25mg is stored at: 40 ± 2°C & 75 ± 5% RH. Table 2 provides the stability study data.
Table 2

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
Appearan ce Green - white coloured, bilayered, oval shaped, biconvex, plain tablets IN/MCT(25+6.25)01/05 Complies Complies
IN/MCT(25+6.25)02/05 Complies Complies
IN/MCT(25+6. 25)04C/05 Complies Complies
Dissoluti on Metoprolol Succinate 1Hr. :NMT25% 4Hrs:25^0%<-50% 8Hrs.: 45-60%<-75% 20Hrs.: NLT 80% IN/MCT(25+6.25)01/05 12.08%-12..59% 36.91%-39.38% 55.08%-55.64% 93.51%-96.96% 14.75%~15.21 % 37.18%«39.26% 59.61%-59.94 % 94.60%-94.62-%
IN/MCT(25+6.25)02/05 H.62%-12.98% 36.85°/ir40.86% 61.26%-64.39% 93.85%-98.10% 13.40%~16.26 % 37.46%~41.11% 60.95%-62.55 % 93.21%-95.58%
IN/MCT(25+6. 25J04C/05 I4.19%-15.23% 36.58%-38.14% 58.70%-61.65% 93.76%-95..80% 6.78%--13.35 % 27..20%~36.07% 53.85%~57.81 % 88.42%-91.67%
Chlorthalidone NLT 70% in 60 min IN/MCT(25-K. 25)01/05 92.27%-104.64% 97.35%105.51%
TN/MCT(25+6. 25)02/05 101..74%-108.04% 99.00%-101.51%
MMCT(25+6.25)04C/05 95.57%-104.79% 90.89%-101.I6
Assay Metoprolol succinate: 90%-105% IN/MCT(25+6. 25)01/05 99.80% 99.50%
IN/MCT(25+6. 25)02/05 100.10% 99.72%
IN/MCT(25+6.25)04C/05 99.80% 98.49%
Chlorthalidone: 90%-105% IN/MCT(25+6.25)01/05 100.13% 99.18%
IN/MCT(25+6.25)02/05 101.-70% 99.07%
IN/MCT(25-H>. 25J04C/05 99.10% 104.49%
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The sample comprising Metoprolol succinate extended release + Chlorthalidone Tablets (50+12.5) mg, each bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg (as extended release part) and Chlorthalidone 12.5mg is stored at: 25 ± 2°C & 60 ± 5% RH. Table 3 provides the stability study data.
Table 3

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
Appearan ce Green-white coloured, bilayered, oval shaped, biconvex, plain tablets IN/MCT(50+12.5)01/05 Complies Complies
IN/MCT(50+12.5)02/05 Complies Complies
Green-white coloured, bilayered, circular shaped, biconvex, plain tablets IN/MCT(50+12.5)03C/05 Complies Complies
Dissoluti on Metoprolol Succinate1Hr. :NMT25%4Hrs.: 25-40%<-50%8Hrs.: 40-60% <-70%20Hrs.: NLT 80% IN/MCT(50+12.5)01/05 13.30%-14.52% 38.08%-44.84% 58.97%-44.84% 91.78%-107.49°/« 13.44%-15.04% 38.24%-38.88% 58.34%-59.55% 86.62%-88.12%
IN/MCT(50+12.5)02/05 13.03%---42.21%-44.13% 62.57%-64.17% 92.14%-94.09% 16.19%-16.80% 42.26%43.60% 63.62%-65.47% 94.18%-97.72%
IN/MCT(50+I2.5)03C/05 15.82%-16.48% 40.22%-42.29% 61.64%-65.66% 91.83%-95.45% 16.11%-17.51% 40.83%-42.15% 60.80%-62.63% 93.54%-94.99%
Chlorthalidone NLT 70%in60min IN/MCT(50+12.5)01/05 102.19%-109.59% 96.83%102.62%
IN/MCT(50+12.5)02/05 105.98%-1I1.66% 103.38%-105.68%
IN/MCT (50+12.5)03C/05 95.89%-107.94% 79.29%-91.08%
Assay Metoprolol Succinate: 95 % -105 % IN/MCT(50+12.5)01/05 100.07% 99.89%
IN/MCT(50+12.5)02/05 101.20% 99.94%
IN/MCT (50+12.5)03C/05 100.70% 99.31%
Chlorthalidone: 95%-105% IN/MCT(50+12.5)01/05 101.20% 100.51%
IN/MCT(50+12.5)02/05 100.70% 98.33%
IN/MCT (50+12.5)03C/05 101.10% 99.37%
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The sample comprising Metoprolol succinate extended release + Chlorthalidone Tablets (50+12.5) mg, each bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg (as extended release part) and Chlorthalidone 12.5mg is stored at: 40 ± 2°C & 75 ± 5% RH. Table 4 provides the stability study data.
Table 4

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
Appearan ce Green-white coloured, bilayered, oval shaped, biconvex, plain tablets IN/(50+12.5)01/05 Complies Complies
IN/(50+12.5)02/05 Complies Complies
Green-white coloured, bilayered, circular shaped, biconvex, plain tablets IN/(5(H-12.5)03C/05 Complies Complies
Dissoluti on Metoprolol Succinate 1Hr.: NMT 25% 4Hrs.:20-40% <-50% 8Hrs.:40-60% <-70% 20Hrs.: NLT 80% IN/(5(H-12.5)01/05 13.30%-14.52% 38.08%-44.84% 58.97%-44.84% 91.78%-107.49% 11.68%-12.49% 34.58%-36.39% 54.51%-57.72% 82.30%-86.23%
IN/(50+12.5)02/05 13.03%-— 42.21%-44.13% 62.57%-64.17% 92.14%-94.09% 14.62%-17.11% 40.36%-41.65% 59.99%-62.46% 91.09%-93.53%
IN/(50+I2.5)03C/05 15.82%-16.48% 40.22%-42.29% 61.64%-65.66% 91.83%-95.45% 14.94%42.04% 42.04%-43.69% 62.49%-66.23% 93.54%-96.88%
Chlorthalidone NLT 70% in 60 min M(50+12.5)01/05 102.19%-109.59% 102.90%-111.29%
IN/(50+12.5)02/05 105.98%-111.66% 99.77%-106.26%
IN/(50+l 2.5)03(705 95. 89%-107.94% 90.38%-97.00%
Assay Metoprolol Succinate : 95 % - 105 % IN/50+12.5)01/05 100.07% 100.54%
IN/(50+12.5)02/05 101.20% 101.58%
IN/(50+12.5)03C/05 100.70% 100..62%
Chlorthalidone :95%-105% IN/(50+12.5)01/05 101.20% 101.89%
IN/(50+12.5)02/05 100.70% 100.48%
IN/(50+12.5)03C/05 101.10% 101.13%
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It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. Stable bilayered oral pharmaceutical tablet compositions prepared with duredas
technology comprising a diuretic such as Chlorthalidone and a beta-selective
adrenoreceptor blocking agent, such as Metoprolol, wherein Chlorthalidone is
incorporated as an immediate release component and Metoprolol incorporated as an
extended release component comprising monolithic matrix technology along with
pharmaceutically acceptable excipients; the said composition prepared by a process
comprising;
a. 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 are used both in granulation and
blending stage;
b. granulating Chlorthalidone together with selected excipients by moist
granulation process and blending the said granules of Chlorthalidone with
disintegrants, lubricants and glidants or blending the Chlorthalidone with
disintegrants, lubricants and glidants;
c. compressing the said two blends of step (a) and step (b) into a bilayered tablet
where each layer represents blend comprising a single active ingredient with
excipients.
2. The stable pharmaceutical compositions as claimed in claim 1, wherein the amount of said Chlorthalidone is in the range of 6.25 tol00mg equivalent to Chlorthalidone free base, preferably 12.5mg and 6.25mg
3. The stable pharmaceutical compositions as claimed in claim 1, wherein the amount of said Metoprolol succinate is in the range of 12.5 to 200mg equivalent to Metoprolol tartrate, preferably 50mg and 25mg.
4. The stable pharmaceutical compositions as claimed in claim 1, wherein the said pharmaceutically acceptable excipients are selected from diluents, binders,
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disintegrants, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof.
5. The stable pharmaceutical composition as claimed in claim 1 and claim 4, wherein the said diluents are selected from the group consisting microcrystalline cellulose, lactose monohydrate, maize starch or their modified forms and are used in the range of 5% to 95% of tablet weight.
6. The stable pharmaceutical compositions as claimed in claim 1 and claim 4, wherein the said binders are selected from the group consisting maize starch, polyvinylpyrrolidone; wherein the preferred binder is polyvinylpyrrolidone in the range of 3 to 15% for extended release layer and maize starch in the range of 2 to 10% for immediate layer.
7. The stable pharmaceutical compositions as claimed in claim 1 and claim 4, wherein the said disintegrants are selected from the group consisting starch, derivatives of starch, wherein the preferred disintegrant is sodium starch glycolate and is in the range of 1% to 6%.
8. The stable pharmaceutical compositions as claimed in claim 1 and claim 4, wherein the said lubricants and glidants are selected from the group consisting magnesium stearate in the range of 0.25% to 5% and colloidal silicon dioxide in the range of 0.1% to 0.5%.
9. The stable pharmaceutical compositions as claimed in claim 1 and claim 4, wherein the said film formers are selected from group consisting polymers such as carbomer in the range of 5% to 10% and hydroxy propyl methyl cellulose of different viscosity in the range of 0.45% to 1.0%.
10. The stable pharmaceutical compositions as claimed in claim 1, wherein the two active ingredients are provided in two strengths of (50+12.5mg) and (25+6.25mg) respectively for the first and second active ingredients.
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11. The stable pharmaceutical compositions as claimed in claim 1, wherein the release of the active ingredient from the extended release layer is extended about 6 to 24 hours after predetermined time delay and the release of the active ingredient from the immediate release layer is between 30 to 60min after ingestion.
12. The stable pharmaceutical compositions as claimed in any of the preceding claims 1 to 11, their process of preparation as substantially described herein with reference to the foregoing examples.

Dr. Gopakumar G. Nair Agent for the Applicant
Dated this 14th day of December 2006
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Abstract:
Disclosed herein are 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) adrenoreceptor blocking agent Metoprolol succinate in the form of an extended release formulation and a diuretic Chlorthalidone in the form of an immediate release formulation and process of preparation thereof.