DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title: AZELNIDIPINE COMPOSITIONS

Applicant:
GLENMARK PHARMACEUTICALS LIMITED,
An Indian Company registered under
The Companies Act, 1956, India
and having its office at

Glenmark Pharmaceuticals Limited
B/2, Mahalaxmi Chambers,
22, Bhulabhai Desai Road,
Mumbai, 400026

The following specification describes the invention.

AZELNIDIPINE COMPOSITIONS

TECHNICAL FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising Azelnidipine. Further the present invention also relates to a fixed dose pharmaceutical combination of Azelnidipine with a beta-blocker such as Metoprolol.

BACKGROUND OF THE INVENTION
Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension. Azelnidipine is represented by a structural formula (I)

Formula (I)
Azelnidipine is available commercially in the form of Calblock® tablets having strengths of 8 mg and 16 mg. The tablets also include- D- mannitol, carmellose calcium, low substituted hydroxypropylcellulose, sodium bicarbonate, polysorbate 80, magnesium metasilicate aluminate, light anhydrous silicic acid, hydroxypropyl cellulose, talc and magnesium stearate as inactive ingredients.
United States patent application publication no. 2003/0073670 discloses pharmaceutical compositions of azelnidipine with alkaline material such as sodium bicarbonate and calcium silicate. The compositions disclosed in this application contain alkaline material in an amount of at least 20% by weight of the composition.
The present invention discloses an alternative method for preparing stable pharmaceutical compositions comprising azelnidipine and at least one basic solubilizing agent. Such compositions can be used for the treatment of hypertension.
Secondly, for treatment of hypertension combination therapy is prevalent since it offers the potential to lower blood pressure more quickly, obtain target blood pressure, and decrease adverse effects. Antihypertensive agents from different classes may offset adverse reactions from each other, such as a diuretic decreasing edema occurring secondary to treatment with a calcium channel blocker. Most of the patients with hypertension require more than a single antihypertensive agent, particularly if they have comorbid conditions. Various combinations of azelnidipine with ACE inhibitors, AT1 and AT2 receptor blockers, renin-angiotensin system inhibitors, diuretics, epoxy-steroidal aldosterone receptor antagonists and HMG CoA reductase inhibitors are known. Tablets containing fixed dose combination of azelnidipine with AT1 receptor blocker olmesartan have recently been approved in Japan for the treatment of hypertension.
The present invention discloses an alternative fixed dose combination comprising azelnidipine with a beta-blocker such as metoprolol and at least one basic solubilizing agent.

SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising azelnidipine and one or more pharmaceutically acceptable excipients. Further the present invention also relates to a fixed dose pharmaceutical combination of Azelnidipine with a beta-blocker such as metoprolol.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; wherein the basic solubilizing agent is present in an amount of less than 20% by weight of the composition.
In another embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent ; wherein the basic solubilizing agent is present in an amount of less than 5% by weight of the composition; and wherein the total weight of the composition is greater than 100 mg and less than 600 mg.
In another embodiment, the present invention relates to a pharmaceutical composition according to any of the above embodiments comprising azelnidipine; one or more excipients including at least one basic solubilizing agent selected from meglumine and arginine; one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, hydroxypropylcellulose, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids; one or more disintegrants selected from a group consisting of sodium starch glycolate, sodium croscarmellose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose and optionally one or more surfactants selected from a group consisting of poloxamers, polyethylene glycols, polysorbates, sodium lauryl sulfate, polyethoxylated castor oil and hydroxylated castor oil. In a further embodiment, the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns. In a further embodiment, the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns.
In one embodiment, the pharmaceutical composition of the present invention is further combined with a beta-blocker such as metoprolol to provide a fixed dose pharmaceutical combination. In one aspect, metoprolol is in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In one aspect of the said embodiment, the present invention relates to a fixed dose pharmaceutical combination, wherein metoprolol and azelnidipine are present as separate unit dosage forms enclosed in a capsule, and wherein the basic solubilizing agent is present in an amount of less than about 20% by weight of the pharmaceutical composition comprising azelnidipine. In a further aspect, the basic solubilizing agent is present in an amount of less than about 5% by weight of the pharmaceutical composition comprising azelnidipine.
In one embodiment, the present invention relates to a process for preparation of a pharmaceutical composition of the invention comprising steps of-
a) blending one or more excipients;
b) preparing a dispersion including azelnidipine, a basic solubilizing agent, binder and optionally a surfactant;
c) granulating the blend of step a) with the dispersion of step b) to form granules;
d) lubricating the granules of step c) and compressing them to form tablets or filling them into capsules; and; optionally;
e) filling one or more tablets of step d) with one or more tablets comprising metoprolol and at least one excipient suitable for extended release of the drug; in a capsule.
In an aspect, the above process is carried out in a fluid-bed processor. In another aspect, the above process is carried out in a rapid mixer-granulator.
In one embodiment, the present invention relates to a process for preparation of a pharmaceutical composition of the invention comprising steps of-
a) blending one or more excipients with azelnidipine;
b) preparing a dispersion including a basic solubilizing agent, binder and optionally a surfactant;
c) granulating the blend of step a) with the dispersion of step b) to form granules;
d) lubricating the granules of step c) and compressing them to form tablets or filling them into capsules; and; optionally;
e) filling one or more tablets of step d) with one or more tablets comprising metoprolol and at least one excipient suitable for extended release of the drug; in a capsule.
In an aspect, the above process is carried out in a rapid mixer-granulator.
In a separate embodiment, the present invention relates to use of the pharmaceutical compositions according to any of the above embodiments, for the treatment of a cardiovascular disorder in a subject in need thereof. In a further aspect, the cardiovascular disorder is hypertension.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising azelnidipine and one or more pharmaceutically acceptable excipients. Further the present invention also relates to a fixed dose pharmaceutical combination of Azelnidipine with a beta-blocker such as metoprolol.
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
The term “drug” as used herein, unless mentioned otherwise, means azelnidipine or metoprolol, as defined below.
The term “azelnidipine” as used herein, unless mentioned otherwise mentioned, means 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-[1-(diphenylmethyl)-3-azetidinyl] 5-(1-methylethyl) ester, hydrates, solvates or salts thereof.
The term “metoprolol” as used herein, unless mentioned otherwise, means metoprolol, hydrate or a salt thereof.
The term “salt” or “pharmaceutically acceptable salt” as used herein, means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include hydrochloride, dihydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
The term “basic solubilizing agent” as used herein, means organic bases like meglumine and arginine.
The term “pharmaceutically acceptable excipients” as used herein, means any of the components of the pharmaceutical composition other than azelnidipine and metoprolol and which are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients may include one or more of a diluent, lubricant, binder, fluidizing agent, disintegrating agent, solubilizing agent and the like
The term “% by weight” unless otherwise mentioned, means percentage w/w with respect to finished dosage form or composition.
The term “azelnidipine composition” as used herein, means a composition or a dosage form comprising azelnidipine.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent.
In one embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; wherein the basic solubilizing agent is present in an amount of less than 20% by weight of the composition.
In another embodiment, the present invention relates to a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; wherein the basic solubilizing agent is present in an amount of less than 5% by weight of the composition wherein the total weight of the composition is greater than 100 mg and less than 600 mg.
The pharmaceutical compositions comprising azelnidipine as contemplated by this invention can be made of azelnidipine in association with pharmaceutically acceptable excipients selected from one or more of a diluent, lubricant, binder, fluidizing agent, disintegrating agent, solubilizing agent and the like.
Suitable diluents include but are not limited to, mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium hydrogen phosphate, sodium carboxymethyl cellulose and the like. The diluents can be quantitatively adjusted to manipulate the percentage content of azelnidipine in granules as well as the finished dosage form. Preferably, the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns.
Suitable lubricants include but are not limited to, magnesium stearate, colloidal silicon dioxide, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, starch, calcium stearate, talc, stearic acid, sucrose, ester of fatty acid and the like. Preferably, the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns.
Suitable binders include but are not limited to, hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose and the like.
In another embodiment, the present invention relates to a pharmaceutical composition according to any of the above embodiments comprising azelnidipine; one or more excipients including at least one basic solubilizing agent selected from meglumine and arginine; one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, hydroxypropylcellulose, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids; one or more disintegrants selected from a group consisting of sodium starch glycolate, sodium croscarmellose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose and optionally one or more surfactants selected from a group consisting of poloxamers, polyethylene glycols, polysorbates, sodium lauryl sulfate, polyethoxylated castor oil and hydroxylated castor oil. In a further embodiment, the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns. In a further embodiment, the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns.
In one embodiment, the pharmaceutical composition of the present invention is further combined with a beta-blocker such as metoprolol to provide a fixed dose pharmaceutical combination. In one aspect, metoprolol is in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In one aspect of the said embodiment, the present invention relates to a fixed dose pharmaceutical combination, wherein metoprolol and azelnidipine are present as separate unit dosage forms enclosed in a capsule; and; wherein the basic solubilizing agent is present in an amount of less than about 20% by weight of the pharmaceutical composition comprising azelnidipine. In a further aspect, the basic solubilizing agent is present in an amount of less than about 5% by weight of the pharmaceutical composition comprising azelnidipine.
In one embodiment, the present invention relates to a process for preparation of a pharmaceutical composition of azelnidipine comprising steps of-
a) blending one or more excipients;
b) preparing a dispersion including azelnidipine, a basic solubilizing agent, binder and optionally a surfactant;
c) granulating the blend of step a) with the dispersion of step b) to form granules;
d) lubricating the granules of step c) and compressing them to form tablets or filling them into capsules; and; optionally;
e) filling one or more tablets of step d) with one or more tablets comprising metoprolol and at least one excipient suitable for extended release of the drug; in a capsule.
In an aspect, the above process is carried out in a fluid-bed processor. In another aspect, the above process is carried out in a rapid mixer-granulator.
In one embodiment, the present invention relates to a process for preparation of a pharmaceutical composition of azelnidipine comprising steps of-
a) blending one or more excipients with azelnidipine;
b) preparing a dispersion including a basic solubilizing agent, binder and optionally a surfactant;
c) granulating the blend of step a) with the dispersion of step b) to form granules;
d) lubricating the granules of step c) and compressing them to form tablets or filling them into capsules; and; optionally;
e) filling one or more tablets of step d) with one or more tablets comprising metoprolol and at least one excipient suitable for extended release of the drug; in a capsule.
In an aspect, the above process is carried out in a rapid mixer-granulator.
In a separate embodiment, the present invention relates to use of the pharmaceutical compositions according to any of the above embodiments, for the treatment of a cardiovascular disorder in a subject in need thereof. In a further aspect, the cardiovascular disorder is hypertension.
In an embodiment, the pharmaceutical composition comprising azelnidipine comprises 1.5%-15% by weight of azelnidipine, 1%-5% by weight of basic solubilizing agent, 1%-80% by weight of diluent, 0.1%-10% by weight of binder; and; 0.5%-30% by weight of lubricant. In one aspect of this embodiment, the basic solubilizing agent is meglumine or arginine. In another aspect, the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns. In yet another aspect, the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns. In a still further aspect the pharmaceutical composition of the said embodiment is further combined with metoprolol to get a fixed dose combination, wherein metoprolol is in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In a preferred embodiment, the pharmaceutical composition comprising azelnidipine comprises 7%-10% by weight of azelnidipine, 1%-5% by weight of basic solubilizing agent, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%-10% by weight of lubricant. In one aspect of this embodiment, the basic solubilizing agent is meglumine or arginine. In another aspect, the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns. In yet another aspect, the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns. In a still further aspect the pharmaceutical composition of the said embodiment is further combined with metoprolol to get a fixed dose combination, wherein metoprolol is in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
The pharmaceutical composition comprising azelnidipine of the present invention can be supplied with compositions of other actives selected from the group comprising ACE inhibitors, AT1 and AT2 receptor blockers, ß- blockers, renin-angiotensin system inhibitors, diuretics, epoxy-steroidal aldosterone receptor antagonists and HMG CoA reductase inhibitors in combination as a kit containing two compositions of different actives to be administered to the subject in need thereof simultaneously or sequentially. Alternatively the combination can be present in a unit dosage form such as tablets, capsules, granules etc.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient.
In another embodiment, the present invention relates to a fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
In one aspect of the said embodiment, the present invention relates to a fixed dose pharmaceutical combination, wherein metoprolol and azelnidipine are present as separate unit dosage forms enclosed in a capsule; and; wherein the basic solubilizing agent is present in an amount of less than about 20% by weight of the pharmaceutical composition comprising azelnidipine. In a further aspect, the basic solubilizing agent is present in an amount of less than about 5% by weight of the pharmaceutical composition comprising azelnidipine.
The metoprolol compositions as contemplated by this invention can be made of metoprolol in association with one or more excipients suitable for extended release of the drug; wherein the excipients may further include diluents, lubricants, binders, fluidizing agents, disintegrating agents, solubilizing agents and the like.
The excipient suitable for extended release of the drug can be selected from, but not limited to, excipients such as spermaceti wax, carnauba wax, beeswax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, glyceryl monostearate, glyceryl behenoate, lauroyl polyoxylglycerides, oleoyl macrogolglycerides, hydrogenated oil, stearic acid, palmitic acid, lauric acid, myristic acid, cetyl alcohol, stearyl alcohol or mixtures thereof.
In a separate embodiment, the present invention relates to use of the pharmaceutical compositions according to any of the above embodiments, for the treatment of a cardiovascular disorder in a subject in need thereof. In a further aspect, the cardiovascular disorder is hypertension.
The pharmaceutical compositions of the present invention mat ne administered once daily or twice daily. Preferably the administration is once daily.
Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention. Analytical data such as dissolution studies, related substances and assay was generated for example 3 and comparative examples 1-3.
Dissolution studies were performed on azelnidipine tablets prepared according to example 3 and comparative examples 1-3 using IP Apparatus -I (Paddle) at the speed of 75 Revolutions per minute (RPM) for a period of 45 minutes using 900 ml Phosphate buffer pH 7.5+2.0% sodium lauryl sulphate at a temperature of 37°C ± 0.5°C. The samples were analysed by HPLC.
Also related substances and assay of Azelnidipine content were performed by methods known to a person skilled in the art. The chromatographic conditions included-
Column : Inertsil ODS-3V, 150 X 4.6 mm, 5 micron or equivalent.
Wavelength : 258 nm
Flow Rate : 1.7 ml / min.
Injection Volume : 50 µl
Column Oven : 30°C
Run Time : 12 minutes

Preparation of buffer: 1.54 gm of Ammonium acetate was dissolved in 1000ml of water. 5.0ml of Acetic acid was added and mixed. The buffer was filtered through 0.45 µm membrane filter paper.
Preparation of Mobile Phase: Buffer and Methanol were mixed in the ratio (200: 800) v/v and degassed with ultrasonic bath.

EXAMPLES
EXAMPLE 1: Azelnidipine tablets
S. No. Ingredient mg/tablet
1. Azelnidipine 8
2. Meglumine 5
3. Mannitol 122.6
4. Carboxymethyl cellulose calcium 8
5. Polysorbate 80 1.6
6. Hydroxypropyl cellulose 2
7. Colloidal silicon dioxide 0.8
8. Hydroxypropyl cellulose 8
9. Talc 1.6
10. Magnesium stearate 2.4
Total weight 160

Manufacturing Process
Azelnidipine, meglumine, mannitol, carboxy methylcellulose calcium were sifted twice through sieve #40 followed by loading and blending in a rapid mixer granulator. Polysorbate 80 and hydroxypropyl cellulose were dissolved in purified water to form a binder solution. The active blend was granulated with binder solution to get desired granules. The granules were dried and sifted through sieve# 20. The granules were lubricated with colloidal silicon dioxide, hydroxypropyl cellulose, talc and magnesium stearate. The lubricated granules were compressed into tablets.

EXAMPLE 2: Azelnidipine tablets
S. No. Ingredient mg/tablet
1. Azelnidipine 16
2. Meglumine 5
3. Mannitol 201.2
4. Carboxy methyl cellulose Calcium 13
5. Polysorbate 80 2.6
6. Hydroxypropyl cellulose 2.6
7. Colloidal silicon dioxide 1.3
8. Hydroxypropyl cellulose 13
9. Talc 1.3
10. Magnesium stearate 4.0
Total weight 260

Manufacturing Process
Azelnidipine, meglumine, mannitol, carboxymethylcellulose calcium through were sifted twice through sieve #40 and blended. The blend was loaded in rapid mixer granulator and mixed for 10 minutes. Polysorbate 80 and hydroxypropyl cellulose were dissolved in purified water to form a binder solution. The active blend was granulated with binder solution to form granules. The granules were dried and sifted through sieve #20. The granules were lubricated with colloidal silicon dioxide, hydroxypropyl cellulose, talc and magnesium stearate. The lubricated granules were compressed into tablets.

EXAMPLE 3: Azelnidipine tablets
S. No. Ingredient % w/w mg/tab % w/w mg/tab
1. Mannitol 30.8 80 30.8 40
2. Microcrystalline cellulose 27.7 72 27.7 36
3. Meglumine 4.6 12 4.6 6
4. Polyvinylpyrrolidone 5 13 5 6.5
5. Polysorbate 80 2.3 6 2.3 3
6. Azelnidipine 6.2 16 6.2 8
7. Mannitol 10 26 10 13
8. Colloidal silicon dioxide 1.5 4 1.5 2
9. Croscarmellose Sodium 8.1 21 8.1 10.5
10. Talc 1.2 3 1.2 1.5
11. Magnesium Stearate 2.7 7 2.7 3.5
Total 100 260 100 130

Manufacturing Process
Mannitol and microcrystalline cellulose were sifted through sieve # 40 & loaded in top spray bowl of fluid-bed processor. Meglumine was dissolved in purified water under stirring. Polyvinylpyrrolidone was added to the meglumine solution and stirred till clear solution was obtained. Under slow stirring, polysorbate 80 was added to the meglumine and polyvinylpyrrolidone solution. To this solution azelnidipine was added under stirring to form dispersion and homogenized. In the processor, mixture of mannitol and microcrystalline cellulose were sprayed with the dispersion to form wet granules. The granules were dried at 70°C to 80°C and passed through sieve # 20. Mannitol, colloidal silicone dioxide, croscarmellose sodium and talc were sifted through sieve #40 and mixed with granules for 12 minutes in blender. To the blend, magnesium stearate was added and mixed to form a lubricated blend. The lubricated blend was compressed in a tabletting machine to form azelnidipine tablets.
In-vitro Dissolution data for Example 3 composition
Time points (Minutes) In-vitro Drug release (% w/v)
0 0
5 47
10 86
15 97.3
30 100.2
45 100.4
Related substances (% w/w)
Single maximum impurity 0.11
Total impurities 0.51
Assay % w/w 105.1

COMPARATIVE EXAMPLE 1: Azelnidipine tablets prepared as per US20030073670 A1
S. No. Ingredients % w/w mg/ tablet
1. Colloidal silicon dioxide 7.4 19.2
2. Magnesium Aluminometasilicate 30.8 80
3. Polysorbate 80 14.8 38.4
4. Azelnidipine 6.2 16
5. Mannitol 18.2 47.2
6. Hydroxy propyl cellulose 9.2 24
7. Calcium Carboxy Methyl Cellulose 3.1 8
8. Sodium bicarbonate 6.2 16
9. Hydroxy propyl cellulose 3.1 8
10. Talc 0.6 1.6
11. Magnesium Stearate 0.6 1.6
Total 100 260

Manufacturing Process:
Hydroxy propyl cellulose was dissolved under stirring in purified water. In a rapid mixer granulator, polysorbate 80 was adsorbed on magnesium aluminometasilicate and colloidal silicon dioxide. To this, azelnidipine, mannitol, hydroxypropyl cellulose, calcium carboxymethyl cellulose and sodium bicarbonate were added & mixed for 10 minutes. The mass was granulated by adding the aqueous hydroxypropyl cellulose solution. The granules were dried in a fluid-bed drier at 60º - 70°C and passed through sieve# 20. Talc was sifted through sieve# 40 & mixed with above granules for 12 minutes in suitable blender. Magnesium stearate was sifted through sieve # 60 and mixed with the blend for 3 minutes. The blend was then compressed into tablets in a tabletting machine.
In-vitro Dissolution data for Comparative Example 1
Time points (Minutes) In-vitro Drug release (% w/v)
45 96.0
Related substances (% w/w)
Single maximum impurity 0.11
Total impurities 0.43
Assay % w/w 102.5

COMPARATIVE EXAMPLE 2: Azelnidipine tablets prepared as per US20030073670 A1
S. No. Ingredient % w/w mg/tab
1. Colloidal silicone dioxide 7.4 19.2
2. Magnesium aluminometasilicate 30.8 80
3. Polysorbate 80 11.9 31
4. Azelnidipine 6.2 16
5. Mannitol 20.8 54
6. Sodium bicarbonate 6.2 16
7. Purified water q.s.
8. Hydroxy propyl cellulose 3.1 8
9. Purified water q.s.
10. Hydroxy propyl cellulose 9.2 24
11. Calcium carboxy methyl cellulose 3.1 8
12. Talc 0.6 1
13. Magnesium Stearate 0.8 2
Total 100 260

Manufacturing Process
Magnesium aluminometasilicate and colloidal silicone dioxide were sifted through sieve #40 and transferred to a rapid mixer granulator. Polysorbate 80 was adsorbed on magnesium aluminometasilicate and colloidal silicon dioxide. Azelnidipine and mannitol were added and the blend was mixed for 10 minutes. Sodium bicarbonate solution was added to the blend. The mass was granulated by adding hydroxy propyl cellulose solution. The granules were dried in fluid-bed drier at 60º – 70°C and passed through sieve# 20. The granules were mixed with hydroxypropyl cellulose, calcium carboxy methyl cellulose and talc for 12 minutes in suitable blender. Magnesium stearate was mixed with the blend for 3 minutes. The blend was then compressed in a tabletting machine.
In-vitro Dissolution data for Comparative Example 2
Time points (Minutes) In-vitro Drug release (% w/v)
0 0
5 25.4
10 51.2
15 67.6
30 85.2
45 89.7
Related substances (% w/w)
Single maximum impurity 0.21
Total impurities 0.46
Assay % w/w 101.4

COMPARATIVE EXAMPLE 3: Azelnidipine tablets prepared by granulation in rapid mixer granulator with azelnidipine not in meglumine solution
S. No. Ingredient % w/w mg/tab
1. Colloidal silicon dioxide 15.4 40
2. Polysorbate 80 6.2 16
3. Azelnidipine 6.2 16
4. Mannitol 29.2 76
5. Microcrystalline cellulose 23.8 62
6. Meglumine 2.9 7.5
7. Hydroxy propyl cellulose 3.1 8
8. Purified water q.s.
9. Colloidal Silicon Dioxide 1.5 4
10. Croscarmellose Sodium 8.1 21
11. Talc 1.2 3
12. Magnesium Stearate 2.5 6.500
Total 100 260

Manufacturing Process
Colloidal silicone dioxide was sifted through sieve#40 and transferred to the rapid mixer granulator. Polysorbate 80 was dissolved in isopropyl alcohol and was adsorbed on colloidal silicon dioxide. To this, azelnidipine, mannitol and microcrystalline cellulose were added and mixed for 10 minutes. Then meglumine aqueous solution was added to it. The mass was granulated by adding hydroxy propyl cellulose aqueous solution. The granules were dried in fluid-bed drier at 60° – 70°C and passed through sieve# 20. Colloidal silicon dioxide, croscarmellose sodium, talc were sifted through sieve # 40 and mixed with above granules for 12 minutes in a blender. Magnesium stearate was sifted through sieve # 60 and mixed with pre-lubricated blend for 3 minutes. The blend was compressed in a tabletting machine.
In-vitro Dissolution data for Comparative Example 3
Time points (Minutes) In-vitro Drug release (% w/v)
45 67.0
Related substances (% w/w)
Single maximum impurity 0.06
Total impurities 0.35
Assay % w/w 103

EXAMPLES 4-7: Combination product of Azelnidipine immediate release and Metoprolol extended release tablets
S.No. Ingredients Quantity (% w/w) Quantity (mg)
EX. 4
(8+25) mg EX 5
(8+50) mg EX 6 (16+25) mg EX 7 (16+50) mg
Azelnidipine tablets
1. Azelnidipine 6.2 8 8 16 16
2. Colloidal silicon dioxide 15.4 20 20 40 40
3. Polysorbate 80 6.2 8 8 16 16
4. Isopropyl alcohol -- q.s. q.s. q.s. q.s.
5. Mannitol 29.2 38 38 76 76
6. Microcrystalline cellulose 23.8 31 31 62 62
7. Meglumine 2.9 3.8 3.8 7.5 7.5
8. Hydroxy propyl cellulose 3.1 4 4 8 8
9. Colloidal silicon dioxide 1.5 2 2 4 4
10. Croscarmellose sodium 8.1 10.5 10.5 21 21
11. Talc 1.2 1.5 1.5 3 3
12. Magnesium stearate 2.5 3.3 3.3 6.5 6.5
Total 100 130 130 260 260
Metoprolol extended release tablets
13. Metoprolol succinate 30.6 23.8 47.5 23.8 47.5
14. Carnauba wax 48.3 37.5 75 37.5 75
15. Cetostearyl alcohol 7.9 6.1 12.2 6.1 12.2
16. Hydroxy propyl methyl cellulose 4.3 3.4 6.7 3.4 6.7
17. Polyethylene glycol 8000 7.6 5.9 11.8 5.9 11.8
18. Magnesium stearate 1.3 1 2 1 2
Total 100 77.6 155.2 77.6 155.2
Capsule filling
Capsule size ‘1’ ‘1’ ‘1’ ‘0’
Empty capsule weight 75 75 75 95
Filled capsule weight 282.6 360.2 412.6 510.2

Manufacturing Process
Azelnidipine Tablets: Colloidal silicon dioxide was sifted through sieve #40 and loaded in a rapid mixer granulator. Polysorbate 80 was dissolved in isopropyl alcohol and adsorbed on colloidal silicon dioxide. Azelnidipine, mannitol and microcrystalline cellulose were added and mixed for 10 minutes. Meglumine was dissolved in purified water and added to the mixture. The mixture was then granulated with aqueous hydroxypropyl cellulose solution. The granules were dried at 60ºC- 70ºC and sifted through sieve #20. Colloidal silicon dioxide, croscarmellose sodium, talc and magnesium stearate were sifted through sieve #40 and mixed with the granules in a blender. This blend was compressed in a tabletting machine.

Metoprolol Extended Tablets: Metoprolol succinate, Carnauba wax, Cetostearyl alcohol, hydroxypropyl methyl cellulose & polyethylene glycol 8000 were sifted through sieve # 40 and blended together. The blend was transferred to a hot melt extruder, to prepare granules. The granules were passed through sieve # 16. Magnesium stearate was added to the granules and blended. This blend was compressed in a tabletting machine.

Capsule filling: Tablets of each strength are filled in respective capsules.

EXAMPLES 8-9: Azelnidipine tablets
S. No. Strengths Quantity
Ingredients % w/w EX. 8 EX. 9
mg/tab mg/tab
1. Meglumine 4.6 6 12
2. Povidone 5 6.5 13
3. Polysorbate 80 2.3 3 6
4. Azelnidipine 6.2 8 16
5. Mannitol 30.8 40 80
6. Microcrystalline cellulose 27.7 36 72
7. Colloidal silicon dioxide 1.5 2 4
8. Croscarmellose sodium 8.1 10.5 21
9. Mannitol 11.2 14.5 29
10. Magnesium stearate 2.7 3.5 7
Core Tablet weight 100 130 260

Manufacturing Process
Meglumine, povidone, polysorbate 80 were added and dissolved one by one in purified water under stirring. This was followed by addition of Azelnidipine to form dispersion. This dispersion was homogenized. Mannitol and microcrystalline cellulose were sifted through sieve # 20. This blend was mixed for 5 minutes in a blender and transferred to top spray assembly of fluid bed processor. This blend was granulated by spraying the dispersion and the granules were dried and subsequently passed through sieve # 20. Colloidal silicon dioxide, croscarmellose sodium and mannitol were sifted through sieve # 40 and mixed for 12 minutes in a blender. Sifted magnesium stearate (through sieve # 60) was added and mixed with this blend for 3 minutes. The blend thus formed, was compressed in a tabletting machine to form azelnidipine tablets.

EXAMPLES 10-11: Azelnidipine tablets
S. No. Strengths EX. 10- (8 mg) EX. 11 -(16 mg)
Ingredients % w/w mg/tab % w/w mg/tab
1. Meglumine 4.6 6.0 4.6 12.0
2. Povidone 5.0 6.5 5.0 13.0
3. Polysorbate 80 2.3 3.0 2.3 6.0
4. Sodium Lauryl sulphate (SLS) 9.6 12.5 9.6 25.0
5. Azelnidipine 6.2 8.0 6.2 16.0
6. Mannitol 30.8 40.0 30.8 80.0
7. Microcrystalline cellulose 18.1 23.5 18.1 47.0
8. Colloidal silicone dioxide 1.5 2.0 1.5 4.0
9. Croscarmellose sodium 8.1 10.5 8.1 21.0
10. Mannitol 11.2 14.5 11.2 29.0
11. Magnesium stearate 2.7 3.5 2.7 7.0
Core Tablet weight 100.0 130.0 100.0 260.0

Manufacturing Process
Meglumine, povidone, polysorbate 80 and sodium lauryl sulphate were added and dissolved one by one in purified water under stirring. This was followed by addition of Azelnidipine to form dispersion. This dispersion was homogenized for 2 hours. Mannitol and microcrystalline cellulose were sifted through sieve # 20. This blend was mixed for 5 minutes in a blender and transferred to top spray assembly of fluid bed processor. This blend was granulated by spraying the dispersion and the granules were dried and subsequently passed through sieve # 20. Colloidal silicon dioxide, croscarmellose sodium and mannitol were sifted through sieve # 40 and mixed for 12 minutes in a blender. Sifted magnesium stearate (through sieve # 60) was added and mixed with this blend for 3 minutes. The blend thus formed, was compressed in a tabletting machine to form azelnidipine tablets.

EXAMPLES 12-13: Azelnidipine tablets
S. No. Strengths EX. 12 (8 mg) EX. 13 (16 mg)
Ingredients % w/w mg/tab % w/w mg/tab
1. Microcrystalline cellulose 19.2 25.0 19.2 50.0
2. Silicon dioxide 19.2 25.0 19.2 50.0
3. Maize starch 7.7 10.0 7.7 20.0
4. Isopropyl alcohol - q.s. - q.s.
5. Polysorbate 80 11.9 15.5 11.9 31.0
6. Azelnidipine 6.2 8.0 6.2 16.0
7. Mannitol 5.4 7.0 5.4 14.0
8. Meglumine 9.2 12.0 9.2 24.0
9. Povidone 3.1 4.0 3.1 8.0
10. Maize starch 6.2 8.0 6.2 16.0
11. Colloidal silicone dioxide 1.5 2.0 1.5 4.0
12. Croscarmellose sodium 8.1 10.5 8.1 21.0
13. Magnesium stearate 2.3 3.0 2.3 6.0
Tablet weight 100.0 130.0 100.0 260.0

Manufacturing process
Microcrystalline cellulose, silicone dioxide, maize starch, azelnidipine and mannitol were sifted through sieve # 40. Isopropyl alcohol was added in polysorbate 80 and stirred to get clear solution. Meglumine and povidone k 30 were added in purified water under stirring to get clear solution. Polysorbate solution was adsorbed on microcrystalline cellulose, silicone dioxide, and maize starch in a rapid mixer-granulator. Azelnidipine and mannitol were added to the mixture and mixed for 10 minutes to form a blend. This blend was granulated with povidone and meglumine solution. The granules were dried in a fluid-bed drier and passed through sieve# 30. Colloidal silicone dioxide, maize starch, croscarmellose sodium were sifted through sieve # 40 & mixed with the granules for 12 minutes in a blender. Magnesium stearate was passed through sieve # 60 & mixed with above blend for 3 min. The blend thus formed, was compressed in a tabletting machine to form azelnidipine tablets.

EXAMPLES 14-15: Combination of Azelnidipine immediate release and Metoprolol extended release tablets
S. No. Strengths EX. 14
(8+50) mg EX. 15
(16+50) mg
Ingredients % w/w mg/tab % w/w mg/tab
Azelnidipine tablets
1. Microcrystalline cellulose 19.2 25.0 13.5 35.0
2. Silicon dioxide 19.2 25.0 19.2 50.0
3. Maize starch 7.7 10.0 7.7 20.0
4. Isopropyl alcohol - q.s. - q.s.
5. Polysorbate 80 11.9 15.5 11.9 31.0
6. Azelnidipine 6.2 8.0 6.2 16.0
7. Mannitol 5.4 7.0 5.4 14.0
8. Microcrystalline cellulose - - 12.3 32.0
9. Meglumine 9.2 12.0 9.2 24.0
10. Polyvinylpyrrolidone 3.1 4.0 1,5 4.0
11. Maize starch 6.2 8.0 7.7 20.0
12. Colloidal silicon dioxide 1.5 2.0 - -
13. Croscarmellose sodium 8.1 10.5 3.1 8.0
14. Magnesium stearate 2.3 3.0 2.3 6.0
Tablet weight 100.0 130.0 100.0 260.0
Metoprolol tablets
15. Metoprolol Succinate 30.6 47.5 30.6 47.5
16. Carnauba wax 48.3 75.0 48.3 75.0
17. Cetostearyl alcohol 11.3 17.5 11.3 17.5
18. Hydroxy propyl methyl cellulose 4.0 6.2 4.0 6.2
19. Polyethylene glycol 8000 4.5 7.0 4.5 7.0
20. Magnesium stearate 1.3 2.0 1.3 2.0
Core Tablet weight 100.0 155.2 100.0 155.2
Capsule filling
Capsule size ‘0’ ‘0’
Empty capsule weight (mg) 95.0 95.0
Azelnidipine IR Tablet weight (mg) 130.0 260.0
Metoprolol Succinate ER Tablet weight (mg) 155.2 155.2
Filled capsule weight (mg) 380.2 510.2

Manufacturing process
Azelnidipine tablets: Microcrystalline cellulose, silicone dioxide, maize starch were sifted through # 40 sieve. Isopropyl alcohol was added to polysorbate 80 and stirred to get a clear binder solution. The binder solution was adsorbed on microcrystalline cellulose, silicone dioxide and maize starch in a rapid mixer granulator. Azelnidipine and mannitol were added to this mixture and further mixed. Meglumine and polyvinylpyrrolidone were added in purified water under stirring to get a clear solution. This solution was used to granulate the mixture in the rapid mixer granulator. The granules were dried in a fluid bed dryer and passed through sieve # 30. These granules were lubricated with a blend of colloidal silicone dioxide, maize starch, croscarmellose sodium sifted through sieve # 40 to form a lubricated blend. Magnesium stearate sifted through sieve # 60 was mixed with the lubricated blend for 3 minutes. This mixture was compressed in a tabletting machine to form azelnidipine tablets.

Metoprolol Succinate ER tablets: Metoprolol succinate, carnauba wax, cetostearyl alcohol, hydroxypropyl methyl cellulose, polyethylene glycol 8000 were sifted through sieve # 40 and blended together for 10 minutes. This blend was transferred to a hot melt extruder for granulation. After extrusion, diminution of extrudate was done through sieve # 10 followed by sieve # 16. Magnesium stearate sifted through sieve # 60 was mixed with the granules in a blender. These granules were compressed into tablets in a tabletting machine.

Capsule filling: For 8+50 mg strength- 1 tablet (130 mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet was filled in size ‘0’ hard gelatin capsule.
For 16+50 mg strength- 2 tablets (130 mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet were filled in size ‘0’ hard gelatin capsule.

EXAMPLES 16-17: Combination of Azelnidipine immediate release and Metoprolol extended release tablets
S. No. Strengths EX. 16
(8+50) mg EX. 17
(16+50) mg
Ingredients % w/w mg/tab % w/w mg/tab
Azelnidipine tablets
1. Meglumine 4.6 6.0 4.6 12.0
2. Povidone 5.0 6.5 5.0 13.0
3. Polysorbate 80 2.3 3.0 2.3 6.0
4. Azelnidipine 6.2 8.0 6.2 16.0
5. Mannitol 30.8 40.0 30.8 80.0
6. Microcrystalline cellulose 27.7 36.0 27.7 72.0
7. Colloidal silicone dioxide 1.5 2.0 1.5 4.0
8. Croscarmellose sodium 8.1 10.5 8.1 21.0
9. Mannitol 11.2 14.5 11.2 29.0
10. Magnesium stearate 2.7 3.5 2.7 7.0
Core Tablet weight 100.0 130.0 100.0 260.0
Metoprolol tablets
11. Metoprolol Succinate 30.6 47.5 30.6 47.5
12. Carnauba wax 48.3 75.0 48.3 75.0
13. Cetostearyl alcohol 11.3 17.5 11.3 17.5
14. Hydroxy propyl methyl cellulose 4.0 6.2 4.0 6.2
15. Polyethylene glycol 8000 4.5 7.0 4.5 7.0
16. Magnesium stearate 1.3 2.0 1.3 2.0
Core Tablet weight 100.0 155.2 100.0 155.2
Capsule filling
Capsule size ‘0’ ‘0’
Empty capsule weight (mg) 95.0 95.0
Azelnidipine Tablet weight (mg) 130.0 260.0
Metoprolol Succinate ER Tablet weight (mg) 155.2 155.2
Filled capsule weight (mg) 380.2 510.2

Manufacturing process
Azelnidipine tablets: Meglumine, povidone, polysorbate 80 were dissolved one by one in purified water under stirring. Then azelnidipine was added to the solution and homogenized for 2 hours to form drug dispersion. Mannitol and microcrystalline cellulose were passed through sieve # 20 and mixed to form a blend. This blend was transferred to top spray assembly of a fluid bed processor. The drug dispersion was sprayed over the blend to form granules. The granules were dried and passed through sieve # 20. These granules were mixed in a blender for 10 minutes. Colloidal silicone dioxide, croscarmellose sodium, mannitol were passed through sieve # 40 were added to the granules and mixed. Subsequently magnesium stearate sifted through sieve # 60 was added and blended for 3 min to form a lubricated blend. The lubricated blend was compressed in a tabletting machine to form tablets.

Metoprolol Succinate ER tablets: Metoprolol succinate, carnauba wax, cetostearyl alcohol, hydroxypropyl methyl cellulose, polyethylene glycol 8000 were sifted through sieve # 40 and blended together for 10 minutes. This blend was transferred to a hot melt extruder for granulation. After extrusion, diminution of extrudate was done through sieve # 10 followed by sieve # 16. Magnesium stearate sifted through sieve # 60 was mixed with the granules in a blender. These granules were compressed into tablets in a tabletting machine.

Capsule filling: For 8+50 mg strength- 1 tablet (130 mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet were filled in size ‘0’ hard gelatine capsule.
For 16+50 mg strength- 2 tablets (130 mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet were filled in size ‘0’ hard gelatine capsule.

EXAMPLES 18-19: Combination of Azelnidipine immediate release and Metoprolol extended release tablets
S. NO. Strengths EX. 18
(8+50) mg EX. 19
(16+50) mg
Ingredients % w/w mg/tablet % w/w mg/tablet
Azelnidipine tablets
1. Meglumine 4.6 6.0 4.6 12.0
2. Povidone 5.0 6.5 5.0 13.0
3. Polysorbate 80 2.3 3.0 2.3 6.0
4. Sodium Lauryl sulphate (SLS) 9.6 12.5 9.6 25.0
5. Azelnidipine 6.2 8.0 6.2 16.0
6. Mannitol 30.8 40.0 30.8 80.0
7. Microcrystalline cellulose 18.1 23.5 18.1 47.0
8. Colloidal silicone dioxide 1.5 2.0 1.5 4.0
9. Croscarmellose sodium 8.1 10.5 8.1 21.0
10. Mannitol 11.2 14.5 11.2 29.0
11. Magnesium stearate 2.7 3.5 2.7 7.0
12. Core Tablet weight 100.0 130.0 100.0 260.0
Metoprolol tablets
13. Metoprolol Succinate 30.6 47.5 30.6 47.5
14. Carnauba wax 48.3 75.0 48.3 75.0
15. Cetostearyl alcohol 11.3 17.5 11.3 17.5
16. Hydroxy propyl methyl cellulose 4.0 6.2 4.0 6.2
17. Polyethylene glycol 8000 4.5 7.0 4.5 7.0
18. Magnesium stearate 1.3 2.0 1.3 2.0
Core Tablet weight 100.0 155.2 100.0 155.2
Capsule filling
Capsule size ‘0’ ‘0’
Empty capsule weight (mg) 95.0 95.0
Azelnidipine Tablet weight (mg) 130.0 260.0
Metoprolol Succinate ER Tablet weight (mg) 155.2 155.2
Filled capsule weight (mg) 380.2 510.2

Manufacturing process
Azelnidipine tablets: Meglumine, povidone, polysorbate 80, sodium lauryl sulphate were dissolved one by one in purified water under stirring. Then, azelnidipine was added to the solution and homogenized for 2 hours to form drug dispersion. Mannitol and microcrystalline cellulose were passed through sieve # 20 and mixed to form a blend. This blend was transferred to top spray assembly of a fluid bed processor. The drug dispersion was sprayed over the blend to form granules. The granules were dried and passed through sieve # 20. These granules were mixed in a blender for 10 minutes. Colloidal silicone dioxide, croscarmellose sodium, mannitol were passed through sieve # 40 were added to the granules and mixed. Subsequently magnesium stearate sifted through sieve # 60 was added and blended for 3 min to form a lubricated blend. The lubricated blend was compressed in a tabletting machine to form tablets.

Metoprolol Succinate ER tablets: Metoprolol succinate, carnauba wax, cetostearyl alcohol, hydroxypropyl methyl cellulose, polyethylene glycol 8000 were sifted through sieve # 40 and blended together for 10 minutes. This blend was transferred to a hot melt extruder for granulation. After extrusion, diminution of extrudate was done through sieve # 10 followed by sieve # 16. Magnesium stearate sifted through sieve # 60 was mixed with the granules in a blender. These granules were compressed into tablets in a tabletting machine.

Capsule filling: For 8+50 mg strength- 1 tablet (130 mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet were filled in size ‘0’ hard gelatine capsule.
For 16+50 mg strength- 2 tablets (130mg) of Azelnidipine Tablet & 1 tablet (155.2 mg) of Metoprolol Succinate ER tablet were filled in size ‘0’ hard gelatine capsule.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:CLAIMS
1. A pharmaceutical compositions comprising azelnidipine and one or more pharmaceutically acceptable excipients and at least one basic solubilizing agent.
2. A pharmaceutical compositions of claim 1, wherein the basic solubilizing agent is present in an amount of less than 20% by weight of the composition.
3. A pharmaceutical compositions of claim 1, wherein the basic solubilizing agent is present in an amount of less than 5% by weight of the composition; and wherein the total weight of the composition is greater than 100 mg and less than 600 mg.
4. A pharmaceutical compositions of claim 1, wherein the basic solubilizing agent selected from meglumine and arginine, one or more excipients including binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, hydroxypropylcellulose, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids; one or more disintegrants selected from a group consisting of sodium starch glycolate, sodium croscarmellose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose and optionally one or more surfactants selected from a group consisting of poloxamers, polyethylene glycols, polysorbates, sodium lauryl sulfate, polyethoxylated castor oil and hydroxylated castor oil.
5. A pharmaceutical compositions of claim 4, wherein the diluent is microcrystalline cellulose having bulk density between 220-350 g/l and a particle size distribution such that 30 - 60% particles have particle size greater than 150 microns.
6. A pharmaceutical composition of claim 4, wherein the lubricant is silicon dioxide having bulk density between 50-70 g/l and an average particle size of about 2.5 - 3.7 microns.
7. A pharmaceutical composition of any of the claims 1-6, wherein the pharmaceutical compositions is further combined with a beta-blocker such as metoprolol to provide a fixed dose pharmaceutical combination.
8. A fixed dose pharmaceutical combination comprising: a) a pharmaceutical composition comprising azelnidipine and at least one basic solubilizing agent; and; b) metoprolol in association with at least one pharmaceutically acceptable excipient suitable for extended release of the drug.
9. A fixed dose pharmaceutical combination of claim 8, wherein metoprolol and azelnidipine are present as separate unit dosage forms enclosed in a capsule; and; wherein the basic solubilizing agent is present in an amount of less than about 20% by weight of the pharmaceutical composition comprising azelnidipine.
10. A fixed dose pharmaceutical combination of claim 9, the basic solubilizing agent is present in an amount of less than about 5% by weight of the pharmaceutical composition comprising azelnidipine.