Field of the Invention
The present invention relates to a pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate and process for the preparation thereof. The compositions are useful for the treatment of patients with angina.
Background of the Invention
Angina pectoris is typically described as a substernal chest discomfort perceived as tightness, heaviness, or pressure, or a burning sensation. Angina pectoris results when myocardial oxygen demand is increased to levels that cannot be met through increased coronary blood flow, usually due to obstruction or spasm of the coronary arteries (the heart's blood vessels). The aims of treatment of angina are to minimize or abolish symptoms; and to improve prognosis by preventing myocardial infarction and death.
There is international consensus that a beta blocker should be the first line, unless there are contraindications; a selective beta blocker, such as atenolol is preferred; long-acting nitrates or calcium antagonists in combination with beta-blockers are recommended when initial treatment with beta-blockers is not successful; and special efforts should be made to ensure compliance with the prescribed therapy.
Atenolol is chemically described as 4-[2-hydroxy-3- [(1- methylethyl) amino] propoxy] benzeneacetamide). A significant beta-blocking effect of atenolol is apparent within one hour following oral administration of a single dose.
Isosorbide mononitrates (ISMNS) is chemically described as 8-nitrooxy-2, 6-dioxabicyclo [3.3,0] octan-4-ol, and is alone used as vasodilator that is able to reduce myocardial oxygen demands while maintaining or increasing coronary artery flow.
The combination of isosorbide mononitrate with atenolol provides a synergistic effect, as compared to the monotherapy. While atenolol acts by reducing myocardial oxygen demand through reduction of the (heart rate) X (blood pressure) product, isosorbide mononitrate has beneficial effects on both demand (reduction in preload and afterload) and supply (coronary perfusion).
Isosorbide mononitrate protects against spasm in patients with a vasospastic component (mixed angina). In order to prevent the development of nitrate tolerance, ISMN Retard .is designed to act for only about 16 hours so as to provide the 'nitrate free interval' that restores responsiveness to the drug. However, during this period, rebound of symptoms may occur in those on ISMN Retard therapy alone. This can be obviated by the concomitant use of another class of anti-anginal drug. Atenolol, used in combination with ISMN Retard would continue to provide anti-anginal protection during the 'nitrate free interval' (that is deliberately built into the design of ISMN Retard).
The tendency of ISMN to cause reflex tachycardia is countered by the bradycardic action of atenolol. In patients with contraindications to calcium antagonist therapy, double anti-anginal therapy is possible with this combination. Both atenolol and ISMN Retard are suitable for patients with or without concomitant hypertension.
The dosage of atenolol in angina is 50mg once daily, which can be increased to 100mg once daily. Some patients require 200mg once daily for effective control. The dosage of ISMN Retard in angina is 60mg to 240mg once daily.
Atenolol and isosorbide mononitrate are commercially available in the form of tablets of the individual drugs or in combination with other drugs. The tablets may be in the form of either immediate release (IR) formulations or controlled release (CR) formulations.
U.S. Patent Application No. 2003185887 discloses a controlled release formulation of beta blockers, the formulation is in the form of a capsule containing pellets comprising a beta-adrenergic blocking agents.
U.S. Patent No 6,641,839 discloses a controlled release formulation of isosorbide mononitrate in which the sugar spheres are coated with isosorbide mononitrate and a diffusion control membrane surrounds the core.
U.S. Patent No 5,334,393 discloses a sustained-release tablet of isosorbide mononitrate in which isosorbide is dispersed in a hydrophilic matrix.
U.S. Patent No 5,869,094 discloses a solid form of oral administration of isosorbide 5-mononitrate with a controlled, pH-independent release of the active substance in the gastrointestinal tract and is constituted by a pellet coated with a depot layer and a release prolonging lacquer layer. The lacquer layer contains ethyl cellulose and polymethacrylate.
European patent No. 1088554 discloses controlled release formulation of isosorbide in combination with acetylsalicylic acid. US Patent Application No. 2002077348 discloses a single dosage formulation having a beta-adrenergic blocker and a cholesterol lowering agent that is a statin. U.S. Patent No. 5,032,591 discloses a combination of beta blocker with a potassium channel activator antihypertensive agent.
Though atenolol and Isosorbide Mononitrate (ISMN) Retard are widely used individually and in combination. But there is still a need of fixed dose combination of atenolol with isosorbide mononitrate, which will be safer, effective, and economical and will have better patient compliance.
Thus the present invention relates to pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate, in which atenolol is present in the immediate release form and isosorbide mononitrate is present in the extended release form. The composition has additive antianginal effect, has increased efficacy and improved patience compliance.
Summary Of The Invention
According to one embodiment there is provided a pharmaceutical composition containing^fixed dose combination of atenolol with isosorbide mononitrate, the composition providing extended release of isosorbide mononitrate and immediate release of atenolol.
According to another embodiment there is provided a pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate, wherein the composition comprises: a) an extended release component comprising isosorbide mononitrate, one or more rate controlling agents, and optionally one or more pharmaceutically acceptable excipients, and, b) an immediate release component comprising atenolol, one or more disintegrants and optionally one or more pharmaceutically acceptable excipients.
According to another embodiment there is provided a pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate, wherein the composition
comprises: a) an extended release tablet comprising isosorbide mononitrate, one or more rate controlling agents, and optionally one or more pharmaceutically acceptable excipients, and b) an immediate release atenolol coating surrounding the tablet.
According to another embodiment there is provided a pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate, wherein the composition comprises: a) a core comprising isosorbide mononitrate, b) a controlled release coating surrounding the core, and c) an immediate release atenolol coating above the controlled release coating.
According to further embodiment there is provided a process for preparing a pharmaceutical
composition containing fixed dose combination of atenolol with isosorbide mononitrate,. the
process , comprising the steps ... of:
a) granulating isosorbide mononitrate, one or more rate controlling agents and optionally, one
or more pharmaceutically acceptable excipients, optionally followed by drying to obtain
extended release granules,
b) granulating atenolol, one or more disintegrants and optionally one or more pharmaceutically
acceptable excipients, optionally followed by drying to obtain immediate release granules, and,
c) compressing the extended release granules obtained in step (a) and the immediate release
granules obtained in step (b) to form bilayered tablet.
According to still another embodiment there is provided a process for preparing pharmaceutical
composition containing fixed dose combination of atenolol with isosorbide mononitrate, the
process comprising the steps of:
a) dispersing isosorbide mononitrate in one or more of molten hydrophobic substance followed
by solidifying and, optionally mixing with one or more hydrophilic polymers to obtain extended
release granules,
b) granulating atenolol, one or more disintegrants and optionally one or more pharmaceutically
acceptable excipients, followed by drying to obtain immediate release granules, and,
c) compressing the extended release granules obtained in step (a) and the immediate release
granules obtained in step (b) to form bilayered tablet.
Detailed Description of the Invention
The present invention relates to a pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate for the treatment of angina, in which isosorbide mononitrate is present in an extended release form and atenolol is present in ,an immediate release form.
The 'fixed dose combination' of the present invention comprises atenolol in an amount ranging from 25 to 100mg; and isosorbide mononitrate in an amount ranging from 30 to 120mg. Preferably, the fixed dose combination comprises atenolol in an amount of 50mg and isosorbide mononitrate in an amount of 30 and 60mg.
The term "isosorbide mononitrate" as used herein and in the appended claims may include isosorbide-2-mononitrate or isosorbide-5-mononitrate.
The term "atenolol" as used herein and in the appended claims refers to atenolol, single enatiomers, pharmaceutically acceptable salts or mixtures thereof.
The "composition" of the present invention includes an extended release component and an immediate release component. The composition may be in the form of tablets or capsules. The tablets may be uncoated tablets, coated tablets or bilayered tablets. The immediate release/ extended release components may be in the form of pellets, beads, granules, capsules or tablets.
The term "extended release" means that the release of the drug is at a rate such that blood (e.g., plasma) levels are maintained within the therapeutic range but below toxic levels over a period of time greater than 6 hours, more preferably for about 12 to about 16 hours.
The term "immediate release" means that the entire drug may be released within two hours or less following administration.
The pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate comprises: a) an extended release component comprising isosorbide mononitrate, one or more rate controlling agents, and optionally one or more pharmaceutically acceptable excipients, and, b) an immediate release component comprising atenolol, one or more disintegrants and optionally one or more pharmaceutically acceptable excipients.
The rate controlling agent may be selected from one or more of hydrophilic polymers, hydrophobic polymers and hydrophobic substance.
The hydrophilic polymers may be selected from one or more of cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or sodium carboxymethyl cellulose; gums such as xanthan gum, karaya gum, locust bean gum, alginic acid or sodium alginate; and vinyl alcohol or vinylpyrrolidone based polymers
such as polyvinyl alcohol, or polyvinylpyrrolidone; polyethylene oxides. The use of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose is preferred. These polymers swell to form a hydrophilic matrix system, which control the release of isosorbide mononitrate. The tablet hydrates on wetting and hydrophilic polymers forms a gel layer. Due to water permeation into the tablet, the thickness of gel layer is increased isosorbide mononitrate diffuses slowly out of the gel layer.
Suitable hydrophobic polymers may be selected from one or more of ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene), poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and/or mixtures thereof.
The hydrophobic substance may be selected from one or more of Fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Examples of hydrophobic substances include beeswax, carnauba wax, paraffin wax, stearic acid, stearyl alcohol and glyceryl behenate.
These rate-controlling agents can be used alone or in combination. The rate controlling agent can be used in a concentration of 2% to 60% depending on the agent used.
Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch, low substituted hydroxyl propyl cellulose, starch and mixtures thereof.
The 'pharmaceutically acceptable excipients' may include diluent, binder, lubricant, glidant and coloring agent. The diluent may be selected from microcrystalline cellulose, lactose, mannjtol, dicalcium phosphate, starch or mixtures thereof. The binder may be selected from starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers or mixtures thereof. Lubricant and glidant may be selected from talc, colloidal silicon dioxide, magnesium stearate or mixtures thereof. Examples of coloring agents include any FDA approved colors for oral use.
According to one embodiment, the pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate is in the form of a bilayered tablet. The bilayered tablet includes two separate drug layers of atenolol and isosorbide mononitrate, and
has only one surface in contact with each other, i.e., the bilayered tablet may comprise one extended release layer comprising isosorbide mononitrate and one immediate release layer comprising atenolol.
According to another embodiment the pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate comprises: a) an extended release isosorbide mononitrate tablet, and b) an immediate release atenolol coating surrounding the tablet. The immediate release atenolol coating surrounding the tablet releases the atenolol substantially immediately upon ingestion. Alternatively, the extended release isosorbide mononitrate may be in the form of multiparticulate system, i. e. granules, beads or pellets, which may be coated with the immediate release atenolol coating.
The immediate release atenolol coating may include water-soluble polymers such as pplyvinyl pyrrolidine, hydroxypropyl cellulose, polyvinyl alcohol or hydroxypropyl methylcellulose. Further, conventional pharmaceutically acceptable excipients like diluents, plasticizers and lubricants may also be incorporated into this coating.
According to another embodiment the pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate comprises a) a core comprising isosorbide mononitrate, b) a controlled release coating surrounding the core, and c) an immediate release atenolol coating above the controlled release coating.
The core may be in the form of pellets, beads, granules, or tablets, comprising isosorbide
mononitrate. Preferably, the core is in the form of a bead wherein, an inert carrier is. layered
with isosorbide mononitrate. The inert carrier comprises one or more of
starch, microcrystalline cellulose or nonpareil sugar seeds. ...
The controlled release coating comprises one or more rate controlling agents. The coating may optionally also include water soluble polymers, plasticizers and lubricants. The compositions of the present invention may be prepared by conventional processes known to person skilled in the art. The tablets may be prepared by wet granulation, dry granulation or direct compression process.
According to one embodiment there is provided a process for preparing a pharmaceutical
composition containing fixed dose combination of atenolol with isosorbide mononitrate,.the
process comprising the steps of:
a) granulating isosorbide mononitrate, one or more rate controlling agents and optionally, one
or more pharmaceutically acceptable excipients, optionally followed by drying to obtain extended release granules,
b) granulating atenolol, one or more disintegrants and optionally one or more pharmaceutically
acceptable excipients, optionally followed by drying to obtain immediate release granules, and,
c) compressing the extended release granules obtained in step (a) and the immediate release
granules obtained in step (b) to form bilayered tablet.
According to another embodiment there is provided a process for preparing pharmaceutical
composition containing fixed dose combination of atenolol with isosorbide mononitrate, the
process comprising the steps of:
a) dispersing isosorbide mononitrate in one or more molten hydrophobic substance followed by
solidifying and, optionally mixing with one or more hydrophilic polymers to obtain extended
release granules,
b) granulating atenolol, one or more disintegrants and optionally one or more pharmaceuticaj.ly
acceptable excipients, optionally followed by drying to obtain immediate release granules, and,
c) compressing the extended release granules obtained in step (a) and the immediate release
granules obtained in step (b) to form bilayered tablet.
The following non-limiting examples illustrate the pharmaceutical composition containing ;fixed dose combination of atenolol with isosorbide mononitrate disclosed in various embodiments, of the specification:
Examples 1 -2
(Table Removed)

Procedure:
GRANULATION
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Lactose monohydrate,
Microcrystalline Cellulose, and Hypromellose were sifted through # 22 BSS and lake of
Quinoline Yellow/lake of erythrosine was sifted through # 100 BSS and mixed to obtain a
mixture.
2. The mixture of step 1 was granulated with Povidone (part 2) solution in a mixture of
Isopropyl Alcohol and Purified Water to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain the dried granules; the dried granules
obtained were then lubricated with Colloidal Anhydrous Silica, Talc, and Magnesium
Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution in Purified Water to
obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules were
milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Dissolution Profile:
The dissolution for isosorbide mononitrate was carried out in USP Apparatus Type 2 at a speed of 50 rpm. The medium was 900 ml 0.1 N hydrochloric acid.
The dissolution for atenolol was carried out in USP Apparatus Type I at a speed of 100 rpm. The medium was 900 ml 0.1 N hydrochloric acid.
The data obtained is disclosed in Table 1.
Table 1
(Table 1 Removed)
The above results shows the extended release profile of isosorbide mononitrate, in which only 39% of isosorbide mononitrate is release over a period of 2 hours and the immediate release profile of atenolol, in which 100% of drug is release within 60 minutes.
Example 3
(Table Removed)

Procedure: A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Microcrystalline Cellulose, and
Hypromellose were sifted through # 22 BSS and lake of Erythrosine was sifted through
# 100 BSS and mixed to obtain a mixture.
2. The mixture of step 1 was granulated with Povidone (part 2) solution in a mixture of
Isopropyl Alcohol and Purified Water to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules obtained were milled and lubricated with Colloidal Anhydrous Silica, Talc, and Magnesium Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution (in Purified Water)
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 4
(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Dibasic Calcium Phosphate-
dihydrate, Microcrystalline Cellulose, and Hypromellose were sifted through # 22 BSS
and lake of Erythrosine was sifted through # 100 BSS and mixed to obtain a mixture.
2. Granulate mix of step 1 with Povidone (part 2) solution (in a mixture of Isopropyl Alcohol
and Purified Water) to obtain wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
obtained were milled and lubricated with Colloidal Anhydrous Silica, Talc, and
Magnesium Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution (in Purified Water)
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 5
(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Glyceryl. behenate,
Microcrystalline Cellulose, and Hypromellose were sifted through # 22 BSS and lake of
Erythrosine was sifted through # 100 BSS and were mixed to obtain a mixture.
2. The mixture obtained in step 1 was granulated with Povidone (part 2) solution in a
mixture of Isopropyl Alcohol and Purified Water to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
obtained were lubricated with Colloidal Anhydrous Silica, Talc, and Magnesium Stearate
to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution (in Purified Water)
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 6

(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), ethylcellulose (Ethocel 100 FP), Microcrystalline Cellulose, and Hypromellose were sifted through # 22 BSS and lake of Erythrosine was sifted through #100 BSS and mixed to obtain a mixture.
2. The mixture obtained in step 1 was granulated with Povidone (part 2) solution in a
mixture of Isopropyl Alcohol and Purified Water to obtain wet mass.
3. The wet mass of step 2 was dried to obtain dried granules, the dried granules obtained
were milled and lubricated with Colloidal Anhydrous Silica, Talc, and Magnesium
Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution in Purified Water
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magjiesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 7

(Table Removed)
(Table Removed)
Procedure:
A. ISOSORBIOE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Microcrystalline Cellulose, and
Hypromellose were sifted through # 22 BSS and lake of Erythrosine was sifted through
# 100 BSS and mixed to obtain a mixture.
2. The mixture obtained in step 1 was granulated with Povidone (part 2) solution in a
mixture of Isopropyl Alcohol and Purified Water to obtain wet mass.
3. The wet mass obtained in step 2 was milled and dried to obtain dried granules, the dried
granules obtained were mixed with ethylcellulose (Ethocel 100 FP).
4. The granules obtained in step 3 were lubricated with Colloidal Anhydrous Silica, Talc,
and Magnesium Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution in Purified Water
to obtain a wet mass. ., .,
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 8

(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted, Povidone (part 1), Microcrystalline Cellulose, and
Hypromellose were sifted through # 22 BSS and lake of Erythrosine was sifted through
# 100 BSS to obtain a mixture.
2. Granulate mixture obtained in step 1 with Povidone (part 2) solution in a mixture of
Isopropyl Alcohol and Purified Water to obtain a wet mass.
3. Wet mass obtained after step 2 was dried, milled and then lubricated with Colloidal
Anhydrous Silica, Talc, and Magnesium Stearate to obtain a blend.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution (in Purified Water)
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 9

(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Isosorbide Mononitrate 80% diluted was granulated with ethylcellulose (Ethocel 20 cps)
solution to obtain granules.
2. Microcrystalline Cellulose, and Hypromellose were sifted through # 22 BSS and lake of
Erythrosine through was sifted through # 100 BSS to obtain a mixture.
3. The mixture obtained in step 2 was mixed with granules of step 1 to obtain a blend.
4. The blend obtained in step 3 was lubricated with Colloidal Anhydrous Silica, Talc, and
Magnesium Stearate.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution in Purified Water
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 10

(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Carnauba wax was melted and to this stearic acid and Isosorbide Mononitrate 80%
diluted were added while stirring.
2. All the melt of step 1 was solidified and milled, and passed through BSS #22 to obtain
fine solid.
3. The fine solid obtained in step 2 was lubricated with Colloidal Anhydrous Silica, Talc,
and Magnesium Stearate.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution in Purified Water
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2). -, ,
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
Example 11

(Table Removed)
Procedure:
A. ISOSORBIDE MONONITRATE LAYER
1. Carnauba wax was melted and to this stearic acid and Isosorbide Mononitrate 80%
diluted were added while stirring.
2. All melt of step 1 was solidified and milled, and passed through BSS #22 to obtain fine
solid.
3. The fine solid obtained in step 2 was mixed with hypromellose to obtain a blend.
4. The blend of step 3 was lubricated with Colloidal Anhydrous Silica, Talc, and
Magnesium Stearate.
B. ATENOLOL LAYER
1. Atenolol, Microcrystalline Cellulose, and Sodium Starch Glycolate (Part 1) were sifted
through # 22 BSS and mixed to obtain a mixture
2. The mixture obtained in step 1 was granulated with Povidone solution (in Purified Water)
to obtain a wet mass.
3. The wet mass obtained in step 2 was dried to obtain dried granules, the dried granules
were milled and then mixed with Sodium Starch Glycolate (Part 2).
4. The granules of step 3 were lubricated with Colloidal Anhydrous Silica and Magnesium
Stearate to obtain a blend.
The Bilayer tablets were compressed using the blend of isosorbide mononitrate layer obtained in (A) and blend of atenolol layer obtained in (B).
While several particular pharmaceutical compositions containing fixed dose combination of atenolol with isosorbide have been described above, it will be apparent that various modifications and combinations of the composition detailed in the text can be made without departing from the spirit and scope of the invention. For example, additional exemplary tablet formulations are contemplated to make pharmaceutical composition containing fixed dose combination of atenolol with isosorbide mononitrate, as disclosed in the examples 12 and 13.
Example12
1. Coating of isosorbide retard tablets with Atenolol layer

(Table Removed)
Procedure:
GRANULATION
A. ISOSORBIDE MONONITRATE LAYER
1. Sift Isosorbide Mononitrate 80% diluted, Povidone (part 1), Lactose monohydrate,
Microcrystalline Cellulose, and Hypromellose through # 22 BSS and lake of Quinoline
Yellow through #100 BSS.
2. Granulate mix of step 1 with Povidone (part 2) solution in a mixture of Isopropyl Alcohol
and Purified Water.
3. After drying the wet mass obtained after step 2, mill the dried granules and lubricate with
Colloidal Anhydrous Silica, Talc, and Magnesium Stearate to obtain a blend.
4. Compress the blend obtained in step 3 to obtain tablet.
B. ATENOLOL COATING
1. Add Atenolol, hypromellose (methocel E5), sodium starch glycolate, povidone, and
Colloidal Anhydrous Silica in IPA/water mixture to obtain a coating solution.
2. Coat tablets obtained in A (4) with coating solution of step B (1) to obtain the
pharmaceutical composition.
Example 13

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General procedure:
1. Drug layering on non-pareil sugar beads with isosorbide mononitrate using an aqueous solution of hydroxypropyl methylcellulose.
2. Coating the above drug layered beads with polymer composition comprising ethyl
cellulose and plasticizer (e.g., diethyl phthalate, triacetin, PEG-400), and optionally
hydroxypropyl methylcellulose dissolved in isopropyl alcohol and water mixture thereof.
3. Applying an immediate release layer of Atenolol on the above beads.
4. Drying and filling the above prepared beads in capsules.

WE CLAIM:
1. A pharmaceutical composition containing fixed dose combination of atenolol with
isosorbide mononitrate, the composition providing extended release of isosorbide
mononitrate and immediate release of atenolol.
2. The composition according to claim 1, wherein the composition comprises: a) an
extended release component comprising isosorbide mononitrate, one or more rate
controlling agents, and optionally one or more pharmaceutically acceptable excipients,
and, b) an immediate release component comprising atenolol, one or more disintegrants
and optionally one or more pharmaceutically acceptable excipients.
3. The composition according to claim 1, wherein the composition comprises: a) an
extended release tablet comprising isosorbide mononitrate, one or more rate controlling
agents, and optionally one or more pharmaceutically acceptable excipients, and b) an
immediate release atenolol coating surrounding the tablet.
4. The composition according to claim 1, wherein the composition comprises: a) a core
comprising isosorbide mononitrate, b) a controlled release coating comprising one or
more rate controlling agents surrounding the core, and c) an immediate release atenolol
coating above the controlled release coating.
5. The pharmaceutical composition according to any of claims 2, 3 or 4, wherein the
one or more rate-controlling agents comprises hydrophilic polymer, hydrophobic polymer, hydrophobic substance or mixtures thereof.
6. The composition according to claim 2, wherein the one or more disintegrants comprise
sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch or mixtures
thereof.
7. The composition according to claim 2, wherein the immediate release component and
the extended release component comprises pellets, beads, granules, capsules or
tablets.
8. The pharmaceutical composition according to claim 2, wherein the composition is a
bilayered tablet.
9. The composition according to claim 1, wherein after oral administration the isosorbide
mononitrate is released over a period of about 6 to about 16 hours.
10. A pharmaceutical composition containing fixed dose combination of atenolol with
isosorbide mononitrate, and processes of preparation thereof as described and
exemplified herein.