Description:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1.Title of the invention – AN ORAL LIQUID SOLUTION OF BISOPROLOL FUMARATE
2. Applicant(s)
NAME: AUXILLA PHARMACEUTICALS AND RESEARCH LLP
NATIONALITY: Indian
ADDRESS: 5th FLOOR, 5001-5002, Prerna Aartika, Sanand-Viramgam Highway, Sanand, Ahmedabad, Gujarat, 382110, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

AN ORAL LIQUID SOLUTION OF BISOPROLOL FUMARATE

FIELD OF THE INVENTION
The present invention is related to an oral liquid solution of bisoprolol fumarate. The present invention is also related to an oral liquid solution of bisoprolol fumarate which is comprising bisoprolol fumarate with sweetening agent, preservatives, flavouring agent, buffering agent and vehicle. The present invention also related to process of preparation of an oral liquid solution of bisoprolol fumarate.

BACKGROUND OF THE INVENTION
Beta-blockers, as a class of drugs, are primarily used to treat cardiovascular diseases and other conditions. Beta-blockers are indicated and have FDA approval for the treatment of tachycardia, hypertension, myocardial infarction, congestive heart failure, cardiac arrhythmias, coronary artery disease, hyperthyroidism, essential tremor, aortic dissection, portal hypertension, glaucoma, migraine prophylaxis, and other conditions. The catecholamines, epinephrine, and norepinephrine bind to beta receptors and increase cardiac automaticity as well as conduction velocity. Beta receptors also induce renin release, and this leads to an increase in blood pressure. Beta blockers work by blocking the effects of the hormone epinephrine, also known as adrenaline. Beta blockers cause the heart to beat more slowly and with less force, which lowers blood pressure. Beta blockers also help in widening of veins and arteries to improve blood flow.

Beta-blockers are available for administration in three primary forms: oral, intravenous, and ophthalmic, and the route of administration often depends on the acuity of the illness (parenteral use in arrhythmias), disease type (topical use in glaucoma), and chronicity of the disease. Beta blockers are classified as being non-selective and selective. Non-selective beta blockers, such as propranolol, are active in blocking adrenaline and noradrenaline in other areas of the body, as well as the heart. This can cause some unwanted side effects, including cold hands and a predisposition to asthma attacks. Selective beta blockers, such as atenolol and bisoprolol, are used more commonly by cardiologists because their activity mostly affects the heart and has less pronounced effects in other parts of the body. However, Bisoprolol is more cardio-specific than atenolol, means, it works specifically on the beta-receptors of your cardiovascular system (as opposed to beta-receptors found in other parts of the body, such as your lungs).

Bisoprolol is a cardio selective ß1-adrenergic blocking agent used to treat high blood pressure. Selective B1-blockers are used to treat multiple heart diseases such as congestive heart failure without having the unwanted effect of the B2 receptor blocking, which can affect various systems in the body. Bisoprolol is a BCS Class I drug (highly soluble and highly permeable drug). Its balanced hydrophilic and lipophilic properties make it a great competitor over other ß-blockers, and give it ideal pharmacokinetic profile. The high absorption of bisoprolol after oral administration reflects a high bioavailability of approximately 90% compared to most beta-blockers with lower bioavailability since they have high first-pass metabolism in the liver. It has a long half-life of 10–12 hr, subsequently once daily administration is sufficient to produce the therapeutic effect of bisoprolol, which in turn provides better patient compliance.

Currently, Bisoprolol is present in the market as a solid dosage form and more particularly, in the form of film coated tablet. Though solid dosage forms offer the advantages of greater pharmaceutical stability, dosing accuracy, improved transportability, ease of storage and lower cost compared to liquid dosage form. The liquid dosage forms also provides many advantages over solid dosage form: better patient compliance especially to paediatric, geriatric or to patients having difficulty in swallowing, they are available in different flavours which masks the taste of drug, they are more quickly absorbed on oral administration and hence give quicker onset of action.

Currently there is no liquid formulation of Bisoprolol fumarate is present in the market. Hence, there is need to develop an oral liquid formulation of Bisoprolol fumarate which will overcome the above stated disadvantages of solid dosage form and will also provide faster onset of action in life-threatening heart disease.

Therefore, the inventors in the present invention have arrived to an oral liquid solution of bisoprolol fumarate with aims to overcome problems cited above by preparing an oral liquid solution of bisoprolol fumarate as described herein.

OBJECTIVES OF THE INVENTION
The main objective of the present invention is to develop an oral liquid solution of bisoprolol fumarate.

Another objective of this invention is to provide an oral liquid solution of bisoprolol fumarate which is stable.

Yet another objective of this invention is to provide an oral liquid solution of bisoprolol fumarate which provides better patient compliance.

Yet another objective of this invention is to provide an oral liquid solution of bisoprolol fumarate which is easy to manufacture at large scale.

Yet another objective of this invention is to provide an oral liquid solution of bisoprolol fumarate which gives faster absorption and quicker onset of action.

SUMMARY OF THE INVENTION

The present invention is all about to provide an oral liquid solution of bisoprolol fumarate.

The main aspect of the present invention is to provide an oral liquid solution of bisoprolol fumarate comprising bisoprolol fumarate with sweetening agent, preservatives, flavouring agent, buffering agent and vehicle.

Another aspect of the present invention provides a process for the preparation of an oral liquid solution of bisoprolol fumarate.

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is an oral liquid solution of bisoprolol fumarate.

The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and/or utilized. The description sets forth the functions and the sequence of steps for constructing and/or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences which may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention.

As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As stated in the present invention herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term “about” is used herein to means approximately, in the region of, roughly, or around.

As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components

The following terms are used interchangeably herein:
"active", "drug", and "active ingredient" are interchangeable;

A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount.

The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe. Thus compositions slightly outside the cited ranges are also encompassed by the scope of the present claims.

By the term "pH", as used herein, is meant "apparent pH" wherein the pH measurement is carried out on the Bisoprolol fumarate containing composition in final form, for example, by measuring the pH of the solution.

The main embodiment of the present invention is to provide an oral liquid solution of bisoprolol fumarate comprising bisoprolol fumarate with sweetening agent, preservatives, flavouring agent, buffering agent and vehicle.

As per one embodiment of the present invention, bisoprolol fumarate can be present in the suspension of composition of present invention in an amount from about 0.1 to 500 mg/mL, preferably in the range from about 0.5 to about 150 mg/mL, preferably in the range from about 0.5 to about 100mg/mL, more preferably in the range from about 0.5 to 50 mg/mL, more preferably in the range from about 0.5 to 40 mg/mL, more preferably in the range from about 0.5 to 30 mg/mL, more preferably in the range from about 0.5 to 20 mg/mL, more preferably in the range from about 0.5 to 10 mg/mL, most preferably in the range from about 0.5 to 5 mg/mL or any other range in between thereof.

As per one embodiment of the present invention, the sweetening agent can be selected from but not limited to Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin and the like.

As per preferred embodiment of the present invention, sucralose is used as sweetening agent.

As per one embodiment of the present invention, sweetening agent can be used in the range of 0.1-20 mg, preferably 0.1-10 mg, more preferably 0.5-10 mg and most preferably 0.5-5 mg.

As per one embodiment of the present invention, the preservatives can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol, ethanol, butyl paraben, propyl paraben and methyl paraben benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gamma picolinium chloride, phenol, 2-phenoxyethanol, phenyl mercuric nitrate, phenyl ethyl alcohol, EDTA or combinations thereof.

As per one embodiment of the present invention, one or more preservatives can be used in the composition, preferably combination of two preservatives are used.

As per preferred embodiment of the present invention, combination of methyl paraben and ethyl paraben are used as preservatives.

As per one embodiment of the present invention, methyl paraben can be used in the range of 0.01-10 mg, preferably 0.01-8 mg, more preferably 0.05-5 mg, and most preferably 0.05-3 mg.

As per one embodiment of the present invention, ethyl paraben can be used in the range of 0.01-1 mg, preferably 0.01-0.5 mg, more preferably 0.05-0.5 mg, and most preferably 0.1-0.5 mg.

As per one embodiment of the present invention, the flavouring agent can be selected from but not limited to vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, Tutti Frutti flavor and so forth and the like or any combinations thereof.

As per preferred embodiment of the present invention, frozen peppermint flavor is used as flavouring agent.

As per one embodiment of the present invention, flavouring agent can be used in the range of 0.01-1 mg, preferably 0.05-1 mg, more preferably 0.05-0.8 mg, and most preferably 0.05-0.5 mg.

The buffers used in the present invention is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. The pH of the liquid solution of the present invention can be adjusted in the range from 5 to 11.

As per one embodiment of the present invention, buffering agent can be selected from sodium acetate trihydrate, phosphate, citrate, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, and triethanolamine.

As per preferred embodiment of the present invention, phosphate buffer is used as buffering agent which contains Sodium dihydrogen phosphate dihydrate and Dibasic Sodium phosphate dihydrate.

As per one embodiment of the present invention, Sodium dihydrogen phosphate dihydrate can be used in the range of 0.1-10 mg, preferably 0.5-10 mg, more preferably 0.5-8 mg, and most preferably 0.5-5 mg.

As per one embodiment of the present invention, Dibasic Sodium phosphate dihydrate can be used in the range of 0.01-5 mg, preferably 0.05-5 mg, more preferably 0.1-5 mg, and most preferably 0.1-3 mg.

As per one embodiment, the pH of the liquid oral formulation of bisoprolol fumarate is in the range from 5 to 11, more preferably in the range from 5 to 8, and most preferably 5.5-7.5.

Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the liquid composition of present invention in order to make the liquid solution of the present invention suitable form.

As per one embodiment of the present invention, the vehicle can be selected from water, hydro-alcoholic, polyhydric alcohols, water containing buffers or combination thereof.

As per one embodiment of the present invention, water is used for making flavour solution and to adjust the volume of the final formulation.

As per another main embodiment of the present invention, the process of preparation of an oral liquid solution of bisoprolol fumarate comprises steps of:
a) Taking required quantity of water and heating it upto 80?;
b) Adding required quantity of preservatives in heated water of step (a) and mixing with stirrer at speed of 500-1000 rpm for 15-45 minutes for complete solubilization;
c) Cooling the solution of step (b) upto room temperature, 25 °C ± 5 °C;
d) Adding buffers in cooled solution of step (c) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes till complete solubilization and maintaining pH of the solution between 5.5-7.0;
e) Adding sweetening agent in solution of step (d) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes;
f) Adding Bisoprolol fumarate in solution of step (e) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes;
g) Dissolving flavouring agent in required amount of hot water and mixing with stirrer at speed of 500-1000 rpm for 5-15 minutes;
h) Filtering the solution of step (f) twice using filtration assembly, through Single 25-micron Polypropylene or equivalent filter pad;
i) Adding filtered solution of step (g) into solution step (f) and mixing with stirrer at speed of 500-1000 rpm for 10-15 minutes;
j) Adjusting the final volume with water and mixing with stirrer at speed of 500-1000 rpm for 5-10 minutes to get clear solution;
k) Filtering the clear solution using 25 µm Polypropylene or equivalent filter;
l) Storing the final solution in the suitable container.
One embodiment of present invention is to provide an oral liquid solution of bisoprolol fumarate comprising 0.1-500 mg/mL Bisoprolol fumarate, 0.1-20 mg/mL sucralose, 0.01-10 mg/mL methyl paraben, 0.01-1 mg ethyl paraben, 0.01-1 mg frozen peppermint flavour, 0.1-10 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.01-5 mg Dibasic Sodium phosphate dihydrate, and water.

One embodiment of present invention is to provide an oral liquid solution of bisoprolol fumarate comprising 0.5-100 mg/mL Bisoprolol fumarate, 0.1-10 mg/mL sucralose, 0.01-8 mg/mL methyl paraben, 0.01-0.5 mg/mL ethyl paraben, 0.05-1 mg frozen peppermint flavour, 0.5-10 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.05-5 mg Dibasic Sodium phosphate dihydrate, and water.

One embodiment of present invention is to provide 0.5-10 mg/mL Bisoprolol fumarate, 0.5-10 mg/mL sucralose, 0.05-5 mg/mL methyl paraben, 0.05-0.5 mg ethyl paraben, 0.05-0.8 mg/mL frozen peppermint flavour, 0.5-8 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.1-5 mg Dibasic Sodium phosphate dihydrate, and water.

One preferred embodiment of present invention is to provide an oral liquid solution of bisoprolol fumarate comprising 0.5-5 mg/mL Bisoprolol fumarate, 0.5-5 mg/mL sucralose, 0.05-3 mg/mL methyl paraben, 0.1-0.5 mg ethyl paraben, 0.05-0.5 mg frozen peppermint flavour, 0.5-5 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.1-3 mg Dibasic Sodium phosphate dihydrate, and water.

As per one embodiment of the present invention, an oral liquid solution of bisoprolol fumarate is stable and provides better patient compliance.

As per one embodiment of the present invention, an oral liquid solution of bisoprolol fumarate can be useful in the treatment of cardiovascular diseases.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

EXAMPLE 1: SELECTION OF VEHICLE
For the selection of vehicle, different trials batches were taken with different vehicle like water, citrate buffer and Phosphate buffer and the batches were evaluated. Compositions are summarized in below table.

Batch No. Composition
B1 API (1 mg/mL) + Citrate buffer (Q.S to 1 mL)
B2 API (1 mg/mL) + Purified water (Q.S to 1 mL)
B3 API (1 mg/mL) + Phosphate buffer (Q.S to 1 mL)
Table 1: Trial batches for selection of vehicle

Result:
Batch No. B1 B2 B3
Condition Initial Initial Initial
Assay of Bisoprolol Fumarate 99.2 98.10% 100.30%
pH 3.94 6.46 7.05
Single Unknown Max. (%) 0.195 BQL BQL
Total Impurity (%) 0.26 ND ND
Table 2: Evaluation of Trial batches for selection of vehicle
Based on above data it was concluded that, Bisoprolol fumarate was not stable at acidic pH. To avoid change in pH during stability, phosphate buffer was finalized to be used as a vehicle.

EXAMPLE 2: EFFECT OF BUFFER ON STABILITY OF ORAL LIQUID FORMULATION OF BISOPROLOL FUMARATE
To check the effect of buffer on stability of oral liquid formulation of Bisoprolol fumarate, different trials batches were taken with and without phosphate buffer pH 7.0 and the batches were evaluated. Compositions are summarized in below table.
Batch details B4 B5
Bisoprolol fumarate 1.00 1.00
Methyl Paraben 0.18 0.18
Ethyl paraben 0.02 0.02
Sucralose 1.00 1.00
frozen peppermint 0.10 0.10
Sodium dihydrogen phosphate dihydrate - 2.25
Dibasic Sodium phosphate dihydrate - 1.00
Water Q.S to 1 mL Q.S to 1 mL
Table 3: Trial batches for effect of buffer

Result:
Test B4 B5
Initial 60°C – 7 days Initial 60°C – 7 days
Description A clear colourless Solution A clear colourless Solution A clear colourless Solution A clear colourless Solution
Assay 95.0% 94.90% 103.90% 102.10%
pH 6.07 5.94 6.59 6.55
Related Substance
Single Max unknown (%) BQL BQL BQL BQL
Total impurities(%) ND 0.06 ND 0.05
Table 4: Evaluation of Trial batches for effect of buffer
Based on above data it was concluded that there was drop in pH in batch B4, while there was no drop in pH found in presence of phosphate buffer (B5). Therefore, phosphate buffer was finalized to be used as a vehicle.

EXAMPLE 3: OPTIMIZED FORMULATION OF ORAL LIQUID FORMULATION OF BISOPROLOL FUMARATE (F1)
Sr. No. Ingredients Quantity (mg) /mL
1 Bisoprolol fumarate* 1.00
2 Methyl Paraben 1.80
3 Ethyl paraben 0.20
4 sucralose 1.00
5 Sodium dihydrogen phosphate dihydrate 2.25
6 Dibasic Sodium phosphate dihydrate 1.00
7 frozen peppermint 501500 T 0.10
8 Water Q.S to 1 mL
Table 5: Optimized formulation of oral liquid formulation of Bisoprolol fumarate
Procedure:
The process of preparation of oral liquid solution of bisoprolol fumarate comprises steps of:
a) Required quantity of water was heated upto 80?;
b) Required quantity of methyl paraben and propyl paraben were added in heated water of step (a) and mixed with stirrer at speed of 500-1000 rpm for 15-45 minutes for complete solubilization;
c) The solution of step (b) was cooled upto room temperature, 25 °C ± 5 °C;
d) Buffer was added in cooled solution of step (c) and mixed with stirrer at speed of 800-1200 rpm for 5-10 minutes till complete solubilization and pH of the solution was maintained between 5.5-7.0;
e) Sweetening agent was added in solution of step (d) and mixed with stirrer at speed of 800-1200 rpm for 5-10 minutes;
f) Bisoprolol fumarate was added in solution of step (e) and mixed with stirrer at speed of 800-1200 rpm for 5-10 minutes;
g) Flavouring agent was dissolved in required amount of hot water and mixed with stirrer at speed of 500-1000 rpm for 5-15 minutes;
h) The solution of step (f) was filtered twice using filtration assembly, through Single 25-micron Polypropylene or equivalent filter pad;
i) The filtered solution of step (g) was added into solution step (f) and mixed with stirrer at speed of 500-1000 rpm for 10-15 minutes;
j) The final volume was adjusted with water and mixed with stirrer at speed of 500-1000 rpm for 5-10 minutes to get clear solution;
k) The clear solution of step (j) was filtered using 25 µm Polypropylene or equivalent filter;
l) The final solution was stored in the suitable container.

EXAMPLE 4: THERMAL STABILITY OF THE OPTIMIZED FORMULATION OF ORAL LIQUID FORMULATION OF BISOPROLOL FUMARATE (F1)
To determine the thermal stability of final oral solution, it was stored in HDPE bottle and thermal stability study was conducted at 40°C±2°C/NMT 25% RH and 25°C±2°C/60±5%RH for 1 month, 3 month and 6 month.

Result:
Batch No. F1
Pack Details 185 CC HDPE bottle packed in secondary white box

Test parameters Storage condition Initial 40°C±2°C/NMT 25% RH 25°C±2°C/60±5%RH
1M 3M 6M 1M 3M 6M
Specification Invert Invert Invert Invert Invert Invert
Description A clear colourless to light yellow color solution. Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution Clear colourless solution
Assay of Bisoprolol fumarate Bisoprolol : 95.0% to 105.0% of labelled amount 99.7 101.4 99.6 100.5 101.8 99.2 100.9
Assay of Methyl paraben 80.0% to 110.0% of labelled amount 101.8 97.5 93.3 91.4 98.0 96.2 97.7
Assay of Ethyl paraben 80.0% to 110.0% of labelled amount 101.9 97.6 95.8 95.1 98.9 97.3 98.4
pH Between 5.5 to 7.5 6.51 6.45 6.39 6.26 6.44 6.42 6.31
Color of solution The intensity of the color of the sample preparation should not more intense than the matching fluid. Complies Complies Complies Complies Complies Complies Complies
Related Substances
Single maximum unknown impurity A) Any unspecified Impurity: NMT 0.2%,
B)Total impurities : NMT 0.5% BQL BQL 0.06 0.08 0.05 0.05 0.05
Total impurities 0.10 0.05 0.16 0.21 0.10 0.15 0.14
* NMT- Not more than; BQL – Below limit of quantification.
Table 6: Thermal stability of optimized formulation (F1)

From the above study data it can be concluded that the present invention provides a stable liquid oral formulation of Bisoprolol fumarate.
, Claims:CLAIMS
We claim,
1. An oral liquid solution of bisoprolol fumarate comprising bisoprolol fumarate with sweetening agent, preservatives, flavouring agent, buffering agent and vehicle.
2. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 wherein said bisoprolol fumarate used in the range of 0.1 to 500 mg/mL, preferably, 0.1-150 mg/mL, more preferably, 0.5-10 mg/mL, and most preferably, 0.5-5 mg/mL.
3. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 wherein said sweetening agent can be selected from but not limited to Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin and the like.
4. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 wherein said preservative can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol, ethanol, butyl paraben, propyl paraben and methyl paraben benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gamma picolinium chloride, phenol, 2-phenoxyethanol, phenyl mercuric nitrate, phenyl ethyl alcohol, EDTA or combinations thereof.
5. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 wherein said flavouring agent can be selected from but not limited to vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, Tutti Frutti flavor and so forth and the like or any combinations thereof.
6. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 wherein said buffering agent can be selected sodium acetate trihydrate, phosphate, citrate, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, triethanolamine, preferably phosphate buffer.
7. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 comprising 0.1-500 mg/mL Bisoprolol fumarate, 0.1-20 mg/mL sucralose, 0.01-10 mg/mL methyl paraben, 0.01-1 mg ethyl paraben, 0.01-1 mg frozen peppermint flavour, 0.1-10 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.01-5 mg Dibasic Sodium phosphate dihydrate, and water.
8. The oral liquid solution of bisoprolol fumarate as claimed in claim 1 comprising 0.5-5 mg/mL Bisoprolol fumarate, 0.5-5 mg/mL sucralose, 0.05-3 mg/mL methyl paraben, 0.1-0.5 mg ethyl paraben, 0.05-0.5 mg frozen peppermint flavour, 0.5-5 mg/mL of Sodium dihydrogen phosphate dihydrate, 0.1-3 mg Dibasic Sodium phosphate dihydrate, and water.
9. The process of preparation of oral liquid solution of bisoprolol fumarate comprises steps of:
a) Taking required quantity of water and heating it upto 80?;
b) Adding required quantity of preservatives in heated water of step (a) and mixing with stirrer at speed of 500-1000 rpm for 15-45 minutes for complete solubilization;
c) Cooling the solution of step (b) upto room temperature, 25 °C ± 5 °C;
d) Adding buffers in cooled solution of step (c) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes till complete solubilization and maintaining pH of the solution between 5.5-7.0;
e) Adding sweetening agent in solution of step (d) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes;
f) Adding Bisoprolol fumarate in solution of step (e) and mixing with stirrer at speed of 800-1200 rpm for 5-10 minutes;
g) Dissolving flavouring agent in required amount of hot water and mixing with stirrer at speed of 500-1000 rpm for 5-15 minutes;
h) Filtering the solution of step (f) twice using filtration assembly, through Single 25-micron Polypropylene or equivalent filter pad;
i) Adding filtered solution of step (g) into solution step (f) and mixing with stirrer at speed of 500-1000 rpm for 10-15 minutes;
j) Adjusting the final volume with water and mixing with stirrer at speed of 500-1000 rpm for 5-10 minutes to get clear solution;
k) Filtering the clear solution using 25 µm Polypropylene or equivalent filter;
l) Storing the final solution in the suitable container.

Dated this 19th July, 2023