DESC:TECHNICAL FIELD OF THE INVENTION

The invention relates to an oral liquid pharmaceutical composition comprising phenylephrine or a salt thereof in combination with additional pharmaceutical active agents. In particular, the invention relates to stable oral liquid composition comprising phenylephrine or a salt thereof with one or more antioxidant and one or more chelating agent. The invention further relates to use of such composition in the treatment of respiratory illness.

BACKGROUND OF THE INVENTION

Phenylephrine, is a selective a1-adrenergic receptor agonist, is designated chemically as (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol. Phenylephrine is having a molecular formula of C9H13NO2 and has a molecular weight of 167.20 with the following structural formula:

Phenylephrine is susceptible to degradation. The degradation is typically facilitated by the different conditions and selective excipients type typically used in composition. Applicants believe without wishing to be held to the theory that phenylephrine degradation is facilitated by the presence of aldehydes and reducing sugars and may also degrade in the presence of oxygen, certain acids including citric acid and metals. The degradation of phenylephrine, even in solid dose forms, has also been reported.

Aldehydes and reducing sugars are compounds that are well known to the ordinarily skilled artisan. Flavors are well known for use in health products for improving consumer acceptance and many such flavors are aldehydic in nature and further they often cause degradation of the phenylephrine.

U.S. Patent Application No. 20070197661 discloses an oral, aqueous-based, phenylephrine liquid pharmaceutical composition.

U.S. Patent Application No. 20080014274 discloses phenylephrine composition substantially aldehyde-free polyethylene glycol.

U.S. Patent Application No. 20070249566 discloses phenylephrine liquid compositions having a pH of about 2 to about 5 and is substantially free of aldehydes.

U.S. Patent Application No. 20070249727 discloses clear device comprising a composition contained in a device.

Many liquid cough and cold compositions contain large amounts of sorbitol and other sugars, typically included to improve palatability. US Patent No. 5,730,997 discloses a composition containing about 20% to about 45% by weight sorbitol and about 10% to about 15% by weight hydrogenated maltose syrup. Such compositions are purported to improve palatability but high levels of sorbitol and maltose may contribute to the degradation of active ingredients such as phenylephrine.

Accordingly, it would be desirable to have a palatable, liquid dosage form comprising phenylephrine with reduced propensity for degradation of phenylephrine even in presence of free aldehydes & reducing sugars and further more in presence of flavor and sugars typically used in liquid composition.

The inventors of the inventions have surprisingly found that by the legitimate selection of one or more antioxidant and one or more chelating agents, it is possible to achieve stable oral liquid phenylephrine or a salt thereof in combination with additional pharmaceutical active agents even in presence of free aldehydes & reducing sugars.

Further, the inventors of the invention have also found that such composition of phenylephrine or a salt thereof can impart excellent taste masking properties to the formulation and exhibit storage stability.

The composition may further comprise one or more additional pharmaceutical agents selected from analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.

The composition may be a solution or a suspension. Suspension may further comprise viscosity modifying agents.

SUMMARY OF THE INVENTION

In one general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) one or more antioxidant;
(c) one or more chelating agent; and
(d) one or more other pharmaceutical acceptable excipients;
wherein the composition comprises free aldehydes and reducing sugars.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) one or more second active agent;
(c) one or more antioxidant;
(d) one or more chelating agent; and
(e) one or more other pharmaceutical acceptable excipients,
wherein the composition comprises free aldehydes and reducing sugars.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or salt thereof;
(c) chlorpheniramine or salt thereof;
(d) one or more antioxidant;
(e) one or more chelating agent; and
(f) one or more other pharmaceutical acceptable excipients,
wherein the composition comprises free aldehydes and reducing sugars.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) one or more second active agent;
(c) one or more antioxidant;
(d) one or more chelating agent;
(e) one or more preservative; and/or
(f) one or more other pharmaceutical acceptable excipients.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or a salt thereof;
(c) chlorpheniramine or a salt thereof;
(d) one or more antioxidant;
(e) one or more preservative; and
(f) one or more other pharmaceutical acceptable excipients,
wherein the composition comprises free aldehydes and reducing sugars.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or a salt thereof;
(c) chlorpheniramine or a salt thereof;
(d) one or more antioxidant;
(e) one or more chelating agent;
(f) one or more preservative; and/or
(g) one or more other pharmaceutical acceptable excipients.

In another general aspect, a stable liquid oral pharmaceutical composition comprises of:
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or salt thereof;
(c) chlorpheniramine or salt thereof;
(d) sodium metabisulphite;
(e) disodium edetate;
(f) benzoic acid;
(g) sodium benzoate and/or
(g) one or more other pharmaceutical acceptable excipients.

In another embodiment, a stable liquid oral pharmaceutical composition comprises of
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or salt thereof;
(c) chlorpheniramine or salt thereof;
(d) sodium metabisulphite;
(e) benzoic acid;
(f) sodium benzoate and
(g) one or more other pharmaceutical acceptable excipients.

In another embodiment, a stable liquid oral pharmaceutical composition comprises of:
(a) 0.01% w/w phenylephrine or a salt thereof;
(b) 0.3% w/w dextromethorphan or a salt thereof;
(c) 0.04% w/w chlorpheniramine or a salt thereof;
(d) about 0.05% w/w to about 0.25% w/w sodium metabisulphite;
(e) about 0.005% w/w to about 0.10% w/w disodium edetate;
(f) about 0.015% w/w to about 0.15% w/w benzoic acid;
(g) about 0.010% w/w to about 0.10% w/w sodium benzoate and/or
(g) one or more other pharmaceutical acceptable excipients.

In another embodiment, a stable liquid oral pharmaceutical composition comprises of:
(a) 0.01% w/w phenylephrine or a salt thereof;
(b) 0.3% w/w dextromethorphan or a salt thereof;
(c) 0.04% w/w chlorpheniramine or a salt thereof;
(d) about 0.05% w/w to about 0.25% w/w sodium metabisulphite;
(e) about 0.005% w/w to about 0.10% w/w disodium edetate;
(f) about 0.015% w/w to about 0.15% w/w benzoic acid;
(g) about 0.010% w/w to about 0.10% w/w sodium benzoate and/or
(g) one or more other pharmaceutical acceptable excipients, wherein the composition contains not less than 50% of pharma grade sugar and not less than 15% of glucose.

While developing the oral liquid composition for phenylephrine or a salt thereof in combination with another pharmaceutical active agent, the inventors found that the manufacturing process plays significant role in the stability of the final composition.

The invention further relates to a process of preparing a stable oral liquid composition comprising phenylephrine and one or more other pharmaceutically active, wherein the composition is stable over the shelf life of not less than 3 months.

In another general aspect, a process of preparing a stable oral liquid pharmaceutical composition comprising:
(a) phenylephrine or a salt thereof;
(b) dextromethorphan or a salt thereof;
(c) chlorpheniramine or a salt thereof;
(d) sodium metabisulphite;
(e) disodium edetate;
(f) benzoic acid;
(g) sodium benzoate and/or
(g) one or more other pharmaceutical acceptable excipients, wherein the composition is stable over the shelf life of not less than 3 months.

In a still further aspect, the invention provides a process for preparing a stable oral liquid composition of this invention which comprises adding a phenylephrine compound to a liquid oral composition so that phenylephrine is in the range of 0.001 to 0.5% w/w.

The invention further relates to a process of preparing a stable oral liquid composition comprising phenylephrine and one or more other pharmaceutically active agent, wherein the process comprises steps of: a) preparing solution of chelating agent and preservative in purified water; b) preparing solution of different sugar and/ or sweetener used in composition and antioxidant respectively to add in step a) solution, c) dissolving anti-tussive (dextromethorphan HBr), decongestant (phenylephrine HCl) and antihistamine (chlorpheniramine maleate) subsequently in above solution and one or more pharmaceutically acceptable excipient with stirring in solution of step b) until each ingredient is completely dissolved.

The invention further comprises a clear device comprising a composition, wherein said composition comprises a phenylephrine or a salt thereof; dextromethorphan hydrobromide, chlorpheniramine maleate, other pharmaceutical acceptable excipient and wherein said device comprises a polyethylene terephthalate material having a ROPP caps.

The invention can also comprise a kit. The kit of the invention can comprises: a composition contained in a device; wherein said composition comprises a phenylephrine or salt thereof; dextromethorphan HBr, chlorpheniramine maleate, other pharmaceutical acceptable excipient and wherein said device comprises a polyethylene terephthalate material having a ROPP caps. The kit may further comprise a set of instructions. These instructions may also include illustrations.

Preferably the phenylephrine is in a salt form. Suitable salt forms include, but are not limited to, phenylephrine hydrochloride (HCI), hydrobromide (HBr), bitartarate and tannate salt. Phenylephrine may be used in an amount of about 0.001% w/w to about 10% w/w. Preferably, phenylephrine is used in an amount of about 0.005% w/w to about 2.5% w/w.

The composition may contain one or more additional pharmaceutical actives (also referred to as second active agent or actives). Herein reference to "first pharmaceutical active" means phenylephrine and reference to "second active" means any active other than phenylephrine. Further, the term second active may refer to a single species of active or a plurality of species of actives other than phenylephrine (e.g., the total number of actives in the compositions may be greater than two.

Pharmaceutical actives include but are not limited to dextromethorphan, acetaminophen, ephedrine, pseudoephedrine, phenylpropanolamine, ibuprofen, aspirin, ketoprofen, guaifenesin, ambroxyl, bromhexine, chlorpheniramine, diphenhydramine, doxylamine, clemastine, pyrilamine, promethazine, cetirizine, loratidine, oxycodone, hydrocodone, naproxen, brompheniramine, pheniramine, the free and the addition salt forms thereof and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term "stable" as used herein refers to physical and chemical stability of liquid pharmaceutical composition of phenylephrine or a salt thereof with another pharmaceutical active agents liquid composition with no significant change in pH and assay value, when stored at conditions specified by ICH guidelines for stability testing for not less than 3 months.

The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient may include, but are not limited to antioxidants, humectants, defoaming agents, chelating agents, preservatives, solubilizers, buffers, electrolytes, sweeteners, syrup viscolyser, syrup base, flavours, colours, co-solvents, taste masking agents and/or mixture thereof. The excipients that are useful in preparing a pharmaceutical composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.

It has been found that trace amounts of heavy metal ions may catalyze auto-oxidation reactions that may compromise stability of the final composition.

The invention further relates to a stable liquid oral composition comprising of phenylephrine or a salt thereof alone or in combination with other pharmaceutical active agent containing low concentrations of one or more antioxidant agent and one or more chelating agent.

The antioxidant have a beneficial chemical stabilizing effect on the pharmaceutical actives used in the invention and may be chosen, but is not limited to, sodium metabisulphite, sodium bisulphite, ascorbic acid or salt thereof, derivatives of vitamin E, butylhydroxyanisole, butylhydroxytoluene, propylgallate and mixture thereof.

The liquid compositions of invention may comprise a antioxidant from about 0.001% to about 1% of the total composition.

Non-limiting examples of chelating agents include but are not limited to the salt of disodium and calcium salts of ethylene diamine tetraacetic acid (EDTA), tetrasodium EDTA, sodium hexametaphosphate (SHMP), citric acid, phosporic acid, di(hydroxyethyl)glycine, 8-hydroxyquinoline, and mixtures thereof. Trivalent metal chelating agents such as galactomannans complexed with iron may also be useful.

The liquid compositions of invention may comprise a chelating agent from about 0.001% to about 1% of the chelating agent, alternatively from about 0.008% to about 0.1%, and alternatively from about 0.009% to about 0.08% of the chelating agent, all by weight of the composition.

Advantageously, the ratio of chelating agent(s)/antioxidant(s) is comprised between 0.05 and 12, preferably between 0.09 and 11.05, most preferably the ratio is 1 and 10. The concentration of the chelating agent with respect with the total composition is advantageously between about 0.001% to about 1%, preferably between 0.009% to about 0.08 w/w%.

The ratio between the antioxidant and phenylephrine or a salt thereof is advantageously comprised between 1:5 and 1:0.5, preferably between 1: 3 and 1:0.8, most preferably between 1:0.9 and 1:1.5.

Preservatives useful in the invention include but are not limited to benzoic acid, sodium benzoate, sorbates, such as potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid or EDTA, such as disodium edetate), benzaldionium chloride, parabens (such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid esters) or mixture thereof.

Preservatives are generally present in amounts of up to 0.5 gram per 100 ml of the pharmaceutical composition. Preferably the preservatives are present in amounts in the range of from about 0.010 w/w to about 0.35 w/w of the composition. Typically, the preservative such as benzoic acid and sodium benzoate would be present in the range of about 0.01 w/w to about 0.15 w/w of the composition. For example, benzoic acid used in a concentration of about 0.070 w/w in an exemplary embodiment of the composition.

Examples of suitable flavoring agents include, but are not limited to, natural and artificial flavors such as mints (i.e., peppermint, etc.), menthol, chocolate, artificial chocolate, bubblegum, both artificial and natural fruit flavors (i.e., cherry, grape, orange, strawberry, etc.) and combinations of two or more thereof. Flavoring agents are generally provided as a minor component of the composition in amounts effective to provide palatable flavor to the compositions. Typically, flavoring agents are present in amounts in the range of about 0 grams to about 5 grams per 100 ml of the composition. Preferably Menthol, Essence Mixed Fruit VSA S 2535 (IFF) and Flavor RSW 786 can be used.

Coloring agents may also be incorporated in the pharmaceutical composition to provide an appealing color to the composition. The coloring agents should be selected to avoid chemical incompatibilities with other ingredients in the composition. Suitable coloring agents are well known to those skilled in the art. Preferably Brilliant Blue FCF often used in invention.

The liquid composition comprises a sugar and/or other sweetener to provide sweetness and taste masking of pharmaceutical active(s) as well as to provide some body and thickness. Sucrose, glucose or table sugar, often in liquid form, may be used.

For example, the compositions of the invention contains sugar, such as sucrose, in a liquid solution in the range of from about 10% to about 70% sugar solution by weight of the composition, and alternatively from about 15% to about 60% sugar solution by weight of the composition, wherein the sugar solution can comprise from about 50% to about 70% sugar by weight of the sugar solution.

Alternatively, or additionally if greater sweetening is desired, sugar alcohols such as glycerin, sorbitol, maltitol, and mannitol can be used to provide sweetness and body.

If such sugar alcohol solutions are used, they can be used in a range of from about 0% to about 30% solution by weight of the composition and alternatively from about 10% to about 25% solution by weight of the composition, wherein the sugar alcohol solution may comprise from about 60% to about 80% sugar alcohol by weight of the sugar alcohol solution. For example, a 70% by weight sugar alcohol solution can be used at 20% by weight of the composition, resulting in 14% sugar alcohol by weight of the composition.

Sweetness levels can also be supplemented with the use of an artificial sweetener. Non-limiting examples of artificial sweeteners are selected from sodium saccharine, acesulfame potassium, sucralose, aspartame, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, cyclamates, and mixtures thereof. Generally, such artificial sweeteners are solids when used in sweetening compositions such as those of the invention.

Wherein an artificial sweetener is utilized in the inventive compositions, the compositions may comprise from about 0.0001% to about 5% artificial sweetener, alternatively from about 0.0425% to about 3.5% artificial sweetener, and alternatively from about 0.05% to about 2.0% artificial sweetener, all by weight of the composition.

The compositions are defined herein in a number of embodiments, all relating to the discoveries made by the inventors. In particular, the inventors have discovered that the compositions of the invention are made acceptable stable even in presence of free aldehyde and reducing sugars through formulation by the legitimate selection of suitable antioxidant/s and chelating agent/s.

In one embodiment, the liquid compositions of the invention comprise phenylephrine; its free and addition salt forms, and mixtures thereof, wherein the composition further comprises another pharmaceutical active agent. Illustrative salts of phenylephrine include phenylephrine hydrochloride and phenylephrine hydrobromide.

In one embodiment, the compositions of the invention may comprise an amount of phenylephrine in the range of about 0.0001 mg to about 10 mg of phenylephrine, alternatively from about 0.005 mg to about 8 mg, and alternatively from about 0.01 mg to about 0.25 mg of phenylephrine, all per 100ml of the composition. By way of non-limiting example, an embodiment of the invention may comprise about 0.1% w/w of phenylephrine, per 100ml of composition.

In one embodiment, specific additional pharmaceutical actives include but are not limited to dextromethorphan, chlorpheniramine, doxylamine and guaifenesin or pharmaceutical acceptable salt thereof.

In another embodiment, the compositions of the invention may comprises an amount of additional pharmaceutical active agent in the range of about 0% w/w to about 1% w/w of each of at least one additional pharmaceutical active, alternatively from about 0.01% w/w to about 0.8% w/w of each of at least one additional pharmaceutical active, all per 100ml of the composition.

In another embodiment, the stable liquid oral pharmaceutical composition comprising phenylephrine or a salt thereof, one or more antioxidant, one or more chelating agent, one or more other pharmaceutical acceptable excipients and the composition further comprises free aldehydes and reducing sugars.

In another embodiment, the stable liquid oral pharmaceutical composition comprising phenylephrine or a salt thereof, one or more second active agent, one or more antioxidant, one or more chelating agent, one or more other pharmaceutical acceptable excipients and the composition further comprises free aldehydes and reducing sugars.

In another embodiment, a stable liquid oral composition comprises of phenylephrine or a salt thereof, dextromethorphan or a salt thereof, chlorpheniramine or salt thereof, sodium metabisulphite, disodium edetate, one or more other pharmaceutical acceptable excipients and free aldehydes and reducing sugars.

In another embodiment, the ration of phenylephrine or a salt thereof to dextromethorphan or salt thereof is between about 0.1:0.5 to 0.1:0.7.

In another embodiment, the ratio of chlorpheniramine or a salt thereof to dextromethorphan or salt thereof is between about 0.1:0.4 to 0.1:0.8.

In another embodiment, the ration of phenylephrine or a salt thereof to chlorpheniramine or a salt thereof is between about 1:10 to 10:1.

The total amount of preservative present in the composition may be in the range of about 0.10 w/w to about 0.2 w/w.

In another embodiment, a process of preparing a stable oral liquid composition comprising phenylephrine and one or more other pharmaceutically active, wherein the process comprises steps of: a) preparing solution of disodium edetate and benzoic acid in purified water; b) preparing solution of 60% w/w sugar in hot water and then add to step a) solution c) dissolving liquid glucose, sorbitol solution and sodium metabisulphite respectively in step b) solution, d) dissolving dextromethorphan, phenylephrine and chlorpheniramine subsequently in above solution and one or more pharmaceutically acceptable excipient with stirring in solution of step c) until each ingredient is completely dissolved.

In another embodiment, a clear device comprising a composition, wherein said composition comprising a phenylephrine or a salt thereof; dextromethorphan HBr, chlorpheniramine maleate, one or more other pharmaceutical acceptable excipient and wherein said device comprises a polyethylene terephthalate material having a ROPP caps.

In another embodiment, a clear device comprising a composition, wherein said composition comprising a phenylephrine or salt thereof; dextromethorphan HBr, chlorpheniramine maleate, antioxidant/s, preservative, chelating agents, any other pharmaceutical acceptable excipients and wherein said device comprises a polyethylene terephthalate material having a ROPP caps.

In another embodiment, a clear device comprising a composition contained in a device, wherein said composition comprising:
(a) 0.01% w/w phenylephrine or a salt thereof;
(b) 0.3% w/w dextromethorphan or a salt thereof;
(c) 0.04% w/w chlorpheniramine or a salt thereof;
(d) about 0.05% w/w to about 0.25% w/w sodium metabisulphite;
(e) about 0.005% w/w to about 0.10% w/w disodium edetate;
(f) about 0.015% w/w to about 0.15% w/w benzoic acid;
(g) about 0.010% w/w to about 0.10% w/w sodium benzoate;
(h) one or more other pharmaceutical acceptable excipients and wherein said device comprises a polyethylene terephthalate material having a ROPP caps.

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

The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example 1-3: Stable Oral Liquid Composition

Sr.
No. Ingredient Quantity (% w/w)
Example 1 Example 2 Example 3
1. Chlorpheniramine Maleate 0.040 0.0402 0.0398
2. Dextromethorphan Hydrobromide 0.300 0.3015 0.2985
3. Phenylephrine Hydrochloride 0.100 0.1005 0.0995
4. Disodium Edetate 0.010 0.0101 0.00995
5. Menthol 0.050 0.0503 0.0498
6. Pharma Grade Sugar 60.000 60.3000 59.7000
7. Liquid Glucose 20.000 20.1000 19.9000
8. Sorbitol Solution 70% Non Crystallizing 10.000 10.0500 9.9500
9. Benzoic Acid 0.070 0.0704 0.0697
10. Sodium Benzoate 0.035 0.0352 0.0348
11. Sodium Metabisulphite 0.100 0.1005 0.0995
12. Sodium Saccharin 0.300 0.3015 0.2985
13. Color Brilliant Blue FCF 0.00125 0.0013 0.0012
14. Essence Mixed Fruit VSA S 2535 (IFF) 0.100 0.1005 0.0995
15. Flavor RSW 786 0.050 0.0503 0.0498
16. Purified Water q.s to
100 ml q.s to
100 ml q.s to
100 ml

Process:
A predetermined amount of water is added into the vessel for preparing an solution of disodium edetate and benzoic acid first then separately preparing an solution of 60% w/w sugar in hot water and then added to above solution, dissolving liquid glucose, sorbitol solution and sodium metabisulphite respectively in above solution and then dissolving dextromethorphan, phenylephrine and chlorpheniramine subsequently in above solution and finally the other pharmaceutically acceptable excipient including color and flavor added with stirring in vessel until each ingredient is completely dissolved. After all ingredients are added and mixed sufficiently to dissolve, water is added to bring the total volume of the composition to the predetermined final volume and mixing is continued for approximately 10 minuites and then said composition placed in a device comprising the material PET having ROPP caps.

Comparative Examples: Oral liquid composition having aldehyde and reducing sugar and Oral liquid composition devoid of free aldehyde and reducing sugar

Sr. No Ingredients Quantity (%w/w)
Composition having Aldehyde and Reducing Sugar Composition without free Aldehyde and Reducing Sugar
1 Chlorpheniramine Maleate 0.040 0.040
2 Dextromethorphan Hydrobromide 0.300 0.300
3 Phenylephrine Hydrochloride 0.100 0.100
4 Menthol 0.050 0.050
5 Pharma Grade Sugar 60.000 NA
6 Sodium Carboxymethyl Cellulose NA 0.750
7 Sorbitol Solution 70% Non Crystallizing NA 15.000
8 Liquid Glucose 30.000 NA
9 Benzoic Acid 0.070 0.140
10 Sodium Benzoate 0.035 0.040
11 Sodium Saccharin 0.300 NA
12 Sucralose NA 0.300
13 Propylene Glycol NA 2.500
14 Polyoxyl 40 hydrogenated castor oil NA 0.400
15 Color Brilliant Blue FCF 0.00125 0.00125
16 Essence Mixed Fruit VSA S 2535 0.100 0.100
17 Flavor RSW 786 0.050 0.050
18 Purified Water q.s to
100 ml q.s to
100 ml
NA: Not Available

The further stability data will give a more comprehensive view of the invention.
Stability data of Phenylephrine with chelating agent and antioxidant in presence of free aldehydes & reducing sugars (Example I)

Time Points Initial Accelerated Stability Study (40°C ± 2°C/ 25%RH)
1 Month 2 Month 3 Month
Phenylephrine Assay 101.2 102.0 100.6 100.5

Stability data of phenylephrine composition in presence of free aldehydes & reducing sugars

Time Points Initial Accelerated Stability Study (40°C ± 2°C/ 25%RH)
1 Month 2 Month 3 Month
Phenylephrine Assay 97.7 92.5 84.0 80.0

Stability data of phenylephrine composition in absence of free aldehydes & reducing sugars

Time Points Initial Accelerated Stability Study (40°C ± 2°C/ 25%RH)
1 Month 2 Month 3 Month
Phenylephrine Assay 99.3 98.8 100.4 99.4

,CLAIMS:1. A stable liquid oral pharmaceutical composition comprising:
(a) phenylephrine or a salt thereof;
(b) one or more second active agent,
(c) one or more antioxidant,
(d) one or more chelating agent;
(e) one or more preservative; and
(f) one or more other pharmaceutical acceptable excipients, wherein the ratio of chelating agent to antioxidant ranges between 0.09 and 11.05; and wherein the composition contains not less than about 50% of pharma grade sugar and not less than about 15% of glucose.

2. The composition of claim 1, wherein the one or more second active agent selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.

3. The composition of claim 1-2, wherein one or more second active agent is selected from the group consisting of chlorpheniramine, dextromethorphan, guaifenesin, acetaminophen, chlophendianol, diphenhydramine, brompheniramine, loratadine, aspirin and doxylamine succinate.

4. The composition of claim 1, wherein the antioxidant is sodium benzoate.

5. The composition of claim 1, wherein chelating agent is disodium edetate.

6. The composition of claim 1, wherein the preservative is selected from the group consisting of benzoic acid, sodium benzoate, sorbates, parabens and combinations thereof.

7. The composition of claim 1, wherein one or more other pharmaceutical acceptable excipients is selected from the group consisting of humectants, defoaming agents, sweeteners, buffers, electrolytes, taste masking agents, flavoring, coloring agents and/or combination thereof.

8. A stable liquid oral composition comprising:
(a) 0.01% w/w phenylephrine or a salt thereof;
(b) 0.3% w/w dextromethorphan or a salt thereof;
(c) 0.04% w/w chlorpheniramine or a salt thereof;
(d) about 0.05% w/w to about 0.25% w/w sodium metabisulphite;
(e) about 0.005% w/w to about 0.10% w/w disodium edetate;
(f) about 0.015% w/w to about 0.15% w/w benzoic acid;
(g) about 0.010% w/w to about 0.10% w/w sodium benzoate; and
(h) one or more other pharmaceutical acceptable excipients, wherein the composition contains not less than about 50% of pharma grade sugar and not less than about 15% of glucose.

9. A process of preparing a stable oral liquid composition comprising phenylephrine and one or more other pharmaceutically active agent, wherein the process comprises steps of: a) preparing solution of chelating agent and preservative in purified water; b) preparing solution of different sugar and/ or sweetener used in present composition and antioxidant respectively to add in step (a) solution, and c) dissolving anti-tussive, decongestant and antihistamine subsequently in above solution and one or more pharmaceutically acceptable excipient with stirring in solution of step (b) until each ingredient is completely dissolved.

10. The composition of claim 1-9, wherein the composition is stable over the shelf life of not less than 3 months.