TITLE
A Pharmaceutical Composition in Form of Aqueous Syrup Comprising Levocetirizine Dihydrochloride and Montelukast Sodium
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical compositions. Particularly, the present invention relates to a stable pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium, which is essentially free of sugar.
BACKGROUND OF THE INVENTION
The term"cetirizine"refers to the racemate of [2- [4- [ (4 chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy]-acetic acid and its dihydrochloride salt which is well known as cetirizine dihydrochloride ; its levorotatory and dextrorotatory enantiomers are known as levocetirizine and dextrocetirizine. Cetirizine is a second generation H1 histamine receptor antagonist. In its racemic form, it generally offers some significant advantages over the first generation antihistaminics.
US 5,698,558 discloses that the administration of optically pure enantiomer (-) cetirizine i.e. levocetirizine can reduce or avoid adverse side effects associated with the use of racemic cetirizine. These side effects include sedation, somnolence, headache, gastrointestinal disturbance, dizziness, nausea, cardiac arrhythmias, and other cardiovascular effects. WO 94/06429 describes a method utilising levo cetirizine for the treatment of seasonal and perennial allergic rhinitis.
Montelukast is apparently a selective, orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTl receptor. The chemical name for montelukast sodium is [R-(E)]-1 -[[[ 1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-( 1 -hydroxy-
l-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid, monosodium salt. U.S. patent No. 5,565,473 ("'473 patent") is listed in the FDA's Orange Book for montelukast sodium. US 5,565,473 discloses montelukast and use of montelukast in pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, inflammation such as arthritis or inflammatory bowel disease, pain, skin disorders such as psoriasis, atopic eczema, cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like.
There have been several reports on the combination of cetirizine, or its enantiomer or salt with one or more leukotriene inhibitors provides synergistic effect for the treatment or prevention of inflammation, asthma or allergic disorder. Furthermore, said combination also avoids or reduces certain side effects associated with H1 histamine receptor antagonists.
US 6,384,038 disclose a combination of cetirizine and a leukotriene inhibitor for the treatment or prevention of inflammation, asthma or allergic disorder. WO 99/32125 discloses a combination of montelukast and antihistaminic drugs for the treatment of inflammation, asthma or allergic disorder and the like.
891/DEL/2007 discloses a pharmaceutical composition comprising montelukast sodium and levocetirizine dihydrochloride in a single dosage form. It teaches pharmaceutical composition in the form of tablet, capsule or pills. It observed an incomplete in vitro release for montelukast sodium, when both the drugs are mixed and granulated together to prepare a pharmaceutical composition of montelukast sodium and levocetirizine dihydrochloride.
However, none of the prior art discloses a stable pharmaceutical composition comprising montelukast sodium and levocetirizine dihydrochloride in liquid dosage form, particularly in a syrup form. The liquid dosage form is the safest and easiest route of
drug administration. Further, syrup has better patient acceptability and suitable for immediate and modified release drug products. Thus, there is a need in the art to prepare stable aqueous syrup compositions of Levocetirizine dihydrochloride and Montelukast sodium having better patient compliance and improved efficacy.
However, Montelukast sodium is poorly soluble in water. It is a sodium salt of Montelukast acid. If montelukast sodium is mixed with levocetirizine dihydrochloride, under normal condition it causes precipitation of Montelukast acid, which is insoluble in water. Unexpectedly and surprisingly, inventors of the present invention have able to develop an aqueous syrup composition, wherein the aqueous system do not permit levocetirizine dihydrochloride and Montelukast sodium to interact and thereby providing stable and effective syrup composition of incompatible drug substances. Further, the composition of present invention may be used as pediatric formulation, which will result in increase patient compliance.
Hence, the present invention provides a stable pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium intended for decreasing the symptoms of persistent allergic disorders and improving the quality of life. Further, the aqueous syrup composition of present invention is essentially free of sugar.
OBJECT OF THE INVENTION
The main object of the present invention is to develop a stable pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium.
Another object of present invention is to prepare aqueous syrup composition essentially free of sugar.
Yet another object of present invention is to prepare aqueous syrup composition for paediatric use and improve the patient compliance.
SUMMARY OF THE INVENTION
The present invention relates to a stable pharmaceutical composition in form of aqueous syrup for oral administration comprising Levocetirizine dihydrochloride and Montelukast sodium together with pharmaceutically acceptable carrier, diluents or excipient. Further, the said syrup composition is essentially free of sugar.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a stable pharmaceutical composition in form of aqueous syrup for oral administration comprising Levocetirizine dihydrochloride and Montelukast sodium together with pharmaceutically acceptable carrier, diluents or excipient, wherein there is minimum interaction between Levocetirizine dihydrochloride and Montelukast sodium.
In one of the embodiment, the syrup composition of the present invention is essentially free of sugar.
As mentioned before that Montelukast sodium is poorly soluble in water. It is a sodium salt of Montelukast acid. If montelukast sodium is mixed with levocetirizine dihydrochloride, under normal condition it causes precipitation of Montelukast acid, which is insoluble in water. In the present invention micro-emulsion of montelukast sodium have been prepared using Poly oxy hydrogenated castor oil. And Levocetirizine is present in the aqueous phase. This system do not permit dihydrochloride and Montelukast sodium to interact. This technique may be used to prepare aqueous solution of incompatible drug substance. This formulation may be used as a pediatric formulation in order to increase patient compliance.
In one of the embodiment, the syrup composition of the present invention comprising Levocetirizine dihydrochloride and Montelukast sodium together with an alkali to maintain the pH in the range of 7 to 9, and a preservative.
In one of the embodiment, the syrup compositions of the present invention are characterized by their physicochemical stability. The term "physicochemically stable" as herein defined refers to a solution wherein, after storage for a period up to 24 weeks at a temperature of 40°C or below, the residual amount of Levocetirizine dihydrochloride and Montelukast sodium is 90% or more of the initial Levocetirizine dihydrochloride and Montelukast sodium concentration.
Hereinafter, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total volume of the formulation. Ratios are intended to define weight-by-weight ratios.
In one of the embodiment, the amount of Levocetirizine dihydrochloride in the present compositions ranges from about 0.01% to about 1%, preferably from about 0.02% to about 0.2%, most preferably from about 0.05% to about 0.1%, and in particular is about 0.05%.
In one of the embodiment, the amount of Montelukast sodium in the present compositions ranges from about 0.01% to about 1%, preferably from about 0.02% to about 0.5%, most preferably from about 0.05% to about 0.2%, and in particular is about 0.08 to about 0.10%.
In one of the embodiment, the syrup composition according to the present invention have a pH from about 7 to about 11, preferably from about 7.50 to about 9 and most preferably from about 7.75 to about 8.75. The pH of the composition may be maintained upon the addition of a buffer system. Buffer systems may be selected from group comprising but not limited to mixtures of appropriate amounts of an acid such as phosphoric, acetic acid, glacial acetic acid, succinic, tartaric, lactic, or citric acid, and a base, in particular sodium
hydroxide or disodium hydrogen phosphate. The desired pH range is advantageously obtained using a tartaric, acetic acid / sodium hydroxide buffer.
In another embodiment, the said syrup composition comprise a pharmaceutically acceptable carrier, diluents or excipient such as sweetening agents, flavouring substances, solubility enhancers, viscosity regulating agents, colouring agent, preservative, buffering agent, water and the like additives.
In another embodiment, the said syrup composition comprising one or more sweetening agents and/or flavouring agents.
In order to prevent the growth of micro-organisms such as bacteria, yeasts and fungi in the subject compositions, a preservative agent is added. Suitable preservatives should be physicochemically stable and effective in the pH range mentioned above. Preservative may be selected from group comprising but not limited to benzoic acid, sorbic acid, methylparaben, propylparaben, imidazolidinyl urea (Germall 115.RTM.) and diazolidinyl urea (Germall II.RTM.), phenoxetol, benzyl alcohol, quaternary compounds, e.g. benzylalkonium chloride, and the like. Some preservatives, such as benzoic acid, sorbic acid, Germall 115.RTM., Germall II.RTM. and benzyl alcohol, have the advantage that they yield clear, transparant solutions which do not show any clouding upon storage. The concentration of the preservatives may range from 0.05% to 1%, particularly from 0.1% to 0.5%, and most particularly is about 0.2%. The most preferred preservative is benzoic acid.
In one of the embodiment, the syrup compositions of the present invention optionally comprise further additives known in the art of formulation may be selected from group comprising but not limited to sweetening agents, flavouring substances, solubility enhancers, viscosity regulating agents and the like additives. For example, the aqueous solubility of the active ingredient may be enhanced by the addition of a pharmaceutically acceptable co-solvent, or a cyclodextrin or a derivative thereof, to the solution.

The bitter taste of Levocetirizine dihydrochloride and Montelukast and the unpleasant taste associated with the pH of the formulation may be masked by the presence of one or more sweetening agents such as sucralose, saccharin, sodium, potassium, calcium saccharin, acesulfame potassium or sodium cyclamate. The concentration of the sweetening agent may range from about 0.04% to about 0.15% and in particular is about 0.1%. In a particular embodiment of the invention, the solution does not comprise mannitol, fructose, sucrose, maltose and the like, as sweetening agents. The palatability of the subject solutions may further be optimized by adding of one or more flavouring substances. Suitable flavouring substances are fruit flavours such as cherry, raspberry, black currant or strawberry flavour, or stronger flavours, such as Caramel Chocolate flavour, Mint Cool flavour, Fantasy flavour and the like. Combinations of flavours are advantageously used. A combination of two cherry flavours was found to yield very good taste masking results in the present compositions. The total concentration of the flavouring substances may range from about 0.01% to about 1.0 %, preferably from about 0.03% to about 0.8% and most preferably from about 0.05% to about 0.4 %.
In one of the embodiment, aqueous syrup composition according to the present invention comprises:
(a) about 0.02% to about 0.5%) Levocetirizine dihydrochloride
(b) about 0.02 to about 0.5 % Montelukast sodium
(c) about 0.1%) to about 0.5%) preservatives;
(d) a suitable amount of buffer to adjust the pH in the range from 7 to 9; and
(e) water q.s. ad 100%.
The most preferred embodiment, aqueous syrup composition according to the present invention comprises:
(a) about 0.05 % Levocetirizine dihydrochloride
(b) about 0.08 to about 0.1%> Montelukast sodium
(c) about 0.1%) Sodium methylparaben
(d) Sodium citrate and sufficient sodium hydroxide 1 N to adjust the pH in the range from 7 to 9; and
(e) water q.s. ad 100%.
In one of the embodiment, the aqueous syrup composition of the present invention may be store at room temperature or below 25° C. It should not be freeze and care should be taken to protect the composition from direct light.
In a further aspect, the present invention relates to a process of preparing solutions of Levocetirizine dihydrochloride and Montelukast syrup as described hereinabove, characterized by dissolving the active ingredient Levocetirizine dihydrochloride and Montelukast sodium, the preservative, and the acid and base components of the buffer in water. In particular, the process comprises the following steps: A process of preparing syrup composition comprising Levocetirizine dihydrochloride and Montelukast sodium as claimed in claim 1, wherein the process comprises the following steps: (a) Heating base with solubilizer, preservative and Montelukast sodium, followed by cooling, (b) diluting the solution with about an equal amount of water, (c) adding the buffer and the active ingredient Levocetirizine dihydrochloride thereto, (d) stirring the mixture until complete dissolution and cooling the solution to room temperature, (e) adjusting the pH with the base component of the buffer and further diluting the solution with water to the required end-volume, and (f) optionally, one or more sweetening agents and flavouring substances may be added during these process steps to obtain a final syrup composition.
Surprisingly, the invertors of the present invention have found that the present invention provides a stable pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium wherein there is minimum interaction between Levocetirizine dihydrochloride and Montelukast sodium. The syrup system according to the present invention do not permit Levocetirizine dihydrochloride and Montelukast sodium to interact. This technique may be used to prepare aqueous solution of incompatible drug substance. Further, the syrup composition may be used as a pediatric formulation and thus, it will increase patient compliance.
The syrup composition of the present invention comprising Levocetirizine dihydrochloride and Montelukast sodium showed unexpected, surprising and enhanced effects. Therefore, the said syrup composition is a synergistic composition and not a mere admixture. The syrup composition has better and improved patient compliance and minimum interaction with active agents.
The use of the terms, "synergistic" and "synergistically effective," are used in the present invention to mean a biological effect created from the application of two or more agents to produce a biological effect that is greater than the sum of the biological effects produced by the application of individual agents.
EXAMPLES
The invention is illustrated by the following examples which are not meant to restrict the scope of the invention in any manner
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined. In the examples, "part" and "parts" mean "part by weight" and "parts by weight", respectively, unless otherwise specified.
General Procedure of manufacturing of Levocetirizine dihydrochloride and Montelukast sodium syrup
1) Collect water in a vessel, Add Liquid syrup base (which is a mixture of solublilizer,
Glycerin and water). Mix well heat at 60 °C.
2) Stir and add Montelukast Sodium using mechanical stirrer.
3) Add the preservative solution into the above solution

4) Add Levocetirizine dihydrochloride and mix well.
5) Optionally add Colouring or flavouring agent.
6) Make up the volume up to 10000 ml with purified water
7 ) Pass the solution through 200 # sieve and fill into amber coloured PET bottle.
EXAMPLE 1
Example 2
Example 3
(Table Removed)
* The values are added to compensate for Assay and LOD of Levocetirizine dihydrochloride and Montelukast sodium .
Example 4
1) Strength of Syrup
a) Each 5 ml contains
Levocetirizine dihydrochloride 2.5 mg
Montelukast sodium
Equivalent to Monteluksat 4 mg
Flavoured syrup base q.s.
Color : Quinoline yellow and Erythrocin supra Flavour : Mixed Fruit
b) Each 5 ml contains
Levocetirizine dihydrochloride 2.5 mg
Montelukast sodium
Equivalent to Monteluksat 5 mg
Flavoured syrup base q.s.
Color : Quinoline yellow and Brilliant blue Flavour : Mixed Fruit
2) pH Range: 7.5 to 9.0
3) Description :Yellow colored clear liquid syrup
Example 5: Quality Assessment
Table 1
 Levocetirizine Dihydrochloride 2.5mg & Montelukast 4.0mg Syrup
 Batch Size : 10 Litres
Example 6: Quality Assessment
Table 2
 Levocetirizine Dihydrochloride 2.5mg & Montelukast 5.0mg Syrup
 Batch Size : 10 Litres
 Example 7: STABILITY TEST OF SYRUP COMPOSITION. Table 3
 Storage condition: 40 ± 2°C, 75 ± 5% Relative Humidity Packed in 60 ml Amber Color Pet Bottle
 Each 5ml contains: Montelukast Sodium eq. to Montelukast 4.0 mg & Levocetrizine Dihydrochloride 2.5 mg.
Example 8: STABILITY TEST OF SYRUP COMPOSITION. Table 4
 Storage condition: 40 ± 2°C, 75 ± 5% Relative Humidity Packed in 60 ml Amber Color Pet Bottle
 Each 5ml Contains: Montelukast Sodium eq. to Montelukast 5 mg & Levocetirizine (Table Removed)
Dihydrochloride 2.5 mg
Results: The syrup composition of the present invention comprising Levocetirizine dihydrochloride and Montelukast were found to be stable and under compliance with the required specification even at the accelerated conditions temperature of 40 C and 75% RH (relative humidity) for the period of six months.
It was also noted that the syrup composition according to the present invention has the therapeutic advantage that it can achieve a therapeutically useful effect using lower concentrations of each active component. This, in turn, enables the side-effects of the individual drugs to be minimised and also having patient compliance.
UTILITY
The present invention provides a stable pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium intended for decreasing the symptoms of persistent allergic disorders and improving the quality of life.

We Claim:
1. A pharmaceutical composition in form of aqueous syrup comprising Levocetirizine dihydrochloride and Montelukast sodium together with a pharmaceutically acceptable carrier, diluents or excipient.
2. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup composition is essentially free of sugar.
3. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup composition is physicochemically stable after storage for a period up to 24 weeks at a temperature of 40°C or below, the residual amount of Levocetirizine dihydrochloride and Montelukast sodium is 90% or more of the initial Levocetirizine dihydrochloride and Montelukast sodium concentration.
4. The pharmaceutical composition as claimed in Claim 1, wherein the amount of Levocetirizine dihydrochloride is present in ranges from about 0.01% to about 1%, preferably from about 0.02% to about 0.2%, most preferably from about 0.05% to about 0.1%, and in particular is about 0.05%.
5. The pharmaceutical composition as claimed in Claim 1, wherein the amount of Montelukast sodium is present in ranges from about 0.01% to about 1%, preferably from about 0.02% to about 0.5%, most preferably from about 0.05% to about 0.2%, and in particular is about 0.08% to about 0.10%.
6. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup composition have a pH from about 7 to about 11, preferably from about 7.50 to about 9 and most preferably from about 7.75 to about 8.75.
7. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup composition comprise a pharmaceutically acceptable carrier, diluents or excipient such as sweetening agents, flavouring substances, solubility enhancers, viscosity

regulating agents, colouring agent, preservative, buffering agent, water and the like additives.
8. The pharmaceutical composition as claimed in Claim 1, wherein the pH of the composition maintained by addition of a buffer system comprise mixtures of appropriate amounts of an acid such as phosphoric, acetic acid, glacial acetic acid, succinic, tartaric, lactic, or citric acid, and a base, in particular sodium hydroxide or disodium hydrogen phosphate.
9. The pharmaceutical composition as claimed in Claim 1 or 6 or 8, wherein the desired pH range is obtained using a tartaric, acetic acid and sodium hydroxide buffer.
10. The pharmaceutical composition as claimed in Claim 1 or 7, wherein the said syrup composition comprising one or more sweetening agents and/or flavouring agents.
11. The pharmaceutical composition as claimed in Claim 7 or 10, wherein the said syrup composition comprise one or more sweetening agents such as sucralose, saccharin sodium, calcium saccharin, acesulfame potassium or sodium cyclamate in the range from about 0.04% to about 0.15%, in particular is about 0.1%.
12. The pharmaceutical composition as claimed in Claim 7 or 10, wherein the said syrup composition comprise one or more flavouring substances like fruit flavours such as cherry, raspberry, black currant or strawberry flavour, or stronger flavours, such as Caramel Chocolate flavour, Mint Cool flavour, Fantasy flavour and the like, or combination thereof in the total concentration in range from about 0.01% to about 1.0 %, preferably from about 0.03% to about 0.8% and most preferably from about 0.05% to about 0.4 %.
13. The pharmaceutical composition as claimed in Claim 7 or 10 or 12, wherein the said syrup composition comprise flavouring substances as combination of two cherry flavours in the total concentration in range from about 0.01% to about 1.0 %,
preferably from about 0.03% to about 0.8% and most preferably from about 0.05% to about 0.4 %.
14. The pharmaceutical composition as claimed in Claim 1 or 7, wherein the said syrup composition comprise a preservative selected from the group comprise benzoic acid, sorbic acid, methylparaben, propylparaben, imidazolidinyl urea, diazolidinyl urea, phenoxetol, benzyl alcohol, quaternary compounds such as benzylalkonium chloride, and the like, most preferably preservative is benzoic acid.
15. The pharmaceutical composition as claimed in Claim 7 or 14, wherein the concentration of the preservatives range from about 0.05% to about 1%, particularly from about 0.1% to about 0.5%, and most particularly is about 0.2%).
16. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup composition comprises:

(a) about 0.02% to about 0.5%) Levocetirizine dihydrochloride;
(b) about 0.02 to about 0.5 % Montelukast sodium;
(c) about 0.1%) to about 0.5% preservatives;
(d) a suitable amount of buffer to adjust the pH in the range from 7 to 9; and
(e) water q.s. ad 100%.
17. The pharmaceutical composition as claimed in Claim 1, wherein the said syrup
composition comprises:
(a) about 0.05 % Levocetirizine dihydrochloride;
(b) about 0.08 to 0.1% Montelukast sodium;
(c) about 0.1%o Sodium methylparaben ;
(d) Sodium citrate and sufficient sodium hydroxide 1 N to adjust the pH in the range from 7 to 9; and
(e) water q.s. ad 100%.

18. A process of preparing syrup composition comprising Levocetirizine dihydrochloride and Montelukast sodium as claimed in claim 1, wherein the process comprises the following steps:
a) heating base with solubilizer, preservative and Montelukast sodium, followed
by cooling,
b) diluting the solution with about an equal amount of water,
c) adding the buffer and the active ingredient Levocetirizine dihydrochloride
thereto,
d) stirring the mixture until complete dissolution and cooling the solution to room
temperature,
e) adjusting the pH with the base component of the buffer and further diluting the
solution with water to the required end-volume, and
f) optionally, one or more sweetening agents and flavouring substances may be added during these process steps to obtain a final syrup composition.