DESC:FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutical compositions. Particularly, the present invention relates to ? stable pharmaceutical composition in the form of aqueous syrup comprising Desloratadine and Montelukast Sodium, which is essentially free of sugar.

TECHNICAL FIELD

The present invention is directed towards obtaining a combination of Desloratadine (or a pharmaceutically acceptable salt, an ester, a solvate) and Montelukast (or a pharmaceutically acceptable salt, an ester, a solvate, a derivative), that provides the desired effect starting from the synergic effect of the said agents in anti-allergic and anti-inflammatory treatments.
Desloratadine, a metabolic derivative of Loratadine is a long acting tricyclic antihistamine with selective Hi -receptor antagonist activity. Desloratadine is chemically 8-chloro-6, l 1-dihydro-l l-(4-piperidylidene)-5H-benzo[5,6]-cyclohepta 1,2- b]pyridine. U.S. Patent No. 4,659,716 discloses Desloratadine possessing antihistaminic properties with substantially no sedative properties.
Montelukast and the known pharmaceutically acceptable salts thereof are leukotriene receptor antagonists used for the treatment of asthma and for relieving the symptoms of the seasonal allergies. Montelukast is a CysLTl antagonist, which blocks the activity of leukotriene D4 on the leukotriene receptor CysLTl in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction caused by the leukotriene, thereby resulting in less inflammation.
OBJECTIVE OF THE INVENTION
The present invention relates to the field of pharmaceutical compositions. Particularly, the present invention relates to ? stable pharmaceutical composition in form of aqueous syrup comprising Desloratadine and Montelukast Sodium, which is essentially free of sugar.
An important goal in formulating liquid pharmaceutical compositions is minimizing the degradation of active ingredients by using antioxidants and chelating agents and entrapment of one active ingredient with the help of viscosity polymers, thus enabling better stability and patient compliance of Desloratadine and Montelukast Sodium syrup.
Another object of the present invention is to provide a syrup composition with reduced bitter taste of Desloratadine drug using bitter taste masker in combination with different flavors.
DETAILED DESCRIPTION OF THE INVENTION
According, the present invention provides a stable pharmaceutical composition in the form of aqueous syrup for oral administration comprising Desloratadine and Montelukast sodium together with pharmaceutically acceptable carrier, diluents or excipient, wherein there is minimum interaction between Desloratadine and Montelukast sodium. Bitter taste of Desloratadine drug is masked by taste masker in combination with flavors to improve taste and compliance to patient.
Desloratadine is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. Chemically (+)-(1S, 2S)-2-methylamino-1-phenylpropan-1-ol, is an orally effective sympathomimetic nasal decongestant.
Desloratadine and its compositions are prone to oxidation and decomposition by acidic environment to form impurities such as Deschlorodesloratadine, Dehydrodesloratadine and N-formyldesloratadine.
The present invention relates to obtaining a combination of Desloratadine (or pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof) and Montelukast (or pharmaceutically acceptable, salt, ester, solvate, derivative, polymorph or hydrate thereof) to prepare a combination that provides desired effect starting from the synergistic effect of Desloratadine and Montelukast on anti-allergic and anti-inflammatory treatment. However, the course of the research carried out for this purpose, as mentioned before, stability problems for each of the components have raised. It is necessary to develop a stable pharmaceutical composition and a method of production thereof to obtain a combination of Montelukast and Desloratadine that would provide the desired effect.
In one the embodiment the syrup composition of present invention is essentially free of sugar.
As mentioned before, Montelukast sodium is poorly soluble in water. If Montelukast sodium is mixed under normal conditions, it causes precipitation of Montelukast Sodium, which is insoluble in water. In the present invention, emulsion of Montelukast sodium has been prepared using Polyoxyhydrogenated castor oil (Acrysol K-140) separately and Desloratadine is entrapped in the aqueous phase with Polymer PVPK-30 and HPMC K4-M or PEG 400 along with antioxidant sodium metabisulphite alone or in combination with synergistic agents (chelating agent) disodium EDTA, whose role is to form complex of heavy metals catalyzing the oxidation process. This technique may be used to prepare aqueous solution of unstable drug substance.
In one of the embodiment, the syrup composition of the present invention comprising Desloratadine and Montelukast sodium together with an alkali to maintain the pH in the range of 6 to 9.
Herein, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total volume of the formulation.
In one of the embodiment, the amount of Desloratadine is present in range from 0.050% to 0.105% and the amount of Montelukast sodium is present in range from 0.08% to 0.21% by weight of the total composition.
In one of the embodiment, the syrup composition according to the present invention has a pH from about 6 to about 10, preferably from about 6 to about 9 and most preferably from about 6.0 to about 7.6. The pH of the composition may be maintained on the addition of a pH adjusting agent. The desired pH range is advantageously obtained using a citric acid, tartaric acid, acetic acid and sodium hydroxide buffer.
Antioxidants are included in pharmaceutical solutions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation. Typically antioxidants are molecules that are redox systems that exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Typically in aqueous solution antioxidants are oxidized (and hence, degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition. Examples of antioxidants that are commonly used include sodium sulphite, sodium metabisulphite, antioxidant sodium metabisulphite alone or in combination with synergistic agents (chelating agent) disodium EDTA at a concentration of 0.02% whose role is to form complex of heavy metals catalyzing the oxidation process sodium formaldehyde sulphoxylate and ascorbic acid. Examples of antioxidants that may be used in oil-based solutions include: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl gallate. Typically, antioxidants are employed in low concentrations (0.01% w/w) and it is usual for the concentration of antioxidant in the finished product to be markedly less than the initial concentration, due to oxidative degradation during manufacture of the dosage form.
In order to prevent growth of micro-organisms such as bacteria, yeasts and fungi in the subject compositions, a preservative agent is added. Suitable preservatives should be physicochemical stable and effective in the pH range mentioned above. Preservatives may be selected from a group comprising but not limited to benzoic acid, sorbic acid, methylparaben, propylparaben, imidazolidinylurea and diazolidinyl, phenoxetol, benzyl alcohol, quaternary compounds, e.g. benzylalkonium chloride, and the like. Some preservatives, such as benzoic acid, sorbic acid, and benzyl alcohol, have the advantage that they yield clear, transparent solutions which do not show any clouding upon storage. The concentration of the preservatives may range from 0.015% to 1%, particularly from 0.1% to 0.5%, and most particularly is about 0.2%.
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 a 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.
The bitter taste of Desloratadine and Montelukast Sodium and the unpleasant taste masked by the presence of one or more sweetening agents such as Sucralose, Aspartame, Sodium saccharin. The concentration of the sweetening agent may range from about 0.04% to about 0.15% and in particular is about 0.1%. The palatability of the subject solutions may further be optimized by adding of one or more flavoring substances. Suitable flavoring substances are such as American ice cream, cherry, raspberry, black currant or strawberry flavor, or stronger flavors, such as caramel chocolate flavor, mixed fruit, mint cool flavor, fantasy flavor and the like. Combinations of flavors are advantageously used. A combination of two cherry flavors was found to yield very good taste masking results in the present compositions. The total concentration of the flavoring 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 0.02% to about 0.4 %,
In one of the embodiments, the aqueous syrup composition of the present invention may be stored at room temperature or below 25°C. It should not 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 Desloratadine and Montelukast syrup as described herein above, characterized by dissolving the active ingredient Desloratadine and Montelukast sodium, the preservative, and the acid and base components in water.
In particular, the process comprises the following steps: A process of preparing syrup composition comprising Desloratadine and Montelukast sodium as claimed in claim 1, wherein the process comprises the following steps: (a) Heating Montelukast sodium followed by cooling, (b) Entrapment of Desloratadine in aqueous solution with Polymer PVPK-30, xanthum gum, PEG-400 and HPMC K4-M along with antioxidant sodium metabisulphite alone or in combination with synergistic agents (chelating agent) disodium EDTA whose role is to form complex of heavy metals catalyzing the oxidation process, (c) diluting the solution with about an equal amount of water, (d) stirring the mixture until complete dissolution and cooling the solution to room temperature, (e) adjusting the pH with citric acid and further diluting the solution with water to the required end-volume, and (f) optionally, one or more sweetening agents and flavoring substances may be added during these process steps to obtain a final syrup composition.
Surprisingly, the inventors of the present invention have found that the present invention provides a stable pharmaceutical composition in form of aqueous syrup comprising Desloratadine and Montelukast sodium wherein there is minimum interaction between Desloratadine and Montelukast sodium. The syrup system according to the present invention does not permit Desloratadine and Montelukast sodium to interact. 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 Desloratadine and Montelukast sodium showed unexpected, surprising and enhanced effects. Therefore, the said syrup composition is a synergistic composition. 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 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.
Example 1:- Montelukast Sodium and Desloratadine Syrup with different flavour.
Indigents Batch (1.0 L) Batch (1.0 L) Batch (1.0 L) Quantity, %
Montelukast Sodium* 0.800 gm 0.800gm 0.800 gm 0.080 %
Acrysol K-140 35.0 gm 35.0 gm 35.0 gm 3.5 %
Desloratadine* 0.500gm 0.500 gm 0.500gm 0.050%
Propylene Glycol 25.0 gm 25.0 gm 25.0 gm 2.5%
Sodium Metabisulfite 0.5 gm 0.5 gm 0.5 gm 0.05%
Disodium EDTA 0.20gm 0.20 gm 0.20 gm 0.02%
Sodium Methyl Paraben 2.0 gm 2.0 gm 2.0 gm 0.2%
Sodium Propyl Paraben 0.2 gm 0.2 gm 0.2 gm 0.02%
PVPk-30 25 gm 25 gm 25 gm 2.5%
HPMC-K-4M 1.0 gm 1.0 gm 1.0 gm 0.01%
Glycerin 25.0gm 25.0gm 25.0gm 2.5%
Xanthan Gum 0.5gm 0.5gm 0.5gm 0.05%
Sorbitol-70% 400 gm 400 gm 400 gm 40.0%
Citric Acid Anhydrous 0.855gm 0.855gm 0.855gm 0.085%
Masking flavor ID 22068 2.0 gm 2.0 gm 2.0 gm 0.02%
American ice cream 4.0 gm Nil Nil 0.4%
Mixed fruit flavor Nil 4.0 gm Nil 0.4%
Orange flavor Nil Nil 4.0 gm 0.4%
Tartrazine Supra 0.02gm 0.02gm 0.02gm 0.002%
Sucralose 0.125 gm 0.125 gm 0.125 gm 0.0125%
Purified Water q.s to 1.0 Litre q.s to 1.0 Litre q.s to 1.0 Litre ---
pH 7.50 7.50 7.50
*The potency calculation for assay and LOD of Montelukast Sodium and Desloratadine to be done
Example 2:- Formula of Montelukast Sodium and Desloratadine Syrup
Indigents Batch (1.0 L) Quantity, %
Montelukast Sodium* 0.800 gm 0.080 %
Acrysol K-140 35.0 gm 3.50 %
Desloratadine* 0.500 gm 0.050 %
Propylene Glycol 25.0 gm 2.5%
Sodium Metabisulfite 0.50 gm 0.05%
Disodium EDTA 0.20gm 0.02%
Sodium Methyl Paraben 2.00 gm 0.20%
Sodium Propyl Paraben 0.20 gm 0.020%
PVPk-30 25.00 gm 2.5%
HPMC-K-4M 1.00 gm 0.01%
Glycerin 25.00gm 2.50%
Xanthan Gum (Clear) 0.50gm 0.05%
Sorbitol-70% 400 gm 40%
Citric Acid Anhydrous 0.855gm 0.085%
Masking flavour ID 22068 2.00 gm 0.02%
American ice cream 2.00 gm 0.02%
Tartrazine Supra 0.010gm 0.001%
Sucralose 0.125 gm 0.012%
Purified Water q.s to 1.0 Litre ---
pH 7.51
*The potency calculation for assay and LOD of Montelukast Sodium and Desloratadine to be done
Example 3:- Formula of Montelukast Sodium and Desloratadine Syrup
Indigents Batch (1.0 L) Quantity, %
Montelukast Sodium* 0.80 gm 0.080 %
Acrysol K-140 20.00 gm 2.00 %
Desloratadine* 0.50 gm 0.050 %
Propylene Glycol 30.00 gm 3.00%
Sodium Metabisulfite 2.00 gm 0.20%
Disodium EDTA 0.30gm 0.03%
Sodium Methyl Paraben 2.00 gm 0.20%
Sodium Propyl Paraben 0.20 gm 0.020%
PEG-400 80.00 gm 8.00
Glycerin 25.00gm 2.50%
Xanthan Gum (Clear) 1.00 gm 0.1%
Sorbitol-70% 400.00 gm 40.00%
Citric Acid Anhydrous 0.85gm 0.085%
Masking Flavour ID 22068 2.0 gm 0.02%
Tartrazine Supra 0.05gm 0.005%
Sucralose 0.30 gm 0.03%
American ice cream flavor 4.00gm 0.40%
Masking flavor 4.00gm 0.40%
Purified water q.s to 1.0 Liter ---
pH 7.0

*The potency calculation for assay and LOD of Montelukast Sodium and Desloratadine to be done
Example 4:- Formula of Montelukast Sodium and Desloratadine Syrup
Indigents Batch (1.0 L) Quantity, %
Montelukast Sodium* 0.80 gm 0.080 %
Acrysol K-140 2.75 gm 0.275%
Disodium EDTA 0.20gm 0.02%
Desloratadine* 0.50 gm 0.05 %
Propylene Glycol 40.00 gm 4.00%
Sodium Metabisulfite 0.20 gm 0.02%
Sodium Methyl Paraben 2.00 gm 0.20%
Sodium Propyl Paraben 0.20 gm 0.020%
PVP K-30 10.00gm 1.00%
Xanthan Gum (Clear) 1.00 gm 0.1%
Sorbitol-70% 400.00 gm 40.00%
Citric Acid Anhydrous 0.90gm 0.09%
Tartrazine Supra 0.05gm 0.005%
Sucralose 0.30 gm 0.03%
American ice cream flavor 4.00gm 0.40%
Masking flavor ID 22068 4.00gm 0.40%
Purified water q.s to 1.0 Liter ---
pH 6.6

*The potency calculation for assay and LOD of Montelukast Sodium and Desloratadine to be done.
General Procedure of manufacturing of Desloratadine and Montelukast sodium syrup
a) Take base sorbitol 70% and add sodium metabisulphite, disodium EDTA water solution under stirring and mix well.
b) Dissolve Desloratadine in Propylene Glycol separately at a temperature of 50- 60 °C followed by entrapping in aqueous solution with Polymer HPMC K4M and or PVPK-30 or PEG 400 under continuous mixing for 1 hour and finally cool up to 30-35 °C; then, transfer the solution to Step 1 under stirring and mixing.
c) Heat Acrysol K-140 up to 70- 80 °C and dissolve Montelukast sodium into it under continuous stirring and cool up to 30-35 °C followed by adding the preservative solution.
d) Transfer Step 3 solution into Step 1 solution under continuous stirring and mix for 1 hour.
e) Soak and mix xanthum gum clear in glycerine under stirring and transfer to Step 1 solution.
f) Add sweetener, bitter taste masker and flavouring agent to Step 1 solution under stirring.
g) Add colouring agent into Step 1 solution under continuous stirring.
h) Adjust the pH using citric acid up to desired range.
i) Make the desired volume with purified water.
j) Pass the solution through 200 # sieve and fill into amber coloured PET bottle.

WE CLAIM:

1. A pharmaceutical composition in form of aqueous syrup comprising Desloratadine and Montelukast Sodium together with pharmaceutical acceptable carriers, solvent or excipients, wherein the amount of Desloratadine is present in the range 0.050% to 0.105% and the amount of Montelukast sodium is present in the range from 0.08% to 0.21% by weight of the total composition.

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 pharmaceutically acceptable carrier, diluents or excipients are selected from a group comprising sweetening agents, flavoring substances, taste masking agents, solubility enhancers, viscosity regulating agents, coloring agent, antioxidant preservative, chelating agents, buffering agent and water.

4. The pharmaceutical composition as claimed in claim 1, wherein the concentration of antioxidant butylated hydroxytoluene, butylated hydroxyanisole, DL-alpha-tocopherol, propyl gallate, octylgallate, ascorbyl palmitate, acetyl cysteine, ascorbic acid, sodium ascorbate, fumaric acid, lecithin, Sodium Metabisulfite, sodium sulfite is in the range 0.02 to 5.0% by weight of total composition.

5. The pharmaceutical composition as claimed in claim 3, wherein the concentration of chelating agent disodium EDTA is in the range of 0.1 to 2% by weight of total composition.
6. The pharmaceutical composition as claimed in claims 1 or 3, wherein the concentration of sweetening agent, 70% sorbitol aqueous solution, glycerin and xylitol range 2.0 to 50% by weight of total composition.

7. The pharmaceutical composition as claimed in claims 1 or 3, wherein the concentration of thickening agents, xanthan gum, PVPK-30, PVPK-90, PEG 400, hydroxyethyl cellulose, methyl cellulose, sodium Carboxymethyl cellulose, Hydroxy propyl cellulose, Hydroxyl propyl methylcellulose K4 M, K100 M, and a water-soluble Carboxyvinyl polymer range 0.01% to 10.0%.

8. The syrup formulation as claimed in claim 1, wherein the said syrup composition has a pH from 6 to 10.

9. The pharmaceutical composition as claimed in claims 1 or 3 or 7, wherein the desired pH range using tartaric acid, citric acid, malic acid, acetic acid, glacial acetic acid, lactic acid and disodium hydrogen phosphate.

10. The pharmaceutical composition as claimed in claims 1 or 3, wherein the said syrup composition comprises a preservative selected from the group comprising benzoic acid, sorbic acid, methyl paraben sodium, propyl paraben sodium, imidazolidinylurea, benzyl alcohol, quaternary compounds such as benzalkonium chloride.

11. The pharmaceutical composition as claimed in claims 1 or 3, wherein the concentration of preservative ranges 0.05% to 1.0% by weight of total composition.
12. The pharmaceutical composition as claimed in claims 1 or 3, wherein said the syrup composition comprises one or more flavoring substance like American ice cream, Kiwi flavor, raspberry black berry, strawberry, mint cool flavor, lemon, orange, peppermint and lemon grass, essential oils in range from 0.01% to 2.0%, masking flavor ID 22068, bitter taste masker 501522S.

13. The pharmaceutical composition as claimed in claim 1, wherein the said syrup composition comprises:
a) 0.0500% to 0.105% Desloratadine
b) 0.08 to 0.21% Montelukast sodium
c) 0.1 to 0.3 % Sodium Methyl paraben
d) 0.01% to 0.04% Sodium Propyl paraben
e) 0.02 to 0.3% Sodium Metabisulfite
f) 0.01to 0.1% Disodium EDTA
g) Citric acid to adjust the pH in range from 6.0 to 10.0
h) Water q.s to 100%.
14. A process of preparing the syrup composition comprising Desloratadine and Montelukast sodium as claimed in claim 1, wherein the process comprises the following steps:
a) take base sorbitol 70% and add sodium metabisulphite, disodium EDTA water solution under stirring and mix well;
b) dissolve Desloratadine in Propylene Glycol separately at temperature of 50- 60°C followed by entrapping in aqueous solution with polymer HPMC K4M and or PVPK-30 or PEG 400 under continuous mixing for 1 hour and finally cool up to 30-35°C; then, transfer the solution to step 1 under stirring and mixing;
c) heat Acrysol K-140 up to 70- 80°C and dissolve Montelukast sodium into it under continuous stirring and cool up to 30-35°C followed by adding the preservative solution;
d) transfer the Step 3 solution into Step 1 solution under continuous stirring and mix for 1 hour;
e) soak and mix xanthum gum clear in glycerine under stirring and transfer to Step 1 solution;
f) add sweetener, bitter taste masker and flavouring agent to Step 1 solution under stirring;
g) add colouring agent into Step 1 solution under continuous stirring;
h) adjust the pH using citric acid up to the desired range;
i) make up the desired volume with purified water; and
j) pass the solution through 200 # sieve and fill into amber coloured PET bottle.