The present invention concerns the stable pharmaceutical formulations comprising montelukast or the salts thereof. TECHNICAL FIELD

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.

Because of its mechanism of action, montelukast is not able to be used in the treatment of the acute asthma attacks. Moreover, due to this specific mechanism of action, it is also unable to interact with the known asthma medications.

Montelukast is generally used in the sodium salt form and is commercially available in film coated tablet, powder granule or chewable tablet form.

However, the low dissolution rate of the montelukast tablets according to the state of the art causes the active agent to exhibit its action with delay. Consequently, there is a need for the montelukast formulations that are rapidly dispersed and that exhibit biological action in a rapid manner. Moreover, the elderly and child patients or the patients with difficulty in swallowing are not able to efficiently use the known dosage forms of tablet and chewable table, which in turn affects the efficacy of the treatment. The powder granule formulation is used for the pediatric patients wherein it is administered in a glass of water or by way of addition to the foods. The difficulty of administration is involved for the pediatric patients due to the great volume of the solution prepared. When prepared along with the foods, there exists the necessity to consume all the added food in order to attain an effective dosing. Another problem encountered in the formulations comprising montelukast is that montelukast is not stable enough and it degrades very rapidly particularly in the moist environments. Due to said problem of stability, the problems are faced in preparing the liquid forms that comprise montelukast or the salts thereof. SUMMARY OF THE INVENTION

The present invention relates to the formulations in liquid form, which comprise montelukast or a pharmaceutically acceptable salt thereof as the active ingredient.

The formulations in liquid form according to the present invention comprise montelukast or a pharmaceutically acceptable salt thereof as the active ingredient and also at least one auxiliary substance selected from the group comprising the buffering agent, solvent, preservative, sweetening agent, flavoring agent, pH adjusting agent and surfactant.

Montelukast sodium is preferably used as the active ingredient in the formulation according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

The present invention aims, through the preparation of the stable and liquid-form formulations comprising montelukast sodium, to provide a solution for the problems of difficulty in swallowing faced by various patient groups, of delayed biological action as a result of prolonged dispersion observed in tablet forms, of the difficulties in the preparation and administration of the powder granule form, and of the degradation of montelukast sodium.

The present invention solves the problems mentioned above by utilizing a solvent or solvent combination comprising at least one -OH group in the formulation in liquid form. Accordingly, the liquid formulations according to the present invention comprising montelukast sodium comprise as the auxiliary substance an organic solvent or solvent mixture having at least one -OH group. The solvent according to the present invention is selected from the group comprising ethanol, propanol, ethylene glycol, 1,4-butanediol, butanol, 2-butanol, N-butanol, tert- butyl alcohol, diethylene glycol, furfuryl alcohol, glycerol, isobutanol, isopropyl alcohol, methanol, neopentyl alcohol, 2-pentanol, 1,3-propanediol, 1 -propanol, propylene glycol or two- or three-component combinations of the solvents mentioned above. Preferably, propylene glycol and/or glycerol is/are used, and particularly preferably, a combination of propylene glycol and glycerol is used as the solvent in the formulations according to the present invention.

The solvent is present in said formulation at a quantity of 10 to 95% by weight, based on the total weight of the formulation.

In case the combination of propylene glycol and glycerol is used as the solvent, propylene glycol is present in said formulation at a quantity of 20-95% by weight, while glycerol is present in said formulation at a quantity of 5-40% by weight, based on the total weight of the formulation. The buffering agent is selected from the group comprising sodium carbonate, sodium hydrogen carbonate, sodium phosphate and sodium hydrogen phosphate, potassium phosphate and potassium hydrogen phosphate. Potassium hydrogen phosphate is preferably used as the buffering agent in the formulation according to the present invention. The buffering agent is present in the formulation according to the present invention at a quantity in the range of 0.1-0.7% by weight, based on the total weight of the formulation.

The preservative may be selected from the group comprising benzoic acid, sodium benzoate, lactic acid, nitrite, nitrate, propionic acid, sodium propionate, sulfur dioxide, sorbic acid and sodium sorbate. Sodium benzoate is preferably used as the preservative agent in the formulation according to the present invention. The preservative is present in the formulation according to the present invention at a quantity in the range of 0.05-0.5% by weight, based on the total weight of the formulation.

The sweetening agent may be selected from the group comprising aspartam, dextrose, fructose, mannitol, sodium saccharin, sorbitol, sucralose, sucrose and glucose. Sodium saccharin is preferably used as the sweetener. The sweetening agent is present in the formulation according to the present invention at a quantity in the range of 0.005 - 0.15% by weight, based on the total weight of the formulation.

A flavoring agent such as lemon, vanillin, strawberry, banana, caramel, etc. may be present in the formulation according to the present invention. Said flavoring agent is present in the formulation according to the present invention at a quantity in the range of 0.005 - 0.5% by weight, based on the total weight of the formulation.

The pH adjusting agent is selected from the group comprising carbonic acid, sodium bicarbonate, citric acid, citric acid monohydrate and acetic acid. Citric acid monohydrate is preferably used as the pH adjusting agent. The pH adjusting agent is used in the formulation according to the present invention at a quantity in the range of 0.02 - 0.2% by weight, based on the total weight of the formulation.

The surfactant is selected from the group comprising sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, alkyl benzene sulfonate, benzalconium chloride, phosphatidyl serine, phosphatidyl choline, polysorbate and dodecyl dimethylamine oxide. Sodium lauryl sulfate is used as the surfactant in the formulations according to the present invention. The use of said auxiliary agent in the formulations according to the present invention has been observed to enable montelukast sodium to be effectively dissolved in the solvent, thereby obtaining a formulation with higher bioavailability as compared to the formulations of the state of the art. The surfactant is used in the formulation according to the present invention at a quantity in the range of 0.5 - 5% by weight, based on the total weight of the formulation.

The formulations according to the present invention may, in addition to the aforesaid solvent having at least one -OH group, also comprise deionized water.

Montelukast sodium to be used in the formulations according to the present invention may be in amorphous or crystalline form. In case crystalline form is used, any polymorph existing in the state of the art may be employed in the formulation according to the present invention. In another aspect, the present invention relates to the formulations comprising montelukast sodium at a ratio of 0.01-0.2% by weight, a surfactant at a ratio of 0.5- 5% by weight, a buffering agent at a ratio of 0.1-0.7% by weight, a solvent at a ratio of 10-95% by weight, a preservative at a ratio of 0.05-0.5 by weight, a sweetening agent at a ratio of 0.005-0.15% by weight, a flavoring agent at a ratio of 0.005-0.5% by weight and a pH adjusting agent at a ratio of 0.02-0.2% by weight.

According to a preferred form of the invention, said formulation comprises montelukast sodium at a ratio of 0.01-0.2%, sodium lauryl sulfate at a ratio of 0.5-5%, potassium hydrogen phosphate at a ratio of 0.1-0.7%, propylene glycol and glycerol combination at a ratio of 10-95%, sodium benzoate at a ratio of 0.05-0.5%, saccharin at a ratio of 0.005-0.15%, lemon flavor at a ratio of 0.005-0.5% and citric acid monohydrate at a ratio of 0.02-0.2%.

The formulations according to the present invention are manufactured via the methods known in the art. The steps such as dry mixing, dry granulation, wet granulation, compaction, drying, etc. may be employed during the manufacture.

The formulations according to the present invention may be used in forms such as syrup, liquid in soft capsules or liquid in hard capsules, liquid in single-dose vials or liquid in multi-dose vials, etc. Multiple doses may be used in a single dosage form or the single dose may be used in a single dosage form. According to a preferred embodiment of the invention, the pharmaceutical formulations described above comprise, in addition to montelukast sodium employed as the active ingredient, at least one active ingredient belonging to the group of antihistamines selected from the group comprising azelastine, bilastine, brompheniramine, cetirizine, desloratadine, doxylamine, ebastine, fexofenadine, levocetirizine, loratadine, pheniramine, promethazine, pyrilamine or pharmaceutically acceptable salts thereof. In a preferred embodiment, levocetirizine is used as the active ingredient of antihistamine group in said combination. In another preferred embodiment of the invention, desloratadine is used as the active of antihistamine group in said combination. Herein the term "levocetirizine" should be construed to mean all pharmaceutically available derivatives of levocetirizine, for example levocetirizine dihydrochloride. Thus the terms "levocetirizine" and "levocetirizine dihydrochloride" are referring the same structure and can be used interchangeably. A formulation example according to the present invention is presented in the following table.

In case said pharmaceutical composition comprises a second active ingredient selected from the aforesaid group, e.g. levocetirizine, in addition to montelukast, levocetirizine and at least one auxiliary substance, e.g. a diluent, are used at the quantities indicated below. Lactose monohydrate is preferably used as the diluent. It is possible to add, during the manufacture, the mix formed by the second active ingredient and at least one auxiliary substance to the mix comprising montelukast sodium, while it is also possible to separately prepare and store the same in a reservoir cap wherein said mix may be added by the patient to the montelukast-containing mix prior to use. An example for the levocetirizine formulation according to the present invention is given in the following table.

In another embodiment of the invention, in case said pharmaceutical composition comprises desloratadine, which is a second active ingredient selected from the group of antihistamines, in addition to montelukast, desloratadine and at least one auxiliary substance, e.g. a diluent, are used at the quantities indicated below. Maltitol is preferably used as the diluent. It is possible to add, during the manufacture, the mix formed by the second active ingredient and at least one auxiliary substance to the mix comprising montelukast sodium, while it is also possible to separately prepare and store the same in a reservoir cap wherein said mix may be added by the patient to the montelukast-containing mix prior to use. An example for the desloratadine formulation according to the present invention is given in the following table.

In another aspect, the present invention relates to a therapy kit containing together a formulation that comprises montelukast sodium and a formulation that comprises levocetirizine. Said kit contains

• a pharmaceutical composition comprising montelukast sodium in an organic solvent or solvent mixture having at least one -OH group and

· a dry powder mix comprising levocetirizine and at least one auxiliary substance, preferably a diluent, especially preferably lactose monohydrate, wherein said kit is characterized in that the liquid formulation comprising montelukast sodium is present in a bottle and the dry powder formulation of levocetirizine is present in a reservoir inside the bottle cap.

In another aspect, the present invention relates to a therapy kit containing together a formulation that comprises montelukast sodium and a formulation that comprises desloratadine. Said kit contains

• a pharmaceutical composition comprising montelukast sodium in an organic solvent or solvent mixture having at least one -OH group and

• a dry powder mix comprising desloratadine and at least one auxiliary substance, preferably a diluent, especially preferably maltitol wherein said kit is characterized in that the liquid formulation comprising montelukast sodium is present in a bottle and the dry powder formulation of desloratadine is present in a reservoir inside the bottle cap.

The formulations in liquid form according to the present invention are to be used in the manufacture of a medication effective for treating the persistent asthma or relieving the asthma symptoms accompanied by the seasonal allergic rhinitis and perennial allergic rhinitis or the seasonal allergic rhinitis.

In another aspect, the present invention relates to a method for use in the manufacture of the formulations described above. Said method comprises the following steps; i. The solvent or solvents 1 and 2 is/are mixed by heating at a temperature in the range 40-60 C in the primary vessel,

ii. The surfactant is added to the mixture in the primary vessel and dissolved by way of stirring,

iii. The preservative is dissolved in some water in a separate vessel and is added to the solution in the primary vessel obtained in step ii and is stirred, iv. The chelating agent, sweetening agent and buffering agent are dissolved in some water in a separate vessel and added to the mixture in the primary vessel, v. Butylhydroxytoluene is added to ethanol, stirred, added to the primary vessel and stirred,

vi. The flavoring agent is added to the mixture in the primary vessel and stirred, vii. The resulting mixture is completed to the respective volume with water. According to another embodiment of the invention, the solvent or solvents is/are mixed by heating at a temperature of 45 C.

The example illustrating the present invention is presented below, but the scope of the invention is not limited to the example provided below. EXAMPLE 1 : Montelukast and Levocetirizine Syrup Formulation

Propylene glycol and glycerol are mixed by heating to about 45 C in the primary vessel. Sodium lauryl sulfate is added to the primary vessel and is dissolved by stirring. Sodium benzoate is dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel. EDTA disodium, sodium saccharin and potassium hydrogen phosphate are dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel and stirred. Butylhydroxytoluene is dissolved in ethanol in a separate vessel, added to the primary vessel and stirred. The lemon flavor is added to the resulting mixture and stirred. The resulting solution is completed to the respective volume with water.

For the reservoir cap; Lactose monohydrate and levocetirizine dihydrochloride are mixed via the geometric dilution technique and filled into the reservoir cap.

The reservoir cap is used for capping the bottle, which contains the montelukast sodium-containing syrup formulation. In use, the patient adds the levocetirizine powder mixture in the reservoir cap to the montelukast syrup mixture. Example 2: Montelukast Sodium Syrup Formulation

Propylene glycol and glycerol are mixed by heating to about 45 C in the primary vessel. Sodium lauryl sulfate is added to the primary vessel and is dissolved by stirring. Sodium benzoate is dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel. EDTA disodium, sodium saccharin and potassium hydrogen phosphate are dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel and stirred. Butylhydroxytoluene is dissolved in ethanol in a separate vessel, added to the primary vessel and stirred. The lemon flavor is added to the resulting mixture and stirred. The resulting solution is completed to the respective volume with water and filled in the bottles.

EXAMPLE 3: Montelukast and Desloratadine Syrup Formulation

Propylene glycol and glycerol are mixed by heating to about 45 C in the primary vessel. Sodium lauryl sulfate is added to the primary vessel and is dissolved by stirring. Sodium benzoate is dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel. EDTA disodium, sodium saccharin and potassium hydrogen phosphate are dissolved in some water in a separate vessel and the resulting solution is added to the primary vessel and stirred. Butylhydroxytoluene is dissolved in ethanol in a separate vessel, added to the primary vessel and stirred. The lemon flavor is added to the resulting mixture and stirred. The resulting solution is completed to the respective volume with water.

For the reservoir cap;

Maltitol and desloratadine are mixed via the geometric dilution technique and filled into the reservoir cap.

The reservoir cap is used for capping the bottle, which contains the montelukast sodium-containing syrup formulation. In use, the patient adds the desloratadine powder mixture in the reservoir cap to the montelukast syrup mixture.