WO2016140633A1 - Formulations comprising montelukast - Google Patents

Formulations comprising montelukast Download PDF

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Publication number
WO2016140633A1
WO2016140633A1 PCT/TR2016/000029 TR2016000029W WO2016140633A1 WO 2016140633 A1 WO2016140633 A1 WO 2016140633A1 TR 2016000029 W TR2016000029 W TR 2016000029W WO 2016140633 A1 WO2016140633 A1 WO 2016140633A1
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Prior art keywords
formulation
ratio
weight
sodium
solvent
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PCT/TR2016/000029
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French (fr)
Inventor
BERAN Mehmet BERAT
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BERAN Mehmet BERAT
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Publication of WO2016140633A1 publication Critical patent/WO2016140633A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention concerns the stable pharmaceutical formulations comprising montelukast or the salts thereof.
  • 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.
  • montelukast 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • levocetirizine is used as the active ingredient of antihistamine group in said combination.
  • desloratadine is used as the active of antihistamine group in said combination.
  • levocetirizine should be construed to mean all pharmaceutically available derivatives of levocetirizine, for example levocetirizine dihydrochloride.
  • 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.
  • 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.
  • a second active ingredient selected from the aforesaid group e.g. levocetirizine
  • auxiliary substance e.g. a diluent
  • 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.
  • 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
  • kits 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.
  • 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
  • kits • 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.
  • 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,
  • the surfactant is added to the mixture in the primary vessel and dissolved by way of stirring,
  • 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,
  • 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.
  • the solvent or solvents is/are mixed by heating at a temperature of 45 C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the patient adds the desloratadine powder mixture in the reservoir cap to the montelukast syrup mixture.

Abstract

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

Description

FORMULATIONS COMPRISING MONTELUKAST DESCRIPTION
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.
Figure imgf000007_0001
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.
Figure imgf000008_0001
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.
Figure imgf000008_0002
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
Figure imgf000010_0001
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
Figure imgf000011_0001
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
Figure imgf000012_0001
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.

Claims

1. A pharmaceutical composition in liquid form comprising montelukast sodium characterized in that it comprises as the solvent an organic solvent or solvent mixture having at least one -OH group.
2. A pharmaceutical composition according to Claim 1 characterized in that the solvent or solvent mixture 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 and propylene glycol.
3. A pharmaceutical composition according to Claims 1 and 2 characterized in that propylene glycol and/or glycerol is/are used as the solvent.
4. A formulation according to Claims 1 -3 characterized in that the solvent is present at a quantity of 10-95% by weight, based on the total weight of the formulation.
5. A formulation according to Claim 3 characterized in that propylene glycol is present in the formulation at a quantity of 20-95% by weight, while glycerol is present in the formulation at a quantity of 5-40% by weight, based on the total weight of the formulation.
6. A formulation according to Claims 1-5 wherein said formulation comprises at least one auxiliary substance selected from the group comprising the buffering agent, preservative, sweetening agent, flavoring agent, pH adjusting agent and surfactant.
7. A formulation according to Claim 6 wherein 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.
8. A formulation according to Claim 7 wherein sodium lauryl sulfate is used as the surfactant.
9. A formulation according to Claim 8 wherein the surfactant is used at a quantity in the range of 0.5-5% by weight, based on the total weight of the formulation.
10. A formulation according to Claims 1-9 wherein said formulation comprises 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.
11. A formulation according to Claims 1-10 wherein 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%, sodium 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%.
12. A formulation according to Claims 1-11 characterized in that said formulation comprises, in addition to montelukast 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.
13. A formulation according to Claim 12 wherein levocetirizine is used as the active ingredient of the group of antihistamines.
14. A formulation according to Claim 12 wherein desloratadine is used as the active ingredient of the group of antihistamines.
15. A therapy kit comprising a formulation according to claims 1-13, such that said kit comprises a formulation comprising montelukast sodium and a formulation that comprises levocetirizine wherein 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 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 and the liquid formulation and dry powder formulation are mixed before use.
16. A therapy kit comprising a formulation according to claims 1-12 and 14, such that said kit comprises a formulation comprising montelukast sodium and a formulation that comprises desloratadine wherein 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 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 and the liquid formulation and dry powder formulation are mixed before use.
17. Use of a formulation according to Claims 1-16 in the manufacture of a medication 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.
18. A method of manufacturing a formulation according to Claims 1-16 wherein said method comprises, in the respective order, the steps of;
i. mixing the solvent or solvent combination by heating at a temperature in the range 40-60 C in the primary vessel,
ii. adding the surfactant to the mixture and dissolving the same by way of stirring,
iii. dissolving the preservative in some water in a separate vessel and adding the obtained mixture to the mixture resulting from step ii,
iv. dissolving the sweetening agent and buffering agent in some water in a separate vessel and adding the same to the mixture in the primary vessel, v. adding the flavoring agent to the mixture in the primary vessel and stirring, and
vi. completing the resulting mixture to the respective volume with water.
PCT/TR2016/000029 2015-03-05 2016-03-07 Formulations comprising montelukast WO2016140633A1 (en)

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CN110840833A (en) * 2019-11-22 2020-02-28 南京知和医药科技有限公司 Sugar-free desloratadine oral solution and preparation process thereof
WO2020049505A1 (en) * 2018-09-06 2020-03-12 Innopharmascreen Inc. Methods and compositions for treatment of asthma or parkinson's disease
GB2577248A (en) * 2018-09-13 2020-03-25 Syri Ltd A pharmaceutical liquid composition of leukotriene receptor antagonist

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US20060147482A1 (en) * 2005-01-04 2006-07-06 Center Laboratories, Inc. Oral liquid pharmaceutical composition of leukotriene antagonists
EP2716279A1 (en) * 2012-10-04 2014-04-09 Lamda UK Ltd. Oral solutions containing leukotriene antagonists

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Publication number Priority date Publication date Assignee Title
WO2003101434A2 (en) * 2001-12-21 2003-12-11 Sampad Bhattacharya Intranasal pharmaceutical compositions comprising an antihistamine and a leukotriene inhibitor
US20060147482A1 (en) * 2005-01-04 2006-07-06 Center Laboratories, Inc. Oral liquid pharmaceutical composition of leukotriene antagonists
EP2716279A1 (en) * 2012-10-04 2014-04-09 Lamda UK Ltd. Oral solutions containing leukotriene antagonists

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WO2020049505A1 (en) * 2018-09-06 2020-03-12 Innopharmascreen Inc. Methods and compositions for treatment of asthma or parkinson's disease
US10966943B2 (en) 2018-09-06 2021-04-06 Innopharmascreen Inc. Methods and compositions for treatment of asthma or parkinson's disease
GB2577248A (en) * 2018-09-13 2020-03-25 Syri Ltd A pharmaceutical liquid composition of leukotriene receptor antagonist
CN110840833A (en) * 2019-11-22 2020-02-28 南京知和医药科技有限公司 Sugar-free desloratadine oral solution and preparation process thereof

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