WO2012064304A2 - Combinations comprising montelukast - Google Patents

Combinations comprising montelukast Download PDF

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Publication number
WO2012064304A2
WO2012064304A2 PCT/TR2011/000246 TR2011000246W WO2012064304A2 WO 2012064304 A2 WO2012064304 A2 WO 2012064304A2 TR 2011000246 W TR2011000246 W TR 2011000246W WO 2012064304 A2 WO2012064304 A2 WO 2012064304A2
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formulation
sodium
lubricant
montelukast
formulations
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PCT/TR2011/000246
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French (fr)
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WO2012064304A3 (en
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/2036—Silicones; Polysiloxanes
    • 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 relates to pharmaceutical formulations designed to remove negative effects of excipients, which are used in the formulations comprising montelukast and/or a pharmaceutically acceptable salt and at least one other active agent, on the active agent.
  • Montelukast is a leukotriene receptor antagonist which was firstly disclosed in the patent numbered EP480717 Al (Formula I):
  • Montelukast is an orally used, potent and selective antagonist of leukotriene D4 (LTD 4 ) which is effective on cysteinyl leukotriene receptor (CysLTi) in the respiratory tract.
  • Cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) are strong inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors located in the respiratory tract and lead to a series of respiratory tract activities such as bronchoconstriction, intensive mucus secretion, vascular permeability and accumulation of eosinophils.
  • the active agent montelukast is highly incompatible with excipients used in pharmaceutical formulations. This incompatibility induces fast disintegration in the end product.
  • This sulfoxide impurity appears when the sulphide group in montelukast sodium is oxidized to sulfoxide group and it is not in an active form. However, its presence reduces the effective dose of montelukast sodium in the treatment and this reduces the efficiency of the treatment.
  • stabile formulations comprising excipients which are used in montelukast formulations and do not cause stability or incompatibility problems with the active agent have been designed.
  • WO/2010/041277 discloses tablet formulations which comprise montelukast, microcrystalline cellulose and a flavoring agent together with magnesium stearate.
  • the application WO/2007/092031 discloses montelukast formulations which do not comprise microcrystalline cellulose.
  • magnesium stearate is used as lubricant.
  • Montelukast sodium is currently marketed in chewable tablet, film coated tablet and pediatric granule form under the trade name Singulair®.
  • Film coated Singulair® formulations comprise microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose as excipient and magnesium stearate as lubricant.
  • magnesium stearate as a lubricant in the production of montelukast sodium formulations leads to incompatibility in the pharmaceutical composition and also the rate of sulfoxide impurity appears to be higher than expected in these formulations.
  • Use of magnesium stearate results in faster degradation of montelukast sodium, which is considerably susceptible to and highly incompatible with pharmaceutical excipients, than expected.
  • use of magnesium stearate as lubricant in the formulations does not provide sufficient flow to formulations; therefore, the formulations adhere to metal members through the production line. This kind of adhesion causes loss of active ingredient and thus, reduction of bioavailability.
  • the inventors have developed new formulations by using a pharmaceutically acceptable lubricant or lubricant combinations which would not cause incompatibility or degradation to provide sufficient fluidity in montelukast formulations. Said formulations are also convenient to use with at least one other active agent.
  • the present invention relates to stabile montelukast formulations with improved flow characteristics which are produced without causing incompatibility with excipients; and combinations of said formulations with at least one other active agent.
  • accelerated storage conditions refers to storage of formulations at 60 % of relative humidity and at 45 °C for 4 weeks.
  • a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof in the formulations prevented adhesion of the formulation on the surfaces of the machines during the process and minimized active agent loss.
  • the lubricant used formed a considerably smooth film layer on montelukast particles and thus provided to improve flow characteristic.
  • the amount of the lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof used as lubricant in the formulations of the present invention is in the range of 0.1 to 10 % by weight, preferably in the range of 0.1 to 5 % by weight, more preferably in the range of 2 to 5 % by weight.
  • the term "montelukast” used throughout the text refers to montelukast or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof; though it is preferably in salt form.
  • Montelukast used in the formulations of the present invention is preferably in the form of sodium salt and used in the range of 1 to 30 % by weight, preferably in the range of 1 to 20% by weight, more preferably in the range of 1 to 10% by weight.
  • sicone oil used throughout the text refers to dimethicone and/or silicone analogs of carbon based organic compounds including simethicone which is activated form of dimethicone.
  • the formulations of the present invention can comprise at least one other pharmaceutically acceptable lubricant in addition to these lubricants.
  • the other lubricants that can be used in the formulations of the present invention can be selected from a group comprising lauric acid, palmitic acid, stearic acid, behenic acid and/or pharmaceutically acceptable salts thereof; siliconized talc, simethicone, dimethicone, liquid paraffin, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium stearate, lecithine, L-leucine, phosphatidylcholines, phosphateidylglycerides, triglycerides and they are comprised in the formulations in the range of 0.1 to 5 % by weight.
  • Montelukast formulations of the present invention comprise at least one other pharmaceutically acceptable excipient in addition to the lubricant.
  • the said excipients are selected from a group comprising disintegrants, viscosity enhancing components, filling agents, drying agents, diluents, stabilizing agents, binders, glidants, antifoaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.
  • the preferred excipients in the montelukast formulations of the present invention can comprise at least one binder, at least one diluent, at least one disintegrant, at least one stabilizing agent; though the formulations can optionally comprise one other excipient.
  • Formulations of the present invention can be combined with a second active agent.
  • the second active agent can be selected from nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants.
  • the second active agent used in the formulations of the present invention is preferably an antihistaminic though it can be selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, tripelamine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastine, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs,
  • the second active agent preferred is selected from a group comprising levocetirizine or a pharmaceutically acceptable salt, anhydrate, hydrate, dihydrate or combinations thereof.
  • the second active agent used in the formulations of the present invention can be used with montelukast simultaneously, sequentially or separately.
  • the two active agents are combined in a single dosage form as formulated together or separately in the preferred embodiment of the invention.
  • the second active agent used in the montelukast formulations of the present invention is preferably levocetirizine dihydrochloride; though one characteristic of the formulation is that the formulations of the active agents are prepared separately and are compressed in bilayer tablet form by being fed to tablet compression machine separately.
  • the formulations comprise levocetirizine dihydrochloride in the range of 0.5 to 10 %, preferably in the range of 0.5 to 8%, more preferably in the range of 0.5 to 5% in proportion to total weight of the formulation.
  • montelukast and levocetirizine dihydrochloride formulations of the present invention Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof as a lubricant is used in montelukast formulations; while a lubricant selected from a group comprising magnesium stearate or colloidal silicone dioxide or binary combinations thereof is used in levocetirizine dihydrochloride formulations.
  • total lubricant amount used in levocetirizine dihydrochloride formulations is in the range of 0.1 to 5%, preferably in the range of 0.1 to 4 %, more preferably in the range of 0.1 to 3% in proportion to total formulation weight.
  • the ratio of these two lubricants to each other is in the range of 0.1 to 5, preferably in the range of 0.5 to 3, more preferably in the range of 0.75 to 2 by weight.
  • levocetirizine dihydrochloride formulations of the present invention Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that levocetirizine dihydrochloride formulations comprise at least one other pharmaceutically acceptable excipient.
  • montelukast and levocetirizine dihydrochloride formulations of the present invention Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that the pharmaceutically acceptable excipient used in levocetirizine dihydrochloride formulations is at least one diluent.
  • the pharmaceutically acceptable diluent used in levocetirizine dihydrochloride formulations is selected from the same group as the diluents in montelukast formulations.
  • the pharmaceutically acceptable disintegrants that can be used in the present invention can be selected from polymers having high disintegrating characteristics, for instance cross-linked hydroxypropyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, corn starch, sodium starch glycolate, povidone, alginic acid, sodium alginate.
  • the pharmaceutically acceptable binders that can be used in the present invention can be selected from potato starch, wheat starch or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose and polyvinylpyrrolidone.
  • the pharmaceutically acceptable diluents that can be used in the present invention can be selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, cellulose powder, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, directly compressible mannitol, directly compressible lactose, sorbitol and xylitol.
  • the pharmaceutically acceptable film coating material that can be used in the present invention is composed of the following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, triacetine, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.
  • the pharmaceutically acceptable stabilizing agent and/or agents that can be used in the present invention can be selected from antioxidants, chelating agents, alkalinizing agents and photoprotectives.
  • the antioxidants can be selected from substances such as butylated hydroxyl anisole (BHA), sodium ascorbate, butylated hydroxyl toluene (BHT), sodium sulfite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithine, ascorbyl palmitate, ethylendiamine tetraacetate.
  • BHA butylated hydroxyl anisole
  • BHT butylated hydroxyl toluene
  • gallates such as propyl gallate
  • tocopherol citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithine, ascorbyl palmitate,
  • the chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof. These agents prevent oxidation by surrounding and masking the metal ions which may catalyze the oxidation process.
  • the alkalinizing agents can be selected from alkaline metal salts such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophospate, calcium hydrogen phosphate dihydrate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines; ⁇ , ⁇ '-dibenzyl ethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate.
  • alkaline metal salts such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium
  • the photoprotective agents can be selected from metal oxides such as titamum oxide, iron oxide or zinc oxide.
  • Montelukast formulations of the present invention are used orally.
  • Pharmaceutical formulations to be administered orally can be in the form of tablets, capsules, soluble tablets, layered tablets, effervescent tablets, chewable tablets, film coated tablets, soluble granules, soluble powders, emulsions, suspensions, solutions or combinations thereof.
  • the formulations of the present invention are preferably in tablet form; though the formulations can optionally be coated with film.
  • Montelukast formulations of the present invention can be produced by any methods in the prior art. These methods include wet granulation, dry granulation, direct compression, dry blending.
  • the formulations of the present invention are used for relieving, preventing and/or treating seasonal allergic rhinitis; perennial allergic rhinitis; asthma; the symptoms of aspirin-sensitive asthma patients and exercise-induced bronchoconstriction.
  • Example 1 Tablet Formulation Comprising Montelukast Sodium and Levocetirizine
  • the method proposed for preparation of the formulation given above is as follows: 1. Levocetirizine and the diluent in levocetirizine formulation are mixed; the mixture is treated with magnesium stearate. Montelukast and the diluent in the montelukast formulation are mixed with the binder and the disintegrant and the stabilizing agent; the mixture is treated with siliconized talk.
  • the two separate formulations prepared are compressed in bilayer tablet form by being fed to tablet compression machine separately and the tablets are coated with film.
  • Example 2 Tablet Formulation Comprising Montelukast Sodium ve Levocetirizine Dihydrochloride
  • Levocetirizine and colloidal silicon dioxide are mixed; the diluent in the levocetirizine formulation is added into the mixture and mixed again; the lubricant is added into the final mixture and mixed again,
  • Montelukast and the diluent in the montelukast formulation are mixed with the binder and the disintegrant and the stabilizing agent; the mixture is treated with dimethicone,
  • the two different formulations are compressed in bilayer tablet form by being fed to tablet compression machine separately; and the formulations are coated with film.

Abstract

The present invention relates to compositions designed to remove negative effects of excipients used in the formulations comprising montelukast and/or a pharmaceutically acceptable salt thereof on the active agent.

Description

COMBINATIONS COMPRISING MONTELUKAST
The present invention relates to pharmaceutical formulations designed to remove negative effects of excipients, which are used in the formulations comprising montelukast and/or a pharmaceutically acceptable salt and at least one other active agent, on the active agent. Montelukast is a leukotriene receptor antagonist which was firstly disclosed in the patent numbered EP480717 Al (Formula I):
Figure imgf000002_0001
Formula (I)
Montelukast is an orally used, potent and selective antagonist of leukotriene D4 (LTD4) which is effective on cysteinyl leukotriene receptor (CysLTi) in the respiratory tract. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are strong inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors located in the respiratory tract and lead to a series of respiratory tract activities such as bronchoconstriction, intensive mucus secretion, vascular permeability and accumulation of eosinophils.
However, the active agent montelukast is highly incompatible with excipients used in pharmaceutical formulations. This incompatibility induces fast disintegration in the end product.
The most important impurity generated with the disintegration of montelukast sodium is sulfoxide impurity illustrated in the following formula (II):
Figure imgf000003_0001
Formula (II)
This sulfoxide impurity appears when the sulphide group in montelukast sodium is oxidized to sulfoxide group and it is not in an active form. However, its presence reduces the effective dose of montelukast sodium in the treatment and this reduces the efficiency of the treatment.
In the prior art, stabile formulations comprising excipients which are used in montelukast formulations and do not cause stability or incompatibility problems with the active agent have been designed.
For instance, the patent application numbered WO/2010/041277 discloses tablet formulations which comprise montelukast, microcrystalline cellulose and a flavoring agent together with magnesium stearate.
The application WO/2007/092031, on the other hand, discloses montelukast formulations which do not comprise microcrystalline cellulose. In this application, magnesium stearate is used as lubricant. Montelukast sodium is currently marketed in chewable tablet, film coated tablet and pediatric granule form under the trade name Singulair®. Film coated Singulair® formulations comprise microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose as excipient and magnesium stearate as lubricant.
However, the inventors found that use of magnesium stearate as a lubricant in the production of montelukast sodium formulations leads to incompatibility in the pharmaceutical composition and also the rate of sulfoxide impurity appears to be higher than expected in these formulations. Use of magnesium stearate results in faster degradation of montelukast sodium, which is considerably susceptible to and highly incompatible with pharmaceutical excipients, than expected. In addition, use of magnesium stearate as lubricant in the formulations does not provide sufficient flow to formulations; therefore, the formulations adhere to metal members through the production line. This kind of adhesion causes loss of active ingredient and thus, reduction of bioavailability.
The inventors have developed new formulations by using a pharmaceutically acceptable lubricant or lubricant combinations which would not cause incompatibility or degradation to provide sufficient fluidity in montelukast formulations. Said formulations are also convenient to use with at least one other active agent.
Detailed Description of the Invention
The present invention relates to stabile montelukast formulations with improved flow characteristics which are produced without causing incompatibility with excipients; and combinations of said formulations with at least one other active agent.
The studies conducted with the formulations of the present invention have indicated that use of a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof does not cause any incompatibility and/or degradation in the formulations. HPLC measurements which were taken after the montelukast formulations produced according to the present invention were kept under accelerated storage conditions have indicated that sulfoxide impurity is below 0.6% in the formulations.
The term "accelerated storage conditions" used herein refers to storage of formulations at 60 % of relative humidity and at 45 °C for 4 weeks. In addition; use of a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof in the formulations prevented adhesion of the formulation on the surfaces of the machines during the process and minimized active agent loss. The lubricant used formed a considerably smooth film layer on montelukast particles and thus provided to improve flow characteristic. The amount of the lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof used as lubricant in the formulations of the present invention is in the range of 0.1 to 10 % by weight, preferably in the range of 0.1 to 5 % by weight, more preferably in the range of 2 to 5 % by weight. The term "montelukast" used throughout the text refers to montelukast or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof; though it is preferably in salt form.
Montelukast used in the formulations of the present invention is preferably in the form of sodium salt and used in the range of 1 to 30 % by weight, preferably in the range of 1 to 20% by weight, more preferably in the range of 1 to 10% by weight.
The term "silicone oil" used throughout the text refers to dimethicone and/or silicone analogs of carbon based organic compounds including simethicone which is activated form of dimethicone. The formulations of the present invention can comprise at least one other pharmaceutically acceptable lubricant in addition to these lubricants.
The other lubricants that can be used in the formulations of the present invention can be selected from a group comprising lauric acid, palmitic acid, stearic acid, behenic acid and/or pharmaceutically acceptable salts thereof; siliconized talc, simethicone, dimethicone, liquid paraffin, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium stearate, lecithine, L-leucine, phosphatidylcholines, phosphateidylglycerides, triglycerides and they are comprised in the formulations in the range of 0.1 to 5 % by weight.
Montelukast formulations of the present invention comprise at least one other pharmaceutically acceptable excipient in addition to the lubricant. The said excipients are selected from a group comprising disintegrants, viscosity enhancing components, filling agents, drying agents, diluents, stabilizing agents, binders, glidants, antifoaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.
The preferred excipients in the montelukast formulations of the present invention can comprise at least one binder, at least one diluent, at least one disintegrant, at least one stabilizing agent; though the formulations can optionally comprise one other excipient.
Formulations of the present invention can be combined with a second active agent. The second active agent can be selected from nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants. The second active agent used in the formulations of the present invention is preferably an antihistaminic though it can be selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, tripelamine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastine, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.
The second active agent preferred is selected from a group comprising levocetirizine or a pharmaceutically acceptable salt, anhydrate, hydrate, dihydrate or combinations thereof. The second active agent used in the formulations of the present invention can be used with montelukast simultaneously, sequentially or separately.
However, the two active agents are combined in a single dosage form as formulated together or separately in the preferred embodiment of the invention.
The second active agent used in the montelukast formulations of the present invention is preferably levocetirizine dihydrochloride; though one characteristic of the formulation is that the formulations of the active agents are prepared separately and are compressed in bilayer tablet form by being fed to tablet compression machine separately.
Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that the formulations comprise levocetirizine dihydrochloride in the range of 0.5 to 10 %, preferably in the range of 0.5 to 8%, more preferably in the range of 0.5 to 5% in proportion to total weight of the formulation.
Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof as a lubricant is used in montelukast formulations; while a lubricant selected from a group comprising magnesium stearate or colloidal silicone dioxide or binary combinations thereof is used in levocetirizine dihydrochloride formulations.
Another characteristic of montelukast and levocetirizine dihydrochloride formulations is that total lubricant amount used in levocetirizine dihydrochloride formulations is in the range of 0.1 to 5%, preferably in the range of 0.1 to 4 %, more preferably in the range of 0.1 to 3% in proportion to total formulation weight.
In the case that colloidal silicon dioxide and magnesium stearate are used together in levocetirizine formulations of the present invention, the ratio of these two lubricants to each other is in the range of 0.1 to 5, preferably in the range of 0.5 to 3, more preferably in the range of 0.75 to 2 by weight.
Use of lubricants and lubricant amounts in this manner has caused a positive improvement in the formulations comprising levocetirizine dihydrochloride and montelukast sodium.
Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that levocetirizine dihydrochloride formulations comprise at least one other pharmaceutically acceptable excipient.
Another characteristic of montelukast and levocetirizine dihydrochloride formulations of the present invention is that the pharmaceutically acceptable excipient used in levocetirizine dihydrochloride formulations is at least one diluent. The pharmaceutically acceptable diluent used in levocetirizine dihydrochloride formulations is selected from the same group as the diluents in montelukast formulations.
The pharmaceutically acceptable disintegrants that can be used in the present invention can be selected from polymers having high disintegrating characteristics, for instance cross-linked hydroxypropyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, corn starch, sodium starch glycolate, povidone, alginic acid, sodium alginate.
The pharmaceutically acceptable binders that can be used in the present invention can be selected from potato starch, wheat starch or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose and polyvinylpyrrolidone.
The pharmaceutically acceptable diluents that can be used in the present invention can be selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, cellulose powder, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, directly compressible mannitol, directly compressible lactose, sorbitol and xylitol.
The pharmaceutically acceptable film coating material that can be used in the present invention is composed of the following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, triacetine, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.
The pharmaceutically acceptable stabilizing agent and/or agents that can be used in the present invention can be selected from antioxidants, chelating agents, alkalinizing agents and photoprotectives. The antioxidants can be selected from substances such as butylated hydroxyl anisole (BHA), sodium ascorbate, butylated hydroxyl toluene (BHT), sodium sulfite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithine, ascorbyl palmitate, ethylendiamine tetraacetate.
The chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof. These agents prevent oxidation by surrounding and masking the metal ions which may catalyze the oxidation process.
The alkalinizing agents can be selected from alkaline metal salts such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophospate, calcium hydrogen phosphate dihydrate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines; Ν,Ν'-dibenzyl ethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate.
The photoprotective agents can be selected from metal oxides such as titamum oxide, iron oxide or zinc oxide.
In addition to these, other pharmaceutically acceptable excipients such as solubility modulators, electrolytes, colorants and coating agents can also be used in the formulation. Montelukast formulations of the present invention are used orally. Pharmaceutical formulations to be administered orally can be in the form of tablets, capsules, soluble tablets, layered tablets, effervescent tablets, chewable tablets, film coated tablets, soluble granules, soluble powders, emulsions, suspensions, solutions or combinations thereof. The formulations of the present invention are preferably in tablet form; though the formulations can optionally be coated with film.
Montelukast formulations of the present invention can be produced by any methods in the prior art. These methods include wet granulation, dry granulation, direct compression, dry blending. The formulations of the present invention are used for relieving, preventing and/or treating seasonal allergic rhinitis; perennial allergic rhinitis; asthma; the symptoms of aspirin-sensitive asthma patients and exercise-induced bronchoconstriction.
Examples of pharmaceutical formulations of the present invention are given below. These examples are given in order to explain the invention, yet the invention is not restricted to these examples.
Example 1. Tablet Formulation Comprising Montelukast Sodium and Levocetirizine
Dihydrochloride
Figure imgf000010_0001
The method proposed for preparation of the formulation given above is as follows: 1. Levocetirizine and the diluent in levocetirizine formulation are mixed; the mixture is treated with magnesium stearate. Montelukast and the diluent in the montelukast formulation are mixed with the binder and the disintegrant and the stabilizing agent; the mixture is treated with siliconized talk.
The two separate formulations prepared are compressed in bilayer tablet form by being fed to tablet compression machine separately and the tablets are coated with film.
Example 2. Tablet Formulation Comprising Montelukast Sodium ve Levocetirizine Dihydrochloride
Figure imgf000012_0001
The method proposed for preparation of the formulation given above is as follows:
1. Levocetirizine and colloidal silicon dioxide are mixed; the diluent in the levocetirizine formulation is added into the mixture and mixed again; the lubricant is added into the final mixture and mixed again,
2. Montelukast and the diluent in the montelukast formulation are mixed with the binder and the disintegrant and the stabilizing agent; the mixture is treated with dimethicone,
3. The two different formulations are compressed in bilayer tablet form by being fed to tablet compression machine separately; and the formulations are coated with film.

Claims

A pharmaceutical formulation characterized in that said formulation comprises
I. Montelukast formulation comprising montelukast as active agent; a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof as lubricant; and at least one other pharmaceutically acceptable excipient,
II. Levocetirizine dihydrochloride formulation comprising levocetirizine dihydrochloride as active agent; a lubricant selected from a group comprising magnesium stearate and/or colloidal silicone dioxide or binary combinations thereof as lubricant; and at least one other pharmaceutically acceptable excipient.
The formulation according to claim 1 characterized in that montelukast formulation comprises lubricant in the range of 0.1 to 10 % by weight; levocetirizine dihydrochloride formulation comprises lubricant in the range of 0.1 to 5% by weight.
The formulation according to claim 2 characterized in that montelukast formulation comprises lubricant in the range of 0.1 to 5% by weight; levocetirizine dihydrochloride formulation comprises lubricant in the range of 0.1 to 4% by weight.
The formulation according to claim 3 characterized in that montelukast formulation comprises lubricant in the range of 2 to 5% by weight; levocetirizine dihydrochloride formulation comprises lubricant in the range of 0.1 to 3% by weight.
The formulation according to claim 1 characterized in that the pharmaceutically acceptable excipients that can be used in the formulations are selected from a group comprising disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, diluents, binders, glidants, stabilizing agents, antifoaming agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.
The formulation according to claims 1 and 5 characterized in that said formulation comprises I. Montelukast formulation comprising montelukast as active agent; a lubricant selected from a group comprising silicon oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof as lubricant; and at least one pharmaceutically acceptable stabilizing agent, at least one disintegrant and at least one diluent,
II. Levocetirizine dihydrochloride formulation comprising levocetirizine dihydrochloride as active agent; magnesium stearate or colloidal silicon dioxide or binary or ternary combinations thereof as a lubricant; and at least one pharmaceutically acceptable diluent.
7. The formulation according to claims 5 and 6 characterized in that the diluents comprised in the formulation are selected from a group comprising lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, cellulose powder, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, directly compressible mannitol, directly compressible lactose, sorbitol and xylitol.
8. The formulation according to claims 5 and 6 characterized in that the disintegrants used in the formulation are selected from cross-linked hydroxypropyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, corn starch, sodium starch glycolate, povidone, alginic acid, sodium alginate.
9. The formulation according to claims 5 and 6 characterized in that the binders used in the formulations are selected from a group comprising potato starch, wheat starch or corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
10. The formulation according to claims 5 and 6 characterized in that the stabilizing agents used in the formulation are selected from a group comprising antioxidants, chelating agents, alkalinizing agents and photoprotectives.
11. The formulation according to claim 10 characterized in that the chelating agents are selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof.
12. The formulation according to claim 10 characterized in that the antioxidants are selected from a group comprising butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphide, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
13. The formulation according to claim 10 characterised in that the alkalinizing agents can be selected from alkaline metal salts such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophospate, calcium hydrogen phosphate dihydrate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines; Ν,Ν'-dibenzyl ethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate.
14. A method for production of the formulation according to any preceding claims characterized in that the formulations of the active agents are prepared separately and are combined in a single dosage form.
15. The production method according to claim 14 characterized in that the formulations of the active agents are prepared separately and are compressed in bilayer tablet form by being fed to tablet compression machine separately.
16. The pharmaceutical formulation according to claim 1 characterized in that said formulation is used for relieving, preventing and/or treating seasonal allergic rhinitis; perennial allergic rhinitis; asthma; the symptoms of aspirin-sensitive asthma patients and exercise-induced bronchoconstriction.
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EP2949321A1 (en) * 2014-05-26 2015-12-02 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayer formulations of fexofenadine and montelukast

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