WO2012064303A2 - Improved montelukast combinations - Google Patents
Improved montelukast combinations Download PDFInfo
- Publication number
- WO2012064303A2 WO2012064303A2 PCT/TR2011/000245 TR2011000245W WO2012064303A2 WO 2012064303 A2 WO2012064303 A2 WO 2012064303A2 TR 2011000245 W TR2011000245 W TR 2011000245W WO 2012064303 A2 WO2012064303 A2 WO 2012064303A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- sodium
- agents
- montelukast
- lubricant
- Prior art date
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- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 title claims abstract description 36
- 229960005127 montelukast Drugs 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 119
- 238000009472 formulation Methods 0.000 claims abstract description 111
- 239000013543 active substance Substances 0.000 claims abstract description 30
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 17
- 239000000314 lubricant Substances 0.000 claims description 41
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 34
- 229960001271 desloratadine Drugs 0.000 claims description 34
- 239000000454 talc Substances 0.000 claims description 18
- 229910052623 talc Inorganic materials 0.000 claims description 18
- 229940033134 talc Drugs 0.000 claims description 18
- -1 glidants Substances 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 12
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 10
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 10
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- 239000003381 stabilizer Substances 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
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- 239000003795 chemical substances by application Substances 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- 210000002345 respiratory system Anatomy 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 4
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
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- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 claims description 4
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
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- 239000008117 stearic acid Substances 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- 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
- Montelukast formulations of the present invention comprise at least one other pharmaceutically acceptable excipient in addition to the lubricant.
Abstract
The present invention relates to stabile montelukast formulations with improved flow characteristics which are produced without causing incompatibility with excipients; and combinations of these formulations with at least one other active agent.
Description
IMPROVED MONTELUKAST COMBINATIONS
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 thereof and at least one other active agent, on the active agent.
Montelukast (Formula I) is a leukotriene receptor antagonist which was firstly disclosed in the patent numbered EP480717 Al:
Formula (I) Montelukast is an orally used, strong and selective antagonist of leukotriene D4 (LTD4) which is effective on cysteinyl leukotriene receptor (CysLT]) 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 disintegrations in the end product. The most important impurity generated with the disintegration of montelukast sodium is sulfoxide impurity illustrated in the following formula (II):
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 therefore it 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 discloses pharmaceutical compositions of montelukast 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 have seen 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 is higher than expected.
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 a lubricant in formulations does not provide sufficient flow to formulations; therefore, the formulations produced adhere to metal members through the production line. This kind of adhesion problem 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 and degradation in order to provide sufficient fluidity in montelukast formulations. The 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 these formulations with at least one other active agent.
In the formulations produced according to the invention, it has been seen 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 of 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 prevented adhesion to the machines during the process and minimized active agent loss. The lubricants used formed a considerably smooth film layer on montelukast particles and thus provided to improve flow characteristics.
The amount of the lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof which is 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 its pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer or a combination thereof. Preferably, montelukast is used in sodium salt form in the formulations of the present invention. Montelukast sodium used in the formulations of the present invention is in the range of 1 to 30%, preferably in the range of 1 to 20%, more preferably in the range of 1 to 10% by weight.
The term "silicone oil" used herein refers to dimethicone and/or silicone analogs of carbon based organic compounds including simethicone which is activated form of dimethicone.
Formulations of the present invention can comprise at least one other pharmaceutically acceptable lubricant in addition to these lubricants.
Other lubricants that can be used in the formulations of the present invention can be selected from the substances such as 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 the said lubricant is used in the range of 0.1 to 5% by weight in the case of using a second lubricant selected from the group stated above in addition to lubricant/lubricants used in the formulations.
Montelukast formulations of the present invention comprise at least one other pharmaceutically acceptable excipient in addition to the lubricant.
Said excipients are selected from a group comprising disintegrants, viscosity enhancing agents, filling agents, drying agents, lubricants, diluents, stabilizing agents, binders, glidants, antifoaming agents, wetting agents, effervescent combinations, sweeteners and flavoring agents. The excipients preferred in montelukast formulations of the present invention are least one binder, at least one diluent, at least one disintegrant; and the formulations can optionally comprise at least one other excipient.
The formulations of the present invention are combined with a second active agent. Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be used as the second active agent.
The second active agent used in montelukast formulations of the present invention is preferably an antihistaminic selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, triple amine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastin, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.
The second active agent preferred is desloratadine or a pharmaceutically acceptable derivative thereof. The second active agent in the formulations of the present invention can be used with montelukast together, in sequence or separately.
However, the two active agents are formulated together or separately and combined in a single dosage form in the preferred embodiment of the present invention.
However, the inventor has seen that N-formyl desloratadine impurity which is the major degradation product formed by desloratadine degradation is out of these limits (more than 0.5% by weight) although sulphoxide impurity is at acceptable limits in the case that the formulations comprise desloratadine and montelukast sodium as active agents.
In other words, use of a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof as the lubricant is not sufficient in order to obtain a stabile composition in the case that the formulations comprise desloratadine and montelukast sodium as active agents.
As a result of the studies conducted, the inventor has found that a stabile composition can be obtained by formulating the two active agents separately and by choosing the amount and type of the lubricant used in the desloratadine formulation. One characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is that the two formulations comprising the two active agents are formulated separately and compressed as bilayer tablet by being fed to tablet compression machine separately.
Another characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is that the formulations comprise desloratadine in
the range of 0.1 to 10%, preferably in the range of 0.1 to 8%, more preferably in the range of 0.5 to 5 % in proportion to total weight of the formulation.
Another characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is use of a lubricant selected from a group comprising silicone oil, siliconized talc or liquid paraffin or binary or ternary combinations thereof in montelukast formulations; and use of a lubricant selected from a group comprising talc, sodium stearyl fumarate or colloidal silicone dioxide or binary or ternary combinations thereof in desloratadine formulations.
Another characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is that total lubricant amount used in desloratadine formulations is in the range of 0.5 to 10 %, preferably in the range of 0.6 to 4%, more preferably in the range of 0.7 to 3%.
The formulations of the present invention can optionally comprise the combinations of the lubricants selected from the groups given. While the said combinations can be binary combinations such as talc and sodium stearyl fumarate; talc and colloidal silicone dioxide; colloidal silicone dioxide and sodium stearyl fumarate, they can also be a ternary combination comprising talc, sodium stearyl fumarate and colloidal silicone dioxide.
In the case of using the ternary combination as lubricant in desloratadine formulations, the weight ratio of sodium stearyl fumarate : colloidal silicone dioxide : talc comprised in the formulations is in the range of 0.2:1 :5 to 20:1 :0.2, preferably in the range of 0.5: 1 :20 to 20:1 :0.5.
Another characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is that desloratadine formulations comprise at least one other pharmaceutically acceptable excipient. Another characteristic of the formulations of the present invention comprising montelukast sodium and desloratadine as active agents is that the excipients used in desloratadine formulations are composed of at least one stabilizing agent, at least one disintegrant and at least one diluent.
The pharmaceutically acceptable disintegrants that can be used in the formulations of 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 formulations of 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 formulations of the present invention can be selected from the substances such as lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaoline, 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 formulations of 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 formulations of the present invention can be selected from antioxidants, chelating agents, alkalinizing agents and photoprotectives.
The antioxidants can be selected from substances such as butylated hydroxy anisole (BHA), sodium ascorbate, butylated hydroxy 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 can catalyze the oxidation process.
The alkalinizing agents can be selected from alkaline metal salts such as sodium carbonate, 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 dehydrate, 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 titanium 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.
The formulations of the present invention are used by the oral route. Pharmaceutical formulations to be used 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 and can optionally be film coated.
The 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 prevention and/or treatment of allergic and inflammatory diseases of skin or upper and respiratory tract such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin induced asthma, exercise induced asthma, and removal of symptoms related to said diseases.
Examples of pharmaceutical formulation 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.
EXAMPLES
Example 1. Bilayer Tablet Formulation Comprising Montelukast Sodium and Desloratadine
The method proposed for preparation of the formulation given above is as follows:
1. Desloratadine and stabilizing agent in the desloratadine formulation are mixed with the diluent and the disintegrant; and the mixture is treated with sodium stearyl fumarate,
2. Montelukast and the diluent in the montelukast formulation are mixed with the binder and the disintegrant; and the mixture is treated with siliconized talc.
3. The two formulations prepared are compressed in bilayer tablet form by being fed to tablet compression machine separately and coated with film.
Table 1. Stability Study for Example 1
The bilayer tablet formulation produced according to the formulation and production method given above were stored at 60% of relative humidity rate and at 45 °C for 4 weeks (accelerated storage conditions) and the amounts of sulfoxide and N-formyl desloratadine impurity in the formulations were measured separately with HPLC (High-performance liquid chromatography) device. The results obtained are as follows:
According to the results of the stability study, the formulations comprising desloratadine and montelukast sodium prepared according to the formulation and the production method given in the example are considerably stabile in terms of both desloratadine and montelukast.
This unexpected effect has been achieved by formulating the two formulations separately and surprisingly by use of lubricant in different characteristics and amounts.
Example 2. Bilayer Tablet Formulation Comprising Montelukast Sodium and Desloratadine
The method proposed for preparation of the formulation given above is as follows:
1. Desloratadine and the stabilizing agent in the desloratadine formulation are mixed with the diluent, the disintegrant and colloidal silicone dioxide.
2. Talc is added into the mixture obtained and mixed; this mixture is mixed with sodium stearyl fumarate finally.
3. Montelukast and the diluent in montelukast formulation are mixed with the binder and the disintegrant; and the mixture is treated with siliconized talc.
The two different formulations prepared are compressed in bilayer tablet form being fed to tablet compression machine separately and coated with film.
Table 2. Stability Study for Example 2
The bilayer tablet formulation produced according to the formulation and the production method given above were stored at 60% of relative humidity rate and at 45 °C for 4 weeks (accelerated storage conditions) and the amounts of sulfoxide and N-formyl desloratadine impurity in the formulations were measured separately with HPLC (High-performance liquid chromatography) device. The results obtained are as follows:
According to the results of this stability study, the formulations comprising desloratadine and montelukast sodium prepared according to the formulation and production method given in the example are considerably stabile in terms of both desloratadine and montelukast.
Claims
1. 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. Desloratadine formulation comprising desloratadine as active agent; a lubricant selected from a group comprising talc, sodium stearyl fumarate or colloidal silicone dioxide or binary or ternary combinations thereof as lubricant; and at least one other pharmaceutically acceptable excipient.
2. The formulation according to claim 1 characterized in that montelukast formulation comprises lubricant in the range of 0.1 to 10% by weight; desloratadine formulation comprises lubricant in the range of 1 to 10% by weight.
3. The formulation according to claim 2 characterized in that montelukast formulation comprises lubricant in the range of 0.1 to 5% by weight; desloratadine formulation comprises lubricant in the range of 1 to 5% by weight.
4. The formulation according to claim 3 characterized in that both formulations comprise lubricant in the range of 2 to 5 % by weight.
5. The formulation according to claim 1 characterized in that the pharmaceutically acceptable excipients that can be used in the formulation 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.
6. The formulation according to claim 5 characterized in that said formulation comprises
I. Montelukast formulation comprising montelukast as active agent; a lubricant selected from a group comprising silicone oil, siliconized talk or liquid paraffin or combinations thereof; at least one pharmaceutically acceptable stabilizing agent; at least one disintegrant and at least one diluent,
II. Desloratadine formulation comprising desloratadine as active agent; a lubricant selected from a group comprising talc, sodium stearyl fumarate or colloidal silicone dioxide or binary or ternary combinations thereof; at least one pharmaceutically acceptable binder, at least one diluent, at least one disintegrant.
7. The formulation according to claims 5 and 6 characterized in that the diluents 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, kaoline, 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 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 in the formulation are selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
10. The formulation according to claims 5 and 6 characterized in that the stabilizing agents in the formulation are selected from a group comprising antioxidants, chelating agents, alkalinizing agents and photo protective agents.
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 antioxidants are selected from a group comprising butylated hydroxy anisole (BHA), sodium ascorbate, butylated hydroxy toluene (BHT), sodium sulfite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithine, ascorbyl palmitate, ethylendiamine tetraacetate.
3. The formulation according to claim 10 characterized in that the alkalinizing agents can be selected from alkaline metal salts such as sodium carbonate, 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 dehydrate, 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 production method for 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 prevention and/or treatment of allergic and inflammatory diseases of skin or upper and respiratory tract such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin induced asthma, exercise induced asthma, and removal of symptoms related to said diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2010/9394 | 2010-11-11 | ||
| TR2010/09394A TR201009394A2 (en) | 2010-11-11 | 2010-11-11 | Improved montelukast formulations. |
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| WO2012064303A2 true WO2012064303A2 (en) | 2012-05-18 |
| WO2012064303A3 WO2012064303A3 (en) | 2012-07-19 |
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| PCT/TR2011/000246 WO2012064304A2 (en) | 2010-11-11 | 2011-11-03 | Combinations comprising montelukast |
| PCT/TR2011/000245 WO2012064303A2 (en) | 2010-11-11 | 2011-11-03 | Improved montelukast combinations |
| PCT/TR2011/000244 WO2012064302A2 (en) | 2010-11-11 | 2011-11-03 | Improved montelukast formulations |
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| RU2677649C2 (en) * | 2013-02-21 | 2019-01-18 | Глэнмарк Фармасьютикалс Лимитед | Pharmaceutical compositions of montelucast and levocetirisine |
| KR102226833B1 (en) * | 2013-06-28 | 2021-03-12 | 한미약품 주식회사 | Complex granule formulation having improved stability comprising levocetirizine and montelukast |
| CN104666302B (en) * | 2013-11-27 | 2017-06-30 | 北京韩美药品有限公司 | Composition and preparation method thereof, oral liquid and preparation method thereof |
| CN103655497B (en) * | 2013-12-18 | 2018-05-29 | 北京华禧联合科技发展有限公司 | A kind of Montelukast Sodium oral disnitegration tablet and preparation method thereof |
| CN104840427B (en) * | 2014-02-13 | 2017-09-29 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Menglusitena |
| EP2949321A1 (en) * | 2014-05-26 | 2015-12-02 | Sanovel Ilac Sanayi ve Ticaret A.S. | Multilayer formulations of fexofenadine and montelukast |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0480717A1 (en) | 1990-10-12 | 1992-04-15 | Merck Frosst Canada Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
| WO2007092031A1 (en) | 2006-02-09 | 2007-08-16 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical formulations of montelukast sodium |
| WO2010041277A2 (en) | 2008-10-06 | 2010-04-15 | Jubilant Organosys Limited | Stable pharmaceutical compositions of montelukast or its salts or solvates or hydrates |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009122187A2 (en) * | 2008-04-03 | 2009-10-08 | Cipla Limited | Pharmaceutical composition |
| TR200806298A2 (en) * | 2008-08-22 | 2010-03-22 | Bi̇lgi̇ç Mahmut | Pharmaceutical formulation |
| WO2010107404A1 (en) * | 2009-03-16 | 2010-09-23 | Mahmut Bilgic | Stable pharmaceutical combinations |
-
2010
- 2010-11-11 TR TR2010/09394A patent/TR201009394A2/en unknown
-
2011
- 2011-11-03 WO PCT/TR2011/000246 patent/WO2012064304A2/en active Application Filing
- 2011-11-03 WO PCT/TR2011/000245 patent/WO2012064303A2/en active Application Filing
- 2011-11-03 WO PCT/TR2011/000244 patent/WO2012064302A2/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0480717A1 (en) | 1990-10-12 | 1992-04-15 | Merck Frosst Canada Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
| WO2007092031A1 (en) | 2006-02-09 | 2007-08-16 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical formulations of montelukast sodium |
| WO2010041277A2 (en) | 2008-10-06 | 2010-04-15 | Jubilant Organosys Limited | Stable pharmaceutical compositions of montelukast or its salts or solvates or hydrates |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012064304A2 (en) | 2012-05-18 |
| WO2012064302A3 (en) | 2012-07-19 |
| WO2012064303A3 (en) | 2012-07-19 |
| WO2012064302A2 (en) | 2012-05-18 |
| TR201009394A2 (en) | 2012-06-21 |
| WO2012064304A3 (en) | 2012-08-09 |
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