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WO2012066401A1 - Compositions pharmaceutiques orales stables de montélukast - Google Patents

Compositions pharmaceutiques orales stables de montélukast Download PDF

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Publication number
WO2012066401A1
WO2012066401A1 PCT/IB2011/002661 IB2011002661W WO2012066401A1 WO 2012066401 A1 WO2012066401 A1 WO 2012066401A1 IB 2011002661 W IB2011002661 W IB 2011002661W WO 2012066401 A1 WO2012066401 A1 WO 2012066401A1
Authority
WO
WIPO (PCT)
Prior art keywords
montelukast
composition
desiccant
mineral oil
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2011/002661
Other languages
English (en)
Inventor
Kirtikumar Abhay Tatiya
Dilip Gopalkrishna Saoji
Chintan Sharad Kulkarni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Ltd filed Critical Lupin Ltd
Priority to JP2013538284A priority Critical patent/JP2013545743A/ja
Priority to EP11796805.7A priority patent/EP2640355A1/fr
Publication of WO2012066401A1 publication Critical patent/WO2012066401A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0087—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to stable oral pharmaceutical compositions of Montelukast.
  • the invention also relates to kit for dispensing of oral pharmaceutical compositions of Montelukast.
  • Asthma has close relationship with allergic respiratory disorders such as hay fever, allergic rhinitis etc.
  • the clinical symptoms produced in the course of allergic reaction are the result of an early specific immune response and a late inflammatory reaction.
  • the inhaled allergens mediate the early phase by stimulating high affinity immunoglobulin (I g E) receptors e.g. mast cells and basophils which in turn release histamine and cytokines.
  • I g E immunoglobulin
  • the cytokines released from mast cells and basophils then mediate the late phase by recruiting inflammatory cells into the nasal and upper respiratory tract passages.
  • the influx of eosinophils, macrophages, lymphocytes, neutrophils and platelets starts the vicious inflammatory cycle.
  • This late phase amplifies the initial immune response which in turn triggers the release of more inflammatory cells.
  • allergens e.g. dust, mite
  • the result is bronchoconstriction of the airways (i.e. asthma).
  • the allergen-induced release of leukotrienes is critical in the pathophysiology of asthma.
  • Leukotrienes are produced by mast cells, eosinophils, neutrophils and alveolar macrophages. Leukotriene combines with receptors on the respiratory tract cells, resulting in some symptoms of asthma such as respiratory tract constriction, edema, and the increase of salivary secretion.
  • bronchodilators do not treat the inflammatory reaction or lower the sensitivity of the respiratory tract.
  • antiinflammatory drugs are usually used as preventive medicine, the major anti -inflammatory drugs in use nowadays are steroids, but the use of specific leukotriene receptor antagonists or 5-lipoxygenase pathway inhibitors are preferred which results in increased airflow and reduction of symptoms in asthmatic patients.
  • Montelukast is marketed as Singulair® in USA as oral tablets, granules and chewable tablets.
  • Oral tablet is not a convenient dosage form for some asthmatic patients, especially for children below six years old and the geriatric patients. Geriatric patients may have difficulty in swallowing tablet whereas tablet is usually grounded into powder before administration to children. When the tablet is grounded into powder, impurities are introduced during the grinding process and the drug dosage is difficult to control.
  • Montelukast as a granular dosage form is to be placed directly in the mouth; which can result into unpleasant taste and grittiness in the mouth.
  • Montelukast granules are dissolved in 1 teaspoonful (5 ml) of cold or room temperature baby formula or breast milk; or to be mixed with a spoonful of one of the following soft foods at cold or room temperature: applesauce, mashed carrots, rice, or ice cream, which is inconvenient and can result into inaccurate dosage administration.
  • Chewable tablets are masticated and swallowed at once, with a drink of water. These tablets are sipped slowly for longer period of time, or otherwise, swallowed like conventional tablets. This wrong usage would either lead to reduced therapeutic efficacy, or may lead to mechanical obstruction of the ileum from impacted chewable tablets.
  • Another major disadvantage with the chewable tablet is unpleasant taste and grittiness mouth feel, leading to poor patient compliance.
  • US patent application US 2006/0147482 discloses an oral liquid pharmaceutical composition
  • an oral liquid pharmaceutical composition comprising leukotriene antagonist, a buffer agent, water, pharmaceutical alcohol, which may be ethanol or propylene glycol and other additives.
  • US 2009/0247575 discloses a pharmaceutical composition for oral administration comprising an exceptionally labile active agent, a stabilizing vehicle comprising liquid triglycerides and a desiccant.
  • Montelukast compositions are susceptible to degradation during manufacture and storage. This degradation is pronounced in the presence of agents such as UV light, heat, oxidizing agents and/or water or moisture. This degradation of Montelukast leads to formation of corresponding sulfoxide.
  • the sulfoxide is an inactive impurity, which reduces the effective dosage of Montelukast when it is administered to a patient. Montelukast undergoes photo- isomerization to form inactive CIS isomer when exposed to UV Light.
  • the CIS isomer is an inactive impurity, which reduces the effective dosage of Montelukast when it is administered to a patient. It also forms biologically inactive, non-absorbable S-enantiomer on exposure to light and/or water.
  • the invention provides stable oral pharmaceutical compositions comprising Montelukast, a vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable additives.
  • Yet another embodiment provides stable oral liquid pharmaceutical compositions comprising Montelukast, a vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable additives.
  • Yet another embodiment provides a kit for dispensing pharmaceutical compositions comprising Montelukast, a vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable additives.
  • kits for dispensing pharmaceutical compositions comprising a first container comprising pharmaceutical composition of Montelukast and optionally desiccant, a second container comprising a vehicle comprising mineral oil, optionally desiccant and pharmaceutically acceptable additives, and instructions for use.
  • Montelukast and mineral oil occupy pre-measured volume into the respective unit of the kit.
  • the present invention provides stable oral pharmaceutical compositions of Montelukast and a kit containing pharmaceutical compositions of Montelukast.
  • Montelukast refers to Montelukast as pharmaceutically acceptable complexes, salts, polymorphs, hydrates, or solvates. Sodium salt of Montelukast is preferred.
  • the term “stable” means that the amount of the corresponding sulfoxide within the montelukast in the packaged pharmaceutical composition has not increased by more than 1.0 % by weight from the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding sulfoxide content has not increased by more than 0.5% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding sulfoxide content has not increased by more than 0.3% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the term “stable” means that the amount of the corresponding CIS isomer within the montelukast in the packaged pharmaceutical composition has not increased by more than 1.0 % by weight from the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding CIS isomer content has not increased by more than 0.5% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding CIS isomer content has not increased by more than 0.3% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the term “stable” means that the amount of the corresponding S-enantiomer within the montelukast in the packaged pharmaceutical composition has not increased by more than 0.5 % by weight from the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding S-enantiomer content has not increased by more than 0.3% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • the corresponding S-enantiomer content has not increased by more than 0.2% by weight of the initial amount of montelukast after storage at 40°C and 75% relative humidity for 3 months.
  • compositions may be in the form of liquid.
  • pharmaceutical compositions are in form of powder or granules which can be reconstituted (extemporaneous preparations) in the form of liquid.
  • pharmaceutical compositions can be suspension or solution.
  • the pharmaceutical composition is a suspension.
  • “suspension” and “solution” are interchangeable with each other.
  • “Suspension” encompasses a system in which a solid is dispersed in a liquid for example in particles of larger than colloidal size.
  • “Solution” encompasses any system in which one substance is dissolved in another.
  • extemporaneous preparation of a pharmaceutical composition is one performed at the time of use, which is before the administration of the drug to the patient.
  • the term "extemporaneous preparation” also includes a preparation done by a pharmacist or other healthcare practitioner and administered to a patient in a relatively short period of time after the preparation. More preferably, an extemporaneous preparation is a pharmaceutical composition that is not directly prepared by the pharmaceutical industry and put on the market to be used as it is, but prepared at a time usually at a time close to the administration to the patient.
  • stable oral pharmaceutical compositions comprise Montelukast, a vehicle comprising mineral oil, desiccant and optionally pharmaceutically acceptable additives.
  • the mineral oil is a mixture of alkanes in the C 15 to C 40 range from a non- vegetable (mineral) source.
  • the mineral oil is employed in an amount ranging from about 1.0 % w/v to about 99.0 % w/v, preferably about 25.0 % w/v to about 99.0 % w/v and most preferably from about 92.0 % w/v to about 99.0 % w/v based on the total volume of the composition.
  • the desiccants are selected from polyhydric alcohols, such as mannitol, sorbitol, xylitol, isomalt and maltitol, as well as tribasic calcium phosphate ⁇ dibasic calcium phosphate, calcium phosphate, kaolin, lactose, microcrystalline cellulose, powdered cellulose, precipitate calcium carbonate, starch, dextrose, dextrate, sucrose, anhydrous silicon dioxide, anhydrous ethanol, sodium metabisulfite, sodium sulfate, magnesium sulfate, magnesium oxide and mixtures thereof.
  • the preferred desiccants are colloidal silicon dioxide and magnesium oxide and mixtures thereof.
  • These agents may be employed in an amount ranging from about 0.1 % w/v to about 30.0 % w/v, preferably about 0.1 % w/v to about 10.0 % w/v and most preferably from about 0.1 % w/v to about 5.0 % w/v based on the total volume of the composition.
  • the pharmaceutically acceptable additives may include sweeteners, flavours, and preservatives.
  • Sweeteners are selected from sucrose, fructose, dipotassium glycirhizinate. Artificial sweeteners like saccharin, saccharin sodium, aspartame; mannitol, xylitol or acesulfame potassium and mixtures thereof are suitable for administration to children.
  • the sweeteners may be employed in an amount ranging from about 0.1% to about 10% w/v, preferably about 0.1% to about 7% w/v and most preferably from about 0.1% w/v to about 2% w/v based on the total volume of the composition.
  • the preservatives are selected from butylated hydroxy toluene, butylated hydroxy anisole, methyl parahydroxybenzoate, propyl parahydroxybenzoate and sodium benzoate and mixtures thereof.
  • the amount of preservative to be used is less than about 0.1 % w/v.
  • the preferred amount of the preservative to be used is less than about 0.02 %w/v.
  • the flavoring agents may be selected from cherry, vanilla, strawberry, lemon, yoghurt, cardamom, fennel, peppermint, or anise etc.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use.
  • kits comprising one or more pharmaceutical compositions of the invention.
  • the kits of the invention comprise a container or other means for holding the compositions of the invention.
  • the kit comprises (a) a first container or other means for containing a therapeutically effective amount of the Montelukast in form of powder or granules and (b) a second container or other means for containing a vehicle comprising mineral oil.
  • the kit can have additional containers or other means for containing comprising a therapeutically effective amount of additional agents. Powder or granules of montelukast and salt thereof can be prepared by methods known by one of skill in the art.
  • the minimum number of containers in the given kit will be two. In a preferred embodiments, the maximum number of containers in the kit will be less than or equal to five. In the most preferred embodiment the number of containers in the kit will be two.
  • the containers may be formed in any size or shape useful for the mixing or transferring of components from one container to another. Either or both of the first container and second container can be light-
  • the kit comprises a container or other means for containing for the separate compositions, such as, a divided bottle or a divided foil packet; however, the separate compositions can also be contained within a single, undivided container.
  • the kit may contain mixing element for example a stirrer to physically mix the Montelukast and a vehicle.
  • the kit contains printed labeling instructions.
  • the printed labeling may provide instructions for administering any of the compositions, using any of the kits, or performing any other method herein described.
  • Suitable containers or other means for containing pharmaceutical composition(s) and pharmaceutically acceptable carrier include, but are not limited to, bottles made of high- density polyethylene (HDPE), polypropylene (PP), glass, and metal.
  • the container is an amber colored glass bottle with a child resistant cap.
  • the kit is a unit dose packet (sometimes referred to in the art as a "sachet"), which is typically emptied into the mineral oil in preparing an oral suspension.
  • the invention in another aspect provides a simple one-step transfer method for preparing a pharmaceutical composition(s).
  • a single dose sachet is designed to be emptied into the mineral oil or alternatively the mineral oil is added to a bottle containing the single dose pharmaceutical composition followed by gentle mixing for about 1-2 minutes result in a homogeneous and uniform dispersion or solution of the drug.
  • step-1 Dissolve Silicon Dioxide in step-1 solution to get a clear solution.
  • step-2 Disperse Sucralose and Magnesium Oxide in step-2 solution with stirring to get uniform suspension.
  • step-3 suspension Disperse Montelukast Sodium in step-3 suspension with stirring. Add Peppermint Oil to step 3 suspension with stirring and stir for 10 min.
  • step- 1 Dissolve Silicon Dioxide in step- 1 solution to get a clear solution.
  • step-2 Disperse Saccharin and Magnesium Oxide in step-2 solution with stirring to get uniform suspension.
  • step-1 Disperse Magnesium Oxide in step-1 solution with stirring to get uniform suspension.
  • step-2 Disperse Montelukast Sodium in step-2 suspension with stirring.
  • step 4 Add Peppermint Oil to step 2 suspension with stirring and stir for 10 min.
  • step-2 Disperse Magnesium Oxide in step-1 solution with stirring to get uniform suspension. 3. Disperse Montelukast Sodium in step-2 suspension with stirring.
  • step 4 Add Peppermint Oil to step 2 suspension with stirring and stir for 10 min.
  • Example 4 Composition of Example 4 was subjected to stability studies at 40° C and 75% RH for 3 months. After one month, two month and three month sample was removed and checked for various parameters. Data of 1, 2 and 3 month stability studies is shown in Table 1.
  • Stability Conditions 40° C and 75% RH for 1 Month, 2 Month and 3 Month

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pulmonology (AREA)
  • Transplantation (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale, liquide et stable comprenant du montélukast, un véhicule comprenant une huile minérale, un agent dessicant et facultativement des additifs pharmaceutiquement acceptables. L'invention concerne en outre un kit d'administration de compositions pharmaceutiques orales de montélukast. Le kit comprend du montélukast, un véhicule comprenant une huile minérale, un agent dessicant et facultativement des additifs pharmaceutiquement acceptables. Le kit comprend un premier récipient comprenant une composition pharmaceutique de montélukast et facultativement un agent dessicant, un second récipient comprenant un véhicule comprenant une huile minérale, facultativement un agent dessicant et des additifs pharmaceutiquement acceptables, ainsi qu'un mode d'emploi. Le montélukast et l'huile minérale occupent un volume pré-mesuré dans l'unité respective du kit.
PCT/IB2011/002661 2010-11-16 2011-11-10 Compositions pharmaceutiques orales stables de montélukast Ceased WO2012066401A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2013538284A JP2013545743A (ja) 2010-11-16 2011-11-10 モンテルカストの安定な経口医薬組成物
EP11796805.7A EP2640355A1 (fr) 2010-11-16 2011-11-10 Compositions pharmaceutiques orales stables de montélukast

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1301KO2010 2010-11-16
IN1301/KOL/2010 2010-11-16

Publications (1)

Publication Number Publication Date
WO2012066401A1 true WO2012066401A1 (fr) 2012-05-24

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PCT/IB2011/002661 Ceased WO2012066401A1 (fr) 2010-11-16 2011-11-10 Compositions pharmaceutiques orales stables de montélukast

Country Status (3)

Country Link
EP (1) EP2640355A1 (fr)
JP (1) JP2013545743A (fr)
WO (1) WO2012066401A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015163978A1 (fr) * 2014-04-25 2015-10-29 R.P. Scherer Technologies, Llc Solution stable de montélukast
WO2015170835A1 (fr) * 2014-05-07 2015-11-12 Hanmi Pharm. Co., Ltd. Préparation liquide plus stable comprenant du montélukast ou un sel de montélukast pharmaceutiquement acceptable, et procédé de préparation associé

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565473A (en) 1990-10-12 1996-10-15 Merck Frosst Canada, Inc. Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists
US20060147482A1 (en) 2005-01-04 2006-07-06 Center Laboratories, Inc. Oral liquid pharmaceutical composition of leukotriene antagonists
US20070184108A1 (en) * 2006-02-09 2007-08-09 Julia Hrakovsky Stable pharmaceutical formulations of montelukast sodium
WO2007126865A2 (fr) * 2006-03-30 2007-11-08 Patrin Pharma Administration nasale d'antagonistes de leukotriènes
US20090247575A1 (en) 2008-03-26 2009-10-01 Taro Pharmaceuticals North America, Inc. Stabilizing lipid compositions for oral pharmaceutical agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565473A (en) 1990-10-12 1996-10-15 Merck Frosst Canada, Inc. Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists
US20060147482A1 (en) 2005-01-04 2006-07-06 Center Laboratories, Inc. Oral liquid pharmaceutical composition of leukotriene antagonists
US20070184108A1 (en) * 2006-02-09 2007-08-09 Julia Hrakovsky Stable pharmaceutical formulations of montelukast sodium
WO2007126865A2 (fr) * 2006-03-30 2007-11-08 Patrin Pharma Administration nasale d'antagonistes de leukotriènes
US20090247575A1 (en) 2008-03-26 2009-10-01 Taro Pharmaceuticals North America, Inc. Stabilizing lipid compositions for oral pharmaceutical agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015163978A1 (fr) * 2014-04-25 2015-10-29 R.P. Scherer Technologies, Llc Solution stable de montélukast
US9717684B2 (en) 2014-04-25 2017-08-01 R.P. Scherer Technologies, Llc Stable montelukast solution
WO2015170835A1 (fr) * 2014-05-07 2015-11-12 Hanmi Pharm. Co., Ltd. Préparation liquide plus stable comprenant du montélukast ou un sel de montélukast pharmaceutiquement acceptable, et procédé de préparation associé

Also Published As

Publication number Publication date
EP2640355A1 (fr) 2013-09-25
JP2013545743A (ja) 2013-12-26

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