WO2009122187A2 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2009122187A2
WO2009122187A2 PCT/GB2009/000891 GB2009000891W WO2009122187A2 WO 2009122187 A2 WO2009122187 A2 WO 2009122187A2 GB 2009000891 W GB2009000891 W GB 2009000891W WO 2009122187 A2 WO2009122187 A2 WO 2009122187A2
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WO
WIPO (PCT)
Prior art keywords
leukotriene
receptor antagonist
pharmaceutical composition
coating material
coated
Prior art date
Application number
PCT/GB2009/000891
Other languages
English (en)
Other versions
WO2009122187A3 (fr
Inventor
Amar Lulla
Geena Malhotra
Original Assignee
Cipla Limited
Curtis, Philip, Anthony
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 Cipla Limited, Curtis, Philip, Anthony filed Critical Cipla Limited
Publication of WO2009122187A2 publication Critical patent/WO2009122187A2/fr
Publication of WO2009122187A3 publication Critical patent/WO2009122187A3/fr

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Classifications

    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a pharmaceutical composition, especially a stable pharmaceutical composition. More particularly, the invention is directed to a stable pharmaceutical composition comprising leukotriene receptor antagonist and a method to manufacture the same.
  • Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid. Leukotrienes work to contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells in the airways of patients with asthma. The action of leukotriene can be blocked through either of two specific mechanisms: (1) inhibition of leukotriene production and/or (2) antagonism of leukotriene binding to cellular receptors.
  • Leukotriene-receptor antagonists have a unique profile in that they are a hybrid of antiinflammatory effects (antagonism of proinflammatory activities of leukotrienes) and bronchodilator effects (antagonism of leukotriene-induced smooth-muscle bronchoconstriction). Leukotriene-receptor antagonists are also effective in treating allergic rhinitis, which commonly coexists in patients with asthma.
  • US5565473 (to Merck Frosst Canada Inc, filed on February 23, 1995) teaches a process of preparation of leukotriene antagonists and their use as anti-asthmatic, anti-allergic, antiinflammatory, and cytoprotective agents. They are also said to be useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.
  • WO0021536 (to Sheftell Fred D., filed on October 12, 1999) discusses a method of treatment using leukotriene antagonist drugs to prevent and treat recurrent primary headaches, which includes migraine headaches and cluster headaches.
  • WO2007005965 (to Teva Pharmaceutical Industries Limited, filed on July 5, 2006) describes a method of purifying montelukast sodium, isolating impurities like MLK-SO, MLK-D and formulating the same. The patent discloses that there are impurities present during the processing of montelukast sodium.
  • EP 1059917 discloses a sustained-release delivery system and a method of administering leukotriene receptor antagonists in a rate- controlled dose over time.
  • US6221880 (to Schering Corporation, filed on October 6, 1999) teaches a pharmaceutical composition comprising a combination of a neurokinin antagonist and a leukotriene receptor antagonist and a method of treatment of allergic rhinitis and other respiratory diseases using the same.
  • WOO 160407 (to Asta Medica, filed on February 5, 2001) describes a pharmaceutical composition comprising a combination of a non sedating antihistamine and a leukotriene receptor antagonist or a FLAP antagonist to be administered topically and orally.
  • WO03035036 discloses flowable and dispersible granule compositions for packaging. The patent further mentions that these granules can be medicated and can be directly or indirectly mixed with food or other comestibles.
  • WO2007092031 discloses a pharmaceutical composition comprising montelukast sodium and excipients which reduce sulfoxide impurities. More particularly, the patent discloses that the impurity results from microcrystalline cellulose and thus a stable pharmaceutical composition devoid of microcrystalline was formulated into film-coated and chewable tablets.
  • the degradation of montelukast during storage and manufacture to its sulfoxide impurity still presents a problem in montelukast compositions of the state of the art.
  • the degradation inter alia, reduces the effective dosage of montelukast of the dosage form.
  • An object of the present invention is to provide a pharmaceutical composition comprising a plurality of coated leukotriene antagonist and manufacture of the same. Another object is to provide a stable pharmaceutical composition of this form.
  • Another object of the invention is to provide a process for the preparation of a coated leukotriene antagonist, which is capable of withstanding formulation and storage conditions that otherwise may cause its decomposition and degradation.
  • Yet another object of the invention is to provide a taste-masked composition of a leukotriene antagonist.
  • Further object of the invention is to provide a method of treatment and prevention of leukotriene-mediated diseases and disorder using the stable pharmaceutical composition.
  • a pharmaceutical composition comprising a plurality of coated leukotriene antagonist particles along with suitable pharmaceutical excipients to achieve an effective taste masked composition.
  • a process of manufacturing a pharmaceutical composition according to the present invention there is provided a pharmaceutical composition for use in the treatment/prophylaxis of conditions requiring alleviation of asthma, allergic rhinitis and related disorders.
  • a pharmaceutical composition comprising a plurality of coated leukotriene antagonist particles with at least one of the drugs of class selected from 5-lipooxygenase inhibitor, corticosteroids, antihistamine or neurokinin inhibitors.
  • leukotriene antagonist encompasses the free from of the active material, and also its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its pharmaceutically acceptable enantiomers, its pharmaceutically acceptable derivatives, its pharmaceutically acceptable polymorphs or its pharmaceutically acceptable prodrugs. This especially applies to the preferred leukotriene antagonist, which is montelukast.
  • the at least some of the particles of the leukotriene receptor antagonist are at least partially coated with the coating material.
  • the amount of coating material should be selected to provide taste-masking and improved stability of the pharmaceutical composition. It is an important feature of the invention that the coating does not substantially interfere with the release properties of the pharmaceutical composition, i.e., the composition should be an immediate release formulation, rather than a sustained release one.
  • montelukast compositions are subject to degradation during manufacture and storage. It is believed that the montelukast degrades into corresponding sulfoxide impurity.
  • the sulfoxide is an inactive impurity, which reduces the effective dosage of montelukast when it is administered to patients.
  • a stable pharmaceutical composition comprising a leukotriene-receptor antagonist optionally in combination with one or more pharmaceutical excipients, wherein the leukotriene-receptor antagonist, or combination of the leukotriene-receptor antagonist and the or each excipient, is coated with a suitable material.
  • coating refers to a process for covering or surrounding a single or plurality of particle(s) with one or more layers of a coat forming material to stabilize the particle(s).
  • coated has a somewhat different meaning compared to “coating” and refers to a single or plurality of particle(s) which is covered with or surrounded by a coat forming material, wherein the coat forming material remains distinct from the single particle that it covers, and with whose aid the particle is stabilized. While the covering by the coat forming material does not necessarily need to be uniform or to cover or surround the entire particle surface, the covering by the coat forming material should be sufficient to impart improved stability.
  • the coating can also completely cover or encase the particle in a substantially uniform layer.
  • the coated particles as defined herein may include not only completely or partially coated particles but also mixtures thereof. It is also preferable that the coated particle, when dried, has no substantial gain in moisture relative to its uncoated form.
  • stable means that the increase in the amount of the sulfoxide impurity within the montelukast or salt thereof coated in accordance with the present invention is less than the increase in the corresponding amount of sulfoxide impurity within uncoated montelukast or salt thereof stored and/or manufactured under the same conditions.
  • sulfoxide impurity refers to montelukast or a salt thereof wherein the sulfide group in the [beta] -position relative to the cyclopropane group has been oxidized to a sulfoxide group.
  • Leukotriene-receptor antagonists which are non-steroidal, are also known as LTRAs or antiinflammatory bronchoconstriction preventors.
  • the leukotrience antagonist may be, for example, zafirlukast, montelukast, pranlukast, zileuton, leucettamine A and related imidazole alkaloids from the marine sponge Leucetta micro or aphis, which is a specific leukorriene B4 (LTB4) receptor antagonist which inhibits human neutrophil aggregation, chemotaxis and degranulation induced by LTB4 and LY2931 1 1 (2- [2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]- phenoxy] benzoic acid sodium salt).
  • LTB4 leukorriene B4
  • the various available salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof of the various leukorriene antagonists mentioned above may be used.
  • the preferred one is montelukast, preferably montelukast sodium
  • Montelukast sodium is the common name of the compound: [R-(E)J-I -[[[ 1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l -hydro-xy-1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
  • Montelukast sodium is a hygroscopic, optically active, and white to off-white powder.
  • Montelukast sodium is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.
  • the present invention involves coating the leukotriene antagonist with suitable polymer such as water soluble polymers, water insoluble polymers, water swellable polymers or mixtures thereof.
  • Said polymer may be selected from water soluble polymers like cellulose polymers, povidones, polyvinyl alcohols; water insoluble polymers like acrylic polymers; pharmaceutically acceptable waxes like synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono, di or tribehenates, glyceryl tristearate, glyceryl tripalmitate; long-chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures thereof.
  • suitable water soluble polymers include, but are not limited to, alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose ; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; starches; pectins such as sodium carboxymethylamylopectin; chitin derivatives such as chitosan; polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans,galactomannans, tragacanth, agar-agar, gum arabicum, guar gum and
  • the water insoluble polymer that may be used, according to the present invention, comprises acrylic copolymers e.g. Eudragit ElOO or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 3OD (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.). These polymers are used alone or in admixtures.
  • acrylic copolymers e.g. Eudragit ElOO or Eudragit EPO
  • Eudragit L30D-55 Eudragit FS30D
  • Eudragit RL30D Eudragit RS30D
  • Eudragit NE30D Eudragit NE30D
  • Acryl-Eze
  • the present invention also encompasses a process for the preparation of the coated leukotriene antagonist(s).
  • Coating advantageously involves spraying the coating solution over powder bed of leukotriene-receptor antagonist.
  • the coated leukotriene antagonist particles are dried and then formulated into required dosage form.
  • coating processes or techniques which may be envisaged by the present invention includes spray drying, turbo drying, pan coating, fluidized bed coating. Fluidized bed coating methods, however, are preferred.
  • a formulation having a plurality of coated leukotriene antagonist(s) particles.
  • the coated particles so obtained are then further mixed with other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients comprise one or more diluents, one or more binders, one or more disintegrants, and/or one or more lubricants/glidants.
  • Suitable diluents may include, for example, calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powders, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, lactose anhydrous, tablettose, mannitol, Pearlitol SD 200, sorbitol, Microcelac, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof, and mixtures thereof.
  • the amount of diluent is preferably in the range of 10% to 80% by weight of the composition.
  • Suitable binders may include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, microcelac, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof, and mixtures thereof.
  • the amount of binder is preferably in the range of 2% to 10% by weight of the composition.
  • Suitable disintegrants may include, for example, hydroxypropyl cellulose, low substituted- hydroxypropylcellulose, L-HPC, carboxymethyl cellulose, calcium carboxymethylcellulose, sodiumcarboxymethycellulose, croscarmellose sodium, starch, crystalline cellulose sodium starch glycollate, starch, pregelatinized starch, crospovidone and equivalents thereof, and mixtures thereof.
  • the amount of disintegrant is preferably in the range of 3% to 30% by weight of the composition.
  • Suitable lubricants/glidants may include, for example, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and sucrose esters fatty acid, microcrystalline wax, colloidal silicon dioxide, and equivalents thereof, and mixtures thereof.
  • the amount of lubricant/glidant is preferably in the range of 0.25% to 5% by weight of the composition.
  • the pharmaceutical composition may also include other pharmaceutical acceptable excipients such as anti-caking agents, coloring agents, which include, but are not limited to, red oxide of iron, yellow oxide of iron; ready color mix system, which includes, but is not limited to, Opadry; and suitable pharmaceutically acceptable sweeteners and flavoring agents.
  • pharmaceutical acceptable excipients such as anti-caking agents, coloring agents, which include, but are not limited to, red oxide of iron, yellow oxide of iron; ready color mix system, which includes, but is not limited to, Opadry; and suitable pharmaceutically acceptable sweeteners and flavoring agents.
  • the pharmaceutical composition comprising a plurality of coated leukotriene antagonist, a diluent; a disintegrant; a binding agent; lubricant/glidant and optionally suitable pharmaceutical excipients like anti-caking agent, colorant, sweetener, flavoring agent.
  • the pharmaceutical composition of the present invention may be administered in various preparations depending on the age, sex, and symptoms of the patient.
  • the pharmaceutical compositions can be administered, for example, as tablets, capsules (either solid-filled, semisolid filled or liquid filled), pills, powders, liquids, suspensions, emulsions, granules, dispersible granules, powders for constitution, oral gels, elixirs, suppositories, topical composition includes inhalers, sprays, creams, lotions, gels and injection preparations (solutions and suspensions), and the like.
  • the composition is a solid composition, especially a granule, tablet, chewable tablet, capsule, or pellet and the like. More preferably the composition is tablet.
  • the tablet composition is especially film coated, sugar coated, chewable, multilayer, and dispersible and the like.
  • the pharmaceutical composition comprises plurality of coated montelukast sodium or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs along with one or more excipients which includes, but are not limited to, one or more diluents, one or more disintegrants, one or more lubricants and glidants.
  • the present invention may be in combination comprising coated leukotriene antagonist with atleast one of the drugs of class like 5-lipooxygenase inhibitors, corticosteroids, FLAP inhibitors, antihistamines, long-acting beta-2 antagonist or salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof.
  • drugs of class like 5-lipooxygenase inhibitors, corticosteroids, FLAP inhibitors, antihistamines, long-acting beta-2 antagonist or salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof.
  • the present invention further provides a method of prophylaxis and/or treatment of asthma, COPD (chronic obstructive pulmonary disease) and related disorders; relief of symptoms of seasonal allergic rhinitis and perennial allergic rhinitis; prevention of exercise-induced bronchospasm by use of a therapeutically effective amount of the coated drug in a suitable pharmaceutical composition of the present invention to a mammal in need thereof.
  • COPD chronic obstructive pulmonary disease
  • a coating solution was prepared by dissolving hypromellose in purified water and sprayed over powder bed continuously.
  • Step 1 Dry mix formed in Step 1 which was then compressed into tablet.
  • Step 2 Dry mix formed in Step 1 which was then compressed into tablet.
  • a binder solution of Povidone in purified water was prepared.
  • Granules were prepared using the binder solution; dried and blended with L-HPC, aspartame, and magnesium stearate and compressed into tablets.
  • Step 2 Dry mix formed in Step 1 which was then compressed into tablet.
  • Granules were prepared using the binder solution; dried and blended with low substituted-hydroxypropyl cellulose and magnesium stearate and compressed into tablets.
  • a binder solution prepared by dissolving Povidone in purified water.
  • Granules were prepared using the binder solution; dried and blended with disintegrant, sweetener and lubricant and compressed to form a tablet layer.
  • Levocetrizine Dihydrochloride Layer 4 Sifted Levocetrizine dihydrochloride, tabelettose, lactose, lactose anhydrous, avicel, red oxide of iron, Crospovidone and magnesium stearate was loaded in a blender to form a dry mix.
  • Step 4 The dry mix obtained in Step 4 was compressed to form Levocetrizine dihydrochloride layer onto compressed Montelukast Sodium layer formed in Step 3 to form a bilayer tablet.
  • Montelukast sodium was coated with coating solution containing HPMC, Mannitol and purified water in fluidized bed granulator.
  • step 2 The blend of step 2 was then sifted and lubricated with magnesium stearate.
  • a comparative stability testing was carried out for the formulations comprising plain API and coated API (as per the invention) for the amount of sulfoxide impurity as shown in the table below.
  • the table above depicts that the amount of sulfoxide impurity in the formulation comprising coated montelukast sodium is relatively less than that in the formulation comprising uncoated montelukast sodium. This demonstrates the surprising improved stability of the pharmaceutical composition comprising coated montelukast sodium during storage and manufacture.
  • a preservative includes a single preservative as well as two or more different preservatives
  • reference to a surfactant refers to a single surfactant or combination of two or more surfactants, and the like.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une composition pharmaceutique comprenant un antagoniste des récepteurs des leucotriènes, facultativement en combinaison avec un ou plusieurs excipients pharmaceutiques, l'antagoniste des récepteurs des leucotriènes comprenant une pluralité de particules, et une partie ou la totalité des particules étant enrobée d'un matériau d'enrobage approprié. L'invention porte également sur un procédé de fabrication de la composition, en particulier à l'aide d'un séchage par atomisation en lit fluidisé.
PCT/GB2009/000891 2008-04-03 2009-04-03 Composition pharmaceutique WO2009122187A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN789/MUM/2008 2008-04-03
IN789MU2008 2008-04-03

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WO2009122187A2 true WO2009122187A2 (fr) 2009-10-08
WO2009122187A3 WO2009122187A3 (fr) 2010-06-24

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CN103720672A (zh) * 2014-01-26 2014-04-16 新疆特丰药业股份有限公司 孟鲁司特钠咀嚼片及其粉末直接压片制备方法
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CN106491556A (zh) * 2016-10-21 2017-03-15 江苏阿尔法药业有限公司 一种稳定的孟鲁司特钠肠溶微丸

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Cited By (11)

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Publication number Priority date Publication date Assignee Title
WO2009153305A2 (fr) * 2008-06-19 2009-12-23 Sandoz Ag Compositions pharmaceutiques de sodium de montélukast
WO2009153305A3 (fr) * 2008-06-19 2010-12-29 Sandoz Ag Compositions pharmaceutiques de sodium de montélukast
WO2012064302A3 (fr) * 2010-11-11 2012-07-19 Mahmut Bilgic Préparations de montélukast améliorées
WO2012064301A3 (fr) * 2010-11-11 2012-07-19 Mahmut Bilgic Formulations de comprimés aux propriétés physiques améliorées
WO2012064303A3 (fr) * 2010-11-11 2012-07-19 Mahmut Bilgic Combinaisons améliorées de montélukast
US20150072961A1 (en) * 2012-01-18 2015-03-12 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
US11813256B2 (en) 2012-01-18 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions
US11857545B2 (en) * 2012-01-18 2024-01-02 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
CN103655497A (zh) * 2013-12-18 2014-03-26 北京华禧联合科技发展有限公司 一种孟鲁司特钠口腔崩解片及其制备方法
CN103720672A (zh) * 2014-01-26 2014-04-16 新疆特丰药业股份有限公司 孟鲁司特钠咀嚼片及其粉末直接压片制备方法
CN106491556A (zh) * 2016-10-21 2017-03-15 江苏阿尔法药业有限公司 一种稳定的孟鲁司特钠肠溶微丸

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