WO2007054968A2 - Compositions pharmaceutiques atypiques de mesylate de clopidogrel - Google Patents

Compositions pharmaceutiques atypiques de mesylate de clopidogrel Download PDF

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Publication number
WO2007054968A2
WO2007054968A2 PCT/IN2006/000375 IN2006000375W WO2007054968A2 WO 2007054968 A2 WO2007054968 A2 WO 2007054968A2 IN 2006000375 W IN2006000375 W IN 2006000375W WO 2007054968 A2 WO2007054968 A2 WO 2007054968A2
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WO
WIPO (PCT)
Prior art keywords
clopidogrel
pharmaceutical composition
solid oral
oral pharmaceutical
clopidogrel mesylate
Prior art date
Application number
PCT/IN2006/000375
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English (en)
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WO2007054968A3 (fr
Inventor
Rakesh Sheth
Original Assignee
Torrent Pahrmaceuticals Limited
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Publication of WO2007054968A2 publication Critical patent/WO2007054968A2/fr
Publication of WO2007054968A3 publication Critical patent/WO2007054968A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive 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
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/48—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
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to stabilized pharmaceutical compositions of clopidogrel mesylate, which is highly hygroscopic, unstable salt and the process for preparing such compositions.
  • Clopidogrel and its salts by virtue of its anti platelet aggregation effect, acts as an anti thrombotic agent.
  • Clopidogrel is a compound disclosed in US4847265.
  • Clopidogrel (Clopidogrel bisulfate) is available in the United States and elsewhere under the trade name of PLAVIX' * '. (Sanofi Pharma/Bristol-Myers Squibb Partnership, New York, USA).
  • PLAVIX ⁇ contains Hydrogenaied Castor Oil, Hydroxypropylcellulose, M ⁇ mitol, Microcrystalline Cellulose and Polyethylene Glycol 6000 as inactive ingredients.
  • the pink film coating contains ferric oxide, Hydroxypropyl Methylcellulose 2910, Lactose Monohydrate, Titanium Dioxide and Triacetin.
  • the tablets are polished with Carnauba Wax. (Physician's Desk Reference, 59 U1 Ed, pp. 1052-1055 (2005).)
  • WO2004026879 discloses clopidogrel, or a pharmaceutically acceptable salt thereof, in an amorphous form. This prior art describes stabilization of amorphous clopidogrel salts by complexation of at least a homopolymer or copolymer of N- vinyl pyrrolidone.
  • WO2004074215 discloses various salts of clopidogrel along with compositions and process related with the same.
  • the prior art describes hygroscopic nature of various salts of clopidogrel.
  • This prior art discusses variety of formulations like tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs, creams, ointments, gels, lozenges, aerosol, parenteral (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing.
  • the tablets of clopidogrel salts can be coated with polymers like ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, Eudragit ElOO and their combinations thereof for providing protection against moisture.
  • the tablets can be moisture protected by suitable excipients by making tablet in tablet formulation by compression coating.
  • suitable excipients by making tablet in tablet formulation by compression coating.
  • WO2005048992 also teaches about the process of preparing clopidogrel compositions.
  • the composition described comprises a) a polymer coating selected from polyvinyl acetate or a polyvinyl alcohol, and b) a hydrophobic component comprising a hydrogenated vegetable oil on clopidogrel.
  • the process is carried out in a low or ultra low humidity enviroment.
  • the said prior art describes manufacturing of clopidogrel composition by compaction of clopidogrel with other excipients then compressing the granules into tablets, which is coated with moisture barrier coating. This moisture barrier coating of tablet prevents the hygroscopic active ingredient from degradation.
  • WO 2005048992 doesn't provide any conclusive evidence to prove the stability of the fo ⁇ nulation.
  • the prior art emphasizes on film coating of tablets with Opadry® AMB, due to single coat over the moisture labile core, any small damage to coated tablet can result in product detonation and cause stability problems. This damage to the coat may happen during coating, or packaging.
  • coating of compacted granules or particles as discussed in the prior art may cause problems due to friable nature of the compacted granules.
  • US2005256152 Al discloses formulation of various sulphonic acid derivatives of clopidogrel.
  • the application discloses preparation of adsorbates of sulphonic acid derivatives of clopidogrel with mannitol, lactose, microcrystalline cellulose, etc and their subsequent use in manufacturing of tablets. It only discusses the decrease of active ingredient content during 15 days of storage at elevated temperature/humidity condition.
  • WO 2006074066 Al discloses non crystalline formulation comprising clopidogrel.
  • the process of manufacturing involves complex technologies like "SEDS” (Solution Enhanced Dispersion by Supercritical Fluids), freeze drying, spray freeze drying etc.
  • SEDS Solution Enhanced Dispersion by Supercritical Fluids
  • the present invention relates to stabilized pharmaceutical compositions of clopidogrel mesylate, which is highly hygroscopic, unstable salt and the process for preparing such compositions.
  • the inert granular core is optionally seal coated with hydrophobic polymers or waxes to provide a strong core for drug loading, and then subsequent drug loading on core is done.
  • These drug layered multiple units are again seal coated using polymers and optionally with other moisture barrier agents.
  • These coated plurality of individual active compound units are then compressed into tablets by using suitable excipients. These tablets are filmcoated with moisture barrier agent and other excipients required for film coating.
  • Another object of the present invention is to provide a process for the preparation of stabilized compositions of clopidogrel mesylate.
  • Present invention provides stabilized pharmaceutical compositions of clopidogrel mesylate.
  • an stabilized pharmaceutical composition for manufacturing oral dosage form of clopidogrel mesylate which is liquid, unstable, and highly hygroscopic in nature.
  • an administration form which comprises a plurality of individual active compound units, along with various excipients compressed into tablets, shows good stability.
  • the plurality of individual active compound units is manufactured by using inert granular core, the inert granular core is optionally seal coated with hydrophobic polymers or waxes to provide a strong core for drug loading, and then subsequent drug loading on core is done. These drug layered multiple units are again seal coated using polymers and optionally other moisture barrier agents. These coated plurality of individual active compound units are either filled in to capsules or compressed into tablets by using suitable excipients. These tablets are film coated with moisture barrier agent and other excipients required for film coating.
  • an immediate release pharmaceutical composition comprising plurality of inert cores coated with clopidogrel mesylate solution, which is further coated with moisture barrier agents.
  • the pluralities of inert cores are seal coated with hydrophobic agents, anti tacking agents and suitable non-aqueous solvents.
  • the seal coating of inert cores will provide following advantages: a) The seal coated pluralities of inert cores will reduce the friability of the inert granular core, which will improve the further coating quality. b) The seal coating of pluralities of inert cores will reduce the drug loss during further coating. c) The seal coating of inert core with hydrophobic agents may improve the stability of the product.
  • the hydrophobic agent for the seal coating may be selected from ethylcellulose or cellulose derivatives, waxes or the combination thereof. These seal coated pluralities of inert cores, are further coated with clopidogrel mesylate, binder, anti tacking agent and suitable non-aqueous solvents. These pluralities of active cores are then coated with moisture barrier layer.
  • the seal coating moisture barrier agent may be selected from ethyl cellulose, hydrogenated castor oil, beeswax, or Eudragit. In preferred embodiment, moisture barrier agent may be ethyl cellulose, beeswax and hydrogenated castor oil. These coated cores are either filled into capsules or compressed in tablets using suitable excipients known to the person skilled in the art.
  • the tablet is film coated, which has moisture barrier properties. Hence, the moisture barrier is applied in several steps; this will result in improved stable product. Also, a friability issue related with coating of compacted granules is resolved in instant invention by using seal coated inert core followed by drug layering. '
  • the coated plurality of individual active compound units is then compressed into tablets by using suitable excipients. These tablets are filmcoated with moisture barrier agent and other excipients required for film coating.
  • the plurality of individual active compound units is manufactured by using inert granular core, the inert granular core is coated with drug and one or more pharmaceutically acceptable excipients. These drug layered multiple units are again seal coated using filmcoating polymer and one or more pharmaceutically acceptable excipients. These seal coated plurality of individual active compound units are either filled in to capsules or compressed into tablets by using suitable excipients. These tablets are film coated with moisture barrier agent and other excipients required for film coating.
  • an immediate release pharmaceutical composition of clopidogrel mesylate comprising of plurality of individual active compound units coated by Wurster process in Fluid bed processor (e.g GPGC 3, Glatt Air Technique, Ramsey, N.J.; Glatt) alongwith at least one or more excipients to give stable product, which can be packed in HDPE containers, PVC blister, PVC-PVDC blister or AIu-AIu blister.
  • Fluid bed processor e.g GPGC 3, Glatt Air Technique, Ramsey, N.J.; Glatt
  • an immediate release pharmaceutical composition comprising a drug; wherein the pharmaceutical composition is manufactured under controlled humidity, for example relative humidity of less than about 40% and, more particularly, less than about 20%.
  • composition according to the present invention can be prepared in a form of tablet, hard gelatine capsule or sachet, preferably in the form of a tablet or capsule.
  • the active ingredient used in the present pharmaceutical composition is clopidogrel mesylate.
  • compositions as used herein includes solid dosage forms such as tablet, capsule, pill, and the like.
  • the tablets can be prepared by techniques known in the art and contain a therapeutically effective amount of the active ingredient and such excipients as are necessary to form the tablet by such techniques.
  • the pharmaceutical composition of the present invention typically comprises from 30mg to 180mg of clopidogrel mesylate.
  • the formulation of this invention preferably comprises 25mg to 150mg clopidogrel.
  • the term "individual active compound unit” as used herein refers to an individual unit comprising at least one active compound particle. Preferably in the individual units, the active compound is surrounded by at least one polymer.
  • the individual active compound unit may include granule, pellet, bead, particle, tablet, mini tablet and the like.
  • plurality refers one or more than one, preferably more than one active compound unit
  • the solid dosage form tablet or capsule of the present invention is prepared using active ingredient i.e., clopidogrel mesylate and pharmaceutically acceptable excipients selected from the group comprising of diluents, disintegrants, binders, lubricants, glidants and optionally an anti oxidants as a stabilizer with other pharmaceutically acceptable excipients
  • active ingredient i.e., clopidogrel mesylate
  • pharmaceutically acceptable excipients selected from the group comprising of diluents, disintegrants, binders, lubricants, glidants and optionally an anti oxidants as a stabilizer with other pharmaceutically acceptable excipients
  • Diluents can be selectee! from the group comprising of lactose, starch, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, kaolin sucrose mannitol, precipitated calcium carbonate, sorbitol, maltodextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose or other materials known to one of ordinary skill in the art .
  • the diluents in the dosage from ranges from 5% t o80 % by weight of the composition.
  • Binders can be selected from the group comprising of polyvinylpyrrolidone or hydroxypropyl methylcellulose, acacia, alginic acid, hydroxy propyl cellulose, low substituted hydroxy propyl cellulose, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch or other materials known to one of ordinary skill in the art.
  • the preferred binder in the dosage form may be selected from the group of hydroxy propyl cellulose, low substituted hydroxy propyl cellulose.
  • the binders in the dosage form ranges from 0.5% to 50% by weight of the composition, preferably between 3% to 15% by the weight of the composition.
  • the film coating can be polymer based or wax based and can be selected from hydroxypropyl methylcellulose, hydrogenated castor oil, hydroxypropyl cellulose, ethyl cellulose, beeswax, Eudragits. methyl cellulose, povidone, copovidone, starch derivatives, sugar derivatives, or other materials known to one of ordinary skill in the art. It was found that hydrogenated castor oil, beeswax and ethyl cellulose provide required protection against moisture.
  • the preferred film coating polymer or wax for film coating may be selected from the group consit ⁇ ng of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose. hydrogenated castor oil or beeswax.
  • the polymers and/or waxes used for the film coating in the dosage form ranees from 0.5% to 15% by weight of the composition, preferably between 5% to 12% and more preterabiv between 7% to 10%.
  • Disintegrants can be selected from the group comprising of starch, hydroxy propyl cellulose sodium starch glycolate, croscarmeliose sodium, crospovidone. alginic acid. carboxymethyl cellulose sodium low substituted hydroxy propyi cellulose guar gum or other materials known TO one of ordinary skill in the art
  • the preferred disintegrant may be low substituted hydroxy propyl cellulose.
  • the disintegrants i n the dosage form ranges from 0 .5% to 25% by weight of the composition preferably between 1% to 10% by weight of the composition.
  • Lubricants can be selected from the group comprising of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, sodium stearyl fumarate, silicon hydrogel or other materials known to one of ordinary skill in the art.
  • the preferred lubricant may be selected from the group of hydrogenated castor oil and stearic acid.
  • the lubricants in the dosage form ranges from 0.5% to 20% by weight of the composition, preferably between 1% to 10% by weight of the composition.
  • Glidants or flow enhancer can be selected from the group comprising of colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, or other materials known to one of ordinary skill in the art.
  • the glidents in the dosage form ranges from 0.25% to 5% by weight of the composition.
  • Anti sticking agents can be selected from talc, magnesium stearate, stearic acid, hydrogenated castor oil or other materials known to one of ordinary skill in the art.
  • the anti sticking agents in the dosage form ranges from 0.25% to 20% by weight of the composition.
  • Plasticizers useful in the invention comprise, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly (propylene glycol), multi-block polymers, single block polymers, poly (ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin.
  • plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3- butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol, monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetylributycitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate.
  • plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation.
  • the plasticizers in the dosage form ranges from 1% to 35% by weight of the film forming polymer.
  • the moisture barrier agent may be selected from ethyl cellulose, hydrogenated castor oil, beeswax, or Eudragits or other materials known to one of ordinary skill in the art.
  • the preferred moisture barrier agent may be selected from the group of hydrogenated castor oil and beeswax.
  • the moisture barrier agent in the dosage form ranges from 0.15% to 25% by weight of the composition, preferably between 0.2% to 5% by weight of the composition.
  • the Stabilizer may be selected from butylated hydroxy anisole, butylated hydroxy toluene, citric acid anhydrous or hydrous, benzoic acid, lanoline, sulphated derivatives, Ortho-phosphoric acid alone or in combinations there of.
  • the antioxidant in the dosage form ranges from 0.1% to 15% by weight of the composition.
  • the inert granular core in the instant invention can be selected from mannitol (Pearlitol SD 200), microcrystalline cellulose, sugar globules, non-peril seed or other materials known to one of ordinary skill in the art.
  • the inert granular core may include inert granules, pellet, bead, particle, tablet, mini tablet and the like.
  • the inert granular core in the dosage form ranges from 10% to 75% by weight of the composition.
  • the solvent may be selected from the group of methanol, methylene chloride, isopropyl alcohol, n-heptane, n-pentane, tetrahydrofuran , acetone or other materials known to one of ordinary skill in the art.. Surprisingly it was also found that use of n-heptane alongwith solvents like methanol or acetone, will help in reducing the levels of solvents in the formulation.
  • Other components may include talc as antitacking agent, titanium dioxide as opacifier, and iron oxides as colouring agents, hydrogenated castor oil as anti sticking agent. Beeswax white can also be used as polishing agent for filmcoating.
  • the dissolution of the present invention was determined by following method:
  • Dissolution Medium 90OmL, 0.1 N HCl, pH 2.0
  • composition of the present instant invention comprises of two phases:
  • Step I Preparation of seal coated drug layered pellets of CIopidogreI Mesylate:
  • Mannitol in the form directly compressible powder is taken as an inert core.
  • inert coating on mannitol is done by spraying the spraying solution on to the mannitol by a wurster spray (Glatt).
  • the spraying solution is prepared by the following method:
  • Binder or film forming polymer(s) is dissolved in a mixture of methanol and Methylene chloride. Anti sticking agent is milled in presence of sufficient mixture of methanol and Methylene chloride in a colloidal mill. Above milled dispersion is added to the binder or the film forming polymer(s) solution and stirred to get a uniform homogenous suspension and the same is passed through sieve 60#. 2. Mannitol prepared in step 1 is further layered by a suspension containing active ingredient i.e. Clopidogrel Mesylate in dissolved form. Binder or film forming polymer(s) is dissolved in methanol. Anti sticking agent is milled in presence of sufficient methanol in a colloidal mill.
  • seal coating is applied on to the drug layered mannitol prepared in step 2 above by wurster apparatus (Glatt).
  • the seal coating suspension is prepared by following method:
  • Film forming polymer(s) is dissolved in a methanol and stirred to get a clear homogenous suspension and the same is passed through sieve 60#. The same solution is applied onto drug layered pellets by wuster apparatus (Glatt).
  • Step II Preparation of film coated immediate release formulation of the said seal coated drug layered portion:
  • the compressible mixture comprising of glidants, anti sticking agents and lubricants are sieved through mesh #60.
  • step 1 and 2 The shifted ingredients of step 1 and 2 are blended together and are compressed in to tablets.
  • the compressed tablets are further film coated by spray coating.
  • the film coating suspension is prepared by following method: Film forming polymer(s) is dissolved in a mixture of methanol and Methylene chloride. Coloring and opacifying agent are milled in presence of sufficient mixture of methanol and Methylene chloride in a colloidal mill. Above milled dispersion is added to the film forming polymer(s) solution and stirred to get a clear homogenous suspension and the same is passed through sieve 60#.
  • the polishing solution is prepared by following method:
  • Polishing agent is dissolved in Methylene chloride by the aid of gentle heating to get clear solution.
  • Example 1 The invention described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
  • Example 1 The invention described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
  • ethyl cellulose 0.97 %w/w of ethyl cellulose was dissolved in a mixture of methanol and Methylene chloride. Milled 0.19 %w/w talc purified with sufficient quantity of methanol and methylene chloride. Added the milled dispersion of the above to the binder solution and stirred to get a clear solution and passed through sieve 60#. The above solution was sprayed on to the mannitol by wurster spray (Glatt process)
  • the final blend thus obtained was compressed into 550mg tablets on a tablet compression machine using 11.20 mm biconvex bevel edged punches.
  • Hydroxypropyl methylcellulose E 15LV 1.36 %w/w, polyethylene glycol 6000 0.16 %w/w and hydrogenated castor oil 0.25 %w/w were dissolved in a mixture of methanol and methylene chloride. Red oxide of iron 0.01 %w/w and titanium dioxide 0.55 %w/w were milled in presence of sufficient mixture of methanol and methylene chloride in a colloidal mill. Above milled dispersion was added to the film forming polymer(s) solution and stirred to get a clear homogenous suspension and the same was passed through sieve 60#. The solution was used to film coat the tablet.
  • the manufacturing process is divided into two parts:
  • Hydroxy propyl cellulose (Klucel LF) was dissolved in Methanol in 10 liter HDPE container. 2. Talc was dispersed in the above suspension and continued stirring for 10 min. The suspension was passed through 40# ss sieve.
  • Mannitol was sifted through #30 mesh ss sieve collected in a suitable container.
  • Mannitol of Step I was loaded in the wurster product container of Glatt GPCG 3 fluid bed granulator/coater. Preheated the mannitol until the product temperature reaches to 35°C.
  • the drug layered pellets were dried in the product container for 2 hours at the product temperature 45 °C. Recorded the LOD using halogen moisture analyzer. It should be not more than 1.25% (optimum 0.90%)
  • the drug layered pellets were sifted through # 24 s.s. sieve on a vibratory sifter and collected.
  • Hydroxypropyl cellulose (Klucel LF) was dissolved in Methanol under mechanical stirring till clear solution obtained.
  • the drug layered pellets from step I were sifted using #24 mesh ss sieve and collected in a container.
  • the sifted drug layered Pellets from Step I were loaded in the wurster product container of Glatt GPCG 3 fluid bed granulator/coater. The drug layered pellets were preheated until the product temperature reaches 35°C.
  • the polymer coated Pellets were dried in the product container for 5hours at the product temperature 48-52°.
  • the LOD was recorded using halogen moisture analyzer. It should be less than 1.00% (optimum 0.75%).
  • the methanol content in pellets at this stage was found to be 2674 ppm.
  • step no. 1 and 2 were loaded into airtight cage blender and blended for 30 mih.
  • Hypromellose, Hydrogenated castor oil, Polyethylene glycol 6000 were added ⁇ to the milled solution of step 1 and stirred with the aid of a mechanical stirrer for 30min, till a clear homogenous dispersion was obtained.
  • the tablets were loaded in to clean dry neocota and film coated the tablets by spraying the film coating suspension.
  • the suspension was stirred gently throughout the coating process.
  • the spraying of Polishing solution was started.
  • the tablets were dried for 25 minutes in pan at 35 - 40 0 C inlet air temperature by inching the pan.
  • the tablets (675.600 g) were loaded in to multiple clean dry HDPE trays into a clean dry vacuum oven.
  • Di phosphorous pentoxide 500.00g was loaded in another clean dry HDPE tray into the above vacuum oven.
  • the vacuum was applied into the oven at -760mm Hg at a temperature of 25 0 C ⁇ 2°C and kept for 24 hours. .
  • the tablets were removed after the 24 hours cycle by loading into a HDPE container with the application of nitrogen purging.
  • the partially layered mannitol with clopidogrel mesylate and Mannitol were sifted through 24# s.s. sieve.
  • the low substituted hydroxypropylcellulose, Hydrogenated castor oil, colloidal silicon dioxide and Stearic acid were sifted through 60# s.s. sieve.
  • the tablets were found to have sufficient hardness and further with effective DT between 5-8 min, where in the compression parameters were found to be satisfactory.
  • the formulation includes the use of 5% w/w of ortho phosphoric acid with respect to clopidogrel mesylate quantity used in formulation.
  • the same manufacturing process described in example 2 was followed with additionally using ortho phosphoric acid as a stabilizer.
  • the tablets were packed in HDPE bottles containing 2 gram molecular sieve and induction sealed with nitrogen purging.
  • Solvent like Methanol or Acetone and n-Heptane were used as solvent systems and free n-Heptane spraying was done on drug layered pellets, further, Methanol or Acetone and n-Heptane were used as solvent systems in polymer coated pellets of clopidogrel mesylate to . provide for stabilized and scalable formulation of Clopidogrel mesylate which was further compressed into tablets and film coated.
  • STEP-I Drug Layering Of Mannitol.
  • Hydroxy propyl cellulose was dissolved in of methanol (example 5) or acetone (example 6) in lOltr HDPE container under mechanical stirring.
  • Talc was dispersed in the above suspension and continued stirring for 10 min. The suspension was passed through 40# ss sieve.
  • Mannitol was sifted through #30 mesh ss sieve and collected in a suitable container.
  • the shifted mannitol of Step I was loaded in the wurster product container of Glatt GPCG 3 fluid bed granulator/coater. The mannitol was preheated until the product temperature reaches to 35°C.
  • the drug layered pellets were sifted through # 30 s.s. sieve on a vibratory sifter and collected.
  • the above drug layered pellets were sprayed with free n-Heptane of a concentration of 1:1 ratio to the clopidogrel mesylate present in the pellets.
  • the drug layered pellets were sifted through #30 mesh ss sieve.
  • the sifted drug layered pellets were loaded in the wurster product container of Glatt GPCG 3 fluid bed granulator/coater. The pellets were preheated until the product temperature reaches to 35°C.
  • the drug layered pellets were sifted using a ss sieve using a #30 mesh ss sieve and collected in a container.
  • the sifted drug layered Pellets were loaded in the wurster product container of Glatt GPCG 3 fluid bed granulator/coater. The drug layered Pellets were preheated until the product temperature reaches 35°C.
  • the pellets are further compressed into tablets and film coated as follows:
  • Hypromellose, Hydrogenated castor oil, Polyethylene glycol 6000 were added to the milled solution of step 1 and stirred with the aid of a mechanical stirrer for 30min.
  • the tablets were loaded in to clean dry neocota and film coated the tablets by spraying the film coating suspension.
  • the suspension was gently stirred throughout the coating process.
  • the spraying of Polishing solution was started.
  • tablets were dried for 25 minutes in pan at 35 - 40 0 C inlet air temperature by inching the pan.
  • the tablets were found to have sufficient hardness and further with effective DT between 7 - 9 minutes, where in the compression parameters were found to be satisfactory.

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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques stabilisées de mésylate de clopidogrel, qui est un sel instable hautement hygroscopique et au procédé de préparation de telles compositions.
PCT/IN2006/000375 2005-09-20 2006-09-19 Compositions pharmaceutiques atypiques de mesylate de clopidogrel WO2007054968A2 (fr)

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IN1140MU2005 2005-09-20
IN1140/MUM/2005 2005-09-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010009745A1 (fr) * 2008-07-25 2010-01-28 Pharmathen S.A. Forme galénique orale solide contenant l’agent anti-plaquettaire clopidogrel et son procédé de préparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004072085A2 (fr) * 2003-02-13 2004-08-26 Helm Ag Sel d'un acide sulfonique comprenant du clopidogrel et son utilisation pour produire des formulations pharmaceutiques
WO2004074215A1 (fr) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques
WO2005048992A1 (fr) * 2003-11-03 2005-06-02 Sandoz Ag Procede permettant de preparer des compositions de clopidogrel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074215A1 (fr) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques
WO2004072085A2 (fr) * 2003-02-13 2004-08-26 Helm Ag Sel d'un acide sulfonique comprenant du clopidogrel et son utilisation pour produire des formulations pharmaceutiques
WO2005048992A1 (fr) * 2003-11-03 2005-06-02 Sandoz Ag Procede permettant de preparer des compositions de clopidogrel

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010009745A1 (fr) * 2008-07-25 2010-01-28 Pharmathen S.A. Forme galénique orale solide contenant l’agent anti-plaquettaire clopidogrel et son procédé de préparation

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