WO2012144964A1 - Thiocolchicoside, diclofenac and lansoprazole combinations - Google Patents

Thiocolchicoside, diclofenac and lansoprazole combinations Download PDF

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Publication number
WO2012144964A1
WO2012144964A1 PCT/TR2012/000060 TR2012000060W WO2012144964A1 WO 2012144964 A1 WO2012144964 A1 WO 2012144964A1 TR 2012000060 W TR2012000060 W TR 2012000060W WO 2012144964 A1 WO2012144964 A1 WO 2012144964A1
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WIPO (PCT)
Prior art keywords
lansoprazole
thiocolchicoside
pharmaceutical composition
diclofenac potassium
enteric
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PCT/TR2012/000060
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French (fr)
Inventor
Ibrahim Mustafa Iskender Pisak
Mehmet Levent Selamoglu
Semra Bingol
Original Assignee
Ak Kimya Ithalat-Lhracat Ve Sanayii A.S.
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Publication of WO2012144964A1 publication Critical patent/WO2012144964A1/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—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
    • A61K9/5073—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 the pharmaceutical compositions in unit dosage form comprising thiocolchicoside as a muscle relaxant, diclofenac potassium as a non-steroidal anti-inflammatory drug and lansoprazole as a gastroprotectant; and to the preparation methods thereof.
  • Pharmaceutical compositions of the invention are used in the treatment of muscular and skeletal system diseases as well as inflammation and pain; and are safe due to the reduced gastrointestinal side effects.
  • the present invention relates to the unit dosage forms comprising
  • NSAID non-steroidal anti-inflammatory drug
  • Unit dosage forms of the invention comprises
  • thiocolchicoside or a pharmaceutically acceptable salt thereof as a muscle relaxant
  • diclofenac or a pharmaceutically acceptable salt thereof as an NSAID
  • lansoprazole or a pharmaceutically acceptable salt thereof as a gastroprotectant.
  • Unit dosage forms of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; diclofenac potassium as an NSAID in an amount of from 12.5 to 225 mg, preferably in an amount of 50 mg; and lansoprazole as a gastroprotectant in an amount of from 15 to 180 mg, preferably in an amount of 30 mg.
  • Thiocolchicoside is a glycosulfurated analogue of colchicine and is a well known centrally acting muscle relaxant used in the treatment of muscular and skeletal system diseases. Its chemical structure is shown in Formula 1.
  • thiocolchicoside N-[3-(P-D-glucopyranosyloxy)-l,2-dimethoxy-10- (methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide.
  • the usual initial dose is 16 mg daily by oral administration in the form of capsule or tablet. It is also used for intramuscular administration in doses up to 8 mg per day or for topical application as cream, ointment, gel or aerosol.
  • Diclofenac is an NSAID used in the treatment of inflammation and pain. It possesses analgesic and antipyretic properties as well as anti-inflammatory activity. Its chemical structure is shown in Formula 2.
  • diclofenac 2[(2,6-dichlorophenyl)amino]benzeneacetic acid.
  • Lansoprazole is a proton pump inhibitor used in the treatment of gastrointestinal diseases. It protects the gastric mucosa against irritation. Its chemical structure is shown in Formula 3.
  • lansoprazole 2-( ⁇ 3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl)methyl ⁇ sulfinyl benzimidazole.
  • the usual initial dose is 30 mg daily by oral administration in the form of tablet, capsule and suspension or intravenous administration.
  • Centrally acting skeletal muscle relaxants are generally prescribed either as single agents or as components of combination products.
  • Several commercial combinations of a muscle relaxant and aspirin (carisoprodol + aspirin, carisoprodol + aspirin + codeine, methocarbamol + aspirin and orphenadrine + aspirin + caffeine) have been approved by the U.S. Food and Drug Administration (U.S. FDA) and are marketed in the USA.
  • NSAIDs can cause gastrointestinal ulseration, bleeding and perforation; especially in case of high dose usage, long-term treatments, history of a gastrointestinal disease or sensitivity to develop disease; additional use of gastroprotectant drugs for reducing gastrointestinal irritation is needed.
  • the present invention is directed to the pharmaceutical compositions in unit dosage form wherein the patient compliance is increased, the composition is used for the treatment of muscular and skeletal system diseases as well as inflammation and pain, and gastrointestinal side effects are reduced.
  • Pharmaceutical compositions of the invention comprise thiocolchicoside as muscle relaxant, diclofenac potassium as NSAID and lansoprazole as gastroprotectant in a single dosage form.
  • European patent EP 0837684 Bl (Sanofi-Synthelabo) relates to a new combination comprising a diclofenac salt (diclofenac sodium) and thiocolchicoside with at least one pharmaceutically acceptable excipient, wherein said combination is in solid form which is stable over time.
  • French patent FR 2725134 Bl (Laboratoire Lederle) relates to a new combination comprising ibuprofen or a pharmaceutically acceptable salt thereof and thiocolchicoside or a pharmaceutically acceptable salt thereof in a weight ratio of between about 1 :50 and about 1 :200 for oral administration in the form of a capsule, tablet or granule.
  • European patent application EP 1992333 Al (Sanovel) relates to a combination comprising flurbiprofen and an alpha-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist, particularly tizanidine and thiocolchicoside.
  • European patent EP 1411900 Bl (Pozen) relates to a multi-layer tablet suitable for oral administration comprising an outer layer of an acid inhibitor (H2-receptor antagonist, preferably famotidine, or proton pump inhibitor), an inner core of an NSAID (preferably aspirin or naproxen) and a barrier coating surrounding the inner core of said NSAID.
  • H2-receptor antagonist preferably famotidine, or proton pump inhibitor
  • an inner core of an NSAID preferably aspirin or naproxen
  • compositions for the treatment of pain and inflammation with reduced gastrointestinal irritation comprising at least one NSAID (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ranitidine).
  • NSAID preferably naproxen or ibuprofen
  • acid blocking agent preferably ranitidine
  • European patent EP 0814839 Bl (AstraZeneca) relates to a multiple unit tablet wherein a proton pump inhibitor (preferably omeprazole, esomeprazole, lansoprazole or pantoprazole) in the form of individually enteric coating layered pellets, at least one NSAID (preferably ibuprofen, diclofenac sodium, piroxicam or naproxen) and optionally pharmaceutically acceptable excipients are compressed together.
  • a proton pump inhibitor preferably omeprazole, esomeprazole, lansoprazole or pantoprazole
  • NSAID preferably ibuprofen, diclofenac sodium, piroxicam or naproxen
  • NSAIDs preferably aspirin, naproxen, diclofenac sodium, ibuprofen or piroxicam
  • gastroprotectants preferably famotidine, misoprostol, ranitidine, omeprazole, esomeprazole, lansoprazole or pantoprazole.
  • gastroprotectants preferably famotidine, misoprostol, ranitidine, omeprazole, esomeprazole, lansoprazole or pantoprazole.
  • gastroprotectants preferably famotidine, misoprostol, ranitidine, omeprazole, esomeprazole, lansoprazole or pantoprazole.
  • the present invention relates to a pharmaceutical composition in unit dosage form for use in the treatment of muscular and skeletal system diseases, inflammation and pain comprising a) thiocolchicoside as muscle relaxant;
  • the present invention encompasses unit dosage forms comprising a muscle relaxant, a nonsteroidal anti-inflammatory drug (NSAID) and a gastroprotectant.
  • NSAID nonsteroidal anti-inflammatory drug
  • the muscle relaxant of the invention is preferably thiocolchicoside or a pharmaceutically acceptable salt thereof.
  • the NSAID of the invention may preferably be selected from an acetic acid derivative, a propionic acid derivative, an enolic acid derivative, a fenamic acid derivative, a COX-2 inhibitor, a salicylate and other NSAI drugs.
  • the acetic acid derivative of the invention may be selected from, but is not limited to, diclofenac, etodolac, ketorolac, indomethacin, sulindac and nabumeton; and is preferably diclofenac.
  • Diclofenac may be in free form or in the form of a pharmaceutically acceptable salt thereof, preferably in the form of potassium salt.
  • the propionic acid derivative of the invention may be selected from, but is not limited to, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and loxoprofen.
  • the enolic acid derivative of the invention may be selected from, but is not limited to, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam.
  • the fenamic acid derivative of the invention may be selected from, but is not limited to, mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid.
  • the COX-2 inhibitor of the invention may be selected from, but is not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and etoricoxib.
  • the salicylate of the invention may be selected from, but is not limited to, acetylsalicylic acid, salsalate and diflunisal.
  • the other NSAI drugs of the invention may be selected from, but are not limited to, nimesulide and licofelone.
  • the gastroprotectant of the invention may preferably be selected from a proton pump inhibitor, an H2-receptor antagonist, an antiacid or a prostaglandin.
  • the proton pump inhibitor of the invention may be selected from, but is not limited to, lansoprazole, omeprazole, esomeprazole, dexlansoprazole, pantoprazole, rabeprazole and leminoprazole; and is preferably lansoprazole.
  • Lansoprazole may be in free form or in the form of a pharmaceutically acceptable salt thereof.
  • the H2-receptor antagonist of the invention may be selected from, but is not limited to, famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine.
  • the antiacid of the invention may be selected from, but is not limited to, CaC0 3 , MgC0 3 , Mg(OH) 2 , Al(OH) 3 , NaHC0 3 and KHC0 3 .
  • the prostaglandin of the invention may be selected from, but is not limited to, misoprostol and enprostil.
  • the active components of the invention may be in the form of a racemic mixture, or in the form of substantially pure enantiomers or salts of enantiomers thereof.
  • the present invention relates to a combination of thiocolchicoside or a pharmaceutically acceptable salt thereof as muscle relaxant; diclofenac or a pharmaceutically acceptable salt thereof as NSAID; lansoprazole or a pharmaceutically acceptable salt thereof as gastroprotectant and at least one pharmaceutically acceptable excipient, wherein said combination is developed for unit dose application.
  • Combinations of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; diclofenac potassium as an NSAID in an amount of from 12.5 to 225 mg, preferably in an amount of 50 mg; and lansoprazole as a gastroprotectant in an amount of from 15 to 180 mg, preferably in an amount of 30 mg.
  • thiocolchicoside to a standard NSAID treatment has shown more effective results for the treatment of muscular and skeletal system diseases as well as inflammation and pain than NSAID treatment alone.
  • Combinations of the invention may be used for oral, buccal, ocular, otic, rectal, topical, implantal, mucosal, parenteral, sublingal, nasal or pulmonary administration in the form of gel, cream, ointment, tablet, capsule, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution; and are preferably in oral dosage form; more preferably in tablet or capsule form.
  • Dosage forms of the invention may be administered once or twice a day.
  • Therapeutically effective amount of thiocolchicoside included in the dosage forms of the invention is between 4 mg and 16 mg, preferably 8 mg.
  • Therapeutically effective amount of diclofenac potassium included in the dosage forms of the invention is between 12.5 mg and 225 mg, preferably 50 mg.
  • Therapeutically effective amount of lansoprazole included in the dosage forms of the invention is between 15 mg and 180 mg, preferably 30 mg.
  • Oral dosage forms of the invention may comprise neutral cores.
  • Pharmaceutically acceptable neutral cores of the invention may be selected from suitable diluents, and preferably are sugar spheres.
  • Oral dosage forms of the invention may also comprise suitable diluents, binders, lubricants, disintegrating agents, surfactants, sweetening agents, coloring agents and coating agents.
  • Pharmaceutically acceptable diluents of the invention may be selected from lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like.
  • Pharmaceutically acceptable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycol, waxes, sodium alginate, alcohols, water and the like.
  • Pharmaceutically acceptable lubricants of the invention may be selected from metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride, talk and the like.
  • Pharmaceutically acceptable disintegrating agents of the invention may be selected from starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like.
  • Pharmaceutically acceptable surfactants of the invention may be selected from sulfates, sulfonates, phosphates, carboxylates, primary-secondary-tertiary amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatty acids, glycerides of fatty acids, polyoxy ethylene glycol alkyl ethers, polisorbates, sorbitan alkyl esters, poloxamers and the like.
  • the present invention may also comprise modified release (controlled, delayed, extended, sustained, timed release) or immediate release layered tablet and capsule to provide the control of the release of the active components, preferably thiocolchicoside and/or diclofenac potassium and/or lansoprazole in order to optimize the therapeutic effects and minimize the undesirable side effects.
  • modified release controlled, delayed, extended, sustained, timed release
  • immediate release layered tablet and capsule to provide the control of the release of the active components, preferably thiocolchicoside and/or diclofenac potassium and/or lansoprazole in order to optimize the therapeutic effects and minimize the undesirable side effects.
  • compositions of the invention are used in the treatment of muscular and skeletal system diseases as well as inflammation and pain; and have reduced gastrointestinal side effects.
  • Pharmaceutical compositions of the invention may be administered once or twice a day in unit doses.
  • compositions of the invention in tablet form are provided.
  • Bilayer tablets of the invention comprise the mixture of thiocolchicoside and diclofenac potassium in the first layer, and lansoprazole pellets in the second layer.
  • Second layer comprising lansoprazole consists of a core, optionally an intermediate coating surrounding the core, and an enteric coating surrounding the intermediate-coated pellets.
  • thiocolchicoside, diclofenac potassium and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants are mixed together; and the mixture is ready for pre-compression.
  • lansoprazole together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion.
  • Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water.
  • Said binder of the invention is more preferably a mixture of hydroxypropyl methylcellulose (HPMC) and water.
  • HPMC hydroxypropyl methylcellulose
  • the core portion in the second layer is optionally coated with an intermediate coating.
  • Intermediate coating is a portion that separates the core portion from outer coating and that contributes to provide stability.
  • Pharmaceutically acceptable binders used in the intermediate coating portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water.
  • Said binder of the invention is more preferably a mixture of HPMC, polyethylene glycol, ethanol and water.
  • at least one excipient selected from the pharmaceutically acceptable diluents, lubricants, disintegrating agents and surfactants may also be added into this portion.
  • Intermediate-coated pellets are obtained by spraying said suspension onto the core portion.
  • Enteric coating is applied to protect the intermediate-coated pellets in the second layer against gastric acid.
  • Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like.
  • a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion.
  • a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution.
  • Enteric-coated pellets are obtained by spraying enteric coating solution onto the intermediate-coated pellets. Enteric-coated pellets so- obtained are optionally mixed with at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants; and the mixture is ready for tablet press. Finally, pre-compression is applied to the powder mixture of thiocolchicoside and diclofenac potassium in the first layer; lansoprazole mixture in the second layer is added onto the pre- compressed tablet; and tablet press is applied so as to obtain bilayer tablet.
  • compositions of the invention in capsule form are provided.
  • Oral dosage forms of the invention are preferably in the form of capsule.
  • Preparation method of the capsules of the invention has four stages. Thiocolchicoside mixture or tablet is obtained in the first stage; diclofenac potassium pellets are obtained in the second stage; lansoprazole pellets are obtained in the third stage; and they are all filled into the capsules, in the fourth stage.
  • Diclofenac potassium pellets consist of a core and an enteric coating surrounding the core.
  • Lansoprazole pellets consist of a core, optionally an intermediate coating surrounding the core, and an enteric coating surrounding the intermediate-coated pellets.
  • thiocolchicoside and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants are mixed together; and the mixture is optionally compressed.
  • the mixture or tablet is ready for capsule fill.
  • diclofenac potassium together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion.
  • Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC and water.
  • the core portion is obtained by spraying the solution comprising diclofenac potassium onto the neutral cores.
  • Enteric coating is applied to protect the pellets in the second stage against gastric acid.
  • Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like.
  • a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion.
  • a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution.
  • Enteric-coated pellets are obtained by spraying enteric coating solution onto the pellets of the core portion. Following the addition of talk, enteric-coated pellets so- obtained are dried at 40 °C; and said enteric-coated pellets are ready for capsule fill.
  • lansoprazole together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion.
  • Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC and water.
  • the core portion is obtained by spraying the solution comprising lansoprazole onto the neutral cores. ⁇
  • the core portion in the third stage is optionally coated with an intermediate coating.
  • Intermediate coating is a portion that separates the core portion from outer coating and that contributes to provide stability.
  • Pharmaceutically acceptable binders used in the intermediate coating portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water.
  • Said binder of the invention is more preferably a mixture of HPMC, polyethylene glycol, ethanol and water.
  • at least one excipient selected from the pharmaceutically acceptable diluents, lubricants, disintegrating agents and surfactants may also be added into this portion.
  • Intermediate-coated pellets are obtained by spraying said suspension onto the core portion.
  • Enteric coating is applied to protect the intermediate-coated pellets in the third stage against gastric acid.
  • Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like.
  • a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion.
  • a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution.
  • Enteric-coated pellets are obtained by spraying enteric coating solution onto the intermediate-coated pellets. Enteric-coated pellets so- obtained are optionally mixed with at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants; and said enteric- coated pellets are ready for capsule fill.
  • thiocolchicoside powder mixture or tablet obtained in the first stage; enteric-coated diclofenac potassium pellets obtained in the second stage; and enteric-coated lansoprazole pellets obtained in the third stage are filled into the capsules together.
  • Preparation method of the 1 st layer comprises the steps of mixing thiocolchicoside 8 mg and diclofenac potassium 50 mg together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and tablet pressing by applying pre-compression to the final mixture.
  • Preparation method of the 2nd layer comprises four stages. Core is obtained in the first stage, intermediate coating is obtained in the second stage, enteric coating is obtained in the third stage, and final mixture suitable for tablet press is obtained in the fourth stage. Fluid bed granulator is used for the spraying process applied in the first three stages.
  • Preparation method of the core portion of the 2nd layer comprises the steps of dissolving lansoprazole 30 mg and HPMC in a sufficient quantity of distilled water; and spraying the solution so-obtained onto the neutral cores.
  • Preparation method of the intermediate coating portion of the 2nd layer comprises the steps of dissolving talk in a sufficient quantity of ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; and obtaining intermediate-coated pellets.
  • Preparation method of the enteric coating portion of the 2nd layer comprises the steps of spraying the sufficient quantity of ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; and obtaining enteric-coated pellets.
  • Preparation method of the 2nd layer for tablet press comprises the step of mixing enteric- coated lansoprazole pellets so-obtained with microcrystalline cellulose and croscarmellose sodium.
  • 1 st layer of the bilayer tablets of the invention comprising thiocolchicoside and diclofenac potassium exhibit immediate release
  • 2nd layer of the bilayer tablets of the invention comprising lansoprazole exhibit delayed release.
  • Preparation method of the mixture in the 1st stage comprises the steps of mixing thiocolchicoside 8 mg together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and optionally applying compression to the final mixture.
  • Preparation method of the enteric-coated diclofenac potassium pellets in the 2nd stage comprises two stages. Core is obtained in the first stage, and enteric coating is obtained in the second stage. Fluid bed granulator is used for the spraying process applied in these stages.
  • Preparation method of the core portion of the 2nd stage comprises the steps of diluting 10% (w/w) aqueous solution of HPMC with a sufficient quantity ' of deionized water; adding diclofenac potassium 50 mg into said HPMC solution and mixing until a homogeneous mixture is obtained; and spraying the solution so-obtained onto the neutral cores.
  • Preparation method of the enteric coating portion of the 2nd stage comprises the steps of preparing 15% (w/w) dispersion of magnesium stearate by using magnesium stearate and a sufficient quantity of deionized water; adding talk into the sufficient quantity of deionized water and mixing until a homogeneous mixture is obtained; adding 15%) (w/w) dispersion of magnesium stearate into the talk mixture and mixing; adding 30% (w/w) dispersion of methacrylic acid copolymer into the magnesium stearate and talk mixture and mixing; spraying said enteric coating solution onto the pellets of the core portion; and following the addition of talk, drying enteric-coated pellets so-obtained at 40 °C.
  • Preparation method of the enteric-coated lansoprazole pellets in the 3rd stage comprises three stages. Core is obtained in the first stage, intermediate coating is obtained in the second stage, and enteric coating is obtained in the third stage. Fluid bed granulator is used for the spraying process applied in these stages.
  • Preparation method of the core portion of the 3rd stage comprises the steps of dissolving lansoprazole 30 mg and HPMC in a sufficient quantity of distilled water; and spraying the solution so-obtained onto the neutral cores.
  • Preparation method of the intermediate coating portion of the 3rd stage comprises the steps of dissolving talk in a sufficient quantity of ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; and obtaining intermediate-coated pellets.
  • Preparation method of the enteric coating portion of the 3rd stage comprises the steps of spraying the sufficient quantity of ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; and obtaining enteric-coated pellets.
  • Enteric-coated lansoprazole pellets so-obtained are optionally mixed with microcrystalline cellulose and croscarmellose sodium.
  • thiocolchicoside powder mixture or tablet obtained in the first stage; enteric-coated diclofenac potassium pellets obtained in the second stage; and enteric-coated lansoprazole pellets obtained in the third stage are filled into the capsules together.
  • Thiocolchicoside portion of the capsules of the invention exhibits immediate release; diclofenac potassium pellets and lansoprazole pellets of the invention exhibit delayed release.
  • Pharmaceutical dosage forms prepared by the processes of the invention have not met any stability problems during long term stability studies performed at 25 ⁇ 2 °C and 60 ⁇ 5 % RH across a 0-, 3- and 6-month follow-up period; and accelerated stability studies performed at 40 ⁇ 2 °C and 75 ⁇ 5 % RH across a 0-, 3- and 6-month follow-up period.

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Abstract

The present invention relates to the unit dosage forms comprising a. thiocolchicoside or a pharmaceutically acceptable salt thereof as a muscle relaxant, b. diclofenac or a pharmaceutically acceptable salt thereof as an NSAID, and c. lansoprazole or a pharmaceutically acceptable salt thereof as a gastroprotectant.

Description

DESCRIPTION
THIOCOLCHICOSIDE, DICLOFENAC AND LANSOPRAZOLE COMBINATIONS Field of the invention
The present invention relates to the pharmaceutical compositions in unit dosage form comprising thiocolchicoside as a muscle relaxant, diclofenac potassium as a non-steroidal anti-inflammatory drug and lansoprazole as a gastroprotectant; and to the preparation methods thereof. Pharmaceutical compositions of the invention are used in the treatment of muscular and skeletal system diseases as well as inflammation and pain; and are safe due to the reduced gastrointestinal side effects.
Background of the invention
The present invention relates to the unit dosage forms comprising
a. a muscle relaxant,
b. a non-steroidal anti-inflammatory drug (an NSAID), and
c. a gastroprotectant.
Unit dosage forms of the invention comprises
a. thiocolchicoside or a pharmaceutically acceptable salt thereof as a muscle relaxant, b. diclofenac or a pharmaceutically acceptable salt thereof as an NSAID, and
c. lansoprazole or a pharmaceutically acceptable salt thereof as a gastroprotectant.
Unit dosage forms of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; diclofenac potassium as an NSAID in an amount of from 12.5 to 225 mg, preferably in an amount of 50 mg; and lansoprazole as a gastroprotectant in an amount of from 15 to 180 mg, preferably in an amount of 30 mg.
Pharmaceutical combinations of the invention used in the treatment of muscular and skeletal system diseases as well as inflammation and pain can reduce the gastrointestinal side effects induced by the NSAID content in the composition due to the presence of the gastroprotectant in said composition. Thiocolchicoside is a glycosulfurated analogue of colchicine and is a well known centrally acting muscle relaxant used in the treatment of muscular and skeletal system diseases. Its chemical structure is shown in Formula 1.
Figure imgf000003_0001
Formula 1
The chemical name of thiocolchicoside is N-[3-(P-D-glucopyranosyloxy)-l,2-dimethoxy-10- (methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide.
The usual initial dose is 16 mg daily by oral administration in the form of capsule or tablet. It is also used for intramuscular administration in doses up to 8 mg per day or for topical application as cream, ointment, gel or aerosol.
Diclofenac is an NSAID used in the treatment of inflammation and pain. It possesses analgesic and antipyretic properties as well as anti-inflammatory activity. Its chemical structure is shown in Formula 2.
Figure imgf000003_0002
Formula 2
The chemical name of diclofenac is 2[(2,6-dichlorophenyl)amino]benzeneacetic acid.
The usual initial dose is 50 mg daily by oral administration in the form of tablet, capsule or dragee. It is also used for intramuscular and intravenous administration or for topical application as gel, suppository or ophthalmic preparation. Lansoprazole is a proton pump inhibitor used in the treatment of gastrointestinal diseases. It protects the gastric mucosa against irritation. Its chemical structure is shown in Formula 3.
Figure imgf000004_0001
Formula 3
The chemical name of lansoprazole is 2-({3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl)methyl}sulfinyl benzimidazole.
The usual initial dose is 30 mg daily by oral administration in the form of tablet, capsule and suspension or intravenous administration.
Centrally acting skeletal muscle relaxants are generally prescribed either as single agents or as components of combination products. Several commercial combinations of a muscle relaxant and aspirin (carisoprodol + aspirin, carisoprodol + aspirin + codeine, methocarbamol + aspirin and orphenadrine + aspirin + caffeine) have been approved by the U.S. Food and Drug Administration (U.S. FDA) and are marketed in the USA.
Due to the fact that NSAIDs can cause gastrointestinal ulseration, bleeding and perforation; especially in case of high dose usage, long-term treatments, history of a gastrointestinal disease or sensitivity to develop disease; additional use of gastroprotectant drugs for reducing gastrointestinal irritation is needed.
In cases where use of more than one medicine is needed, patient compliance is an important factor to be considered. According to the research, 50% of the patients fail to take medicines as prescribed and to fulfill the requirements of the treatment (Sabate, E. "Adherence to Long- Term Therapies: Evidence for Action". World Health Organization. Geneva, 2003. 212 pp.). Patients fail to take their medicines prescribed so as to include a complicated treatment regimen requiring use of more than one medicine due to the facts such as forgetfulness, busy lifestyle, different methods of the administration of the medicines, lack of suitable environment for taking medicines, misunderstanding of the disease or treatment, patient's perspective of the disease or treatment, side effects, depression, cognitive disorders and financial problems. In this case, combining the active components in a single dosage form will increase patient compliance to the treatment.
The present invention is directed to the pharmaceutical compositions in unit dosage form wherein the patient compliance is increased, the composition is used for the treatment of muscular and skeletal system diseases as well as inflammation and pain, and gastrointestinal side effects are reduced. Pharmaceutical compositions of the invention comprise thiocolchicoside as muscle relaxant, diclofenac potassium as NSAID and lansoprazole as gastroprotectant in a single dosage form.
Binary combinations of thiocolchicoside as muscle relaxant and NSAIDs as well as NSAIDs and gastroprotectants have been disclosed in the prior art. But, any information relating to the combinations of the invention comprising all active components (thiocolchicoside, diclofenac potassium and lansoprazole) combined in unit dosage form has not been disclosed.
European patent EP 0837684 Bl (Sanofi-Synthelabo) relates to a new combination comprising a diclofenac salt (diclofenac sodium) and thiocolchicoside with at least one pharmaceutically acceptable excipient, wherein said combination is in solid form which is stable over time.
French patent FR 2725134 Bl (Laboratoire Lederle) relates to a new combination comprising ibuprofen or a pharmaceutically acceptable salt thereof and thiocolchicoside or a pharmaceutically acceptable salt thereof in a weight ratio of between about 1 :50 and about 1 :200 for oral administration in the form of a capsule, tablet or granule.
European patent application EP 1992333 Al (Sanovel) relates to a combination comprising flurbiprofen and an alpha-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist, particularly tizanidine and thiocolchicoside.
International patent application WO2010084500 Al (Sanofi-Synthelabo) relates to a combination in the form of a solid dosage form containing ketoprofen and thiocolchicoside, wherein the active ingredients are present in the free form or in the form of a salt and not being intimately mixed in the composition. Above-mentioned patents relate to the combined use of thiocolchicoside and specific NSAIDs (diclofenac sodium, ibuprofen, flurbiprofen and ketoprofen, respectively). But, said patents do not include the triple combinations of the invention.
European patent EP 1411900 Bl (Pozen) relates to a multi-layer tablet suitable for oral administration comprising an outer layer of an acid inhibitor (H2-receptor antagonist, preferably famotidine, or proton pump inhibitor), an inner core of an NSAID (preferably aspirin or naproxen) and a barrier coating surrounding the inner core of said NSAID.
American patent application US 20070237820 Al (Andrx) relates to a solid oral dosage form comprising a first portion comprising an NSAID (preferably diclofenac); and a coating comprising an antiulcerative compound (preferably misoprostol); said coating at least partially surrounding said first NSAID portion.
American patent application US 20090233970 Al relates to a pharmaceutical composition for the treatment of pain and inflammation with reduced gastrointestinal irritation, the composition comprising at least one NSAID (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ranitidine).
European patent EP 0814839 Bl (AstraZeneca) relates to a multiple unit tablet wherein a proton pump inhibitor (preferably omeprazole, esomeprazole, lansoprazole or pantoprazole) in the form of individually enteric coating layered pellets, at least one NSAID (preferably ibuprofen, diclofenac sodium, piroxicam or naproxen) and optionally pharmaceutically acceptable excipients are compressed together.
International patent application WO 2005076987 A2 (Santarus) relates to a pharmaceutical composition comprising at least one proton pump inhibitor (preferably omeprazole), at least one NSAID and at least one buffering agent.
Above-mentioned patents relate to the combined use of NSAIDs (preferably aspirin, naproxen, diclofenac sodium, ibuprofen or piroxicam) and gastroprotectants (preferably famotidine, misoprostol, ranitidine, omeprazole, esomeprazole, lansoprazole or pantoprazole). But, said patents do not include the triple combinations of the invention. As a result, the present invention discloses novel and stable unit dosage forms comprising thiocolchicoside as muscle relaxant, diclofenac potassium as NSAID and lansoprazole as gastroprotectant.
Summary of the invention
The present invention relates to a pharmaceutical composition in unit dosage form for use in the treatment of muscular and skeletal system diseases, inflammation and pain comprising a) thiocolchicoside as muscle relaxant;
b) diclofenac potassium as NSAID;
c) lansoprazole as gastroprotectant; and
d) at least one pharmaceutically acceptable excipient.
Detailed description of the invention
The present invention encompasses unit dosage forms comprising a muscle relaxant, a nonsteroidal anti-inflammatory drug (NSAID) and a gastroprotectant.
The muscle relaxant of the invention is preferably thiocolchicoside or a pharmaceutically acceptable salt thereof.
The NSAID of the invention may preferably be selected from an acetic acid derivative, a propionic acid derivative, an enolic acid derivative, a fenamic acid derivative, a COX-2 inhibitor, a salicylate and other NSAI drugs.
The acetic acid derivative of the invention may be selected from, but is not limited to, diclofenac, etodolac, ketorolac, indomethacin, sulindac and nabumeton; and is preferably diclofenac. Diclofenac may be in free form or in the form of a pharmaceutically acceptable salt thereof, preferably in the form of potassium salt.
The propionic acid derivative of the invention may be selected from, but is not limited to, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and loxoprofen.
The enolic acid derivative of the invention may be selected from, but is not limited to, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam. The fenamic acid derivative of the invention may be selected from, but is not limited to, mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid.
The COX-2 inhibitor of the invention may be selected from, but is not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and etoricoxib.
The salicylate of the invention may be selected from, but is not limited to, acetylsalicylic acid, salsalate and diflunisal.
The other NSAI drugs of the invention may be selected from, but are not limited to, nimesulide and licofelone.
The gastroprotectant of the invention may preferably be selected from a proton pump inhibitor, an H2-receptor antagonist, an antiacid or a prostaglandin.
The proton pump inhibitor of the invention may be selected from, but is not limited to, lansoprazole, omeprazole, esomeprazole, dexlansoprazole, pantoprazole, rabeprazole and leminoprazole; and is preferably lansoprazole. Lansoprazole may be in free form or in the form of a pharmaceutically acceptable salt thereof.
The H2-receptor antagonist of the invention may be selected from, but is not limited to, famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine.
The antiacid of the invention may be selected from, but is not limited to, CaC03, MgC03, Mg(OH)2, Al(OH)3, NaHC03 and KHC03.
The prostaglandin of the invention may be selected from, but is not limited to, misoprostol and enprostil.
The active components of the invention may be in the form of a racemic mixture, or in the form of substantially pure enantiomers or salts of enantiomers thereof.
The present invention relates to a combination of thiocolchicoside or a pharmaceutically acceptable salt thereof as muscle relaxant; diclofenac or a pharmaceutically acceptable salt thereof as NSAID; lansoprazole or a pharmaceutically acceptable salt thereof as gastroprotectant and at least one pharmaceutically acceptable excipient, wherein said combination is developed for unit dose application.
Combinations of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; diclofenac potassium as an NSAID in an amount of from 12.5 to 225 mg, preferably in an amount of 50 mg; and lansoprazole as a gastroprotectant in an amount of from 15 to 180 mg, preferably in an amount of 30 mg.
The addition of thiocolchicoside to a standard NSAID treatment has shown more effective results for the treatment of muscular and skeletal system diseases as well as inflammation and pain than NSAID treatment alone. The addition of a gastroprotectant to said combination has substantially reduced the gastrointestinal side effects of the NSAID.
Combinations of the invention may be used for oral, buccal, ocular, otic, rectal, topical, implantal, mucosal, parenteral, sublingal, nasal or pulmonary administration in the form of gel, cream, ointment, tablet, capsule, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution; and are preferably in oral dosage form; more preferably in tablet or capsule form. Dosage forms of the invention may be administered once or twice a day. Therapeutically effective amount of thiocolchicoside included in the dosage forms of the invention is between 4 mg and 16 mg, preferably 8 mg. Therapeutically effective amount of diclofenac potassium included in the dosage forms of the invention is between 12.5 mg and 225 mg, preferably 50 mg. Therapeutically effective amount of lansoprazole included in the dosage forms of the invention is between 15 mg and 180 mg, preferably 30 mg.
Oral dosage forms of the invention may comprise neutral cores. Pharmaceutically acceptable neutral cores of the invention may be selected from suitable diluents, and preferably are sugar spheres. Oral dosage forms of the invention may also comprise suitable diluents, binders, lubricants, disintegrating agents, surfactants, sweetening agents, coloring agents and coating agents. Pharmaceutically acceptable diluents of the invention may be selected from lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like. Pharmaceutically acceptable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycol, waxes, sodium alginate, alcohols, water and the like. Pharmaceutically acceptable lubricants of the invention may be selected from metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride, talk and the like. Pharmaceutically acceptable disintegrating agents of the invention may be selected from starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like. Pharmaceutically acceptable surfactants of the invention may be selected from sulfates, sulfonates, phosphates, carboxylates, primary-secondary-tertiary amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatty acids, glycerides of fatty acids, polyoxy ethylene glycol alkyl ethers, polisorbates, sorbitan alkyl esters, poloxamers and the like.
The present invention may also comprise modified release (controlled, delayed, extended, sustained, timed release) or immediate release layered tablet and capsule to provide the control of the release of the active components, preferably thiocolchicoside and/or diclofenac potassium and/or lansoprazole in order to optimize the therapeutic effects and minimize the undesirable side effects.
Pharmaceutical compositions of the invention are used in the treatment of muscular and skeletal system diseases as well as inflammation and pain; and have reduced gastrointestinal side effects. Pharmaceutical compositions of the invention may be administered once or twice a day in unit doses.
Pharmaceutical compositions of the invention in tablet form
Oral dosage forms of the invention are preferably in the form of bilayer tablet. Bilayer tablets of the invention comprise the mixture of thiocolchicoside and diclofenac potassium in the first layer, and lansoprazole pellets in the second layer. Second layer comprising lansoprazole consists of a core, optionally an intermediate coating surrounding the core, and an enteric coating surrounding the intermediate-coated pellets.
In the first layer, thiocolchicoside, diclofenac potassium and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants are mixed together; and the mixture is ready for pre-compression.
In the second layer, lansoprazole together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion. Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of hydroxypropyl methylcellulose (HPMC) and water. The core portion is obtained by spraying the solution comprising lansoprazole onto the neutral cores.
The core portion in the second layer is optionally coated with an intermediate coating. Intermediate coating is a portion that separates the core portion from outer coating and that contributes to provide stability. Pharmaceutically acceptable binders used in the intermediate coating portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC, polyethylene glycol, ethanol and water. Optionally at least one excipient selected from the pharmaceutically acceptable diluents, lubricants, disintegrating agents and surfactants may also be added into this portion. Intermediate-coated pellets are obtained by spraying said suspension onto the core portion.
Enteric coating is applied to protect the intermediate-coated pellets in the second layer against gastric acid. Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like. In addition, a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion. Besides the polymer and plasticizer; a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution. Enteric-coated pellets are obtained by spraying enteric coating solution onto the intermediate-coated pellets. Enteric-coated pellets so- obtained are optionally mixed with at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants; and the mixture is ready for tablet press. Finally, pre-compression is applied to the powder mixture of thiocolchicoside and diclofenac potassium in the first layer; lansoprazole mixture in the second layer is added onto the pre- compressed tablet; and tablet press is applied so as to obtain bilayer tablet.
Pharmaceutical compositions of the invention in capsule form
Oral dosage forms of the invention are preferably in the form of capsule. Preparation method of the capsules of the invention has four stages. Thiocolchicoside mixture or tablet is obtained in the first stage; diclofenac potassium pellets are obtained in the second stage; lansoprazole pellets are obtained in the third stage; and they are all filled into the capsules, in the fourth stage. Diclofenac potassium pellets consist of a core and an enteric coating surrounding the core. Lansoprazole pellets consist of a core, optionally an intermediate coating surrounding the core, and an enteric coating surrounding the intermediate-coated pellets.
In the first stage, thiocolchicoside and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants are mixed together; and the mixture is optionally compressed. The mixture or tablet is ready for capsule fill.
In the second stage, diclofenac potassium together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion. Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC and water. The core portion is obtained by spraying the solution comprising diclofenac potassium onto the neutral cores.
Enteric coating is applied to protect the pellets in the second stage against gastric acid. Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like. In addition, a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion. Besides the polymer and plasticizer; a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution. Enteric-coated pellets are obtained by spraying enteric coating solution onto the pellets of the core portion. Following the addition of talk, enteric-coated pellets so- obtained are dried at 40 °C; and said enteric-coated pellets are ready for capsule fill.
In the third stage, lansoprazole together with neutral cores and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants is present in the core portion. Pharmaceutically acceptable binders used in the core portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC and water. The core portion is obtained by spraying the solution comprising lansoprazole onto the neutral cores. ·
The core portion in the third stage is optionally coated with an intermediate coating. Intermediate coating is a portion that separates the core portion from outer coating and that contributes to provide stability. Pharmaceutically acceptable binders used in the intermediate coating portion may preferably be selected from starches, natural sugars, cellulose derivatives, PVP, polyethylene glycol, alcohols and water. Said binder of the invention is more preferably a mixture of HPMC, polyethylene glycol, ethanol and water. Optionally at least one excipient selected from the pharmaceutically acceptable diluents, lubricants, disintegrating agents and surfactants may also be added into this portion. Intermediate-coated pellets are obtained by spraying said suspension onto the core portion.
Enteric coating is applied to protect the intermediate-coated pellets in the third stage against gastric acid. Enteric coating polymers used in the enteric coating portion may be selected from methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like. In addition, a plasticizer selected from phthalates, trimellitates, adipates, sebacates, maleates, benzoates, sulfonamides, organophosphates, glycols/polyethers, acetylated monoglycerides, alkyl citrates, polysorbates, triacetine, cetyl alcohol, and the like may also be used to improve the properties of coating such as elasticity, hardness and adhesion. Besides the polymer and plasticizer; a pure solvent or a solvent mixture and optionally at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants may also be added to prepare enteric coating solution. Enteric-coated pellets are obtained by spraying enteric coating solution onto the intermediate-coated pellets. Enteric-coated pellets so- obtained are optionally mixed with at least one excipient selected from the pharmaceutically acceptable diluents, binders, lubricants, disintegrating agents and surfactants; and said enteric- coated pellets are ready for capsule fill.
Finally, thiocolchicoside powder mixture or tablet obtained in the first stage; enteric-coated diclofenac potassium pellets obtained in the second stage; and enteric-coated lansoprazole pellets obtained in the third stage are filled into the capsules together.
The examples of pharmaceutical formulations and preparation methods of the invention are shown below. Said examples are only given to illustrate the invention.The extent of the invention should not be limited by the examples.
Examples
Example 1: Bilayer tablet
Figure imgf000014_0001
2nd LAYER - Intermediate Coating
Content Weight (mg) / unit dose
Core 66.0
HPMC 6.0
Polyethylene glycol 0.7
Talk 1 1.3
Ethanol q.s.
Distilled water q.s.
Total 84.0
2nd LAYER - Enteric Coating
Content Weight (mg) / unit dose
Intermediate-coated pellets 84.0
Hydroxypropyl methylcellulose phthalate 32.0
Tributyl citrate 8.0
Ethanol q.s.
Acetone q.s.
Total J 24.0
2nd LAYER
Content Weight (mg) / unit dose
Lansoprazole pellets 124.0
Microcrystalline cellulose 286.0
Croscarmellose sodium 28.0
Total 438.0
Preparation method of the 1 st layer comprises the steps of mixing thiocolchicoside 8 mg and diclofenac potassium 50 mg together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and tablet pressing by applying pre-compression to the final mixture.
Preparation method of the 2nd layer comprises four stages. Core is obtained in the first stage, intermediate coating is obtained in the second stage, enteric coating is obtained in the third stage, and final mixture suitable for tablet press is obtained in the fourth stage. Fluid bed granulator is used for the spraying process applied in the first three stages. Preparation method of the core portion of the 2nd layer comprises the steps of dissolving lansoprazole 30 mg and HPMC in a sufficient quantity of distilled water; and spraying the solution so-obtained onto the neutral cores.
Preparation method of the intermediate coating portion of the 2nd layer comprises the steps of dissolving talk in a sufficient quantity of ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; and obtaining intermediate-coated pellets.
Preparation method of the enteric coating portion of the 2nd layer comprises the steps of spraying the sufficient quantity of ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; and obtaining enteric-coated pellets.
Preparation method of the 2nd layer for tablet press comprises the step of mixing enteric- coated lansoprazole pellets so-obtained with microcrystalline cellulose and croscarmellose sodium.
Finally, the final powder mixture of 2nd layer is added onto the tablet of 1 st layer, and tablet press is applied so as to obtain bilayer tablet.
1 st layer of the bilayer tablets of the invention comprising thiocolchicoside and diclofenac potassium exhibit immediate release; and 2nd layer of the bilayer tablets of the invention comprising lansoprazole exhibit delayed release.
Example 2: Capsule
Figure imgf000016_0001
2nd STAGE - Core
Content Weight (mg) / unit dose
Diclofenac potassium 50.0
Neutral core 35.0
10% (w/w) aqueous solution of HPMC 150.0
Deionized water q.s.
Total 100.0
2nd STAGE - Enteric Coating
Content Weight (mg) / unit dose
Pellets 100.0
30% (w/w) dispersion of methacrylic acid 24.0 copolymer
15%) (w/w) dispersion of magnesium 4.0 stearate
Talk 2.2
Deionized water q.s.
Total 110.0
3rd STAGE - Core
Content Weight (mg) / unit dose
Lansoprazole 30.0
Neutral core 30.0
HPMC 6.0
Distilled water q.s.
Total 66.0
3rd STAGE - Intermediate Coating
Content Weight (mg) / unit dose
Core 66.0
HPMC 6.0
Polyethylene glycol 0.7
Talk 11.3
Ethanol q.s.
Distilled water q.s.
Total 84.0 3rd STAGE - Enteric Coating
Content Weight (mg) / unit dose
Intermediate-coated pellets 84.0
Hydroxypropyl methylcellulose phthalate 32.0
Tributyl citrate 8.0
Ethanol q.s.
Acetone q.s.
Total 124.0
Preparation method of the mixture in the 1st stage comprises the steps of mixing thiocolchicoside 8 mg together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and optionally applying compression to the final mixture.
Preparation method of the enteric-coated diclofenac potassium pellets in the 2nd stage comprises two stages. Core is obtained in the first stage, and enteric coating is obtained in the second stage. Fluid bed granulator is used for the spraying process applied in these stages.
Preparation method of the core portion of the 2nd stage comprises the steps of diluting 10% (w/w) aqueous solution of HPMC with a sufficient quantity' of deionized water; adding diclofenac potassium 50 mg into said HPMC solution and mixing until a homogeneous mixture is obtained; and spraying the solution so-obtained onto the neutral cores.
Preparation method of the enteric coating portion of the 2nd stage comprises the steps of preparing 15% (w/w) dispersion of magnesium stearate by using magnesium stearate and a sufficient quantity of deionized water; adding talk into the sufficient quantity of deionized water and mixing until a homogeneous mixture is obtained; adding 15%) (w/w) dispersion of magnesium stearate into the talk mixture and mixing; adding 30% (w/w) dispersion of methacrylic acid copolymer into the magnesium stearate and talk mixture and mixing; spraying said enteric coating solution onto the pellets of the core portion; and following the addition of talk, drying enteric-coated pellets so-obtained at 40 °C.
Preparation method of the enteric-coated lansoprazole pellets in the 3rd stage comprises three stages. Core is obtained in the first stage, intermediate coating is obtained in the second stage, and enteric coating is obtained in the third stage. Fluid bed granulator is used for the spraying process applied in these stages.
Preparation method of the core portion of the 3rd stage comprises the steps of dissolving lansoprazole 30 mg and HPMC in a sufficient quantity of distilled water; and spraying the solution so-obtained onto the neutral cores.
Preparation method of the intermediate coating portion of the 3rd stage comprises the steps of dissolving talk in a sufficient quantity of ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; and obtaining intermediate-coated pellets.
Preparation method of the enteric coating portion of the 3rd stage comprises the steps of spraying the sufficient quantity of ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; and obtaining enteric-coated pellets. Enteric-coated lansoprazole pellets so-obtained are optionally mixed with microcrystalline cellulose and croscarmellose sodium.
Finally, thiocolchicoside powder mixture or tablet obtained in the first stage; enteric-coated diclofenac potassium pellets obtained in the second stage; and enteric-coated lansoprazole pellets obtained in the third stage are filled into the capsules together.
Thiocolchicoside portion of the capsules of the invention exhibits immediate release; diclofenac potassium pellets and lansoprazole pellets of the invention exhibit delayed release.
Pharmaceutical dosage forms prepared by the processes of the invention have not met any stability problems during long term stability studies performed at 25 ± 2 °C and 60 ± 5 % RH across a 0-, 3- and 6-month follow-up period; and accelerated stability studies performed at 40 ± 2 °C and 75 ± 5 % RH across a 0-, 3- and 6-month follow-up period.

Claims

1. A pharmaceutical composition in unit dosage form comprising
a) a muscle relaxant;
b) an NSAID;
c) a gastroprotectant; and
d) at least one pharmaceutically acceptable excipient.
2. Pharmaceutical composition according to claim 1 comprising thiocolchicoside or a pharmaceutically acceptable salt thereof as muscle relaxant.
3. Pharmaceutical composition according to claim 1 comprising diclofenac or a pharmaceutically acceptable salt thereof as NSAID.
4. Pharmaceutical composition according to claim 1 comprising lansoprazole or a pharmaceutically acceptable salt thereof as gastroprotectant.
5. A pharmaceutical composition in unit dosage form for use in the treatment of muscular and skeletal system diseases, inflammation and pain comprising
a) thiocolchicoside as muscle relaxant;
b) diclofenac potassium as NSAID;
c) lansoprazole as gastroprotectant; and
d) at least one pharmaceutically acceptable excipient.
6. Pharmaceutical composition according to claim 1 or 5 comprising thiocolchicoside in an amount of from 4 to 16 mg, diclofenac potassium in an amount of from 12.5 to 225 mg and lansoprazole in an amount of from 15 to 180 mg.
7. Pharmaceutical composition according to claim 1 or 5 comprising thiocolchicoside in an amount of 8 mg, diclofenac potassium in an amount of 50 mg and lansoprazole in an amount of 30 mg.
8. Pharmaceutical composition according to claim 1 or 5 adapted for oral administration of the pharmaceutical dosage form.
9. Pharmaceutical composition according to claim 8 adapted for oral administration in the form of tablet.
10. Pharmaceutical composition according to claim 8 adapted for oral administration in the form of bilayer tablet.
1 1. Pharmaceutical dosage form according to claim 9 or 10 comprising thiocolchicoside preformulated separately from at least one of the active components consisting of diclofenac potassium and lansoprazole.
12. Pharmaceutical dosage form according to claim 1 1 comprising thiocolchicoside in the form of powder mixture.
13. Pharmaceutical dosage form according to claim 9 or 10 comprising diclofenac potassium preformulated separately from at least one of the active components consisting of thiocolchicoside and lansoprazole.
14. Pharmaceutical dosage form according to claim 13 comprising diclofenac potassium in the form of powder mixture.
15. Pharmaceutical dosage form according to claim 9 or 10 comprising lansoprazole preformulated separately from at least one of the active components consisting of thiocolchicoside and diclofenac potassium.
16. Pharmaceutical dosage form according to claim 15 comprising lansoprazole in the form of enteric-coated pellet.
17. Pharmaceutical dosage form according to any one of the claims from 9 to 16 comprising thiocolchicoside and diclofenac potassium in the form of powder mixture in the first layer of the bilayer tablet; and lansoprazole in the form of enteric-coated pellet in the second layer of the bilayer tablet.
18. Preparation process of the first layer of the bilayer tablet form according to any one of the claims from 9 to 17 comprising the steps of mixing thiocolchicoside and diclofenac potassium together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and tablet pressing by applying pre-compression to the final mixture.
19. Preparation process of the second layer of the bilayer tablet form according to any one of the claims from 9 to 17 comprising the steps of dissolving lansoprazole and HPMC in distilled water; spraying the solution so-obtained onto the neutral cores; dissolving talk in ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; obtaining intermediate-coated pellets; spraying ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; obtaining enteric-coated pellets; and mixing enteric-coated lansoprazole pellets so-obtained with microcrystalline cellulose and croscarmellose sodium.
20. Preparation process of the bilayer tablet form according to any one of the claims from 9 to 19 comprising the steps of adding the final powder mixture of second layer onto the tablet of first layer, and applying tablet press so as to obtain bilayer tablet.
21. Pharmaceutical dosage form according to any one of the claims from 9 to 20 comprising a thiocolchicoside portion exhibiting immediate release.
22. Pharmaceutical dosage form according to any one of the claims from 9 to 20 comprising a diclofenac potassium portion exhibiting immediate release.
23. Pharmaceutical dosage form according to any one of the claims from 9 to 20 comprising a lansoprazole portion exhibiting delayed release.
24. Pharmaceutical composition according to claim 8 adapted for oral administration in the form of capsule.
25. Pharmaceutical dosage form according to claim 24 comprising thiocolchicoside preformulated separately from at least one of the active components consisting of diclofenac potassium and lansoprazole.
26. Pharmaceutical composition according to claim 25 comprising thiocolchicoside in the form of powder mixture.
27. Pharmaceutical composition according to claim 25 comprising thiocolchicoside in the form of tablet.
28. Pharmaceutical composition according to claim 24 comprising diclofenac potassium preformulated separately from at least one of the active components consisting of thiocolchicoside and lansoprazole.
29. Pharmaceutical composition according to claim 28 comprising diclofenac potassium in the form of enteric-coated pellet.
30. Pharmaceutical composition according to claim 24 comprising lansoprazole preformulated separately from at least one of the active components consisting of thiocolchicoside and diclofenac potassium.
31. Pharmaceutical composition according to claim 30 comprising lansoprazole in the form of enteric-coated pellet.
32. Pharmaceutical dosage form according to any one of the claims from 24 to 31 comprising thiocolchicoside in the form of powder mixture or tablet in the thiocolchicoside portion of the capsule; diclofenac potassium in the form of enteric- coated pellet in the diclofenac potassium portion of the capsule; and lansoprazole in the form of enteric-coated pellet in the lansoprazole portion of the capsule.
33. Preparation process of the thiocolchicoside portion of the capsule form according to any one of the claims from 24 to 32 comprising the steps of mixing thiocolchicoside together with lactose monohydrate, microcrystalline cellulose and pregelatinized starch; adding magnesium stearate into said mixture and remixing; and optionally applying compression to the final mixture.
34. Preparation process of the diclofenac potassium portion of the capsule form according to any one of the claims from 24 to 32 comprising the steps of diluting 10% (w/w) aqueous solution of HPMC with deionized water; adding diclofenac potassium into said HPMC solution and mixing until a homogeneous mixture is obtained; spraying the solution so-obtained onto the neutral cores; preparing 15% (w/w) dispersion of magnesium stearate by using magnesium stearate and deionized water; adding talk into deionized water and mixing until a homogeneous mixture is obtained; adding 15% (w/w) dispersion of magnesium stearate into the talk mixture and mixing; adding 30% (w/w) dispersion of methacrylic acid copolymer into the magnesium stearate and talk mixture and mixing; spraying said enteric coating solution onto the pellets of the core portion; and following the addition of talk, drying enteric-coated pellets so- obtained.
35. Preparation process of the lansoprazole portion of the capsule form according to any one of the claims from 24 to 32 comprising the steps of dissolving lansoprazole and HPMC in distilled water; spraying the solution so-obtained onto the neutral cores; dissolving talk in ethanol/water solution comprising HPMC/polyethylene glycol; spraying the suspension so-obtained onto the core portion; obtaining intermediate- coated pellets; spraying ethanol/acetone solution comprising HPMC phthalate and tributyl citrate onto the intermediate-coated pellets; obtaining enteric-coated pellets; and optionally mixing enteric-coated lansoprazole pellets so-obtained with microcrystalline cellulose and croscarmellose sodium.
36. Preparation process of the capsule form according to any one of the claims from 24 to 35 comprising the steps of filling thiocolchicoside powder mixture or tablet; enteric- coated diclofenac potassium pellets; and enteric-coated lansoprazole pellets into the capsules together.
37. Pharmaceutical dosage form according to any one of the claims from 24 to 36 comprising a thiocolchicoside portion exhibiting immediate release.
38. Pharmaceutical dosage form according to any one of the claims from 24 to 36 comprising a diclofenac potassium portion exhibiting sustained release.
39. Pharmaceutical dosage form according to any one of the claims from 24 to 36 comprising a lansoprazole portion exhibiting delayed release.
40. Pharmaceutical composition according to any one of the preceding claims adapted to be administered once a day in unit doses.
41. Pharmaceutical composition according to any one of the preceding claims adapted to be administered twice a day in unit doses.
42. Use of a pharmaceutical composition according to any one of the preceding claims in the treatment of muscular and skeletal system diseases, inflammation and pain in mammalian organism.
PCT/TR2012/000060 2011-04-18 2012-04-18 Thiocolchicoside, diclofenac and lansoprazole combinations WO2012144964A1 (en)

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TR2011/03752A TR201103752A2 (en) 2011-04-18 2011-04-18 Combinations of thiocolchicoside, diclofenac and lansoprazole.

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WO2016102661A1 (en) * 2014-12-23 2016-06-30 Krka, D.D., Novo Mesto Pharmaceutical tablet composition
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