WO2019203748A2 - Combinaison comprenant du raloxifène et au moins un agent antipsychotique - Google Patents

Combinaison comprenant du raloxifène et au moins un agent antipsychotique Download PDF

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Publication number
WO2019203748A2
WO2019203748A2 PCT/TR2018/050780 TR2018050780W WO2019203748A2 WO 2019203748 A2 WO2019203748 A2 WO 2019203748A2 TR 2018050780 W TR2018050780 W TR 2018050780W WO 2019203748 A2 WO2019203748 A2 WO 2019203748A2
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Prior art keywords
pharmaceutical composition
tablets
raloxifene
composition according
tablet
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PCT/TR2018/050780
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English (en)
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WO2019203748A3 (fr
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Merve ERGUN DONMEZ
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Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Publication of WO2019203748A2 publication Critical patent/WO2019203748A2/fr
Publication of WO2019203748A3 publication Critical patent/WO2019203748A3/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • 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
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    • 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
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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Definitions

  • the present invention relates to a composition which comprises raloxifene or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent or the pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable excipient for simultaneous, separate or sequential use.
  • Schizophrenia is a mental illness which affects how a person thinks, feels and acts. It's not known what causes schizophrenia, but researchers believe that a combination of genetics, brain chemistry and environment contribute to the development of the disorder.
  • the symptoms of schizophrenia are described as positive, negative, and cognitive.
  • negative symptoms include reducing expression of emotions via facial expression or voice, reducing feelings of pleasure in everyday life, difficulty beginning and sustaining activities, reducing speaking
  • estrogen may be a beneficial treatment for women with schizophrenia. Patients with schizophrenia were treated with estrogen and conjugated estrogens modulate various neurotransmitter symptoms involved in the pathogenesis of schizophrenia. There was significant improvement in their positive symptoms. Furthermore, negative symptoms did not progress. So, estrogen is used for both men and women in the treatment of schizophrenia.
  • raloxifene is [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]- [4-[2-(l -piperidyl) ethoxy] phenyl]-methanone. Its chemical structure, shown below (Formula I), has a formula of C H NO S, with the molecular weight of 473.587 g/mol.
  • Raloxifene is a benzothiophene-derived selective estrogen receptor modulator and widely used for the treatment and prevention of osteoporosis in postmenopausal women. It is disclosed in U.S. patent number 4,418,068. In pharmaceutical formulations, it is used in the form of a hydrochloride salt and is marketed under the brand name Evista ® by Eli Lilly.
  • raloxifene with at least one antipsychotic agent is more effective compared to antipsychotic agent alone because, this combination also helps to reduce positive symptoms (hallucinations, delusions, problem of memory and attention) due to the disease. Furthermore, there is no combination of raloxifene with at least one antipsychotic agent in the prior art.
  • combining more than one molecule in one dosage form increases the patient’s compliance. Flowever, while this combination is increasing the patients’ quality of life, combining more than one molecule in one dosage form is also reduce undesired schizophrenia symptoms which can be hallucinations, delusions, problem of memory and attention.
  • the main object of the present invention is to provide stable dosage form with desired dissolution profiles, eliminating schizophrenia symptoms and bringing additional advantages to the relevant prior art.
  • Another object of the present invention is to provide improved compositions which are less irritating, stable, rapid and effective treatment.
  • Another object of the present invention is to provide rapid penetration of drug substances and provide high stability.
  • composition means that when drugs are administered together, a combined action is obtained which is higher than the individual actions of the respective drugs when they are used separately.
  • raloxifene refers to raloxifene in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • antipsychotic agent refers to an antipsychotic agent in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • Antipsychotic agents are drugs that are used to treat symptoms of psychosis such as delusions, hallucinations, paranoia, or confused thoughts.
  • An embodiment of this present invention is to provide a pharmaceutical composition comprising raloxifene and at least one antipsychotic agent.
  • An embodiment of this present invention is to combine raloxifene and at least one antipsychotic agent in a same or stable dosage form with desired dissolution profiles.
  • suitable antipsychotic agents are selected from the group comprising paliperidone, aripiprazole, brexpiprazole, olanzapine, amisulpride or mixtures thereof.
  • molecules should be compatible with each other to achieve desired stability and dissolution for the patient’s compliance.
  • the pharmaceutical composition is raloxifene with paliperidone.
  • the pharmaceutical composition is raloxifene with aripiprazole.
  • the pharmaceutical composition is raloxifene with brexpiprazole. According to one embodiment in the present invention, the pharmaceutical composition is raloxifene with olanzapine.
  • the pharmaceutical composition is raloxifene with amisulpride.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactants, modified release agents, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings agents, melting components, inert agents, stabilizers, antioxidants, coating agents, coloring agents, pH adjusters or mixtures thereof.
  • Suitable fillers are selected from the group comprising anhydrous lactose, lactose monohydrate, microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, , mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta
  • Suitable binders are selected from the group comprising microcrystalline cellulose and guar gum, pregelatinized starch, polyvinylpyrrolidone, sugars, glucose syrup, natural gums, gelatin, collagen, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, povidone, starch, corn starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide
  • Suitable disintegrants are selected from the group comprising mannitol, sodium starch glycolate, polyvinilpyrrolidone, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
  • Suitable surfactans are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide or mixtures thereof.
  • Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, iota carregeenan, furcellaran
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • Suitable glidants are selected from the group comprising talc, aluminium silicate, colloidal silicon dioxide, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • Suitable plasticizers are selected from the group comprising polyethylene glycols of different molecular weights, triacetin, tributyl citrate, triethyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols or mixtures thereof.
  • Suitable preservatives are selected from the group comprising methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, benzyl alcohol, citric acid, benzoic acid, m-cresol, phenol or mixtures thereof.
  • Suitable sweeteners are selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars, sucrose, glucose, lactose, fructose, mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable flavoring agents are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin, fruit essences, cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.
  • Suitable melting components are selected from the group comprising gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butyl pthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethly phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
  • gelucire stearyl macrogolglyceride
  • poloxamer polyoxyethylene-polyoxypropylene block copolymer
  • polyethylene glycol povidone
  • povidone soluplus
  • cationic methacrylate copovidone
  • Suitable inert agents between the two molecules wherein the inert agents are selected from starch, lactose, sugar alcohol like D-mannitol, erythritol, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
  • Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium chloride, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
  • Suitable antioxidants are selected from the group comprising alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, thymol or mixtures thereof.
  • Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, lecithin, xanthan gum, hydroxypropyl cellulose, polyvinyl alcohol, titanium dioxide, colloidal silica, polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers, ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, macrogol, coloring agents or mixtures thereof.
  • coating agents are Opadry® AMB and Kollicoat® IR.
  • Opadry® AMB comprises polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum and coloring agents.
  • Kollicoat® IR comprises polyvinyl alcohol, polyethylene glycol copolymers and colloidal silica
  • Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • Suitable pH adjusters are selected from the group comprising alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, preferably pH adjusters are citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate, glycin, glutamic acid or mixtures thereof.
  • the pharmaceutical composition is administrated orally.
  • the pharmaceutical composition is in the form of tablets, capsules, orally disintegrating tablets, strips, syrups, powders, pastilles, sachet, effervescent compositions, pills, hard or soft gelatin capsules, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions or emulsions.
  • the pharmaceutical composition is in the form of tablets, capsules, pastilles or strips.
  • the pharmaceutical composition is in the form of tablet. Tablet may be consisted of separated compartments or layer.
  • the pharmaceutical composition is formulated as tablets comprising film-coated tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablets, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, gastric disintegrating tablets, chewable tablet, dispersing tablets or lozenges.
  • the pharmaceutical composition is formulated as film coated tablet or orally disintegrating tablets.
  • the pharmaceutical composition is formulated as tablet form.
  • Tablet comprises at least one type of particle, for example; mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof.
  • each type of particle comprises at least one active agent.
  • the pharmaceutical composition may further comprise a film coating if necessary.
  • the pharmaceutical composition is formulated as capsule form.
  • Capsule comprises at least one type of particle, for example; mini-capsules, mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof.
  • the pharmaceutical composition is formulated as mini-capsules in capsule wherein the mini-capsules comprise at least one active agent.
  • the pharmaceutical composition is formulated as mini-tablets in capsule wherein a mini-tablets comprise at least one active agent.
  • the pharmaceutical composition is formulated as pellets in capsule wherein pellets comprise at least one active agent.
  • the pharmaceutical composition of raloxifene HCI and paliperidone comprises mini-tablets and granules.
  • compositions of invention may be developed into oral dosage form comprising immediate release, extended release, sustained release, controlled release, modified release and delayed release or combination thereof.
  • the composition may be prepared using modified release agents.
  • the pharmaceutical composition wherein said composition comprises at least one of the following drug compositions for combined, separate or sequential administration:
  • -raloxifene paliperidone or their pharmaceutically acceptable salt, solvate or polymorph -raloxifene, aripiprazole or their pharmaceutically acceptable salt, solvate or polymorph -raloxifene, brexpiprazole or their pharmaceutically acceptable salt, solvate or polymorph -raloxifene, olanzapine or their pharmaceutically acceptable salt, solvate or polymorph -raloxifene, amisulpride or their pharmaceutically acceptable salt, solvate or polymorph
  • the pharmaceutical composition comprises;
  • the pharmaceutical composition comprises;
  • the pharmaceutical composition comprises;
  • the pharmaceutical composition comprises; a) 10.0 - 50.0% by weight of raloxifene HCI
  • the pharmaceutical composition comprises; a) 10.0 - 50.0% by weight of raloxifene HCI
  • magnesium stearate 0.1 - 5.0% by weight of magnesium stearate
  • the pharmaceutical composition comprises; a) 5.0 - 30.0% by weight of raloxifene HCI
  • the pharmaceutical composition comprises;
  • magnesium stearate 0.1%-5.0% by weight of magnesium stearate
  • the pharmaceutical composition of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the stable composition is obtained by using a wet granulation method or dry granulation and therefore a simple and low-cost production method was employed.
  • Example 1 Film coated tablet comprising raloxifene and antipsychotic agents
  • Example 2 Orally disintegrating tablet comprising raloxifene and antipsychotic agents
  • Example 3 Film coated tablet comprising aripiprazole and raloxifene
  • Example 4 Film coated tablet comprising aripiprazole and raloxifene
  • the process for preparation of the pharmaceutical composition comprises the following steps:
  • Example 6 Orally disintegrating tablets comprising aripiprazole and raloxifene
  • the process for preparation of the pharmaceutical composition comprises the following steps:
  • Example 7 Film coated tablet comprising brexpiprazole and raloxifene
  • Example 8 Film coated tablet comprising brexpiprazole and raloxifene
  • the process for preparation of the pharmaceutical composition comprises the following steps:
  • step (c) Adding step (c) mixture on step (b) mixture and mixing
  • Example 10 Film coated tablet comprising olanzapine and raloxifene
  • the process for preparation of the pharmaceutical composition comprises the following steps:
  • Example 12 Film coated tablet comprising comprising amisulpride and raloxifene
  • the process for preparation of the pharmaceutical composition comprises the following steps:
  • Example 14 Capsule comprising paliperidone and raloxifene According to example 13 or 14, form of raloxifene HCI is granule and form of paliperidone is mini-tablet.

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition qui comprend du raloxifène ou un sel pharmaceutiquement acceptable de celui-ci et au moins un agent antipsychotique ou un sel pharmaceutiquement acceptable de celui-ci et éventuellement au moins un excipient pharmaceutiquement acceptable pour une utilisation simultanée, séparée ou séquentielle.
PCT/TR2018/050780 2017-12-08 2018-12-07 Combinaison comprenant du raloxifène et au moins un agent antipsychotique WO2019203748A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/19911A TR201719911A2 (tr) 2017-12-08 2017-12-08 Raloksi̇fen ve en az bi̇r anti̇psi̇koti̇k ajan i̇çeren kompozi̇syon
TR2017/19911 2017-12-08

Publications (2)

Publication Number Publication Date
WO2019203748A2 true WO2019203748A2 (fr) 2019-10-24
WO2019203748A3 WO2019203748A3 (fr) 2020-01-09

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PCT/TR2018/050780 WO2019203748A2 (fr) 2017-12-08 2018-12-07 Combinaison comprenant du raloxifène et au moins un agent antipsychotique

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TR (1) TR201719911A2 (fr)
WO (1) WO2019203748A2 (fr)

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WO2019203748A3 (fr) 2020-01-09
TR201719911A2 (tr) 2019-06-21

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