WO2019203746A2 - Combinaison pharmaceutique comprenant du raloxifène et de l'aripiprazole - Google Patents

Combinaison pharmaceutique comprenant du raloxifène et de l'aripiprazole Download PDF

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Publication number
WO2019203746A2
WO2019203746A2 PCT/TR2018/050772 TR2018050772W WO2019203746A2 WO 2019203746 A2 WO2019203746 A2 WO 2019203746A2 TR 2018050772 W TR2018050772 W TR 2018050772W WO 2019203746 A2 WO2019203746 A2 WO 2019203746A2
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WO
WIPO (PCT)
Prior art keywords
tablets
weight
pharmaceutical combination
combination according
tablet
Prior art date
Application number
PCT/TR2018/050772
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English (en)
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WO2019203746A3 (fr
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Merve ERGUN DÖNMEZ
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Filing date
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Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2019203746A2 publication Critical patent/WO2019203746A2/fr
Publication of WO2019203746A3 publication Critical patent/WO2019203746A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/0012—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a combination which comprises raloxifene or a pharmaceutically acceptable salt thereof and aripiprazole or 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 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
  • 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.
  • aripiprazole 7-[4-[4-(2,3-dichlorophenyl)-1 -piperazinyl]butoxy]- 3,4-dihydrocarbostyril, has partial agonist effect on dopamine D2 receptors. Its chemical structure is illustrated with formula II given below.
  • Aripiprazole works in a slightly different way to other antipsychotic medicines. It acts on various receptors in the brain, particularly dopamine receptors and serotonin receptors. Dopamine and serotonin are natural compounds called neurotransmitters, and are involved in transmitting messages between brain cells. Psychotic illness is considered to be caused by disturbances in the activity of neurotransmitters (mainly dopamine) in the brain. Aripiprazole is thought to work mainly by stabilizing the dopamine activity in the brain. It is considered to be a dopamine D2 receptor partial agonist.
  • a dopamine D2 receptor partial agonist has affinity toward the dopamine D2 receptor and an intrinsic activity that is less than the activity of the endogenous full dopamine agonist, that is, it can bind to the dopamine D2 receptor and cause a similar set of reaction but the magnitude of the reaction is smaller.
  • aripiprazole is more safe and tolerable in comparison to the existent typical and atypical antipsychotics.
  • 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 with aripiprazole 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.
  • 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 a combination of raloxifene and aripiprazole, eliminating positive symptoms of schizophrenia which is hallucinations, delusions, problem of memory and attention and bringing additional advantages over the relevant prior art.
  • Another object of the present invention is to provide improved combination which are less irritating, stable, rapid and effective treatment.
  • a further object of the present invention is to provide a stable combination with a desired dissolution profiles.
  • Another object of the present invention is to provide rapid penetration of drug substances and to provide high stability.
  • the term“combination” 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.
  • aripiprazole refers to aripiprazole in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • An embodiment of this present invention is to provide a pharmaceutical combination comprising raloxifene and aripiprazole.
  • An embodiment of this present invention is to combine raloxifene and aripiprazole in a same and stable dosage form with desired dissolution profiles.
  • molecules should be compatible with each other to achieve desired stability and dissolution for the patient’s compliance.
  • the amount of raloxifene in the combination is between 0.1 % and 80.0% by weight, 4.5% and 60.0%, preferably between 5.0% and 45.0%.
  • the amount of aripiprazole in the combination is between 0.1 % and 70.0% by weight, 0.7% and 55.0%, preferably between 0.5% and 45.0%.
  • the combination comprises at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactants, lubricants, glidants, plasticizers, preservatives, sweeteners, flavouring agents, melting components, inert agents, stabilizers, antioxidants, coating agents, coloring agents, pH adjusters or mixtures thereof.
  • pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactants, lubricants, glidants, plasticizers, preservatives, sweeteners, flavouring 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, 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- cyclodextrin, talc
  • Suitable binders are selected from the group comprising microcrystalline cellulose and guar gum, pregelatinized starch, polyvinylpyrrolidone, sugars, glucose syrup, natural gums, 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, stearic
  • 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 surfactants 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 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, 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, sucrose, glucose, lactose, fructose, mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable flavouring 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, co-povidone, 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.
  • Suitable inert agents are used between the two molecules that are selected from starch, lactose, D-mannitol, erythritol, lowsubstituted 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; preferably the stabilizers are 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, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), macrogol-PEG, talc, polyvinyl alcohol- polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
  • 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.
  • pH adjusters are citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate, glycin, glutamic acid or mixtures thereof.
  • the pharmaceutical combination is administered orally.
  • said combination 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 combination is preferably in the form of tablet or capsule or pastille or strip.
  • the pharmaceutical combination is more preferably in the tablet form.
  • Tablet comprises separated compartments or layers.
  • the pharmaceutical combination is formulated as tablet comprising film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets or lozenges.
  • pharmaceutical combination can be prepared 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 combination may further comprise a film coating if necessary.
  • the tablets are formulated as film coated tablet or orally disintegrating tablets.
  • These dosage forms provide desired stability and dissolution. Also, these dosage forms provide ease of use for the patient.
  • the pharmaceutical combination 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 dosage form of combination is mini-capsules in capsule wherein mini capsules comprise at least one active agent.
  • the dosage form of combination is mini-tablets in capsules wherein mini-tablets comprise at least one active agent.
  • the dosage form of combination is pellets in capsule wherein pellets comprise at least one active agent.
  • the combination of invention can be developed into oral dosage form comprising immediate release, extended release, sustained release, controlled release, modified release or delayed release or combinations thereof.
  • the combination comprises; a) 0.1 - 80.0% by weight of raloxifene HCI
  • the film coated tablet of combination comprises; a) 0.1 - 50.0% by weight of raloxifene HCI
  • magnesium stearate 0.1 - 5.0% by weight of magnesium stearate
  • the orally disintegrating tablet of combination comprises;
  • the pharmaceutical combination of the present invention can be prepared by 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 or solvent evaporation.
  • the stable combination is preferably prepared by using a wet granulation method or dry granulation and therefore a simple and low-cost production method was employed.
  • a desired dissolution of the combination is obtained and a desired content uniformity and a simple preparation process are in favour of industrial production.
  • Example 1 Film coated tablet comprising raloxifene and aripiprazole
  • Example 2 Film coated tablet comprising aripiprazole and raloxifene
  • the process for preparation of the pharmaceutical combination comprises the following steps:
  • Example 3 Orally disintegrating tablets aripiprazole and raloxifene
  • Example 4 Orally disintegrating tablets aripiprazole and raloxifene
  • the process for preparation of the pharmaceutical formulation comprises the following steps:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une combinaison qui comprend du raloxifène ou un sel pharmaceutiquement acceptable de celui-ci et de l'aripiprazole ou un sel pharmaceutiquement acceptable de celui-ci et éventuellement au moins un excipient pharmaceutiquement acceptable pour une utilisation simultanée, séparée ou séquentielle.
PCT/TR2018/050772 2017-12-08 2018-12-06 Combinaison pharmaceutique comprenant du raloxifène et de l'aripiprazole WO2019203746A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/19919A TR201719919A2 (tr) 2017-12-08 2017-12-08 The pharmaceutical combination comprising raloxifene and aripiprazole
TR2017/19919 2017-12-08

Publications (2)

Publication Number Publication Date
WO2019203746A2 true WO2019203746A2 (fr) 2019-10-24
WO2019203746A3 WO2019203746A3 (fr) 2020-01-16

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Application Number Title Priority Date Filing Date
PCT/TR2018/050772 WO2019203746A2 (fr) 2017-12-08 2018-12-06 Combinaison pharmaceutique comprenant du raloxifène et de l'aripiprazole

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TR (1) TR201719919A2 (fr)
WO (1) WO2019203746A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070014864A1 (en) * 2005-07-15 2007-01-18 Teva Pharmaceutical Industries, Ltd. Novel pharmaceutical granulate
WO2015082562A1 (fr) * 2013-12-05 2015-06-11 Alrise Biosystems Gmbh Procédé de production de formulations médicamenteuses pour une administration par voie orale
US20190060300A1 (en) * 2016-03-04 2019-02-28 Sharon Anavi-Goffer Self-Emulsifying Compositions of CB2 Receptor Modulators

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WO2019203746A3 (fr) 2020-01-16
TR201719919A2 (tr) 2019-06-21

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