WO2010009900A1 - Composition de palipéridone comprenant des particules de matrice solide - Google Patents

Composition de palipéridone comprenant des particules de matrice solide Download PDF

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Publication number
WO2010009900A1
WO2010009900A1 PCT/EP2009/005427 EP2009005427W WO2010009900A1 WO 2010009900 A1 WO2010009900 A1 WO 2010009900A1 EP 2009005427 W EP2009005427 W EP 2009005427W WO 2010009900 A1 WO2010009900 A1 WO 2010009900A1
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Prior art keywords
pharmaceutical composition
active substance
matrix
composition according
solid
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PCT/EP2009/005427
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English (en)
Inventor
Grega Hudovornik
Maja Preskar
Franc Vrecer
Robert Pisek
Matej Pavli
Original Assignee
Krka, D.D. Novo Mesto
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Application filed by Krka, D.D. Novo Mesto filed Critical Krka, D.D. Novo Mesto
Priority to EP09777460A priority Critical patent/EP2326312A1/fr
Publication of WO2010009900A1 publication Critical patent/WO2010009900A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention provides for a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance.
  • the invention further relates to a process of making said solid pharmaceutical composition.
  • the invention particularly relates to suitable oral formulations comprising the active substance paliperidone, using such a technology.
  • Schizophrenia is a chronic, severe, and disabling psychotic disorder characterized by extreme disturbances of cognition and thought, affecting language, perception and sense of self. It is a mental illness with a lifetime estimated risk of 1%.
  • Schizophrenia is characterized by positive symptoms (auditory hallucinations, disorganized or playful thoughts, delusions and irrational fears) and negative symptoms of social withdrawal, poor motivation, poverty of speech, apathy and lack of energy.
  • the treatment of schizophrenia is multifactorial, with antipsychotic medications comprising a major part of treatment.
  • Chlorpromazine and other first-generation antipsychotics antagonize the dopamine D 2 -like class of receptors. Although effective against psychosis, they do not improve and may even exacerbate the negative symptoms of schizophrenia and are associated with dose-limiting extrapyramidal symptoms (EPS).
  • EPS extrapyramidal symptoms
  • the second-generation dual-action dopamine and serotonine D 2 /5-HT 2A receptor blockers retain the antipsychotic effect of the typical antipsychotics, but show a much reduced propensity to cause EPS, and also may improve negative symptoms of schizophrenia.
  • Paliperidone represents the most recent atypical antipsychotic indicated for the short- and long-term treatment of schizophrenia.
  • Paliperidone a benzisoxazole derivative and the principal active metabolite of risperidone, is commonly referred to as 9-hydroxyrisperidone.
  • Prolonged release formulations offer the possibility of reducing dosage regimes for drugs, especially for those drugs administered orally to patients, by prolonging the time period during which pharmacologically effective levels of the active substance are present in the body. Prolonged release formulations thereby result in a better assurance of compliance, reduction of severity and frequency of side effects, since the drug level in the blood is more constant, and drug level fluctuations associated with conventional immediate release formulations administered several times a day are avoided.
  • osmotic-controlled release dosage forms formulated by using OROS drug delivery technology
  • osmotic pressure to generate a driving force for imbibing fluid into a compartment formed, at least in part, by a semipermeable membrane that permits free diffusion of fluid but not drug or osmotic agent(s), if present.
  • WO 2004/010981 relates to dosage forms and methods for providing a substantially ascending rate of release of paliperidone.
  • the patent is concerned with a dosage form comprising a capsule shaped tablet core containing a plurality of layers wherein the paliperidone is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer; (b) a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and (c) an orifice formed through the semipermeable membrane and into the capsule shaped tablet core to permit paliperidone to be released from within the compartment into the external fluid environment.
  • OROS dosage forms are further disclosed in the following documents WO 2005/048952, WO 2006/085856, WO 2006/101815, WO 2007/016388, WO 2007/081736, WO 2007/044234.
  • osmotic pump dosage forms include complex manufacture and the use of harsh solvents in their preparation.
  • OROS osmotic-controlled release oral delivery system
  • Current medical research and opinion 2006, 22(10), pp. 1879-1892 describe that the OROS tablet is excreted in the faeces and this may be problematic in some patient groups, for example, schizophrenia patients, where the excretion of foreign bodies may be disturbing. Some patients, as with any oral medication, may have difficulty swallowing the tablet and this may limit its utility in this population of patients.
  • An object underlying the present invention is to provide a further simplified and thus inexpensive solid pharmaceutical formulation that provides for prolonged release of the active substance paliperidone.
  • the present invention relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance.
  • Such solid dosage forms offer the advantage of an easier scale-up, better cost-effectiveness due to lower cost of production, no need for sophisticated equipment and less time-consuming production processes.
  • the particles according to the present invention can be prepared by direct compression or by wet/dry/melt granulation (fluid bed or high shear granulator) which represents a very simple and easy method.
  • Such solid dosage forms can optionally be coated.
  • the present invention provides for a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance.
  • the present invention provides for a monolithic matrix system (MMS) comprising one solid matrix particle and comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance wherein the solid pharmaceutical composition provides for prolonged release of said active substance.
  • MMS monolithic matrix system
  • the present invention provides for a multi particulate matrix system (MPMS) comprising at least two solid matrix particles each comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance wherein the solid pharmaceutical composition provides for prolonged release of said active substance.
  • MPMS multi particulate matrix system
  • the present invention is directed to a process for the manufacture of a solid pharmaceutical composition comprising at least one solid matrix particle.
  • the solid pharmaceutical composition according to the present invention is prepared by a process comprising steps selected from sieving and mixing powder ingredients, granulation of powder mixture such as dry, wet and melt granulation, compression such as direct compression of mixture of ingredients in powder form and compression of pregranulated ingredients, coating of solid matrix particles such as film and sugar coating, mixing of the respective separately obtained solid matrix particles, filling into hard capsules or sachets, film coating of capsules filled with solid matrix particles.
  • the present invention includes any combination of the above processes.
  • the present invention relates to a process for forming a solid pharmaceutical composition
  • a process for forming a solid pharmaceutical composition comprising the step of melt granulation of a mixture containing at least the active substance, one or more matrix forming agents and a low melting binder to obtain granules, followed by either directly incorporation of these granules into capsules or sachets, or by compressing them into tablets.
  • the present invention provides for a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance, for use in the treatment of schizophrenia.
  • Figure 1 shows in vitro dissolution profiles of the composition of example 9 at different PH.
  • Active substance in the context of this invention means paliperidone or a pharmaceutically acceptable salt thereof.
  • Prolonged release in the context of this invention means that the formulation exhibits a dissolution profile such that after 2 hours less than 30% of the active substance originally contained in a particle type is released, after 12 hours 30 to 70% of the active substance contained in a particle type is released, and after 24 hours more than 70% of the active substance contained in a particle type is released after dissolving the dosage formulation in 500 ml USP buffer pH 6.8 at 37°C in an Apparatus 2 (Ph.Eur. or USP, paddles, 50 rpm). Unless stated otherwise, all percentages given herein are by weight.
  • One type of solid matrix particles in the context of this invention means that the solid matrix particles have the same composition and approximately the same size and shape, manufacturing process and release kinetics, e.g. 2, 3 or more micro or mini tablets can be produced by the same process.
  • the present invention provides for a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance.
  • composition when the solid pharmaceutical composition according to the present invention comprises one solid matrix particle said composition is named monolithic matrix system (MMS) and when the solid pharmaceutical composition according to the present invention comprises at least two solid matrix particles said composition is named multi particulate matrix system (MPMS).
  • MMS monolithic matrix system
  • MPMS multi particulate matrix system
  • the present invention provides for a monolithic matrix system (MMS) comprising one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance wherein the solid pharmaceutical composition provides for prolonged release of said active substance.
  • MMS monolithic matrix system
  • the monolithic matrix system according to the present invention is in the form of a tablet wherein the tablet can be coated or uncoated.
  • the tablet can have a diameter of 5 mm to 20 mm, preferably of 6 mm to 15 mm, more preferably of 7 mm to 13 mm.
  • the height of this tablet is typically 1 to 15 mm, preferably 2 to 12 mm, more preferably 3 to 10 mm.
  • the shape of such tablet can be round, oblong capsule-like, wherein the ratio of minimal to maximal diameter of such tablet is in the range of 1:2 to 1:10.
  • the ratio between surface area and volume of the solid matrix particle is very important and is crucial for active substance release kinetics behaviour. This ratio is preferably in the range 0.2 to 5 cm 2 /cm 3 , more preferably 0.5 to 4 cm 2 /cm 3 .
  • the present invention provides for a multi particulate matrix system (MPMS) comprising at least two solid matrix particles each comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance wherein the solid pharmaceutical composition provides for prolonged release of said active substance.
  • MPMS multi particulate matrix system
  • At least two solid matrix particles can be the same or different in respect to size, shape, composition, manufacturing process and/or release kinetics of active substance wherein at least one type of solid matrix particles provides for prolonged release of said active substance, and wherein the solid matrix particles present in the MPMS are coated or uncoated.
  • the MPMS according to the present invention can be in the form of a capsule or a sachet.
  • the MPMS of the present invention may contain one, two, three, four or more types of solid matrix particles that differ in their compositions so as to provide for different release kinetics of the active substance and optionally other characteristics.
  • the MPMS of the present invention may differ either in the amount of active substance contained in the respective solid matrix particle types or the types and/or amounts of excipients in the respective solid matrix particle types and/or manufacturing process used in production of such solid matrix particles types.
  • the two, three or more solid matrix particle types respectively differ in the amount of active substance and/or the amount of excipients contained therein, shape and/or size and/or manufacturing process used.
  • the kinetics of active substance release from solid matrix particle types of the MPMS can be the same or different.
  • At least one type of solid matrix particles in the MPMS according to the present invention provides for a prolonged release of the active substance.
  • said at least one type of solid matrix particles providing for prolonged release is combined with other types of solid matrix particles such that the entire MPMS exhibits prolonged release.
  • the solid matrix particles of the MPMS of the present invention may for example be present in the form of micro or mini tablets having a diameter of 1.5 mm to 12 mm, preferably of 2 mm to 10 mm, more preferably of 3 mm to 8 mm and having the thickness of 2 mm to 10 mm, preferably 2 to 8 mm.
  • the number of solid matrix particles which are contained in the MPMS depends on the strength of the dosage unit and the desired particle size.
  • the number of said solid matrix coated or uncoated particles depends on the strength of the dosage unit. This means that the size of a capsule can, within certain limits, be selected independent from the strength and number of solid matrix coated or uncoated particles contained therein, as long as the capsule can host the number of the solid matrix particles needed to provide a certain dose.
  • the MPMS contains between 2 and 50 particles, more preferably between 2 and 40 particles.
  • the solid matrix particles preferably contain 0.5 to 30 w/w%, more preferably 0,8 to 15 w/w% and most preferably 1 to 8 w/w% of active substance (calculated as paliperidone).
  • Hardness minimal 25 N, preferably more than 30 N, more preferably more than 35 N, wherein hardness is preferably tested with a radial hardness tester Erweka MultiCheck laboratory hardness tester .
  • Shape round, oval, with or without bevelled edges, with or without imprint
  • Face surface flat or convex
  • the solid matrix particles consist only of the matrix containing active substance, matrix forming agent and optionally other components, and optionally one or more coatings.
  • the solid matrix particles are covered by a single coating layer.
  • Solid matrix particles of the present invention provide for the prolonged release of the active substance which is controlled by the type and the amount of the matrix forming agent.
  • the prolonged release can be obtained according to the following principles or combinations of them:
  • the gastrointestinal fluid penetrates into the matrix according to the point 1 or 2 above, the active substance is dissolved and the dissolved active substance diffuses out of the matrix and is absorbed.
  • the driving force for diffusion is the concentration of the active substance in the aqueous solution created by the penetrating Gl fluid.
  • the matrix is the swelling matrix, e.g. crosslinked (ionic) polymer with entrapped solid active substance, the swelling kinetics of the matrix, the dissolution rate of the active substance, and the diffusion of the active substance will all contribute to the overall release rate.
  • swellable and eroding matrix based on e.g. a soluble polymer.
  • the rate with which the active substance will be available at the absorption site is for these matrices a combination of the swelling and erosion rates of the matrix, and the dissolution and diffusion rates of the active substance.
  • a semipermeable membrane is placed around a tablet or an active substance containing particle which allows transport of water into the formulation by osmosis.
  • the formulation does not comprise an orifice formed through the semipermeable membrane.
  • the "semipermeable membrane” is preferably placed around a part of a tablet, such that the tablet actually has a partial coating, with one side of the tablet not being coated but still differing from inlay tablets.
  • the prolonged release can be obtained according to the following principles or combinations of them:
  • insoluble lipohilic matrix based on one or more pharmaceutically acceptable excipients insoluble in physiological fluids optionally admixed with other excipients such as fillers, binders, disintegrating agents, water penetration enhancers, surfactants, glidants and/or lubricants;
  • hydrophilic matrix based on one or more pharmaceutically acceptable hydrophilic polymers capable of swelling in water and/or physiological fluids in the larger extent than microcrystalline cellulose such as Avicel type PH 101, optionally admixed with other excipients such as fillers, binders, disintegrating agents, water penetration enhancers, surfactants, glidants and/or lubricants.
  • the gastrointestinal fluid penetrates into the matrix according to the point 1' or 2' above, the active substance is dissolved and the dissolved active substance diffuses with a controlled rate out of the matrix and is absorbed.
  • the driving force for diffusion is the concentration of the active substance in the aqueous solution created by the penetrating Gl fluid.
  • the matrix is the swelling matrix, e.g. crosslinked (ionic) polymer with entrapped solid active substance, the swelling kinetics of the matrix, the dissolution rate of the active substance, and the diffusion of the active substance will all contribute to the overall release rate.
  • the solid matrix particles can be based on hydrophilic and/or hydrophobic matrix forming agents.
  • the matrix forming agent can be selected from the group consisting of excipients which swell upon contact with physiological fluids, non-swellable polymers, insoluble excipients and any combination thereof.
  • said matrix forming agent is present in an amount of 40 to 99.5 w/w%, more preferably in an amount of 60 to 98 w/w% of the matrix particles.
  • the excipients which swell upon contact with physiological fluids can be selected from hydroxypropylmethylcellulose of different viscosity and/or substitution grades having a viscosity of 2% solution in water (determined according to USP method) in the range of 50 to 250,000 mPas and having methoxyl group content preferably in the range of 16 to 32 w/w%, more preferably in the range of 19-32 w/w% and most preferably in the range of 19-30 w/w% and hydroxypropyl group content preferably in the range of 4 to 32 w/w%, more preferably in the range of 7-12 w/w%, hydroxypropyl cellulose e.g.
  • Klucel HF, HXF, EF or MF types having a viscosity of 1% aqueous solution in the range of 1 ,000 to 4,000 mPas, hydroxypropylmethylcellulose phthalate, poly(ethyleneoxide) of molecular weight in the range of 1,000,000 to 7,000,000 e.g. Polyox WSR303), polylactic acid, xanthan gum, alginates, sodium and calcium carboxymethylcellulose, carrageenan (Carrageenan lota, Kappa, Lambda), carbomer, carbopol (different product types e.g.
  • Carbopol 971 P Carbopol 71G
  • methacrylic ester copolymers sold as Eudragit® NE methacrylic ester copolymers sold as Eudragit® NE
  • methylhydroxyethylcellulose propylhydroxyethylcellulose
  • polyHEMA polyHEMA
  • methylcellulose and other swellable polymers.
  • a combination of above mentioned polymers can also be used. It is for instance preferred to use hydroxypropylmethylcellulose in combination with another matrix forming agent.
  • a preferred combination is a combination of a neutral swelling polymer with a ionic swelling polymer such as a combination of hydroxypropylmethylcellulose or hydroxypropylmethylcellulose phthalate or poly(ethyleneoxide) with an anionic polymer such as carrageenan.
  • Such a combination of polymers can be used to achieve pH independent solubility of the active substance paliperidone, which per se (tested as pure substance) shows pH dependent solubility.
  • the non-swellable polymer can be selected from the group consisting of water insoluble polymers such as for example ethyl cellulose of different viscosity types having the viscosity of 5w/vol% solution in mixture of toluene and alcohol in the range of 3-100 mPas (Ethocel), cellulose acetate propionate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1, sold as Eudragit® RS 100, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 copolymer, commercially available as Eudragit® RL, polyvinylpyrrolidone acetate, Eudragit® RS PO, polyvinyl chloride, polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, commercial
  • the insoluble excipient is a lipidic substance and can be selected from the group consisting of fatty alcohols with 10-18 C atoms such as stearol, and palmitol, esters and ethers of fatty acids with alcohols such as glycerol, sucrose, or fatty alcohols with 10-18 C atoms in the fatty acid residue such as sucrose stearate/palmitate with HLB value of less than 6, glyceryl behenate, glyceryl tristearate or laurylstearate, waxes.
  • the term "insoluble” preferably refers to substances, which according to USP/ Ph. Eur. General Notice/ Solubility; are insoluble or practically insoluble, namely having a solubility of 1g substance or less in 10.000 ml of fluid.
  • the fluid is preferably water (unless specified otherwise).
  • hydrophilic matrix comprising one or more hydrophilic polymers.
  • the hydrophilic polymer or polymers is/are present in an amount of 40 to 99.5 w/w%, more preferably in an amount of 60 to 98 w/w% of the matrix particles.
  • Hydrophilic polymers can be selected from non-ionic or ionic hydrophilic polymers.
  • Non- ionic hydrophilic polymers can be linear or crosslinked polymers having no functional groups capable of ionization at physiological pH, i.e. in the pH range 1 to 8.
  • Nonlimiting examples of non-ionic hydrophilic polymers are hydroxypropylmethylcellulose of different viscosity and/or substitution grades having a viscosity of 2% solution in water (determined according to USP method) in the range of 50 to 250,000 mPas and having methoxyl group content preferably in the range of 16 to 32 w/w%, more preferably in the range of 19-32 w/w% and most preferably in the range of 19-30 w/w% and hydroxypropyl group content preferably in the range of 4 to 32 w/w%, more preferably in the range of 7-12 w/w%, hydroxypropyl cellulose e.g.
  • Klucel HF, HXF, EF or MF types having a viscosity of 1% aqueous solution in the range of 1 ,000 to 4,000 mPas, hydroxypropylmethylcellulose phthalate, poly(ethyleneoxide) of molecular weight in the range of 1 ,000,000 to 7,000,000 e.g. Polyox WSR303), methacrylic ester copolymers sold as Eudragit® NE, methylhydroxyethylcellulose, propylhydroxyethylcellulose, methylcellulose, and other swellable polymers.
  • Ionic hydrophilic polymers can be selected from anionc and/or cationic hydrophilic polymes.
  • Nonlimiting examples of anionic hydrophilic polymers are polylactic acid, xanthan gum, alginates, sodium and calcium carboxymethylcellulose, carrageenan (Carrageenan lota, Kappa, Lambda), carbomer, polyHEMA, carbopol (different product types e.g. Carbopol 971 P, Carbopol 71G) 1
  • Example of cationic hydrophilic polymer is chitosan.
  • hydrophilic polymers can also be used. It is for instance preferred to use a combination of non-ionc hydrophilic polymer such as hydroxypropylmethylcellulose or poly(ethyleneoxide) with aniononic hydrophilic polymer such as carrageenan or hydroxypropylmethylcellulose phthalate. Such a combination of polymers can be used to achieve pH independent solubility of the active substance paliperidone, which per se (tested as pure substance) shows pH dependent solubility.
  • an insoluble matrix comprising an insoluble excipient is used.
  • Said excipient is preferably present in an amount of 40 to 99.5 w/w%, more preferably in an amount of 60 to 98 w/w% of the matrix particles.
  • the insoluble lipophilic matrix can be based on insoluble small molecule having molecular weigh of less than 10,000 g/mole and/or insoluble polymer or the mixture thereof.
  • Insoluble polymer can be selected from the group consisting of water insoluble polymers such as for example ethyl cellulose of different viscosity types having the viscosity of 5w/vol% solution in mixture of toluene and alcohol in the range of 3-100 mPas (Ethocel), cellulose acetate propionate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride)1 :2:0.1 , sold as Eudragit® RS 100, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 copolymer, commercially available as Eudragit® RL, polyvinylpyrrolidone acetate, Eudra
  • non- swellable polymers in combination with another matrix forming agent.
  • matrix forming agents other than hydroxypropylmethylcellulose are particularly preferred.
  • Insoluble small molecule can be selected form esters and/or ethers of glycerole with fatty acids having 8 to 24 carbon atoms such as glyceryl behenate or glyceryl stearate, waxes such as palmitylstearate, sucrose esters with fatty acids having 8 to 24 carbon atoms and having HLB value below 6, fatty alcohols with 10 to 24 carbon atoms such as palmitol, stearol. It is preferred to use the insoluble small molecule and/or insoluble polymer in combination with another matrix forming agent such as hydrophilic polymer.
  • the release rate can be additionally slowed by coating the above described solid matrix particles with modified release coating.
  • At least one solid matrix particle can be coated with a coating having only minor effect on the release rate of an active substance from the solid matrix particle but affecting the other properties of solid matrix particles such as taste, colour, protection against water vapour sorption, protection against oxidation by oxygen from the air, easier swallowing of the solid matrix particle or the like.
  • Prolonged release solid matrix particles can be coated by film coatings which are in one aspect of the present invention soluble in water and are applied onto the solid matrix particles in order to improve the physical appearance of the particles such as colour, taste or smell, ease the swallowing of the particles, improve physical and chemical stability of the ingredients in the particles especially the active substance paliperidone by diminishing the permeation of water vapour and or oxygen into the core resulting in chemical degradation of ingredients especially active substance.
  • Water soluble film coatings are applied by the processes and equipment known from the state of the art such as for example coating in perforated coating pans, Wurster fluid bed equipment by spraying the dispersion of appropriate water soluble polymer and other inactive ingredients such as pigments, plasticizers, glidants, antitacking agents in water, water miscible organic solvents, such as alcohols or ketones or mixtures thereof.
  • Appropriate polymers can be selected from soluble viscosity types of hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, aminoalkyl methacrylate copolymers (Eudragit EPO), sodium carboxymethylcellulose or the like.
  • Pigments can be selected from metal oxides such iron oxides, titanium oxide.
  • the coating thickness can be in the range of 5 to 70 ⁇ m, preferably 10 to 50 ⁇ m.
  • a film coating can be applied onto the solid matrix particles in order to achieve a lag time before the start of dissolution of active substance from the solid matrix particles.
  • lag time means the time period during which less than 5% of active substance is released from the composition.
  • the lag time is preferably determined in vitro using 500 ml of 0.1M HCI at 37°C in an Apparatus 1 - basket (Ph. Eur. or USP 1 100 rpm), of the composition of the present invention. It is preferably in the range of 0.5 to 7 hours, more preferably 1 to 6 hours and most preferably 1.5 to 5 hours.
  • Polymers for achieving lag time in dissolution can be selected from those used for gastro-resistant coatings such as hydroxypropylmethyl cellulose acetate succinate, methacrylic acid ethylacrylate copolymer, hydroxypropylmethyl cellulose acetate phthalate or the like.
  • Lag time can also be achieved by film coating of the solid matrix particles with polymers that swell upon contact with water and form a gel barrier that slowly erodes from the surface.
  • polymers can be selected from the group consisting of methyl cellulose, hydroxypropylmethyl cellulose, methylhydroxyethyl cellulose, propylhydroxyethyl cellulose, polyethyleneoxides and other swellable polymers of higher viscosity grades. To achieve desired lag time, mixtures of different grades of polymers can be used.
  • Active substance release from the solid matrix particles can be further decreased by applying a prolonged release film coating based on water insoluble polymers such as ethyl cellulose, polyvinyl acetate, ammonio methacrylate copolymers (Eudragit RS and/or Eudragit RL), methacrylic ester copolymers (Eudragit NE), methylmetacrylate ethylmetacrylate copolymer (Kollicoat EMM) onto solid matrix particles.
  • Further excipients selected from plasticizers, antitacking agents, pore formers, glidants, pigments can be used in the coating.
  • Pore formers are selected from water soluble substances having molecular weight of less than 10,000 and having solubility at least 1 g in 10 ml of water and from hydrophilic polymers such as low viscosity types of hydroxypropylmethyl cellulose (HPMC) or hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), povidone with K values of less than 50, copovidone.
  • Plasticizers can be selected from substances capable of decreasing the glass transition point (Tg) of the water insoluble polymer such as alkyl esters of citric acid (e.g.
  • Magnesium stearate, partial esters of glycerol with fatty acids with 10 to 18 carbon atoms such as glyceryl monostearate (GMS) or talc can be selected as anti tacking agents.
  • Colloidal silicone dioxide can be used as glidant. The thickness of such coating can be in the range of 5 to 70 ⁇ m, preferably 10 to 50 ⁇ m.
  • the viscosity of ethylcellulose is measured preferably at 25°C using 5% w/v ethylcellulose dissolved in a solvent blend of 80% toluene : 20% alcohol (w/w); the viscosity of hydroxypropyl methylcellulose is preferably measured at 20 0 C using 2% w/w aqueous solution of hydroxypropyl methylcellulose according to the USP measuring method; and the viscosity of hydroxypropyl cellulose is preferably measured at 25 0 C using 1% w/w aqueous solution of hydroxypropyl cellulose.
  • the molecular weight of a substance the present application refers to the weight-average molecular weight, unless specified otherwise.
  • the active substance contained in the solid matrix particles of the MMS or the MPMS may be present in an unionized form or in the form of a salt, hydrate or solvate thereof. It may further be present in a crystalline or non-crystalline form such as a polymorphic, pseudopolymorphic or amorphous form.
  • the term "active substance" should be understood to include any such salt, in crystalline or noncrystalline form including all polymorphic and/or solvated forms of the respective active substance.
  • the active substance is not microencapsulated.
  • the active substance paliperidone can generally be prepared by any known process such as the processes described in EP 0 368 388 B1, WO 2008/024415, WO 2008/021345.
  • Paliperidone used in the present invention can be in any crystalline or noncrystalline form such as for example disclosed in WO 2008/021342 and IPCOM000167996D.
  • paliperidone belongs to the group of low solubility active substances, it is important that the particle size, particle shape and specific surface area of active substance are controlled.
  • Average particle diameter of paliperidone of the present invention is in the range of 1 to 250 ⁇ m, preferably 5 to 150 ⁇ m.
  • the average particle diameter is determined by laser light scattering method using e.g. a Malvern-Mastersizer Apparatus MS 2000 with lsopar L as dilution medium.
  • the average particle diameter is determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles.
  • the amount of the active substance present in the MMS or the MPMS can be 1-50 mg, preferably 1.5-30 mg and more preferably 1.5-15 mg per dosage unit.
  • the solid pharmaceutical composition according to the present invention can further contain any other active substance in a combination with paliperidone.
  • Another active substance can preferably be selected from risperidone, olanzapine, venlafaxine, fluoxetine and paroxetine.
  • the solid matrix particle according to the present invention may, in addition to the active substance and one or more matrix forming agents, further comprise one or more pharmaceutically acceptable excipient(s).
  • Suitable excipients are selected from the group consisting of a diluent, a binder, a disintegrant, a water penetration enhancer, a surfactant, a lubricant, a glidant and an antioxidant.
  • the physical characteristics of particles of incorporated excipients may have an important role in order to achieve the optimal release kinetics and processibility of the composition, especially in case of using direct compression as manufacturing method.
  • the incorporated excipients have an average particle size in the range of from 10 to 350 ⁇ m, more preferably from 20 to 300 ⁇ m.
  • the diluent can be selected from the group consisting of microcrystalline cellulose, powdered cellulose, composite materials combining crystalline cellulose with lactose (Cellactose, Tablettose), guar gum (Avicel CE15) or silicified cellulose (Prosolv), calcium hydrogen phosphate in anhydrous and hydrated form, various types of sugars such as lactose (anhydrous and monohydrate), compressible sugar, fructose, dextrates, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, or other sugars such as saccharose, raffinose, trehalose, fructose or mixture thereof, calcium carbonate, calcium lactate or mixture thereof.
  • lactose anhydrous and monohydrate
  • compressible sugar fructose
  • fructose dextrates
  • sugar alcohols such as mannitol, sorbitol, maltitol,
  • the binder can be selected from the group consisting of polyvinylpyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose of different grades (i.e. viscosity), starch, pregelatinised starch, or polymethacrylate, or mixtures thereof.
  • the disintegrant can be selected from the group consisting of crospovidone, starch, pregelatinised starch, sodium starch glycollate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low-substituted hydroxypropylcellulose or mixtures thereof.
  • the water penetration enhancer can be selected from excipients soluble in physiological fluids or water characterized in that the solubility of such excipient in water at 25 0 C is at least 1g in 10 ml of water, preferably 1g in 5 ml of water such as carbohydrates selected from sucrose, mannitol, sorbitol, dextran, hydrophilic polymers selected from water soluble hydroxypropylmethyl cellulose (HPMC) types having the viscosity of 2% aqueous solution in the range 1 to 20 mPas, preferably 2 to 15 mPas, low viscosity types of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), povidone and copovidone, polyvinyl alcohol, polyethyleneglycols, anorganic soluble salts such as sodium chloride characterized in that 1 g of salt is dissolved in less than 10 ml of water at 20 0 C.
  • HPMC water soluble hydroxypropylmethyl
  • the surfactant if present, can be selected from the group consisting of anionic surfactants, ampholytic surfactants, nonionic surfactants and cationic surfactants.
  • the anionic surfactant can be selected from the group consisting of organic sulphonates (RSO3") or sulphates (ROSO3 " ), wherein R preferably represents alkyls from CgH 17 to C22H45 O r aromatic substituents! alkali metal or earth alkali metal sulphonates or sulphates, potassium laurate, CH3(CH 2 )ioCOO ⁇ K + , and sodium lauryl sulphate, CH3(CH2)nS04 ⁇ Na + .
  • the most preferred anionic surfactant can be sodium lauryl sulphate.
  • the cationic surfactant can be selected from the group consisting of organic quaternary ammonium halides, R4N + CI" with R preferably representing alkyl trimethyl ammonium chloride, wherein R preferably represents alkyls from CsH 17 to C 18 H 37- e -9- dodecyl trimethyl ammoniumchloride, C 12 H 2 5(CH3) 3 NCI, cetrimide, a mixture consisting of tetradecyl (about 68%), dodecyl (about 22%), and hexadecyltrimethylamrnonium bromides (about 7%), as well as benzalkonium chloride, a mixture of alkylbenzyldimethylammonium chlorides of the general formula
  • ampholytic surfactant can be selected from sulfobetaines, RN + (CH3)2CH2CH2S ⁇ 3 ⁇ ), wherein R preferably represents alkyl groups having a chain length of 8-24C atoms, N-Dodecyl-N.N-Dimethylbetaine, Ci2H25N + (CH3) 2 CH2COO- or N-alkyl amino propionates having the structure R-NHCH 2 CH 2 COOH,
  • the nonionic surfactant can be selected from the surfactants containing hydroxyl or polyoxyethylene (-O-CH2CH2-) n groups, and more preferably it can be selected from polyoxyethylated glycol monoethers, cetomacrogol, sorbitan esters (Spans) and polysorbates (Tweens), or from polyoxyethylene-polyoxypropylene copolymers (poloxamers), or from the group of esters such as dioctyl sulphosuccinate and/or sucrose esters with fatty acids such as sucrose stearate or the like.
  • the lubricant and the glidants can be selected from the group consisting of stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols or mixtures thereof.
  • a particularly preferred member of this group can be magnesium stearate.
  • composition according to the present invention may further comprise one or more antioxidants selected from the group consisting of alkyl gallates (e.g. dodecyl-, ethyl-, octyl-, propyl-gallate), butylated hydroxyanisole, butylated hydroxytoluene, tocopherols (e.g. alpha tocopherol), ascorbic acid palmitate, ascorbic acid, sodium ascorbate, potassium and sodium salts of sulphurous acid (e.g. bisulphites, metabisulphites, sulphites), flavonoides (rutin, quercetin, caffeic acid).
  • alkyl gallates e.g. dodecyl-, ethyl-, octyl-, propyl-gallate
  • butylated hydroxyanisole e.g. alpha tocopherol
  • tocopherols e.g. alpha tocopherol
  • ascorbic acid palmitate e
  • the present invention is directed to a process for the manufacture of a solid pharmaceutical composition comprising at least one solid matrix particle as defined above.
  • the solid pharmaceutical composition according to the present invention is prepared by a process comprising steps selected from sieving and mixing powder ingredients, granulation of powder mixture such as dry, wet and melt granulation, compression such as direct compression of mixture of ingredients in powder form and compression of pregranulated ingredients, coating of solid matrix particles such as film and sugar coating, mixing of the respective separately obtained solid matrix particles, filling into hard capsules or sachets, film coating of capsules filled with solid matrix particles.
  • the present invention includes any combination of the above processes.
  • the solid pharmaceutical composition of the present invention is prepared by a process comprising steps of sieving (optionally), mixing the powdered ingredients, compression thereof to form solid matrix particles, and optionally coating of the solid matrix particles. More preferably, compression is effected in the form of direct compression. Similarly, it is more preferred to apply a film or sugar coating to the solid matrix particles.
  • direct compression the process can involve wet or dry granulation, hot melt granulation or hot melt extrusion, followed by either direct incorporation of these granules into capsules or sachets, or by compression.
  • “Dry granulation” means that powder components are mixed in an appropriate blender. The obtained homogenous mixture is agglomerated by roller compaction or slugging. The obtained compacts are crushed into granulate and if necessary sieved. Appropriate particle size fractions are used for manufacturing the solid pharmaceutical composition according to the present invention.
  • Weight granulation means that the powder obtained following the initial mixing of the components is granulated using proper quantities of granulation liquid. A drying step to remove the granulation liquid is necessary.
  • Melt granulation means a granulation process by which granules are obtained through the addition of either a molten binder or a solid binder which melts during the process. In the latter case the plastic properties of the binder are used. After the granulation the binder solidifies at room temperature. The obtained agglomerates can be milled and/or sieved to obtain the required particle size of granulate.
  • Direct compression involves the direct mixing of the dry components of the desired formulation, followed by a compression step to manufacture mini or micro tablets.
  • the process does not involve the use of any liquid which may be the primary cause of instability of dosage forms and moreover requires an additional drying step to remove the granulation liquid in order to give the final dosage form. Therefore and also in view of cost aspects, direct compression is particularly preferred in this invention.
  • the step of direct compression which is a preferred embodiment, includes the direct mixing of the dry components of the desired particle type, followed by a compression step to form a compact.
  • a compact is to be understood as meaning solid matrix particle in form of a tablet having a diameter of 1 mm to 20 mm.
  • the present invention relates to a process for forming a solid pharmaceutical composition as defined above comprising the step of melt granulation of a mixture containing at least the active substance, one or more matrix forming agent and a low melting binder to obtain granules, followed by either directly incorporation of these granules into capsules or sachets, or by compressing them into tablets.
  • the low melting binder has a melting or softening point determined by hot stage microscopy below 150 0 C, preferably below 120 0 C and most preferably below 100°C.
  • the low melting binder include complex glycerides like Gelucire, poloxameres, sugar esters, polyethylene glycols having an average molecular weight in the range of from 1.500 to 10.000, preferably from 3.000 to 8.000, partial or full esters of fatty acids with 8 to 24 carbon atoms with mono, di or poly alcohols such as fatty alcohols with 8 to 24 carbon atoms, ethylene glycole, propylene glycole, glycerol and the like.
  • complex glycerides like Gelucire, poloxameres, sugar esters, polyethylene glycols having an average molecular weight in the range of from 1.500 to 10.000, preferably from 3.000 to 8.000, partial or full esters of fatty acids with 8 to 24 carbon atoms with mono, di or poly alcohols such as fatty alcohols with 8 to 24 carbon atoms, ethylene glycole, propylene glycole, glycerol and the like.
  • Further excipients selected from the group of diluent, glidants, lubricants can be used in manufacturing of granulate.
  • the coating process of solid matrix particles is optional.
  • Low gas permeable primary packaging materials such as aluminium or polychloro-3- fluoroethylene homopolymer/PVC laminate can be used with the thickness in the range 10 to 40 ⁇ m in case of AI/AI blisters and 10 to 110 ⁇ m in case of AI-polychloro-3- fluoroethylene homopolymer/PVC laminate blisters.
  • dosage forms containing paliperidone can be packed into primary packaging with desiccant. Desiccant can be placed inside the packaging unit together with dosage units such as for example tablets and/or in the closure system or can be incorporated into the walls of the primary packaging unit.
  • the final dosage form can be packed in primary packaging under inert atmosphere such as for example nitrogen, argon or xenon resulting in decreased concentration of oxygen in the atmosphere surrounding the dosage form in primary packaging such as for example blisters, strips, plastic or glass containers.
  • inert atmosphere such as for example nitrogen, argon or xenon
  • concentration of oxygen means, that the concentration of residual oxygen in the atmosphere surrounding the individual dosage form such as for example tablet or capsule is below 10 vol/vol%, preferably below 7.5 vol/vol%, more preferably below 5 vol/vol% and most preferably below 2.5 vol/vol%.
  • the present invention provides for a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising at least one solid matrix particle comprising paliperidone or a pharmaceutically acceptable salt thereof as an active substance and wherein said solid pharmaceutical composition provides for prolonged release of said active substance, for use in the treatment of schizophrenia and also related ens disorders such as bipolar mania, autism, insomnia, and obsessive compulsive disorder.
  • Manufacturing method 1A and 1B Matrix polymers (HPMC K4M, HPMC K100LV) are mixed with paliperidone. Magnesium stearate is added and additionally mixed. Prepared tabletting mixture is tableted on tabletting machine.
  • Examples 2A/B Manufacturing method 2A and 2B Matrix polymers (HPMC K4M, HPMC K100LV) and micrcrystaline cellulose (MCC) are mixed with paliperidone. Magnesium stearate is added and additionally mixed. Prepared tabletting mixture is tableted on tabletting machine.
  • Examples 3A/B Manufacturing method 3A and 3B Matrix polymers (Xanthan, HPMC K100LV) are mixed with paliperidone. Magnesium stearate is added and additionally mixed. Prepared tabletting mixture is tableted on tabletting machine.
  • Example 4A/B Manufacturing method 4A and 4B Matrix polymers (Carrageenan iota, HPMC K4M) are mixed with paliperidone. Magnesium stearate is added and additionally mixed. Prepared tabletting mixture is tableted on tabletting machine.
  • Matrix polymers Carrageenan iota, HPMC K4M
  • Manufacturing method 5A and 5B Matrix polymers (Carrageenan iota, HPMC K 100 LV) are mixed with paliperidone. Magnesium stearate is added and additionally mixed. Prepared tabletting mixture is tableted on tabletting machine.
  • Matrix polymers Carrageenan iota, HPMC K 100 LV
  • Paliperidone is mixed with a part of HPMC. Other ingredients are added and mixed.
  • Methyl Cellulose (MC) is dissolved in a part of purified water.
  • Talc is suspended in a part of purified water.
  • Talc suspension is added to the suspension of MC.
  • Paliperidone is mixed with Carrageenan. Other ingredients are added and mixed.
  • Methyl Cellulose (MC) is dissolved in a part of purified water.
  • Talc is suspended in a part of purified water.
  • Talc suspension is added to the suspension of MC.
  • Step 3 Suspension obtained in Step 3 is sprayed onto tablet cores in a pan coater.
  • Paliperidone is mixed with Carrageenan. Other ingredients are added and mixed.
  • Methyl Cellulose (MC) is dissolved in a part of purified water.
  • Talc is suspended in a part of purified water.
  • Talc suspension is added to the suspension of MC.
  • Step 3 Suspension obtained in Step 3 is sprayed onto tablet cores in a pan coater.
  • the in vitro dissolution profile of the sample obtained according to this example is determined at varying pH.
  • the results of these dissolution studies are shown in Figure 1.
  • the pharmaceutical composition of Example 9 exhibits similar in vitro dissolution profiles obtained after being submerged in different pH media (pH 1.0, pH 2.0, pH 3.0, pH 5.5, pH 6.0) at 37°C in an Apparatus 1 - basket (Ph. Eur. or USP, 100 rpm, 500 ml_).
  • the drug release is pH independent if dissolution profiles in media with different pH values do not differ more than 20% in each time point, which is shown in Figure 1 for the pH range of 1.2-6.0.

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Abstract

La présente invention concerne une composition pharmaceutique solide comprenant au moins une particule de matrice solide contenant de la palipéridone ou un sel pharmaceutiquement acceptable de celle-ci en tant que substance active. Ladite composition pharmaceutique solide permet la libération prolongée de ladite substance active.
PCT/EP2009/005427 2008-07-25 2009-07-27 Composition de palipéridone comprenant des particules de matrice solide WO2010009900A1 (fr)

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WO2011018246A3 (fr) * 2009-08-13 2011-04-21 Synthon B.V. Composition de palipéridone à libération contrôlée
WO2012014052A3 (fr) * 2010-07-30 2012-06-07 Micro Labs Limited Nouvelles compositions pharmaceutiques à libération prolongée enrobées contenant de la palipéridone
EP2547206A1 (fr) * 2010-03-15 2013-01-23 Inventia Healthcare Private Limited Composition pharmaceutique stabilisée, à libération prolongée, comprenant un antipsychotique atypique
KR20140087847A (ko) * 2012-12-31 2014-07-09 주식회사 삼양바이오팜 용융 압출된 방출 제어용 약학 조성물, 및 이를 포함하는 경구용 제제
US9555586B2 (en) 2011-08-01 2017-01-31 Messier-Bugatti-Dowty Composite connecting rod having an increased mechanical strength
EP3187176A1 (fr) * 2015-12-29 2017-07-05 Sanovel Ilac Sanayi ve Ticaret A.S. Mini comprimés de palipéridone
WO2017174096A1 (fr) * 2016-04-05 2017-10-12 Pharmathen S.A. Composition pharmaceutique comprenant un agent antipsychotique atypique et son procédé de préparation
EP3501504A1 (fr) 2017-12-22 2019-06-26 Pharmacia Polonica sp. z o.o. Comprimé à libération modifiée de palipéridone et son procédé de préparation
EP3501503A1 (fr) * 2017-12-22 2019-06-26 Cosmo Technologies Ltd. Composition pour administration solide
RU2812928C2 (ru) * 2017-12-22 2024-02-05 Космо Текнолоджиз Лтд. Твердая композиция для доставки

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WO2014027973A1 (fr) 2012-08-14 2014-02-20 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Solution orale à base de palipéridone
WO2014027974A1 (fr) 2012-08-17 2014-02-20 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de palipéridone à désintégration orale

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WO2011018246A3 (fr) * 2009-08-13 2011-04-21 Synthon B.V. Composition de palipéridone à libération contrôlée
EP2547206A1 (fr) * 2010-03-15 2013-01-23 Inventia Healthcare Private Limited Composition pharmaceutique stabilisée, à libération prolongée, comprenant un antipsychotique atypique
EP2547206A4 (fr) * 2010-03-15 2013-08-07 Inventia Healthcare Private Ltd Composition pharmaceutique stabilisée, à libération prolongée, comprenant un antipsychotique atypique
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US9555586B2 (en) 2011-08-01 2017-01-31 Messier-Bugatti-Dowty Composite connecting rod having an increased mechanical strength
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KR101659983B1 (ko) 2012-12-31 2016-09-26 주식회사 삼양바이오팜 용융 압출된 방출 제어용 약학 조성물, 및 이를 포함하는 경구용 제제
EP3187176A1 (fr) * 2015-12-29 2017-07-05 Sanovel Ilac Sanayi ve Ticaret A.S. Mini comprimés de palipéridone
WO2017174096A1 (fr) * 2016-04-05 2017-10-12 Pharmathen S.A. Composition pharmaceutique comprenant un agent antipsychotique atypique et son procédé de préparation
EP3501504A1 (fr) 2017-12-22 2019-06-26 Pharmacia Polonica sp. z o.o. Comprimé à libération modifiée de palipéridone et son procédé de préparation
EP3501503A1 (fr) * 2017-12-22 2019-06-26 Cosmo Technologies Ltd. Composition pour administration solide
WO2019122258A1 (fr) * 2017-12-22 2019-06-27 Cosmo Technologies Ltd. Composition d'administration solide
JP2021506894A (ja) * 2017-12-22 2021-02-22 コスモ・テクノロジーズ・リミテツド 固体送達組成物
RU2812928C2 (ru) * 2017-12-22 2024-02-05 Космо Текнолоджиз Лтд. Твердая композиция для доставки

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