WO2020072008A1 - Nouvelles dispersions solides de sélinexor - Google Patents

Nouvelles dispersions solides de sélinexor

Info

Publication number
WO2020072008A1
WO2020072008A1 PCT/TR2018/050548 TR2018050548W WO2020072008A1 WO 2020072008 A1 WO2020072008 A1 WO 2020072008A1 TR 2018050548 W TR2018050548 W TR 2018050548W WO 2020072008 A1 WO2020072008 A1 WO 2020072008A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid dispersion
selinexor
mixtures
surfactant
present
Prior art date
Application number
PCT/TR2018/050548
Other languages
English (en)
Inventor
Philipp Daniel Haas
Andreas Hartwig STECKEL
Parthasarathy Asari
Original Assignee
Deva Holding Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Deva Holding Anonim Sirketi filed Critical Deva Holding Anonim Sirketi
Priority to PCT/TR2018/050548 priority Critical patent/WO2020072008A1/fr
Publication of WO2020072008A1 publication Critical patent/WO2020072008A1/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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Selinexor is chemically described as (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-l -yl)-N'- (pyrazin-2yl) acrylohydrazide, and it has the following structural formula:
  • US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity.
  • Oral dosage forms are the most preferred and commonly employed dosage forms due to their high patient compliance, ease of administration, least sterility constraints, and flexibility in the design of the dosage form.
  • the major challenge with the design of oral dosage forms lies with their poor bioavailability.
  • Bioavailability is usually defined as "the rate and extent that the active drug is absorbed from a dosage form and becomes available in the systemic circulation.” It has been well known that solubility, dissolution and gastrointestinal permeability are essential parameters that control rate and extent of drug absorption and its bioavailability.
  • Biopharmaceutics Classification System takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: (1) dissolution, (2) solubility, and (3) intestinal permeability. According to the final guidance published by FDA (The Biopharmaceutics Classification System (BCS) Guidance), drugs have been divided into four classes:
  • Class III high soluble and low permeable
  • Class IV low soluble and low permeable.
  • Class II and IV drugs are notorious for their problematic properties for effective oral delivery. Poor water-solubility makes their formulation difficult or even impossible.
  • Selinexor poses problems of low solubility and low dissolution rate and thus low bioavailability, quickly absorbed in the gastrointestinal tract.
  • composition of the dosage form can affect the bioavailability of the drug as well.
  • selecting the dosage form and manufacturing process followed to produce said dosage form becomes more critical.
  • the present inventors faced many problems during the formulation development phase, and tried to find the most convenient manufacturing method for oral compositions of selinexor. They finally succeeded to provide pharmaceutical compositions of selinexor with desired properties by manufacturing them as solid dispersions (SD), and particularly with Hot Melt Extrusion (HME) method.
  • SD solid dispersions
  • HME Hot Melt Extrusion
  • Hot Melt Extrusion method was not enough to obtain stable and bioavailable pharmaceutical compositions of selinexor. Developing a good working HME process and a stable extrudate is very struggling, since there are many things to consider.
  • Factors that may effect in-process stability are processing parameters (like temperature, screw speed, die pressure etc.) and components of solid solution like polymers, plasticizers, surfactants, etc.
  • the dispersion of drug and polymer exists as a single-phase system or as a multi-phase system, depending on their miscibility.
  • a single-phase amorphous solid dispersion system is desired, because it tends to have a better stability in comparison to a multi-phase system.
  • multi-phase systems comprise a drug-rich domain and a polymer-rich domain, and such an inhomogeneous mixture cannot be acceptable in a pharmaceutical composition.
  • the polymer carrier needs to have good miscibility with the drug substance.
  • HME method Another difficulty in HME method is to provide stability after extrusion. Even if active pharmaceutical ingredient is used in amorphous form, this form is susceptible to recrystallization which is not desired. Recrystallization may occur upon cooling based on various factors. For instance, mechanical stress such as milling can induce recrystallization of API after extrusion process. Other factors give rise to recrystallization are water content of the components or API-carrier interactions like a presence of hydrogen bond. Here, polymer selection becomes critically important again. Since, molecular weight of polymer and ratio of polymer content are playing a role in inhibition of recrystallization.
  • Solubility improvement methods can be categorized into physical modification, chemical modifications of the drug substance, and other techniques.
  • Various methods have been known to enhance the bioavailability of low soluble drug molecules, like salt formation, solubilization of APIs in solvent(s), formation of drug-cyclodextrin complex, particle size reduction etc.
  • solid dispersion systems to increase the solubility, dissolution rates and bioavailability of poorly soluble drug molecules.
  • HME hot-melt extrusion
  • present inventors performed many experiments wherein their main goal was to enhance the solubility of selinexor in order to enhance its bioavailability and therapeutic efficacy.
  • present inventors found that selinexor compositions manufactured by hot melt extrusion method showed great properties.
  • the present inventors have developed a suitable hot melt extrusion method specific to selinexor to improve the dissolution and thus the bioavailability of selinexor by preparation of extrudates thereof.
  • oral solid pharmaceutical compositions of selinexor showed required solubility and bioavailability when produced by hot melt extrusion.
  • present inventors By using hot melt extrusion method, present inventors not only achieved increased solubility and bioavailability, but also good stability at changing temperature and moisture levels and thus safe application in human.
  • the present inventors achieved stable amorphous extrudates of selinexor despite many obstacles encountered during hot melt extrusion process.
  • Present inventors prepared pharmaceutical compositions of selinexor by wet granulation and dry granulation methods and compared their findings with those of prepared by hot-melt extrusion. According to the results, the dissolution rate was significantly improved by hot-melt extrusion method compared to that of the dosage forms prepared by wet granulation or dry granulation methods.
  • present process is anhydrous, thus avoids any potential drug degradation occurred by hydrolysis following the addition of aqueous or any other granulating media.
  • present inventors obtained several enhanced properties of selinexor and gained advantages in terms of economical aspects.
  • Another advantage of the present invention is that a solvent-free manufacturing process could be developed to prepare pharmaceutical compositions of selinexor.
  • the present invention contributes to the clean environment.
  • the unique amorphous solid solutions of selinexor obtained by the present invention provide significantly enhanced bioavailability owing to superior dissolution of selinexor resulting from availability of high surface area, high interfacial activity and particle morphology.
  • Figure 1 An exemplary process for manufacturing of the hot melt extrudates
  • the pharmaceutical composition of selinexor is manufactured by solid dispersion technique.
  • Solid dispersions may be defined as the dispersion of one or more active ingredients in molecular and amorphous forms in an inert carrier or matrix in the solid state.
  • the system has small solid-state particles (e.g., essentially non-crystalline or amorphous particles) of one phase dispersed in another solid-state phase.
  • solid dispersions often take the form of "solid solutions", where the drug is molecularly dispersed in a hydrophilic polymer.
  • the solid dispersion in accordance with the present invention comprises selinexor as active pharmaceutical ingredient in an essentially non-crystalline or amorphous form, which is usually more soluble than the crystalline form.
  • An "amorphous form” refers to a particle without definite structure, i.e., lacking crystalline structure.
  • Selinexor as used herein includes a pharmaceutically acceptable and therapeutically effective amount of selinexor or its pharmaceutically acceptable salts, solvates (including hydrates), anhydrates, derivatives, stereoisomers and mixtures of stereoisomers, and/or esters, prodrugs, complex or mixtures thereof in equivalent amount.
  • 'drug', 'API (active pharmaceutical ingredient)', and ' active ingredient' are used herein interchangeably.
  • Various methods are known to prepare solid dispersion systems. These methods are melting method, solvent method, melting solvent method (melt evaporation), melt extrusion methods, lyophilization techniques, melt agglomeration process, the use of surfactant, electrospinning, super critical fluid (Scf) technology.
  • Hot- melt extrusion (HME) is the process of transferring a powder blend of API(s) and carrier(s) by a rotating screw through the heated barrel of an extruder and pressing the melt through a die into a product of uniform shape.
  • solid dispersion or “solid solution”.
  • the mixture is processed at elevated temperature and pressure, which disperses the drug in the matrix at a molecular level through the formation of a solid solution.
  • SSEs Single-screw extruders
  • TSEs Twin-screw extruders
  • the TSE has two agitator assemblies mounted on parallel shafts. The use of two screws permits different types of configurations and also imposes different conditions in all the zones of the extruder, from the feeding of the material via the hopper to the rotating screw and finally to conveying the material to the metered pumping zone.
  • MSEs are the extruders that incorporate more than two screws. Depending upon the number of screws used in the extruder, the assembly may vary.
  • HME hot melt extrusion
  • extrudates having desired properties There are various factors that should be considered to obtain extrudates having desired properties.
  • quality of extrudate changes significantly depending on one of the process parameters or combinations of them.
  • temperature is an important process variable to consider for the proposed invention.
  • the hot-melt extrusion is conducted at an elevated temperature. It is important to select an operating temperature range that will minimize the degradation or decomposition of the compounds during processing.
  • the operating temperature is in the range of about 30°C to 200°C.
  • the elevated temperature in die is 120-180 °C.
  • a further factor to be considered is the pressure. Pressure in extruder and in the die area has a significant impact on the quality of the extrudate.
  • a smooth process should be carried out to obtain better extrudates of selinexor.
  • the pressure should be kept minimum as possible.
  • Polymeric carriers are the most important excipients in HME formulations.
  • Polymers that can be used in HME method are hydrophilic or water-soluble at least in a part of the pH scale, more particularly at a pH occurring in the gastrointestinal (Gl) tract.
  • a useful feature of a polymer determining its usefulness herein is its glass transition temperature (Tg).
  • Suitable water-soluble polymers include, but are not limited to, those having a Tg of about 80° C to about 180° C.
  • the polymer or the polymer mixture should be solid at ambient temperature to be used usefully, and should remain solid even at the highest temperatures typically experienced during storage, transport, and handling of the product.
  • Polyvinylpyrrolidone 17 PF (Kollidon 17 PF), polyvinylpyrrolidone-co-vinyl acetate 64 (Kollidon ® VA 64), and Soluplus ® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG).
  • Copovidone is a copolymer of l-vinyl-2-pyrrolidone and vinyl acetate. Copovidone is manufactured by free-radical polymerization of 6 parts of vinylpyrrolidone and 4 parts of vinyl acetate in 2-propanol according to the cGMP regulations. A water-soluble copolymer with a chain structure is obtained. Copovidone has a glass transition temperature of 105-108°C.
  • Soluplus graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and
  • Soluplus is a water-soluble copolymer with the average molecular weight ranging from 90,000 to 140,000 g/mol, and it is capable of solubilizing poorly water-soluble drugs. It shows high flowability and excellent extrudability during HME process.
  • the ratio of selinexor : polymercarrier can lie between 1: 0.5 to 1: 100 by weight.
  • the ratio of selinexor : polymer carrier is preferably from 2:3 to 2:5 by weight.
  • selinexor is present in base form in an amount of about 5% to about 40% by weight of the extrudate and/or or as pharmaceutically acceptable salts, solvates (including hydrates), anhydrates, derivatives, stereoisomers and mixtures of stereoisomers, and/or esters, prodrugs, complex or mixtures thereof in an equivalent amount.
  • At least one polymeric carrier is present in an amount of about 10% (w/w) to about 60% (w/w) by the total weight of the extrudate.
  • polymer carriers may require the incorporation of a plasticizer into the solid dispersion in order to improve the processing conditions during the manufacturing of the extruded dosage form or to improve the physical and mechanical properties of the final product.
  • Plasticizers reduce brittleness and improve flowability. They increase the intermolecular separation of the polymer carrier molecules and thus improve the workability and flexibility of the polymer. Plasticizers further increase the flexibility of the extrudate. By incorporating a plasticizer, the extrusion temperature and thermal degradation of the material may be reduced.
  • plasticizers may be used in the HME process according to the present invention: triacetin, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, propylene glycol, glycerin, polyethylene glycol, glycol triacetate, diethyl phthalate, dibutyl sebecate, and dibutylsorbiton monolaurate, methyl paraben.
  • the solid dispersions according to the present invention further contains at least one surfactant.
  • Surfactants can also have a plasticizing effect, which allows processing at lower temperatures. Besides, incorporation of surfactant lowers the extrusion torque significantly. Thus, surfactants are mentioned among commonly used plasticizers.
  • surfactants play also an important role here by inhibiting of recrystallization.
  • examples for surfactants that can be incorporated into the solid dispersion are, but not limited to, poloxamers, polysorbates, polyoxyethylene glycerides, fatty acid monoesters of sorbitan, a- tocopheryl polyethylene glycol succinate (TPGS), docusate sodium, sodium lauryl sulfate, and mixtures thereof.
  • polysorbate 80 is used as surfactant with the aim of plasticizing of the polymer.
  • Extrudates can be cut into cylindrical pellets. Those pellets may further spheronized in a traditional spheronizer at an elevated temperature. Alternatively, extrudates can be ground into granules. According to an embodiment ot the present invention, poorly compactable materials can be prepared as tablets without a compression process by cutting an extruded rod to the desired dimensions.
  • Tablets can be coated or non-coated. According to a preferred embodiment of the present invention, tablets are coated. In an embodiment, tablets contain immediate release coating. Immediate release coating agents are, but not limited to, cellulose ethers like hydroxypropy! methylcellulose (HPMC), polyvinyl acetate (PVA) or polyvinyl pyrrolidone (PVP).
  • HPMC hydroxypropy! methylcellulose
  • PVA polyvinyl acetate
  • PVP polyvinyl pyrrolidone
  • the current invention presents the amorphous solid dispersions with representative pXRD patterns of Figure 3, Figure 4 and Figure 5 obtained with the Hot Melt Extrusion of Formula 1, Formula 2 and Formula 3 respectively.
  • compositions of the present invention exhibit either solid solution morphology, or the compositions of the invention are essentially amorphous. Any and all of these morphologies are considered herein by the terms “dissolved in”, “molecularly dispersed in”, “dispersion”, “molecular dispersion”, and “molten dispersion”, and these are used herein to describe the compositions of the invention at various stages of preparation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'objet de la présente invention est de fournir une composition pharmaceutique comprenant une dispersion solide de sélinexor, ayant une biodisponibilité améliorée et des propriétés de dissolution améliorées. Conformément à l'invention, une dispersion solide de sélinexor est produite par un procédé d'extrusion à chaud.
PCT/TR2018/050548 2018-10-04 2018-10-04 Nouvelles dispersions solides de sélinexor WO2020072008A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/TR2018/050548 WO2020072008A1 (fr) 2018-10-04 2018-10-04 Nouvelles dispersions solides de sélinexor

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112245397A (zh) * 2020-10-29 2021-01-22 瑞阳制药股份有限公司 达可替尼速释制剂及其制备方法
EP4023213A1 (fr) * 2020-12-29 2022-07-06 Sanovel Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant de l'alogliptine
WO2024047555A1 (fr) * 2022-08-31 2024-03-07 Sacmi Cooperativa Meccanici Imola Societa' Cooperativa Procédé et appareil de fabrication de médicaments solides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016025904A1 (fr) * 2014-08-15 2016-02-18 Karyopharm Therapeutics Inc. Formes polymorphes de selinexor
US20160193151A1 (en) * 2015-01-06 2016-07-07 Maria Del Pilar Noriega Escobar Dosage form incorporating an amorphous drug solid solution
WO2017118940A1 (fr) * 2016-01-08 2017-07-13 Dr. Reddy's Laboratories Limited Formes solides de sélinexor et leur procédé de préparation
WO2018129227A1 (fr) * 2017-01-05 2018-07-12 Watson Laboratories Inc. Nouvelles formes cristallines de sélinexor et leur procédé de préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016025904A1 (fr) * 2014-08-15 2016-02-18 Karyopharm Therapeutics Inc. Formes polymorphes de selinexor
US20160193151A1 (en) * 2015-01-06 2016-07-07 Maria Del Pilar Noriega Escobar Dosage form incorporating an amorphous drug solid solution
WO2017118940A1 (fr) * 2016-01-08 2017-07-13 Dr. Reddy's Laboratories Limited Formes solides de sélinexor et leur procédé de préparation
WO2018129227A1 (fr) * 2017-01-05 2018-07-12 Watson Laboratories Inc. Nouvelles formes cristallines de sélinexor et leur procédé de préparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112245397A (zh) * 2020-10-29 2021-01-22 瑞阳制药股份有限公司 达可替尼速释制剂及其制备方法
EP4023213A1 (fr) * 2020-12-29 2022-07-06 Sanovel Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant de l'alogliptine
WO2024047555A1 (fr) * 2022-08-31 2024-03-07 Sacmi Cooperativa Meccanici Imola Societa' Cooperativa Procédé et appareil de fabrication de médicaments solides

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