WO2020072008A1 - Novel solid dispersions of selinexor - Google Patents

Novel solid dispersions of selinexor

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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
French (fr)
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/en
Publication of WO2020072008A1 publication Critical patent/WO2020072008A1/en

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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.

Abstract

The object of the present invention is to provide a pharmaceutical composition comprising solid dispersion of selinexor, having enhanced bioavailability and improved dissolution properties. In accordance with the invention, solid dispersion of selinexor is produced by hot melt extrusion method.

Description

NOVEL SOLID DISPERSIONS OF SELINEXOR
Technical Field
The present invention relates to a pharmaceutical composition comprising solid dispersion of selinexor and pharmaceutically acceptable excipients, and a process for preparing thereof.
Background Art
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:
Figure imgf000002_0001
US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity.
Selinexor is the first drug in a new class of agents known as Selective Inhibitor of Nuclear Export (SINE™) compounds. Selinexor works by inhibiting XPO1, a protein found in the nucleus of cancer cells, which activates tumor suppressors by retaining them in the nucleus of cancer cells. This results in apoptosis (death) of cancer cells, while largely sparing normal cells. Selinexor also reduces the levels of onco-proteins such as c-myc and bcl-2, thereby reducing the growth of cancer cells.
Technical Problem
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. However, the major challenge with the design of oral dosage forms lies with their poor bioavailability. In drug development, a high oral bioavailability is desirable. 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.
The solubility behavior is one of the most important rate limiting parameters about drug molecules to achieve their desired concentration in systemic circulation for pharmacological response. However more than one-third of the drugs listed in U.S. Pharmacopeia fall into the poorly water soluble or water insoluble categories.
On average, the body of an adult human contains 60-65% water, and therefore a drug must possess a certain aqueous solubility and have an acceptable bioavailability degree. Drugs having poor aqueous solubility tend to be eliminated from the gastrointestinal tract before they get the chance to fully dissolve and be absorbed into the blood circulation, and this leads to low bioavailability.
Because of this reason, enhancement of oral bioavailability of low-soluble drugs by improving their solubility remains one of the greatest challenges to scientist active in pharmaceutical research.
Drug substances are classified based on their solubility and intestinal permeability. When combined with the dissolution of the drug product, the Biopharmaceutics Classification System (BCS) 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 I— high soluble and high permeable,
Class II— low soluble and high permeable,
Class III— high soluble and low permeable, and
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. As one of the drugs under "low soluble drugs" Class, Selinexor poses problems of low solubility and low dissolution rate and thus low bioavailability, quickly absorbed in the gastrointestinal tract.
The bioavailability of selinexor after oral administration is low and subject to large inter-individual variation. Selinexor's bioavailability is limited by its dissolution. Because of this reason, selinexor might be judged as a poor candidate for drug development. However, selinexor cannot be ignored because of its poor aqueous solubility, and all attempts should be made to improve its bioavailability.
In addition to the poor solubility and bioavailability properties of the active pharmaceutical ingredient, composition of the dosage form can affect the bioavailability of the drug as well. Thus, selecting the dosage form and manufacturing process followed to produce said dosage form becomes more critical.
Common methods for improving solubility of API, such as salt formation and particle size reduction do not always result in sufficient bioavailability required for therapeutic efficacy.
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.
Still, selecting 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.
Selection of the polymer carrier system is critical for the successful development of the composition and manufacturing process. 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. Due to phase separation, 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. In order to minimize the risk of phase separation, the polymer carrier needs to have good miscibility with the drug substance.
Further problems may arise when a proper selection of polymer to be used in HME method is not made. Hot-melt extrusion applies a significant amount of heat and shear stresses on the materials being subjected to the hot-melt extrusion process. As a result of this, active pharmaceutical ingredient(s) and the polymeric carrier(s) may undergo chemical reactions which lead to the disruption of drug/polymer stability. To avoid this, the chemical properties and the stability of the components must be monitored in order to eliminate any degradation concerns, and an appropriate polymer should be used in the process which is resistant to chemical degradation during the hot-melt extrusion process. The polymeric carrier to be used in hot melt extrusion process should be heat and pressure resistant. Hot melt extrusion method cannot be applied to heat-labile materials owing to the elevated temperatures involved.
As another factor that effects the in-process stability residence time can be mentioned. Longer residence time in heating barrel may cause a higher percentage of degradation. Therefore prudent options of processing temperature, additives, and residence time in barrel are essential for the best outcome.
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.
Post-extrusion stability and storage stability are mainly influenced by water sorption and storage temperature in a define time frame. Undoubtedly, along the advantages of HME method present inventors had too many obstacles to deal with. Quality of extrudates and final dosage form are highly related to HME formulation and process development. To achieve desired extrudates and final dosage forms many factors should be considered at the same time. Thus, HME feasibility studies and pre-formulation studies must be examined carefully before starting the development.
Solution to Problem
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. In recent years due to the development of increasing number of poorly soluble drug candidates, there is a great interest in solid dispersion systems to increase the solubility, dissolution rates and bioavailability of poorly soluble drug molecules. Especially, the use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing due to its ability to efficiently manufacture novel products.
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. Among all, 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.
It was invented that oral solid pharmaceutical compositions of selinexor showed required solubility and bioavailability when produced by hot melt extrusion.
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.
As another advantage to mention, present process is anhydrous, thus avoids any potential drug degradation occurred by hydrolysis following the addition of aqueous or any other granulating media.
Using this method, present inventors obtained several enhanced properties of selinexor and gained advantages in terms of economical aspects. With the present invention reduced production time, fewer processing steps, thus a fast manufacturing process and a continuous operation provided an economical process to manufacture oral pharmaceutical compositions of selinexor.
Another advantage of the present invention is that a solvent-free manufacturing process could be developed to prepare pharmaceutical compositions of selinexor. Thus, the present invention contributes to the clean environment.
A homogenous extrudate and eventually a final dosage form of selinexor were achieved owing to selection of the suitable polymer carrier. Present inventors evaluated extrudates having different drug loadings. After struggling studies and researches, they optimized selinexor: polymer ratio to reach the best dissolution profile.
Several experiments were carried out by the present inventors to determine the optimum process parameters to be used during hot melt extrusion process of selinexor. These process parameters include temperature, pressure, extruder speed, and material feeding rate. As results of these experiments, optimum values for each was determined and worked at these conditions when preparing bioavailable pharmaceutical composition of selinexor. Powder X-ray Diffraction (PXRD) is used for determining the crystalline properties and quantification of amorphous content of hot-melt extrudates. The extrudates obtained by the present invention were amorphous as desired based on the results of PXRD.
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.
Brief Description of Drawings
Figure 1: An exemplary process for manufacturing of the hot melt extrudates
Figure 2: Dissolution of 20 mg Selinexor tablets manufactured using different techniques
Figure 3: pXRD of hot melt extrudates of Formula 1
Figure 4: pXRD of hot melt extrudates of Formula 2
Figure 5: pXRD of hot melt extrudates of Formula 3
Description of embodiments
In view of the existing technologies, it is the object of the invention to provide a pharmaceutical composition comprising selinexor suitable for oral administration.
Particularly, it is the object of the present invention to provide a pharmaceutical composition comprising selinexor for oral administration which provides a high bioavailability, low variation in oral bioavailability and increased stability.
In a first embodiment of the present invention, 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. For formulations targeting dissolution and bioavailability improvement, 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.
The terms '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. During this process, polymers are melted, often forming a solid dispersion of the drug in the polymer, and formed into products of different shapes and sizes by forcing the molten through an orifice or die under controlled temperature, pressure, feeding rate and screw speed. Obtained product is called 'extrudate'. The end product, extrudate, often is referred to as
"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.
As it can be understood from the context, the terms 'solid dispersion' and 'solid solution' encompass the term 'extrudate'.
Pharmaceutical screw extruders are designed based on the desired extrudate and are classified as follows: i. Single-screw extruders (SSEs): The SSE consists of one continuously rotating screw in a barrel. The SSE receives the raw material in the feeding area and then conveys it along a flighted screw enclosed in the barrel. ii. Twin-screw extruders (TSEs): 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. The screws in the TSEs can either be co-rotating (same direction) or be counter-rotating (opposite direction). The two types of TSEs can be further classified as fully intermeshing or non-intermeshing. iii. Multi-screw extruders (MSEs): MSEs are the extruders that incorporate more than two screws. Depending upon the number of screws used in the extruder, the assembly may vary.
Any type of the extruder mentioned above can be used by manufacturing pharmaceutical compositions of selinexor according to the present invention. In recent years, hot melt extrusion (HME) has gained great interest in pharmaceutical field. HME offers many advantages compared with traditional processing techniques that have been typically used to produce oral solid dosage forms. In particular, solvents are not required, which makes the process more environmentally friendly and cost effective. The scalable continuous processing is another advantage of hot melt extrusion.
There are various factors that should be considered to obtain extrudates having desired properties. The quality of extrudate changes significantly depending on one of the process parameters or combinations of them. To name some 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.
According to the present invention, the operating temperature is in the range of about 30°C to 200°C. According to the present invention, 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. Preferably, a smooth process should be carried out to obtain better extrudates of selinexor. According to the present invention, for a smooth process, the pressure should be kept minimum as possible.
In another embodiment of the present invention, a feed rate of 0.1 kg/h to 2,0.kg/h is preferred. In a further embodiment of the present invention, extruder speed of 100 rpm - 750 rpm is preferred.
As such, the method of producing extrudates containing selinexor as an API comprises the following steps:
-feeding of the extruder through a hopper
-mixing and melting the API(s) and polymer carrier(s) (and other inactive ingredients) in order to provide a melt,
-extruding the melt through a die thereby forming an extrudate; and
-cooling the extrudate until it solidifies.
Solid dispersion of selinexor according to the present invention may include, but not limited to, at least one polymeric carrier, at least one surfactant, and further excipients.
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. The solid dispersion of the present invention may contain, but are not limited to, one of the following polymers as polymeric carrier: Hydroxypropyl cellulose, Hydroxypropylmethyl cellulose, Ethyl cellulose, Polyethylene glycol, Polyethylene oxide, Polyvinylpyrrolidone (Povidone) polymers, Copovidones, graft PEG-copolymer, acrylic acid ester polymers, and the like. Preferably, the pharmaceutical composition of the present invention incorporates a polymer which is a hydrophilic polymer, such as a polyvinylpyrrolidone, vinyl pyrrolidone/vinyl acetate copolymer (Copovidone), or PVAc-PVCap- PEG copolymer.
Three polymeric carriers particularly preferred in accordance with the present invention are:
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).
Polyvinylpyrrolidone, also known as Povidone, PVP, and polyvidone, is an iodinated polyvinyl polymer. It appears as white to off-white hygroscopic powder in its pure form and is readily soluble in water. PVP is incorporated as a hydrophilic carrier in the present SD formulation due to its ability to increase wetting of poorly soluble API. PVP inhibits and retards the recrystallization process of API via formation of polymer network around the crystal surface or between the drug molecules.
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
polyvinylacetate. 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.
According to the present invention, the ratio of selinexor : polymercarrier can lie between 1: 0.5 to 1: 100 by weight.
According to a preferred embodiment of the invention, the ratio of selinexor : polymer carrier is preferably from 2:3 to 2:5 by weight.
According to the present invention, 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.
According to an embodiment of the present invention, 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.
According to the further aspects of the present invention, 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.
The following plasticizers, but not limited to, 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.
In a preferred embodiment, 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.
Use of water-soluble polymer as carrier in hot melt extrusion increases the possibility of crystallization upon coming in contact with the aqueous medium of gastrointestinal fluid. 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. According to a preferred embodiment of the present invention, polysorbate 80 is used as surfactant with the aim of plasticizing of the polymer.
According to an embodiment of the present invention, at least one surfactant is present in an amount of about 1% (w/w) to about 10% (w/w) by the total weight of the extrudate.
According to the present invention, extrudates of selinexor can include further excipients.
According to a preferred embodiment of the present invention, extrudates of selinexor may include glidants in order to minimize friction between particles and help in free flowing from hopper to die cavity. Examples for glidants are, but not limited to, colloidal silicon dioxide, corn starch, talc, and the like.
According to an embodiment of the present invention, colloidal silicon dioxide is preferred to be used as glidant in hot melt extrusion process.
According to a further embodiment, extrudates of selinexor according to the present invention may include antioxidants to improve the stability of the polymers that are susceptible to degradation. Examples of antioxidants are, but not limited to, ascorbic acid, EDTA, citric acid and the like.
According to the present invention, extrudates of selinexor prepared by hot melt extrusion method are further processed into various final dosage forms.
The terms 'pharmaceutical composition', 'pharmaceutical dosage form', and 'final dosage form' are used herein interchangeably.
After extrudates exit the die, the material is cooled and subjected to downstream processes such as milling, pelletizing, or calendaring for desired profiling. Extrudates of the present invention can be shaped as tablets, granules, pellets, sheets or powder.
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.
According to another embodiment of the present invention, obtained extrudates are cooled to an ambient temperature and subjected to milling and sieving. The obtained powder or granules are filled into the capsules or compressed to get tablets of selinexor.
The powder or granules may be blended with external excipients before filling into the capsules. The capsules here are, but not limited to, hard gelatin capsules, HPMC capsules.
According to another embodiment of the present invention, the milled extrudates are blended with external excipients and compressed into tablets.
External excipients can be selected, but are not limited to, from the group consisting of fillers/diluents, lubricants, glidants and disintegrants.
The term 'filler' and the term 'diluent' are herein used interchangeably. Fillers fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Suitable fillers (iluents) include, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylce!lulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose lactose (e.g. spray-dried lactose, a-lactose, b-iactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), microcrystalline cellulose (Avicel PH-102), methylcellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®), hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropylycellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E®, F and K, Metolose SH® of
Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethyicellulose and other cellulose derivatives, starches or modified starches ( including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol.
According to a most preferable embodiment, filler/iluents is microcrystalline cellulose (Avicel PH-
102).
The presence of a lubricant is particularly preferred when the composition is a tablet as lubricants improve the tabletting process. Lubricants prevent composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improve flowability of the composition mixture. Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.
According to a most preferable embodiment, lubricant is magnesium stearate.
The pharmaceutical composition according to the present invention may also comprise a glidant. Glidants improve the flowability of the composition. Glidants are, but not limited to, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof and the like.
According to a most preferable embodiment, glidant is colloidal silicon dioxide.
A disintegrant is a substance which helps the composition break up once ingested. Disintegrants are, but not limited to, cross linked polyvinylpyrolidone (crospovidone, polyplyplasdone XL®, kollidon CL®); starches such as maize starch and dried sodium starch glycolate; gums such as maize starch and dried sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low- substituted hydroxypropyicellulose, mixtures thereof and the like.
According to a most preferable embodiment, disintegrant is croscarmellose sodium.
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).
The coating can be preferably 2% - 4% by weight of the tablet e.g., cellulose ethers (e.g.,
hydroxypropyl methyl-cellulose (HPMC)), polyvinyl acetate (PVA) or polyvinylpyrrolidone (PVP). The pharmaceutical composition containing an effective amount of selinexor obtained by the present invention is administered to a mammal in need of treatment and thus provides a method of treating disorders associated with CRM1 activity.
The following examples are given for the purpose of illustration of the present invention and should not limit the scope of the invention.
EXAMPLES
Hot Melt Extrusion:
Brief Manufacturing Process:
Dispense all the ingredients accurately. Sift polymeric carrier, surfactant, and other optional ingredients together through a suitable sieve and mix. Sift Selinexor through 500 pm sieve and then mix with the previous mixture. Perform Hot Melt Extrusion and calendaring at following parameters:
Figure imgf000017_0001
Pass the extrudates through the VariCut Pelletizer. Mill the extrudates by using comminuting mill fitted with a suitable sieve and then blend with the extragranular ingredients after sifting through a 500pm sieve. Compress the lubricated blend using suitable tooling and coat the compressed tablets with suitable coating system to get the required weight gain (2% - 4%).
Manufacturing process for pharmaceutical compositions of selinexor is schematically summarized in Figure 1. Hot Melt Extrusion- Formula 1
Figure imgf000018_0001
Hot Melt Extrusion- Formula 2
Figure imgf000018_0002
Hot Melt Extrusion- Formula 3
Figure imgf000018_0003
Comparative Examples:
Figure imgf000019_0001
The in-vitro dissolution rate tests of HME Formula 1, HME Formula 2, HME Formula 3, and two comparative examples prepared by dry granulation and wet granulation methods were performed. Dissolution was carried out using rotating USP Type-2 paddle at an agitation speed of 50 rpm employing 900 ml medium containing 0,1 N HCI. The temperature was maintained at 37°C ± 2°C throughout the experiment. Samples were withdrawn from each vessel at predetermined time intervals and analyzed. Results for all compositions prepared by hot melt extrusion and two comparative examples can be seen on Table 1 and Figure 2. According to these results, it can be clearly seen that hot melt extrusion method enhanced the solubility feature of selinexor. Thus, selinexor dosage forms with desired release profile for administering to a mammal in need could be obtained.
Table 1: Dissolution of Selinexor Tablets 20 mg Manufactured using different techniques
Figure imgf000020_0001
The qualitative PXRD studies were performed using an X-ray diffractometer. Extrudates of Formula 1, 2, and 3, were scanned from 3.0000 to 40.0000 diffraction angle (2q) range under the following measurement conditions: source, nickel filtered Cu-Ka radiation; voltage 40 kV; current 30 mA; and scan speed 2.0000 (deg/min). Extrudates were triturated to get fine powder before taking the scan. X-ray diffractometry was carried out to investigate the crystal structure of extrudates and amorphous structure was observed as desired.
Herewith, 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.
The stability of the solid dispersions was performed by incubating the samples under accelerated conditions at 40ºC/75% RH in open condition for 15 days that allow for rapid selection of stable amorphous solid dispersion. To evaluate the physical state of the drug, the samples were characterized by pXRD. The XRD analysis results of the samples showed that the amorphous form of the drug was maintained during this storage period.
It is believed that the 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.

Claims

1. A pharmaceutical composition comprising solid dispersion of selinexor and at least one pharmaceutically acceptable polymeric carrier.
2. The solid dispersion of claim 1 comprises selinexor in base form and/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.
3. The solid dispersion of claim 1, wherein selinexor is present in an amount of about 5% to about 40% by weight of the solid dispersion.
4. The solid dispersion of claim 1, wherein the selinexor is present in amorphous form.
5. The solid dispersion of claim 1, wherein the at least one polymeric carrier is present in an amount of about 10% to about 60% by weight.
6. The solid dispersion of claim 1, wherein the at least one polymeric carrier is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone (povidone) polymers, copovidones, graft PEG-copolymer, acrylic acid ester polymers, and mixtures thereof.
7. The solid dispersion of claim 1, wherein the at least one polymeric carrier is selected from the group consisting of polyvinylpyrrolidone (Kollidon 17 PF), vinyl pyrrolidone/vinyl acetate copolymer (Copovidone, Kollidon VA64), PVAc-PVCap- PEG copolymer (Soluplus), and mixtures thereof.
8. The solid dispersion of claim 1 further comprises at least one pharmaceutically acceptable surfactant.
9. The solid dispersion of claim 8, wherein the at least one surfactant is non-ionic.
10. The solid dispersion of claim 8, wherein the at least one surfactant is present in an amount of about 1% to about 10% by weight of the solid dispersion.
11. The solid dispersion of claim 8, wherein the at least one surfactant is selected from the group consisting of poloxamers, polyoxyethylene glycerides, fatty acid monoesters of sorbitan, polysorbates, a-tocopheryl polyethylene glycol succinate (TPGS), docusate sodium, sodium lauryl sulfate and mixtures thereof.
12. The solid dispersion of claim 8, wherein the at least one surfactant is Polysorbate 80.
13. The solid dispersion of claim 1 further comprises at least one glidant.
14. The solid dispersion of claim 13, wherein the at least one glidant comprises colloidal silicon dioxide.
15. A process for preparing a solid dispersion, comprising:
(a) mixing Selinexor and at least one polymeric carrier,
(b) subjecting the mixture (a) to elevated temperature
(c) extruding the semi-solid mixture (b), and
(d) cooling the resulting extrudate to provide a solid matrix comprising Selinexor dispersed in an essentially non-crystalline form therein.
16. A solid dispersion prepared according to claim 15 comprises selinexor in base form and/or as pharmaceutically acceptable salts, solvates (including hydrates), an hydrates, derivatives, stereoisomers and mixtures of stereoisomers, and/or esters, prodrugs, complex or mixtures thereof in an equivalent amount.
17. A solid dispersion prepared according to claim 15 comprises selinexor in amorphous form.
18. At least one polymeric carrier according to claim 15 is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone (povidone) polymers, copovidones, graft PEG- copolymer, acrylic acid ester polymers, and mixtures thereof.
19. At least one polymeric carrier according to claim 15 is selected from the group consisting of polyvinylpyrrolidone (Kollidon 17 PF), vinyl pyrrolidone/vinyl acetate copolymer (Copovidone, Kollidon VA64), PVAc-PVCap- PEG copolymer (Soluplus), and mixtures thereof.
20. A solid dispersion prepared according to claim 15 further comprises at least one surfactant.
21. At least one surfactant according to claim 20 is a non-ionic surfactant.
22. At least one surfactant according to claim 20 is selected from the group consisting of poloxamers, polyoxyethylene glycerides, fatty acid monoesters of sorbitan, polysorbates, a- tocopheryl polyethylene glycol succinate (TPGS), docusate sodium, sodium lauryl sulfate and mixtures thereof.
23. At least one surfactant according to claim 20 is Polysorbate 80.
24. A solid dispersion prepared according to claim 15 comprises at least one glidant.
25. At least one glidant according to claim 24 is colloidal silicon dioxide.
26. The process of claim 15, wherein said elevated temperature is about 70° C to about 250° C.
27. The process of claim 15, wherein said elevated temperature is about 120° C to about 180° C.
28. An orally deliverable pharmaceutical dosage form comprising the solid dispersion of claim 1.
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