EP3630069A1 - Formes amorphes de l'acide obéticholique - Google Patents

Formes amorphes de l'acide obéticholique

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Publication number
EP3630069A1
EP3630069A1 EP18730212.0A EP18730212A EP3630069A1 EP 3630069 A1 EP3630069 A1 EP 3630069A1 EP 18730212 A EP18730212 A EP 18730212A EP 3630069 A1 EP3630069 A1 EP 3630069A1
Authority
EP
European Patent Office
Prior art keywords
obeticholic acid
amorphous
amorphous form
eudragit
solid solution
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP18730212.0A
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German (de)
English (en)
Inventor
Iva OBADALOVA
Lukas KREJCIK
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Zentiva KS
Original Assignee
Zentiva KS
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Publication date
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Publication of EP3630069A1 publication Critical patent/EP3630069A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to amorphous forms of obeticholic acid (OCA) of formula I, with the systematic name (3a,5p,6a,7a)-6-ethyl-3,7-dihydroxycholan-24-ic acid, a method of their preparation and their use for the preparation of a pharmaceutical composition.
  • OCA obeticholic acid
  • Obeticholic acid is a semi-synthetic bile acid analog with an agonistic effect on the farnesoid X receptor (FXR). It is designed for the treatment of liver diseases, e.g. primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC).
  • PBC primary biliary cirrhosis
  • NASH nonalcoholic steatohepatitis
  • PSC primary sclerosing cholangitis
  • Obeticholic acid was first mentioned in the patent application WO2002072598.
  • the application describes its isolation by means of column chromatography, which generally yields substances of an amorphous character, no more detailed data concerning the product character being published in this patent application.
  • Crystalline form 1-2 of obeticholic acid exhibits high purifying capability, robust preparability and good filterability.
  • This crystalline form of obeticholic acid can be advantageously used for the preparation of an amorphous form of obeticholic acid.
  • solid compounds can exist in different solid forms that are considered as polymorphs, hydrates/solvates, salts or cocrystals having different crystal units and thus different physicochemical characteristics as the melting point, solubility, dissolution rate as well as bioavailability.
  • solid- state analytic methods can be used, e.g. the X-ray powder diffraction, solid-state NMR, Raman spectroscopy as well as thermoanalytical techniques.
  • An object of this invention are amorphous forms of obeticholic acid and their use for the preparation of a pharmaceutical composition.
  • Both the amorphous obeticholic acid alone and amorphous obeticholic acid stabilized with various pharmaceutically acceptable excipients e.g. polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, advantageously especially polymers, can be used for the drug form.
  • Amorphous forms stabilized this way can form solid compositions (solid dispersions, amorphous solid dispersions or solid solutions).
  • the invention relates to solid forms of amorphous obeticholic acid with at least one pharmaceutically acceptable excipient, which may be selected from the group of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea.
  • the amorphous obeticholic acid is advantageously stabilized with hydroxypropyl methylcellulose (hypromellose, HPMC), hypromellose acetate succinate (HPMC AS) derivatives of polymethacrylate, (Eudragit El 00, Eudragit LI 00, Eudragit SI 00), polyvinyl pyrrolidone (Povidone, PVP), copovidone (Kollidon) or copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (Soluplus).
  • HPMC hydroxypropyl methylcellulose
  • HPMC AS hypromellose acetate succinate
  • amorphous forms exhibit a clear advantage of their higher solubility and thus higher bioavailability.
  • An object of the invention is an amorphous form of obeticholic acid stabilized with at least one pharmaceutically acceptable polymer.
  • An amorphous form stabilized this way exhibits a glass transition temperature of at least 40°C, more preferably at least 70°C, even more preferably at least 100°C.
  • the pharmaceutically acceptable polymer is preferably selected from the group that consists of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, Methocel E5, povidone PVP K30, Soluplus, PEG 6000, copovidone VA64, Eudragit S100, Eudragit L100 and Eudragit E100.
  • Stabilized amorphous forms of obeticholic acid in accordance with the present invention exhibit a characteristic amorphous halo in an X-ray powder pattern with the use of CuKa radiation.
  • the content of obeticholic acid to the polymer is in the weight ratio of 1 : 0.5 to 1 : 5, preferably 1 : 1 to 1 : 3.
  • Another object of the invention is a preparation method of a stabilized amorphous form of obeticholic acid comprising dissolution of obeticholic acid with a pharmaceutically acceptable polymer in a suitable solvent selected from the group of methanol, ethanol, 2-propanol, tert- butanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, water or their mixtures, and subsequent removal of the solvent, providing the amorphous form.
  • the solvent is preferably selected from a group that consists of methanol, dichloromethane, tert-butanol, water or their mixture.
  • Another object of the invention is a preparation method of a stabilized amorphous form of obeticholic acid comprising mixing of obeticholic acid with a pharmaceutically acceptable polymer and subsequent heating of this mixture, producing a melt and providing an amorphous form.
  • Another object of the invention is the use of a stabilized amorphous form of obeticholic acid in accordance with the present invention for the preparation of a pharmaceutically acceptable composition.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising and amorphous form of obeticholic acid stabilized with at least one pharmaceutically acceptable polymer.
  • the pharmaceutical composition in accordance with the present invention can preferably have the form of a tablet.
  • Such pharmaceutical composition can further comprise at least one excipient from the group of binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium carboxymethyl starch), lubricants (e.g. magnesium stearate), surfactants etc.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a solid solution of an amorphous form of obeticholic acid stabilized with at least one pharmaceutically acceptable polymer, the ratio of obeticholic acid to the polymer being in the weight range of 1 : 0.5 to 1 : 5, preferably 1 : 1 to 1 : 3.
  • Another object of the invention is a solid solution of obeticholic acid with povidone PVP K30 in the weight ratio of OCA : polymer 1 : 0.5 to 1 : 3, characterized by a differential scanning calorimetric curve with a glass transition temperature of 111 to 125 °C.
  • Another object of the invention is a solid solution of obeticholic acid with Eudragit El 00 in the weight ratio of OCA : polymer 1 : 1 to 1:3, characterized by a differential scanning calorimetric curve with a glass transition temperature of 58 to 78°C.
  • Another object of the invention is a solid solution of obeticholic acid with Eudragit SI 00 in the weight ratio of OCA : polymer 1 : 1 to 1:3, characterized by a differential scanning calorimetric curve with a glass transition temperature of 101 to 109°C.
  • Another object of the invention is a solid solution of obeticholic acid with Soluplus in the weight ratio of OCA : polymer 1 : 1 to 1 :3, characterized by a differential scanning calorimetric curve with a glass transition temperature of 57 to 75°C.
  • Another object of the invention is a solid solution of obeticholic acid with Kollidon VA64 in the weight ratio of OCA : polymer 1 : 1 to 1 :3, characterized by a differential scanning calorimetric curve with a glass transition temperature of 91 to 92°C.
  • Another object of the invention is a solid solution of obeticholic acid with Methocel E5 in the weight ratio of OCA : polymer 1 : 1, characterized by a differential scanning calorimetric curve with a glass transition temperature of 82°C.
  • Another object of the invention is a solid solution of obeticholic acid with HPMC AS in the weight ratio of OCA : polymer 1 : 1, characterized by a differential scanning calorimetric curve with a glass transition temperature of 93 to 94°C.
  • Another object of the invention is optimized preparation of obeticholic acid alone.
  • Amorphous obeticholic acid can be advantageously prepared from crystalline form 1-2 described in the invention WO2017008773. Crystalline form 1-2 exhibits high purifying capability, robust preparability and good filterability.
  • Amorphous forms can be advantageously used for the preparation of a pharmaceutical composition.
  • Amorphous forms have higher solubility than crystalline forms, thus exhibiting higher bioavailability.
  • Amorphous obeticholic acid can be advantageously stabilized in the form of a solid solution with a pharmaceutically acceptable polymer.
  • a crystalline solid substance is characterized with a regular structural arrangement for a long distance. Conversely, amorphous solid substances do not exhibit this arrangement.
  • the molecular arrangement of an amorphous solid substance can be represented by a "frozen liquid" with rheological properties of a solid substance.
  • a solid mixture consisting of at least two components - the active pharmaceutical ingredient (API) and another at least one chemical compound (matrix) can take several forms.
  • the matrix for stabilization of the API is only assumed to consist of one component. In fact, this matrix may consist of one, two or more components (chemical compounds).
  • Substances of the type of polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea can be advantageously used as matrix components for solid mixtures.
  • solid dispersion represents a solid composition of an active pharmaceutical ingredient (API) that is dispersed in a matrix, this matrix exhibiting a crystalline character.
  • API active pharmaceutical ingredient
  • a conventional "amorphous solid dispersion” represents a solid composition where the active pharmaceutical ingredient (API) and the matrix exhibit an amorphous character as detected by XRPD.
  • this "amorphous solid dispersion” exhibits at least two glass transitions (Tg), one for the dispersed component (active pharmaceutical ingredient) and the other for the matrix, the number of Tg's depending on the number of the matrix components. If both the amorphous components (API as well as matrix) are mixed on the molecular level and the resulting solid mixture only exhibits one glass transition (Tg) temperature in differential scanning calorimetry, it is a special solid composition referred to as a "solid solution”.
  • amorphous solid substances have a different internal arrangement from crystalline solid substances and a larger surface, thus exhibiting higher solubility. If solubility and bioavailability of active pharmaceutical ingredients needs to be increased, they should be prepared in an amorphous form.
  • the temperature of a crystalline material achieves the melting point, the phase will change from the solid to liquid phase. Re-cooling of this melt will cause arrangement of the crystal structure again.
  • the melt is cooled sufficiently quickly, crystallization can be prevented by the occurrence of a subcooled solution.
  • the subcooled solution is cooled to achieve the glass transition (Tg), the molecules are kinetically frozen and the subcooled liquid solidifies into glass. Molecules in a subcooled liquid have much higher mobility than in the glass state, as described by Remington in the publication: The Science and Practice of Pharmacy, Pharmaceutical Press, 21 st edition.
  • the glass transition temperature is at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions. For this reason, it is advantageous to stabilize the amorphous form of the API by increasing the glass transition (Tg) temperature to prevent recrystallization and chemical degradation.
  • Tg glass transition
  • Amorphous obeticholic acid has the glass transition temperature of 93 °C and in its non- stabilized form it may suffer from chemical degradation during storage at an elevated temperature and humidity. For this reason, it is advantageous to stabilize the amorphous form of obeticholic acid by increasing the glass transition (Tg) temperature to prevent chemical degradation and recrystallization.
  • Tg glass transition
  • the prepared solid mixture is then polymorphically and chemically more stable even at elevated temperatures and relative humidity.
  • a possible approach to stabilization of amorphous obeticholic acid consists in producing solid mixtures with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
  • These polymers can come from the groups of polymers that are soluble or insoluble in water.
  • Typical polymers that are soluble in water are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (Soluplus) etc.
  • Typical solvents that are insoluble in water are methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl ethylcellulose etc.
  • HPMC AS hypromellose acetate succinate
  • cellulose acetate phthalate carboxymethyl ethylcellulose etc.
  • the active ingredient is dissolved in a solvent or in any mixture of solvents.
  • the solvent can be water or any organic solvent.
  • suitable organic solvents methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, tert-butanol, ethyl acetate, acetone, dichloromethane, chloroform, tetrahydrofuran, etc. can be mentioned.
  • a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension.
  • the solvent is quickly removed and amorphous solid mass is produced.
  • the solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, freezing of the solvent etc.
  • obeticholic acid is mixed with a stabilizing substance (e.g. a polymer).
  • a stabilizing substance e.g. a polymer
  • This mixture is heated up and melted, producing a melt.
  • Common temperatures to produce a melt vary in the range of 20°C - 40°C above the Tg temperature when the mixture is melted and has a suitable viscosity for processing.
  • the melt is subsequently cooled down, which provides an amorphous solid substance.
  • hot melt extrusion, hot melt granulation, high shear mixer, fluid bed granulation without the use of a solvent etc. can be mentioned.
  • a solvent removal technique e.g. with the use of a rotary vacuum evaporator, spray drying or lyophilization
  • preparation via melt hot melt extrusion
  • the preparation method of a stabilized amorphous form of obeticholic acid using the solvent removal principle comprises the following steps:
  • step a/ For the dissolution in step a/, common organic solvents or water, or their mixtures can be used. To remove solvents in step b/, evaporation at a reduced pressure, spray drying or lyophilization can be used.
  • the preparation method of a stabilized amorphous form of obeticholic acid using the hot melt extrusion comprises the following steps:
  • step a/ hi heating the mixture of step a/ to produce melt and to obtain an amorphous form.
  • amorphous form is generally an irregular arrangement of a substance.
  • This invention focuses on preparation of a pharmaceutical mixture comprising amorphous obeticholic acid with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
  • polymers can be advantageously used to prepare polymer-stabilized amorphous forms of obeticholic acid: polyvinyl pyrrolidone (PVP), copovidone (Kollidon VA64), hydroxypropylcellulose (Klucel), hydroxypropyl methylcellulose (Methocel), derivatized hydroxypropyl methylcellulose (e.g. HPMC AS), derivatives of polymethacrylate (Eudragit LlOO, Eudragit SlOO, Eudragit E100) and copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (Soluplus).
  • Polyvinyl pyrrolidone PVP K30
  • Methocel E5 HPMC
  • Eudragit SlOO Eudragit LlOO
  • copovidone Kollidon VA64
  • HPC hydroxypropylcellulose
  • Soluplus and hypromellose acetate succinate HPMC AS-LF
  • Methocel E5 1 1 evaporation Tg 82°C amorphous API A differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a solid solution. In the case of a solid solution, the amorphous solid substance only exhibits one glass transition (Tg) value in the record.
  • Tg glass transition
  • the prepared amorphous substances in the weight ratio of 1 : 2 (API : polymer) formed stable solid solutions whose stability increases with the increasing Tg value (Hancock and Zografi, 1997).
  • obeticholic acid forms the most stable solid solutions with povidone PVP K30, Eudragit SI 00 or Copovidone VA64.
  • solid solutions with polymers that have a lower glass transition temperature are also usable as such a high temperature does not need to be applied to melt them. This is mainly the case of Soluplus, Eudragit El 00 or Methocel E5.
  • the results of the X-ray powder analysis confirmed an amorphous character of the substances of all the prepared mixtures of obeticholic acid and the polymers.
  • Amorphous obeticholic acid has the glass transition temperature of 93°C.
  • solid solutions of obeticholic acid with different glass transition temperatures were selected.
  • a solid solution of obeticholic acid with Eudragit El 00 was selected in the weight ratio of OCA : Eudragit E100 1 : 3, with the glass transition temperature of 58°C. Further, a solid solution of obeticholic acid with Eudragit El 00 was selected in the weight ratio of OCA : Eudragit El 00 1 : 1, with the glass transition temperature of 78°C.
  • a solid solution of obeticholic acid with Soluplus was selected in the weight ratio of OCA : Soluplus 1 : 3, with the glass transition temperature of 57°C.
  • a solid solution of obeticholic acid with Soluplus was selected in the weight ratio of OCA : Soluplus 1 : 1, with the glass transition temperature of 75°C.
  • a solid solution of obeticholic acid with Copovidone VA64 was selected in the weight ratio of OCA : Copovidone VA64 1 : 3, with the glass transition temperature of 92°C.
  • a solid solution of obeticholic acid with Eudragit SI 00 was selected in the weight ratio of OCA : Eudragit SI 00 1 : 3, with the glass transition temperature of 101°C.
  • a solid solution of obeticholic acid with povidone PVP K30 was selected in the weight ratio of OCA : PVP K30 1 : 3, with the glass transition temperature of 125°C.
  • the stability testing shows that amorphous obeticholic acid (OCA) starts to degrade under higher temperature (60°C) and increased humidity (75% RH) loading and after three days, DSC analysis shows a less stable form of obeticholic acid. This means that it is physically less stable than obeticholic acid stabilized in the form of a solid solution with a pharmaceutically acceptable excipient.
  • OCA amorphous obeticholic acid
  • Another such example is a solid solution or obeticholic acid with Soluplus in the weight ratio of OCA : Soluplus 1 : 3, which has the glass transition temperature of 57°C, where the loading with a higher temperature and a low relative humidity results in an increase of the glass transition temperature, namely to 74°C (40°C / 0% RH / 7 days), or 66°C (60°C / 0% / 3 days), respectively.
  • This solid solution also has a similar temperature (127°C) after being stored for 3 days at 60°C and 0% relative humidity.
  • An even higher glass transition temperature of this sample was measured when it was exposed to the conditions of 40°C and 75% relative humidity for 7 days or 60°C and 75% relative humidity for 3 days.
  • a solid solution of obeticholic acid with Copovidone VA64 in the weight ratio of 1 : 3 with the original glass transition temperature of 92°C increased its glass transition temperature to 103°C or 104°C after maturation at 40°C and 75% relative humidity for 7 days or at 60°C and 75% relative humidity for 3 days, respectively.
  • Amorphous obeticholic acid can be advantageously prepared from crystalline form 1-2 of obeticholic acid, described in the patent application WO2017008773. Crystalline form 1-2 exhibits high purifying capability, robust preparability and good filterability.
  • the procedure based on precipitation through the ammonium salt of obeticholic acid, described in the patent application WO2006122977 was first used, but the product obtained this way, when crystalline for 1-2 of obeticholic acid was used as the input material, had lower chemical purity than the input material and higher contents of residual solvents. Therefore, the procedure required optimization.
  • the amorphous solid forms of obeticholic acid prepared according to this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g.. tablets.
  • Such pharmaceutical compositions can comprise at least one excipient from the group of binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium carboxymethyl starch), lubricants (e.g. magnesium stearate), surfactants etc.
  • binders e.g. microcrystalline cellulose
  • disintegrants e.g. sodium carboxymethyl starch
  • lubricants e.g. magnesium stearate
  • surfactants e.g. magnesium stearate
  • Fig. 1 DSC record of the amorphous form of obeticholic acid (OCA)
  • Fig. 2 DSC record of a solid solution of OCA : PVP K30 1 : 3
  • Fig.3 DSC record of a solid solution of OCA : Eudragit SI 00 1 : 3
  • Fig. 4 DSC record of a solid solution of OCA : Eudragit E100 1 : 1
  • Fig. 5 DSC record of a solid solution of OCA : Eudragit E100 1 : 3
  • Fig. 7 DSC record of a solid solution of OCA : Soluplus 1 : 3
  • Fig. 8 DSC record of a solid solution of OCA : Copovidone VA64 1 : 3
  • Fig. 9 DSC record of a solid solution of OCA : HPMC AS 1 : 1
  • Fig. 10 DSC record of a solid solution of OCA : Methocel E5 1 : 1 Examples
  • Obeticholic acid was prepared in accordance with the procedure disclosed in the patent application WO2002072598.
  • Amorphous obeticholic acid was further prepared by means of the optimized procedures described in Examples 1 and 2. All the products were verified for *H and 13 C NMR.
  • the laboratory temperature refers to the temperature of 25°C ⁇ 3°C.
  • Tg glass transition
  • Obeticholic acid (500 mg) and povidone K30 (250 mg) were dissolved in a mixture of methanol (3 ml) and dichloromethane (2 ml) by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 111°C.
  • Tg glass transition
  • Obeticholic acid (500 mg) and povidone K30 (500 mg) were dissolved in a mixture of methanol (3 ml) and dichloromethane (2 ml) by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 116°C.
  • Obeticholic acid (5 g) and povidone 30 (5 g) were dissolved in 300 ml of a mixture of water and tert-butanol in the ratio of 1 : 1 by means of ultrasound. The obtained solution was frozen in liquid nitrogen and subsequently lyophilized. DSC confirmed a solid solution with the glass transition (Tg) temperature of 1 17°C.
  • Tg glass transition
  • Obeticholic acid (50 g) and povidone K30 (150 g) were dissolved in 150 ml of methanol by means of ultrasound. The obtained solution was subsequently spray dried in a Buchi spray drier. DSC confirmed a solid solution with the glass transition (Tg) temperature of 125°C.
  • Obeticholic acid (500 mg) and Eudragit SI 00 (500 mg) were dissolved in 50 ml of methanol by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 109°C.
  • Obeticholic acid (3 g) and Eudragit SI 00 (9 g) were dissolved in 250 ml of a mixture of water and tert-butanol in the ratio of 1 : 1 by means of ultrasound. The obtained solution was frozen in liquid nitrogen and subsequently lyophilized. DSC confirmed a solid solution with the glass transition (Tg) temperature of 101°C.
  • This product was further exposed to maturation conditions at the temperatures of 40°C to 60°C and a relative humidity below 30%, ideally below 15%.
  • the product was stabilized and the obtained solid solution exhibited the glass transition (Tg) temperature of 127°C.
  • Obeticholic acid (3 g) and Eudragit LI 00 (3 g) were dissolved in 50 ml of methanol by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 69°C.
  • Obeticholic acid (20 g) and Eudragit LI 00 (20 g) were dissolved in 500 ml of methanol by means of ultrasound. The obtained solution was subsequently spray dried in a Buchi spray drier. DSC confirmed a solid solution with the glass transition (Tg) temperature of 78°C.
  • Tg glass transition
  • Obeticholic acid (20 g) and Eudragit LI 00 (60 g) were dissolved in 700 ml of methanol by means of ultrasound. The obtained solution was subsequently spray dried in a Buchi spray drier. DSC confirmed a solid solution with the glass transition (Tg) temperature of 58°C.
  • Obeticholic acid (2 g) and Soluplus (2 g) were dissolved in a mixture of methanol (12 ml) and dichloromethane (4 ml) by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 75°C.
  • Obeticholic acid (2 g) and copovidone VA64 (2 g) were dissolved in a mixture of methanol (12 ml) and dichloromethane (8 ml) by means of ultrasound. The obtained solution was subsequently evaporated in a rotary vacuum evaporator, which provided amorphous foam. DSC confirmed a solid solution with the glass transition (Tg) temperature of 91 °C.
  • Obeticholic acid (2 g) and copovidone VA64 (6 g) were dissolved in 250 ml of a mixture of water and tert-butanol in the ratio of 1 : 1 by means of ultrasound. The obtained solution was frozen in liquid nitrogen and subsequently lyophilized. DSC confirmed a solid solution with the glass transition (Tg) temperature of 92°C.
  • Obeticholic acid (1 g) and HPMC AS LF (1 g) were dissolved in 50 ml of a mixture of water and tert-butanol in the ratio of 1 : 1 by means of ultrasound.
  • the obtained solution was frozen in liquid nitrogen and subsequently lyophilized.
  • DSC confirmed a solid solution with the glass transition (Tg) temperature of 93°C.
  • Solid solutions of obeticholic acid with all the above mentioned polymers can also be prepared by melting (hot melt extrusion).
  • Obeticholic acid was first mixed with a polymer at the particular ratio, then the mixture was homogenized for at least 5 min and subsequently extruded at the temperature shown in Table 3.
  • the extrudates were subsequently ground in a hammer mill with a 1-mm sieve and analyzed by means of XRPD. Table 3:
  • amorphous form of obeticholic acid stabilized with povidone PVP K30, microcrystalline cellulose and sodium carboxymethyl starch The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate was added and the mixture was homogenized for another 3 min at 20 rpm.
  • the tableting matter obtained in the above mentioned manner was compressed on a rotary tableting machine and used for the production of cores with the approximate weight of 200 mg.
  • the resulting cores may possibly be coated (a mixture of hypromellose, PEG , talc, titanium dioxide, iron oxide).
  • Magnesium stearate 2.0 Ingredients were placed into a homogenizer: amorphous form of obeticholic acid stabilized with Eudragit SI 00, microcrystalline cellulose and sodium carboxymethyl starch. The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate was added and the mixture was homogenized for another 3 min at 20 rpm. The tableting matter obtained in the above mentioned manner was compressed on a rotary tableting machine and used for the production of cores with the approximate weight of 200 mg. The resulting cores may possibly be coated (a mixture of hypromellose, PEG , talc, titanium dioxide, iron oxide).
  • amorphous form of obeticholic acid stabilized with Eudragit El 00, microcrystalline cellulose and sodium carboxymethyl starch The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate was added and the mixture was homogenized for another 3 min at 20 rpm.
  • the tableting matter obtained in the above mentioned manner was compressed on a rotary tableting machine and used for the production of cores with the approximate weight of 200 mg.
  • the resulting cores may possibly be coated (a mixture of hypromellose, PEG , talc, titanium dioxide, iron oxide).
  • DSC differential scanning calorimetry
  • the primary optical system programmable divergence slits with the irradiated sample area of 10 mm 0.02 rad Soller slits and a 1 ⁇ 4° anti-dispersion slit were used.
  • an X'Celerator detector with the maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-dispersion slit were used.

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Abstract

L'invention concerne les formes solides d'acide obéticholique amorphe de formule I avec au moins un excipient pharmaceutiquement acceptable, qui peut être choisi dans le groupe des polymères, des saccharides, des oligosaccharides, des polysaccharides, des graisses, des cires ou de l'urée. L'acide obéticholique amorphe est avantageusement stabilisé à l'aide d'hydroxypropylméthylcellulose (hypromellose, HPMC), de succinate d'acétate d'hypromellose (HPMC AS), de dérivés de polyméthacrylate (Eudragit E100, Eudragit L100, Eudragit S100), de polyvinylpyrrolidone (Povidone, PVP), de copovidone (Kollidon) ou de copolymères de polyvinylcaprolactame-acétate de polyvinyle-polyéthylène glycol (Soluplus).
EP18730212.0A 2017-05-26 2018-05-28 Formes amorphes de l'acide obéticholique Withdrawn EP3630069A1 (fr)

Applications Claiming Priority (2)

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CZ2017-298A CZ2017298A3 (cs) 2017-05-26 2017-05-26 Amorfní formy obeticholové kyseliny
PCT/CZ2018/000022 WO2018215002A1 (fr) 2017-05-26 2018-05-28 Formes amorphes de l'acide obéticholique

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US11168107B2 (en) 2016-02-10 2021-11-09 Dr. Reddy's Laboratories Limited Amine salt of obeticholic acid
CA3112411A1 (fr) 2018-09-18 2020-03-26 Metacrine, Inc. Agonistes du recepteur farnesoide x et leurs utilisations
JP2023518398A (ja) * 2020-03-18 2023-05-01 メタクリン，インク． ファルネソイドｘ受容体アゴニストの製剤

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ATE303399T1 (de) 2001-03-12 2005-09-15 Intercept Pharmaceuticals Inc Steroide als agonisten für fxr
ITMI20050912A1 (it) 2005-05-19 2006-11-20 Erregierre Spa Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici
US8338628B2 (en) 2007-08-28 2012-12-25 City Of Hope Method of synthesizing alkylated bile acid derivatives
EA201990211A1 (ru) 2012-06-19 2019-06-28 Интерсепт Фармасьютикалз, Инк. Получение, применение и твердые формы обетихолевой кислоты
CZ2015504A3 (cs) 2015-07-16 2017-01-25 Zentiva, K.S. Krystalické formy obeticholové kyseliny
CN106539771A (zh) * 2015-09-21 2017-03-29 天津市汉康医药生物技术有限公司 一种奥贝胆酸片及其制备方法
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