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WO2025098332A1 - Composition comprenant un phosphonate cyclique et son procédé de préparation - Google Patents

Composition comprenant un phosphonate cyclique et son procédé de préparation Download PDF

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Publication number
WO2025098332A1
WO2025098332A1 PCT/CN2024/129952 CN2024129952W WO2025098332A1 WO 2025098332 A1 WO2025098332 A1 WO 2025098332A1 CN 2024129952 W CN2024129952 W CN 2024129952W WO 2025098332 A1 WO2025098332 A1 WO 2025098332A1
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Prior art keywords
mixture
parts
present disclosure
components
capsule
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PCT/CN2024/129952
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English (en)
Chinese (zh)
Inventor
吴劲梓
柴旭煜
董堃华
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Gannex Pharma Co Ltd
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Gannex Pharma Co Ltd
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Publication of WO2025098332A1 publication Critical patent/WO2025098332A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present disclosure relates generally to the field of medicine, and more particularly to compositions comprising cyclic phosphonates and methods for preparing the same.
  • the compound represented by formula (I) is a novel oral thyroid hormone beta receptor agonist (THR-beta agonist), which selectively activates THR- ⁇ , regulates the gene expression of downstream CYP7A and SREBP-1c, etc., effectively promotes the decomposition of fatty acids and stimulates mitochondrial biogenesis, reduces low-density lipoprotein and triglyceride levels, thereby reducing fat toxicity and improving liver function, reducing liver fat. It is a highly effective and low-toxic candidate drug for nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • the compound represented by formula (I) is a poorly soluble drug with strong lipid solubility.
  • the equilibrium solubility of the compound represented by formula (I) was measured at 37°C ⁇ 0.5°C and the results showed that the equilibrium solubility was less than 0.5 ng/mL in hydrochloric acid solution, buffer solution and water without surfactant at pH 1.0-pH 9.0.
  • the dissolution of the drug in the gastrointestinal tract is a prerequisite for transmembrane transport and absorption into the human body to exert its efficacy.
  • the extremely low solubility of the compound represented by formula (I) limits its prospects for development as a candidate drug.
  • Solid dispersion technology is the most common and widely used solubilization technology, which usually includes grinding method, melting method, solvent method, solvent spray drying method, etc. Among them, hot melt extrusion and solvent spray drying to prepare solid dispersions are the two most widely used solid dispersion preparation technologies in industrial application.
  • the present disclosure relates to micropellets comprising a pellet core and a pharmaceutical composition sprayed onto the pellet core by a fluidized bed spray process, wherein, in parts by weight, the pharmaceutical composition comprises:
  • the present disclosure relates to a method for preparing the micropellets described in the present disclosure, comprising:
  • the solution is sprayed onto the pellet core by a fluidized bed spraying process to obtain the Describe the micro-pill.
  • the present disclosure relates to a capsule comprising the pellets described in the present disclosure.
  • the present disclosure relates to a method of treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure to a subject in need thereof.
  • the present disclosure relates to a self-emulsifying solution comprising, in parts by weight:
  • it further comprises (b) 0.5 to 100 parts of an oily solvent;
  • components (a), (b) and (c) are mixed and heated with stirring to obtain the self-emulsifying solution.
  • the present disclosure relates to a method for preparing the self-emulsifying solution of the present disclosure, comprising:
  • the component (a) is dispersed and dissolved in the component (c) and heated and stirred to obtain the self-emulsifying solution.
  • the present disclosure relates to a capsule or a tablet comprising the self-emulsifying solution of the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a solid dispersion comprising, in parts by weight:
  • components (a) and (b) are mixed and the solid dispersion is obtained by a solvent method or a hot melt extrusion method.
  • the present disclosure relates to a method for preparing the solid dispersion described in the present disclosure, comprising:
  • the solid dispersion is prepared by mixing components (a) and (b) by a solvent method or hot melt extrusion.
  • the present disclosure relates to a capsule comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a tablet comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • cyclodextrin inclusion compound which comprises, by weight:
  • the present disclosure relates to a method for preparing the cyclodextrin inclusion compound of the present disclosure.
  • the law includes:
  • the components (a) and (b) are formed into the cyclodextrin inclusion complex by mixing, grinding mixing, freeze drying or spray drying.
  • the present disclosure relates to a capsule comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a tablet comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to an oily solution comprising, by weight:
  • components (a) and (b) are mixed and heated with stirring to obtain the oily solution.
  • the present disclosure relates to a method for preparing the oily solution of the present disclosure, comprising:
  • Component (a) is dispersed and dissolved in (b) to form the oily solution.
  • the present disclosure relates to a capsule comprising the oily solution of the present disclosure.
  • the present disclosure relates to a method of treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure to a subject in need thereof.
  • the present disclosure relates to a solubilizing composition
  • a solubilizing composition comprising, in parts by weight:
  • the present disclosure relates to a method for preparing the solubilized composition of the present disclosure, comprising:
  • Components (a) and (b) are mixed and then dry granulated or wet granulated to form powder or granules.
  • the present disclosure relates to a capsule comprising the solubilizing composition described in the present disclosure.
  • the present disclosure relates to a tablet comprising the solubilized composition described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • components (a) and (b) are mixed and subjected to hot melt extrusion.
  • the present disclosure relates to a method for preparing the enteric composition of the present disclosure, comprising:
  • the mixture of components (a) and (b) is extruded by hot melt extrusion to form an extrudate.
  • the present disclosure relates to a capsule comprising the enteric composition of the present disclosure.
  • the present disclosure relates to a tablet comprising the enteric composition of the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a particle comprising, by weight:
  • components (a), (b) and (c) are mixed and granulated by fluidized bed spraying.
  • the present disclosure relates to a method of preparing the particles of the present disclosure, comprising:
  • the solution is subjected to a fluidized bed spray granulation process at a temperature ranging from 20° C. to 80° C. to prepare the granules.
  • the present disclosure relates to a capsule comprising the particles described in the present disclosure.
  • the present disclosure relates to a tablet comprising the granules described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure or the tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a porous adsorbent material comprising, by weight:
  • components (a) and (b) are mixed and dissolved by heating and stirring, and then mixed and adsorbed with component (c).
  • the present disclosure relates to a method for preparing the porous adsorbent material of the present disclosure, comprising:
  • the solution is added to (c) under stirring conditions to prepare the porous adsorption material.
  • the present disclosure relates to a capsule comprising the porous adsorbent material described in the present disclosure.
  • the present disclosure relates to a tablet comprising the porous adsorption material described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure or the tablet of the present disclosure to an individual in need thereof.
  • the pharmaceutical composition mentioned containing "a compound or a pharmaceutically acceptable salt thereof represented by the general formula (I)” includes one compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof.
  • compounds of the present disclosure includes compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), including compounds of the Examples. In some embodiments, “compounds of the present disclosure” include compounds of formula (I).
  • pharmaceutically acceptable excipient includes, but is not limited to, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.
  • terapéuticaally effective amount refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound sufficient to affect treatment of a disease when administered to a subject being treated for the disease.
  • the effective amount will vary depending on factors such as the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.
  • the effective amount may include a range of amounts.
  • an effective amount may be one or more doses, i.e., one dose or multiple doses may be required to achieve the desired treatment.
  • the effective amount may be considered in the context of administering one or more therapeutic agents, and if the desired or beneficial result may or has been achieved when used with one or more other agents, then the single agent may be considered to be administered in an effective amount. Due to the combined effect of the compounds (e.g., additive or synergistic effect), the appropriate dose of any co-administered compound may be selectively lowered.
  • co-administration refers to administration of a unit dose of a compound of the present disclosure before or after administration of a unit dose of one or more additional therapeutic agents, for example, administration of a compound of the present disclosure within a few seconds, minutes, or hours of administration of one or more additional therapeutic agents.
  • a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within a few seconds or minutes.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within a few seconds or minutes.
  • a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents a few hours later (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure a few hours later (e.g., 1-12 hours).
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administration of a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject's body.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.
  • the compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases.
  • Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound which possess the desired pharmacological activity of the free base. These salts may be extracted from inorganic or organic acids or bases.
  • a compound containing a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of salts include sulfates, pyrosulfates, disulfates, sulfites, disulfates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates.
  • Benzenesulfonates xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates.
  • Lists of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006".
  • Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein also include salts derived from appropriate bases, such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and N(C 1 -C 4 alkyl) 4 + . Also included are base addition salts, such as sodium or potassium salts.
  • bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and N(C 1 -C 4 alkyl) 4 + .
  • base addition salts such as sodium or potassium salts.
  • a deuterium atom is a non-radioactive isotope of a hydrogen atom.
  • Such compounds may increase resistance to metabolism and may therefore be used to increase the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof when administered to a mammal. See “Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984)".
  • Such compounds are synthesized by methods well known in the art, such as using starting materials in which one or more hydrogen atoms are replaced by deuterium.
  • isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N , 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I.
  • isotopes such as 11 C, 18 F, 15 O, and 13 N, may be useful in positron emitting isotopes.
  • PET Polymer radiography
  • Isotopically labeled compounds of formula (IA-1) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the examples below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.
  • the compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. All such possible isomers are intended to be included, as well as their racemates and optically pure forms.
  • Optically active (+) and (-), (R) and (S), or (D) and (L)-isomers may be prepared using chiral syntheses or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization.
  • scalar mixture refers to a mixture of stereoisomers in a ratio other than 1:1.
  • stereoisomers refer to compounds that are bound by the same atoms but have different three-dimensional structures and are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.
  • tautomer refers to a proton transfer from one atom of one molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of the compounds.
  • solvate refers to the result of the interaction between a solvent and a compound. Solvates of the salts of the compounds described herein are provided. Also provided are hydrates of the compounds described herein.
  • hydrate refers to a compound of the present invention chemically bound to one or more water molecules.
  • Prevention refers to any treatment of a disease or condition that results in clinical symptoms of the disease or condition not developing.
  • the compounds may be administered to subjects (including humans) who are at risk for or have a family history of the disease or condition.
  • prodrug refers to a derivative of a drug that is converted into a parent drug according to a certain chemical or enzymatic pathway after administration to the human body.
  • a prodrug is a biologically active derivative of a drug that is converted into a biologically active parent drug according to some chemical or enzymatic pathway after administration to the human body.
  • treatment refers to a method of obtaining a beneficial or desired result.
  • a beneficial or desired result includes, but is not limited to, alleviating symptoms and/or alleviating the extent of symptoms and/or preventing the worsening of symptoms associated with a disease or condition.
  • treatment includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and/or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating a disease or condition, for example, causing regression of clinical symptoms, improving the disease state, delaying disease progression, improving quality of life, and/or prolonging survival.
  • at-risk individual refers to an individual who is at risk of developing a disease that requires treatment.
  • An “at-risk” individual may or may not have a detectable disease or condition, and may or may not have exhibited a detectable disease prior to the treatment methods described herein.
  • “At risk” means that the individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art to increase the probability of individuals with one or more of these risk factors developing the disease or condition compared to individuals without these risk factors.
  • the present disclosure relates to micropellets comprising a pellet core and a pharmaceutical composition sprayed onto the pellet core by a fluidized bed spray process, wherein, in parts by weight,
  • the pharmaceutical composition comprises:
  • illustrative examples of good solvents that can be used in the present disclosure include, but are not limited to, ethanol, ethyl ether, acetone, anisole, butanol, ethyl acetate, pentanol, and any mixture thereof.
  • illustrative examples of high molecular weight polymers that can be used in the present disclosure include, but are not limited to, polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, and any mixture thereof.
  • the high molecular weight polymer is selected from copovidone, hypromellose and any mixture thereof;
  • the high molecular weight polymer is 10 to 35 parts.
  • components (a), (b) and (c) are sprayed onto the pellet cores through a fluidized bed at a temperature ranging from 20°C to 80°C.
  • the present disclosure relates to a method for preparing the micropellets described in the present disclosure, comprising:
  • the solution is sprayed onto the pellet cores through a fluidized bed spraying process, thereby obtaining the micropellets.
  • the present disclosure relates to a capsule or a tablet comprising the micro- pill.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a self-emulsifying solution comprising, in parts by weight:
  • it further comprises (b) 0.5 to 100 parts of an oily solvent;
  • (a), (b) and (c) are mixed and heated with stirring to obtain the self-emulsifying solution.
  • oily solvents that can be used in the present disclosure include, but are not limited to, castor oil, soybean oil, sesame oil, coconut oil, cottonseed oil, medium chain triglycerides (MCT), long chain triglycerides (LCT), benzyl benzoate, oleic acid, monolinoleylglycerol, and any mixture thereof.
  • the oily solvent is selected from monolinoleylglycerol, oleic acid and any mixture thereof;
  • the oily solvent is 5 to 15 parts.
  • illustrative examples of surfactants that can be used in the present disclosure include, but are not limited to, polyethylene glycol (15)-hydroxystearate, Tween 80, Tween 20, polyoxyethylene (35) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, lauric acid macrogol glyceride, vitamin E polyethylene glycol succinate (TPGS), caprylic capric macrogol glyceryl, lauroyl polyoxyl-32 glyceride, and any mixture thereof.
  • the surfactant is selected from lauric acid macrogol glyceride, polyoxyethylene (40) hydrogenated castor oil and any mixture thereof;
  • the surfactant is 5 to 50 parts.
  • the self-emulsifying solution of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, polyethylene glycol, propylene glycol, ethanol, benzyl alcohol, glycerol, isopropanol, ethylene glycol monoethyl ether, and any mixture thereof.
  • the auxiliary material is selected from diethylene glycol monoethyl ether, polyethylene glycol and any mixture thereof;
  • the auxiliary material is 5 to 50 parts.
  • components (a), (b), (c) and (d) are mixed and heated with stirring at a temperature ranging from 20° C. to 80° C. to obtain the self-emulsifying solution.
  • the present disclosure relates to a method for preparing the self-emulsifying solution of the present disclosure, comprising:
  • the component (a) is dispersed and dissolved in the component (c) and heated and stirred to obtain the self-emulsifying solution.
  • the present disclosure relates to a capsule comprising the self-emulsifying solution of the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a solid dispersion comprising, in parts by weight:
  • components (a) and (b) are mixed and the solid dispersion is obtained by a solvent method, a hot melt extrusion method or a high-speed shear method.
  • porous excipients that can be used in the present disclosure include, but are not limited to, carriers selected from polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer, polyoxyethylene (40) hydrogenated castor oil, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, and any mixture thereof.
  • the carrier is selected from copovidone, polyoxyethylene (40) hydrogenated castor oil and any mixture thereof;
  • the carrier is 10 to 50 parts.
  • components (a) and (b) are mixed and dispersed and dissolved in a solvent, the solvent is evaporated, and dried to obtain the solid dispersion.
  • components (a) and (b) are subjected to hot melt extrusion at a temperature between 60°C and 200°C to obtain the solid dispersion;
  • Components (a) and (b) are subjected to high-speed shear fusion to obtain the solid dispersion.
  • the solid dispersion of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, silicon dioxide, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate, and any mixture thereof.
  • the auxiliary material is selected from lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silicon dioxide, cross-linked carboxymethyl cellulose sodium, magnesium stearate, sodium stearyl fumarate and any mixture thereof.
  • the present disclosure relates to a method for preparing the solid dispersion described in the present disclosure, comprising:
  • the solid dispersion is prepared by mixing components (a) and (b) by a solvent method or hot melt extrusion.
  • the present disclosure relates to a capsule comprising the solid dispersion described in the present disclosure. body.
  • the present disclosure relates to a tablet comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • cyclodextrin inclusion compound which comprises, by weight:
  • illustrative examples of cyclodextrins that can be used in the present disclosure include, but are not limited to, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, sulfobutyl ⁇ -cyclodextrin, methyl ⁇ -cyclodextrin, or any mixture thereof.
  • components (a) and (b) are formed into the cyclodextrin inclusion complex by simple physical mixing, grinding mixing, freeze drying, or spray drying.
  • the cyclodextrin inclusion complex of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, purified water, soybean oil, lactose, microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, silicon dioxide, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate, and any mixture thereof.
  • the auxiliary material is selected from purified water, soybean oil, lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silicon dioxide, cross-linked sodium carboxymethyl cellulose, magnesium stearate, stearic acid Sodium fumarate and any mixture thereof.
  • the present disclosure relates to a method for preparing the cyclodextrin inclusion compound of the present disclosure, comprising:
  • the components (a) and (b) are formed into the cyclodextrin inclusion complex by mixing, grinding mixing, freeze drying or spray drying.
  • the present disclosure relates to a capsule comprising the solid dispersion described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to an oily solution comprising, by weight:
  • components (a) and (b) are mixed and heated with stirring to obtain the oily solution.
  • oily solvents that can be used in the present disclosure include, but are not limited to, castor oil, soybean oil, sesame oil, coconut oil, cottonseed oil, medium chain triglycerides (MCT), long chain triglycerides (LCT), benzyl benzoate, oleic acid, and any mixture thereof.
  • oily solution of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, polyethylene glycol, propylene glycol, ethanol, benzyl alcohol, Glycerol, isopropyl alcohol, ethylene glycol monoethyl ether and any mixture thereof.
  • components (a), (b) and (c) are mixed and heated with stirring at a temperature ranging from 20° C. to 80° C. to obtain the oily solution.
  • the present disclosure relates to a method for preparing the oily solution of the present disclosure, comprising:
  • Component (a) is dispersed and dissolved in (b) to form the oily solution.
  • the present disclosure relates to a capsule comprising the oily solution of the present disclosure.
  • the present disclosure relates to a method of treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure to a subject in need thereof.
  • the present disclosure relates to a solubilizing composition
  • a solubilizing composition comprising, in parts by weight:
  • solubilizing agents that can be used in the present disclosure include, but are not limited to, sodium lauryl sulfate, poloxamer 188, poloxamer 338, poloxamer 407, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, Tween 80, polyethylene glycol, sorbitan laurel, vitamin E polyethylene glycol succinate, and any mixture thereof.
  • the solubilizing composition of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, silicon dioxide, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate, and any mixture thereof.
  • components (a), (b) and (c) are prepared by dry granulation or wet granulation. Granulation, forming powder or granules
  • the present disclosure relates to a method for preparing the solubilized composition of the present disclosure, comprising:
  • Components (a) and (b) are mixed and then dry granulated or wet granulated to form powder or granules.
  • the present disclosure relates to a capsule comprising the solubilizing composition described in the present disclosure.
  • the present disclosure relates to a tablet comprising the solubilized composition described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to an enteric composition
  • an enteric composition comprising, by weight:
  • components (a) and (b) are mixed and subjected to hot melt extrusion.
  • enteric solvents that can be used in the present disclosure include, but are not limited to, hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, ethyl cellulose, and any mixture thereof.
  • components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature ranging from 80°C to 250°C.
  • the enteric composition of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, powder, calcium hydrogen phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, silicon dioxide, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate and any mixture thereof.
  • the present disclosure relates to a method for preparing the enteric composition of the present disclosure, comprising:
  • the mixture of components (a) and (b) is extruded by hot melt extrusion to form an extrudate.
  • the present disclosure relates to a capsule comprising the enteric composition described in the present disclosure.
  • the present disclosure relates to a tablet comprising the enteric composition of the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule or tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a particle comprising, by weight:
  • components (a), (b) and (c) are mixed and granulated by fluidized bed spraying.
  • illustrative examples of good solvents that can be used in the present disclosure include, but are not limited to, ethanol, ethyl ether, acetone, anisole, butanol, ethyl acetate, pentanol, and any mixture thereof.
  • illustrative examples of high molecular weight polymers that can be used in the present disclosure include, but are not limited to, polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, poloxamer, polyvinyl caprolactam-polyvinyl acetate- Polyethylene glycol graft copolymer (Soluplus), polyethylene glycol and any mixture thereof.
  • components (a), (b), and (c) are mixed and subjected to fluidized bed spray granulation at a temperature ranging from 20°C to 80°C.
  • the particles of the present disclosure further comprise:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate, and any mixture thereof.
  • the present disclosure relates to a method of preparing the particles of the present disclosure, comprising:
  • the solution is subjected to a fluidized bed spray granulation process at a temperature ranging from 20° C. to 80° C. to prepare the granules.
  • the present disclosure relates to a capsule comprising the particles described in the present disclosure.
  • the present disclosure relates to a tablet comprising the granules described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure or the tablet of the present disclosure to an individual in need thereof.
  • the present disclosure relates to a porous adsorbent material comprising, by weight:
  • Components (a) and (b) are mixed and dissolved by heating and stirring, and then mixed and adsorbed with component (c).
  • illustrative examples of soluble carriers that can be used in the present disclosure include, but are not limited to, polyethylene glycol, Tween 80, Tween 20, sorbitan laurel, vitamin E polyethylene glycol succinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (40) hydrogenated castor oil, caprylic capric acid polyethylene glycol glyceryl, lauroyl polyoxyl-32 glyceride, and any mixture thereof.
  • the soluble carrier is selected from polyoxyethylene (40) hydrogenated castor oil.
  • porous adsorbent materials that can be used in the present disclosure include, but are not limited to, colloidal silica, magnesium aluminum silicate, anhydrous calcium hydrogen phosphate, calcium carbonate, spray-dried mannitol, spray-dried lactose, and any mixture thereof.
  • components (a) and (b) are mixed and dissolved by heating and stirring at a temperature range of 20°C to 100°C, and then adsorbed by mixing with component (c).
  • the porous adsorbent material of the present disclosure further comprises:
  • illustrative examples of pharmaceutically acceptable excipients that can be used in the present disclosure include, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, mannitol, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, sodium stearyl fumarate, and any mixture thereof.
  • the present disclosure relates to a method for preparing the porous adsorbent material of the present disclosure, comprising:
  • the solution is added to (c) under stirring conditions to prepare the porous adsorption material.
  • the present disclosure relates to a capsule comprising the porous adsorbent material described in the present disclosure.
  • the present disclosure relates to a tablet comprising the porous adsorption material described in the present disclosure.
  • the present disclosure relates to a method for treating steatohepatitis, comprising administering a therapeutically effective amount of the capsule of the present disclosure or the tablet of the present disclosure to an individual in need thereof.
  • the compound represented by formula (I), copolyvidone Kollidon VA64 and hydroxypropyl methylcellulose E3 LV are dispersed and dissolved in ethanol by stirring to form a solution.
  • the solution is sprayed onto sucrose blank pellet cores at a temperature between 20° C. and 80° C. using a fluidized bed spray coating process, and then dried to remove the solvent to prepare drug-containing pellets.
  • Micropellets are multi-unit preparations and belong to dose-dispersed preparations. After oral administration, they form a uniformly dispersed microparticle system in the gastrointestinal tract, avoiding irritation to the gastric mucosa caused by excessive local drug concentration, which is beneficial to drug absorption, thereby improving bioavailability and reducing individual differences.
  • the drug release behavior of multi-unit preparations is the sum of the drug release behaviors of multiple small pellets that make up a dose. Defects in the preparation of individual small pellets will not have a serious impact on the drug release behavior of the entire preparation, ensuring the safety of clinical medication.
  • the components (a), (c) and (d) are dispersed and dissolved in (b) by heating and stirring at a temperature between 20°C and 80°C to form a self-emulsifying solution, wherein the component (a) comprises a compound represented by formula (I), the component (b) comprises monolinoleyl glyceryl and oleic acid, and the component (c) comprises polyoxyethylene (40) hydrogenated castor oil.
  • RH 40, component (d) is selected from diethylene glycol monoethyl ether and polyethylene glycol 400.
  • self-emulsifying capsule preparations can deliver drugs to the absorption site more quickly and uniformly.
  • they When in contact with gastrointestinal fluid, they can form small emulsions containing dissolved drugs.
  • the fine emulsions have a large interfacial area and the drugs can be maintained in a dissolved state in the gastrointestinal tract, which can better pass through the gastrointestinal mucosa, effectively increasing the bioavailability of the drugs.
  • the drugs can be absorbed not only from the submucosal capillaries, but also through the submucosal lymphatic vessels, which can further improve drug absorption and improve efficacy.
  • the production process is dust-free, less polluting, and easy to protect the environment.
  • the component (a) is dispersed and dissolved in (c) by heating and stirring at a temperature between 20°C and 80°C to form a self-emulsifying solution, wherein the component (a) comprises a compound represented by formula (I), and (c) is selected from polyoxyethylene (40) hydrogenated castor oil. RH 40, and then add other pharmaceutical excipients and press into tablets.
  • the active ingredient comprising the compound represented by formula (I) is prepared into a solid dispersion, and the auxiliary material comprises polyoxyethylene (40) hydrogenated castor oil RH 40, copolyvidone Kollidon VA64, the active ingredient and the excipients are mixed and hot-melt extruded at 80 to 200°C to prepare a solid dispersion.
  • the auxiliary material comprises polyoxyethylene (40) hydrogenated castor oil RH 40, copolyvidone Kollidon VA64, the active ingredient and the excipients are mixed and hot-melt extruded at 80 to 200°C to prepare a solid dispersion.
  • the active ingredient comprising the compound represented by formula (I) is prepared into a solubilized preparation, and the excipients include copovidone Kollidon VA64 and polyethylene glycol 6000.
  • the process is to place the physical mixture in an oven at 110°C for 10 minutes, and then grind it in a grinder at 30,000 rpm for 10 seconds, and grind it three times in total to obtain powder or granules, which are then filled into gelatin capsules.
  • the active ingredient comprising the compound represented by formula (I) is prepared into cyclodextrin inclusion capsules, and the excipients include ⁇ -cyclodextrin, purified water, and soybean oil.
  • the process is as follows: the active ingredient is mixed with ⁇ -cyclodextrin and purified water and shaken, and then soybean oil is added and mixed and shaken, and finally high shearing is performed at 16000 rpm for 1.5 minutes to obtain a white emulsion, which is then filled into gelatin capsules.
  • the active ingredient comprising the compound represented by formula (I) is prepared into an enteric preparation, and the excipients include hydroxypropyl methylcellulose acetate succinate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), which is prepared into an enteric preparation by hot melt extrusion, wherein the hot melt temperature is 135°C.
  • the excipients include hydroxypropyl methylcellulose acetate succinate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), which is prepared into an enteric preparation by hot melt extrusion, wherein the hot melt temperature is 135°C.
  • the compound represented by formula (I), copolyvidone Kollidon VA64 and hydroxypropyl methylcellulose E3 LV are dispersed and dissolved in 80% ethanol aqueous solution by stirring to form a solution.
  • the solution is sprayed into lactose or microcrystalline cellulose by fluidized bed spray granulation process at a temperature range of 20°C to 80°C, and dried to remove the solvent to prepare drug-containing granules or powder, which are filled into capsules or compressed into tablets.
  • the fluidized bed spray granulation method can make the particles more uniform, the drug and carrier excipients are more fully combined, and the preparation process is simple, energy-saving, innovatively improves the equipment, and is easy to industrialize and mass produce. Compared with the traditional premix production process, this preparation process avoids the generation of dust and static electricity.
  • Components (a) and (b) are mixed and heated and stirred at a temperature range of 20° C. to 100° C. to dissolve, and then mixed and adsorbed with component (c).
  • Component (a) includes a compound of formula I and its stereoisomers, pharmaceutically acceptable salts or deuterated compounds, (b) is polyoxyethylene (40) hydrogenated castor oil, and (c) is anhydrous calcium hydrogen phosphate or magnesium aluminum silicate.
  • relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any such actual relationship or order between these entities or operations.

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  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention concerne une composition comprenant (a) un composé de formule (I) et (b) au moins un support pharmaceutiquement acceptable.
PCT/CN2024/129952 2023-11-06 2024-11-05 Composition comprenant un phosphonate cyclique et son procédé de préparation Pending WO2025098332A1 (fr)

Applications Claiming Priority (6)

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CN202311466964 2023-11-06
CN202311466964.0 2023-11-06
US202363548074P 2023-11-10 2023-11-10
US63/548,074 2023-11-10
CN202410431293 2024-04-10
CN202410431293.2 2024-04-10

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200113863A1 (en) * 2017-06-29 2020-04-16 Yale University Compositions and Methods of Treating or Preventing Fibrotic Lung Diseases
US20210259977A1 (en) * 2020-02-20 2021-08-26 Gannex Pharma Co., Ltd. Pharmaceutical compositions comprising a thyroid hormone beta agonist, method of use and method making thereof
US20210308155A1 (en) * 2020-03-27 2021-10-07 Gannex Pharma Co., Ltd. Pharmaceutical compositions, method of making and method of using thereof
WO2023004002A1 (fr) * 2021-07-21 2023-01-26 Cyta Therapeutics, Inc. Administration de particules d'agonistes et d'antagonistes de récepteur d'hormone thyroïdienne
WO2023163795A1 (fr) * 2022-02-24 2023-08-31 Gannex Pharma Co., Ltd. Composition de phosphonate cyclique et son procédé de préparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200113863A1 (en) * 2017-06-29 2020-04-16 Yale University Compositions and Methods of Treating or Preventing Fibrotic Lung Diseases
US20210259977A1 (en) * 2020-02-20 2021-08-26 Gannex Pharma Co., Ltd. Pharmaceutical compositions comprising a thyroid hormone beta agonist, method of use and method making thereof
US20210308155A1 (en) * 2020-03-27 2021-10-07 Gannex Pharma Co., Ltd. Pharmaceutical compositions, method of making and method of using thereof
WO2023004002A1 (fr) * 2021-07-21 2023-01-26 Cyta Therapeutics, Inc. Administration de particules d'agonistes et d'antagonistes de récepteur d'hormone thyroïdienne
WO2023163795A1 (fr) * 2022-02-24 2023-08-31 Gannex Pharma Co., Ltd. Composition de phosphonate cyclique et son procédé de préparation

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Title
CABLE, E.E. ET AL.: "Reduction of Hepatic Steatosis in Rats and Mice After Treatment with a Liver-Targeted Thyroid Hormone Receptor Agonist", HEPATOLOGY, vol. 49, no. 2, 28 February 2009 (2009-02-28), XP055563720, DOI: 10.1002/hep.22572 *

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