WO2018029699A1 - Formes à l'état solide de (2e)-n-hydroxy-3-[3- (phénylsulfamoyl) phényl] prop-2-énamide et leur procédé de préparation - Google Patents

Formes à l'état solide de (2e)-n-hydroxy-3-[3- (phénylsulfamoyl) phényl] prop-2-énamide et leur procédé de préparation Download PDF

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Publication number
WO2018029699A1
WO2018029699A1 PCT/IN2017/000114 IN2017000114W WO2018029699A1 WO 2018029699 A1 WO2018029699 A1 WO 2018029699A1 IN 2017000114 W IN2017000114 W IN 2017000114W WO 2018029699 A1 WO2018029699 A1 WO 2018029699A1
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formula
compound
phenyl
prop
hydroxy
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PCT/IN2017/000114
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English (en)
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Gutta Madhusudhan
Sagyam RAJESHWAR REDDY
Revu Satyanarayana
Boge RAJESHAM
Ambati SRINIVASA RAO
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Msn Research & Development Center
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Publication of WO2018029699A1 publication Critical patent/WO2018029699A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to solid state forms of (2E)-N-hydroxy-3-[3-(phenyl sulfamoyl)phenyl]prop-2-enamide represented by the following structural formula- 1 and process for the preparation thereof.
  • the present invention also relates to process for the preparation of (2E)-N-hydroxy-3- [3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1.
  • Belinostat is marketed in US by TopoTarget under the brand name of "Beleodaq" for the treatment of hematological malignancies and solid tumors.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures.
  • the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non- crystal line form.
  • the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007).
  • one bioavailability pattern may be favored over another.
  • the first aspect of the present invention is to provide amorphous form of (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1.
  • the second aspect of the present invention is to provide a process for the preparation of amorphous form of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound o f formul a- 1.
  • the third aspect of the present invention is to provide amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1 and at least one pharmaceutically acceptable excipient.
  • the fourth aspect of the present invention is to provide process for the preparation of amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl] prop- 2-enamide compound of formula- 1 and at least one pharmaceutically acceptable excipient.
  • the fifth aspect of the present invention is to provide a process for the preparation of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1.
  • Figure-1 Illustrates the PXRD pattern of amorphous (2E)-N-hydroxy-3-[3-(phenyl sulfamoyI)phenyl]prop-2-enamide compound of formula-1 obtained according to example- 1.
  • Figure-2 Illustrates the PXRD pattern of amorphous (2E)-N-hydroxy-3- [3 -(phenyl sulfamoyl)phenyl]prop-2-enamide compound of formula-1 obtained according to example-2.
  • Figure-3 Illustrates the PXRD pattern of amorphous solid dispersion comprising (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1 and PVP-K- 30.
  • Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1 and HPMC.
  • Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1 and HPC.
  • Figure-6 Illustrates the PXRD pattern of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl] prop-2-enamide compound of formula-1 obtained according to reference example- 1.
  • suitable solvent used in the present invention can be selected from but not limited to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as di
  • the first aspect of the present invention provides an amorphous form of (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1.
  • the amorphous form of (2E)-N-hydroxy-3- [3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1 is characterized by its P-XRD pattern as illustrated in figure- 1.
  • the second aspect of the present invention provides a process for the preparation of amorphous form of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1, comprising of:
  • the suitable solvent can be selected from but not limited to chloro solvents, ketone solvents, C 1 -C 6 alcohol solvents, ester solvents, nitrile solvents, ether solvents or their mixtures; and the dissolution of compound of formula-1 in a suitable solvent or mixture of solvents can be carried out at 25-30°C or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed;
  • suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any other suitable techniques.
  • a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any
  • the solvent may be removed at temperatures ranging from 25°C to 100°C optionally under reduced pressures.
  • the preferred embodiment of the present invention provides a process for the preparation of amorphous form of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2- enamide compound of formula- 1, comprising of:
  • step-b) distilling the solvent from the filtrate obtained in step-b) to provide amorphous form of (2E)-N-hydroxy-3-[3 -(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1.
  • step-b) spray drying the filtrate obtained in step-b) to provide amorphous form of (2E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1.
  • the third aspect of the present invention is to provide amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1 and at least one pharmaceutically acceptable excipient.
  • the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS),
  • the fourth aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl] prop- 2-enamide compound of formula- 1 and at least one pharmaceutically acceptable excipient, the said process comprising of:
  • the suitable excipient is same as defined in the third aspect of the present invention;
  • the suitable solvent is same as defined in step-a) of the second aspect of the present invention;
  • the suitable temperature ranges from 0°C to reflux temperature of the solvent used;
  • the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution
  • step-b) the suitable techniques which may be used for the removal of solvent from the reaction mixture are same as defined in step-c) of the second aspect of the present invention.
  • the solvent may be removed at temperatures ranging from 25°C to 100°C optionally under reduced pressures.
  • the ratio of the amount of weight of (2E)-N-hydroxy-3-[3- (phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1 within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1 :0.05 to about 1 :5.
  • the (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula- 1 utilized as starting material in the present invention can be prepared according to the present invention or by any of the process known in the art.
  • the fifth aspect of the present invention provides a process for the preparation of (2E)- N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1, comprising of the following steps:
  • the suitable base is selected from organic or inorganic base
  • the suitable reducing agent is selected from Fe, Fe in acidic media like NH 4 Cl or
  • HC1 or acetic acid Sn in acidic media like HC1, Zn dust, Zn in acidic media like HC1 or NH 4 Cl or acetic acid, stannous chloride (SnCh), NaBH 4 , LiAIH 4 , LiBH 4 , diborane, borane-
  • THF complex hydrazine hydrate
  • hydrogenation catalysts such as Pd/C, Pt/C, PtCO 2 Pd(OH) 2 ,
  • the suitable solvent is selected from alcohol solvents, ester solvents, chloro solvents, hydrocarbon solvents, ketone solvents, ether solvents, nitrile solvents, polar aprotic solvents and polar solvents like water and mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide compound of formula-1, comprising of the following steps: a) Reacting 3-nitrobenzaldehyde compound of formula-2 with methyl 2-(dimethoxy phosphoryl)acetate compound of formula-3 in presence of potassium carbonate in methanol to provide methyl (2E)-3-(3-nitrophenyl)acrylate compound of formula-4, b) reducing the compound of formula-4 with iron and ammonium chloride in a mixture of ethyl acetate and water to provide methyl (2E)-3-(3-aminophenyl)acrylate compound of formula-5,
  • US6888027 B2 discloses process for the preparation of (2E)-N-hydroxy-3-[3-(phenyl sulfamoyl)phenyl]prop-2-enamide compound of formula- 1 which involves longer reaction time, expensive and toxic reagents and reaction solvents like pyridine, benzene, chloroform, cumbersome workups, tedious column chromatography purifications and provides intermediate compounds as well as (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2- enamide compound of formula- 1 with lower yields and purity.
  • the present invention is simple, involves cheaper and mild reagents and solvents easy to handle on the commercial scale.
  • the present invention is cost effective, avoids toxic reagents and more advantageous when compared over the prior art process.
  • solid state forms of compound of formula- 1 of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
  • solid state forms of compound of formula- 1 of the present invention can be micronized to achieve the desired better particle size distribution in order to make suitable formulation.
  • the rocess of the present invention is represented schematically as below:
  • PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • PSD method of Analysis Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • Example-1 Preparation of amorphous form of (2E)-N-hydroxy-3-[3-(phenylsuIfamoyl) phenyl]prop-2-enamide: (Formula-1)
  • Example-2 Preparation of amorphous form of (2E)-N-hydroxy-3-[3-(phenylsuIfamoyl) phenyl] prop-2-enamide: (Formula-1)
  • the obtained solid was collected from the spray dryer and dried at 40-45°C under vacuum to get the title compound.
  • Example-4 Preparation of amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3- (phenyIsulfamoyl)phenyl]prop-2-enamide and hydroxypropyl methylcellulose (HPMC) (1:1)
  • Example-5 Preparation of amorphous solid dispersion comprising (2E)-N-hydroxy-3-[3- (phenylsulfamoyl)phenyl]prop-2-cnarnide and hydroxypropylcellulose (HPC) (1:1)
  • Example-8 Preparation of methyl (2E)-(3-(N-phenylsulfamoyl)phenyl)acrylate: (Formula-7)
  • Hydroxyl amine hydrochloride (105.1 gms) was added to a mixture of sodium hydroxide (105.8 gms) and water (360 ml) at 0-5 °C and stirred for 10 minutes at the same temperature.
  • the reaction mixture was slowly added to a mixture of methanol (360 ml) and methyl (2E)-(3-(N-phenylsulfamoyl)phenyl)acrylate (120 gms) at - 10 to -15°C and stirred for 5 hours at the same temperature. Water was slowly added to the reaction mixture at -10 to - 15°C. Reaction mixture was neutralized using hydrochloric acid solution at 0-5°C.
  • Example-10 Purification of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2- enamide: (Formula-1) A mixture of acetone (300 ml), water (200 ml) and (2E)-N-hydroxy-3-[3- (phenylsulfamoyl) phenyl]prop-2-enamide (100 gms) was stirred for 30 minutes at 25-30°C. Filtered the reaction mixture and washed with acetone and water mixture. Water (1000 ml) was slowly added to the obtained filtrate at 25-30°C within 60 minutes and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
  • Particle size distribution D(10) is 4.73 ⁇ m; D(50) is 17.9 ⁇ m; D(90) is 60.23 ⁇ .

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Abstract

La présente invention concerne des formes à l'état solide de (2E)-N-hydroxy-3-[3- (N-phényl sulfamoyl) phényl] prop-2-énamide représenté par la formule structurale suivante 1 et son procédé de préparation.
PCT/IN2017/000114 2016-08-11 2017-08-11 Formes à l'état solide de (2e)-n-hydroxy-3-[3- (phénylsulfamoyl) phényl] prop-2-énamide et leur procédé de préparation WO2018029699A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110314146A (zh) * 2019-08-11 2019-10-11 天津乾丰瑞科技有限公司 一种含有活性成分左亚叶酸钙的药物组合物
JP2020525499A (ja) * 2017-06-30 2020-08-27 オンクセオＯｎｘｅｏ ベリノスタットの新規経口製剤

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2006120456A1 (fr) * 2005-05-13 2006-11-16 Topotarget Uk Limited Formulations pharmaceutiques d'inhibiteurs de hdac
WO2009040517A2 (fr) * 2007-09-25 2009-04-02 Topotarget Uk Limited Procédés de synthèse de certains composés d'acide hydroxamique

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2006120456A1 (fr) * 2005-05-13 2006-11-16 Topotarget Uk Limited Formulations pharmaceutiques d'inhibiteurs de hdac
WO2009040517A2 (fr) * 2007-09-25 2009-04-02 Topotarget Uk Limited Procédés de synthèse de certains composés d'acide hydroxamique

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Title
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LEI YANG ET AL.: "Simple and Efficient Synthesis of Belinostat", SYNTHETIC COMMUNICATIONS, vol. 1, no. 40, 5 August 2010 (2010-08-05), pages 2520 - 2524, XP005543915, ISSN: 0039-7911, Retrieved from the Internet <URL:https://DOI.org/10.1080/00397910903277870> *
LEUNER C. ET AL.: "Improving drug solubility for oral delivery using solid dispersions", EUR. J. PHARM. BIOPHARM., vol. 50, no. 1, July 2000 (2000-07-01), pages 47 - 60, XP004257179 *
XUEFEI BAO , DAKE SONG ET AL.: "The Development of an Effective Synthetic Route of Belinostat", ORG. PROCESS RES. DEV., vol. 20, no. 8, 12 July 2016 (2016-07-12), Route C, pages 1482 - 1488, XP055411617 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020525499A (ja) * 2017-06-30 2020-08-27 オンクセオＯｎｘｅｏ ベリノスタットの新規経口製剤
JP7247122B2 (ja) 2017-06-30 2023-03-28 アクロテック バイオファーマ リミティド ライアビリティ カンパニー ベリノスタットの新規経口製剤
AU2018294561B2 (en) * 2017-06-30 2023-12-07 Acrotech Biopharma, Inc. New oral formulations of belinostat
CN110314146A (zh) * 2019-08-11 2019-10-11 天津乾丰瑞科技有限公司 一种含有活性成分左亚叶酸钙的药物组合物

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