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WO2018167652A1 - Procédé de préparation d'une forme amorphe du vénétoclax - Google Patents

Procédé de préparation d'une forme amorphe du vénétoclax Download PDF

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Publication number
WO2018167652A1
WO2018167652A1 PCT/IB2018/051641 IB2018051641W WO2018167652A1 WO 2018167652 A1 WO2018167652 A1 WO 2018167652A1 IB 2018051641 W IB2018051641 W IB 2018051641W WO 2018167652 A1 WO2018167652 A1 WO 2018167652A1
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Prior art keywords
venetoclax
amorphous form
solution
water
solvent
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Ceased
Application number
PCT/IB2018/051641
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English (en)
Inventor
Uma Maheswer Rao VASIREDDI
Srinivasa Rao BUDDEPU
Sanjay Kumar Dehury
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Laurus Labs Pvt Ltd
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Laurus Labs Pvt Ltd
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Publication of WO2018167652A1 publication Critical patent/WO2018167652A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention generally relates to processes for preparation of amorphous form of Venetoclax and pharmaceutical composition containing the same.
  • Venetoclax also known as 4-(4- ⁇ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl ⁇ piperazin-l-yl)-N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4yl-methyl)-amino]- phenyl ⁇ sulfonyl)-2-(lH-pyrrolo[2,3- ⁇ ]pyridin-5-yloxy)benzamide) of Formula I:
  • Venetoclax is marketed by Abbvie under the trade name Venclexta in US and Venclyxto ® in EP for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.
  • CLL chronic lymphocytic leukemia
  • U.S. Patent No. 8,546,399 discloses venetoclax and process for preparation thereof.
  • the '399 patent process involves purification of venetoclax as a solid by column chromatography using a mixture of 25- 100% ethyl acetate/hexanes and then with a mixture of 10% methanol/ethyl acetate with 1% acetic acid to obtain venetoclax as a white solid.
  • the '399 patent does not disclose any polymorphic information on resulted venetoclax. Repetition of the '399 patent process by the present inventors and found that venetoclax obtained as an amorphous form and the same was characterized by XRD.
  • U.S. Patent No. 8,722,657 discloses crystalline forms including solvates of venetoclax such as anhydrate Pattern A, anhydrate Pattern B, hydrate pattern C, hydrate pattern D, methylene chloride solvate (pattern E), ethyl acetate solvate (pattern F), acetonitrile solvate (pattern G & I), acetone solvate (pattern J), tetrahydrofuran solvate (pattern N), and venetoclax salts such as crystalline venetoclax HC1 salt (pattern K), HC1 hydrate (pattern L), sulfate salt (pattern M) and its characterization data by PXRD.
  • solvates of venetoclax such as anhydrate Pattern A, anhydrate Pattern B, hydrate pattern C, hydrate pattern D, methylene chloride solvate (pattern E), ethyl acetate solvate (pattern F), acetonitrile solvate (pattern G & I),
  • PCT publication No. 2017/063572 discloses crystalline forms of venetoclax such as Form B, Form D, Form F, Form G and its process for preparation.
  • PCT publication No. 2017/156398 discloses crystalline forms and solvates of venetoclax such as Form 1 (MIBK mono solvate), Form 2 (anhydrous), Form 2A (cyclohexane solvate), Form 3 (toluene mono solvate), Form 4, Form 5 (anhydrous), Form 6 (MIBK hemi solvate), Form 7 (n-propyl acetate mono solvate), Form 8 (anhydrous), Form 9 (dimethyl carbamate solvate), Form 10 (dioxane solvate), Form 11 (isobutyl acetate solvate), Form 12, Form 13 (dimethyl carbonate solvate), Form 14, Form 15 (methyl ethyl ketone solvate) and its process for preparation.
  • Form 1 MIBK mono solvate
  • Form 2A cyclohexane solvate
  • Form 3 toluene mono solvate
  • Form 4 discloses crystalline forms and solvates of venetoclax
  • PCT publication No. 2017/212431 discloses crystalline forms of venetoclax such as Form RTl, Form RT2, Form RT3, Form RT4 and Form RT5.
  • the '431 publication also discloses a process for preparation of amorphous form of venetoclax from dichloromethane and from a mixture of dichloromethane/methanol, and dimethylsulfoxide/ water.
  • PCT publication No. 2017/029711 discloses a process for preparation of amorphous form of venetoclax from acetonitrile.
  • solid forms are possible for some compounds.
  • a single compound may exist in different solid forms.
  • Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability.
  • solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substance.
  • Amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)].
  • the more crystalline the pharmaceutical agent the lower is its bioavailability or vice versa, reducing the degree of crystallinity has a positive effect on bioavailability.
  • Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability.
  • the present invention encompasses processes for the preparation of amorphous form of venetoclax with high product yield and quality, and greater stability.
  • the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
  • step b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
  • the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
  • a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
  • the one or more solvents are selected from the group consisting of alcohols, ketones, esters, nitriles, ethers, sulfoxides, amides and the like and mixtures thereof;
  • the suitable anti-solvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
  • the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
  • step b) adding water to the step a) solution or vice- versa;
  • the present invention provides an amorphous form of venetoclax having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC).
  • the present invention provides a pharmaceutical composition comprising amorphous form of venetoclax prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous venetoclax prepared according to reference example.
  • Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous venetoclax.
  • the present invention provides a process for the preparation of amorphous from of venetoclax and pharmaceutical compositions containing the same.
  • the amorphous from of venetoclax of the present invention obtained by process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern.
  • the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
  • step b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
  • the starting material venetoclax used in the present invention is known in the art and can be prepared by any known methods, for example venetoclax may be synthesized as disclosed in U.S. Patent No. 8,546,399.
  • the starting venetoclax used herein in step a) may be any crystalline or other form of venetoclax, including various solvates, hydrates, salts and cocrystals as long as amorphous venetoclax is produced during the process of the invention or venetoclax obtaining as existing solution from a previous processing step.
  • Step a) of providing a solution of venetoclax may include dissolving any form of venetoclax in one or more solvents.
  • the one or more solvents include, but are not limited to alcohols, ketones, esters, nitriles, ethers, sulfoxides, amides and the like and mixtures thereof.
  • the alcohols include but are not limited to methanol, ethanol, isopropanol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; amides include, but are not limited to di
  • the step a) reaction may optionally be heated to dissolve all solids in one or more solvents.
  • the dissolution temperature for the venetoclax may range from about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 25°C to about 80°C.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • Step b) of the aforementioned process involves precipitation of amorphous form of venetoclax by either addition of suitable anti- solvent to the venetoclax solution of step a) or addition of step a) solution of venetoclax into a suitable anti-solvent; preferably precipitation of amorphous form of venetoclax is carried out by addition of step a) solution of venetoclax into a suitable anti- solvent.
  • an optional step of precooling the antisolvent to less than 10°C.
  • the step b) is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C. Then the resultant mass is stirred for sufficient period of time, preferably for a period of about 30 min to 5 hours. Typically, if stirring is involved, the temperature during stirring can range from about 0°C to about 15°C and the resultant product may optionally be further dried at a temperature of about 50°C to about 85°C.
  • the suitable anti- solvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
  • the ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, 1,4- dioxane and the like;
  • aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like;
  • alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably water.
  • the isolation of the resultant product is accomplished by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere.
  • the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin- film drying; preferably isolated by filtration.
  • the resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 20 hours.
  • Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like; preferably drying is carried out under vacuum at a temperature of about 50°C to about 75°C for about 2 hours to 10 hours.
  • the venetoclax recovered using the process of the present invention is in the form of substantially pure amorphous form.
  • the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
  • step b) adding water to the step a) solution or vice- versa;
  • the starting material venetoclax used in the present invention is known in the art and can be prepared by any known methods, for example venetoclax may be synthesized as disclosed in U.S. Patent No. 8,546,399.
  • the starting venetoclax used herein the step a) may be any crystalline or other form of venetoclax, including various solvates, hydrates, salts and cocrystals as long as amorphous venetoclax is produced during the process of the invention or venetoclax obtaining as existing solution from a previous processing step.
  • the step of providing a solution of venetoclax may include dissolving any form of venetoclax in acetone.
  • the step a) reaction may optionally be heated to dissolve all solids in one or more solvents.
  • the dissolution temperature for the venetoclax may range from about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 35°C to about 65 °C.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • Step b) of the aforementioned process involves precipitation of amorphous form of venetoclax by either addition of water to the venetoclax solution of step a) or addition of step a) solution of venetoclax into water; preferably precipitation of amorphous form of venetoclax is carried out by addition of step a) solution of venetoclax into water.
  • an optional step of precooling the antisolvent to less than 10°C prior to combining of step a) solution and the antisolvent.
  • addition of water is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C.
  • the resultant mass is stirred for sufficient period of time, preferably for a period of about 30 min to 5 hours.
  • the temperature during stirring can range from about 0°C to about 15°C and the resultant product may optionally be further dried at a temperature of about 50°C to about 85°C.
  • the isolation of the resultant product is accomplished by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere.
  • the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin- film drying; preferably isolated by filtration.
  • the resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 20 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like; preferably drying is carried out under vacuum at a temperature of about 50°C to about 75°C for about 2 hours to 10 hours.
  • the amorphous form of venetoclax is stable during storage. This property is important and advantageous for the desired use of venetoclax in pharmaceutical product formulations.
  • the amorphous form of venetoclax of the present invention has commercially acceptable pharmacokinetic characteristics, solubility, flow properties, stability, and the like.
  • the products may optionally be milled to get the desired particle size distributions. Milling or micronization may be performed prior to drying, or after the completion of drying of the products.
  • the present invention further provides an amorphous form of venetoclax, having a chemical purity of 98% or more as measure by HPLC, preferably 99% or more, more preferably 99.8% or more.
  • the amorphous form of venetoclax may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities.
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of venetoclax with at least one pharmaceutically acceptable carrier or other excipients.
  • the present invention further provides, when a pharmaceutical composition comprising amorphous from of venetoclax prepared according to the present invention is formulated for oral administration or parenteral administration.
  • D50 and D90 particle size of the unformulated amorphous venetoclax of the present invention used as starting material in preparing a pharmaceutical composition generally is less than 300 microns preferably less than about 200 microns, more preferably less than 100 microns, still more preferably less than about 50 microns and still more preferably less than about 10 microns.
  • any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the solid state amorphous venetoclax of the present invention into any desired particle size range as set forth above.
  • Amorphous venetoclax described in the present invention may be formulated into solid pharmaceutical products for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active ingredient is combined with one or more pharmaceutically acceptable excipients.
  • the drug substance also may be formulated into liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffins.
  • compositions for parenteral administration may be suspensions, emulsions or aqueous or non-aqueous, sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • Suitable pharmaceutical compositions are solid dosage forms, such as tablets with immediate release or sustained release of the active principle, effervescent tablets or dispersion tablets and capsules.
  • compositions include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium phosphate dibasic, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, maltose, dextrose and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose and starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, polacrilin potassium, polacrilin sodium and silicified microcrystalline cellulose; lubricants such as sodium stearyl fumarate, stearic acid, talc, magnesium
  • amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of venetoclax and additional excipient.
  • the additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of venetoclax.
  • Additional excipient may include, but not limited to an inorganic oxide such as Si0 2 , Ti0 2 , Zn0 2 , Zno, A1 2 0 3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/poly vinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross- linked styrene divinyl benzene or any other excipient at any aspect of present application.
  • an inorganic oxide such as Si0 2 , Ti0 2 , Zn0 2 , Zno, A1 2 0 3 and zeolite
  • a water insoluble polymer is selected from the group consisting of cross-linked polyviny
  • Venetoclax (1 g) was dissolved in a mixture of 10% methanol in ethyl acetate with 1% acetic acid (20 mL) at ambient temperature. The solvent was distilled completely at below 50°C under vacuum in a Buchi Rotavapor and maintained for about 15 min after complete evaporation. The obtained solids were dried at 60-70°C under vacuum for 10 hrs. Yield: 0.8 g.
  • Amorphous Form obtained according to the reference examples was analyzed by PXRD and is represented according to Fig. 1.
  • Acetonitrile (20 mL) and venetoclax (1 gm) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred the solution at same temperature and the resulting solution was filtered and added to pre cooled water (100 mL) at 2°C to 8°C. Stirred for about 1 to 2 hours at this temperature and the precipitated solid was filtered and washed with water (10 mL), dried the solid in an oven under vacuum at 60°C-70°C for about 4 hrs. Yield: 0.9 g.
  • Acetone (10 mL) and venetoclax (1 gm) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 50°C to 55°C and stirred the solution at same temperature and the resulting solution was filtered and added to pre cooled water (100 mL) at 2°C to 8°C. Stirred for about 1 to 2 hours at this temperature and the precipitated solid was filtered and washed with water (10 mL), dried the solid in an oven under vacuum at 60°C-70°C for about 4 hrs. Yield: 0.93 g; HPLC Purity: 99.9%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une forme amorphe du 4-(4-{[2-(4-chlorophényl)-4,4-diméthylcyclohex-1-én-1-yl]méthyl}pipérazin-1-yl)-N-({3-nitro-4-[(tétrahydro-2H-pyran-4yl-méthyl)-amino]-phényl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (vénétoclax) et une composition pharmaceutique la contenant.
PCT/IB2018/051641 2017-03-13 2018-03-13 Procédé de préparation d'une forme amorphe du vénétoclax Ceased WO2018167652A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020127503A1 (fr) 2018-12-18 2020-06-25 Argenx Bvba Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
WO2020225738A1 (fr) * 2019-05-07 2020-11-12 Alembic Pharmaceuticals Limited Composition pharmaceutique comprenant du vénétoclax
WO2022043538A1 (fr) 2020-08-29 2022-03-03 argenx BV Méthode de traitement de patients ayant une sensibilité réduite à un inhibiteur de bcl-2
CN117771177A (zh) * 2023-08-02 2024-03-29 首都医科大学附属北京儿童医院 维奈克拉自微乳化释药系统及其制备方法和应用
WO2025114919A1 (fr) 2023-11-28 2025-06-05 Sanofi Polythérapie par activation de cellules tueuses naturelles multifonctionnelles (nk) pour le traitement de troubles néoplasiques hématologiques

Citations (5)

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US8546399B2 (en) * 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US8580794B2 (en) * 2009-05-26 2013-11-12 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US8722657B2 (en) * 2010-11-23 2014-05-13 Abbvie Inc. Salts and crystalline forms of an apoptosis-inducing agent
WO2017212431A1 (fr) * 2016-06-09 2017-12-14 Dr. Reddy’S Laboratories Limited Formes solides de vénétoclax et procédés de préparation de vénétoclax
WO2018069941A2 (fr) * 2016-10-14 2018-04-19 Mylan Laboratories Limited Formes polymorphes de vénétoclax

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8546399B2 (en) * 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US8580794B2 (en) * 2009-05-26 2013-11-12 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US8722657B2 (en) * 2010-11-23 2014-05-13 Abbvie Inc. Salts and crystalline forms of an apoptosis-inducing agent
WO2017212431A1 (fr) * 2016-06-09 2017-12-14 Dr. Reddy’S Laboratories Limited Formes solides de vénétoclax et procédés de préparation de vénétoclax
WO2018069941A2 (fr) * 2016-10-14 2018-04-19 Mylan Laboratories Limited Formes polymorphes de vénétoclax

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020127503A1 (fr) 2018-12-18 2020-06-25 Argenx Bvba Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
EP4218761A1 (fr) 2018-12-18 2023-08-02 Argenx BVBA Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
WO2020225738A1 (fr) * 2019-05-07 2020-11-12 Alembic Pharmaceuticals Limited Composition pharmaceutique comprenant du vénétoclax
WO2022043538A1 (fr) 2020-08-29 2022-03-03 argenx BV Méthode de traitement de patients ayant une sensibilité réduite à un inhibiteur de bcl-2
CN117771177A (zh) * 2023-08-02 2024-03-29 首都医科大学附属北京儿童医院 维奈克拉自微乳化释药系统及其制备方法和应用
WO2025114919A1 (fr) 2023-11-28 2025-06-05 Sanofi Polythérapie par activation de cellules tueuses naturelles multifonctionnelles (nk) pour le traitement de troubles néoplasiques hématologiques

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