WO2021169974A1 - Composition pharmaceutique combinée permettant de résister aux lymphomes à double impact et son utilisation - Google Patents

Composition pharmaceutique combinée permettant de résister aux lymphomes à double impact et son utilisation Download PDF

Info

Publication number
WO2021169974A1
WO2021169974A1 PCT/CN2021/077567 CN2021077567W WO2021169974A1 WO 2021169974 A1 WO2021169974 A1 WO 2021169974A1 CN 2021077567 W CN2021077567 W CN 2021077567W WO 2021169974 A1 WO2021169974 A1 WO 2021169974A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
combination
combined
double
combined pharmaceutical
Prior art date
Application number
PCT/CN2021/077567
Other languages
English (en)
Chinese (zh)
Inventor
徐兵
袁德琳
鲁先平
李志峰
查洁
赵海军
Original Assignee
厦门大学附属第一医院
深圳微芯生物科技股份有限公司
成都微芯药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 厦门大学附属第一医院, 深圳微芯生物科技股份有限公司, 成都微芯药业有限公司 filed Critical 厦门大学附属第一医院
Publication of WO2021169974A1 publication Critical patent/WO2021169974A1/fr

Links

Images

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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the application belongs to the field of biomedicine, and specifically relates to a combined pharmaceutical composition for anti-double-hit lymphoma and its application.
  • Diffuse large B-cell lymphoma is the most common non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of NHL cases.
  • BCL2, BCL6 and MYC are the most common mutant genes in DLBCL.
  • Double-hit lymphomas are a group of high-grade B-cell lymphomas with simultaneous chromosomal translocations of MYC and BCL2 or BCL6.
  • BCL2 and MYC gene translocations are the most common, accounting for 62 of all DHL. %about.
  • DHL World Health Organization
  • BBL diffuse large B-cell lymphoma
  • BCLU Burkitt lymphoma
  • DHL is not sensitive to traditional chemotherapy. Whether it is an enhanced regimen or a regimen containing rituximab, the effect is unsatisfactory, with a median overall survival of 0.2-1.5 years.
  • the incidence is low, and there is a lack of large-scale clinical studies at home and abroad.
  • the treatment plan includes CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), R-CHOP (rituximab, Cyclophosphamide, vincristine, doxorubicin, prednisone), R-Hyper CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose chemotherapy Combining hematopoietic stem cell transplantation, palliative treatment, etc., which chemotherapy regimen is better is still controversial.
  • This application provides a combined pharmaceutical composition for anti-double-hit lymphoma and its application.
  • this application provides a combined pharmaceutical composition for anti-double-hit lymphoma.
  • the combined pharmaceutical composition includes the drug Venetoclax and the drug Chiauranib.
  • Venetoclax (ABT-199) is a highly effective, selective and orally active Bcl-2 inhibitor that can be combined with obinutuzumab to treat untreated adult patients with chronic lymphocytic leukemia (CLL).
  • Chiauranib (CS2164, Cioroni) is a highly selective inhibitor of AuroraB/VEGFR/PDGFR/c-Kit/CSF1R targets. It can simultaneously inhibit tumor angiogenesis, inhibit tumor cell mitosis, and regulate tumor microenvironment. Play a comprehensive anti-tumor effect, and at the same time have better animal pharmacodynamic activity and good safety than drugs of the same mechanism. It is currently in clinical stage I/II (ovarian cancer).
  • This application creatively uses the drug Venetoclax and the drug Chiauranib as a combined drug composition for anti-double-strike lymphoma, which has a significant killing effect on a variety of DHL cell lines (such as TMD8, MCA, LY19, etc.), and presents a concentration And time-dependent, the results of the in vivo tumor formation experiment also proved that it can inhibit the growth of DHL cells in the body, reduce the tumor burden and the degree of infiltration, and has no obvious side effects.
  • DHL cell lines such as TMD8, MCA, LY19, etc.
  • the dosage form of the combined pharmaceutical composition includes any pharmaceutically acceptable dosage form.
  • any pharmaceutically acceptable dosage form for example, tablets, powders, suspensions, capsules, injections, sprays, solutions, enemas, emulsions, films, suppositories, patches, nasal drops or pills, etc.
  • the combined pharmaceutical composition further includes any one or a combination of at least two of the pharmaceutically acceptable pharmaceutical excipients.
  • the combination pharmaceutical composition described in the present application can be administered alone or in combination with adjuvants to form an appropriate dosage form for administration.
  • the adjuvants include diluents, binders, wetting agents, disintegrants, emulsifiers, and adjuvants. Any one or a combination of at least two of solvents, solubilizers, osmotic pressure regulators, surfactants, pH regulators, antioxidants, bacteriostatic agents, or buffers.
  • the at least two combinations such as the combination of a diluent and a binder, a combination of a wetting agent and a disintegrant, a combination of a solubilizer and an osmotic pressure regulator, etc., other arbitrary combinations will not be repeated here.
  • the combined pharmaceutical composition is a single compound preparation.
  • the combined pharmaceutical composition is a combination of two separate formulations, Venetoclax formulation and Chiauranib formulation.
  • the two separate formulations are administered simultaneously.
  • the two separate formulations are administered sequentially.
  • the combined pharmaceutical composition may be in the form of a single compound preparation, or a combination of two separate preparations; when it is a combination of two separate preparations, the mode of administration may be simultaneous administration or sequential administration
  • the mode of administration may be simultaneous administration or sequential administration
  • Venetoclax can be administered first and Chiauranib can be administered after a period of time
  • Chiauranib can be administered first and Venetoclax can be administered after a period of time, or the two can be administered alternately.
  • the administration route of the combined pharmaceutical composition includes intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration, or transdermal administration.
  • the combined pharmaceutical composition is a combined pharmaceutical composition loaded on a pharmaceutical carrier.
  • the pharmaceutical carrier includes liposomes, micelles, dendrimers, microspheres or microcapsules.
  • the present application provides an application of the combination pharmaceutical composition as described above in the preparation of an anti-double-strike lymphoma drug.
  • this application provides an application of the above-mentioned combination pharmaceutical composition in the preparation of a double-hit lymphoma cell proliferation inhibitor.
  • the present application provides an application of the combination pharmaceutical composition as described above in the preparation of a double-hit lymphoma cell apoptosis inducer.
  • the combination pharmaceutical composition involved in this application induces cell apoptosis by activating the mitochondrial-mediated intrinsic pathway, and the mitochondrial membrane potential after treatment with the combination pharmaceutical composition is significantly reduced, and it also affects Bcl-2, Bcl-xL, and BAX. , The expression level of PUMA and PARP.
  • the present application provides an application of the above-mentioned combination pharmaceutical composition in preparing double-hit lymphoma cells PI3K-AKT-mTOR signaling pathway or DNA damage repair pathway inhibitor.
  • the anti-double-hit lymphoma of the combined pharmaceutical composition may be related to the inhibition of the PI3K-AKT-mTOR pathway or the DNA damage repair pathway.
  • this application provides a novel combination therapy against double-hit lymphoma, the combination therapy being a combination therapy of Venetoclax and Chiauranib.
  • This therapy has stronger anti-double-strike lymphoma activity than single Venetoclax therapy or Chiauranib therapy, and can more effectively inhibit the growth of tumors in vivo, providing new strategies and ideas for the treatment of double-strike lymphoma.
  • This application creatively uses the drug Venetoclax and the drug Chiauranib as a combined drug composition for anti-double-strike lymphoma, which has a significant killing effect on a variety of DHL cell lines (such as TMD8, MCA, LY19, etc.), and presents a concentration And time-dependent, the results of the in vivo tumor formation experiment also proved that it can inhibit the growth of DHL cells in the body, reduce the tumor burden and the degree of infiltration, and has no obvious side effects.
  • DHL cell lines such as TMD8, MCA, LY19, etc.
  • Figure 1 is the result of CCK8 method detecting the inhibitory effect of drugs on the proliferation of MCA cells for 24 hours;
  • Figure 2 is the result of CCK8 method detecting the inhibitory effect of drugs on the proliferation of TMD8 cells for 24 hours;
  • Figure 3 is a graph showing the results of the CCK8 method detecting the inhibitory effect of the drug on the proliferation of MCA cells for 48 hours;
  • Figure 4 is the result of CCK8 method detecting the inhibitory effect of drugs on the proliferation of TMD8 cells for 48 hours;
  • Figure 5 is a graph showing the results of MCA cell apoptosis induced by Annexin V/PI kit after 24 hours of drug action;
  • Figure 6 is a graph showing the results of the Annexin V/PI kit detecting the apoptosis of TMD8 cells after 24 hours of drug action;
  • Figure 7 is a graph showing the results of the Annexin V/PI kit detecting the apoptosis of MCA cells after 48 hours of drug action;
  • Fig. 8 is a graph showing the result of apoptosis of TMD8 cells induced by Annexin V/PI kit after 48 hours of drug action;
  • Figure 9 is a diagram of each group of mice and their removed tumor bodies in Example 3.
  • Figure 10 is a graph of changes in tumors of each group of mice (a is a graph of changes in tumor volume, b is a graph of changes in tumor weight);
  • Figure 11 is a graph showing changes in body weight of mice in each group.
  • Figure 12 is a graph showing the results of HE staining of tumor tissues in each group of mice.
  • Figure 13 is a graph showing the effect of each group of drugs on the expression level of PI3K-AKT-mTOR signal pathway after 24 hours of action on MCA cells;
  • Figure 14 is a graph showing the effect of each group of drugs on the expression level of PI3K-AKT-mTOR signal pathway after acting on LY19 cells for 24 hours;
  • Figure 15 is a graph showing the statistical results of mitochondrial membrane potential of each group of drugs acting on MCA cells for 24 hours;
  • Figure 16 is a graph showing the effect of each group of drugs on the expression levels of Bcl-2, Bcl-xL, BAX, PUMA and PARP after acting on MCA cells for 24 hours;
  • Figure 17 is a graph showing the effect of each group of drugs on the expression levels of Bcl-2, Bcl-xL, BAX, PUMA and PARP after acting on LY19 cells for 24 hours;
  • Figure 18 is a graph showing the effect of each group of drugs on the expression levels of ⁇ H2A.X and Rad51 proteins after acting on MCA cells for 24 hours;
  • Figure 19 is a graph showing the effect of each group of drugs on the expression levels of ⁇ H2A.X and Rad51 proteins after acting on LY19 cells for 24 hours.
  • a CI less than 1 indicates a synergistic effect, and a CI greater than 1 means antagonistic effect, CI equal to 1 means superimposing effect, the smaller the CI value, the stronger the synergistic effect of the two drugs on cytotoxicity.
  • MCA 24h Figure 1
  • TMD8 24h Figure 2
  • MCA 48h Figure 3
  • TMD8 48h Figure 4
  • the combination index value (CI) of Chiauranib and Venetoclax in the combination pharmaceutical composition involved in this application is shown in Table 1 and Table 2. From the data in Table 1 and Table 2, it can be seen that the combination of the two drugs has a certain synergistic effect, especially After 48h of drug treatment.
  • SPF-grade nude mice were purchased from Shanghai Slack, 4-6 weeks old, half male and half male. All operations on the mice were performed in a sterile laminar flow chamber. Suspend MCA cells in 0.2mL medium containing 0.5% FBS (5 ⁇ 10 6 cells per 0.2mL), and inoculate them under the skin of the right forelimb of mice. When the tumor volume grows to 75-150mm 3 , the body can be started Medication experiment.
  • Control group (reagent is normal saline), Venetoclax group (20 ⁇ g/g/day), Chiauranib group (40 ⁇ g/g/day), Venetoclax combined with Chiauranib group, administered daily for two weeks, monitoring mice every two days Body weight and tumor size.
  • mice were directly euthanized and the tumors were taken and photographed, as shown in Figure 9 (it can be seen from the figure that the combined pharmaceutical composition involved in this application can significantly inhibit the growth of tumors in the body), and used for calculation Weight and pathological section.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Sont divulguées, une composition pharmaceutique combinée destinée aux lymphomes à double impact et son utilisation. La composition pharmaceutique combinée comprend le médicament Vénétoclax et le médicament Chiauranib. Le médicament Vénétoclax et le médicament Chiauranib sont combinés de manière créative afin d'être utilisés sous forme de la composition pharmaceutique combinée pour résister aux lymphomes à double impact. Il a été découvert que la composition pharmaceutique combinée présente des effets de destruction considérables sur diverses souches de cellules DHL, et présente une dépendance à la concentration et une dépendance au temps ; le résultat de recherche d'expériences de formation de tumeur in vivo prouve également que la composition pharmaceutique combinée peut inhiber la croissance de cellules DHL in vivo, atténuer la charge tumorale et le degré d'invasion, et ne présente pas d'effets secondaires toxiques évidents. La composition pharmaceutique combinée présente une activité de résistance aux lymphomes à double impact supérieure à celle du Vénétoclax ou du Chiauranib tout seul, et peut inhiber plus efficacement la croissance de tumeurs in vivo, et une nouvelle stratégie et de nouvelles idées sont fournies pour le traitement de lymphomes à double impact.
PCT/CN2021/077567 2020-02-25 2021-02-24 Composition pharmaceutique combinée permettant de résister aux lymphomes à double impact et son utilisation WO2021169974A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010116116.7 2020-02-25
CN202010116116.7A CN111214475B (zh) 2020-02-25 2020-02-25 一种抗双重打击淋巴瘤的联合用药物组合物及其应用

Publications (1)

Publication Number Publication Date
WO2021169974A1 true WO2021169974A1 (fr) 2021-09-02

Family

ID=70826833

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/077567 WO2021169974A1 (fr) 2020-02-25 2021-02-24 Composition pharmaceutique combinée permettant de résister aux lymphomes à double impact et son utilisation

Country Status (3)

Country Link
CN (1) CN111214475B (fr)
TW (1) TWI768686B (fr)
WO (1) WO2021169974A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115177620A (zh) * 2022-07-18 2022-10-14 厦门大学附属第一医院 西奥罗尼或其药学上可接受的盐在制备预防或治疗滤泡淋巴瘤的药物中的应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007745A1 (fr) * 2020-07-08 2022-01-13 深圳微芯生物科技股份有限公司 Utilisation de chiauranib et d'une combinaison médicamenteuse le comprenant dans le traitement d'un lymphome non hodgkinien

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109908143A (zh) * 2018-12-18 2019-06-21 厦门大学附属第一医院 西奥罗尼在制备治疗急性髓系白血病药物的新用途
WO2019178267A2 (fr) * 2018-03-13 2019-09-19 University Of Iowa Research Foundation Régénération inductive des voies respiratoires par modulation du facteur transcriptionnel de cellules souches myoépithéliales glandulaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019178267A2 (fr) * 2018-03-13 2019-09-19 University Of Iowa Research Foundation Régénération inductive des voies respiratoires par modulation du facteur transcriptionnel de cellules souches myoépithéliales glandulaires
CN109908143A (zh) * 2018-12-18 2019-06-21 厦门大学附属第一医院 西奥罗尼在制备治疗急性髓系白血病药物的新用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CROMBIE JENNIFER; LOSSOS CHEN; SAROSIEK KRISTOPHER; CHRISTIE AMANDA L; FRASER CAMERON; BHATT SHRUTI; DENG JING; DAVIDS MATTHEW S.;: "Dynamic BH3 Profiling Reveals Novel Therapeutic Strategies for the Treatment of Double-Hit Lymphoma", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 130, 8 December 2017 (2017-12-08), US, pages 2764, XP086631870, ISSN: 0006-4971, DOI: 10.1182/blood.V130.Suppl_1.2764.2764 *
DENG MANMAN; SHI YUANFEI; CHEN KAI; ZHAO HAIJUN; WANG YAN; XIE SITING; ZHAO JINTAO; LUO YIMING; FANG ZHIHONG; FAN YAQUN; XU BING: "CS2164 exerts an antitumor effect against human Non-Hodgkin's lymphomasin vitroandin vivo", EXPERIMENTAL CELL RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 369, no. 2, 1 June 2018 (2018-06-01), AMSTERDAM, NL, pages 356 - 362, XP085432993, ISSN: 0014-4827, DOI: 10.1016/j.yexcr.2018.05.038 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115177620A (zh) * 2022-07-18 2022-10-14 厦门大学附属第一医院 西奥罗尼或其药学上可接受的盐在制备预防或治疗滤泡淋巴瘤的药物中的应用

Also Published As

Publication number Publication date
CN111214475B (zh) 2021-05-18
TWI768686B (zh) 2022-06-21
TW202131919A (zh) 2021-09-01
CN111214475A (zh) 2020-06-02

Similar Documents

Publication Publication Date Title
WO2021169974A1 (fr) Composition pharmaceutique combinée permettant de résister aux lymphomes à double impact et son utilisation
Dorn et al. The effect of cantharidins on leukemic stem cells
McCarthy et al. In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer
WO2017043633A1 (fr) Agent thérapeutique ou méthode de traitement pour la leucémie lymphoïde aiguë (lla) à chromosome philadelphie positif (ph+) présentant la mutation ikzf1
US20030004117A1 (en) Methods for inhibiting angiogenesis
BR112021014112A2 (pt) Usos de composto pró-fármaco de don e inibidor de ponto de controle imunológico para tratar câncer, bem como composto e composição farmacêutica compreendendo o mesmo
TW201806600A (zh) Bcl-2抑制劑及mcl1抑制劑之組合、其用途及醫藥組合物
Jiang et al. Polyporus polysaccharide ameliorates bleomycin-induced pulmonary fibrosis by suppressing myofibroblast differentiation via TGF-β/Smad2/3 pathway
WO2015172712A1 (fr) Composition pharmaceutique pour injection avec effet synergique de la vitamine c et des médicaments antitumoraux
RU2746705C2 (ru) Комбинация bcl-2 ингибитора и mcl-1 ингибитора, их применения и фармацевтические композиции
CN109568313B (zh) 一种抗肿瘤联合用药物及其在制备抗癌药物中的应用
TW202038960A (zh) Mcl-1抑制劑及米哚妥林(midostaurin)之組合，其用途及醫藥組合物
US20040048808A1 (en) Methods for inhibiting angiogenesis
JP2015531355A (ja) 腫瘍治療のための薬剤組成物及びその適用
TWI542348B (zh) 含４－乙醯基－安卓奎諾－ｂ之組合物用於製備抑制癌細胞生長之藥物的用途
EP1313459B1 (fr) Dianthraquinones polycycliques utilisees comme agents anticancereux et anti-angiogeniques
WO2016065674A1 (fr) Utilisation d'ibrutinib pour une leucémie aiguë avec mutation flt3-itd
CN111195250A (zh) 西达本胺联合dice的应用及联合药物
CN111773388A (zh) A-失碳-5α雄甾烷化合物类药物与抗癌药物的联合应用
KR20030058019A (ko) 삼산화비소(Ａｓ₂Ｏ₃)를 유효 성분으로 포함하는 방사선치료증진제
MX2015006592A (es) Terapia de combinacion con volasertib.
CN110721188B (zh) 一种治疗白血病的药物组合物
CN114732816B (zh) 2-芳基-1,3二氢苯并咪唑衍生物在制备治疗肾癌药物中的用途
CN117442738A (zh) 一种联合用药物组合物在制备预防或治疗t细胞淋巴瘤的药物中的应用
CN116271057A (zh) 一种预防或治疗滤泡淋巴瘤的联合用药物组合物及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21760105

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21760105

Country of ref document: EP

Kind code of ref document: A1