CN104000804A - Application of probucol and derivative thereof in resisting tumor metastasis - Google Patents

Application of probucol and derivative thereof in resisting tumor metastasis Download PDF

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Publication number
CN104000804A
CN104000804A CN201310062316.9A CN201310062316A CN104000804A CN 104000804 A CN104000804 A CN 104000804A CN 201310062316 A CN201310062316 A CN 201310062316A CN 104000804 A CN104000804 A CN 104000804A
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Prior art keywords
probucol
metastasis
purposes
breast cancer
pharmaceutical composition
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CN201310062316.9A
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Chinese (zh)
Inventor
李亚平
张志文
刘泽莹
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Priority to CN201310062316.9A priority Critical patent/CN104000804A/en
Priority to PCT/CN2014/072632 priority patent/WO2014131360A1/en
Publication of CN104000804A publication Critical patent/CN104000804A/en
Pending legal-status Critical Current

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    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pregnancy & Childbirth (AREA)
  • Gynecology & Obstetrics (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an application of probucol and a derivative thereof in preparing drugs for suppressing tumor metastasis, preferably breast cancer metastasis and more preferably pulmonary metastasis of breast cancer. The invention also relates to an application of a probucol pharmaceutical composition in preparing the drugs for suppressing the tumor metastasis, preferably breast cancer metastasis and more preferably the pulmonary metastasis of breast cancer. The probucol pharmaceutical composition comprises therapeutically effective amounts of compounds or drug excipients that are one or more selected from probucol and derivatives thereof.

Description

The purposes of probucol and derivant anti metastasis thereof
Technical field
The present invention relates to the new purposes of probucol and derivant thereof, be specifically related to probucol and derivant has anti metastasis in preparation, reduce Malignant tumor of bonal metastasis incidence rate, reduce the number of metastasis, improve the purposes in the medicine of tumor animal survival rate.
Background technology
Neoplasm metastasis (Cancer metastasis) refers to that tumor cell is free from primary tumor, and tissue infiltration, attacks and enter blood circulation and shift in vivo thereupon towards periphery, and adheres to endotheliocyte processes such as infiltrating formation metastatic tumor.Neoplasm metastasis is that tumor is difficult to the one of the main reasons of curing and recurring, and is also the key factor that causes tumor patient death.The demonstration of clinical diagnosis result, approximately more than 60% first visit tumor patient shifts, and its 5 years survival rates are less than 20%.At present, only have the neoplasm metastasis patient of only a few effectively to treat by operation, and other clinical treatment mode effects are very limited.Therefore, the control of neoplasm metastasis is faced with very stern challenge.
The process of neoplasm metastasis is very complicated, mainly comprise that various matrix metalloproteinases are as MMP-2, MMP-9 etc., inflammatory factor is as IL-6, TNF-α etc., and signal transduction pathway and various adhesion molecule are as the common participation of the multiple transfer correlation factors such as VCAM-1, integrin and selection element.Neoplasm metastasis approach mainly contains lymphatic metastasis, Blood route metastasis, plantation transfer and local diffusion transfer etc., and wherein lymph metastasis and blood transfer are topmost approach.Therefore, effectively the multiple correlation factor in the transfer processes such as invasion and attack, migration and implantation of inhibition tumor cell, improves the lympha targeted property of medicine and the selective distribution of neoplasm metastasis lesions position, prevents and treats neoplasm metastasis.
Probucol (probucol) has another name called probacol, is the hypolipidemic first going on the market in the U.S. for 1977.Because it has reduced HDL-C (HDL) market of fading out in cholesterol reducing.The main pharmacological of probucol comprises reduction cholesterol biosynthesis and promotes cholesterol decomposition, change character and the function of high density lipoprotein hypotype, antioxidation, suppresses the formation of foam cell, delay the formation of atheromatous plaque, established atherosclerotic lesion disappears.It is reported, probucol (Probucol) and derivant (AGI-1067) thereof can significantly reduce matrix metalloproteinase MMP-2, MMP-9 and inflammation-related factor IL-6, TNF-α, and can reduce the expression of blood vessel adhesion factor VCAM-1, thereby consider whether it can reduce neoplasm metastasis.
Summary of the invention
The inventor finds that probucol and compositions thereof have the effect of anti metastasis, can reduce Malignant tumor of bonal metastasis incidence rate, reduces the number of metastasis, improves tumor animal survival rate.
The object of this invention is to provide probucol and derivant thereof for the preparation of suppressing neoplasm metastasis, preferred Metastasis in Breast Cancer, the purposes in the medicine that more preferably breast carcinoma lung shifts.
The object of this invention is to provide a kind of probucol pharmaceutical composition for the preparation of suppressing neoplasm metastasis, preferred Metastasis in Breast Cancer, the purposes in the medicine that more preferably breast carcinoma lung shifts.
Described in the application, derivatives of probucol can be probucol succinic acid AGI-1067.
Described probucol pharmaceutical composition comprise treatment effective dose one or more be selected from compound and the excipient substance in probucol and derivant thereof.
Described probucol pharmaceutical composition can be self-microemulsion, nanosuspension, nanoparticle or nano-emulsion.Described probucol pharmaceutical composition can be capsule, tablet, solid dispersion or granule.
Advantage of the present invention and good effect are to have opened up probucol and derivant inhibition neoplasm metastasis thereof, especially the new purposes that anti-breast cancer lung shifts, it can effectively suppress the generation that breast carcinoma lung shifts, improved survival rate, reduced transfer incidence rate, shown that this compound and compositions thereof are suppressing to have development prospect aspect Malignant tumor of bonal metastasis.
Accompanying drawing explanation
Fig. 1 probucol and derivant thereof suppress breast carcinoma lung and shift experiment in vitro
Fig. 2 probucol and derivant thereof suppress at body the generation that breast carcinoma lung shifts
The specific embodiment
Embodiment 1 probucol solution
By probucol raw material medicine (Wuyi, Hebei merciful ferry pharmaceutcal corporation, Ltd, purity is 99.7%) be scattered in water, buffer, in the solution that contains 0.5% sodium carboxymethyl cellulose or 0.1% hydroxypropyl cellulose.
Embodiment 2 derivatives of probucol AGI-1067 solution
By derivatives of probucol AGI-1067(Shanghai Chemexpress Technology Co., Ltd., purity 98.0%) be scattered in water, buffer, in the solution that contains 0.5% sodium carboxymethyl cellulose or 0.1% hydroxypropyl cellulose.
Embodiment 3 probucol granules
Probucol and employing wet granulation, the dry granulations such as starch, pregelatinized Starch, microcrystalline Cellulose, lactose, polyvidone or the method for directly mixing are prepared into containing drug particles.
Embodiment 4 Lorelcos
Probucol and employing wet granulation, the dry granulations such as starch, pregelatinized Starch, microcrystalline Cellulose, lactose, polyvidone or the method for directly mixing are prepared into containing drug particles, then with tablet machine, suppress Lorelco.
Embodiment 5 probucol capsules
Probucol and employing wet granulation, the dry granulations such as starch, pregelatinized Starch, microcrystalline Cellulose, lactose, polyvidone or the method for directly mixing are prepared into containing drug particles, and then are loaded in capsule shells, prepare probucol capsule.
Embodiment 6 probucol porous carrier complex
By probucol with containing pertusate porous material as porous-starch, polyvinylpolypyrrolidone mix, be scattered in together in ethanol, ultrasonic mixing, then evaporate to dryness is removed organic solvent, obtains.
Embodiment 7 derivatives of probucol (AGI-1067) porous carrier complex
Derivatives of probucol (AGI-1067) is mixed with mesoporous silicon oxide, kieselguhr etc., be scattered in together in ethanol, ultrasonic mixing, then evaporate to dryness is removed organic solvent, obtains.
Embodiment 8 probucol nano-emulsions
By probucol and Tween80, middle triglyceride and polyglycol distearate HS-15 mix, and in ethanol, dissolve, and evaporate to dryness is removed organic solvent, adds water and mixes and get final product.
Embodiment 9 derivatives of probucol (AGI-1067) self-microemulsion
By derivatives of probucol (AGI-1067) and Cremphol EL, middle triglyceride and Transcutol HP mix, and ultrasonic dissolution adds water and mixes during administration.
Embodiment 10 probucol solid dispersions
Probucol is mixed with phospholipid, sodium cholate, in methanol, dissolve, evaporate to dryness is removed organic solvent, obtains.
Embodiment 11 probucol nanoparticles
Probucol is mixed according to 1:2 ratio with surfactant polyethylene vitamin e succinate TPGS, be dissolved in ethanol, 37 ℃ of evaporates to dryness are removed organic solvent, add water jolting, obtain.
Embodiment 12 derivatives of probucol (AGI-1067) nanoparticle
Derivatives of probucol (AGI-1067) is mixed according to 1:2 ratio with surfactant triton x-100, be dissolved in ethanol, 37 ℃ of evaporates to dryness are removed organic solvent, add water jolting, obtain.
Embodiment 13 probucol nano suspensions
Probucol is mixed with polyvidone PVP and sodium lauryl sulphate, in planetary beveller, grind 30 minutes, obtain probucol nano suspension.
Experimental example 1: external migration experiment
Utilize transwell cell to check the inhibitory action of probucol to the tumor cell transferance of In vitro culture.The compositions of embodiment 8,11,12 preparations and cell are not cultivated altogether in the little indoor culture medium that does not contain FBS, and the drug level of medicine probucol or AGI1067 is 100ngmL -1, the blank cell that does not wherein add any medicine is matched group, cultivates altogether after 24h, by crystal violet, cell is dyeed, and with cotton swab, removes in cell not after migrating cell, uses microscope observing cell migration situation.Result as shown in Figure 1, shows that the compositions that contains probucol or derivatives of probucol AGI-1067 can significantly suppress the migration of breast cancer cell 4T1 cell.
Experimental example 2: suppress Metastasis in Breast Cancer experiment in body
At mammary gland of mouse fat pad inoculation 4T1-Luc cell, the oral compositions that gives embodiment 1,11 and 12 preparations, dosage is 200mgkg -1, be administered once every day, and successive administration 30 days is investigated breast carcinoma lung transfer case, and result is as Fig. 2, shown in table 1.
Table 1 probucol and self-assembled nanometer grain thereof suppress breast carcinoma lung at body to be shifted
Result shows that the compositions of probucol or derivatives of probucol AGI-1067 compares the probability that normal saline group generation lung shifts and reduce, and mice survival rate improves, and pulmonary's metastasis number also significantly reduces simultaneously.

Claims (10)

1. a probucol and derivant thereof are in the purposes for the preparation of suppressing in the medicine of neoplasm metastasis.
2. purposes according to claim 1, wherein, described neoplasm metastasis is Metastasis in Breast Cancer.
3. purposes according to claim 2, wherein, described Metastasis in Breast Cancer is that breast carcinoma lung shifts.
4. according to the purposes described in any one in claim 1～3, wherein, described derivatives of probucol is probucol succinic acid AGI-1067.
5. a probucol pharmaceutical composition is in the purposes for the preparation of suppressing in the medicine of neoplasm metastasis, wherein, described probucol pharmaceutical composition comprise treatment effective dose one or more be selected from compound and the excipient substance in probucol and derivant thereof.
6. purposes according to claim 5, wherein, described neoplasm metastasis is Metastasis in Breast Cancer.
7. purposes according to claim 6, wherein, described Metastasis in Breast Cancer is that breast carcinoma lung shifts.
8. purposes according to claim 5, wherein, described probucol pharmaceutical composition is self-microemulsion, nanosuspension, nanoparticle or nano-emulsion.
9. purposes according to claim 5, wherein, described probucol pharmaceutical composition is capsule, tablet, solid dispersion or granule.
10. according to the purposes described in any one in claim 5～9, wherein, described derivatives of probucol is probucol succinic acid AGI-1067.
CN201310062316.9A 2013-02-27 2013-02-27 Application of probucol and derivative thereof in resisting tumor metastasis Pending CN104000804A (en)

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CN201310062316.9A CN104000804A (en) 2013-02-27 2013-02-27 Application of probucol and derivative thereof in resisting tumor metastasis
PCT/CN2014/072632 WO2014131360A1 (en) 2013-02-27 2014-02-27 Use of probucol and derivatives thereof for anti-tumour metastasis

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106581680A (en) * 2015-10-16 2017-04-26 山东亨利医药科技有限责任公司 Pharmaceutical composition for lowering food influences on drug absorption
CN111671759A (en) * 2020-07-15 2020-09-18 五邑大学 Pharmaceutical composition for synergistically resisting pancreatic cancer stem cells

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220096398A1 (en) * 2019-01-31 2022-03-31 Macquarie University Complexes and compositions comprising probucol and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086418A1 (en) * 2002-04-11 2003-10-23 Children's Medical Center Corporation Methods for the treatment of cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086418A1 (en) * 2002-04-11 2003-10-23 Children's Medical Center Corporation Methods for the treatment of cancer

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106581680A (en) * 2015-10-16 2017-04-26 山东亨利医药科技有限责任公司 Pharmaceutical composition for lowering food influences on drug absorption
CN106581680B (en) * 2015-10-16 2021-05-25 山东亨利医药科技有限责任公司 A pharmaceutical composition for reducing food influence on drug absorption
CN111671759A (en) * 2020-07-15 2020-09-18 五邑大学 Pharmaceutical composition for synergistically resisting pancreatic cancer stem cells

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