CN107714650A - A kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes - Google Patents

A kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes Download PDF

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Publication number
CN107714650A
CN107714650A CN201610657285.5A CN201610657285A CN107714650A CN 107714650 A CN107714650 A CN 107714650A CN 201610657285 A CN201610657285 A CN 201610657285A CN 107714650 A CN107714650 A CN 107714650A
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liposome
glutamine metabolism
inhibitor
polymethacrylates
inhibitors
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CN201610657285.5A
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Chinese (zh)
Inventor
阮奔放
阮健昵福
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Hangzhou Jian Fu In Biological Technology Co Ltd
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Hangzhou Jian Fu In Biological Technology Co Ltd
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Priority to CN201610657285.5A priority Critical patent/CN107714650A/en
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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Abstract

The present invention relates to a kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes, significantly improves fat-soluble glutaminase allosteric site inhibitor and its combines the antitumor activity of other drugs；It is intended to increase by the lipophilic portion of liposome the solubility of the glutamine metabolism inhibitor of poorly water-soluble, and can be modified by liposome by additives such as polymethacrylates, further improves the pharmacological activity of glutamine metabolism inhibitor；The screening and optimizing of formula, we are using to increasing the inhibiting rate of tumour cell and the evaluation of preparation being carried out eventually through animal subcutaneous tumors model；Test result indicates that liposome can significantly improve the antitumor activity of glutamine metabolism inhibitor and improve the survival rate of animal.

Description

A kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes
Technical field
The invention belongs to biomedicine field, and in particular to a kind of novel dosage forms liposome formula, significantly improve liposoluble Property glutaminase allosteric site inhibitor and its combine other drugs antitumor activity.
Background technology
Liposome carries a kind of preparation as medicine, is that clinical practice is more early, a kind of development preparation the most ripe.Liposome (liposome) it is a kind of artificial membrane, in water in phospholipid molecule hydrophilic head insertion water, fat body hydrophobic tail is stirred towards air The ball-type liposome of double-deck fat molecule, 25~1000nm of diameter are formed after dynamic.Using liposome can and cell membrane fusion The characteristics of, medicine is sent into cell interior.The medicine of U.S. FDA approval listing has amphotericin B, Evacet.
The allosteric site inhibitor of glutaminase is tumor metabolic inhibitor, is controlled by tumour the characteristics of its high-efficiency low-toxicity Pay close attention in treatment field.But BPTES the and CB-839 compounds of document report, and the glutamine allostery of our latest finds The inhibitor of site and/or glutamte dehydrogenase all has the characteristics of dissolubility difference；In order to increase the dissolubility of this kind of compound, I Investigated influence of the liposome containing various additives to the pharmacological property of compound.
Application of the polymethacrylates in pharmaceutical preparation is very wide, but the report for using it to modified liposome is more rare See；Recently, have been reported that display polymethacrylates modification can significantly improve the stability of liposome, skin infiltration, envelop rate, glue Attached property etc.；We have attempted a variety of polymethacrylates, improve the antitumor pharmacological activity of compound；Connection is investigated simultaneously Share the collaboration reciprocal effects of liposome and the administering mode of liposome of the medicine to glutamine metabolism inhibitor.
The content of the invention
Liposome can increase the solubility of the compound of poorly water-soluble with its lipophilic portion, and can melt with cell membrane The characteristics of conjunction.And liposome can be modified by additives such as polymethacrylates, its stability and some drugses are improved Pharmacotoxicological effect, we, which devise some form formulas, is：Comprising glutamine metabolism inhibitor, contain and without cFDA or FDA The marketed drug of approval, the phospholipid liposome comprising polymethacrylates and other additives.
We are intended to increase by the lipophilic portion of liposome the solubility of the glutamine metabolism inhibitor of poorly water-soluble, And can be modified by liposome by additives such as polymethacrylates, further to improve glutamine metabolism inhibitor Pharmacological activity.The screening and optimizing of formula, we are using to increasing the inhibiting rate of tumour cell and eventually through animal subcutaneous tumors mould Type carries out the evaluation of preparation.Test result indicates that liposome can significantly improve the antitumor activity of glutamine metabolism inhibitor And improve the survival rate of animal.Pass through the formulation optimization of the additives such as polymethacrylates, at present glutamine metabolism suppression Under 10mg/kg dosage, the tumour relied on glutamine has very strong rejection ability, and can by drug combination for agent Further significantly improve cancer suppressing ratio.
Glutamine metabolism inhibitor compound liposome is modified by using polymethacrylates, significantly carried Stability, skin infiltration, envelop rate, the adhesiveness of high liposome, combine other antineoplastics, all kinds of to glutamy for treating Amine have dependence cancer and tumour for example liver cancer, lung cancer, prostate cancer, carcinoma of urinary bladder, kidney, leukemia, osteocarcinoma, intestinal cancer, breast cancer, Brain tumor, cancer of pancreas, stomach cancer；The invention specifically includes following content：A kind of glutamine metabolism inhibitors liposomes, described fat Plastid includes liposome main ingredient and lipidosome drug carrier；Described liposome main ingredient includes glutamine metabolism inhibitor；
Described lipidosome drug carrier includes polymethacrylates, phosphatide, cholesterol and pharmaceutically required auxiliary Material；
The drug-loaded liposome of described glutamine metabolism inhibitors liposomes and the proportioning of antineoplastic are 1:(0.5 ~0.001)；
The phospholipid liposome of described drug-loaded liposome and the proportioning of polymethacrylates are 1:(0.1~4).
Preferably, the glutamine metabolism inhibitor in described glutamine metabolism inhibitors liposomes is with combination Glutaminase (KGA)) allosteric site, and the compound of KGA activity can be suppressed；
BPTES derivatives including poor solubility, BC839 derivatives, selenium beautiful jade analog derivative, or the glutamy that structure is following The compound of amine metabolic poison：
Or：
Or：
Wherein R1、R2、R3、R4、R5、R6、R7、R8Independent substituent to represent respectively includes aromatics heterocycle, substitutes alkane Base, acid amides, ether, lipid, halogen, silanes, thioether, amine, phosphate group, sulfoxide type, sulfonyl；
Described X or X ＇ are that substituent is selected from C, N, O, S and Se atom comprising 1~15, and X ＂ are that S atom or C are former Son；
The Y and Z are respectively one kind in C, N, O and S atom；
N the or n ＇ are taken respectively from the different digital for 0~5.
Including but not limited to following compound：
Preferably, the polymethacrylates in described glutamine metabolism inhibitors liposomes includes polymethyl Acid esters contains quaternary ammonium salt, amine, aromatics heterocycle, substitution alkyl, acid amides, ether, lipid, halogen, silanes, thioether, phosphate Group, sulfonyl group high-molecular compound, such asEPO, RL100, RL、 RS、 L、 S、 E、 NE、NM etc..
Preferably, the phosphatide in described glutamine metabolism inhibitors liposomes includes natural phospholipid such as phosphatidyl courage Alkali, PC classes lecithin and synthetic phospholipid such as DPPC, DPPE, DSPC.
Preferably, the pharmaceutically required auxiliary material in described glutamine metabolism inhibitors liposomes include cholesterol, One or more in polyethylene glycol 200~800, NP40, the ethanol less than 10%, sorbierite, Tween (0.01~1%).
A kind of antitumor liposome medicament, its main ingredient include glutamine metabolism inhibitor or other from cFDA or FDA The antineoplastic of listing for example adriamycin, rapamycin, taxol, actinomycin D, epirubicin, Doxorubicin, more west he Match, mitomycin, fluorouracil, cis-platinum, Ai Ke replace Buddhist nun, PD-1 antibody (such as nivolumab), steroid hormone and its derivative Deng, the liposome component include polymethacrylates containing quaternary ammonium salt, amine, substitution alkyl mixing high-molecular compound (such as Eudragit NM, Eudragit RS, Eudragit E, Eudragit RL, Eudragit).
Preferably, the described pharmaceutical composition including glutamine metabolism inhibitors liposomes is used to treat glutamine The purposes of all kinds of malignant tumours relied on, including liver cancer, lung cancer, prostate cancer, carcinoma of urinary bladder, kidney, leukemia, osteocarcinoma, intestinal cancer, breast Gland cancer, brain tumor, cancer of pancreas.
Preferably, the described pharmaceutical composition for including glutamine metabolism inhibitors liposomes, described drug regimen The administering mode of thing include intravenously administrable, muscle and hypodermic injection, oral administration, dosing eyes, pulmonary administration, percutaneous dosing, Nasal-cavity administration approach；
Described glutamine metabolism inhibitor is contained with other antineoplastics in same liposome or two kinds of masters Medicine is mixed administration or two kinds of main ingredients from liposome and is administered using the different method of administration of different dosage forms.
A kind of preparation method of glutamine metabolism inhibitors liposomes, described preparation method include injection method, film Dispersion method, ultrasonic dispersion, reverse evaporation.
Preferably, the preparation method of described glutamine metabolism inhibitors liposomes, described preparation method are included such as Lower step：
Step 1: phosphatide, cholesterol, polymethacrylates mixing is taken to be stirred by heating ultrasonic dissolution after ethanol It is lower that (NH4) is added dropwise2SO4The aqueous solution；
Step 2: after step 1 gained mixture rotary evaporation is removed into ethanol, with normal saline buffer solution dialysed overnight；
Step 3: various main ingredient things and liposome are heated into mixed dissolution.
Brief description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing There is the required accompanying drawing used in technology description to be briefly described, it should be apparent that, drawings in the following description are only this Some embodiments of invention, for those of ordinary skill in the art, without having to pay creative labor, may be used also To obtain other accompanying drawings according to these accompanying drawings.
Accompanying drawing for after the glutamine metabolism inhibitor-thioether selenium beautiful jade poly-methyl acrylate plastid encapsulating of the present invention with Other Comparative formulations suppress tumor cell viability effect contrast figure.
Figure 1A：The thioether selenium beautiful jade group that concentration is 800nM suppresses activity of tumor cells figure.
Figure 1B：The thioether selenium beautiful jade group that concentration is 400nM suppresses activity of tumor cells figure.
Fig. 1 C：Control groups (blank control group) growth of tumour cell condition diagram.
Fig. 1 D：LP2+ thioether selenium beautiful jades (800nM) group suppresses activity of tumor cells figure.
Fig. 1 E：LP2+ thioether selenium beautiful jades (400nM) group suppresses activity of tumor cells figure.
Fig. 1 F：LP2 blank groups suppress activity of tumor cells figure.
Embodiment
With reference to embodiment, the present invention is described in further detail, following examples be explanation of the invention and The invention is not limited in following examples.
Embodiment：
1. the preparation of each lipoid plastid
Phosphatide (100mg) is weighed, cholesterol (100mg), adds or is not added with polymethacrylates, and by mixture by adding Hot ultrasonic dissolution stirs lower dropwise addition (NH4) after ethanol2SO4The aqueous solution；It is slow with physiological saline etc. after rotary evaporation removes ethanol Fliud flushing dialysed overnight；Liposomal particle size is 100~200nm or so；Then by various medicines and liposome in 50~120 degree of heating Mixed dissolution；LP1, LP2 (cationic polymethacrylates RL), LP3 (cationic polymethacrylates EPO).
2. the ratio of various prescriptions：Contain the ratio (w/w%) of a component in the liposome prescription of medicine
A. phosphatide optimizes
B. polymethacrylates optimizes
C. drug combination optimizes
Collaboration mutual assistance effect of the drug combination to glutamine metabolism inhibitor (exemplified by H22 liver cancer cells)
Physiological saline, conventional liposome (LP1), cation polymethacrylates liposome (LP2, LP3), to anti- The influence of the suppression A549 cell growths of tumor promotion medicine
Compound IC50 Physiological saline LP1 LP2 LP3
BPTES 2μM 50% 60-75% 85-90% 85-90%
CB839 2μM 50% 60-75% 85-90% 85-90%
Thioether selenium beautiful jade 0.5μM 50% 60-75% 85-90% 85-90%
Hexane selenium beautiful jade 0.5μM 50% 60-75% 85-90% 85-90%
Propane selenium beautiful jade 1μM 50% 60-75% 85-90% 85-90%
Rhzomorph D 2nM 50% 60-75% 85-90% 85-90%
Adriamycin 2nM 50% 60-75% 85-90% 85-90%
Taxol 10nM 50% 60-75% 85-90% 85-90%
Mitomycin 300nM 50% 60-75% 85-90% 85-90%
5 FU 5 fluorouracil 170nM 50% 60-75% 85-90% 85-90%
Rapamycin 1nM 50% 60-75% 85-90% 85-90%
All kinds of polymethacrylates liposomes can improve the antitumor activity of hexane selenium beautiful jade (400nM)
Cation polymethacrylates liposome can improve hexane selenium beautiful jade (400nM) to the anti-swollen of various tumour cells Tumor activity：
3. zoopery is used for Formula Evaluation
In order to further confirm the antitumor action that the lipid physical efficiency of polymethacrylates modification improves medicine, we adopt Solid tumor is built with ICR mouse.By the liver cancer cells H22 (1,000,000) of inoculated with subcutaneous injections mouse, after 1-4d It can be seen that small lump occurs in injection site, show to model successfully.Then observed by tail vein, abdominal cavity or subcutaneous administration after 10 days As a result.
Furthermore, it is necessary to illustrate, the specific embodiment described in this specification, the shape of its parts and components, it is named Title etc. can be different.The equivalent or simple change that all construction, feature and principles according to described in inventional idea of the present invention are done, is wrapped Include in the protection domain of patent of the present invention.Those skilled in the art can be to described specific implementation Example is made various modifications or supplement or substituted using similar mode, structure without departing from the present invention or surmounts this Scope as defined in the claims, protection scope of the present invention all should be belonged to.

Claims (10)

  1. A kind of 1. antitumor medicinal liposome of inhibitor containing glutamine metabolism, it is characterised in that：Described liposome includes Liposome main ingredient and lipidosome drug carrier；Described liposome main ingredient includes the antineoplastic of the inhibitor containing glutamine metabolism Thing；
    Described lipidosome drug carrier includes polymethacrylates, phosphatide, cholesterol and pharmaceutically required auxiliary material；
    The drug-loaded liposome of described glutamine metabolism inhibitors liposomes and the proportioning of antineoplastic are 1:(0.5~ 0.001)；
    The phospholipid liposome of described drug-loaded liposome and the proportioning of polymethacrylates are 1:(0.1~4).
  2. 2. the antitumor medicinal liposome of the inhibitor according to claim 1 containing glutamine metabolism, it is characterised in that：Institute The glutamine metabolism inhibitor stated is with combination glutaminase (KGA)) allosteric site, and the change of KGA activity can be suppressed Compound；
    BPTES derivatives including poor solubility, BC839 derivatives, selenium beautiful jade analog derivative, or the glutamine generation that structure is following Thank to the compound of inhibitor：
    Or：
    Or：
    Wherein R1、R2、R3、R4、R5、R6、R7、R8Independent substituent to represent respectively includes aromatics heterocycle, substitutes alkyl, Acid amides, ether, lipid, halogen, silanes, thioether, amine, phosphate group, sulfoxide type, sulfonyl；
    Described X or X ＇ are that substituent is selected from C, N, O, S and Se atom comprising 1~15, and X ＂ are S atom or C atoms；
    The Y and Z are respectively one kind in C, N, O and S atom；
    N the or n ＇ are taken respectively from the different digital for 0~5.
  3. 3. the antitumor medicinal liposome of the inhibitor according to claim 1 containing glutamine metabolism, it is characterised in that：Institute The polymethacrylates stated include polymethacrylates containing quaternary ammonium salt, amine, aromatics heterocycle, substitution alkyl, acid amides, Ether, esters, halogen, silanes, thioether, phosphate group, sulfonyl group high-molecular compound.
  4. 4. the antitumor medicinal liposome of the inhibitor according to claim 1 containing glutamine metabolism, it is characterised in that：Institute The phosphatide stated includes natural phospholipid such as phosphatidyl choline, PC classes lecithin and synthetic phospholipid such as DPPC, DPPE, DSPC.
  5. 5. inhibitors liposomes containing glutamine metabolism according to claim 1, it is characterised in that：Described pharmaceutically must Need auxiliary material include cholesterol, polyethylene glycol 200~800, NP40, the ethanol less than 10%, sorbierite, Tween (0.01~ 1%) one or more in.
  6. 6. a kind of pharmaceutical composition for including any described glutamine metabolism inhibitors liposomes of the claims 1~5, It is characterized in that：Described pharmaceutical composition also includes other antineoplastics, including：Adriamycin, rapamycin, Japanese yew Alcohol, actinomycin D, epirubicin, Doxorubicin, docetaxel, mitomycin, fluorouracil, cis-platinum, Ai Ke are for Buddhist nun, PD-1 Antibody, steroid hormone and its derivative.
  7. 7. the pharmaceutical composition according to claim 6 including glutamine metabolism inhibitors liposomes is used to treat paddy ammonia The purposes for all kinds of malignant tumours that acid amides relies on, including liver cancer, lung cancer, prostate cancer, carcinoma of urinary bladder, kidney, leukemia, osteocarcinoma, intestines Cancer, breast cancer, brain tumor, cancer of pancreas, stomach cancer.
  8. 8. the pharmaceutical composition according to claim 6 for including glutamine metabolism inhibitors liposomes, it is characterised in that： The administering mode of described pharmaceutical composition includes intravenously administrable, muscle and hypodermic injection, oral administration, dosing eyes, lung Administration, percutaneous dosing, nasal-cavity administration approach；
    Described glutamine metabolism inhibitor contained with other antineoplastics in same liposome or two kinds of main ingredients with Liposome mixing administration or two kinds of main ingredients are administered using the different method of administration of different dosage forms.
  9. 9. a kind of preparation method for including any described glutamine metabolism inhibitors liposomes of the claims 1~5, its It is characterised by：Described preparation method includes injection method, film dispersion method, ultrasonic dispersion, reverse evaporation.
  10. 10. a kind of antitumor liposome medicament, its main ingredient includes glutamine metabolism inhibitor, adriamycin, rapamycin, Japanese yew Alcohol, actinomycin D, epirubicin, Doxorubicin, docetaxel, mitomycin, fluorouracil, cis-platinum, Ai Ke are for Buddhist nun, PD-1 One or more in antibody, it is characterised in that：Described liposome includes polymethacrylates and contains quaternary ammonium salt, amine, takes The high-molecular compound of substituted alkyl mixing.
CN201610657285.5A 2016-08-11 2016-08-11 A kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes Pending CN107714650A (en)

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Cited By (4)

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CN109223778A (en) * 2018-11-16 2019-01-18 上海市肺科医院 C24H24N6O2S3Preparing the purposes in anti-tubercle bacillus drugs
WO2020067910A3 (en) * 2018-09-27 2020-05-14 Narodowy Instytut Leków W Warszawie Pharmaceutical formulation containing a selenitetriglyceride and a cytostatic for use in treatment of tumour
CN115192524A (en) * 2021-04-13 2022-10-18 杭州汉菁生物科技有限公司 Polymeric micelle for encapsulating chain-like indissolvable drug, preparation method and application
WO2023169163A1 (en) * 2022-03-09 2023-09-14 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) Use of cb-839 in preparation of drug for inhibiting corneal neovascularization

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020067910A3 (en) * 2018-09-27 2020-05-14 Narodowy Instytut Leków W Warszawie Pharmaceutical formulation containing a selenitetriglyceride and a cytostatic for use in treatment of tumour
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CN109223778B (en) * 2018-11-16 2021-07-27 上海市肺科医院 C24H24N6O2S3Application in preparation of anti-tubercle bacillus drugs
CN115192524A (en) * 2021-04-13 2022-10-18 杭州汉菁生物科技有限公司 Polymeric micelle for encapsulating chain-like indissolvable drug, preparation method and application
WO2022218345A1 (en) * 2021-04-13 2022-10-20 杭州汉菁生物科技有限公司 Polymeric micelle coated with chain-like poorly soluble drug, preparation method and application
CN115192524B (en) * 2021-04-13 2023-08-29 杭州汉菁生物科技有限公司 Polymeric micelle encapsulating chain insoluble drug and preparation method and application thereof
WO2023169163A1 (en) * 2022-03-09 2023-09-14 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) Use of cb-839 in preparation of drug for inhibiting corneal neovascularization

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