CN109078189A - Composition containing kinases inhibitor and resveratrol - Google Patents
Composition containing kinases inhibitor and resveratrol Download PDFInfo
- Publication number
- CN109078189A CN109078189A CN201811233677.4A CN201811233677A CN109078189A CN 109078189 A CN109078189 A CN 109078189A CN 201811233677 A CN201811233677 A CN 201811233677A CN 109078189 A CN109078189 A CN 109078189A
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- Prior art keywords
- kinases inhibitor
- resveratrol
- composition according
- inhibitor
- buddhist nun
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- 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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
Present invention firstly provides a kind of composition containing kinases inhibitor and resveratrol, it is characterized in that, the kinases inhibitor is selected from Sutent (sunitinib), Lapatinib (lapatinib), it trains azoles pa Buddhist nun (pazopanib), Afatinib (afatinib), bosutinib (bosutinib), gram azoles replaces Buddhist nun (crizotinib), the solvate of one of pazopanib (axitinib) and Rui Gefeini (regorafenib) or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt, and the molar ratio of resveratrol and the kinases inhibitor is in (0.01~100): between 1.Extracorporeal bacteria inhibitor test discovery, resveratrol of the present invention is with the combination of kinases inhibitor in (0.01~100): can the various bacterias such as Kluyvera cryocrescens be generated with the bacteriostasis (generating interaction index CI < 1 when 30% inhibition produces) cooperateed in 1 molar ratio.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the composition containing kinases inhibitor and resveratrol.
Background technique
Infectious diseases is the major class disease caused by the microorganism infections such as bacterium, helminth, fungi or virus, can be passed through
Various approach are directly or indirectly propagated between human body.It is posted including antibiotic, antiviral agent, antifungal with anti-although having at present
A variety of anti-infectives such as infested medicine can be used for the treatment of infectious diseases, cause a disease in this disease still global range or lethal
One of the main reason for.2010, there are about 15,000,000 to die of infectious diseases in the whole world.
First kinases inhibitor Imatinib listing in 2001 is used for the treatment of leukaemia, thus the tumor target pulled open
To the prelude for the treatment of.To in October, 2018, FDA has had been approved by more than ten kinases inhibitors controlling for kinds cancer
It treats.In recent years, application of the kinases inhibitors such as Imatinib in infectious diseases is more and more concerned, such as Sarah
A.Stanley et al. is according to the report, Imatinib can inhibit big by the process for blocking mycobacterium to enter rat macrophage
The duplication of tubercle bacillus in mouse model.In the prior art without other kinases inhibitors to infectious diseases therapeutic effect
Data.The present inventor determines multiple protein kinase inhibitor to the antibacterial activity of various bacteriums in early-stage study, but big
Part antibacterial activity does not reach IC50.
Resveratrol (resveratrol) is a kind of Polyphenols that Takaoka in 1940 is separated from hair leaf black false hellebore
Compound, the entitled resvertrol (3,5,4 '-trihydroxies-stilbene) of chemistry.The compound is many plants by fungi
A kind of antitoxin generated under infection, ultraviolet light irradiation or pathological state.In more than 70 kinds of natural plants containing resveratrol and its
Glycosides, including black false hellebore, Cassia, brave battle, grape, Sang Zi, peanut, pineapple etc..Studies have shown that resveratrol not only have antithrombotic,
Anti- the effects of being mutated, is anti-oxidant, anti-inflammatory, good antibacterial activity is also embodied to the bacterium of plurality of classes.
The technology of synergetic antibacterial effect is temporarily generated without kinases inhibitor and resveratrol drug combination in the prior art
Enlightenment
Summary of the invention
The purpose of the present invention is to provide a kind of composition containing kinases inhibitor and resveratrol, the composition
Antibacterial action with collaboration.
To achieve the goals above, the group containing kinases inhibitor and resveratrol that present invention firstly provides a kind of
Close object, which is characterized in that the kinases inhibitor is selected from Sutent (sunitinib), Lapatinib
(lapatinib), training azoles pa Buddhist nun (pazopanib), Afatinib (afatinib), bosutinib (bosutinib), a gram azoles replace
One of Buddhist nun (crizotinib), pazopanib (axitinib) and Rui Gefeini (regorafenib) or its pharmaceutically may be used
The salt or solvate of receiving or the solvate of pharmaceutically acceptable salt, and resveratrol and the protein kinase inhibit
The molar ratio of agent is in (0.01~100): between 1.
Preferably, kinases inhibitor of the present invention is Sunitinib malate.
Preferably, kinases inhibitor of the present invention is two tosilate monohydrate of Lapatinib.
Preferably, kinases inhibitor of the present invention is hydrochloric acid training azoles pa Buddhist nun.
Preferably, kinases inhibitor of the present invention is Afatinib 2-maleate.
Preferably, kinases inhibitor of the present invention is bosutinib monohydrate.
Preferably, kinases inhibitor of the present invention is gram azoles for Buddhist nun.
Preferably, kinases inhibitor of the present invention is pazopanib.
Preferably, kinases inhibitor of the present invention is Rui Gefeini monohydrate.
Invention further provides the oral solid formulation for containing composition as previously described, dosage form is selected from particle
One of agent, capsule and tablet.
Preferably, the oral solid formulation further contains diluent and lubricant, wherein dilution of the present invention
Agent is preferably pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, phosphoric acid hydrogen
One of calcium and calcium phosphate；Lubricant of the present invention is preferably sodium stearyl fumarate, stearic acid, magnesium stearate, tristearin
Sour calcium, paraffin oil, paraffin, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-leucine, laruyl alcohol
One of sodium sulphate, magnesium laurylsulfate, polyethylene glycol, polyoxyl 40 stearate and Brij30.
Oral solid formulation of the present invention can be used method well known to those of ordinary skill in the art and be prepared,
The method that specific method can refer to but be not limited in " pharmacy " (the 8th edition) that Fang Liang is edited, People's Health Publisher publishes.This
The preparation method of the invention granule be by resveratrol, kinases inhibitor, diluent, mix lubricant to get
To the granule comprising kinases inhibitor and resveratrol.
The preparation method of capsule of the present invention is by resveratrol, kinases inhibitor, diluent, lubricant
After mixing, filling capsule to get arrive the capsule comprising kinases inhibitor and resveratrol.
The preparation method of tablet of the present invention is to mix resveratrol, kinases inhibitor, diluent, lubricant
After conjunction, tabletting is carried out to get the tablet comprising kinases inhibitor and resveratrol is arrived.
It the content of kinases inhibitor and resveratrol in oral solid formulation of the present invention and thus relates to
And dosage can be screened and be optimized by pharmacological testing well known to those of ordinary skill in the art, the present invention is to this
Without specifically limited.
Supplementary product consumption in oral solid formulation of the present invention can be by well known to those of ordinary skill in the art
Formulation method is screened and is optimized, and the present invention is to this without specifically limited.
Extracorporeal bacteria inhibitor test discovery, the combination of resveratrol and kinases inhibitor of the present invention (0.01~
100): in 1 molar ratio can to Kluyvera cryocrescens, bacteroides uniformis, Wdwardsiella hoshinae, produce indoles peptostreptococcus,
Candida lambica, Acinebobacter lwoffi, shigella flexneri, actinomyces viscosus, pseudomonas putida, comma bacillus, butyric acid shuttle
Bacterium, candida magnoliae bacterium, candidiasis, cryptococcus nuiguttulatus bacterium, clostridium perfringen, staphylococcus xylosus, country Bu Qiu
The bacteriostasis that bacterium, pichia farinose, the various bacteria in pig streptococcus generate collaboration (it is mutual when inhibiting to produce to generate 30%
Action index CI < 1).
Specific embodiment
Below with reference to the embodiment of the present invention, description that is clear, finishing is carried out to technical solution of the present invention, it is clear that retouched
The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
The bacteriostasis that 1 resveratrol of test example is combined with protein kinase kinase inhibitor
It measures resveratrol, kinases inhibitor and resveratrol respectively using filter paper enzyme and protein kinase inhibits
Bacteriostatic activity of the combined system of agent to various bacteria.Specifically, drawing prepared bacterial suspension (1 with liquid-transfering gun
×106/ mL), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.Sterilizing filter paper piece is taken, lets off 6 respectively
Impregnate 1h in the tested material methanol solution of kind of concentration gradient, by the 6mm circular filter paper piece impregnated be attached to it is above-mentioned make containing bacterium
On plate, each culture dish (diameter 90mm) sticks the filter paper (filter of 3 dipped same mass concentration tested material methanol solutions
The scraps of paper are spaced identical as far as possible), using 50% methanol solution as blank control.Processed plate containing bacterium is placed in 37 DEG C of insulating boxs
Middle culture measures colony diameter for 24 hours, using crossing method, and calculates inhibiting rate (IR) according to following formula.
It is mapped with logarithm of the inhibiting rate (IR) to drug concentration (μM), and carries out linear regression with Excel, according to recurrence
Equation extrapolates the concentration of resveratrol and kinases inhibitor when generating 30% inhibition, respectively IC30(A)With IC30(B)Value.
For drug combination, then made with the logarithm (log (c)) of inhibiting rate (IR) to the concentration (μM) of resveratrol in drug combination
Figure, and linear regression is carried out with Excel, resveratrol when extrapolating 30% inhibition according to regression equation in combined system is dense
Degree, i.e. IC30(mixA), further according to the molar ratio of resveratrol in combined system and kinases inhibitor, extrapolate 30% inhibition
When combined system in kinases inhibitor concentration, i.e. IC30(mixB)。
Resveratrol is calculated according to the following formula, and the interaction index for inhibiting various bacteriums is combined with protein kinase enzyme inhibitor
CI。
As CI < 1, synergistic effect is indicated, and the smaller representative synergistic effect of CI is stronger.The results are shown in Table 1.
Table 1
Although as it can be seen from table 1 resveratrol and kinases inhibitor of the present invention individually medication when
50% is not crossed to the maximal percentage inhibition of each bacterium, but highest inhibiting rate is greatly improved with different mol ratio combinations, and
In part, molar ratio range can generate the inhibiting effect of collaboration in 30% inhibiting rate.
Under 30% depression effect, resveratrol generates various bacteriums with the combined system of kinases inhibitor and cooperates with
The molar ratio of bacteriostasis is as shown in table 2 below
Table 2
Embodiment 1 includes the preparation of resveratrol and the capsule of Sunitinib malate (molar ratio 0.01:1)
Prescription
Preparation method
Resveratrol, Sunitinib malate, microcrystalline cellulose and the sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed,
Filling capsule, packing.
Embodiment 2 includes resveratrol and two tosilate monohydrate (molar ratio 0.5:1) of Lapatinib
The preparation of tablet
Prescription
Preparation method
Take the resveratrol, two tosilate monohydrate of Lapatinib, microcrystalline cellulose, stearic rich horse of recipe quantity
Sour sodium, is sufficiently mixed, tabletting.
Embodiment 3 includes the preparation of resveratrol and gram azoles for the granule of Buddhist nun (molar ratio 1:1)
Prescription
Preparation method
It takes resveratrol, gram azoles of recipe quantity for Buddhist nun, microcrystalline cellulose, sodium stearyl fumarate, is sufficiently mixed, dispense.
Embodiment 4 includes the preparation of the capsule of resveratrol and hydrochloric acid training azoles pa Buddhist nun (molar ratio 50:1)
Prescription
Preparation method
Resveratrol, hydrochloric acid training the azoles pa Buddhist nun, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed, filling
Capsule, packing.
Embodiment 5 includes the preparation of the tablet of resveratrol and Afatinib 2-maleate (molar ratio 100:1)
Prescription
Preparation method
The resveratrol, Afatinib 2-maleate, microcrystalline cellulose, sodium stearyl fumarate of recipe quantity are taken, it is sufficiently mixed
It closes, tabletting.
Embodiment 6 includes the preparation of resveratrol and the granule of pazopanib (molar ratio 0.01:1)
Prescription
Preparation method
Resveratrol, pazopanib, microcrystalline cellulose, the sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed, packing.
Embodiment 7 includes the preparation of the capsule of resveratrol and Rui Gefeini monohydrate (molar ratio 1:1)
Prescription
Preparation method
The resveratrol, Rui Gefeini monohydrate, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed,
Filling capsule, packing.
Embodiment 8 includes the preparation of the capsule of resveratrol and bosutinib monohydrate (molar ratio 1:1)
Prescription
Preparation method
The resveratrol, bosutinib monohydrate, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed,
Filling capsule, packing.
Claims (10)
1. a kind of composition containing kinases inhibitor and resveratrol, which is characterized in that the protein kinase inhibits
Agent is selected from Sutent, Lapatinib, training azoles pa Buddhist nun, Afatinib, bosutinib, gram azoles for Buddhist nun, pazopanib and auspicious dagger-axe
The solvate of one of non-Buddhist nun or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt, Er Qiebai
The molar ratio of veratryl alcohol and the kinases inhibitor is in (0.01~100): between 1.
2. composition according to claim 1, which is characterized in that the kinases inhibitor is Sunitinib malate.
3. composition according to claim 1, which is characterized in that the kinases inhibitor is Lapatinib two to toluene
Sulfonate monohydrate.
4. composition according to claim 1, which is characterized in that the kinases inhibitor is hydrochloric acid training azoles pa Buddhist nun.
5. composition according to claim 1, which is characterized in that the kinases inhibitor is two maleic acid of Afatinib
Salt.
6. composition according to claim 1, which is characterized in that the kinases inhibitor is that bosutinib one is hydrated
Object.
7. composition according to claim 1, which is characterized in that the kinases inhibitor is gram azoles for Buddhist nun.
8. composition according to claim 1, which is characterized in that the kinases inhibitor is pazopanib.
9. composition according to claim 1, which is characterized in that the kinases inhibitor is that Rui Gefeini mono- is hydrated
Object.
10. the oral solid formulation containing the composition of any one according to claim 1~9, which is characterized in that the solid
The dosage form of preparation is selected from one of granule, capsule and tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811233677.4A CN109078189A (en) | 2018-10-23 | 2018-10-23 | Composition containing kinases inhibitor and resveratrol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811233677.4A CN109078189A (en) | 2018-10-23 | 2018-10-23 | Composition containing kinases inhibitor and resveratrol |
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| CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
| CN110643528A (en) * | 2019-09-06 | 2020-01-03 | 哈尔滨师范大学 | Kluyveromyces intermedia with good degradation effect on cellulose |
| CN110652512A (en) * | 2018-12-28 | 2020-01-07 | 暨南大学 | Application of crizotinib in preparation of anti-gram-positive-bacteria drugs |
| WO2023206896A1 (en) * | 2022-04-29 | 2023-11-02 | 澳门大学 | Use of akt inhibitor iv in preparation of reagent for inhibiting bacterial metabolism and growth |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110652512A (en) * | 2018-12-28 | 2020-01-07 | 暨南大学 | Application of crizotinib in preparation of anti-gram-positive-bacteria drugs |
| CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
| CN110643528A (en) * | 2019-09-06 | 2020-01-03 | 哈尔滨师范大学 | Kluyveromyces intermedia with good degradation effect on cellulose |
| CN110643528B (en) * | 2019-09-06 | 2022-05-13 | 哈尔滨师范大学 | Kluyveromyces intermedia with good degradation effect on cellulose |
| WO2023206896A1 (en) * | 2022-04-29 | 2023-11-02 | 澳门大学 | Use of akt inhibitor iv in preparation of reagent for inhibiting bacterial metabolism and growth |
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