CN106361697B - A kind of load taxol micellar copolymerization object, preparation and preparation method containing brufen - Google Patents
A kind of load taxol micellar copolymerization object, preparation and preparation method containing brufen Download PDFInfo
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Abstract
The present invention provides a kind of load taxol micellar preparation containing brufen, said preparation is using poly glycol monomethyl ether-polylactide-brufen block copolymer as micellar carrier.Wherein the chemical structural formula of block copolymer is as shown in formula<I>, wherein n=20~265, m=5~100.The stability of micella and the rejection ability to tumour can be improved in the present invention；The preparation process of carrier micelle of the present invention is simple, is easy to industrial application；The present invention uses poly glycol monomethyl ether-polylactide-brufen of hypotoxicity for micellar carrier, and without adding other auxiliary materials in micellar preparation, highly-safe.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of load taxol micellar copolymerization object containing brufen, system
Agent and preparation method.
Background technique
Malignant tumour is a kind of disease for seriously threatening human life's safety, research safety, effective antitumour drug pair
The life quality and life span for improving tumour patient are of great significance.
Taxol is a kind of broad-spectrum anti-cancer drug, its mechanism of action is unique, effective to many drug resistance tumor strains.It is clinical
On, taxol is mainly used for the treatment of breast cancer and oophoroma, to lung cancer, colorectal cancer, melanoma, head-neck carcinoma, leaching
Bar tumor also has certain curative effect.Due to covering the treatment of several frequently-occurring cancers, taxol is in daily use in clinical tumor chemotherapy,
The always phytogenic anticarcinogen of global sales first.
Since taxol is insoluble in water, clinically need for taxol to be prepared into the preparation of injectable.Initially face
The formulation for paclitaxel applied on bed is paclitaxel injection, is by Emulsifier EL-60 (cremophor EL) and dehydrated alcohol
The mixed solvent of composition is to increase the water solubility of taxol.But clinically discovery paclitaxel injection has significant defect.
Ethyl alcohol has cytotoxicity, and discharges histamine when Emulsifier EL-60 degradation in vivo, will lead to patient and allergic reaction occurs
Probability increase.Most importantly paclitaxel injection to tumor locus lack targeting, tumor tissues concentration relatively
It is low, and it is also easy to produce pharmacokinetics drug resistance.In order to reduce the toxicity of formulation for paclitaxel and improve its drug efficiency, in recent years clinically
The paclitaxel nano preparation of no-solvent type is applied successively.Wherein such as the taxol albumin nano granular of Bristol-Myers Squibb Co.
Suspension (Abraxane), the Paclitaxel liposome (power flutters element) of Nanjing greenery Cisco medicine company and also not in Korea Spro of Discussion on Chinese Listed
The taxol micellar preparation (Genexol-PM) of Samyang company, state exploitation.Compare paclitaxel injection, the above formulation for paclitaxel
Using carrier, to taxol, into load, therefore with not having to, antiallergy is pre-processed, clinical efficacy is good, the lower spy of toxicity
Point.Nevertheless, these formulation for paclitaxel with nano-scale are in upper still the lacking there are blood stability difference of application when participating in the cintest
It falls into.It being mainly manifested in, formulation for paclitaxel is injected to after human body can quickly disintegrate in blood, and discharge entrained drug, and
Desired tumour passive target effect (EPR effect) is not reached.In addition to this, for example white egg of above-mentioned paclitaxel carrier
White nanoparticle, liposome and polymer micelle are substantially excipient substances, have no any Synergistic anti-cancer function with taxol.
Summary of the invention
The enhancing paclitaxel carried medicine micella stability containing brufen that one of the objects of the present invention is to provide a kind of is gathered
Object is closed, chemical structural formula is as shown in formula<I>:
Wherein, n=20~265, m=5~100.
Preferably, in the polymer, the molecular weight of poly glycol monomethyl ether block is 1000~3000.
Preferably, in the polymer, the molecular weight of polylactide block is 500~5000.
In the present invention, one kind is provided with poly glycol monomethyl ether-polylactide-brufen (mPEG-PLA- cloth Lip river
It is fragrant) block copolymer material, the introducing of brufen can be effectively reduced the critical micelle concentration of carrier micelle, can improve hydrophobic medicine
The compatibility of hydrophobic chain segment in object molecule and block copolymer obtains the carrier micelle with high stability.
It has recently been demonstrated that anticancer drug and the combination of anti-inflammatory drug brufen can produce effective Synergistic anti-cancer function
(H Endo et al.Ibuprofen enhances the anticancer activity of cisplatin in lung
cancer cells by inhibiting the heat shock protein 70,Cell Death and Disease
(2014)5,e1027).Because brufen is proved the heat shock protein Hsp70 that can inhibit to over-express on tumour cell, and
This shock protein all plays a part of promotion to the formation of tumour, development and transfer, can increase after brufen inhibits swollen
Tumor is to the sensibility of anticancer drug, to enhance carrier micelle preparation to the anticancer activity of tumour.Therefore, provided in the present invention
Not only blood stability enhances poly glycol monomethyl ether-polylactide-brufen micellar carrier, can also Synergistic anti-cancer drug to swollen
The inhibition of tumor.
It is another object of the present invention to provide the method for preparing above-mentioned micellar copolymerization object, this method includes following step
It is rapid:
(1) under nitrogen protection, poly glycol monomethyl ether is added in dry polymerization bottle, is heated to 80-100 DEG C and to gather
Glycol monoethyl ether dissolution, opens and stirs and vacuumize 30 minutes or more；It then cools to room temperature, is added and polyethyleneglycol first
Ether mass ratio is the D of 1:1, and L- lactide and weight are poly glycol monomethyl ether and D, L- lactide total weight 0.1%-
0.3% octoate catalyst stannous, and the toluene solvant after appropriate water removal is added, it vacuumizes 30 minutes or more, during which uses nitrogen
Displacement is three times；After sealing polymerization bottle under vacuum, the polyase 13-20 hours in 120-140 DEG C of oil bath is opened polymerization bottle after cooling, is added
Methylene chloride dissolution, ether precipitating, filtering obtain poly glycol monomethyl ether-polylactide block copolymer after dry；
(2) gained poly glycol monomethyl ether-polylactide block copolymer, brufen and dicyclohexylcarbodiimide is pressed
Molar ratio 1:2:2.1 dissolves in methylene chloride, after room temperature reaction 10-30 hours, ether precipitating, and filtering, up to institute after drying
State copolymer.
Preferably, the partial size of the micella is 20~25nm.
Another object of the present invention is that providing the method for preparing above-mentioned load taxol micellar preparation, this method includes
Following steps:
(1) by the micellar copolymerization object and taxol investment container, organic solvent is added and is dissolved, then rotation is steamed
Hair falls organic solvent, and by vacuum drying removal residual organic solvents, obtains the mixed with polymers film containing dewatering medicament；
(2) resulting polymers hybrid films are hatched in 40-60 DEG C of water-bath to transparence, the super of identical preheating temperature is added
Pure water or physiological saline, phosphate buffer, shake well aquation obtain transparent polypeptide drug-loaded micelle solution；
(3) it by 0.45 μm of filtering with microporous membrane of gained polypeptide drug-loaded micelle solution, obtains carrying taxol micellar preparation.
Preferably, the detailed process of the step (1) are as follows: by the micellar copolymerization object and taxol investment container, add
Enter acetonitrile to be dissolved, be evaporated organic solvent completely to 2 hours within rotary evaporation 30 minutes at 40-60 DEG C, it is true at 40 DEG C
Sky drying 2-12 hours or more the remaining organic solvent of removal, obtains the mixed with polymers film containing taxol.
Preferably, gained carries in the micellar preparation of taxol, and remaining ethane nitrile content is less than 10ppm.
Beneficial effects of the present invention:
1, present invention introduces brufen can not only improve the stability of micella, moreover it is possible to help carrier micelle for tumour
Rejection ability；
2, the preparation process of carrier micelle of the present invention is simple, is easy to industrial application；
3, the present invention uses the lower poly glycol monomethyl ether-polylactide-brufen of toxicity for micellar carrier, and micella
Without adding other auxiliary materials in preparation, safety is higher.
It, can also additionally it is important to note that the load taxol micellar preparation provided by the present invention containing brufen
Carrier as other antitumor dewatering medicaments uses, and the polylactide section in polymer micelle can also use other degradable polymerizations
Object segment replaces.
Detailed description of the invention
Fig. 1 is the nuclear-magnetism figure of mPEG-PLA and mPEG-PLA- brufen；
Fig. 2 is the graph of molecular weight distribution of mPEG-PLA and mPEG-PLA- brufen；
Fig. 3 is the critical micelle concentration map of mPEG-PLA；
Fig. 4 is the critical micelle concentration map of mPEG-PLA- brufen micella；
Fig. 5 is the chemical structural drawing of resulting polymers of the present invention, wherein n=20~265, m=5~100.
Fig. 6 is the vitro drug release figure for carrying taxol mPEG-PLA and carrying taxol mPEG-PLA- brufen micella.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
It is further detailed in the present invention, should not be understood as limiting the scope of the invention, which is skilled in technique
Some nonessential modifications and adaptations that personnel are made according to foregoing invention content, still fall within protection scope of the present invention.
Embodiment 1
The synthesis of mPEG-PLA- brufen block copolymer
Under nitrogen protection, the poly glycol monomethyl ether that 2.5g molecular weight is 2000 is added in dry polymerization bottle, is heated
To 100 DEG C poly glycol monomethyl ether is dissolved, opens and stir and vacuumize 30 minutes or more；It then cools to room temperature, is added
The D of 2.5g, L- lactide, the octoate catalyst stannous of poly glycol monomethyl ether and D, L- lactide total weight 0.1%, and be added
Toluene solvant after appropriate water removal is vacuumized 30 minutes or more, is during which replaced three times with nitrogen；After sealing polymerization bottle under vacuum,
It polymerize 20 hours in 120 DEG C of oil baths, breaks polymerization bottle after cooling, adds methylene chloride dissolution, ether precipitating, filtering, after dry
Obtain poly glycol monomethyl ether-polylactide block copolymer (mPEG-PLA).
By above-mentioned mPEG-PLA block copolymer, brufen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In methylene chloride, after room temperature reaction 30 hours, ether precipitating, filtering obtains poly glycol monomethyl ether-polylactide-after dry
Brufen block copolymer A (mPEG-PLA- brufen A).Fig. 1 is synthesized mPEG-PLA and mPEG-PLA- brufen block
The nuclear-magnetism figure of copolymer.Fig. 2 is the graph of molecular weight distribution of two kinds of block copolymers.Wherein, the molecular weight of mPEG block is 2000,
The degree of polymerization is 44；The degree of polymerization of PLA block is 27.
Embodiment 2
The synthesis of mPEG-PLA- brufen block copolymer B
Under nitrogen protection, the poly glycol monomethyl ether that 2.5g molecular weight is 2000 is added in dry polymerization bottle, is heated
To 100 DEG C poly glycol monomethyl ether is dissolved, opens and stir and vacuumize 30 minutes or more；It then cools to room temperature, is added
The D of 1.25g, L- lactide, the octoate catalyst stannous of poly glycol monomethyl ether and D, L- lactide total weight 0.1%, and add
Toluene solvant after entering appropriate water removal is vacuumized 30 minutes or more, is during which replaced three times with nitrogen；Polymerization bottle is sealed under vacuum
Afterwards, it polymerize 20 hours in 120 DEG C of oil baths, breaks polymerization bottle after cooling, adds methylene chloride dissolution, and ether precipitating filters, dry
After obtain poly glycol monomethyl ether-polylactide block copolymer (mPEG-PLA).
By above-mentioned mPEG-PLA block copolymer, brufen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In methylene chloride, after room temperature reaction 30 hours, ether precipitating, filtering obtains poly glycol monomethyl ether-polylactide-after dry
Brufen block copolymer B (mPEG-PLA- brufen B).Wherein, the molecular weight of mPEG block is 2000, the degree of polymerization 44；
The degree of polymerization of PLA block is 14.
Embodiment 3
The synthesis of mPEG-PLA- brufen block copolymer C
Under nitrogen protection, the poly glycol monomethyl ether that 2.5g molecular weight is 5000 is added in dry polymerization bottle, is heated
To 100 DEG C poly glycol monomethyl ether is dissolved, opens and stir and vacuumize 30 minutes or more；It then cools to room temperature, is added
The D of 2.5g, L- lactide, the octoate catalyst stannous of poly glycol monomethyl ether and D, L- lactide total weight 0.1%, and be added
Toluene solvant after appropriate water removal is vacuumized 30 minutes or more, is during which replaced three times with nitrogen；After sealing polymerization bottle under vacuum,
It polymerize 20 hours in 120 DEG C of oil baths, breaks polymerization bottle after cooling, adds methylene chloride dissolution, ether precipitating, filtering, after dry
Obtain poly glycol monomethyl ether-polylactide block copolymer (mPEG-PLA).
By above-mentioned mPEG-PLA block copolymer, brufen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In methylene chloride, after room temperature reaction 30 hours, ether precipitating, filtering obtains poly glycol monomethyl ether-polylactide-after dry
Brufen block copolymer C (mPEG-PLA- brufen C).Wherein, the molecular weight of mPEG block is 5000, the degree of polymerization 110；
The degree of polymerization of PLA block is 52.
Embodiment 4
The mPEG-PLA and mPEG-PLA- brufen block copolymer synthesized in Example 1, according to taxol and block
The different feed ratio of copolymer (being shown in Table 1) weighs raw material.It puts the raw materials into container, acetonitrile is added and is dissolved, at 60 DEG C
Organic solvent is evaporated by lower rotary evaporation for 1 hour completely, is dried in vacuo 12 hours at 40 DEG C and is removed remaining organic solvent, obtains
To the mixed with polymers film containing taxol；Hybrid films are hatched in 40 DEG C of water-baths to transparence, and the super of identical preheating temperature is added
Pure water or physiological saline, phosphate buffer, shake well aquation obtain transparent polypeptide drug-loaded micelle solution；By the load medicine glue
0.45 μm of filtering with microporous membrane of beam solution, obtains a series of carrier micelle preparations.With high effective liquid chromatography for measuring drugloading rate,
Partial size is measured with dynamic light scattering.The result shows that the drugloading rate of mPEG-PLA- brufen micella is higher than the load medicine of mPEG-PLA
Amount.
Table 1mPEG-PLA- brufen and drugloading rate and partial size of the mPEG-PLA as carrier
Embodiment 5
The mPEG-PLA and mPEG-PLA- brufen block polymer synthesized in Example 1, by thin in embodiment 4
Film hydration method prepares blank micella, with the critical micelle concentration of pyrene fluorescence spectrometry micella.Configure the glue of a certain concentration gradient
The acetone soln of beam solution and pyrene.The acetone soln of a certain amount of pyrene is added in bottle, makes acetone volatilization dry under vacuum, then plus
Enter the micellar solution of the various concentration prepared, pyrene concentration is controlled at 0.6 μM.Ultrasound 30 minutes to 60 minutes, water bath with thermostatic control shaking table
It is shaken 3 hours to 4 hours at 30 DEG C, then stands one day.The fluorescence that solution is measured under Fluorescence Spectrometer 394nm launch wavelength is inhaled
It receives, according to the peak value of absorption peak after offset and before deviating, the peak value of absorption peak calculates CMC than drawing, and test result is shown in Table 2, CMC
Figure is shown in attached drawing 3.The result shows that the CMC value of mPEG-PLA- brufen micella will be lower than mPEG-PLA micella, illustrate that its solution is steady
It is qualitative more excellent.
2 carrier Determination of Critical Micelle Concentration of table
Embodiment 6
Micellar solution stability test.Load taxol micella obtained in embodiment 4, which is diluted to paclitaxel concentration, is about
2mg/mL, respectively under 4 DEG C, 20 DEG C, 30 DEG C, normal indoor light conditions, whether the micellar solution that every two hours detects by an unaided eye
There is precipitating to generate.If there is precipitating generates, then illustrate that micella terminates stable state, and record the time that stable state terminates.Surely
Qualitative test the results are shown in Table 3, table 4.The result shows that the mPEG-PLA- cloth Lip river micella for carrying taxol is more purple than carrying under the same terms
The mPEG-PLA micella storage time of China fir alcohol is longer.
Table 3mPEG-PLA- brufen stability test result
Table 4mPEG-PLA stability test result
Embodiment 7
The vitro drug release of carrier micelle is tested.Load taxol micella obtained in embodiment 4 is diluted to taxol
Concentration is about 2mg/mL, and wherein 2mL is taken to be added in the bag filter that molecular cut off is 3500.Such as by bag filter sealing postposition
In the PBS solution of 50mL pH7.4, the release speed of high performance liquid chromatography measurement taxol is utilized under conditions of at 37 DEG C and being protected from light
Rate.As a result it as shown in fig. 6, showing that the mPEG-PLA- cloth Lip river micella for carrying taxol can effectively stablize contained dewatering medicament, reduces
Drug leakage during transportation, to reduce the toxic side effect of drug.
Claims (7)
1. a kind of polymer of the enhancing paclitaxel carried medicine micella stability containing brufen, which is characterized in that its chemical structure
Formula is as shown in formula<I>:
Wherein, n=20~265, m=5~100；
In the polymer, the molecular weight of poly glycol monomethyl ether block is 1000~3000；The molecular weight of polylactide block
It is 500~5000.
2. a kind of polymer for preparing the enhancing paclitaxel carried medicine micella stability containing brufen as described in claim 1
Method, which is characterized in that described method includes following steps:
(1) under nitrogen protection, poly glycol monomethyl ether is added in dry polymerization bottle, is heated to 80-100 DEG C and is made poly- second two
The dissolution of alcohol monomethyl ether, opens and stirs and vacuumize 30 minutes or more；It then cools to room temperature, is added and poly glycol monomethyl ether matter
For amount than the D for 1:1~0.5, L- lactide and weight are poly glycol monomethyl ether and D, L- lactide total weight 0.1%-
0.3% octoate catalyst stannous, and the toluene solvant after appropriate water removal is added, it vacuumizes 30 minutes or more, during which uses nitrogen
Displacement is three times；After sealing polymerization bottle under vacuum, the polyase 13-20 hours in 120-140 DEG C of oil bath is opened polymerization bottle after cooling, is added
Methylene chloride dissolution, ether precipitating, filtering obtain poly glycol monomethyl ether-polylactide block copolymer after dry；
(2) by gained poly glycol monomethyl ether-polylactide block copolymer, brufen and dicyclohexylcarbodiimide by mole
In methylene chloride than 1:2:2.1 dissolution, after room temperature reaction 10-30 hours, ether precipitating, filtering, up to described poly- after drying
Close object.
3. using polymer as described in claim 1 or the polymer being prepared by claim 2 the method as carrier
Carry taxol micellar preparation.
4. load taxol micellar preparation according to claim 3, which is characterized in that the partial size of the micella be 20~
25nm。
5. the method that preparation carries taxol micellar preparation as described in claim 3 or 4, which is characterized in that the method includes such as
Lower step:
(1) by the polymer and taxol investment container, organic solvent is added and is dissolved, then rotary evaporation falls organic
Solvent, and by vacuum drying removal residual organic solvents, obtain the mixed with polymers film containing dewatering medicament；
(2) resulting polymers hybrid films are hatched in 40-60 DEG C of water-bath to transparence, the ultrapure of identical preheating temperature is added
One of water, physiological saline, phosphate buffer, shake well aquation obtain transparent polypeptide drug-loaded micelle solution；
(3) it by 0.45 μm of filtering with microporous membrane of gained polypeptide drug-loaded micelle solution, obtains carrying taxol micellar preparation.
6. according to the method described in claim 5, it is characterized in that, the detailed process of the step (1) are as follows: by the polymer
In taxol investment container, acetonitrile is added and is dissolved, it rotary evaporation 30 minutes to 2 hours at 40-60 DEG C will be organic molten
Agent is evaporated completely, and 2-12 hours or more the remaining organic solvent of removal is dried in vacuo at 40 DEG C, obtains the polymerization containing taxol
Object hybrid films.
7. according to the method described in claim 6, it is characterized in that, remaining ethane nitrile content is less than in gained micellar preparation
10ppm。
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| CN107242166A (en) * | 2017-08-04 | 2017-10-13 | 安徽省泾县丰瑞水产科技有限公司 | The integrated cultural method of a kind of sturgeon, Pelteobagrus fulvidraco |
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