CN106361697A - Taxol-carrying micelle polymer containing ibuprofen, preparation, and preparation methods - Google Patents
Taxol-carrying micelle polymer containing ibuprofen, preparation, and preparation methods Download PDFInfo
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- CN106361697A CN106361697A CN201610729243.8A CN201610729243A CN106361697A CN 106361697 A CN106361697 A CN 106361697A CN 201610729243 A CN201610729243 A CN 201610729243A CN 106361697 A CN106361697 A CN 106361697A
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- 239000000693 micelle Substances 0.000 title claims abstract description 46
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229920000642 polymer Polymers 0.000 title claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 50
- 229930012538 Paclitaxel Natural products 0.000 claims description 48
- 229960001592 paclitaxel Drugs 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 229920000151 polyglycol Polymers 0.000 claims description 29
- 239000010695 polyglycol Substances 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 28
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- 238000006116 polymerization reaction Methods 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
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- 229940079593 drug Drugs 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000007334 copolymerization reaction Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
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- 239000002244 precipitate Substances 0.000 claims description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
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- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
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- 231100000135 cytotoxicity Toxicity 0.000 description 1
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Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a taxol-carrying micelle preparation containing ibuprofen. In the preparation, a polyethylene glycol monomethyl ether-polylactide-ibuprofen segmented copolymer serves as a micelle carrier, wherein the chemical structure formula of the segmented copolymer is represented as (I), n = 20-265 and m = 5-100. The taxol-carrying micelle preparation is improved in stability and inhibition capability on tumors. A preparation method of the drug-carrying micelle is simple and is easy to carry out in industrial application. The low-toxicity polyethylene glycol monomethyl ether-polylactide-ibuprofen is used as the micelle carrier without necessity of addition of other auxiliary to the micelle preparation, so that high safety is achieved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations is and in particular to a kind of load paclitaxel micellar copolymerization thing containing ibuprofen, system
Agent and preparation method.
Background technology
Malignant tumor is the disease that a class seriously threatens human life's safety, research safety, effective antitumour medicine pair
The life quality and the life span that improve tumour patient are significant.
Paclitaxel is a kind of broad-spectrum anti-cancer drug, and its mechanism of action is unique, all effective to a lot of drug resistance tumor strains.Clinical
On, paclitaxel is mainly used in the treatment of breast carcinoma and ovarian cancer, to pulmonary carcinoma, colorectal carcinoma, melanoma, incidence cancer, pouring
Bar tumor also has certain curative effect.Due to covering the treatment of several frequently-occurring cancers, paclitaxel is in daily use in clinical tumor chemotherapy,
It is always the phytogenic anticarcinogen of global sales first.
Because paclitaxel is insoluble in water, therefore clinically need for paclitaxel to be prepared into injectable preparation.Initially face
On bed, the formulation for paclitaxel of application is paclitaxel injection, is by polyoxyethylene castor oil (cremophor el) and dehydrated alcohol
The water solublity to increase paclitaxel for the mixed solvent of composition.But clinically find that paclitaxel injection has significant defect.
Ethanol has cytotoxicity, and discharges histamine during polyoxyethylene castor oil degradation in vivo, can lead to patient that anaphylaxiss occur
Probability increase.Above all paclitaxel injection to tumor locus lack targeting, tumor tissues concentration relatively
Low, and it is also easy to produce pharmacokineticss drug resistance.In order to reduce the toxicity of formulation for paclitaxel and improve its drug efficiency, in recent years clinically
Apply the paclitaxel nano preparation of no-solvent type successively.Wherein as the paclitaxel albumin nano granular of Bristol-Myers Squibb Co.
Suspension (abraxane), the Paclitaxel liposome (power flutters element) of Nanjing greenery Cisco Pharmaceutical and also not in Korea Spro of Discussion on Chinese Listed
The paclitaxel micellar preparation (genexol-pm) of samyang company of state exploitation.Contrast paclitaxel injection, above formulation for paclitaxel
All using carrier, paclitaxel is entered with load, therefore had without antiallergic pretreatment, clinical efficacy is good, toxicity is relatively low spy
Point.Even so, still there is lacking of blood stability difference in application when participating in the cintest in these formulation for paclitaxel with nano-scale
Fall into.It is mainly manifested in, formulation for paclitaxel can quickly disintegrate after being injected to human body in blood, and discharge entrained medicine, and
It is not reaching to desired tumor passive target effect (epr effect).In addition, for example white egg of above-mentioned paclitaxel carrier
White nanoparticle, liposome and polymer micelle are all substantially excipient substances, have no any Synergistic anti-cancer function with paclitaxel.
Content of the invention
An object of the present invention is to provide a kind of the poly- of enhancing paclitaxel carried medicine micelle stability containing ibuprofen
Compound, shown in its chemical structural formula such as formula<>:
Wherein, n=20～265, m=5～100.
Preferably, in described polymer, the molecular weight of poly glycol monomethyl ether block is 1000～3000.
Preferably, in described polymer, the molecular weight of polylactide block is 500～5000.
In the present invention, there is provided one kind is with poly glycol monomethyl ether-polylactide-ibuprofen (mpeg-pla- cloth Lip river
Fragrant) block copolymer material, the introducing of ibuprofen, can effectively reduce the critical micelle concentration of carrier micelle, can improve hydrophobic medicine
The compatibility of hydrophobic chain segment in thing molecule and block copolymer, obtains the carrier micelle with high stability.
It has recently been demonstrated that cancer therapy drug can produce effective Synergistic anti-cancer function with the combination of anti-inflammatory drug ibuprofen
(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 ibuprofen is proved to suppress the heat shock protein hsp70 of overexpression on tumor cell, and
This shock protein all plays a part promotion to formation, development and the transfer of tumor, can increase swollen after ibuprofen suppression
The sensitivity to cancer therapy drug for the tumor, thus strengthen the active anticancer to tumor for the carrier micelle preparation.Therefore, provide in the present invention
Not only blood stability strengthens poly glycol monomethyl ether-polylactide-ibuprofen micellar carrier, also can Synergistic anti-cancer medicine to swollen
The suppression of tumor.
Further object is that providing the method preparing above-mentioned micellar copolymerization thing, the method includes walking as follows
Rapid:
(1) under nitrogen protection, poly glycol monomethyl ether is added in dry polymerization bottle, is heated to 80-100 DEG C and makes to gather
Glycol monoethyl ether dissolves, and opens stirring simultaneously evacuation more than 30 minutes；It is subsequently cooled to room temperature, add 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 gross weight 0.1%-
0.3% octoate catalyst stannous, and add the toluene solvant after appropriate eliminating water, evacuation more than 30 minutes, period nitrogen
Displacement three times；After sealing by fusing polymerization bottle under vacuum, polyase 13-20 hours in 120-140 DEG C of oil bath, open polymerization bottle after cooling, plus
Dichloromethane dissolves, and ether precipitates, and filters, and obtains poly glycol monomethyl ether-polylactide block copolymer after being dried；
(2) gained poly glycol monomethyl ether-polylactide block copolymer, ibuprofen and dicyclohexylcarbodiimide are pressed
Mol ratio 1:2:2.1 is dissolved in dichloromethane, and after room temperature reaction 10-30 hour, ether precipitates, and filters, and obtains final product institute after being dried
State copolymer.
Preferably, the particle diameter of described micelle is 20～25nm.
Another object of the present invention is to provide the method preparing above-mentioned load paclitaxel micellar preparation, and the method includes
Following steps:
(1) described micellar copolymerization thing and paclitaxel are put in container, add organic solvent to be dissolved, then rotation is steamed
Send out organic solvent, and residual organic solvents are removed by vacuum drying, obtain the polymer mixed film containing dewatering medicament；
(2) resulting polymers hybrid films are hatched to transparence in 40-60 DEG C of water-bath, add the super of identical preheating temperature
Pure water or normal saline, phosphate buffer, shake well aquation, obtain transparent polypeptide drug-loaded micelle solution；
(3) by gained polypeptide drug-loaded micelle solution with 0.45 μm of filtering with microporous membrane, obtain carrying paclitaxel micellar preparation.
Preferably, the detailed process of described step (1) is: described micellar copolymerization thing is put in container with paclitaxel, plus
Enter acetonitrile to be dissolved, at 40-60 DEG C, organic solvent was evaporated completely by rotary evaporation for 30 minutes to 2 hours, true at 40 DEG C
Sky is dried the organic solvent that more than 2-12 hour removes residual, obtains the polymer mixed film containing paclitaxel.
Preferably, gained carries in the micellar preparation of paclitaxel, and the ethane nitrile content of residual is less than 10ppm.
Beneficial effects of the present invention:
1 present invention introduces ibuprofen can not only improve the stability of micelle moreover it is possible to help carrier micelle for tumor
Rejection ability；
2nd, the preparation process is simple of carrier micelle of the present invention is it is easy to commercial Application；
3rd, the present invention adopts the lower poly glycol monomethyl ether-polylactide-ibuprofen of toxicity is micellar carrier, and micelle
Other adjuvants need not be added, safety is higher in preparation.
Additionally it is important to note that the load paclitaxel micellar preparation containing ibuprofen provided by the present invention, also may be used
Carrier as other antitumor dewatering medicaments uses, and the polylactide section in polymer micelle also can use other degradable polymerization
Thing segment replaces.
Brief description
Fig. 1 is the nuclear-magnetism figure of mpeg-pla and mpeg-pla- ibuprofen；
Fig. 2 is the graph of molecular weight distribution of mpeg-pla and mpeg-pla- ibuprofen；
Fig. 3 is the critical micelle concentration figure of mpeg-pla；
Fig. 4 is the critical micelle concentration figure of mpeg-pla- ibuprofen micelle；
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 carrying paclitaxel mpeg-pla with carrying paclitaxel mpeg-pla- ibuprofen micelle.
Specific embodiment
Below by embodiment, the present invention is specifically described it is necessary to it is pointed out here that be following examples be use
In being further detailed it is impossible to be interpreted as limiting the scope of the invention to the present invention, being skilled in technique of this field
Personnel made according to foregoing invention content some nonessential improve and adjust, still fall within protection scope of the present invention.
Embodiment 1
The synthesis of mpeg-pla- ibuprofen block copolymer
Under nitrogen protection, 2.5g molecular weight is that 2000 poly glycol monomethyl ether is added in dry polymerization bottle, heating
To 100 DEG C, poly glycol monomethyl ether is dissolved, open stirring simultaneously evacuation more than 30 minutes；It is subsequently cooled to room temperature, add
The d of 2.5g, l- lactide, poly glycol monomethyl ether and d, the octoate catalyst stannous of l- lactide gross weight 0.1%, and add
Toluene solvant after appropriate eliminating water, evacuation more than 30 minutes, period is with nitrogen displacement three times；After sealing by fusing polymerization bottle under vacuum,
120 DEG C of oil baths are polymerized 20 hours, break polymerization bottle after cooling, add methylene chloride dissolving, ether precipitates, filter, after being dried
Obtain poly glycol monomethyl ether-polylactide block copolymer (mpeg-pla).
By above-mentioned mpeg-pla block copolymer, ibuprofen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In dichloromethane, room temperature reaction is after 30 hours, and ether precipitates, and filters, obtain after being dried poly glycol monomethyl ether-polylactide-
Ibuprofen block copolymer a (mpeg-pla- ibuprofen a).Fig. 1 is synthesized mpeg-pla and mpeg-pla- ibuprofen 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- ibuprofen block copolymer b
Under nitrogen protection, 2.5g molecular weight is that 2000 poly glycol monomethyl ether is added in dry polymerization bottle, heating
To 100 DEG C, poly glycol monomethyl ether is dissolved, open stirring simultaneously evacuation more than 30 minutes；It is subsequently cooled to room temperature, add
The d of 1.25g, l- lactide, poly glycol monomethyl ether and d, the octoate catalyst stannous of l- lactide gross weight 0.1%, and plus
Enter the toluene solvant after appropriate eliminating water, evacuation more than 30 minutes, period is with nitrogen displacement three times；Sealing by fusing polymerization bottle under vacuum
Afterwards, it is polymerized 20 hours in 120 DEG C of oil baths, breaks polymerization bottle after cooling, add methylene chloride dissolving, ether precipitates, filter, be dried
After obtain poly glycol monomethyl ether-polylactide block copolymer (mpeg-pla).
By above-mentioned mpeg-pla block copolymer, ibuprofen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In dichloromethane, room temperature reaction is after 30 hours, and ether precipitates, and filters, obtain after being dried poly glycol monomethyl ether-polylactide-
Ibuprofen block copolymer b (mpeg-pla- ibuprofen b).Wherein, the molecular weight of mpeg block is 2000, and the degree of polymerization is 44；
The degree of polymerization of pla block is 14.
Embodiment 3
The synthesis of mpeg-pla- ibuprofen block copolymer c
Under nitrogen protection, 2.5g molecular weight is that 5000 poly glycol monomethyl ether is added in dry polymerization bottle, heating
To 100 DEG C, poly glycol monomethyl ether is dissolved, open stirring simultaneously evacuation more than 30 minutes；It is subsequently cooled to room temperature, add
The d of 2.5g, l- lactide, poly glycol monomethyl ether and d, the octoate catalyst stannous of l- lactide gross weight 0.1%, and add
Toluene solvant after appropriate eliminating water, evacuation more than 30 minutes, period is with nitrogen displacement three times；After sealing by fusing polymerization bottle under vacuum,
120 DEG C of oil baths are polymerized 20 hours, break polymerization bottle after cooling, add methylene chloride dissolving, ether precipitates, filter, after being dried
Obtain poly glycol monomethyl ether-polylactide block copolymer (mpeg-pla).
By above-mentioned mpeg-pla block copolymer, ibuprofen, 1:2:2.1 is dissolved in dicyclohexylcarbodiimide in molar ratio
In dichloromethane, room temperature reaction is after 30 hours, and ether precipitates, and filters, obtain after being dried poly glycol monomethyl ether-polylactide-
Ibuprofen block copolymer c (mpeg-pla- ibuprofen c).Wherein, the molecular weight of mpeg block is 5000, and the degree of polymerization is 110；
The degree of polymerization of pla block is 52.
Embodiment 4
The mpeg-pla of synthesis and mpeg-pla- ibuprofen block copolymer in Example 1, according to paclitaxel and block
The different rate of charges of copolymer (being shown in Table 1) weighs raw material.Raw material is put in container, adds acetonitrile to be dissolved, at 60 DEG C
Organic solvent is evaporated by lower rotary evaporation for 1 hour completely, and vacuum drying at 40 DEG C removes the organic solvent of residual for 12 hours, obtains
To the polymer mixed film containing paclitaxel；Hybrid films are hatched to transparence in 40 DEG C of water-baths, add the super of identical preheating temperature
Pure water or normal saline, phosphate buffer, shake well aquation, obtain transparent polypeptide drug-loaded micelle solution；By described load medicine glue
Bundle solution, with 0.45 μm of filtering with microporous membrane, obtains a series of carrier micelle preparations.Use high effective liquid chromatography for measuring drug loading,
Measure particle diameter with dynamic light scattering.Result shows that the drug loading of mpeg-pla- ibuprofen micelle is higher than the load medicine of mpeg-pla
Amount.
Table 1mpeg-pla- ibuprofen and mpeg-pla are as the drug loading of carrier and particle diameter
Embodiment 5
The mpeg-pla of synthesis and mpeg-pla- ibuprofen block polymer in Example 1, by thin in embodiment 4
Film hydration method prepares blank micella, with the critical micelle concentration of pyrene fluorescence spectrometry micelle.The glue of configuration finite concentration gradient
Bundle solution and the acetone soln of pyrene.The acetone soln of a certain amount of pyrene is added in bottle, under vacuum, makes acetone volatilization dry, then plus
Enter the micellar solution of the variable concentrations preparing, pyrene concentration controls at 0.6 μm.Ultrasonic 30 minutes to 60 minutes, water bath with thermostatic control shaking table
Shake 3 hours to 4 hours at 30 DEG C, then stand one day.The fluorescence measuring solution under fluorescence spectrophotometer 394nm launch wavelength is inhaled
Receive, before the peak value according to absworption peak after skew and skew, the peakedness ratio of absworption peak is drawn and calculated cmc, and test result is shown in Table 2, cmc
Figure is shown in accompanying drawing 3.Result shows, the cmc value of mpeg-pla- ibuprofen micelle will be less than mpeg-pla micelle, illustrates that its solution is steady
Qualitative more excellent.
Table 2 carrier Determination of Critical Micelle Concentration
Embodiment 6
Micellar solution stability test.The load obtaining in embodiment 4 paclitaxel micelle is diluted to paclitaxel concentration be about
2mg/ml, respectively at 4 DEG C, 20 DEG C, 30 DEG C, under normal indoor light conditions, whether the micellar solution that every two hours detects by an unaided eye
Precipitation is had to produce.Produce if there are precipitation, then explanation micelle terminates steady statue, and records the time that steady statue terminates.Surely
Qualitative test the results are shown in Table 3, table 4.Result shows under the same terms, and the mpeg-pla- cloth Lip river micelle carrying paclitaxel is more purple than carrying
The mpeg-pla micelle storage time of China fir alcohol is longer.
Table 3mpeg-pla- ibuprofen stability test result
Table 4mpeg-pla stability test result
Embodiment 7
The vitro drug release test of carrier micelle.The load obtaining in embodiment 4 paclitaxel micelle is diluted to paclitaxel
Concentration is about 2mg/ml, in take wherein 2ml to be added to bag filter that molecular cut off is 3500.By bag filter seal rearmounted such as
In the pbs solution of 50ml ph7.4, using the release speed of high-performance liquid chromatogram determination paclitaxel under conditions of 37 DEG C and lucifuge
Rate.Result, as shown in fig. 6, showing that the mpeg-pla- cloth Lip river micelle carrying paclitaxel can effectively stablize contained dewatering medicament, reduces
Medicine in transportation is revealed, thus reducing the toxic and side effects of medicine.
Claims (9)
1. a kind of polymer of the enhancing paclitaxel carried medicine micelle stability containing ibuprofen is it is characterised in that its chemical constitution
Shown in formula such as formula<>:
Wherein, n=20～265, m=5～100.
2. micellar copolymerization thing according to claim 1 is it is characterised in that in described polymer, poly glycol monomethyl ether is embedding
The molecular weight of section is 1000～3000.
3. micellar copolymerization thing according to claim 1 and 2 is it is characterised in that in described polymer, polylactide block
Molecular weight is 500～5000.
4. a kind of prepare containing ibuprofen enhancing paclitaxel carried medicine micelle stability polymer method it is characterised in that
Methods described comprises the steps:
(1), under nitrogen protection, poly glycol monomethyl ether is added in dry polymerization bottle, is heated to 80-100 DEG C and makes poly- second two
Alcohol monomethyl ether dissolves, and opens stirring simultaneously evacuation more than 30 minutes；It is subsequently cooled to room temperature, add and poly glycol monomethyl ether matter
Than the d for 1:1～0.5, l- lactide and weight are poly glycol monomethyl ether and d to amount, l- lactide gross weight 0.1%-
0.3% octoate catalyst stannous, and add the toluene solvant after appropriate eliminating water, evacuation more than 30 minutes, period nitrogen
Displacement three times；After sealing by fusing polymerization bottle under vacuum, polyase 13-20 hours in 120-140 DEG C of oil bath, open polymerization bottle after cooling, plus
Dichloromethane dissolves, and ether precipitates, and filters, and obtains poly glycol monomethyl ether-polylactide block copolymer after being dried；
(2) by gained poly glycol monomethyl ether-polylactide block copolymer, ibuprofen and dicyclohexylcarbodiimide press mole
It is dissolved in dichloromethane than 1:2:2.1, after room temperature reaction 10-30 hour, ether precipitates, and filters, and obtains final product described common after being dried
Polymers.
5. with micellar copolymerization thing as described in claim 1-3 or the micellar copolymerization thing that prepared by claim 4 methods described
Load paclitaxel micellar preparation for carrier.
6. according to claim 5 carry paclitaxel micellar preparation it is characterised in that described micelle particle diameter be 20～
25nm.
7. preparation as described in claim 5 or 6 carry paclitaxel micellar preparation method it is characterised in that methods described include as
Lower step:
(1) described micellar copolymerization thing and paclitaxel are put in container, add organic solvent to be dissolved, then rotary evaporation falls
Organic solvent, and residual organic solvents are removed by vacuum drying, obtain the polymer mixed film containing dewatering medicament；
(2) resulting polymers hybrid films are hatched to transparence in 40-60 DEG C of water-bath, add the ultrapure of identical preheating temperature
One of water, normal saline, phosphate buffer, shake well aquation, obtain transparent polypeptide drug-loaded micelle solution；
(3) by gained polypeptide drug-loaded micelle solution with 0.45 μm of filtering with microporous membrane, obtain carrying paclitaxel micellar preparation.
8. method according to claim 7 is it is characterised in that the detailed process of described step (1) is: described micelle is gathered
Compound and paclitaxel put in container, add acetonitrile to be dissolved, rotary evaporation will have for 30 minutes to 2 hours at 40-60 DEG C
Machine solvent is evaporated completely, more than vacuum drying 2-12 hour at 40 DEG C removes the organic solvent of residual, obtains containing paclitaxel
Polymer mixed film.
9. method according to claim 8 is it is characterised in that in gained micellar preparation, the ethane nitrile content of residual is less than
10ppm.
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