CN105520906B - A kind of temperature sensitive self-healing hydrogel and preparation method thereof being loaded with doxorubicin hydrochloride - Google Patents
A kind of temperature sensitive self-healing hydrogel and preparation method thereof being loaded with doxorubicin hydrochloride Download PDFInfo
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- CN105520906B CN105520906B CN201511003648.5A CN201511003648A CN105520906B CN 105520906 B CN105520906 B CN 105520906B CN 201511003648 A CN201511003648 A CN 201511003648A CN 105520906 B CN105520906 B CN 105520906B
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- doxorubicin hydrochloride
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The present invention relates to a kind of temperature sensitive self-healing hydrogel and preparation method thereof for being loaded with doxorubicin hydrochloride, composition includes chitosan, and sodium β-glycerophosphate and both ends have the polyethylene glycol of benzaldehyde base.The present invention is reacted using the amino in chitosan structure with the benzaldehyde base at polyethylene glycol both ends, form the imine linkage with self-healing performance, and in conjunction with chitosan/sodium β-glycerophosphate thermo-sensitive gel, doxorubicin hydrochloride is loaded by physics inclusion and wherein prepares a kind of novel temperature sensitive self-healing hydrogel drug delivery system.The drug delivery system is liquid at room temperature, it can be gelled rapidly under body temperature after being injected into tumor locus, drug depot be formed, compared with traditional situ-gel, temperature sensitive self-healing gel has stronger mechanical strength, and under external force or disorganization's effect, quick self-regeneration may be implemented, to avoid burst drug release, further delay drug release, to extend drug in the residence time of tumor locus, enhances drug effect, reduce toxic side effect.
Description
Technical field
The present invention relates to a kind of temperature sensitive self-healing hydrogel and preparation method thereof for being loaded with doxorubicin hydrochloride, belongs to pharmaceutical preparation neck
Domain.
Background technique
Currently, the main means of oncotherapy are operation excision, radiation and chemotherapy.During treating malignant tumour,
What Most patients considered first is tumor tissues as much as possible to be cut off by operation, but the indication performed the operation is only limitted to morning
Phase tumour, the surrounding wetting occurred for the tumour middle and later periods or DISTANT METASTASES IN, treatment then need to assist preoperation radiotherapy or chemotherapy,
A part of patient will also carry out after surgery Radiotherapy chemotherapy to carry out steadiness treatment.However in the process of Radiotherapy chemotherapy, residual
Tumour cell the recurrence or transfer of tumour may be caused due to system chemotherapy or the administration mode of local radiotherapy.Cause
This, the opposite recurrence for improving and effectivelying prevent cancer of anti-tumor drug anticancer activity may be implemented in the administration mode of intratumor injection
And transfer.The drug concentration that this administration mode can reduce Systemic drug concentrations, improve tumor locus is reducing side effect
On the basis of improve antitumor action.
Situ-gel is at room temperature liquid, after being injected into agents area, by organism physiology condition also known as in body gel
Or the influence of other environmental factors, that is, the preparation that phase transition forms semi-solid gel state occurs.Most study is shell at present
Glycan/sodium β-glycerophosphate (β-glycerophosphate) temperature sensing in situ gel rubber system, chitosan and sodium β-glycerophosphate
Mixed liquor is liquid condition at room temperature, and under the physiological temp of human body, phase transition, which occurs, becomes semi-solid gel.Chitosan temperature
Quick gel has the advantages that nontoxic, good biocompatibility and biodegradable.After the gel systems locally injecting, can with
Medicine position forms drug depot, is conducive to slow release drug, extends the time that drug is retained in injection site, enhances drug effect.
However, that there is also intensity is inadequate for existing intratumor injection thermo-sensitive gel drug delivery system, the problems such as burst drug release.
Self-healing hydrogel is the bioengineering scholar invention in California, USA university San Diego branch school, can make to be implanted into human body
Interior hydrogel material bracket or drug delivery system can heal automatically after being wound repeatedly.It has been reported that being with chitosan
Primary raw material is synthesized by simple material, has prepared the hydrogel with self-healing ability.Current self-healing gel is mainly solid
Volume morphing can only be applied by heeling-in of performing the operation, complicated for operation.The present invention is by synthesizing a kind of both ends with benzaldehyde base
Polyethylene glycol (diabenzaldehyde-terminated telechelic polyethyleneglycol, DF-PEG), benefit
Esterification is carried out with the benzaldehyde base of amino and polyethylene glycol both ends in chitosan structure, forms the Asia with self-healing performance
Amine key, and in conjunction with traditional chitosan/sodium β-glycerophosphate thermo-sensitive gel, prepare it is a kind of it is novel can inject it is temperature sensitive from
More hydrogel system.The system is easier to be accepted by patients for that it(?) can be easier to operate to avoid wound when treating；Improve simultaneously
Traditional thermo-sensitive gel intensity is weak, easily burst release the shortcomings that.
Doxorubicin hydrochloride (Doxorubicin Hydrochloride, DOX), also known as Doxorubicin, mechanism of action are main
It is the DOX molecule intercalation of DNA, inhibits the synthesis of nucleic acid, be clinically used anthracycline anti-malignant tumor antibiotic, has antitumor
The features such as spectrum is wide, activity is strong and good effect, but the serious toxic side effect of doxorubicin hydrochloride greatly limits its answering in chemotherapy
With.The present invention dexterously combines self-healing property with thermo-sensitive gel system, using doxorubicin hydrochloride as drug model, by simple
Doxorubicin hydrochloride is loaded in gel solution by physical mixed, is injected directly into tumor locus, does not need to bury by surgical operation
It plants, it is simple and convenient, and the hydrogel being crushed in injection process can realize rapidly selfreparing, by drug " fixation " in expection portion
Position, then slow release, avoid burst drug release, reach therapeutic purposes.
Summary of the invention
The purpose of the present invention is provide a kind of doxorubicin hydrochloride temperature of practical and convenient, reliable and stable treatment tumour for clinic
Quick self-healing hydrogel and preparation method thereof, it is intended to overcome mechanical strength present in traditional thermo-sensitive gel weak and burst drug release etc. no
Foot.
In order to achieve the above object, the present invention the following technical schemes are provided:
A kind of temperature sensitive self-healing hydrogel and preparation method thereof being loaded with doxorubicin hydrochloride, it is characterised in that the gel is gathered by shell
Sugar, sodium β-glycerophosphate and DF-PEG composition, load doxorubicin hydrochloride by physical mixed.
The temperature sensitive self-healing hydrogel intratumor injection preparation of doxorubicin hydrochloride provided by the invention, wherein DF-PEG is by PEG2000
It is synthesized with p formylbenzoic acid by esterification, dosage is 1.0~2.0mg/mL.
The temperature sensitive self-healing hydrogel intratumor injection preparation of doxorubicin hydrochloride provided by the invention, the shell that wherein chitosan solution is
Glycan glacial acetic acid aqueous solution, dosage are 10.0~15.0mg/mL.
The temperature sensitive self-healing hydrogel intratumor injection preparation of doxorubicin hydrochloride provided by the invention, the wherein use of sodium β-glycerophosphate
Amount is 10.0~20.0mg/mL.
The temperature sensitive self-healing hydrogel intratumor injection preparation of doxorubicin hydrochloride provided by the invention, preparation method mainly include with
Under several steps:
(1) a certain amount of PEG is weighed2000With p formylbenzoic acid, in 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne
Diimmonium salt hydrochlorate (1Ethyl3 (3dimethyllaminopropyl) carbodiie hydrochlide, EDC.HCL) and 4-
18h is reacted under dimethylamino naphthyridine (4-dimethylaminopyridine, DMAP) reaction condition, after product is precipitated with ether
It filters, operates repeatedly three times, obtain white solid；DF-PEG is obtained after being dialysed with bag filter (MWCO:8000-14000).
(2) DF-PEG that step (1) obtains is dissolved in deionized water, it is water-soluble to be configured to certain density DF-PEG for ultrasound
Liquid.
(3) a certain amount of chitosan is weighed, is dissolved in glacial acetic acid solution, the ice vinegar of certain density chitosan is configured to
Aqueous acid, 4 DEG C store for future use.
(4) it weighs a certain amount of sodium β-glycerophosphate to be dissolved in deionized water, is configured to certain density β-phosphoglycerol
Sodium water solution.
(5) a certain amount of doxorubicin hydrochloride is weighed in chitosan solution, and stirring makes it completely dissolved, to chitosan solution
In DF-PEG solution is added dropwise, stir, sodium β-glycerophosphate solution be added dropwise under condition of ice bath, continuing stirring makes its mixing
Uniformly to get invention formulation.
Invention formulation is liquid at room temperature, after being injected into tumor locus, can be gelled rapidly to be formed under physiological temp
Semi-solid gel, as drug depot slow release drug, compared with traditional temperature sensitive type in-situ gel, temperature sensitive self-healing gel tool
There is stronger mechanical strength, and under external force or disorganization's effect, quick self-regeneration is may be implemented in self-healing gel, to keep away
Exempt from burst drug release, further delays the release of drug.The present invention is expected to pass through as a kind of novel intratumor injection drug delivery system
Slowly drug release reaches therapeutic purposes, easy to operate, reduces drug toxicity, solves in traditional vein and heeling-in medication not
Foot.
Detailed description of the invention
Attached drawing 1: (a) of the resulting DF-PEG of specific embodiment 1 is infrared with (b) nuclear magnetic spectrum.
Attached drawing 2: the external gelling figure of the resulting temperature sensitive self-healing aqueogel of specific embodiment 1.
Attached drawing 3: the investigation of the 1 temperature sensitive self-healing hydrogel self-healing performance of gained of specific embodiment.
Attached drawing 4: the drug release patterns in vitro of 1 gained gel preparation of specific embodiment, wherein DOX-CG, which is represented, loads salt
The chitosan of sour adriamycin/sodium β-glycerophosphate thermo-sensitive gel, chitosan/β-that DOX-CGD represents loading doxorubicin hydrochloride are sweet
The temperature sensitive self-healing hydrogel of oleophosphoric acid sodium/DF-PEG.
Specific embodiment
The present invention is further explained and is illustrated combined with specific embodiments below, it should be understood that given embodiment
Being merely illustrative property, any restrictions are not constituted to the scope of the present invention in any way.
Specific embodiment 1
Weigh a certain amount of PEG2000, p formylbenzoic acid and DMAP are dissolved in the methylene chloride of 50mL, are added suitable
EDC.HCL is measured, reaction 18h is stirred at room temperature, suction filtration obtains white solid.Reaction obtained solid is redissolved in methylene chloride,
It is precipitated, is operated repeatedly three times with ice ether.Obtained solid is placed in bag filter and is dialysed two days, DF-PEG is obtained after freeze-drying.
Nuclear-magnetism and infared spectrum are shown in attached drawing 1.
Chitosan (0.04g) is dissolved in the glacial acetic acid solution (0.1M) of 2mL, and doxorubicin hydrochloride powder, which is added, keeps its molten
Solution, DF-PEG solution is added dropwise under agitation, sodium β-glycerophosphate solution is added dropwise under condition of ice bath, continues to stir
It is uniformly mixed it to get the temperature sensitive self-healing aqueogel of doxorubicin hydrochloride.Said preparation is liquid condition, syringeability in room temperature
Well, 3min can be gelled under 37 DEG C of water bath conditions.Attached drawing 2 is shown in external gelling test.
Specific embodiment 2
Temperature sensitive self-healing hydrogel resulting to the specific embodiment of the invention 1 carries out the investigation of self-healing performance, sees attached drawing 3.
The preliminary examinations of self-healing ability: the temperature sensitive self-healing hydrogel prepared is cut in half from centre, and uses methylene
Indigo plant dyes wherein half.The gel of incision is put together again, observe two kinds of gels whether can completely self-healing it is extensive
Again at original complete gel.Whether repetitive operation, observation gel may be implemented self-healing repeatedly.
The further investigation of self-healing ability: suitable chitosan/sodium β-glycerophosphate (CS/ β-GP) solution and shell are taken respectively
Glycan/sodium β-glycerophosphate/DF-PEG (CS/ β-GP/DF-PEG) solution in 2.5mL syringe, is placed in 37 ± 1 DEG C of water-baths
Until complete gelation.Syringe is taken out, is injected to gel in cillin bottle completely using 0.5mm syringe needle, until gel rubber system is complete
It is destroyed entirely.A period of time is stood, gel form in cillin bottle is observed.
Specific embodiment 3
Temperature sensitive self-healing hydrogel resulting to the specific embodiment of the invention 1 carries out tablets in vitro behavior test, release profiles
As shown in Fig. 4.
Take 1mL be loaded with doxorubicin hydrochloride CS/ β-GP solution and each 3 parts of CS/ β-GP/DF-PEG solution in bag filter,
It seals, after making its complete gelation for a period of time under the conditions of 37 ± 1 DEG C, the phosphate buffer of 100mL pH 6.8 is added,
100rpm isothermal vibration.It samples at a set point in time, is sampled as 2ml every time, while the fresh phosphate that same amount is added is slow
Solution is rushed to keep the effect of bakie, sample time 1h, 2h, 4h, 8h, 12h, for 24 hours, then 48h, 72h take every three days
Sample.The sample of taking-up takes subsequent filtrate sample introduction through 0.45 μm of filtering with microporous membrane, and doxorubicin hydrochloride is measured under 490nm wavelength
Amount calculates cumulative release amount.
Claims (3)
1. a kind of temperature sensitive self-healing hydrogel for being loaded with doxorubicin hydrochloride, it is characterised in that: by chitosan, sodium β-glycerophosphate, two
It is terminal modified to be formed by the polyethylene glycol of benzaldehyde base and by the doxorubicin hydrochloride that physical mixed loads.
2. the temperature sensitive self-healing hydrogel according to claim 1 for being loaded with doxorubicin hydrochloride, it is characterised in that: repair at the both ends
The polyethylene glycol for being decorated with benzaldehyde base is to synthesize to obtain by esterification by PEG2000 and p formylbenzoic acid.
3. the preparation method of the temperature sensitive self-healing hydrogel described in claim 1 for being loaded with doxorubicin hydrochloride, it is characterised in that: including
Following steps:
Step 1, by PEG2000 and p formylbenzoic acid in 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
18h is reacted under the conditions of salt, 4-dimethylaminopyridine, product filters after being precipitated with ether, is operated three times repeatedly, gained white is consolidated
Body obtains the polyethylene glycol that benzaldehyde base is modified with to both ends after being dialysed with bag filter；
Step 2, the polyethylene glycol that both ends are modified with benzaldehyde base is dissolved in deionized water, ultrasound obtains to both ends and is modified with benzene first
The Aqueous Solutions of Polyethylene Glycol of aldehyde radical, concentration are 1.0~2.0mg/mL；
Step 3, chitosan being dissolved in glacial acetic acid aqueous solution, obtains the glacial acetic acid aqueous solution of chitosan, concentration is 10.0~
15.0mg/mL, 4 DEG C store for future use；
Step 4, sodium β-glycerophosphate being dissolved in deionized water, obtains sodium β-glycerophosphate aqueous solution, concentration is 10.0~
20.0mg/mL；
Step 5, doxorubicin hydrochloride is dissolved in the glacial acetic acid aqueous solution of chitosan, the poly- second that both ends are modified with benzaldehyde base is added dropwise
Sodium β-glycerophosphate aqueous solution is added dropwise under condition of ice bath for two alcohol solutions, stirring, continue stirring be uniformly mixed it to get.
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| CN106474050B (en) * | 2016-11-09 | 2019-10-29 | 中国药科大学 | It is a kind of to be loaded with aptamer-doxorubicin conjugates temperature sensing in situ gel rubber intratumor injection preparation and preparation method thereof |
| CN106832060A (en) * | 2017-03-10 | 2017-06-13 | 中国科学院长春应用化学研究所 | Shitosan, its preparation method and injectable anti-bacterial hydrogel that arginine is modified |
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