CN106188649A - A kind of slow releasing carrier of medication hydrogel and preparation method thereof - Google Patents
A kind of slow releasing carrier of medication hydrogel and preparation method thereof Download PDFInfo
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- CN106188649A CN106188649A CN201610524329.7A CN201610524329A CN106188649A CN 106188649 A CN106188649 A CN 106188649A CN 201610524329 A CN201610524329 A CN 201610524329A CN 106188649 A CN106188649 A CN 106188649A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/02—Dextran; Derivatives thereof
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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
- 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
- A61K47/38—Cellulose; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/02—Dextran; Derivatives thereof
Abstract
The present invention relates to technical field of bioengineering, be specifically related to a kind of slow releasing carrier of medication hydrogel and preparation method thereof.Wherein, described slow releasing carrier of medication hydrogel is prepared by polysaccharide derivates, Fmoc L Phe solution；Described polysaccharide derivates is prepared by dehydration condensation with Fmoc L phenylalanine by polysaccharide.This hydrogel mechanical property is good；It is suitable as medicine carrying gel, medicine can be made slowly to discharge within the longer time, reach the effect of medicament slow release, so that medicine is fully used.Present invention also offers the preparation method of above-mentioned hydrogel, by the dehydration condensation of polysaccharide Yu Fmoc L phenylalanine, it is thus achieved that polysaccharide derivates；Gained polysaccharide derivates, Fmoc L Phe solution and gluconic acid lactone is utilized to prepare slow releasing carrier of medication hydrogel.
Description
[technical field]
The present invention relates to technical field of bioengineering, be specifically related to a kind of slow releasing carrier of medication hydrogel and preparation side thereof
Method.
[background technology]
In recent years, the research of supramolecular hydrogel receives the extensive concern of people.The change of supramolecular hydrogel can be formed
Compound is referred to as gelator, and gelator is typically some micromolecular compounds；Under suitable conditions, gelator can be certainly
Assemble and form three-dimensional net structure, make water lose flowability and obtain supramolecular hydrogel.Different from traditional chemical gel
It is that little molecular gel cytokine network structure is to be formed by non-bonding effects such as hydrogen bond, electrostatic interaction or Van der Waals forces
, therefore avoid radiation and other chemical cross-linking agent during gel formation to the impact of gel subsequent applications and restriction.
As bioactive substance, the good biocompatibility of amino acids material, wide material sources, application prospect is wide.Therefore
Using amphipathic aminoacid and polypeptide as the research of a kind of supermolecular gel factor by the common concern of people.In recent years, learn
Persons prepare and have studied RGD (peptides arginine-gly cine-aspartic acid, arginine-glycine-sky
Winter propylhomoserin polypeptide) sequence, lysine, histidine, the amino acidic group gelator such as valine and isoleucine.
But, owing to supramolecular hydrogel is the network structure formed by non-bonding active force, this gel-like material
Viscoelasticity and hardness more weak, water retention property is generally poor, greatly limit its application.The most how to improve supramolecular hydrogel
Mechanical performance become study hotspot.In prior art, there is following evolutionary approach: strengthen micromolecular water by Molecular Recognization
The elasticity of gel；By regulating the viscoelasticity of gel with nano Au particle hydridization；Be blended by itself and agarose improve solidifying
The mechanical performance of glue；By itself and clay and glucosan being blended the viscoelasticity etc. improving gel.But research is right at present
Gel mechanical property improves limited, limits its application.
[summary of the invention]
For the problem that the mechanical property overcoming current hydrogel is poor, the present invention provides a kind of slow releasing carrier of medication hydrogel
And preparation method thereof.
The present invention solves that a technical scheme of above-mentioned technical problem is to provide a kind of slow releasing carrier of medication hydrogel, it is extremely
Few by polysaccharide derivates, Fmoc-L-phenylalanine (N-fluorenylmethyloxycarbonyl-L-phenylalanine, Fmoc-L-phenyl alanine)
Solution prepares；Described polysaccharide derivates is prepared by dehydration condensation with Fmoc-L-phenylalanine by polysaccharide.
Preferably, the concentration of described Fmoc-L-Phe solution is 0.015-0.02g/mL, Fmoc-L-phenylalanine
The amount ratio of solution and polysaccharide derivates is 1mL:2-10mg；The elastic modelling quantity of described hydrogel is 20-6000Pa.
Preferably, the microstructure of described hydrogel is the regular arrangement of thin filamentary fibers.
The present invention solves above-mentioned technical problem provide another technical scheme: the preparation of a kind of slow releasing carrier of medication hydrogel
Method, in it comprises the steps: to provide polysaccharide, Fmoc-L-phenylalanine, Fmoc-L-Phe solution and gluconic acid
Ester；Dehydration condensation by polysaccharide Yu Fmoc-L-phenylalanine, it is thus achieved that polysaccharide derivates；Utilize gained polysaccharide derivates,
Fmoc-L-Phe solution and gluconic acid lactone prepare slow releasing carrier of medication hydrogel.
Preferably, in the polysaccharide dehydration condensation with Fmoc-L-phenylalanine, polysaccharide and Fmoc-L-phenylalanine
Mass ratio be 1:0.3-0.5.
Preferably, it is thus achieved that the step of described polysaccharide derivates farther includes: polysaccharide is dissolved in organic solvent, Xiang Qijia
Enter Fmoc-L-phenylalanine；After Fmoc-L-phenylalanine dissolves, sequentially add dicyclohexylcarbodiimide and 4-diformazan
Aminopyridine dissolves and obtains mixed solution；After mixed solution is reacted 18-36h at room temperature, it is thus achieved that polysaccharide derivates.
Preferably, the mass ratio of described polysaccharide, dicyclohexylcarbodiimide and DMAP is 1:(0.2-
0.3):(0.06-0.1)。
Preferably, the concentration of described Fmoc-L-Phe solution is 0.015-0.02g/mL, described Fmoc-L-phenylpropyl alcohol
Propylhomoserin solution is 1mL:2-10mg with the amount ratio of polysaccharide derivates.
Preferably, the preparation of described Fmoc-L-Phe solution is farther included: added by Fmoc-L-phenylalanine
In deionized water, stir at 35-50 DEG C, and add alkaline solution, after dissolving, obtain Fmoc-L-Phe solution.
Preferably, the preparation method of described slow releasing carrier of medication hydrogel farther includes:
Taking gained polysaccharide derivates to add in deionized water, stirring 5-20min at 70-90 DEG C, to obtain polysaccharide derivates water-soluble
Liquid, and after being cooled to room temperature, be sequentially added into gluconic acid lactone and Fmoc-L-Phe solution, stir static after formed
Slow releasing carrier of medication hydrogel.
Relative to prior art, in a kind of slow releasing carrier of medication hydrogel provided by the present invention and preparation method thereof, make
Primary raw material be wide material sources, there is good biocompatibility and the polysaccharide of biodegradable and Fmoc-L-phenylpropyl alcohol
Propylhomoserin；Obtained hydrogel mechanical property is good.Therefore this hydrogel is suitable as medicine carrying gel, can make medicine when longer
Interior slowly release, reaches the effect of medicament slow release, so that medicine is fully used.
[accompanying drawing explanation]
Fig. 1 is the photo of prepared hydrogel scanning electron microscope in experimental group 1.
Fig. 2 is the photo of prepared hydrogel scanning electron microscope in experimental group 2.
Fig. 3 is the photo of prepared hydrogel scanning electron microscope in experimental group 3.
Fig. 4 is the photo of prepared hydrogel scanning electron microscope in contrast groups 1.
Fig. 5 is the photo of prepared hydrogel scanning electron microscope in contrast groups 2.
Fig. 6 is experimental group 1-3 and the medicament slow release curve synoptic diagram of contrast groups 1,2 medicine carrying gel.
[detailed description of the invention]
In order to make the purpose of the present invention, technical scheme and advantage are clearer, below in conjunction with accompanying drawing and embodiment,
The present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention,
It is not intended to limit the present invention.
First embodiment of the invention provides a kind of slow releasing carrier of medication hydrogel, and it is by polysaccharide derivates, Fmoc-L-benzene
Alanine (limpid) solution prepares；Described polysaccharide derivates is passed through dehydration condensation system by polysaccharide with Fmoc-L-phenylalanine
?.Polysaccharide derivates structure is shown below:
I.e. Fmoc-L-phenylalanine grafts on polysaccharide so that the polysaccharide derivates of gained has regulation and control Fmoc-L-phenylpropyl alcohol
The performance of the formed hydrogel of propylhomoserin.
The mechanical property of this hydrogel is relevant with the amount ratio of polysaccharide derivates to Fmoc-L-phenylalanine clear solution,
The mechanical property of hydrogel can be regulated by changing this amount ratio.Wherein, the concentration of described Fmoc-L-phenylalanine clear solution
For the amount ratio of 0.015-0.02g/mL, Fmoc-L-phenylalanine clear solution and polysaccharide derivates in the range of 1mL:2-
10mg；The elastic modelling quantity scope of described hydrogel is 20-6000Pa.Preferably, Fmoc-L-phenylalanine clear solution and polysaccharide
Derivant amount ratio is in the range of 1mL:5-10mg, and the regulating effect of hydrogel elastic modulus is obvious within the range, prepares water
The elastic modelling quantity scope of gel is 50-6000Pa.The microstructure of described hydrogel is the regular arrangement of thin filamentary fibers.
In this embodiment, described polysaccharide can be glucose, it is also possible to be chitosan, starch, methylcellulose, ethoxy
Any one or a few mixture in cellulose or glycogen.
Second embodiment of the invention provides the preparation method of a kind of slow releasing carrier of medication hydrogel, i.e. institute in first embodiment
State the preparation method of hydrogel, it is provided that in polysaccharide, Fmoc-L-phenylalanine, Fmoc-L-Phe solution and gluconic acid
Ester；Dehydration condensation by polysaccharide Yu Fmoc-L-phenylalanine, it is thus achieved that polysaccharide derivates；Utilize gained polysaccharide derivates,
Fmoc-L-phenylalanine clear solution and gluconic acid lactone prepare slow releasing carrier of medication hydrogel.
By grafting on polysaccharide by Fmoc-L-phenylalanine, the polysaccharide derivates prepared has regulation and control Fmoc-L-phenylpropyl alcohol
The performance of the formed hydrogel of propylhomoserin.Polysaccharide then can affect graft numbers, and then impact with the amount ratio of Fmoc-L-phenylalanine
The performance of its regulation and control formed hydrogel of Fmoc-L-phenylalanine.Preferably, described polysaccharide and Fmoc-L-phenylalanine consumption
Mass ratio be 1:0.3-0.5.It is preferred that the mass ratio of described polysaccharide and Fmoc-L-phenylalanine consumption is 1:0.4, energy
Prepare the polysaccharide derivates that graft numbers is more stable and consistent, its regulating effect can be effectively ensured.
Preferably, it is thus achieved that the step of described polysaccharide derivates farther includes: polysaccharide is dissolved in organic solvent, Xiang Qijia
Enter Fmoc-L-phenylalanine, be specially and 0.5-1g glucose is dissolved in 15-30mL dimethyl sulfoxide, and be added thereto to
0.15-0.5g Fmoc-L-phenylalanine.Wherein glucose can change chitosan, starch, methylcellulose, hydroxy ethyl fiber into
Any one or a few mixture in element or glycogen, dimethyl sulfoxide can change dimethylformamide into.Treat Fmoc-L-benzene
After alanine dissolves, sequentially add 0.1-0.3g dicyclohexylcarbodiimide and 0.03-0.1g4-dimethylamino naphthyridine dissolves
Obtain mixed solution.Wherein dicyclohexylcarbodiimide is dehydrant, and DMAP is catalyst；Dehydrant can also
Select N, N'-DIC or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, naturally it is also possible to do not add
Add catalyst or select other catalyst, such as 4-nafoxidine yl pyridines or 1,8-diazabicylo 11 carbon-7-alkene.Excellent
Selection of land, the mass ratio of described polysaccharide, dicyclohexylcarbodiimide and DMAP consumption is 1:(0.2-0.3):
(0.06-0.1).It is preferred that the mass ratio of described polysaccharide, dicyclohexylcarbodiimide and DMAP consumption is 1:
(0.25-0.3): (0.05-0.08), in this proportion, react relatively stable and rapid.
After mixed solution is reacted 18-36h at room temperature, obtain the product containing glucosan derivative, anti-from this
Answer i.e. available required glucosan derivative in product.This operation is it may be that first filter product to remove dicyclohexyl
Urea precipitates；Gained filtrate is precipitated with ethanol and washs, and removes unreacted Fmoc-L-phenylalanine, naturally it is also possible to use second
Ether or acetone precipitate and wash, and being deposited in 35-60 DEG C of vacuum desiccator of obtaining after washing is repeated several times is dried 36-
60h, obtains the glucosan derivative of white powder.The Fructus Vitis viniferae that can certainly obtain from product by other means
Sugar derivatives, such as sucking filtration.
The hydrogel that the method prepares, its mechanical property is utilized to derive with polysaccharide with Fmoc-L-phenylalanine clear solution
The amount ratio of thing is correlated with, and can regulate the mechanical property of hydrogel by changing this amount ratio.Wherein said Fmoc-L-phenylalanine
The concentration of solution is 0.015-0.02g/mL, and described Fmoc-L-Phe solution is 1mL with the amount ratio of polysaccharide derivates:
2-10mg.The elastic modelling quantity scope of obtained hydrogel is 20-6000Pa.By increasing polysaccharide derivates consumption, water can be improved
The mechanical property of gel.
Concrete, described Fmoc-L-phenylalanine clear solution and polysaccharide derivates amount ratio are in the range of 1mL:2-
5mg, the elastic modelling quantity scope preparing hydrogel is 20-50Pa；Described Fmoc-L-phenylalanine clear solution and polysaccharide derivates
Amount ratio is in the range of 1mL:5-6.7mg, and the elastic modelling quantity scope preparing hydrogel is 50-300Pa；Described Fmoc-L-phenylpropyl alcohol
Propylhomoserin clear solution with polysaccharide derivates amount ratio in the range of 1mL:6.7-10mg, the elastic modelling quantity scope preparing hydrogel is
300-6000Pa.Therefore, when described Fmoc-L-phenylalanine clear solution and polysaccharide derivates amount ratio are in the range of 1mL:5-
10mg, the elastic modelling quantity preparing hydrogel has bigger constant interval, say, that hydrogel elastic modulus in the range of Gai
Regulating effect is obvious.
In the preparation method of described slow releasing carrier of medication hydrogel provided by the present invention, can directly use ready-made
Fmoc-L-phenylalanine clear solution, it is also possible to prepare voluntarily.The preparation of Fmoc-L-phenylalanine clear solution is the most permissible
For, 0.1-0.5gFmoc-L-phenylalanine is added in 4-20mL deionized water, stir at 35-50 DEG C, add 1.5-
6mLNaOH solution, stirring makes Fmoc-L-phenylalanine dissolve, utilizes syringe filters to be filtered to remove undissolved Fmoc-L-benzene
Alanine, naturally it is also possible to take the supernatant after standing, i.e. can get Fmoc-L-phenylalanine clear solution.Wherein NaOH is molten
Liquid can be by KOH solution, Na2CO3Solution and NaHCO3In solution, any one is replaced, and its role is to utilize the alkali provided
Property, improve the dissolubility of Fmoc-L-phenylalanine.
Preferably, the preparation method of described slow releasing carrier of medication hydrogel farther includes: takes gained polysaccharide derivates and adds
Enter in deionized water, stir 5-20min at 70-90 DEG C and obtain polysaccharide derivates aqueous solution, it is also possible to be to utilize ultrasound wave to carry out
Dissolve；And after being cooled to room temperature, be sequentially added into gluconic acid lactone and Fmoc-L-phenylalanine clear solution, stir static
Rear formation hydrogel.The consumption of described gluconic acid lactone is 1-5mg further.
Slow releasing carrier of medication hydrogel provided by the present invention, has good biocompatibility and biodegradable,
There is the advantage that mechanical property is good.This hydrogel is suitable as medicine carrying gel, and medicine can be made slowly to discharge within the longer time,
Reach the effect of medicament slow release, make medicine be fully used.
In the preparation method of slow releasing carrier of medication hydrogel provided by the present invention, utilize wide material sources and have good
Biocompatibility and the polysaccharide of biodegradable and Fmoc-L-phenylalanine, obtain polysaccharide by dehydration condensation and derive
Thing.The performance of this polysaccharide derivates energy Effective Regulation formed hydrogel of Fmoc-L-phenylalanine, i.e. Effective Regulation hydrogel
Mechanical property.Obtained hydrogel has the advantage that mechanical property is good.
Below to using hydrogel provided by the present invention and preparation method thereof to carry out experiment and corresponding test.
Experimental group 1:
The preparation method of employing slow releasing carrier of medication hydrogel as provided in second embodiment of the invention, it specifically wraps
Include:
Step S1, is dissolved in 0.5g glucose in 20mL dimethyl sulfoxide, and is added thereto to 0.2g Fmoc-L-phenylpropyl alcohol
Propylhomoserin.After Fmoc-L-phenylalanine dissolves, sequentially add 0.15g dicyclohexylcarbodiimide and 0.05g4-dimethylamino
Pyridine, and be allowed to dissolving and obtain mixed solution.After mixed solution is reacted 24h at room temperature, obtain containing glucosan derivative
Product.First filter product to remove dicyclohexylurea precipitate；Gained filtrate ether sedimentation, and repeated washing three
Secondary, remove unreacted Fmoc-L-phenylalanine, being deposited in 35 DEG C of vacuum desiccators of obtaining is dried 48h, obtains white powder
The glucosan derivative of powder.
Step S2, prepares Fmoc-L-phenylalanine clear solution, and 0.1gFmoc-L-phenylalanine is added 4mL deionization
In water, stirring at 35 DEG C, add the NaOH solution of the 0.1mol/L of 1.5mL, stirring makes Fmoc-L-phenylalanine dissolve, profit
It is filtered to remove undissolved Fmoc-L-phenylalanine by syringe filters, obtains Fmoc-L-phenylalanine clear solution；Then
Take the glucosan derivative of gained in 5mg step S1, and add 0.5mL deionized water；After stirring 5min at 70 DEG C, it is cooled to room
Temperature；Then add 1mg gluconic acid lactone to it, and take Fmoc-L-phenylalanine clear solution described in 1mL, stir also
Hydrogel is obtained after standing.
Experimental group 2:
The preparation method of employing slow releasing carrier of medication hydrogel as provided in second embodiment of the invention, it specifically wraps
Include:
Step S1, is dissolved in 0.8g glucose in 20mL dimethyl sulfoxide, and is added thereto to 0.3g Fmoc-L-phenylpropyl alcohol
Propylhomoserin.After Fmoc-L-phenylalanine dissolves, sequentially add 0.2g dicyclohexylcarbodiimide and 0.06g4-dimethylamino
Pyridine, and be allowed to dissolving and obtain mixed solution.After mixed solution is reacted 24h at room temperature, obtain containing glucosan derivative
Product.First filter product to remove dicyclohexylurea precipitate；Gained filtrate is precipitated with ethanol, and repeated washing three
Secondary, remove unreacted Fmoc-L-phenylalanine, being deposited in 45 DEG C of vacuum desiccators of obtaining is dried 48h, obtains white powder
The glucosan derivative of powder.
Step S2, prepare Fmoc-L-phenylalanine clear solution, by 0.2gFmoc-L-phenylalanine addition 10mL go from
In sub-water, stirring at 45 DEG C, add the NaOH solution of the 0.2mol/L of 3mL, stirring makes Fmoc-L-phenylalanine dissolve, profit
It is filtered to remove undissolved Fmoc-L-phenylalanine by syringe filters, obtains Fmoc-L-phenylalanine clear solution；Then
Take the glucosan derivative of gained in 10mg step S1, and add 1mL deionized water；After stirring 10min at 80 DEG C, it is cooled to room
Temperature；Then add 2mg gluconic acid lactone to it, and take Fmoc-L-phenylalanine clear solution described in 1.5mL, stir
And obtain hydrogel after standing.
Experimental group 3:
The preparation method of employing slow releasing carrier of medication hydrogel as provided in second embodiment of the invention, it specifically wraps
Include:
Step S1, is dissolved in 1g glucose in 20mL dimethyl sulfoxide, and is added thereto to 0.4g Fmoc-L-phenylpropyl alcohol ammonia
Acid.After Fmoc-L-phenylalanine dissolves, sequentially add 0.27g dicyclohexylcarbodiimide and 0.08g4-dimethylamino pyrrole
Pyridine, and be allowed to dissolving and obtain mixed solution.After mixed solution is reacted 24h at room temperature, obtain containing glucosan derivative
Product.First filter product to remove dicyclohexylurea precipitate；Gained filtrate acetone precipitation, and repeated washing three
Secondary, remove unreacted Fmoc-L-phenylalanine, being deposited in 60 DEG C of vacuum desiccators of obtaining is dried 48h, obtains white powder
The glucosan derivative of powder.
Step S2, prepare Fmoc-L-phenylalanine clear solution, by 0.5gFmoc-L-phenylalanine addition 20mL go from
In sub-water, stirring at 50 DEG C, add the NaOH solution of the 0.5mol/L of 6mL, stirring makes Fmoc-L-phenylalanine dissolve, profit
It is filtered to remove undissolved Fmoc-L-phenylalanine by syringe filters, obtains Fmoc-L-phenylalanine clear solution；Then
Take the glucosan derivative of gained in 20mg step S1, and add 2mL deionized water；After stirring 20min at 90 DEG C, it is cooled to room
Temperature；Then add 5mg gluconic acid lactone to it, and take Fmoc-L-phenylalanine clear solution described in 2mL, stir also
Hydrogel is obtained after standing.
On the basis of above-mentioned experimental group 1-3, in the present invention, arrange following contrast groups to compare:
Contrast groups 1:
Prepare hydrogel, specifically comprise the following steps that
(1) 0.5gFmoc-L-phenylalanine is added in 20mL deionized water, stir at 50 DEG C, add 6mL's
The NaOH solution of 0.5mol/L, stirring makes Fmoc-L-phenylalanine dissolve, utilizes syringe filters to be filtered to remove undissolved
Fmoc-L-phenylalanine, obtains Fmoc-L-phenylalanine clear solution.
(2) take 20mgFmoc-L-phenylalanine, be added thereto to 2mL deionized water；After stirring 20min at 90 DEG C, it is cooled to
Room temperature；Then add 5mg gluconic acid lactone to it, and it is limpid molten to take the Fmoc-L-phenylalanine obtained in 2mL step (1)
Liquid, obtains hydrogel after stirring and standing.
Contrast groups 2:
Prepare hydrogel, specifically comprise the following steps that
(1) 0.5gFmoc-L-phenylalanine is added in 20mL deionized water, stir at 50 DEG C, add 6mL's
The NaOH solution of 0.5mol/L, stirring makes Fmoc-L-phenylalanine dissolve, utilizes syringe filters to be filtered to remove undissolved
Fmoc-L-phenylalanine, obtains Fmoc-L-phenylalanine clear solution.
(2) take 20mg glucose, be added thereto to 2mL deionized water；After stirring 20min at 90 DEG C, it is cooled to room temperature；Then
Adding 5mg gluconic acid lactone to it, and take the Fmoc-L-phenylalanine clear solution obtained in 2mL step (1), stirring is all
Even and stand after obtain hydrogel.
For gained hydrogel in above-mentioned experimental group 1-3 and contrast groups 1,2, it is measured for its mechanical property.
Utilize rheological method to carry out the mensuration of hydrogel mechanical property, be specially water intaking gel and be placed in (parallel-plate on flow graph
Fixture, diameter 25mm), space (Gap) value is set to 1mm, and frequency is set to 1Hz, carries out load-deformation curve mensuration, takes maximum answering
Force value is the elastic modelling quantity of gel sample, and the elastic modelling quantity being obtained test carries out record.
Result and analysis:
Record the data obtained is made table 1:
Table 1 experimental group 1-3 and contrast groups 1,2 elastic modelling quantity test result
| Test object | Elastic modelling quantity |
| Experimental group 1 | 50Pa |
| Experimental group 2 | 300Pa |
| Experimental group 3 | 6000Pa |
| Contrast groups 1 | 1Pa |
| Contrast groups 2 | 4Pa |
Understanding from the above, the elastic modelling quantity of experimental group is apparently higher than contrast groups.Contrast groups 1-2 is with experimental group 1-3's
Difference is, polysaccharide derivates is added in the hydrogel that Fmoc-L-phenylalanine is formed by experimental group 1-3, and contrast groups 1-2 is then
It is to add Fmoc-L-phenylalanine or glucose.As can be seen here, after adding polysaccharide derivates, the mechanical property of hydrogel obtains very
Improve well.Hydrogel the most provided by the present invention has good mechanical performance, effectively expands the range of application of hydrogel.
In experimental group, experimental group 1 mechanical property is worst, and experimental group 2 mechanical property is slightly better than experimental group 1, and experimental group 3
Mechanical property is best.Specifically, the difference of experimental group 1-3 is: in experimental group 1, and Fmoc-L-phenylalanine clear solution is with many
The consumption of sugar derivatives is respectively 1mL, 5mg.In experimental group 2, its consumption is respectively 1.5mL, 10mg.In experimental group 3, its consumption
It is respectively 2mL, 20mg.I.e. when, in every milliliter of Fmoc-L-phenylalanine clear solution, adding the most polysaccharide derivates, made
The hydrogel mechanical property obtained is the best.Therefore change the consumption of polysaccharide derivates and Fmoc-L-phenylalanine clear solution, can obtain
To the hydrogel of different mechanical properties, i.e. realize the Modulatory character of hydrogel mechanical property.Concrete, Fmoc-L-phenylalanine
The concentration of solution is 0.015-0.02g/mL, when the amount ratio scope of Fmoc-L-phenylalanine clear solution Yu polysaccharide derivates
Time between 1mL:5-6.7mg, the hydrogel that elastic modelling quantity is 50-300Pa can be prepared；When amount ratio scope is at 1mL:6.7-
Time between 10mg, the hydrogel that elastic modelling quantity is 300-6000Pa can be prepared.
For gained hydrogel in above-mentioned experimental group 1-3 and contrast groups 1,2, scanning electron microscope (SEM) is utilized to carry out
Observe.
Result and analysis:
In experimental group 1-3 and contrast groups 1,2, the SEM picture of gained hydrogel is the most as Figure 1-5.
It can be seen that in experimental group SEM picture (i.e. Fig. 1-3), hydrogel material demonstrates by filamentous fibre from SEM picture
The microscopic appearance that dimension is formed through more regular arrangement.And in contrast groups SEM picture (i.e. Fig. 4,5), the fibre structure of hydrogel is more loose
Dissipate.And in experimental group 1-3, compared to the hydrogel of experimental group 1 gained, the fibre structure arrangement of experimental group 2,3 gained hydrogel
The most regular, show that the intermolecular force forming gel is the strongest, so that the mechanical property of hydrogel is more preferable.Pass through
Corresponding with hydrogel mechanical property i.e. hydrogel elastic modulus measurements result, it is known that the microstructure of hydrogel is that filament shape is fine
During the regular arrangement tieed up, there is the advantage that mechanical property is good, and when fiber alignment is the most regular, mechanical property is the best.
For gained hydrogel in above-mentioned experimental group 1-3 and contrast groups 1,2, it is respectively prepared medicine carrying gel, to contained medicine
Slow release behavior be measured.
The preparation of described medicine carrying gel, will be doped in hydrogel by medicine, medicine doping opportunity be glucosan derivative
After dissolving, before adding Fmoc-L-phenylalanine clear solution.As a example by experimental group 1, specially take gained in 5mg step S1
Glucosan derivative, and add 0.5mL deionized water；After stirring 5min at 70 DEG C, it is cooled to room temperature, is added thereto to 1mg model
Medicine doxorubicin hydrochloride；After it dissolves, it is added thereto to 1mg gluconic acid lactone, and takes the Fmoc-L-phenylalanine of 1mL
Clear solution, obtains medicine carrying gel after stirring and standing.Combine in the same way above-mentioned experimental group 2,3 and contrast groups 1,
2, prepare the medicine carrying gel of correspondence.
The mensuration of medicament slow release behavior, specially takes medicine carrying gel and is placed in deionized water, in the perseverance of simulation human body temperature
Temperature device make medicine slowly discharge.At regular intervals, take out sustained-release liquid, measure its drug content record, will
Curve chart shown in record the data obtained drafting pattern 6.
Result and analysis:
Calculate preparation, and draw medicament slow release curve such as Fig. 6 of medicine carrying gel.The computing formula of preparation
For: preparation=(medicine initial content-real-time content of medicine)/medicine initial content × 100%.
From fig. 6 it can be seen that after 25h, the accumulative release rate of experimental group is below 35%, contrast groups is then point
Do not reach 60% and 80%.Experimental group effect is substantially better than contrast groups, thus, it can be known that hydrogel provided by the present invention, suitable
Share and make medicine carrying gel, medicine can be made slowly to discharge within the longer time, reach the effect of medicament slow release, make medicine be filled
Divide and utilize.
In experimental group 1-3, the preparation of experimental group 2 and 3 is respectively 27% and 25%, and the accumulation of experimental group 1 is released
Rate of putting is then 35%.Therefore the effect of experimental group 2 and 3 is better than experimental group 1, its result and the result of hydrogel mechanics performance determining
Consistent, also illustrate that when the regular arrangement that the microstructure of hydrogel is thin filamentary fibers, can effectively slow down releasing of medicine
Put speed.
Compared with prior art, hydrogel provided in the present invention and preparation method thereof, have the advantage that
(1) hydrogel mechanical property provided by the present invention is good；Use primary raw material be wide material sources, have good
Biocompatibility and the polysaccharide of biodegradable and Fmoc-L-phenylalanine.The polysaccharide prepared by dehydration condensation is spread out
Biology, can improve the mechanical property of hydrogel well.When this hydrogel is suitable as medicine carrying gel, medicine can be made longer
Slowly discharge in time, reach the effect of medicament slow release, make medicine be fully used.
(2) hydrogel provided by the present invention, its mechanical property derives with polysaccharide with Fmoc-L-phenylalanine clear solution
The amount ratio of thing is correlated with；Therefore the hydrogel of corresponding mechanical property can be prepared according to the needs of practical situation, so prepared
Hydrogel have more specific aim and practicality.
(3) hydrogel provided by the present invention, its microstructure is the regular arrangement of thin filamentary fibers so that this hydrogel
There is preferable mechanical property, the advantage that can effectively slow down drug release rate.
(4) preparation method of hydrogel provided by the present invention, the primary raw material of use is wide material sources, has good life
The thing compatibility and the polysaccharide of biodegradable and Fmoc-L-phenylalanine；Obtained hydrogel mechanical property is good.Therefore should
Hydrogel is suitable as medicine carrying gel, medicine can be made slowly to discharge within the longer time, reach the effect of medicament slow release, make medicine
Thing is fully used.
(5) preparation method of hydrogel provided by the present invention, by further determining that polysaccharide and Fmoc-L-phenylalanine
Mass ratio, is regulated effective and stable polysaccharide derivates.
(6) dehydration condensation of the preparation method of hydrogel provided by the present invention, polysaccharide and Fmoc-L-phenylalanine
In, it is dehydrant by selecting dicyclohexylcarbodiimide, DMAP is catalyst, and response speed is fast, the time is short.
(7) preparation method of hydrogel provided by the present invention, is determined by polysaccharide, dicyclohexylcarbodiimide and 4-diformazan
The mass ratio of aminopyridine, can effectively control react gained polysaccharide derivates structure, i.e. graft site on polysaccharide and quantity,
And then ensure the regulating effect of polysaccharide derivates.
(8) preparation method of hydrogel provided by the present invention, can be by regulation Fmoc-L-phenylalanine clear solution with many
The amount ratio of sugar derivatives, obtains the hydrogel of different mechanical properties, thus realizes the Modulatory character of hydrogel mechanical property, bright
Aobvious practical ranges and the effect enhancing hydrogel.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all former in the present invention
Any amendment made within then, within equivalent and improvement etc. all should comprise protection scope of the present invention.
Claims (10)
1. a slow releasing carrier of medication hydrogel, it is characterised in that: it is at least molten by polysaccharide derivates, Fmoc-L-phenylalanine
Liquid prepares；Described polysaccharide derivates is prepared by dehydration condensation with Fmoc-L-phenylalanine by polysaccharide.
Slow releasing carrier of medication hydrogel the most as described in the appended claim 1, it is characterised in that: described Fmoc-L-Phe solution
The amount ratio that concentration is 0.015-0.02g/mL, Fmoc-L-Phe solution and polysaccharide derivates be 1mL:2-10mg；Institute
The elastic modelling quantity scope stating hydrogel is 20-6000Pa.
Slow releasing carrier of medication hydrogel the most as described in the appended claim 1, it is characterised in that: the microstructure of described hydrogel is thin
The regular arrangement of filamentary fibers.
4. the preparation method of a slow releasing carrier of medication hydrogel, it is characterised in that: its comprise the steps: provide polysaccharide,
Fmoc-L-phenylalanine, Fmoc-L-Phe solution and gluconic acid lactone；By polysaccharide and Fmoc-L-phenylalanine
Dehydration condensation, it is thus achieved that polysaccharide derivates；Utilize gained polysaccharide derivates, Fmoc-L-Phe solution and gluconic acid
Lactone prepares slow releasing carrier of medication hydrogel.
The preparation method of slow releasing carrier of medication hydrogel the most as claimed in claim 4, it is characterised in that: at polysaccharide and Fmoc-
In the dehydration condensation of L-phenylalanine, polysaccharide is 1:0.3-0.5 with the mass ratio of Fmoc-L-phenylalanine.
The preparation method of slow releasing carrier of medication hydrogel the most as claimed in claim 5, it is characterised in that: obtain described polysaccharide and spread out
Biological step farther includes:
Polysaccharide is dissolved in organic solvent, adds Fmoc-L-phenylalanine to it；After Fmoc-L-phenylalanine dissolves, then depend on
Secondary addition dicyclohexylcarbodiimide and DMAP dissolve and obtain mixed solution；Mixed solution is reacted at room temperature
After 18-36h, it is thus achieved that polysaccharide derivates.
The preparation method of slow releasing carrier of medication hydrogel the most as recited in claim 6, it is characterised in that: described polysaccharide, bicyclo-
The mass ratio of hexyl carbodiimide and DMAP is 1:(0.2-0.3): (0.06-0.1).
The preparation method of slow releasing carrier of medication hydrogel the most as claimed in claim 4, it is characterised in that: described Fmoc-L-benzene
The concentration of alanine solution is 0.015-0.02g/mL, described Fmoc-L-Phe solution and the amount ratio of polysaccharide derivates
For 1mL:2-10mg.
The preparation method of slow releasing carrier of medication hydrogel the most as claimed in claim 8., it is characterised in that: farther include described
The preparation of Fmoc-L-Phe solution:
Fmoc-L-phenylalanine is added in deionized water, stir at 35-50 DEG C, and add alkaline solution, obtain after dissolving
Fmoc-L-Phe solution.
10. the preparation method of slow releasing carrier of medication hydrogel as according to any one of claim 4-9, it is characterised in that: described
The preparation method of slow releasing carrier of medication hydrogel farther includes:
Take gained polysaccharide derivates and add in deionized water, stir 5-20min at 70-90 DEG C and obtain polysaccharide derivates aqueous solution,
And after being cooled to room temperature, be sequentially added into gluconic acid lactone and Fmoc-L-Phe solution, stir static after form medicine
Slow-released carrier hydrogel.
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