CN106267338A - A kind of high persistency multiple-effect self-crosslinking fluid gel and preparation method and application - Google Patents
A kind of high persistency multiple-effect self-crosslinking fluid gel and preparation method and application Download PDFInfo
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Abstract
The invention provides a kind of high persistency multiple-effect self-crosslinking fluid gel and preparation method and application.The preparation method of fluid gel of the present invention, comprises the steps: 1) water-soluble chitosan is placed in purified water dissolving, obtain water-soluble chitosan aqueous solution；Then filter, collect filtrate；2) described filtrate is carried out multigelation, obtain high persistency self-crosslinking fluid gel；3) described high persistency self-crosslinking fluid gel is mixed with function regulator, i.e. obtain described fluid gel.Fluid gel of the present invention has persistency homogeneous, high, the feature of multiple-effect；Preparation method is simple, uses physics self-crosslinking reaction；Application has biological safety.
Description
Technical field
The present invention relates to a kind of high persistency multiple-effect self-crosslinking fluid gel and preparation method and application, belong to natural life
Thing field of medical materials.
Background technology
Due to aging, damage and wound, overweight, side excessively uses, joint or relevant structure such as skeleton, ligament and
Cartilages etc. lack physical training, may result in a series of degenerative disease of osteoarthrosis, daily life is brought inconvenience.
Most common of which is osteoarthritis (OA).OA is the main cause disabled in the current U.S., and annual relevant of U.S. patient is controlled
Treatment expense about 5700 dollars.And the interior OA in the whole world already leads to 43,000,000 people's moderates to severe disability at present.China's knee joint endoprosthesis
Scorching prevalence is about 9.56%.For OA currently without the method effected a radical cure, it is to alleviate arthritis by injection viscoelasticity supplement
The important method of pain.In operation arthritic for severe, application viscoelasticity supplement are also had to ache as in reduction of patient art
The supplementary means of pain.
Joint viscoelasticity supplement composition the most on the market mostly is hyaluronic acid.To hyaluronic acid goods allergy or trouble
Side knee joint or periarticular have the infected, it is impossible to accept the injection for curing of hyaluronic acid series products.For birds albumen, feather
Or the patient of egg product allergy, then should be cautious use of the hyaluronic acid product extracting from rooster comb, as Synvisc (Xin Wei can),
Synvisc One, Hyalgan, 3H hyaluronic acid sodium and one hundred standby.And hyalomitome acids viscoelasticity supplement remaining time in vivo is relatively
Short, need to inject continuously 3～5 pins in the general course for the treatment of and could maintain the curative effect of 6 months, such as Euflexa, Hyalgan and
Supartz is respectively necessary for injecting 3 times, 5 times and 3 times continuously could maintain the curative effect of 26 weeks, brings all not only to patient and doctor
How inconvenience, too increases patient simultaneously and seeks medical advice cost.Therefore more external producers by select high molecular hyaluronic acid or
Person extends its remaining time at joint by the way of crosslinking, to reaching longer curative effect.Such as Gel one,
Hyaluronic acid in Synvisc (Xin Wei can), Synvisc One, after crosslinking, injects 1 pin, 3 pins and the curative effect of 1 pin respectively
Up to 13 weeks, 26 weeks and 26 weeks.
Owing to joint exists hyaluronidase, the curative effect of hyalomitome acids viscoelasticity supplement to be extended, then need
Its molecular weight or crosslinking degree proposed higher requirement, but also can be greatly increased injection jacking force simultaneously, give injection band
Come difficult.In patent CN105131348A, CN103124558A and CN1326352A, the viscoelasticity supplement of preparation comprise two kinds
Component, one is the hyaluronic acid particles of crosslinking, plays the effect extending preparation remaining time in vivo；Another kind is uncrosslinked
Hyaluronic acid liquid, plays and reduces injection resistance and increase the effect of preparation pliability.But the dosage form of solid-liquid suspendible, deposits
In the problem of dispersing uniformity, and granule has the risk of blocking syringe, causes injections difficult, or needs to use diameter more
Big syringe needle, causes bigger wound to patient.
Compared with hyaluronic acid, chitosan non-immunogenicity, will not cause allergic reaction；Wide material sources, resource is renewable,
Low cost；And structure approximates with sugar ammonia polysaccharide, may participate in the metabolism of proteoglycan；Its viscosity approximates with synovial fluid, has good group
Knit the compatibility；Chitosan class can directly facilitate cartilage propagation, alleviates the cell injury interference to intraarticular environment, thus reaches to protect
Protect and repairing articular cartilage, slow down the generation of articular degeneration lenitive effect, and hyaluronic acid can not induce cartilage to increase
Grow；It addition, chitosan class also has certain antibacterial and anti-inflammation functions.Do not degrade due to joint Chitosan-phospholipid complex
Enzyme, therefore it has relatively good resistance to enzymolysis performance.
The viscoelasticity supplement prepared based on chitosan on the market at present are the most a.Patent CN1306824A describes
The preparation of water soluble medical chitose and be adhered and prevent and treat the application in degenerative arthritis anti-.But chitin prepared by the method
Sugar preparation and medical chitose viscoelasticity supplement are all provided without the modes such as crosslinking, and it still suffers from free radical cracking in vivo
Deng, the most internal remaining time is the most limited, and component is single high molecular component, function singleness, though the injection initial stage can be preferably
Ground plays the effect of cushion pad, but promotees repair function and relatively lag behind.
Xylan polysulfuric acid, has another name called PPS (PPS), comes from beech tree, and primary structure is hemicellulose,
Mean molecule quantity is close to 7500D.PPS can make synovial cell synthesize the hyaluronic acid normalization of high molecular, and suppresses complement to live
The release of the pro-inflammatory mediator of change and leukocyte core synovial cell, thus protect synovial cell, reduce synovial membrane inflammation.PPS also may be used
Promote cartilage synthetic proteins polysaccharide, strength suppression catabolism.Clinical research shows, OA patient applies PPS, OA clinical symptoms
Having clear improvement after treating 1 month, synovial fluid viscoelasticity raises.
Chondroitin sulfate is one of important component constituting cartilage, and molecular weight is relatively low, it is easier to be preferentially absorbed into cartilage,
Can directly participate in the structure of cartilage, accelerate regeneration and the reparation of cartilage, and there is certain analgesic effect.Therefore by chondroitin sulfate
Element and xylan polysulfuric acid carry out compounding preparation pass with carboxymethyl chitosan and save viscoelasticity supplement, can play Synergistic
Effect, improve product absorption repairing effect within the injection complete period, and give the certain pain-relieving functions of product and increase product
Product lubricity.
Crosslinking is the common method improving viscoelasticity supplement curative effect at present.But currently used cross-linking agent mostly is chemistry friendship
Connection agent.Such as, the cross-linking agent toxicity such as DVS, BDDE, epoxychloropropane is big, and biocompatibility is not good enough, there is cross-linking agent residual in product
The risk stayed.When EDC or amino acids are as cross-linking agent, although biocompatibility is preferable, but relatively costly.
Summary of the invention
It is an object of the invention to provide a kind of high persistency multiple-effect self-crosslinking fluid gel and preparation method and application, this
Invention fluid gel has persistency homogeneous, high, the feature of multiple-effect；Preparation method is simple, uses physics self-crosslinking reaction；Application
There is biological safety.
The preparation method of the fluid gel that the present invention provides, comprises the steps: 1) water-soluble chitosan is placed in water
Dissolve, obtain water-soluble chitosan aqueous solution；Then filter, collect filtrate；
2) described filtrate is carried out multigelation, obtain high persistency self-crosslinking fluid gel；
3) described high persistency self-crosslinking fluid gel is mixed with function regulator, i.e. obtain described fluid gel.
In the present invention, step 1) the preferred purified water of described water.
In above-mentioned preparation method, described water-soluble chitosan is carboxymethyl chitosan and/or hydroxypropyl chitosan；
The molecular weight of described water-soluble chitosan can be 100,000～400,000, concretely 100,000,200,000,30 or 100,000～30
Ten thousand；
The concentration of described water-soluble chitosan aqueous solution can be 10～40mg/mL, concretely 10mg/ml, 25mg/ml,
40mg/ml, 10～25mg/mL or 25～40mg/mL.
In the present invention, described carboxymethyl chitosan carboxylation degree can be 80%～100%, concretely 82%；Described hydroxypropyl
The substitution value of base enclosure polysaccharide can be 0.4～1, concretely 0.6 or 0.4～0.6.
In above-mentioned preparation method, step 1) in, the temperature of described dissolving is 10～80 DEG C, concretely 30 DEG C, 50 DEG C,
65 DEG C, 30～50 DEG C, 50～65 DEG C or 30～65 DEG C.
In the present invention, step 1) the middle filter method filtering employing this area routine.In above-mentioned preparation method, step 2)
In, described multigelation comprises the steps: prior to-20 DEG C～-40 DEG C of freezings 12～72h；Defrosting 1 at 0 DEG C～30 DEG C
～5h；The number of times of described multigelation is 1～10 time.
Described multigelation specifically includes any one operating procedure in following 1-4:
1, after being placed in-20 DEG C of refrigerators freezing 24h, defrosting 4h at 10 DEG C, such multigelation 2 times；
2, after being placed in-30 DEG C of refrigerators freezing 36h, defrosting 3h at 25 DEG C, such multigelation 6 times；
3, after being placed in-40 DEG C of refrigerators freezing 48h, defrosting 3h at 20 DEG C, such multigelation 8 times；
4, after being placed in-20 DEG C～-40 DEG C of refrigerators freezing 24～48h, at 10～25 DEG C, 3～4h are thawed, the most repeatedly
Freeze thawing 2～8 times.
In above-mentioned preparation method, prepare described function regulator and comprise the steps: chondroitin sulfate and many sulphuric acid
Xylan is dissolved in pH buffer and makes.
In above-mentioned preparation method, described function regulator includes the component of following concentration, and unit is in terms of mg/ml:
Described function regulator specifically includes the component of following concentration:
In above-mentioned preparation method, the molecular weight of described chondroitin sulfate is 4000～8000 dalton, concretely
4000 dalton, 5000 dalton, 6000 dalton, 4000～5000 dalton, 5000～6000 dalton or 4000～
6000 dalton；
The molecular weight of described xylan polysulfuric acid is 6000～8000 dalton, concretely 6000 dalton, 7000 roads
Er Dun, 8000 dalton, 6000～7000 dalton or 7000～8000 dalton.
In above-mentioned preparation method, described high persistency self-crosslinking fluid gel is 1:1 with the volume ratio of function regulator.
Present invention also offers the described fluid gel that above-mentioned preparation method prepares.
Invention further provides the application in described fluid gel preparation treatment articular cartilage repair materials；Specifically may be used
Preparation treatment of arthritis repair materials.
The invention have the advantages that
1, the main functional component that the present invention selects water-solubility chitosan derivative to be viscoelasticity supplement, has relatively
Good resistance to enzyme；Self-crosslinking preparation extends its internal remaining time the most further so that it is can play long-acting isolation, lubricate and ease up
Rush the effect of external force.
2, when the present invention extends its curative effect further by cross-linking method, less demanding to crosslinking degree, and prepared by the present invention
Gel be monophasic fluid gel, therefore can significantly reduce injection jacking force, there is not the risk of granule blocking syringe needle, and make
Drug administration by injection process can be smoothly completed, hence it is evident that reduce the pain of injection generation and reduce the damage to body area with relatively small pinhead
Wound.
3, the present invention can effectively reduce the chance of infection, promote the synthesis of Dan Baiduotang proteoglycan PG, suppression catabolism and synovitis
Disease.Use the relatively low chondroitin sulfate of relative molecular mass and xylan polysulfuric acid, have the advantages that soon absorb and repair soon, noting
The initial stage of penetrating can play rapidly the function promoting to repair.Along with gradually using up of chondroitin sulfate and xylan polysulfuric acid, macromole
Water-soluble chitosan be gradually degraded into aminopolysaccharide and continue to participate in cartilage synthesis and synovial membrane reparation, and water-soluble chitosan has
Certain anti-inflammation function.In the present invention three's synergism ensure that injection complete period intrinsic articulation inflammation repair promptness,
Effectiveness, persistency and pleiotropy.
4, the gel of the present invention does not uses cross-linking agent, and biological safety is good, only makes shape between macromolecule by multigelation method
Become the three dimensional gell network structure being physical crosslinking point with strong hydrogen bonding and crystal region.Preparation method environmental protection of the present invention, simply
Easy.
Accompanying drawing explanation
Fig. 1 is the injection figure of fluid gel of the present invention.
Fig. 2 is the pathological section figure that the embodiment of the present invention 3 fluid gel implants 4 weeks posterior joint synovial membranes；Wherein Fig. 2 (a) is
Cartilage pathology slice map after arthritis modeling, Fig. 2 (b) is that the embodiment of the present invention 3 fluid gel implants 4 weeks articular cartilage of immobilizeds
Pathological section figure.
Detailed description of the invention
Experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
Quantitative test in following embodiment, is respectively provided with three times and repeats experiment, results averaged.
Embodiment 1, the preparation of fluid gel
1) filter is collected by filtration with G3 sand core funnel after carboxymethyl chitosan is placed in 30 DEG C of purified water stirring fully dissolving
Liquid, the molecular weight of carboxymethyl chitosan, carboxylation degree, concentration are respectively 100,000,82% and 10mg/ml；2) by step 1) carboxylic first
After base enclosure water solution is placed in-20 DEG C of refrigerators freezing 24h, defrosting 4h at 10 DEG C, such multigelation 2 times, obtain height
Persistency self-crosslinking fluid gel；3) chondroitin sulfate and xylan polysulfuric acid are dissolved in pH buffer, chondroitin sulfate
Concentration and molecular weight are respectively 20mg/ml and 4000 dalton, xylan polysulfuric acid concentration and molecular weight be respectively 30mg/ml and
6000 dalton, NaH2PO46.28mg/ml, Na2HPO411.6mg/ml, NaCl9.4mg/ml；4) by step 2) gel with
Step 3) solution by equal-volume than for 1:1 carry out mixing and homogenizing, i.e. obtain fluid gel of the present invention and (hold also known as homogeneous height
Property multiple-effect self-crosslinking fluid gel for a long time).
Embodiment 2, the preparation of fluid gel
1) filter is collected by filtration with G3 sand core funnel after hydroxypropyl chitosan is placed in 50 DEG C of purified water stirring fully dissolving
Liquid, the molecular weight of hydroxypropyl chitosan, substitution value, concentration are respectively 200,000,0.6 and 25mg/ml；2) by step 1) hydroxypropyl
After chitosan aqueous solution is placed in-30 DEG C of refrigerators freezing 36h, defrosting 3h at 25 DEG C, such multigelation 6 times, obtain height and hold
Property self-crosslinking fluid gel for a long time；3) chondroitin sulfate and xylan polysulfuric acid being dissolved in pH buffer, chondroitin sulfate is dense
Degree and molecular weight be respectively 50mg/ml and 5000 dalton, xylan polysulfuric acid concentration and molecular weight be respectively 60mg/ml and
7000 dalton, NaH2PO46.28mg/ml, Na2HPO411.6mg/ml, NaCl 9.4mg/ml；4) by step 2) gel
With step 3) solution carry out mixing and homogenizing than for 1:1 by equal-volume, i.e. obtain fluid gel of the present invention.
Embodiment 3, the preparation of fluid gel
1) filter is collected by filtration with G3 sand core funnel after carboxymethyl chitosan is placed in 65 DEG C of purified water stirring fully dissolving
Liquid, the molecular weight of carboxymethyl chitosan, carboxylation degree, concentration are respectively 300,000,90% and 40mg/ml；2) by step 1) carboxylic first
After base enclosure water solution is placed in-40 DEG C of refrigerators freezing 48h, defrosting 3h at 20 DEG C, such multigelation 8 times, obtain height
Persistency self-crosslinking fluid gel；3) chondroitin sulfate and xylan polysulfuric acid are dissolved in pH buffer, chondroitin sulfate
Concentration and molecular weight are respectively 80mg/ml and 6000 dalton, xylan polysulfuric acid concentration and molecular weight be respectively 60mg/ml and
8000 dalton, NaH2PO46.28mg/ml, Na2HPO411.6mg/ml, NaCl 9.4mg/ml；4) by step 2) gel
With step 3) solution carry out mixing and homogenizing than for 1:1 by equal-volume, obtain fluid gel of the present invention.
Embodiment 4, application
1, pushing force experiment
By each sample balance to room temperature, inject in 5ml needle tubing, 25G injection head is installed, push the air that needle tip is a small amount of
After, to test under pushing the driving velocity that speed is 30mm/min in universal testing machine, reference substance selects certain to close
Joint injection medical chitose and GelResult is as follows:
The pushing force test result of table 1 high persistency multiple-effect self-crosslinking fluid gel
As shown in Table 1, the pushing force of embodiment of the present invention sample is the least with sodium hyaluronate injection on the market,
And much smaller than GelPushing force.This explanation intrinsic safety invention sample is more easy to injection.
2, viscosity test
Use rotary viscosimeter, respectively to embodiment under the conditions of shear rate is not less than 0.25Hz, (25 ± 0.1) DEG C
One, 3 samples of two, three are tested, and Gel selected by reference substanceViscosity results is as follows:
The viscosity test results of table 2 high persistency multiple-effect self-crosslinking fluid gel
As shown in Table 2, the viscosity of embodiment of the present invention sample the most relatively GelLittle, when this advantageously reduces injection
Jacking force, makes product be more easy to injection.
3, cytotoxicity experiment
The cytotoxicity test result of table 3 high persistency multiple-effect self-crosslinking fluid gel
Take experimental liquid, the method test that specifies according to GB/T16886.5 and by GB/T14233.2-2005 regulation grading, knot
Fruit shows that sample cell toxicity prepared by the present invention meets the requirements.
4, biocidal property experiment
Growth rate method is used to measure the sample bacteriostatic activity to staphylococcus aureus.0.5ml sample is added to carefully
Mix homogeneously in bacterium culture medium, with purified water as negative control, with GelFor positive control, measure sample to golden yellow
Staphylococcic inhibition.Culture medium is uniformly added into the culture medium of 2 a diameter of 9cm, after solidifying completely, often
The bacterium cake of individual 2 pieces of a diameter of 5mm of inoculation of medium.After cultivating 48h at 25 DEG C, measure colony diameter, calculate pressing down of sample
Bacterium rate.
The biocidal property experimental result of table 4 high persistency multiple-effect self-crosslinking fluid gel
As shown in Table 2, sample bacteriostasis rate prepared by the present invention can reach 70%-80%, and this notes for preventing arthritis
Infection during penetrating etc. are significant.
5, arthritis treatment effect assessment
Take healthy new zealand rabbit 72, be randomly divided into 12 groups, cause bone by injecting papain solution in articular cavity
Arthropathy model.After modeling, the test group joint cavity injection embodiment of the present invention 1,2,3 is respectively 0.3ml, and negative control group is closed
Joint epicoele injecting normal saline 0.3ml, positive control joint injection medical chitose, inject 0.3ml equally.Upon administration
1, within 2,3,4 weeks, put to death, and carry out pathological observation, record pathology integration.Result is as shown in table 5 and Fig. 2.
The arthritis treatment effect of table 5 high persistency multiple-effect self-crosslinking fluid gel
Each test group result is carried out statistical analysis show: the experimental group of injection viscoelasticity supplement and negative control group
There were significant differences.When 1 week, rabbit arthritis tool is improved significantly by the embodiment of the present invention 3 and reference substance 1；And 2～4
Zhou Shi, the sample of the embodiment of the present invention 3 has more longlasting alleviation and repair to rabbit arthritis；And rabbit is closed by reference substance 1
The alleviation repair of joint inflammation is shorter, needs the most in actual applications to inject weekly once, injects 3～5 times continuously to keep
Relatively long curative effect.
Injecting as shown in Figure 2 after the viscoelasticity supplement of the present invention 4 weeks, chondrocyte proliferation is obvious, synovial membrane epithelial cell
Point-like hypertrophy, and have slight blood vessel hyperplasia, preferably, recovery situation is good for blood fortune.
Claims (10)
1. a preparation method for fluid gel, comprises the steps: 1) water-soluble chitosan is placed in water dissolving, obtain water
Soluble chitosan aqueous solution；Then filter, collect filtrate；
2) described filtrate is carried out multigelation, obtain high persistency self-crosslinking fluid gel；
3) described high persistency self-crosslinking fluid gel is mixed with function regulator, i.e. obtain described fluid gel.
Preparation method the most according to claim 1, it is characterised in that: described water-soluble chitosan is carboxymethyl chitosan
And/or hydroxypropyl chitosan；
The molecular weight of described water-soluble chitosan is 100,000～400,000；
The concentration of described water-soluble chitosan aqueous solution is 10～40mg/mL.
Preparation method the most according to claim 1 and 2, it is characterised in that: step 1) in, the temperature of described dissolving be 10～
80℃。
4. according to the preparation method according to any one of claim 1-3, it is characterised in that: step 2) in, described multigelation
Comprise the steps: prior to-20 DEG C～-40 DEG C of freezings 12～72h；Defrosting 1～5h at 0 DEG C～30 DEG C；Described repeatedly freeze
The number of times melted is 1～10 time.
5. according to the preparation method according to any one of claim 1-4, it is characterised in that: prepare described function regulator and include
Following steps: chondroitin sulfate and xylan polysulfuric acid are dissolved in pH buffer and make.
6. according to the preparation method according to any one of claim 1-5, it is characterised in that: described function regulator includes as follows
The component of concentration, unit is in terms of mg/ml:
7. according to the preparation method according to any one of claim 1-6, it is characterised in that: the molecular weight of described chondroitin sulfate
It is 4000～8000 dalton；
The molecular weight of described xylan polysulfuric acid is 6000～8000 dalton.
8. according to the preparation method according to any one of claim 1-7, it is characterised in that: described high persistency self-crosslinking fluid
Gel is 1:1 with the volume ratio of function regulator.
9. the described fluid gel that the preparation method according to any one of claim 1-8 prepares.
10. the application in fluid gel preparation treatment articular cartilage repair materials described in claim 9.
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