CN104758296A - Chitosan composite material containing novel active molecule, preparation method and application thereof - Google Patents
Chitosan composite material containing novel active molecule, preparation method and application thereof Download PDFInfo
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- CN104758296A CN104758296A CN201510105717.7A CN201510105717A CN104758296A CN 104758296 A CN104758296 A CN 104758296A CN 201510105717 A CN201510105717 A CN 201510105717A CN 104758296 A CN104758296 A CN 104758296A
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Abstract
In the invention, firstly a hemostatic material is prepared with high-molecular-weight chitosan as a main material with addition of a novel active molecule. A plurality of bleeding models show that the chitosan composite material containing the novel active molecule is excellent in a hemostatic function. An important creative point in the invention is that the novel active molecule is introduced into the hemostatic material so that the better hemostatic function is achieved. The chitosan composite material containing the novel active molecule is safe and effective, is simple in preparation, is good in biocompatibility, has bio-functions of protecting a wound, quickly stopping bleeding and promoting the wound to heal, is a quite excellent external-use biological wound dressing and satisfies requirements and development tendencies in clinical medicine.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to a kind of Chitosan Composites containing novel active molecule and its production and use.
Background technology
Hemostasis is an important step of emergency medical service treatment, when there is sudden trauma in patient's operative treatment, daily life, all needs to carry out quick-acting haemostatic powder.When the war in severe war environment and complicated accident, emergency care of trauma treatment, realization is stopped blooding particularly important fast and effectively.At present, according to clinical needs, applied multiple topical hemostatic agent, these hemostatic materials mainly comprise collagen protein and gelatin class, Fibrin Glue class, alginates etc.
Chitin is that a kind of distributed pole is wide, is easy to the high molecular polymer extracted, and is present in the cell wall of the carapace of the crustacean such as shrimp, Eriocheir sinensis and antibacterial, insecticide algae and higher plant.Chitosan is the product of chitin deacetylase degree more than 60%, is a kind of linear, semi-crystal shape polysaccharide.Because the anastalsis of chitosan itself is limited, the haemostatic effect for extensive hemorrhage wound surface is not very desirable.Material prepared by especially current existing chitosan is due to structural defect, and such as sponge material pore size is not at 100-200 micron within the scope of this, and the hemostatic material of preparation is not very good.
There is poor toughness and the inapparent problem of haemostatic effect for chitosan alone hemostatic material, we are by by its and other active substance compound, thus improve the mechanical performance of material, shortening bleeding stopping period.Therefore, we are incorporated into active substance in Novel chitosan hemostatic sponge, to improve the structure of material, promote the anastalsis of chitosan sthptic sponge further.
The object of the invention is to develop the relatively simple chitosan hemostatic material of a kind of processing technology, at raising anthemorrhagic performance, while ensureing biological safety, reduce production cost, avoid consuming in preparation process and wasting a large amount of resources.
Summary of the invention
O-(triazolyl) the ethyl derivative derivant of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention has the significant performance promoting blood coagulation, may be used for preparing blood-clotting agent or material.
Another technical scheme of the present invention is: first using the chitosan of high molecular as main material, and with a certain proportion of glutaraldehyde as cross-linking agent, reaction obtains chitosan gel rubber.In chitosan gel rubber, add a certain amount of novel active, with improve final products structure, increase its anthemorrhagic performance, then adopt Freeze Drying Technique, obtained a kind of hemostatic material.Physicochemical property test and characterization data show chitosan hemostatic material provided by the invention and have unique stuctures and properties.
The hemostatic material that multiple Hemorrhage Models such as rabbit auricular vein, liver wound surface, femoral artery show the present invention's acquisition has extraordinary anthemorrhagic performance.
Of the present invention one large innovation is, the unique texture that chitosan hemostatic material provided by the invention has and performance make the anthemorrhagic performance of material of the present invention incomparable, and the reason of the unique texture that chitosan hemostatic material is had and performance is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
Chitosan Composites containing novel active molecule is safe and effective, makes simple, good biocompatibility; there is again protection wound surface, quick-acting haemostatic powder, the biological effectiveness such as wound healing promoting simultaneously; be the biological wound dressing of a kind of ideal external, meet clinical medical requirement and development trend.
Accompanying drawing explanation
Chitosan Composites scanning electron microscope (SEM) photograph containing novel active molecule prepared by Fig. 1 embodiment 5
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described:
The preparation of embodiment 1 compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound II per (273mg, 0.5mmol) be dissolved in the middle of 20mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and 1,2,3-triazole (2760mg, 40mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects the faint yellow colloidal solid (184.6mg, 67%) that namely faint yellow concentrated elution band obtains compound III.
1H NMR(500MHz,DMSO-d6)δ8.05(d,J＝5.7Hz,2H),4.63(s,1H),4.53(s,1H),4.47(s,1H),4.26(s,1H),4.19(s,1H),3.91(s,2H),2.69(s,1H),2.37(s,1H),2.26(d,J＝13.4Hz,2H),2.20(s,1H),1.89(s,2H),1.81(s,1H),1.64(d,J＝3.5Hz,3H),1.56(s,1H),1.54–1.39(m,3H),1.39–1.35(m,2H),1.30(d,J＝14.4Hz,2H),1.23(d,J＝9.3Hz,2H),1.04(s,6H),0.96(d,J＝1.9Hz,13H),0.86(s,3H),0.78(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.58(s),154.48(s),136.30(s),120.62(s),105.20(s),74.64(s),65.63(s),59.74(s),52.54(s),51.19(s),47.89(s),46.70(s),44.11(s),42.27(s),41.76(s),40.63(s),40.14(s),38.85(s),38.66(s),37.23(s),36.26(s),33.33(s),32.94(s),29.88(s),27.19(s),26.05(s),24.26(s),23.95(s),20.75(s),18.45(s),17.99(s),16.95(s).
HRMS(ESI):m/z[M+H]
+calcd for C
34H
54N
3O
2:536.4216；found:536.4223。
O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone of embodiment 4 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is to the mensuration of fresh whole blood consolidation
Fresh whole blood time of setting test
1.1 material
Compound III prepared by embodiment 3: the O-(triazolyl) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Ethyl derivative derivant (III is called for short compound III)
Art benefit yarn (a kind of commercial hemostatic material)
5ml round bottom centrifuge tube
Liquid nitrogen
1.2 instrument
Mortar
Electric drying oven with forced convection
1.3 method
Art benefit yarn is put into mortar, pours liquid nitrogen into, by art benefit yarn grinds powder, put into baking oven immediately, after dry 20min, taking-up is stored in centrifuge tube for subsequent use.In the centrifuge tube that 10mg art benefit yarn powder or 100 microgram compound III are housed, add people's fresh whole blood (from the normal patient of Genneral Surgery of drum tower hospital coagulation function) that 2ml has just gathered, mix immediately, to tilt a centrifuge tube every about 10s, find the blood coagulation immediate record time.Do compound III group respectively, art benefit yarn group, and blank group.Often organize repetition 5 times.And statistical analysis is done to experimental data.
1.4 results and conclusion
Use fresh blood to mix with anti-hemorrhagic compound, comparing its clotting time is a kind of mode embodying hemostatic material effect intuitively.In this experiment, the clotting time of compound III is 35 ± 7 seconds, and art benefit yarn clotting time is 115 ± 19 seconds, and blank group clotting time is 378 ± 52 seconds.Compound III group and art benefit yarn group are compared with blank group, and all there is remarkable significant difference (P<0.01), clotting time obviously shortens; And the coagulant property of compound III group is significantly higher than art benefit yarn group, compound III group shows excellent external coagulating effectiveness.
Embodiment 5 is containing the preparation of the Chitosan Composites of novel active molecule
Material chitosan (Powdered, molecular weight 200,000, deacetylation 85%), glutaraldehyde, sodium hydroxide, glacial acetic acid, compound III prepared by embodiment 3
Instrument constant-temperature table, magnetic stirring apparatus, vacuum freeze drier, cryogenic refrigerator, 3.5K bag filter, silica gel mould
Experimental procedure
1) dissolve: 100mg Chitosan powder is dissolved in the glacial acetic acid aqueous solution of 10mL 1%, and after mixing, standing 8h treats its complete deaeration.
2) neutralize: the solution after leaving standstill adds the NaOH solution of 0.1M, makes pH value be 5.6, fully after concussion mixing, leave standstill 8h.
3) crosslinked: to add cross-linking agent glutaraldehyde solution (quality is 3% of chitosan mass, and the glutaraldehyde solution volume being converted into 50% is 5.4 μ L), fully after concussion mixing, put into constant-temperature table 12h.
4) dialyse: the bag filter chitosan jelly formed after crosslinked being put into 3.5K, put into the large beaker filling deionized water, magnetic stirring apparatus is dialysed at least 48h, changes a water every 4 hours.The impurity such as the glutaraldehyde that thorough removal is remaining and glacial acetic acid.
5) add compound: take out the jelly after dialysis, compound III prepared by the embodiment 3 adding 0.1mg, fully stir, after concussion mixing, be on average divided into 2 parts, pour in the silica gel mould of square.
6) freezing: to put into the freezing 24h of-20 degree refrigerator.
7) lyophilizing: move on to dry 24h on vacuum freeze-drying machine, namely obtains the final Chitosan Composites finished product containing novel active molecule.
Result and conclusion
Through above-mentioned steps, we obtain quality softness, the Chitosan Composites containing novel active molecule that structure is homogeneous, and color is faint yellow, loose porous, has certain toughness.
The preparation of the common Chitosan Composites of embodiment 6 (not containing novel active molecule)
Material chitosan (Powdered, molecular weight 200,000, deacetylation 85%), glutaraldehyde, sodium hydroxide, glacial acetic acid
Instrument constant-temperature table, magnetic stirring apparatus, vacuum freeze drier, cryogenic refrigerator, 3.5K bag filter, silica gel mould
Experimental procedure
1) dissolve: 100mg Chitosan powder is dissolved in the glacial acetic acid aqueous solution of 10mL 1%, and after mixing, standing 8h treats its complete deaeration.
2) neutralize: the solution after leaving standstill adds the NaOH solution of 0.1M, makes pH value be 5.6, fully after concussion mixing, leave standstill 8h.
3) crosslinked: to add cross-linking agent glutaraldehyde solution (quality is 3% of chitosan mass, and the glutaraldehyde solution volume being converted into 50% is 5.4 μ L), fully after concussion mixing, put into constant-temperature table 12h.
4) dialyse: the bag filter chitosan jelly formed after crosslinked being put into 3.5K, put into the large beaker filling deionized water, magnetic stirring apparatus is dialysed at least 48h, changes a water every 4 hours.The impurity such as the glutaraldehyde that thorough removal is remaining and glacial acetic acid, pour in the silica gel mould of square.
5) freezing: to put into the freezing 24h of-20 degree refrigerator.
6) lyophilizing: move on to dry 24h on vacuum freeze-drying machine, namely obtains final common chitosan material finished product.
The Chitosan Composites physicochemical property containing novel active molecule of embodiment 7 embodiment 5 preparation is tested
1. constructed observation
1.1 material
Chitosan Composites containing novel active molecule prepared by embodiment 5
1.2 instrument
Scanning electron microscope
1.3 method
The Chitosan Composites containing the novel active molecule embodiment 5 of drying prepared is placed in coating chamber and carries out ion sputtering film coating, then observes, takes pictures and preserve under different amplification.
1.4 results and conclusion
As shown in Figure 1, through the observation of scanning electron microscope, visible sponge is the hole of network structure, surface presentation opening, and pore size, at 120-180 μm, is spatially evenly distributed.Clinical hemostasis proves, the aperture that hemostatic material is suitable is very large for the impact of hemostasis.If the aperture of sponge is too large, then bad mechanical strength, can not resist the impact of blood, easily forms secondary hemorrhage.If aperture is too little, then impact absorbs the first oozing of blood of wound surface.So the material of 100-200 μm of pore size is best material.But chitosan material is not so easily control aperture, rule is not had to follow yet.Current chitosan hemostatic material often Shortcomings in this respect.Therefore, pore size control can be have very strong creationary at 120-180 μm by the embodiment of the present invention 5, and the reason that the Chitosan Composites containing novel active molecule prepared by embodiment 5 has this special performance is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
2 porosity measurements
2.1 material
Chitosan Composites (rectangle) containing novel active molecule prepared by embodiment 5
Common chitosan material (rectangle) prepared by embodiment 6
Dehydrated alcohol
2.2 instrument
Electronic analytical balance
Slide gauge
2.3 method
Get the Chitosan Composites correct amount W containing novel active molecule prepared by dry embodiment 5
1, then use length and width and the thickness of vernier caliper measurement sponge, calculate the volume V of sponge, sponge is immersed in completely and fills in the beaker of dehydrated alcohol, after soaking 30min, after taking out sponge, by sponge correct amount W
2, utilize formulae discovery porosity: P=(W
2-W
1)/(V* ρ
ethanol), survey three samples, average.
2.4 results and conclusion
The porosity containing the Chitosan Composites of novel active molecule prepared through measuring known embodiment 5 is 78.23 ± 3.19, and the porosity of conventional composite prepared by embodiment 6 is 56.77 ± 5.49%.The material of high porosity can provide enough space to absorb the initial oozing of blood of wound surface, and has higher surface area and stick on wound surface.So sufficiently high porosity is concerning extremely important sponge kind hemostatic material.Current chitosan hemostatic material often Shortcomings in porosity.The technical scheme that embodiment 5 provides can very perfectly meet this requirement, and the reason having this special performance containing the Chitosan Composites of novel active molecule prepared by embodiment 5 is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
3. water absorption rate measures
3.1 material
Chitosan Composites (rectangle) containing novel active molecule prepared by embodiment 5
Common chitosan material (rectangle) prepared by embodiment 6
Deionized water
3.2 instrument
Electronic analytical balance
3.3 method
Get the Chitosan Composites correct amount W containing novel active molecule prepared by dry embodiment 5
1, immerse 30min in deionized water completely, fully after water suction, clamp one jiao gently, leave the water with tweezers, after stopping 30s, weigh W again
2, according to computing formula water absorption rate=(W
2-W
1)/W
1, try to achieve water absorption rate.Measure 5 samples, average.
3.4 results and conclusion
The mean water absorption rate of the Chitosan Composites containing novel active molecule prepared by embodiment 5 is 4256 ± 365%, and the mean water absorption rate of common chitosan material prepared by embodiment 6 is 2133 ± 357%.
Chitosan Composites containing novel active molecule prepared by embodiment 5 has very high water absorption rate, and lay a good foundation for obtaining good haemostatic effect, in the hemostasis of wound surface, promptly absorbing initial oozing of blood, is very important.Therefore good water absorption rate has reacted the expection haemostatic effect of sponge from another aspect, be an important indicator of high-quality sthptic sponge performance.Current chitosan hemostatic material often Shortcomings in water absorption rate.The technical scheme that embodiment 5 provides can very perfectly meet this requirement, and the reason having this special performance containing the Chitosan Composites of novel active molecule prepared by embodiment 5 is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
4. normal saline resistance test
4.1 material
Chitosan Composites containing novel active molecule prepared by embodiment 5
Common chitosan material (rectangle) prepared by embodiment 6
Normal saline
4.2 instrument
Batch cultur ware
Constant incubator
Superclean bench
4.3 method
The Chitosan Composites containing novel active molecule that embodiment 5 is prepared by sterile working in super-clean bench or common chitosan material prepared by embodiment 6 put into the batch cultur ware that physiological saline solution is housed, after building ware lid good seal, put into incubator, constant temperature 37 DEG C.Respectively at one week, two weeks, surrounding, eight weeks and 12 weeks time observe that sponge is whether damaged decomposes.
4.4 results and conclusion
Chitosan Composites containing novel active molecule prepared by embodiment 5 all can maintain complete form within the time of 12 weeks, not damaged, does not dissolve, does not disperse.Experimental result illustrates that it has good normal saline toleration.And common chitosan material prepared by embodiment 6 starts when 4th week to occur breakage.
The normal saline toleration of sthptic sponge describes the quality of sponge from another one aspect, for the hemostasis that some difficulty is larger, because after pressure hemostatic material is applied on surface, the endovascular pressure moment exists, certain impact can be caused to wound surface, if material is easily damaged, break through material possibly, cause secondary hemorrhage.Current chitosan hemostatic material often Shortcomings in this respect.The technical scheme that embodiment 5 provides can very perfectly meet this requirement, and the reason having this special performance containing the Chitosan Composites of novel active molecule prepared by embodiment 5 is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
5. the test of hot strength and elongation at break
Material
Chitosan Composites containing novel active molecule prepared by embodiment 5
Common chitosan material prepared by embodiment 6
Instrument
Instron universal testing machine
Method
Material is cut into identical specification (long: 25mm, wide: 2.5mm, thick: 2mm), be placed on universal testing machine and test, and record the data of hot strength and elongation at break, test 5 samples, and carry out statistical analysis (see table 1).
The hot strength of table 1 sthptic sponge and elongation at break
Result and conclusion
Known by table 1 result, its hot strength of Chitosan Composites containing novel active molecule prepared by embodiment 5 and elongation at break all meet the high request of hemostasis.
The hemostatic material that mechanical strength is large has good toughness, not cracky, can withstand the hemorrhage impact to hemostatic material of wound surface preferably, effectively play the effect of hemostasis, is one of important indicator evaluating sthptic sponge performance.Current chitosan hemostatic material often Shortcomings in this respect.The technical scheme that embodiment 5 provides can very perfectly meet this requirement, and the reason having this special performance containing the Chitosan Composites of novel active molecule prepared by embodiment 5 is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
The haemostatic effect of the Chitosan Composites containing novel active molecule of embodiment 7 embodiment 5 preparation is studied 1 sthptic sponge and is tested the haemostatic effect of rabbit ear portion wound surface
1.1 material
Healthy adult new zealand white rabbit 16 (male, body weight 2.5kg)
Chitosan Composites containing novel active molecule prepared by embodiment 5
Chitosan-based absorbable hemostatic nonwoven fabric some pieces (trade name: art benefit yarn)
Hospital gauze some pieces
Land dormancy peace Inapsine
Disposable syringe
1.2 instrument
Rustless steel rabbit dissecting table
Various operating theater instruments
High-pressure sterilizing pot
1.3 method
First new zealand white rabbit is fixed on dissecting table, the mixed liquor of slow intramuscular injection 1.5ml land dormancy peace droperidol, preparing experiment after rabbit anesthesia.At rabbit auricular vein place alcohol disinfecting, then make the otch of an about 0.5cm with scalpel, cut off auricular vein.When blood is gushed out, first suck with sterilized hospital gauze, then the various hemostatic materials of 1cm × 1cm × 0.2cm size are applied and be pressed on otch, be auxiliary with sterilized hospital gauze when applying pressure, pressing haemostatic, observes an otch every about 10s, until stop blooding completely, record bleeding stopping period.Often kind of material makees 8 samples respectively.Result adopts software SPSS to carry out statistical analysis, and group difference adopts one factor analysis of variance, and P<0.05 has statistical significance, and P<0.01 has remarkable statistical significance.
1.4 results and conclusion
The bleeding stopping period of the Chitosan Composites containing novel active molecule prepared by embodiment 5 is 21.1 ± 2.6s, and the bleeding stopping period of art benefit yarn is 25.1 ± 6.8s, no difference of science of statistics (P>0.05).Prepared by embodiment 5 compares with hospital gauze (127.9 ± 14.0) containing the Chitosan Composites of novel active molecule, there is significant significant difference (P<0.01) and due to art benefit yarn.
A kind of for compared with clinical hemostasis nonwoven fabric (the beneficial yarn of art) with on the market of the Chitosan Composites containing novel active molecule prepared of embodiment 5, in rabbit auricular vein hemostasis trial, has better haemostatic effect.And our homemade sthptic sponge, namely stops blooding completely when only having part blood to infiltrate sponge, art benefit yarn is then after the complete penetration material of blood, could stop blooding completely.If therefore amount of bleeding is large, when playing anastalsis equally, the amount that Chitosan Composites containing novel active molecule prepared by embodiment 5 needs will be far smaller than art benefit yarn, more save material, and the reason having this special performance containing the Chitosan Composites of novel active molecule prepared by embodiment 5 is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
2. sthptic sponge is tested the haemostatic effect of rabbit liver wound surface
2.1 material
Healthy adult new zealand white rabbit 16 (male, body weight 2.5kg)
Chitosan Composites containing novel active molecule prepared by embodiment 5
Chitosan-based absorbable hemostatic nonwoven fabric some pieces (trade name: art benefit yarn)
Land dormancy peace Inapsine
Disposable syringe
2.2 instrument
Rustless steel rabbit dissecting table
Various operating theater instruments
High-pressure sterilizing pot
2.3 method
First new zealand white rabbit is fixed on dissecting table, the mixed liquor of slow intramuscular injection 1.5ml land dormancy peace droperidol, preparing experiment after rabbit anesthesia.Successively open abdomen, expose liver, on lobe of the liver, make the cross recess of 1 × 1cm of scalpel, occur after oozing of blood until wound surface, first draw with sterile gauze, then the various hemostatic materials of ready 1.5cm × 1.5cm × 0.2cm size are applied and be pressed on wound, be auxiliary with sterilized hospital gauze when applying pressure, pressing haemostatic, observes a wound every about 15s, until stop blooding completely, record bleeding stopping period.Often kind of material makees 8 samples respectively.Experimental data is in table 6, and result adopts software SPSS to carry out statistical analysis, and group difference adopts one factor analysis of variance, and P<0.05 has statistical significance, and P<0.01 has remarkable statistical significance.
2.4 results and conclusion
The bleeding stopping period of the Chitosan Composites containing novel active molecule prepared by embodiment 5 is 41.2 ± 5.1s, and the bleeding stopping period of art benefit yarn is 42.6 ± 5.8, no difference of science of statistics (P>0.05).Compared with hospital gauze (157.8 ± 11.1), there is significant significant difference (P<0.01) in the Chitosan Composites containing novel active molecule prepared by embodiment 5.
Liver is the organ that all internal organs medium vesselses of mammal enrich the most.When wound or operation on liver, the extensive oozing of blood of wound surface, because blood vessel is many and hidden, the main bugbear being selected to us of haemostatic measures, therefore selects animal livers wound surface to carry out haemostatic effect contrast and has stronger cogency.Current chitosan hemostasis effect in the hemostasis of liver wound surface is undesirable, even if hemostatic material can stop blooding when other hemorrhage situations, but not necessarily effective in the hemostasis of liver wound surface, because the hemostasis of liver wound surface is very high to the requirement of material structure and performance.
Chitosan Composites containing novel active molecule prepared by embodiment 5 is compared with art benefit yarn hemostatic material on the market, can stop blooding on liver wound surface, but the Chitosan Composites containing novel active molecule prepared by embodiment 5 can adhere to closely with wound surface, sealing process is formed to wound, wound surface stops blooding immediately, amount of bleeding is less, and the reason having this special performance containing the Chitosan Composites of novel active molecule making embodiment 5 prepare is O-(triazolyl) ethyl derivative derivant (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone being compounded with novel active molecule Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in the material.
Claims (8)
1. Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) with structure shown in formula III and pharmaceutically acceptable salt thereof are preparing the application in haemostatic medicament or material:
2., containing a preparation method for the Chitosan Composites of novel active molecule, it is characterized by step as follows:
1) dissolve: Chitosan powder is dissolved in acetum, mixing, standing, deaeration;
2) neutralize: the solution after leaving standstill adds NaOH solution, makes pH value be 5.6, fully after concussion mixing, leave standstill;
3) crosslinked: to add cross-linking agent glutaraldehyde solution and be cross-linked;
4) dialyse: the chitosan jelly formed after crosslinked is put into the impurity such as the glutaraldehyde of bag filter dialysis removal remnants and glacial acetic acid;
5) add compound: take out the jelly after dialysis, add a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) as claimed in claim 1, pour into afterwards in the silica gel mould of square;
6) freezing: freezing one-tenth ice cube;
7) lyophilizing: move on on vacuum freeze-drying machine dry, namely obtains a kind of Chitosan Composites containing novel active molecule.
3., containing a preparation method for the Chitosan Composites of novel active molecule, it is characterized by step as follows:
1) dissolve: 100mg Chitosan powder is dissolved in the glacial acetic acid aqueous solution of 10mL 1%, and after mixing, standing 8h treats its complete deaeration;
2) neutralize: the solution after leaving standstill adds the NaOH solution of 0.1M, makes pH value be 5.6, fully after concussion mixing, leave standstill 8h;
3) crosslinked: add cross-linking agent glutaraldehyde solution, the quality of glutaraldehyde is 3% of chitosan mass, and the glutaraldehyde solution volume being converted into 50% is 5.4 μ L, fully after concussion mixing, put into constant-temperature table 12h;
4) dialyse: the bag filter chitosan jelly formed after crosslinked being put into 3.5K, put into the large beaker filling deionized water, magnetic stirring apparatus is dialysed at least 48h, changes a water every 4 hours, thoroughly removes the impurity such as remaining glutaraldehyde and glacial acetic acid;
5) add compound: take out the jelly after dialysis, add as claimed in claim 1 a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) of 0.1mg, fully stir, after concussion mixing, pour in the silica gel mould of square;
6) freezing: to put into the freezing 24h of-20 degree refrigerator;
7) lyophilizing: move on to dry 24h on vacuum freeze-drying machine, namely obtains a kind of Chitosan Composites containing novel active molecule.
4. containing a Chitosan Composites for novel active molecule, it is characterized by: prepared by the preparation method of a kind of Chitosan Composites containing novel active molecule described in claim 2 or 3.
5. a kind of Chitosan Composites containing novel active molecule as claimed in claim 4, it is characterized by: the pore size of described chitosan sthptic sponge is between 120-180 μm, porosity is greater than 70%, water absorption rate is greater than 4000%, normal saline tolerance time is more than 12 weeks, hot strength is at more than 0.1MPa, and elongation at break is more than 20%.
6. a kind of Chitosan Composites containing novel active molecule according to claim 5 is preparing the application in hemostatic material.
7. a kind of Chitosan Composites containing novel active molecule is preparing the application in hemostatic material as claimed in claim 6, and it is characterized by described hemostasis is auricular vein hemostasis.
8. a kind of Chitosan Composites containing novel active molecule is preparing the application in hemostatic material as claimed in claim 6, it is characterized by the hemostasis that described hemostasis is liver wound surface.
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