CN105597144A - Absorbable collagen styptic powder and preparing method thereof - Google Patents
Absorbable collagen styptic powder and preparing method thereof Download PDFInfo
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Abstract
The invention provides absorbable collagen styptic powder and a preparing method thereof. The absorbable collagen styptic powder is prepared from collagen particles with a particle size range of 0.1-10mm; the particles constituting the styptic powder are porous, have excellent hydrophilia and can be adhered to a wound surface after absorbing blood or percolate, the collagen cannot be dissolved by water or acid and cannot be swelled. The invention further provides absorbable collagen base composite styptic powder, taking high purity collagen as a base, and is prepared by adding the accessories of chitosan, sodium hyaluronate, etc. The invention further provides the preparing method of the absorbable collagen styptic powder and the collagen base composite styptic powder.
Description
Technical field
The invention belongs to bio-medical material and medical instruments field, relate to one and can absorb collagen hemostasis powder and preparation thereofMethod.
Background technology
Hemostatic material, can be divided into by the main material of its composition: collagen class styptic, shitosan class styptic, starch based(collagen is in hemostatic material for hemostatic material, oxycellulose and oxidized regenerated cellulose class hemostatic material, mineral matter dressing etc.Application, Song Qiang etc., Vol.35No.04, Feb.2013).
In surgery patients with accept in the patient of anticoagulant treatment, for example, hemorrhage can bodily tissue, organ or boneBone band is served problem, finally causes the threat of life, and uncontrollable hemorrhage meeting causes shock and dead. Clinically, often makeOriginally stopped blooding with fibrin ferment or fibrin, still, for keeping the biological styptic activity of these protein formulations, often neededWant the special storage environment such as low temperature, this has also greatly limited the use of protein formulation styptic. In clinical use, hemostatic materialProfile also its application is caused to very large impact, hemostatic material needs to be attached to the surface of complex organ, this just impelsThe generation of styptic powder.
Collagen, as hemostatic material, can be combined with blood platelet, promotes platelet aggregation, in also can directly activatingSource property coagulation pathway, produces hemoglutination, is also conducive to haemocyte and adheres to formation thrombus grumeleuse, effectively stops blood to wash wound openMouthful. In addition, collagen can promote granulation tissue to generate, and accelerates wound healing. Current a large amount of research datas show, collagen-based materialsStyptic activity is obviously better than other polysaccharide hemostatic materials, and can also promote regeneration and reparation. Domestic at present, to collagenThe research of styptic powder or collagen-based styptic powder also rarely has report. Wu Jimin has developed a kind of powder preparation stypticum thing (Granted publication numberCN1186096C), be taking collagenous fibres as raw material, use aldehyde material crosslinked fixing, then add excessive drier, alcohol and saltAcid, after glycerine water solution cleans, vacuum drying, makes pulvis after grinding with pulverizer. This styptic hemostasis rapidly, can also be urgedEnter wound healing and reparation.
But it is by dencichine and I collagen that time etc. have been developed collagen-based compound hemostatic pulvis (publication No. CN103721247A)Carry out modification, after recombination chitosan, be lyophilized into sponge, after then using modifier cross-linking modified, after freeze drying is pulverized again,To collagen-based compound hemostatic powder. Use aldehydes crosslinking agent, have good cross-linking effect, can greatly extend the degraded of collagen-based materialsTime, the mechanical property of raising material, but because aldehyde material has certain cytotoxicity, general cleaning method is difficult to againRemove the residual of aldehyde material, even if the crosslinking agent of trace is residual, also can cause the generation of a lot of bad problems.
Collagen hemostatic material not only has good anthemorrhagic performance, and also has the effect of transmitting tissue's reparative regeneration, is orderOne of best absorbable hemostatic material that front research is found, but the collagen hemostatic material that existing technique is made, main exist withLower shortcoming:
1. when material is crosslinked, use chemical cross-linking agent, not only process complexity, also can cause crosslinking agent residual, forms cytotoxicity;
2. collagen extraction process is single, and purity is inadequate, the fatty residual bad reaction etc. that easily causes.
Summary of the invention
The invention provides the preparation method of a kind of simple collagen hemostasis powder and collagen-based styptic powder, the method is logicalCross enzyme cutting process and removed the end peptide structure of collagen, thoroughly removed the immunogenicity of collagen, simultaneously manufacturing processDo not use chemical cross-linking agent, so greatly improved the security of materials'use.
The present invention is directed to the defect of existing product, object is to provide one can absorb collagen hemostasis powder and preparation side thereofMethod, this can absorb collagen hemostasis powder and have splendid hydrophily, after absorbing blood or diffusate, can be attached to wound surface,Wherein collagen can, by water or acid-soluble solution, can not produce swelling reaction yet; This styptic powder does not contain fibrin ferment, but more solidifying than containingThe gelfoam of hemase has better styptic activity.
Meanwhile, the present invention also provides a kind of preparation method who absorbs collagen-based compound hemostatic powder, makes collagen hemostasisOne or more in powder recombination chitosan, Sodium Hyaluronate, fibrin ferment or calcium chloride, strengthen hemostasis or the anti-effect that is adhered.
The absorbed collagen hemostasis powder of being prepared by the present invention and can absorb collagen-based compound hemostatic powder and can be loaded in onlyIn blood meal container, provide in the lump, under operation endoscope guiding, for the hemostasis of Minimally Invasive Surgery; Also can be used for skin burn, pressHemostasis and the reparative regeneration of the difficult healing such as the sore surface of a wound.
Absorb a preparation method for collagen hemostasis powder, it is characterized in that comprising the following steps:
S1: get mammal heel string or skin removed hair, add one in defatting enzyme, acetone, ethanol, n-butanol, first chlorineKind, slough grease, freezing microtome section;
S2: in the acid solution that is then 1.0 ~ 4.5 in pH value, add protease, enzymolysis 1 ~ 96 hour at 0 ~ 25 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using aqueous slkali to regulate pH value is 5 ~ 8, re-uses salt moltenLiquid salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH1 ~ 6Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 0.5 ~ 1.5%wt solution;
S6: use spray dryer to spray dry, and then use 4 ~ 100 object screen clothes to sieve, only make collagenBlood meal;
S7: styptic powder is carried out to ultra violet lamp is crosslinked or high-temperature vacuum method is crosslinked fixing, then carry out aseptic packaging, use irradiationOr use after dry heat sterilization method sterilizing.
Wherein, in step S1, described mammal is the one in ox, sheep, pig; In step S2, described acid solutionFor one or more in hydrochloric acid, acetic acid, citric acid, sulfuric acid, phosphoric acid; Described protease, for pepsin, trypsase,One or more in cathepsin, papain, subtilopeptidase A and ficin; In step S3, instituteThe aqueous slkali of stating, is a kind of or two kinds of mixing in NaOH, KOH, described salting liquid be potassium sulfate, potassium chloride, potassium nitrate,One or both mixing in sodium sulphate, sodium chloride, sodium sulphate.
Wherein, in step S6,, spray parameters spraying drying parameter is: 100 ~ 130 DEG C of temperature; Step S7 medium ultraviolet lamp shinesPenetrating crosslinked parameter is: 254nm ultraviolet light, irradiates 2 ~ 24h; The crosslinked parameter of high-temperature vacuum is: 100 ~ 150 DEG C of temperature, and vacuum≤0.08MPa, time 2 ~ 48h. .
Wherein, in step S6 and step S7, can also adopt with the following method: the solution that step S5 is configured, uses coldLyophilizer carries out freeze drying and makes sponge, then sponge is carried out to ultra violet lamp is crosslinked or high-temperature vacuum method is crosslinked fixing,Then use pulverizer to pulverize, aseptic packaging after screening.
The preparation method of the absorbed collagen hemostasis powder of above-mentioned change, is characterized in that, the crosslinked parameter of ultra violet lamp is:254nm ultraviolet light, irradiates 2 ~ 24h; The crosslinked parameter of high-temperature vacuum is: 100 ~ 150 DEG C of temperature, and vacuum≤0.08MPa, the time 2 ~48h。。
One can absorb collagen hemostasis powder, is obtained by above-mentioned method preparation, it is characterized in that, this styptic powder is by collagen eggWhite particle composition, grain diameter scope is 0.1 ~ 10mm; Forming the particle of this styptic powder, is cellular, the microscopic aperture of particleScope is 50 ~ 500 μ m; The volume density scope of this styptic powder is 0.01-0.06g/cm3; This styptic powder has splendid hydrophilicProperty, after absorbing blood or diffusate, can be attached to wound surface, wherein collagen can, by water or acid-soluble solution, also can not produceSwelling reaction; This styptic powder does not contain fibrin ferment, but has better styptic activity than the gelfoam that contains fibrin ferment.
One can absorb collagen hemostasis powder, is obtained by above-mentioned method preparation, it is characterized in that the performance symbol of this styptic powderClose the requirement of table 1:
Table 1 can absorb collagen hemostasis powder performance requirement and method of testing
| Performance indications | Performance requirement | Method of testing |
| Collagen purity | ≥95%（m/m） | Require to measure according to YY/T 0606.6 type i collagen protein standard |
| Hydroxyproline content | Should be not less than the 9%(m/m of total protein content) | Require to measure according to YY/T 0606.6 type i collagen protein standard |
| Fat content | Fat content≤1% (m/m) | The method specifying according to GB 5009.6 is measured |
| Content of beary metal (in Pb) | ≤10ug/g(m/m) | Measure according to the method for two annex VIII H the second law regulations of the Pharmacopoeia of the People's Republic of China (version in 2010) |
| Performance indications | Performance requirement | Method of testing |
The preparation method of described absorbed collagen hemostasis powder, wherein, in step S5, in the time of configuration collagen gel, also canAdd one or more in shitosan, Sodium Hyaluronate, fibrin ferment or calcium chloride, be prepared into and can absorb collagen-based compound hemostaticPowder.
The preparation method of above-mentioned absorbed collagen-based compound hemostatic powder, is characterized in that, in step S5, if add shell poly-When sugar, the content of shitosan is 0.1 ~ 2%wt; If while adding Sodium Hyaluronate, the content of Sodium Hyaluronate is 0.1 ~ 2%wt; IfWhile adding fibrin ferment, the content of fibrin ferment is 5 ~ 50mmol/L, if while adding calcium chloride, the content of calcium chloride is 0.2 ~ 1.5%wt。
One can absorb collagen-based compound hemostatic powder, by the preparation of above-mentioned method and obtain, it is characterized in that, this styptic powder byCollagen base composite particles composition, grain diameter scope is 0.1 ~ 10mm; Forming the particle of this styptic powder, is cellular,The microscopic aperture scope of grain is 50 ~ 500 μ m; The volume density scope of this styptic powder is 0.01-0.06g/cm3; This styptic powder toolHave splendid hydrophily, after absorbing blood or diffusate, can be attached to wound surface, wherein collagen can be by water or acid-solubleSeparate, also can not produce swelling reaction.
Can absorb collagen hemostasis powder and can absorb collagen-based compound hemostatic powder, obtaining its feature by above-mentioned method preparationBe that this can, being loaded in styptic powder container, provide in the lump, under operation endoscope guiding, for stopping of Minimally Invasive SurgeryBlood; Also can be used for skin burn, hemostasis and the reparative regeneration of the difficult healing such as the pressure sore surface of a wound.
The advantage that the present invention has has:
1. in material cross-linking method, use the physical crosslinking methods such as UV-irradiation or high-temperature vacuum, do not use chemical agent crosslinking agentBe cross-linked, solved the problem of the residual genotoxic potential bringing of chemical cross-linking agent;
2. operate by enzymolysis the end peptide of having removed animal collagen, collagen purity is high, has significantly reduced immunogenic responsePossibility;
3. by ungrease treatment, effectively control the fat content of material, made fat content in very low level;
4. material, through physical crosslinking processing, can water-solublely not separated after implant into body, can effectively extend hemostasis isolation time, profitIn operation technique and protecting wound surface;
5. physical crosslinking process cross-linking agent-free adds, and has reduced the necessary washing crosslinking agent of chemical cross-linking agent cross-linking process residualThe step of staying, has and has reduced cost of manufacture, is conducive to reduce medical expense.
Detailed description of the invention
Following examples, further describe concrete technical scheme of the present invention in detail, so that the technology people of this areaMember further understands the present invention, and does not form the restriction to its right.
Embodiment 1:
A kind of preparation method who absorbs collagen hemostasis powder is as follows:
S1: get ox-hide and remove hair, add acetone to soak 5h after stripping and slicing, slough grease, freezing microtome section after washing;
S2: in the acetum that is then 2.5 in pH value, add pepsin, enzymolysis 72 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5 ~ 7, re-usesThe sodium chloride salt solution salt of 0.15mol/L is separated out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, at the acetum of pH3.5 ~ 4.5In carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 0.9%wt solution;
S6: use spray dryer to spray dry, 110 DEG C of spraying baking temperatures, and then use 10 object screen clothes to carry outScreening, makes collagen hemostasis powder;
S7: styptic powder is placed in UV-crosslinked case, carries out ultra violet lamp and be cross-linked, 254nm ultraviolet light, irradiates 16h, then enterRow aseptic packaging, is used after irradiation sterilization.
Obtain a kind of collagen hemostasis powder that absorbs by above-mentioned method preparation, it is characterized in that, this styptic powder is by collagen eggWhite particle composition, grain diameter scope is 1 ~ 2mm; Forming the particle of this styptic powder, is cellular, the microscopic aperture scope of particleBe 200 ~ 300 μ m; The volume density scope of this styptic powder is 0.021-0.025g/cm3; This styptic powder soaks purified water or pHBe, in 4 acetum 1h, can, by water or acid-soluble solution, also can not produce swelling reaction; Collagen purity 98.3%(m/M), hydroxyproline content 12.3%, fat content≤0.23% (m/m), content of beary metal≤10ug/g (m/m), water absorbing force is 49Doubly.
Embodiment 2:
A kind of preparation method who absorbs collagen hemostasis powder is as follows:
S1: get pigskin and remove hair, add defatting enzyme after stripping and slicing, low temperature soaks 3h, sloughs grease, freezing microtome section;
S2: in the hydrochloric acid solution that is then 2.0 in pH value, add papain, enzymolysis 96 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using KOH solution to regulate pH value is 5 ~ 7, re-usesThe ammonium sulfate of 0.1mol/L salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, in the acetum of pH3 ~ 4.5Carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 0.5%wt solution;
S6: use spray dryer to spray dry, 120 DEG C of spraying baking temperatures, and then use 6 object screen clothes to sievePoint, make collagen hemostasis powder;
S7: styptic powder is carried out to high-temperature vacuum method crosslinked fixing, the crosslinked parameter of high-temperature vacuum is, 140 DEG C of temperature, vacuum≤0.08MPa, time 12h, then carry out aseptic packaging, after the sterilizing of use dry heat sterilization method, use.
Obtain a kind of collagen hemostasis powder that absorbs by above-mentioned method preparation, it is characterized in that, this styptic powder is by collagen eggWhite particle composition, grain diameter scope is 1 ~ 3.2mm; Forming the particle of this styptic powder, is cellular, the microscopic aperture model of particleEnclosing is 200 ~ 500 μ m; The volume density scope of this styptic powder is 0.010-0.016g/cm3; This styptic powder soak purified water orPH, in 4 acetum 1h, can, by water or acid-soluble solution, can not produce swelling reaction yet; Collagen purity 97.2%(m/m), hydroxyproline content 11.5%, fat content≤0.41% (m/m), content of beary metal≤10ug/g (m/m), water absorbing force is57 times.
Embodiment 3:
A kind of preparation method who absorbs collagen hemostasis powder is as follows:
S1: get ox heel string, add n-butanol after stripping and slicing, slough grease, freezing microtome section;
S2: in the phosphoric acid solution that is then 2.7 in pH value, add trypsase, enzymolysis 56 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5, re-usesThe phosphate sodium solution of 0.05mol/L salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH3 ~ 5Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 1.5%wt solution;
S6: use freeze drier to carry out freeze drying and make sponge, then it is crosslinked that sponge is carried out to ultra violet lamp, uviol lamp shinesPenetrating crosslinked parameter is that 254nm ultraviolet light, irradiates 12h;
S7: then use pulverizer to pulverize, aseptic packaging after 20 object screen cloth screenings, is used after irradiation.
Obtain a kind of collagen hemostasis powder that absorbs by above-mentioned method preparation, it is characterized in that, this styptic powder is by collagen eggWhite particle composition, grain diameter scope is 0.5 ~ 1.5mm; Forming the particle of this styptic powder, is cellular, the microscopic aperture of particleScope is 200 ~ 300 μ m; The volume density scope of this styptic powder is 0.041-0.06g/cm3; This styptic powder soak purified water orPH, in 4 acetum 1h, can, by water or acid-soluble solution, can not produce swelling reaction yet; Collagen purity 99.1%(m/m), hydroxyproline content 13.9%, fat content≤0.12% (m/m), content of beary metal≤10ug/g (m/m), water absorbing force is45 times.
Embodiment 4:
A kind of preparation method who absorbs collagen hemostasis powder is as follows:
S1: get sheepskin and remove hair, enter first chlorine after stripping and slicing, slough grease, use after ethanol and water washing freezing microtome section;
S2: in the citric acid solution that is then 3 in pH value, add protease, enzymolysis 72 hours at 10 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using KOH solution to regulate pH value is 5 ~ 7, re-usesThe potassium salt solution salt of 0.2mol/L is separated out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, at the acetum of pH3.5 ~ 5.5In carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 1.2%wt solution;
S6: use freeze drier to carry out freeze drying and make sponge, then it is crosslinked fixing that sponge is carried out to high-temperature vacuum method, high temperatureVacuum is cross-linked parameter, 140 DEG C of temperature, vacuum≤0.08MPa, time 48h;
S7: then use pulverizer to pulverize, aseptic packaging after 8 object screen cloth screenings, is used after irradiation.
Obtain a kind of collagen hemostasis powder that absorbs by above-mentioned method preparation, it is characterized in that, this styptic powder is by collagen eggWhite particle composition, grain diameter scope is 0.5 ~ 2.5mm; Forming the particle of this styptic powder, is cellular, the microscopic aperture of particleScope is 300 ~ 400 μ m; The volume density scope of this styptic powder is 0.033-0.045g/cm3; This styptic powder soaks purified waterOr in the pH acetum 1h that is 4, can, by water or acid-soluble solution, can not produce swelling reaction yet; Collagen purity 97.2%(m/m), hydroxyproline content 11.5%, fat content≤0.41% (m/m), content of beary metal≤10ug/g (m/m), water absorbing force is57 times.
Embodiment 5:
A kind of preparation method who absorbs collagen-based recombination chitosan styptic powder is as follows:
S1: get ox-hide and remove hair, add acetone to soak 5h after stripping and slicing, slough grease, freezing microtome section after washing;
S2: in the acetum that is then 2.5 in pH value, add pepsin, enzymolysis 72 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using KOH solution to regulate pH value is 5, re-uses salt moltenLiquid salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH3 ~ 5Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S5: the collagen gel that dialysis is completed, add and implant level shitosan, be configured to containing collagen 0.5%wt, containing shellThe solution of glycan 0.5%wt, stirs;
S6: pour into and in rectangular mould, use freeze drier to carry out freeze drying to make collagen recombination chitosan sponge, thenCollagen recombination chitosan sponge is carried out to ultra violet lamp and be cross-linked, the crosslinked parameter of ultra violet lamp is: 254nm ultraviolet light,Irradiate 20h;
S7: then use pulverizer to pulverize, aseptic packaging after 8 object screen cloth screenings, is used after irradiation.
Obtain a kind of collagen-based recombination chitosan styptic powder that absorbs by above-mentioned method preparation, it is characterized in that, should be onlyBlood meal is made up of collagen recombination chitosan particle, and grain diameter scope is 0.5 ~ 2.5mm; Form the particle of this styptic powder,For cellular, the microscopic aperture scope of particle is 300 ~ 450 μ m; The volume density scope of this styptic powder is 0.031-0.044g/cm3; In the acetum 1h that this styptic powder immersion purified water or pH are 4, can, by water or acid-soluble solution, can not produce swelling yetReaction.
Embodiment 6:
A kind of preparation method who absorbs collagen-based composite transparent matter acid sodium styptic powder is as follows:
S1: get ox heel string, add n-butanol after stripping and slicing, slough grease, freezing microtome section;
S2: in the phosphoric acid solution that is then 2.7 in pH value, add trypsase, enzymolysis 56 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5, re-uses salt moltenLiquid salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH3 ~ 5Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S8: the collagen gel that dialysis is completed, add implant level a Sodium Hyaluronate, be configured to containing collagen 0.7%wt,Containing the solution of Sodium Hyaluronate 0.3%wt, using vinegar acid for adjusting pH is 4 ~ 5, stirs;
S5: use freeze drier to carry out freeze drying and make sponge, then it is crosslinked fixing that sponge is carried out to high-temperature vacuum method, high temperatureVacuum is cross-linked parameter, 130 DEG C of temperature, vacuum≤0.08MPa, time 24h;
S6: then use pulverizer to pulverize, aseptic packaging after 10 object screen cloth screenings, is used after irradiation.
Obtain a kind of collagen-based composite transparent matter acid sodium styptic powder that absorbs by above-mentioned method preparation, it is characterized in that,This styptic powder is made up of collagen composite transparent matter acid sodium particle, and grain diameter scope is 0.5 ~ 2mm; Form this styptic powderParticle, is cellular, and the microscopic aperture scope of particle is 300 ~ 450 μ m; The volume density scope of this styptic powder is 0.027-0.041g/cm3; In the acetum 1h that this styptic powder immersion purified water or pH are 4, can, by water or acid-soluble solution, can not yetProduce swelling reaction.
Embodiment 7:
A kind of preparation method who absorbs the compound fibrin ferment styptic powder of collagen-based is as follows:
S1: get pigskin and remove hair, add defatting enzyme after stripping and slicing, low temperature soaks 3h, sloughs grease, freezing microtome section;
S2: in the hydrochloric acid solution that is then 2.0 in pH value, add papain, enzymolysis 96 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using KOH solution to regulate pH value is 5 ~ 7, re-uses saltSolution salt is separated out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH3 ~ 5Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S5: the collagen gel that dialysis is completed, add fibrin ferment and water for injection, be configured to containing collagen 0.8%wt,Content containing fibrin ferment is 20mmol/L solution;
S6: use freeze drier to carry out freeze drying and make sponge, then it is crosslinked fixing that sponge is carried out to high-temperature vacuum method, high temperatureVacuum is cross-linked parameter, 150 DEG C of temperature, vacuum≤0.08MPa, time 3h;
S7: then use pulverizer to pulverize, aseptic packaging after 8 object screen cloth screenings, is used after irradiation.
Obtain a kind of compound fibrin ferment styptic powder of collagen-based that absorbs by above-mentioned method preparation, it is characterized in that, should be onlyBlood meal is made up of the compound fibrin ferment particle of collagen, and grain diameter scope is 0.5 ~ 2.5mm; Form the particle of this styptic powder,For cellular, the microscopic aperture scope of particle is 300 ~ 450 μ m; The volume density scope of this styptic powder is 0.021-0.030g/cm3; In the acetum 1h that this styptic powder immersion purified water or pH are 4, can, by water or acid-soluble solution, can not produce swelling yetReaction.
Embodiment 8:
One can absorb collagen-based complex Ca2+The preparation method of ion styptic powder is as follows:
S1: get ox heel string, add n-butanol after stripping and slicing, slough grease, freezing microtome section;
S2: in the phosphoric acid solution that is then 2.7 in pH value, add trypsase, enzymolysis 56 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using KOH solution to regulate pH value is 5, re-uses salt moltenLiquid salts out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH3 ~ 5Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S5: the collagen gel that dialysis is completed, adds CaCl2And water for injection, be configured to containing collagen 1.0%wt moltenLiquid;
S6: use freeze drier to carry out freeze drying and make sponge, then it is crosslinked fixing that sponge is carried out to high-temperature vacuum method, high temperatureVacuum is cross-linked parameter, 140 DEG C of temperature, vacuum≤0.08MPa, time 10h;
S7: then use pulverizer to pulverize, aseptic packaging after 10 object screen cloth screenings, is used after irradiation.
Obtain a kind of complex Ca that absorbs by above-mentioned method preparation2+Collagen hemostasis powder, is characterized in that, this styptic powder byComplex Ca2+Ion collagen particle composition, grain diameter scope is 0.5 ~ 2mm; Forming the particle of this styptic powder, is porousShape, the microscopic aperture scope of particle is 300 ~ 400 μ m; The volume density scope of this styptic powder is 0.028-0.040g/cm3; ShouldIn the acetum 1h that styptic powder immersion purified water or pH are 4, can, by water or acid-soluble solution, can not produce swelling reaction yet.
The haemostatic effect contrast of the styptic powder rabbit ear portion surface of a wound prepared by table 2: embodiment
| Embodiment | Bleeding stopping period/S | Embodiment | Bleeding stopping period/S |
| Embodiment 1 | 70±3 | Embodiment 5 | 90±8 |
| Embodiment 2 | 71±2 | Embodiment 6 | 105±11 |
| Embodiment 3 | 78±3 | Embodiment 7 | 10±2 |
| Embodiment 4 | 81±5 | Embodiment 8 | 35±4 |
Comparative example 1:
With reference to the method for embodiment 1, remove degreasing method in step S1:
S1: get ox-hide and remove hair, reject adipose tissue, freezing microtome section;
S2: in the acetum that is then 2.5 in pH value, add pepsin, enzymolysis 72 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5 ~ 7, re-uses saltSolution salt is separated out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, at the acetum of pH3.5 ~ 4.5In carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 0.9%wt solution;
S6: use spray dryer to spray dry, 110 DEG C of spraying baking temperatures, and then use 10 object screen clothes to carry outScreening, makes collagen hemostasis powder;
S7: styptic powder is placed in UV-crosslinked case, carries out ultra violet lamp and be cross-linked, 254nm ultraviolet light, irradiates 16h, then enterRow aseptic packaging, is used after irradiation sterilization.
After testing, in the prepared sample of the technique of above-mentioned comparative example, fat content is 3.2%, fat too high levels, meetingThe bad reaction that causes product to use.
Comparative example 2:
According to the method described in embodiment 1, in step S7, use chemical cross-linking agent:
S8: get ox-hide and remove hair, add acetone to soak 5h after stripping and slicing, slough grease, freezing microtome section after washing;
S9: in the acetum that is then 2.5 in pH value, add pepsin, enzymolysis 72 hours at 4 DEG C of temperature;
S10: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5 ~ 7, re-usesSalting liquid salts out collagen;
S11: the collagen salting out is packed in bag filter, by bag filter port sealing, molten at the acetic acid of pH3.5 ~ 4.5In liquid, carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S12: the collagen gel that dialysis is completed, is configured to containing collagen 0.9%wt solution;
S13: use spray dryer to spray dry, 110 DEG C of spraying baking temperatures, and then use 10 object screen clothes to enterRow screening, makes collagen hemostasis powder;
S14: styptic powder is immersed in the formalin of 0.02%wt, crosslinked 24h, uses purified water fully to wash, and again freezesDry, then aseptic packaging, is used after irradiation sterilization.
After testing, in the prepared sample of the technique of above-mentioned comparative example, product serviceability is fine, performance and thisProduct in bright embodiment 1 is basic identical, in the acetum 1h that to soak purified water or pH be 4, and can not be by water or acid-soluble solution,Can not produce swelling reaction yet. Can, by water or acid-soluble solution, can not produce swelling reaction yet.
Comparative example 3:
According to the method described in embodiment 1, remove the crosslinked operation in step S7, directly packaging sterilizing:
S1: get ox-hide and remove hair, add acetone to soak 5h after stripping and slicing, slough grease, freezing microtome section after washing;
S2: in the acetum that is then 2.5 in pH value, add pepsin, enzymolysis 72 hours at 4 DEG C of temperature;
S3: after enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using NaOH solution to regulate pH value is 5 ~ 7, re-uses saltSolution salt is separated out collagen;
S4: the collagen salting out is packed in bag filter, by bag filter port sealing, at the acetum of pH3.5 ~ 4.5In carry out gradient dialysis, to extracellular fluid dialysis use silver nitrate titration without precipitation;
S5: the collagen gel that dialysis is completed, is configured to containing collagen 0.9%wt solution;
S6: use spray dryer to spray dry, 110 DEG C of spraying baking temperatures, and then use 10 object screen clothes to carry outScreening, makes collagen hemostasis powder;
S7: carry out aseptic packaging, use after irradiation sterilization.
After testing, according to the prepared sample of the technique of above-mentioned comparative example, soak the acetum 1h that purified water or pH are 4In, can be by water or acid-soluble solution, the first chance water that uses is defeated and dispersed, and attaching property is poor.
The present invention is described according to specific embodiment, but it will be understood by those skilled in the art that and do not departing from thisWhen bright scope, can carry out various variations or be equal to replacement. In addition, for adapting to specific occasion or the material of the technology of the present invention, can be rightThe present invention carries out many amendments and does not depart from its protection domain. Therefore, the present invention is not limited to specific embodiment disclosed herein,And comprise all embodiment that fall into claim protection domain.
Claims (11)
1. the preparation method that can absorb collagen hemostasis powder, is characterized in that comprising the following steps:
S1: get mammal heel string or skin removed hair, add one in defatting enzyme, acetone, ethanol, n-butanol, first chlorineKind, slough grease, freezing microtome section;
S2: in the acid solution that is then 1.0 ~ 4.5 in pH value, add protease, enzymolysis 1 ~ 96 hour at 0 ~ 25 DEG C of temperature;
After enzymolysis, use the centrifugal enzymolysis liquid of centrifuge to get supernatant, using aqueous slkali to regulate pH value is 5 ~ 8, re-uses salting liquidSalt out collagen;
S3: the collagen salting out is packed in bag filter, by bag filter port sealing, enter in the acetum of pH1 ~ 6Row gradient dialysis, is used silver nitrate titration without precipitation to extracellular fluid dialysis;
S4: the collagen gel that dialysis is completed, is configured to containing collagen 0.5 ~ 1.5%wt solution;
S5: use spray dryer to spray dry, and then use 4 ~ 100 object screen clothes to sieve, only make collagenBlood meal;
S6: styptic powder is carried out to ultra violet lamp is crosslinked or high-temperature vacuum method is crosslinked fixing, then carry out aseptic packaging, use irradiationOr use after dry heat sterilization method sterilizing.
2. the preparation method who absorbs collagen hemostasis powder as claimed in claim 1, is characterized in that, in step S1, describedMammal is the one in ox, sheep, pig; In step S2, described acid solution is hydrochloric acid, acetic acid, citric acid, sulfuric acid, phosphoric acidIn one or more; Described protease is pepsin, trypsase, cathepsin, papain, withered grass barOne or more in mycoproteinase and ficin; In step S3, described aqueous slkali, is the one in NaOH, KOHOr two kinds of mixing, described salting liquid is the one in potassium sulfate, potassium chloride, potassium nitrate, sodium sulphate, sodium chloride, sodium sulphateOr two kinds of mixing.
3. the preparation method who absorbs collagen hemostasis powder as claimed in claim 1, is characterized in that, in step S6, and spraying ginsengNumber spraying drying parameter is: 100 ~ 130 DEG C of temperature; The crosslinked parameter of step S7 medium ultraviolet light irradiation is: 254nm ultraviolet light, irradiates 2~ 24h; The crosslinked parameter of high-temperature vacuum is: 100 ~ 150 DEG C of temperature, vacuum≤0.08MPa, time 2 ~ 48h.
4. the preparation method who absorbs collagen hemostasis powder as claimed in claim 1, is characterized in that, step S6 and step S7In, can also adopt with the following method: the solution that step S5 is configured, uses freeze drier to carry out freeze drying and make seaSilk floss, then sponge is carried out to ultra violet lamp is crosslinked or high-temperature vacuum method is crosslinked fixing, then use pulverizer to pulverize, nothing after screeningBacterium packaging.
5. the preparation method that can absorb as described in claim 4 collagen hemostasis powder, is characterized in that, ultra violet lamp is crosslinkedParameter is: 254nm ultraviolet light, irradiates 2 ~ 24h; The crosslinked parameter of high-temperature vacuum is: 100 ~ 150 DEG C of temperature, and vacuum≤0.08MPa, time 2 ~ 48h.
6. the preparation method who absorbs collagen hemostasis powder as claimed in claim 1, is characterized in that, in step S5, in configurationWhen collagen gel, also can add one or more in shitosan, Sodium Hyaluronate, fibrin ferment or calcium chloride, be prepared intoCan absorb collagen-based compound hemostatic powder.
7. the preparation method who absorbs collagen-based compound hemostatic powder as claimed in claim 6, is characterized in that, in step S5,If while adding shitosan, the content of shitosan is 0.1 ~ 2%wt; If while adding Sodium Hyaluronate, the content of Sodium Hyaluronate is0.1 ~ 2%wt; If while adding fibrin ferment, the content of fibrin ferment is 5 ~ 50mmol/L, if while adding calcium chloride, and the content of calcium chlorideBe 0.2 ~ 1.5%wt.
8. can absorb a collagen hemostasis powder, it adopts the preparation of the method described in any one in claim 1 ~ 5 and obtains its featureBe, this styptic powder is made up of collagen particle, and grain diameter scope is 0.1 ~ 10mm; Form the particle of this styptic powder, forCellular, the microscopic aperture scope of particle is 50 ~ 500 μ m; The volume density scope of this styptic powder is 0.01-0.06g/cm3;This styptic powder has splendid hydrophily, after absorbing blood or diffusate, can be attached to wound surface, and wherein collagen can be byWater or acid-soluble solution, can not produce swelling reaction yet; This styptic powder does not contain fibrin ferment, but than the gelfoam that contains fibrin fermentThere is better styptic activity.
9. can absorb a collagen hemostasis powder, it adopts the preparation of the method described in any one in claim 1 ~ 5 and obtains its featureBe that this styptic powder meets following performance requirement:
1) collagen purity: >=90%(m/m);
2) hydroxyproline content: the 9%(m/m that should be not less than total protein content);
3) fat content: fat content≤1% (m/m);
4) content of beary metal (in Pb): content of beary metal≤10ug/g (m/m);
5) water absorbing force: should be not less than 10 times of own wt.
10. can absorb a collagen-based compound hemostatic powder, its adopt in claim 1 ~ 7 preparation of the method described in any one and, it is characterized in that, this styptic powder is made up of collagen base composite particles, and grain diameter scope is 0.1 ~ 10mm; Composition shouldThe particle of styptic powder, is cellular, and the microscopic aperture scope of particle is 50 ~ 500 μ m; The volume density scope of this styptic powder is0.01-0.06g/cm3; This styptic powder has splendid hydrophily, after absorbing blood or diffusate, can be attached to wound tableFace, wherein collagen can, by water or acid-soluble solution, can not produce swelling reaction yet.
11. absorbed collagen hemostasis powder as described in claim 8 ~ 10 and can absorb collagen-based compound hemostatic powder, its feature existsCan, being loaded in styptic powder container, provide in the lump in this, under operation endoscope guiding, for the hemostasis of Minimally Invasive Surgery;Also can be used for skin burn, hemostasis and the reparative regeneration of the difficult healing such as the pressure sore surface of a wound.
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