CN106267320B - A kind of preparation method of vascular anastomosis agent - Google Patents
A kind of preparation method of vascular anastomosis agent Download PDFInfo
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- CN106267320B CN106267320B CN201610651154.6A CN201610651154A CN106267320B CN 106267320 B CN106267320 B CN 106267320B CN 201610651154 A CN201610651154 A CN 201610651154A CN 106267320 B CN106267320 B CN 106267320B
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- 230000003872 anastomosis Effects 0.000 title claims abstract description 32
- 230000002792 vascular Effects 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 117
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 104
- 239000000463 material Substances 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 40
- 230000001954 sterilising effect Effects 0.000 claims abstract description 37
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 35
- 238000001914 filtration Methods 0.000 claims abstract description 34
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 30
- 238000003756 stirring Methods 0.000 claims description 21
- 238000004090 dissolution Methods 0.000 claims description 19
- 229920001661 Chitosan Polymers 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 5
- 229960001631 carbomer Drugs 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- 229940045110 chitosan Drugs 0.000 claims description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 69
- 238000010992 reflux Methods 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 238000009434 installation Methods 0.000 abstract description 3
- 239000007864 aqueous solution Substances 0.000 description 29
- 230000008569 process Effects 0.000 description 19
- 239000007788 liquid Substances 0.000 description 18
- 239000001856 Ethyl cellulose Substances 0.000 description 10
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 10
- 229920001249 ethyl cellulose Polymers 0.000 description 10
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- 239000012528 membrane Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 239000008215 water for injection Substances 0.000 description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229940044476 poloxamer 407 Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- -1 and wherein Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
Abstract
The present invention relates to injection sterile production field, in particular to a kind of preparation method of vascular anastomosis agent.The preparation method includes: that high molecular material is dissolved in water, and filtration sterilization obtains weak solution；Weak solution is removed water using the method for cross-flow ultrafiltration, obtains vascular anastomosis agent.Mature preparation process degree of the present invention is high, under conditions of not increasing special installation, it is concentrated using film packet cross-flow ultrafiltration, the moisture in dilute vascular anastomosis agent matched is squeezed out by strict control ultrafiltrate temperature, feed liquor end pressure, reflux end pressure and water yield, the concentration for realizing 8-10 times, so that mass production prepares sterile vascular anastomosis agent.
Description
Technical field
The present invention relates to injection sterile production field, in particular to a kind of preparation method of vascular anastomosis agent.
Background technique
With the rapid development of society, because Vascular Injury on Limbs is clinically very common caused by various wounds, to save
Suffering limb, multirow anastomosis of blood vessel.Injection in the vascular that vascular anastomosis uses is carried out in vascular anastomosis agent as clinically doctor,
It is widely used in anastomosis of blood vessel.Vascular anastomosis agent is prepared by high molecular material by techniques such as filtration sterilizations.Mesh
Before, injection can use the technique that absorption method removes heat source and filtration sterilization combines to ensure that sterile and endotoxin is qualified, for
Viscosity is big, solid content is high, and (the vascular anastomosis agent of 16-30% (w/w) even can shape after swelling since material self-molecules present amount is big
At the limitation of micelle and filter sizes, lead to not using existing filtering decarburization and degerming technique, this is current urgent need solution
A technique bottleneck problem certainly.
Ultrafiltration (Ultrafiltration, UF) technology be in solution nano sized particles and shla molecule separate
Method.This separation is based primarily upon bulk of molecule, but the permeability of filter media can be by the chemistry, molecular weight, electricity of sample
The influence of lotus characteristic and viscosity.It has been reported that bio-pharmaceuticals uses cross-flow ultrafiltration technology protein isolate or impurity, shut off point
Son amount range is in 1-1000kD；Also real by controlling molecular cut off it has been reported that using hyperfiltration technique concentrating dilute solution
The separation of existing solvent and solute achievees the purpose that remove solvent concentration.But ultrafiltration concentration is used whether for vascular anastomosis agent
It is feasible, it is reported currently without research.
Under common biological medicament or small-molecule drug solution state (viscosity is small, and solid content is few), no matter the height of viscosity, it is molten
Solvent (such as: water) in liquid is to account for large scale on ratio composition, and wherein, water is continuous for drug dissolution or high degree of dispersion
Phase removes continuous phase using ultrafiltration, is all that by from feasibility and process aspect.But it is every for vascular anastomosis agent
The high molecular material of Zhi Zhonghan 16%-30%, solid content are high；The high molecular material molecular weight of dissolution or dispersion is 8000-
50000KD, viscosity are big.This can make solution the transformation of continuous phase occurring from low concentration to high concentration concentration process, lead to ultrafiltration
A large amount of solvents are not can be removed.Such as certain vascular anastomosis agent: when its low concentration, water exists as continuous phase, material dispersion or swelling
Wherein, apparently solution viscosity is very low (10-20cP)；As ultrafiltration removes water, concentration is gradually increased, and high molecular material therein turns
Become continuous phase, water dispersion is in its mesh space structure, and apparently viscosity dramatically increases (10-20k cP), and at this moment ultrafiltration is just
It can not be pressed further by out the water dispersed in the material, cause product that failure is concentrated by ultrafiltration.As it can be seen that due to vascular anastomosis agent viscosity
Greatly, solid content is high, and there are phase transition temperature, the upper method for concentration that temporarily nothing is suitable for of production leads to no commercialized product.Therefore, raw
It is badly in need of a kind of viable process that can solve the problem in production.
Summary of the invention
In view of this, the present invention provides a kind of preparation methods of vascular anastomosis agent.The preparation method can realize 8-10 times
Concentration, thus production prepare sterile vascular anastomosis agent.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of preparation methods of vascular anastomosis agent, comprising:
High molecular material is dissolved in water, filtration sterilization obtains weak solution；
Weak solution is removed water using the method for cross-flow ultrafiltration, obtains vascular anastomosis agent.
The present invention investigates after study, on existing Research foundation, from reducing cost and do not increase the angle of special installation
It sets out, the process route of " dilute with-filtering-ultrafiltration concentration-finished product " is used to explore invention by many experiments and production pilot scale
Out it is suitable for the production technology of vascular anastomosis agent, solves the problems, such as existing production.
Preferably, high molecular material includes the first high molecular material or the second high molecular material, the first high molecular material
It is for pool Luo Samu, chitosan, carbomer, hypromellose, sodium alginate or hydroxyethyl starch, the second high molecular material
Ethyl cellulose.
In the present invention, the first high molecular material includes the high molecular material of dissolution in low temperature and the macromolecule material of normal-temperature dissolution
Material, the solution temperature of the high molecular material of dissolution in low temperature are 0~10 DEG C, and the solution temperature of the high molecular material of normal-temperature dissolution is 0
~30 DEG C.
In the present invention, the second high molecular material is the high molecular material dissolved by heating, the dissolution of the second high molecular material
Temperature is 50~80 DEG C.
Preferably, pool Luo Samu is POLOXAMER 188 or POLOXAMER 407.
Preferably, high molecular material is POLOXAMER 188, POLOXAMER 407 or carbomer.
Preferably, the equipment that ultrafiltration uses is ultrafiltration column or film packet.
Preferably, the equipment that ultrafiltration uses is film packet.
Preferably, high molecular material is the first high molecular material, cross-flow ultrafiltration use molecular cut off for 3000~
The film packet of 20000KD, temperature be 0~30 DEG C, inlet hydraulic be 2~4bar, return pressure be 1~3bar, water yield be 5~
25mL/min。
In embodiment provided by the invention, high molecular material be the first high molecular material when, inlet hydraulic be 2~
3.5bar, return pressure are 2.4~3bar.
Preferably, high molecular material is the second high molecular material, cross-flow ultrafiltration use molecular cut off for 3000~
The film packet of 20000KD, temperature are higher than the solution temperature of the second high molecular material, and inlet hydraulic is 2~5bar, return pressure 2
~3bar, water yield are 4~25mL/min.
In embodiment provided by the invention, high molecular material be the second high molecular material when, inlet hydraulic be 2.3~
4.7bar, return pressure are 2.2~2.7bar.
Using different high molecular materials, the hyperfiltration process of use is slightly different, and reason is: molten in ultra-filtration process
Liquid can heat up, and can change the viscosity of solution, specific as follows: for the material of dissolution in low temperature, temperature is increased, and will lead to viscosity increasing
Add, this must just control feed liquor end pressure, reduce liquid inlet volume, while improving water yield, reduce solution in film packet and fixture
Hold-up and residence time；And for the material of heating for dissolving, temperature increases, and viscosity reduces, and ultrafiltration is more advantageous to, in order to mention
Highly enriched efficiency can increase liquid inlet volume, less water yield.
In embodiment provided by the invention, the method for dissolution is that dissolution is stirred at room temperature, is stored at room temperature dissolution, heating stirring
Dissolution, heating stand dissolution, the dissolution of low temperature stirring and dissolving, stand at low temperature or emulsion dispersion.
In embodiment provided by the invention, ethyl cellulose use heating stirring dissolution method.
In embodiment provided by the invention, the method that Luo Samu, chitosan, carbomer use low temperature stirring and dissolving is moored.
In embodiment provided by the invention, filter that filtration sterilization uses is stud, filter stick, flat-panel filter or micro-
Hole filter membrane.
In embodiment provided by the invention, the filter pore size of filter is 0.8 micron, 0.45 micron or 0.22 micron.
In embodiment provided by the invention, the mass percent of high molecular material is 0.4%~0.75% in weak solution,
The mass percent of high molecular material is 1.6%~7.5% in vascular anastomosis agent.
Preferably, further including the steps that moist heat sterilization after water removal.
Preferably, the method for moist heat sterilization are as follows: 121 DEG C of sterilizing 30min.
The present invention provides a kind of preparation methods of vascular anastomosis agent, comprising: high molecular material is dissolved in water, crosses and filters out
Bacterium obtains weak solution；Weak solution is removed water using the method for cross-flow ultrafiltration, obtains vascular anastomosis agent.Of the invention has
Beneficial effect are as follows:
The new preparation process maturity is high, under conditions of not increasing special installation, is concentrated using film packet cross-flow ultrafiltration,
By strict control ultrafiltrate temperature, feed liquor end pressure, reflux end pressure and water yield by the moisture in dilute vascular anastomosis agent matched
It squeezes out, 8-10 times of concentration is realized, so that mass production prepares sterile vascular anastomosis agent.Test result is shown by 120 points
The accumulative water yield of clock, can be successfully by 0.4%~0.75% high molecular material water by short time ultrafiltration up to 2554~3048mL
Solution is concentrated by ultrafiltration to 1.6%~7.5% concentrated solution.
Specific embodiment
The invention discloses a kind of preparation method of vascular anastomosis agent, those skilled in the art can use for reference present disclosure,
It is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications carry out those skilled in the art
Say it is it will be apparent that they are considered as being included in the present invention.Method and application of the invention has passed through preferred embodiment
It is described, related personnel can obviously not depart from the content of present invention, in spirit and scope to method described herein and answer
With being modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
Agents useful for same or instrument are available on the market in the preparation method of vascular anastomosis agent provided by the invention.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1
With liquid: taking water for injection 9.96L, be added with stirring ethyl cellulose (Natrosol, Ashland_Aqualon)
40g, main agitating paddle revolution 70-100rpm emulsify fly cutter revolution 2500rpm, emulsion dispersion 1h, obtain 0.4% (w/w) ethyl cellulose
Plain aqueous solution.
Filtration sterilization: 0.4% ethyl cellulose aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the 0.4% ethyl cellulose aqueous solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet is cut
Molecular weight 5000KD, Mi Libo is stayed to provide, weak solution is maintained at 30-40 DEG C (slightly above solution temperature) in ultra-filtration process, will go out
In 4-25mL/min, adjusting feed liquor end pressure is 2-5bar for water control, and reflux end pressure is 2-3bar, and water yield becomes at any time
Change is as follows:
Water yield situation in 1 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 7 | 2.3 | 2.4 |
| 20 | 20.7 | 3 | 2.3 |
| 30 | 25.0 | 4.5 | 2.2 |
| 45 | 23.8 | 4.5 | 2.5 |
| 60 | 24.9 | 4.6 | 2.6 |
| 90 | 4.8 | 4.7 | 2.6 |
| 95 | 4.2 | 4.7 | 2.7 |
| 120 | 24.9 | 4.7 | 2.7 |
The result shows that: adding up water yield by ultrafiltration in 120 minutes is 2940mL, reaches concentration in expected 120 minutes and removes
3000mL water.The high viscosity solution for being 4% by the concentration of 0.4% ethyl cellulose aqueous solution by ultrafiltration in 6 hours, to realize blood vessel
The sterile and concentration production technology of identical agent provides a kind of test basis.
Comparative example 1
With liquid, filtration sterilization operation with embodiment 1.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off 5000KD,
Mi Libo is provided, and to reduce solution viscosity, weak solution is maintained at 30-40 DEG C (slightly above solution temperature), feed liquor in ultra-filtration process
End pressure is 2.5bar, and in 5bar, water yield changes over time to be as follows: the end pressure that flows back
Water yield situation in 2 cross-flow ultrafiltration removal process of table
Test result shows that failure is concentrated by ultrafiltration, and when stage on-test, water yield reaches 2.5-4mL/min, but with
The ultrafiltration time extends, and is discharged slower and slower.Speculate the reason is that reflux end pressure is too big, by the flushing of long-time slipstream,
Film packet surface forms gel layer, blocks film packet, is hardly discharged after final 95 minutes, concentration failure.
Comparative example 2
With liquid, filtration sterilization operation with embodiment 1.
It is concentrated by ultrafiltration: the 0.4% ethyl cellulose aqueous solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet is cut
Molecular weight 5000KD, Mi Libo is stayed to provide, weak solution is maintained at 30-40 DEG C (slightly above solution temperature), feed liquor in ultra-filtration process
End pressure is 2.5bar, and in 0.7bar, water yield changes over time to be as follows: the end pressure that flows back
Water yield situation in 3 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 0.7 | 2.5 | 0.7 |
| 20 | 0.5 | 2.5 | 0.6 |
| 30 | 0.6 | 2.5 | 0.7 |
| 45 | 0.7 | 2.4 | 0.7 |
| 60 | 0.4 | 2.4 | 0.7 |
| 90 | 0.4 | 2.5 | 0.7 |
| 95 | 0.4 | 2.5 | 0.7 |
| 120 | 0.5 | 2.4 | 0.7 |
Test result shows that film packet will not be blocked by reducing reflux end pressure, be conducive to long-time ultrafiltration.But pass through 120 points
The ultrafiltration concentration of clock adds up water yield 80-100mL, and the expected water yield of technique is 3000mL, and too slow, Wu Faman is concentrated in the program
Sufficient mass production needs.Consider to increase feed liquor end pressure on the basis of secondary, while controlling water yield not less than 4mL/min.
Comparative example 3
With liquid, filtration sterilization operation with embodiment 1.
It is concentrated by ultrafiltration: the 0.4% ethyl cellulose aqueous solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet is cut
Molecular weight 5000KD, Mi Libo is stayed to provide, weak solution is maintained at 30-40 DEG C (slightly above solution temperature) in ultra-filtration process, will go out
In 4-5mL/min, adjusting feed liquor end pressure is 4.3~4.8bar for water control, and reflux end pressure is 4.0~4.2bar, water outlet
Amount, which changes over time, to be as follows:
Water yield situation in 4 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 4 | 4.3 | 4.0 |
| 20 | 4.2 | 4.3 | 4.1 |
| 30 | 4.5 | 4.5 | 4.0 |
| 45 | 5 | 4.7 | 4.0 |
| 60 | 5.1 | 4.7 | 4.0 |
| 90 | 4.8 | 4.5 | 4.2 |
| 95 | 5.2 | 4.8 | 4.2 |
| 120 | 4.9 | 4.8 | 4.0 |
Test result shows that adding up water yield by ultrafiltration in 120 minutes is 600mL, significantly improves compared with comparative example 1
Efficiency is concentrated by ultrafiltration.But does not reach concentration in expected 120 minutes still and remove 3000mL water.
Embodiment 2
With liquid: taking water for injection 9.94L, be added with stirring chitosan (4000KD, golden section's medicine company) 60g, main agitating paddle turns
Number 70-100rpm, emulsifies fly cutter revolution 0rpm, and 1mol/l hydrochloric acid solution is added and adjusts pH to 3-4, stirs 1.5h, obtains 0.6%
(w/w) chitosan aqueous solution.
Filtration sterilization: 0.6% chitosan aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: 0.6% chitosan aqueous solution through filtration sterilization being removed water using cross-flow ultrafiltration, the retention point of film packet
Son amount 10000KD, Mi Libo offer, to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, by water yield control
For system in 5-26mL/min, adjusting feed liquor end pressure is 3bar, and reflux end pressure is 2.5~3.0bar, and water yield changes over time
It is as follows:
Water yield situation in 5 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 5.9 | 3.0 | 2.5 |
| 20 | 25.9 | 3.0 | 2.5 |
| 30 | 23.3 | 3.0 | 2.9 |
| 45 | 25.0 | 3.0 | 3.0 |
| 60 | 24.5 | 3.0 | 2.6 |
| 90 | 22.6 | 3.0 | 2.6 |
| 100 | 24.5 | 3.0 | 2.5 |
| 120 | 24.8 | 3.0 | 2.5 |
The result shows that keeping feed liquor end pressure in 2-4bar, for the end pressure that flows back in 1-3bar, water yield is not less than 5mL/
The technique of min can meet production requirement.
Comparative example 4
With liquid, filtration sterilization operation with embodiment 2.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off
10000KD, Mi Libo are provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield control is existed
4-25mL/min, adjusting feed liquor end pressure are 2.4-5.5bar, and reflux end pressure is 3bar, and water yield changes over time as follows
Table:
Water yield situation in 6 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 7.9 | 2.4 | 3.0 |
| 20 | 11.9 | 4.5 | 3.1 |
| 30 | 15.3 | 4.5 | 3.0 |
| 45 | 15.9 | 4.5 | 3.0 |
| 60 | 4.8 | 5.0 | 3.0 |
| 90 | 2.6 | 5.5 | 3.0 |
| 100 | 0.7 | 5.1 | 3.0 |
| 120 | 0.2 | 2.5 | 3.0 |
The result shows that changing over time, water yield is fewer and fewer, and 120 minutes whens only have the water yield of 0.3-0.2mL/min,
0.6% chitosan aqueous solution viscosity is presumably due to higher than ethyl cellulose, film packet can be blocked when liquid feeding end hypertonia, is needed
Readjust technological parameter.
Comparative example 5
With liquid, filtration sterilization operation with embodiment 2.
It is concentrated by ultrafiltration: 0.6% chitosan aqueous solution through filtration sterilization being removed water using cross-flow ultrafiltration, the retention point of film packet
Son amount 10000KD, Mi Libo offer, to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, by water yield control
For system in 4-25mL/min, adjusting feed liquor end pressure is 3.8bar, and reflux end pressure is 3.0bar, and water yield changes over time as follows
Table:
Water yield situation in 7 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 3.9 | 3.8 | 3.0 |
| 20 | 4.9 | 3.8 | 3.0 |
| 30 | 4.3 | 3.8 | 3.0 |
| 45 | 5.9 | 3.8 | 3.0 |
| 60 | 8.8 | 3.8 | 3.0 |
| 90 | 12.6 | 3.8 | 3.0 |
| 100 | 11.7 | 3.8 | 3.0 |
| 120 | 11.2 | 3.8 | 3.0 |
Test result shows that reducing feed liquor end pressure is conducive to be concentrated by ultrafiltration, and does not have blocking film packet occur in 120 minutes
Phenomenon.But since water yield is too low, thickening efficiency is caused to reduce, it attempts on the basis of keeping feed liquor end pressure 2-4bar,
Increase water yield.
Conclusion:
It is can be found that by above-described embodiment 1,2,1~5 test result of comparative example:
For the material of dissolution in low temperature: using the film packet of molecular cut off 3000-20000KD, under 0-10 degrees celsius,
Slipstream mode ultrafiltration weak solution；Keep feed liquor end pressure in 2-4bar, the end pressure that flows back is in 1-3bar, water yield 5-26mL/
min；
For the material of heating for dissolving: using the film packet of molecular cut off 3000-20000KD, being higher than solution temperature condition
Under, slipstream mode ultrafiltration weak solution；Keep feed liquor end pressure in 2-5bar, the end pressure that flows back is in 1-3bar, water 4-26mL/
min。
Embodiment 3
With liquid: taking water for injection 9.94L, be added with stirring chitosan (10000KD, golden section's medicine company) 60g, main agitating paddle turns
Number 70-100rpm, emulsifies fly cutter revolution 0rpm, and 1mol/l hydrochloric acid solution is added and adjusts pH to 3-4, stirs 1.5h, obtains 0.6%
(w/w) chitosan aqueous solution.
Filtration sterilization: 0.6% chitosan aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off
15000KD, Mi Libo are provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield control is existed
5-25mL/min, adjusting feed liquor end pressure are 3.0~3.2bar, and reflux end pressure is 3.0~3.1bar, and water yield becomes at any time
Change is as follows:
Water yield situation in 8 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 7.9 | 3.1 | 3.1 |
| 20 | 24.3 | 3.2 | 3.0 |
| 30 | 24.7 | 3.1 | 3.0 |
| 45 | 24.7 | 3.0 | 3.0 |
| 60 | 24.8 | 3.1 | 3.0 |
| 90 | 25.0 | 3.1 | 3.0 |
| 100 | 24.5 | 3.1 | 3.0 |
| 120 | 24.8 | 3.2 | 3.0 |
The result shows that by 120 minutes accumulative water yields: 2976mL, compared with Example 2, embodiment 3 use more high score
The chitosan of son amount configures solution, but by control feed liquor end pressure in 2-4bar, the end pressure that flows back is in 1-3bar, water yield 5-
Successfully 0.6% chitosan aqueous solution is concentrated by ultrafiltration to 6% concentrated solution by ultrafiltration in 6.2 hours by 26mL/min.
Embodiment 4
With liquid: taking water for injection 9.94L, be added with stirring chitosan (50000KD, golden section's medicine company) 60g, main agitating paddle turns
Number 70-100rpm, emulsifies fly cutter revolution 0rpm, and 1mol/l hydrochloric acid solution is added and adjusts pH to 3-4, stirs 1.5h, obtains 0.6%
(w/w) chitosan aqueous solution.
Filtration sterilization: 0.6% chitosan aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off
30000KD, Mi Libo are provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield control is existed
5-25mL/min, adjusting feed liquor end pressure be 3.0~3.2bar, reflux end pressure be 3.0bar, water yield change over time as
Following table:
Water yield situation in 9 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 6.3 | 3.0 | 3.0 |
| 20 | 9.3 | 3.2 | 3.0 |
| 30 | 14.7 | 3.2 | 3.0 |
| 45 | 17.5 | 3.2 | 3.0 |
| 60 | 21.8 | 3.2 | 3.0 |
| 90 | 25.6 | 3.2 | 3.0 |
| 100 | 25.2 | 3.2 | 3.0 |
| 120 | 24.8 | 3.2 | 3.0 |
The result shows that by 120 minutes accumulative water yields: 2554mL realizes target, success by ultrafiltration in 7 hours
0.6% chitosan aqueous solution is concentrated by ultrafiltration to 4.8% concentrated solution.Embodiment 2 to 4 shows that the shell for different viscosities gathers
Sugar juice, it is only necessary to replace the film packet of different molecular weight cut off, technological parameter according to the invention can be achieved 8-10 times and surpass
Filter concentration technology.
Embodiment 5
With liquid: taking water for injection 9.96L, be added with stirring poloxamer (P188, BASF) 40g, main agitating paddle revolution 70-
100rpm emulsifies fly cutter revolution 0rpm, stirs 1.5h, obtains 0.4% (w/w) P188 aqueous solution.
Filtration sterilization: 0.4%P188 aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off 3000KD,
Mi Libo is provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield is controlled in 5-25mL/
Min, adjusting feed liquor end pressure are 3.4~3.5bar, and reflux end pressure is 2.6~2.9bar, and water yield changes over time as follows
Table:
Water yield situation in 10 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 20.7 | 3.5 | 2.8 |
| 20 | 24.6 | 3.5 | 2.6 |
| 30 | 24.5 | 3.5 | 2.7 |
| 45 | 24.3 | 3.5 | 2.8 |
| 60 | 24.5 | 3.5 | 2.8 |
| 90 | 24.2 | 3.4 | 2.8 |
| 100 | 24.3 | 3.5 | 2.8 |
| 120 | 24.6 | 3.4 | 2.9 |
The result shows that by 120 minutes accumulative water yields: 3048mL realizes target, success by ultrafiltration in 5 hours
0.4%P188 aqueous solution is concentrated by ultrafiltration to 1.6% concentrated solution.
Embodiment 6
With liquid: taking water for injection 9.925L, be added with stirring poloxamer (P188, BASF) 75g, main agitating paddle revolution
70-100rpm emulsifies fly cutter revolution 0rpm, stirs 1.5h, obtains 0.75% (w/w) P188 aqueous solution.
Filtration sterilization: 0.75%P188 aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off 3000KD,
Mi Libo is provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield is controlled in 5-25mL/
Min, adjusting feed liquor end pressure are 2.4~2.6bar, and reflux end pressure is 2.4~2.5bar, and water yield changes over time as follows
Table:
Water yield situation in 11 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 23.5 | 2.5 | 2.5 |
| 20 | 24.9 | 2.5 | 2.4 |
| 30 | 24.8 | 2.4 | 2.5 |
| 45 | 24.7 | 2.5 | 2.5 |
| 60 | 24.8 | 2.4 | 2.5 |
| 90 | 24.6 | 2.6 | 2.4 |
| 100 | 24.6 | 2.5 | 2.5 |
| 120 | 24.7 | 2.5 | 2.5 |
The result shows that by 120 minutes accumulative water yields: 3036mL realizes target by ultrafiltration in 5.5 hours, at
0.75%P188 aqueous solution is concentrated by ultrafiltration to 4.5% concentrated solution function.
Embodiment 7
With liquid: taking water for injection 9.925L, be added with stirring poloxamer (P407, BASF) 75g, main agitating paddle revolution
70-100rpm emulsifies fly cutter revolution 0rpm, stirs 1.5h, obtains 0.75% (w/w) P407 aqueous solution.
Filtration sterilization: 0.75%P407 aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off 3000KD,
Mi Libo is provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield is controlled in 5-25mL/
Min, adjusting feed liquor end pressure are 2.4~2.6bar, and reflux end pressure is 2.4~2.5bar, and water yield changes over time as follows
Table:
Water yield situation in 12 cross-flow ultrafiltration removal process of table
The result shows that by 120 minutes accumulative water yields: 3000mL realizes target by ultrafiltration in 5.4 hours, at
0.75%P407 aqueous solution is concentrated by ultrafiltration to 3.75% concentrated solution function.
Embodiment 8
With liquid: taking water for injection 9.95L, be added with stirring carbomer (974P, Lubrizol) 50g, main agitating paddle revolution
70-100rpm emulsifies fly cutter revolution 1500rpm, is dispersed with stirring 1h, obtains 0.5% (w/w) 974P aqueous solution.
Filtration sterilization: 0.5%974P aqueous solution is successively crossed into 0.45 micron, 0.22 micron membrane filter degerming.
It is concentrated by ultrafiltration: the weak solution through filtration sterilization being removed water using cross-flow ultrafiltration, film packet molecular cut off 3000KD,
Mi Libo is provided, and to reduce solution viscosity, weak solution is maintained at 5-10 DEG C in ultra-filtration process, and water yield is controlled in 5-25mL/
Min, adjusting feed liquor end pressure are 2.0~2.2bar, and reflux end pressure is 2.4~2.5bar, and water yield changes over time as follows
Table:
Water yield situation in 13 cross-flow ultrafiltration removal process of table
| Time (min) | Water yield (mL/min) | Feed liquor end pressure (bar) | It flows back end pressure (bar) |
| 10 | 22.3 | 2.0 | 2.5 |
| 20 | 22.4 | 2.1 | 2.4 |
| 30 | 23.0 | 2.2 | 2.5 |
| 45 | 22.6 | 2.0 | 2.5 |
| 60 | 23.2 | 2.0 | 2.5 |
| 90 | 23.0 | 2.0 | 2.4 |
| 100 | 23.2 | 2.0 | 2.5 |
| 120 | 22.5 | 2.0 | 2.5 |
The result shows that by 120 minutes accumulative water yields: 2736mL realizes target by ultrafiltration in 6.6 hours, at
0.5%P407 aqueous solution is concentrated by ultrafiltration to 5% concentrated solution function.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (6)
1. a kind of preparation method of vascular anastomosis agent characterized by comprising
High molecular material is dissolved in water, filtration sterilization obtains weak solution；
The weak solution is removed water using the method for cross-flow ultrafiltration, obtains vascular anastomosis agent；
The high molecular material includes the first high molecular material or the second high molecular material, and first high molecular material is pool Lip river
Pehanorm, chitosan, carbomer, hypromellose, sodium alginate or hydroxyethyl starch, second high molecular material are second
Base cellulose；
The equipment that the ultrafiltration uses is ultrafiltration column or film packet；
The high molecular material is the first high molecular material, the cross-flow ultrafiltration use molecular cut off for 3000~
The film packet of 20000KD, temperature be 0~30 DEG C, inlet hydraulic be 2~4bar, return pressure be 1~3bar, water yield be 5~
25mL/min；
The high molecular material is the second high molecular material, the cross-flow ultrafiltration use molecular cut off for 3000~
The film packet of 20000KD, temperature are higher than the solution temperature of the second high molecular material, and inlet hydraulic is 2~5bar, return pressure 2
~3bar, water yield are 4~25mL/min.
2. preparation method according to claim 1, which is characterized in that the method for the dissolution is that dissolution, room is stirred at room temperature
The dissolution of temperature standing, heating stirring are dissolved, heating stands dissolution, low temperature stirring and dissolving, stand at low temperature dissolve or emulsion dispersion.
3. preparation method according to claim 1, which is characterized in that the filter that the filtration sterilization uses is stud, mistake
Filter stick, flat-panel filter or miillpore filter.
4. preparation method according to claim 3, which is characterized in that the filter pore size of the filter is 0.8 micron, 0.45
Micron or 0.22 micron.
5. preparation method according to claim 1, which is characterized in that the quality percentage of high molecular material in the weak solution
Than being 0.4%~0.75%, the mass percent of high molecular material is 1.6%~7.5% in the vascular anastomosis agent.
6. preparation method according to any one of claim 1 to 5, which is characterized in that further include damp and hot after the water removal
The step of sterilizing.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035572A (en) * | 2004-10-07 | 2007-09-12 | 纳幕尔杜邦公司 | Polysaccharide-based polymer tissue adhesive for medical use |
| WO2010118285A1 (en) * | 2009-04-09 | 2010-10-14 | E. I. Du Pont De Nemours And Company | Method of dissolving an oxidized polysaccharide in an aqueous solution |
| CN102159274A (en) * | 2007-02-22 | 2011-08-17 | 普拉罗美德公司 | Use of reverse thermosensitive polymers to control biological fluid flow following a medical procedure |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2007257436B2 (en) * | 2006-06-02 | 2013-05-02 | Synedgen, Inc. | Chitosan-derivative compounds and methods of controlling microbial populations |
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2016
- 2016-08-10 CN CN201610651154.6A patent/CN106267320B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035572A (en) * | 2004-10-07 | 2007-09-12 | 纳幕尔杜邦公司 | Polysaccharide-based polymer tissue adhesive for medical use |
| CN102159274A (en) * | 2007-02-22 | 2011-08-17 | 普拉罗美德公司 | Use of reverse thermosensitive polymers to control biological fluid flow following a medical procedure |
| WO2010118285A1 (en) * | 2009-04-09 | 2010-10-14 | E. I. Du Pont De Nemours And Company | Method of dissolving an oxidized polysaccharide in an aqueous solution |
Non-Patent Citations (1)
| Title |
|---|
| Topical hemostatic agents in surgical practice;Masci Emilia et al.;《Transfusion and Apheresis Science》;20111231(第45期);第305-311页 |
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