CN110483767A - A kind of degradable macromolecule hemostatic material and preparation method thereof - Google Patents
A kind of degradable macromolecule hemostatic material and preparation method thereof Download PDFInfo
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- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
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- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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Abstract
The invention discloses a kind of degradable macromolecule hemostatic materials and preparation method thereof.The structural formula of degradable macromolecule hemostatic material of the invention are as follows:Wherein, R isOrThe integer that m is 5~76, the integer that n is 2~28.The preparation method of degradable macromolecule hemostatic material of the invention is the following steps are included: the 1) dehydration of the normal pressure of lactic acid and aminomethylbenzoic acid or tranexamic acid, pre-polymerization, obtains performed polymer；2) performed polymer carries out melt polycondensation under the effect of the catalyst, then polymerizate is purified and dried.Macromolecule hemostatic material of the invention can be long lasting for release small molecule haemostatic medicament, and haemostatic effect is lasting, and its preparation process is simple, production cost is low, can be widely applied to the continued hemostasis of internal and external wound.
Description
Technical field
The present invention relates to a kind of degradable macromolecule hemostatic materials and preparation method thereof.
Background technique
Blood is one of the basic substance for constituting human body and maintaining human life activity, has nutritive issue, adjusts organ
The effect of activity and defence harmful substance.When the blood loss of human body reaches 20% or more of total blood volume, it may appear that apparent to stop
Gram symptom, and when blood loss reaches the 40% of total blood volume, it will be in peril of one's life.Therefore, hemostasis in time is patient vitals' peace
Full necessary guarantee.With the progress of science and technology, hemostatic material has obtained significant progress, has especially been with natural polymer
The high score subclass hemostatic material of raw material is quickly grown.
Currently, common high score subclass hemostatic material is mainly include the following types: 1) with fibrin, cellulose, gelatin, shell
The natural polymers such as glycan are the high score subclass hemostatic material of raw material preparation；2) with natural polymers such as chitosan, sodium alginates
For raw material, the high score subclass hemostatic material prepared by chemical modification；3) it using natural polymer as carrier, is received by physical load
The height of the conventional hemostatic preparation such as rice silicate, insulin, 6-aminocaprolc acid, ethylenediamine diacetic acid, aminomethylbenzoic acid, tranexamic acid
Molecule class hemostatic material.
However, above several high score subclass hemostatic materials or production cost based on natural polymer it is too high or with
The binding force of small molecule haemostatic medicament is too small, causes sustained release timeliness too short, can not meet actual demand well.
Therefore, it is necessary to develop, a kind of haemostatic effect is lasting, preparation process is simple, production cost is low, biodegradable
High score subclass hemostatic material.
Summary of the invention
The purpose of the present invention is to provide a kind of degradable macromolecule hemostatic materials and preparation method thereof.
The technical solution used in the present invention is:
A kind of degradable macromolecule hemostatic material, structural formula are as follows:
Wherein, R isM be 5~
76 integer, the integer that n is 2~28.
Preferably, the weight average molecular weight of the degradable macromolecule hemostatic material is 1000~6000g/mol.
The preparation method of above-mentioned degradable macromolecule hemostatic material the following steps are included:
1) reaction kettle is added in lactic acid, aminomethylbenzoic acid or tranexamic acid, opens stirring, heating carries out normal pressure dehydration, then takes out
Vacuum carries out pre-polymerization, obtains performed polymer；
2) reaction kettle is added in catalyst, carries out melt polycondensation, adds solvent lysate, add water precipitating, filtered, it is right
Filter residue is dried and grinds, and obtains degradable macromolecule hemostatic material.
Preferably, the molar ratio of the step 1) lactic acid, aminomethylbenzoic acid or tranexamic acid is (1~19): 1.
Preferably, step 1) normal pressure dehydration carries out under conditions of 100~140 DEG C of temperature, and dewatering time is 1~
6h。
Preferably, the step 1) pre-polymerization carries out under conditions of 110~190 DEG C of temperature, 1~10kPa of vacuum degree, polymerization
Time is 2~12h.
Preferably, the step 2) catalyst is kreatinin, triphenylphosphine, dodecyl benzene sulfonic acid, p-methyl benzenesulfonic acid, first
Base sulfonic acid, ZnCl2、SnCl2, one of ZnO, SnO, additive amount is the 0.1%~1% of prepolymer mass.
Preferably, the step 2) melt polycondensation carries out under conditions of 110~190 DEG C of temperature, 1~10kPa of vacuum degree,
Polymerization time is 2~12h.
Preferably, the step 2) solvent is methanol, in chloroform, methylene chloride, ether, ethyl acetate, petroleum ether
At least one.
Preferably, the step 2) drying carries out under conditions of 30~45 DEG C of temperature, 1~10kPa of vacuum degree.
The beneficial effects of the present invention are: macromolecule hemostatic material of the invention can be long lasting for release small molecule hemostasis
Drug, haemostatic effect is lasting, and its preparation process is simple, production cost is low, can be widely applied to holding for internal and external wound
Continuous hemostasis.
1) macromolecule hemostatic material of the invention is obtained by direct melt polycondensation, is not needed using expensive raw material
And equipment for customizing, reaction process is simple, and easy control of reaction conditions, purification of products is easy to operate, and yield is high；
2) macromolecule hemostatic material of the invention can release small molecule haemostatic medicament in wound surface with sustaining degradation,
Haemostatic effect is lasting, the continued hemostasis suitable for internal and external wound；
3) macromolecule hemostatic material of the invention can not only be made powdered or gel and directly use, but also can be used as wound
Mouth auxiliary material substrate.
Detailed description of the invention
Fig. 1 is the infrared spectrogram of poly- (lactic acid-aminomethylbenzoic acid).
Fig. 2 is that the instant anthemorrhagic performance of poly- (lactic acid-aminomethylbenzoic acid) tests photo.
Fig. 3 is the degradation rate-time curve of poly- (lactic acid-aminomethylbenzoic acid).
Fig. 4 is the infrared spectrogram of poly- (lactic acid-tranexamic acid).
Fig. 5 is that the instant anthemorrhagic performance of poly- (lactic acid-tranexamic acid) tests photo.
Specific embodiment
The present invention will be further explained combined with specific embodiments below and explanation.
Embodiment 1:
A kind of degradable macromolecule hemostatic material, preparation method includes the following steps:
1) reaction kettle is added in the aminomethylbenzoic acid (ABA) of the lactic acid of 3.5g (LA), 1.5g, opens stirring, is warming up to 140
DEG C, normal pressure is dehydrated 4h, then is vacuumized with vacuum pump using circulatory water and carry out 4h pre-polymerization, obtains performed polymer；
2) reaction kettle is added in the SnO of 0.02g, is vacuumized with rotary vane type vacuum oil pump, 8h melting contracting is carried out at 170 DEG C
It is poly-, methanol lysate is added after polymerization, adds deionized water precipitating, filters, it is dry to carry out vacuum for 24 hours to filter residue at 40 DEG C
Dry, grinding obtains poly- (lactic acid-aminomethylbenzoic acid), i.e. degradable macromolecule hemostatic material.
Performance test:
1) infrared: suitable poly- (lactic acid-aminomethylbenzoic acid) and potassium bromide (drying) being uniformly mixed, pulverized, is set
Thin slice is pressed into compression mold, with the infrared absorption spectrum of Fourier Transform Infrared Spectrometer (FT-IR) measurement group, scanning
Range is 400.0~4000.0cm-1, the infrared spectroscopy of poly- (lactic acid-aminomethylbenzoic acid) is as shown in Figure 1.
The spectrum unscrambling of Fig. 1 is analyzed as follows:
1752cm-1: the stretching vibration absworption peak of C=O on saturation chain carboxylate ester group；
1722cm-1: the stretching vibration absworption peak of C=O on esters of unsaturated carboxylic acids Ar-COOR；
1666cm-1: the stretching vibration absworption peak of C=O on amide groups；
It can be seen that lactic acid and aminomethylbenzoic acid success polycondensation generate poly- (lactic acid-aminomethylbenzoic acid).
2) instant anthemorrhagic performance: 3 rounds a) are chosen on tissue culture plate, the first round is as blank control, second row
It is respectively put into the powdered aminomethylbenzoic acid of 5mg in hole, 5mg powdered poly- (lactic acid-aminomethylbenzoic acid) is respectively put into third round；b)
Ca (the NO of 0.1mL concentration 0.02mol/L is added in each hole3)2Solution；C) sodium citrate of 10mL concentration 0.1mol/L is taken
Conical flask is added in solution, then releases new blood into conical flask out of live chickens body, shakes up, obtains anticoagulated blood, spare；D) In
0.3mL anticoagulated blood is added in each hole；E) a column hole is washed with the NaCl solution of concentration 9g/L every 1min, to stop blood coagulation
Process, and NaCl solution is sucked out with dropper immediately, repeated washing to solution is clarified, to wash out all soluble blood and sample,
Test results are shown in figure 2.
As shown in Figure 2: poly- (lactic acid-aminomethylbenzoic acid) can be obviously shortened clotting time (comparing with blank control), have
Good coagulating effectiveness.
3) long-acting slow-release performance: the poly- of serial molar feed ratio a) is measured with ultraviolet-uisible spectrophotometer (UV-vis)
The absorbance of the PBS buffered aqueous solution (pH=7.4) of (lactic acid-aminomethylbenzoic acid) makes standard curve, intends standard curve
It closes, obtains the functional equation formula of standard curve；B) quantitative poly- (lactic acid-aminomethylbenzoic acid) sample and quantitative PBS are buffered
Aqueous solution (pH=7.4) is placed in degradation bottle, is shaken up, and sealing avoids the evaporation of water, is saved in 37 DEG C of thermostats, every certain
Time take supernatant UV-vis measure absorbance；C) it by the resulting formula of standard curve fit, calculates and is dropped in aqueous solution
The aminomethylbenzoic acid concentration that solution comes out, then pass through the quality that concentration calculates degraded copolymer with the product of degradation solution volume, finally
Degradation rate is found out by the quality of degraded copolymer and the ratio of sample initial mass, obtained degradation rate-time relationship is bent
(ABA5 indicates that the molar ratio of LA and ABA is 95:5 to line as shown in Figure 3；ABA10 indicates that the molar ratio of LA and ABA is 90:10；
ABA20 indicates that the molar ratio of LA and ABA is 80:20；The rest may be inferred).
As shown in Figure 3: poly- (lactic acid-aminomethylbenzoic acid) synthesized according to molar feed ratio n (LA): n (ABA)=95:5
Sample starts to degrade after 1 week, and degradation rate reaches as high as 50% after 3 weeks, and degradation rate reaches as high as 87% after 7 weeks.It is similar
Ground can also degrade according to poly- (lactic acid-aminomethylbenzoic acid) sample that other molar feed ratios synthesize.The result shows that poly- (lactic acid-
Aminomethylbenzoic acid) it can be long lasting for releasing small molecule haemostatic medicament, it can be ensured that and wound is in normal activity or unexpected stress
Still there is enough hemostasis efficiency when rear bleeding again, thus in biologic medical field, especially internal wound and chronic wound
The treatment of mouth, has potential application.
Embodiment 2:
A kind of degradable macromolecule hemostatic material, preparation method includes the following steps:
1) reaction kettle is added in the tranexamic acid (TA) of the lactic acid of 2.4g (LA), 4.1g, opens stirring, is warming up to 120 DEG C,
Normal pressure is dehydrated 6h, then is vacuumized with vacuum pump using circulatory water and carry out 8h pre-polymerization, obtains performed polymer；
2) by the ZnCl of 0.04g2Reaction kettle is added, is vacuumized with rotary vane type vacuum oil pump, 12h melting is carried out at 190 DEG C
Polycondensation is added chloroform lysate, adds deionized water precipitating after polymerization, filter, and it is true to carry out 48h to filter residue at 40 DEG C
Sky is dry, and grinding obtains poly- (lactic acid-tranexamic acid), i.e. degradable macromolecule hemostatic material.
Performance test:
1) infrared: suitable poly- (lactic acid-tranexamic acid) and potassium bromide (drying) being uniformly mixed, pulverized, is set
Thin slice is pressed into compression mold, with the infrared absorption spectrum of Fourier Transform Infrared Spectrometer (FT-IR) measurement group, scanning
Range is 400.0~4000.0cm-1, the infrared spectroscopy of poly- (lactic acid-tranexamic acid) is as shown in Figure 4.
The spectrum unscrambling of Fig. 4 is analyzed as follows:
2936cm-1: hexatomic ring-CH on tranexamic acid2C-H stretching vibration absworption peak；
1746cm-1: the stretching vibration absworption peak of C=O on ester group；
1663cm-1: the stretching vibration absworption peak of C=O on amide groups；
It can be seen that lactic acid and tranexamic acid success polycondensation generate poly- (lactic acid-tranexamic acid).
2) instant anthemorrhagic performance: 3 rounds a) are chosen on tissue culture plate, the first round is as blank control, second row
It is respectively put into the powdered tranexamic acid of 5mg in hole, 5mg powdered poly- (lactic acid-tranexamic acid) is respectively put into third round；b)
Ca (the NO of 0.1mL concentration 0.02mol/L is added in each hole3)2Solution；C) sodium citrate of 10mL concentration 0.1mol/L is taken
Conical flask is added in solution, then releases new blood into conical flask out of live chickens body, shakes up, obtains anticoagulated blood, spare；D) In
0.3mL anticoagulated blood is added in each hole；E) a column hole is washed with the NaCl solution of concentration 9g/L every 1min, to stop blood coagulation
Process, and NaCl solution is sucked out with dropper immediately, repeated washing to solution is clarified, to wash out all soluble blood and sample,
Test results are shown in figure 5.
As shown in Figure 5: poly- (lactic acid-tranexamic acid) can be obviously shortened clotting time (comparing with blank control), have
Good coagulating effectiveness.
3) long-acting slow-release performance: test method is the same as embodiment 1.
Test result shows that poly- (lactic acid-tranexamic acid) can be long lasting for releasing small molecule haemostatic medicament, can be with
Ensure still there is enough hemostasis efficiency when again bleeding of the wound after normal activity or unexpected stress.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of degradable macromolecule hemostatic material, it is characterised in that: structural formula are as follows:
Wherein, R isM is 5~76
Integer, the integer that n is 2~28.
2. degradable macromolecule hemostatic material according to claim 1, it is characterised in that: its weight average molecular weight be 1000~
6000g/mol。
3. the preparation method of degradable macromolecule hemostatic material of any of claims 1 or 2, it is characterised in that: including following step
It is rapid:
1) reaction kettle is added in lactic acid, aminomethylbenzoic acid or tranexamic acid, opens stirring, heating carries out normal pressure dehydration, then vacuumizes
Pre-polymerization is carried out, performed polymer is obtained；
2) reaction kettle is added in catalyst, carries out melt polycondensation, adds solvent lysate, add water precipitating, filtered, to filter residue
It is dried and grinds, obtain degradable macromolecule hemostatic material.
4. preparation method according to claim 3, it is characterised in that: the step 1) lactic acid, aminomethylbenzoic acid or ammonia first ring
The molar ratio of acid is (1~19): 1.
5. preparation method according to claim 3 or 4, it is characterised in that: the dehydration of the step 1) normal pressure temperature 100~
It is carried out under conditions of 140 DEG C, dewatering time is 1~6h.
6. preparation method according to claim 3 or 4, it is characterised in that: the step 1) pre-polymerization is in temperature 110~190
DEG C, carry out under conditions of 1~10kPa of vacuum degree, polymerization time is 2~12h.
7. preparation method according to claim 3, it is characterised in that: the step 2) catalyst is kreatinin, triphenyl
Phosphine, dodecyl benzene sulfonic acid, p-methyl benzenesulfonic acid, methane sulfonic acid, ZnCl2、SnCl2, one of ZnO, SnO, additive amount is pre-polymerization
The 0.1%~1% of weight.
8. preparation method according to claim 3 or 7, it is characterised in that: the step 2) melt polycondensation temperature 110~
190 DEG C, carry out under conditions of 1~10kPa of vacuum degree, polymerization time is 2~12h.
9. preparation method according to claim 3 or 7, it is characterised in that: the step 2) solvent is methanol, three chloromethanes
At least one of alkane, methylene chloride, ether, ethyl acetate, petroleum ether.
10. preparation method according to claim 3 or 7, it is characterised in that: the step 2) drying is in temperature 30~45
DEG C, carry out under conditions of 1~10kPa of vacuum degree.
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