CN109045347A - A kind of degradable load medicine hemostatic microsphere and preparation method thereof - Google Patents
A kind of degradable load medicine hemostatic microsphere and preparation method thereof Download PDFInfo
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- CN109045347A CN109045347A CN201810944692.3A CN201810944692A CN109045347A CN 109045347 A CN109045347 A CN 109045347A CN 201810944692 A CN201810944692 A CN 201810944692A CN 109045347 A CN109045347 A CN 109045347A
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- aqueous solution
- load medicine
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Classifications
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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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of degradable load medicine hemostatic microspheres and preparation method thereof, the preparation method comprises the following steps: the medical high molecular compounds spinning film that (1) preparation hydrophobicity is artificial synthesized；(2) ammonia products are prepared；(3) ammonia products solution is prepared, coupling agent, hydrophilic natural high molecular compound aqueous solution, reaction are sequentially added；(4) it is fitted into bag filter, dialyses in aqueous solution, vacuum freeze drying；Obtain microballoon；(5) solvent evaporation method is utilized, pharmaceutical aqueous solution is sprayed on microballoon, it is dry, obtain degradable load medicine hemostatic microsphere.The present invention is with low in cost, technique is controllable, production cost is low.The hemostatic microsphere that the present invention is self-assembly of by amphipathic degradable macromolecule hydrophobe, avoids the use of crosslinking agent, improves the safety of hemostatic material.Hemostatic microsphere can be provided simultaneously with hemostasis, antibacterial and promote wound healing function, be widely used in various having the blood surface of a wound.
Description
Technical field
The invention belongs to bio-medical materials and medical instruments to combine field, micro- more particularly to a kind of degradable load medicine hemostasis
Ball and preparation method thereof.
Background technique
Battlefield, traffic accident, natural disaster etc. in emergency circumstances, uncontrollable massive blood loss is to lead to that personnel death's is main
Reason.According to statistics, between 2011-2013, there are about 600,000 people to die of traffic accident every year on average in China, and 85% personnel death is former
Because bleeding profusely caused by being wound initial stage, if bleeding can be controlled in 30 minutes after the accident, by
The survival rate for the person of hurting sb.'s feelings can be improved 40% or more.Common capillary hemorrhage or arteriovenous bleeding, using coagulation, compressing or
The conventional methods such as tying can effectively stop blooding.But when for bleeding parts such as head, trunk, visceral injuries, traditional hemostasis
Method is unable to reach satisfactory effect.When the amount of bleeding of the wounded reaches 20% (about 800mL), it may appear that shock disease
Shape then jeopardizes patient vitals.For these damages, accelerating hemostasis using hemostasia products is the treatment that Present clinical is widely used
Means.
Current clinically used hemostasia products can be divided into three kinds: the first is to provide hemostatic composition and accelerates blood coagulation (such as blood coagulation
Enzyme hemostatic material)；Second is gel rubber material by closing damaged tissues, prevents the blood components streams such as red blood cell, blood platelet
It loses, to realize hemostasis (such as α cyanoacrylate hemostatic material).The third is to be made by hemostatic material to the concentration of blood
With agglutination coagulation factor makes wound location accelerate blood coagulation (such as styptic powder class hemostatic material)；However different types of hemostatic material
All there are many bottlenecks.
For the blood product of hemostatic composition etc, the disadvantage is that short supply, storage life are shorter, but also deposit
In risk of adverse side effect, such as the reaction of heat generation non-hemolytic, immunogenicity and Acute pulmonary inflammation etc..For solidifying
Glue class hemostasia products, major defect are that degradation speed is slower, and catabolite has certain bio-toxicity, are had certain
Security risk.For styptic powder class product, it is especially suitable for the wounds of irregular shape, and by absorbing in blood
The hemostatic composition of the impaired surface of a wound is concentrated, to effectively stop blooding in moisture.Styptic powder representative at present is produced in USA
AristaTMStyptic powder, although the problem of its haemostatic effect is pretty good, and there are still some urgent need to resolve: firstly, the product is using small
The epichlorohydrin of molecule is as crosslinking agent, with there are potential bio-toxicities；Second is that the wound surface of bleeding, be one it is warm,
Moist environment, wound surface are easy accumulation bacterium colony and cause wound infection.Therefore, it should also be avoided wound sense while hemostasis
Dye.And this product does not have antibacterial, promoting healing function, and initial stage hemostasis can only be completed to damaged part, cannot accelerate later period wound
Healing；Third is that the valuable product, not only clinical use is limited, but also can not be as emergency stock substance military, natural
The application of disaster etc..Therefore, exploitation is a low in cost, has hemostasis, antibacterial, promoting healing multifunctional novel hemostatic material
Material can better meet the use demand of clinical treatment.
Chinese patent 201810124860.4 discloses a kind of absorbable gelatin styptic powder and preparation method thereof, the patent
By optimization technique, so that crosslinking agent noresidue in styptic powder, avoids presence stimulation caused by organism of crosslinking agent
Property influence, the safety of product is improved, but prepared styptic powder only has single hemostatic function, without antibiotic effect.
Chinese patent 201611121260.X discloses a kind of sustained anti-microbial styptic powder and preparation method thereof.But the styptic powder is with nanometer
Silver is antibacterial agent, although nano silver is a kind of long-acting antibacterial agent, its pharmacokinetics is still not clear, and enters blood
Nano silver has potential genotoxicity and genetoxic, increases clinical use risk.Chinese patent CN201610952251.9
A kind of O- quaternary ammonium salt-N- alkylated chitosan and the preparation method and application thereof is disclosed, although this modification of chitosan is shown
Good antibacterial effect, but since chitosan class hemostasia products water absorbing capacity is limited, it is not suitable for the more surface of a wound of bleeding.
Hydrophobic artificial synthesized medical high molecular compounds are not only suitable for being mass produced, and have preferable raw
Object compatibility and degradability, are widely used in field of biomedicine, such as operation suture thread, tissue renovation material and drug control
Delivery systme processed, however due to the hydrophobic performance of itself, it is applied to hemostasis field and is rarely reported.
In conclusion lacking on Vehicles Collected from Market, one kind is low in cost, is suitble to industrialized production, has both hemostasis, antibacterial, promotion
The high degradable hemostatic material of the biological safety of wound healing function.
Summary of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of degradable load medicine hemostatic microsphere.
A second object of the present invention is to provide a kind of preparation methods of degradable load medicine hemostatic microsphere.
Technical solution of the present invention is summarized as follows:
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
Degree is the spinning solution of 5%-12%, utilizes electrostatic spinning process, 5~25KV of positive voltage, negative voltage (- 2)~(- 0.2) KV condition
Under, the spinning solution is prepared into the artificial synthesized medical high molecular compounds spinning film of hydrophobicity；
(2) mass parts are pressed, the spinning film for taking 0.1~10 part of step (1) to obtain, being placed in 5~50 parts of mass concentrations is 0.1%
In~50% ammonolysis solution, in 4 DEG C~60 DEG C 0.5~72h of ammonolysis, 5min~60min is centrifuged with 500rpm~5000rpm,
Supernatant is abandoned, solid is collected, it is dry, obtain ammonia products；
(3) 0.1~10 part of ammonia products is taken to be dissolved in second of polar organic solvent, preparation mass concentration be 0.01%~
10% ammonia products solution sequentially adds 0.01 part~1 part coupling agent into the ammonia products solution, and 0.5 part~5 parts
The hydrophilic natural high molecular compound aqueous solution of mass concentration 0.01%~10%, in 4 DEG C~80 DEG C 0.5~48h of reaction；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 2000~10000, in aqueous solution
After middle dialysis 1d~7d, vacuum freeze drying；Obtain microballoon；
(5) utilize solvent evaporation method, take 1~20 part of mass concentration be 1%~15% pharmaceutical aqueous solution be sprayed onto 20~
On the microballoon that 800 parts of steps (4) obtain, 25 DEG C~80 DEG C dry 0.5h~48h obtain degradable load medicine hemostatic microsphere.
Preferably, the artificial synthesized medical high molecular compounds of hydrophobicity are the poly- of number-average molecular weight 100000~250000
Lactic acid, poly- (lactic acid-ethanol) that number-average molecular weight is 100000~250000, intrinsic viscosity are 0.40dL/g~2.7dL/g
Polycaprolactone and intrinsic viscosity be 1.5dL/g~2.2dL/g at least one of polydioxanone.
The first polar organic solvent is preferred: chloroform, methanol, dimethyl sulfoxide, methylene chloride, acetone, isopropanol,
At least one of toluene, tetrahydrofuran and N,N-dimethylformamide.
Ammonolysis solution is preferred: ethylenediamine solution, 1,3- propane diamine aqueous solution, 1,6- hexamethylene diamine aqueous solution, 1,7- heptan two
At least one of amine aqueous solution, 1,8- octamethylenediamine aqueous solution and 1,9-nonamethylene diamine aqueous solution.
Second of polar organic solvent is preferred: dimethyl sulfoxide, N,N-dimethylformamide, trifluoroacetic acid, hexamethylene, right
At least one of dimethylbenzene and pyridine.
Coupling agent is preferred: 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide,
At least one of N, N'- diisopropylcarbodiimide and n-hydroxysuccinimide.
Hydrophilic natural high molecular compound is preferred: starch, sodium alginate, carboxymethyl chitosan, glucan, hyalomitome
At least one of acid, chondroitin sulfate and heparin.
Drug is preferred: Amoxicillin Sodium, Benzylpenicillin sodium salt, Ceftriaxone Sodium, kanamycin sulfate, vancomycin hydrochloride, sulphur
In sour gentamicin, aclarubicin hydrochloride, erythromycin lactobionate, hydrochloric acid Epirubicin, metronidazole and Ciprofloxacin Lactate extremely
Few one kind.
The degradable load medicine hemostatic microsphere of above method preparation.
Advantages of the present invention:
(1) present invention is using the artificial synthesized medical high molecular compounds of the controllable hydrophobicity of low in cost, technique as former material
Material extends the artificial synthesized medical high molecular compounds of hydrophobicity in the application in hemostasis field, reduces the life of hemostatic material
Produce cost.
(2) hemostatic microsphere that the present invention is self-assembly of by amphipathic degradable macromolecule hydrophobe, avoids crosslinking
The use of agent solves the problems, such as that various crosslinking agents use in the prior art, improve the safety of hemostatic material.
(3) the degradable load medicine hemostatic microsphere prepared by the present invention can be provided simultaneously with hemostasis, antibacterial and promote wound
Heal function, be widely used in it is various have the blood surface of a wound, have good potential applicability in clinical practice.
Detailed description of the invention
Fig. 1 is gained nano fibrous membrane to be carried out ammonolysis, through scanning after purification using ethylenediamine solution as ammonolysis solution
Electron microscope observation, gained ammonia products are " corynebacterium " product.
Fig. 2 is the pattern of microballoon, is observed through scanning electron microscope, and microballoon entirety pattern is micron order bead, surface light
Sliding, particle diameter distribution is uniform.
Fig. 3 is the pattern of drug bearing microsphere through scanning electron microscope diagram piece, and microballoon still keeps spherical morphology, partial size and load
Before drug, it is not much different.
Fig. 4 is the drug release patterns figure of drug bearing microsphere.By release in two weeks, the cumulative release amount of drug was reachable
30%, this shows that thus obtained microsphere has the function of long-acting slow-release to drug.
Fig. 5 is the antibacterial effect for carrying medicine hemostatic microsphere, and gram-positive bacteria (by taking staphylococcus aureus as an example) is used to examine
The antibacterial effect for examining drug bearing microsphere is capable of forming apparent inhibition zone after load medicine hemostatic microsphere is added.
Fig. 6 is the degradable external haemostatic effect for carrying medicine hemostatic microsphere.Wherein dissolved in deionized water with anticoagulated whole blood
For control group.
Fig. 7 is the cytotoxicity result figure for carrying medicine hemostatic microsphere.Containing 10% tire ox with the logarithmic phase cell of normal growth
Culture is negative control, the benzene with the logarithmic phase cell of normal growth 6% in the fresh sterile RAPI1640 culture medium of serum
Culture is positive control in phenol solution, is cultivated in degradable load medicine hemostatic microsphere leaching liquor with the logarithmic phase cell of normal growth
For experimental group.
Fig. 8 is the anthemorrhagic performance characterization for carrying medicine hemostatic microsphere, by SD rat liver bleeding hemostasis model, to prove this hair
The hemostasia effect of bright material has the effect of quick-acting haemostatic powder.After bleeding part applies and carries medicine hemostatic microsphere, the bleeding surface of a wound is very
In the short time (< 5s), hemostasis is just completed
Specific embodiment
Below by specific embodiment, the present invention is further illustrated.The embodiment of the present invention is to make this field
Those of ordinary skill the present invention, but do not limit the invention in any way is more fully understood.In following embodiments, such as without spy
Different explanation, used experimental method is conventional method, and material therefor, reagent etc. can be bought from biological or chemical company.
Embodiment 1
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
The spinning solution that degree is 5%, using electrostatic spinning process, under the conditions of positive voltage 5KV, negative voltage (- 0.2) KV, by the spinning solution
It is prepared into the artificial synthesized medical high molecular compounds spinning film of hydrophobicity；
The artificial synthesized medical high molecular compounds of the hydrophobicity are the polylactic acid of number-average molecular weight 100000.Described
A kind of polar organic solvent is chloroform/methanol (3:1, v/v) composite solution；
(2) the spinning film for taking 0.1g step (1) to obtain is placed in the ammonolysis solution that 5g mass concentration is 0.1%, in 4 DEG C
Ammonolysis 0.5h is centrifuged 60min with 5000rpm, abandons supernatant, collects solid, dry, obtains ammonia products, the ammonolysis solution
For ethylenediamine solution；
(3) 0.1g ammonia products are taken to be dissolved in second of polar organic solvent, the ammonolysis that preparation mass concentration is 0.01%
Reaction mixture sequentially adds 0.01g coupling agent, the hydrophilic natural of 0.5g mass concentration 0.01% into ammonia products solution
High-molecular compound aqueous solution, in 4 DEG C of reaction 0.5h；
Second of polar organic solvent is dimethyl sulfoxide；
Coupling agent is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；
Hydrophilic natural high molecular compound is sodium alginate；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 2000, dialyse 1d in aqueous solution
Afterwards, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 1g mass concentration is that 1% Amoxicillin sodium water solution is sprayed onto 20g step (4)
On the microballoon of acquisition, 25 DEG C of dry 0.5h obtain degradable load medicine hemostatic microsphere.
Morphology observation experiment
Sample holder is got out, two-sided conductive copper glue, the ammonolysis that will be prepared respectively by embodiment 1 on a small quantity are posted on bracket
Product, the microballoon that step (4) obtains and the degradable load medicine hemostatic microsphere and conductive copper glue finally obtained bond naturally, use
Sputter (Hitachi, E-1045, Japan) to sample carry out surface gold-plating processing, using scanning electron microscope (SEM,
Hitachi S-4800, Japan) carry out surface topography observation.
The scanning electron flying-spot microscope picture of ammonia products is as shown in Figure 1, ammonia products entirety pattern is " corynebacterium "
The pattern of nanofibers before being no longer ammonolysis；
The pattern for the microballoon that step (4) obtains, is observed through scanning electron microscope, as shown in Fig. 2, microballoon entirety pattern is
Micron order bead, surface is smooth, and particle diameter distribution is uniform.
The pattern of degradable load medicine hemostatic microsphere is observed through scanning electron microscope, as shown in figure 3, microballoon still keeps ball
Before shape pattern, partial size and carrying medicament, it is not much different.
Drug release experiment
Configure 0.0625mg/mL, 0.125mg/mL, 0.25mg/mL, 0.5mg/mL, 1mg/mL, a series of differences of 2mg/mL
The Amoxicillin sodium water solution of concentration gradient.
Using the maximum absorption band of ultraviolet-ray visible absorbing light spectral measurement various concentration drug, and standard curve is drawn, claimed
It takes the degradable load medicine hemostatic microsphere prepared in a certain amount of embodiment 1 to be placed in EP pipe, 2mL PBS solution (pH=is added
7.4) in, it is placed in shaking table at room temperature.Every 1d, 7d, 14d, 21d takes 1mLPBS solution, and add the new PBS solution of 1mL in
In former EP pipe.Using the absorbance of the taken 1mLPBS solution of ultraviolet-ray visible absorbing light spectral measurement, calculated not according to standard curve
With time point drug accumulation burst size, and draw drug release patterns.
The experimental results showed that as shown in figure 4, up to 30%, this showed the cumulative release amount of drug by release in two weeks
The degradable load medicine hemostatic microsphere of gained has the function of long-acting slow-release to drug.
Antibacterial experiment
Gram-positive bacteria (by taking staphylococcus aureus as an example) is used to investigate the antibacterial effect of drug bearing microsphere.
Preparing S. aureus bacterium (commercially available) suspension concentration is 105/ mL (uses BP culture medium), solidifies to agar plate
Afterwards, 0.2mL bacterium liquid is added dropwise, coating uniformly, is placed in 37 DEG C of incubators and takes out afterwards for 24 hours, degradable load medicine prepared by embodiment 1
Hemostatic microsphere is placed on bacterium plate, 37 DEG C culture for 24 hours, observation inhibition zone whether there is or not.The experimental results showed that degradable load medicine hemostasis is micro-
Ball has obvious antibacterial functions.As a result as shown in Figure 5.
Whole blood clotting assay
It weighs 10mg to be placed in inside surface plate by degradable load medicine hemostatic microsphere prepared by embodiment 1, be trained at 37 DEG C
It supports in 5min, 200ul anticoagulation is then slowly dropped to sample surfaces, be subsequently added into 20ul, 0.2mol/L calcium chloride solution,
Continue 37 DEG C of culture 5min.Later, 10ml distilled water is carefully added into surface plate and is shaken under 30rpm revolving speed in shaking table
10min is cultivated, while being repeated the above steps so that degradable load medicine hemostatic microsphere is not added as control group, degradable load medicine is observed and stops
Suction-operated of the blood microballoon to red blood cell.Experimental result shows that degradable load medicine hemostatic microsphere prepared by embodiment 1 has
Good hemadsorption effect, has hemostasia effect.As a result anti-instilling as shown in fig. 6, hemostatic microsphere is not added in A disk
After blood coagulation, red blood cell is distributed in distilled water.It is under the same conditions, red in B disk because joined hemostatic microsphere in B disk
Cell has been adsorbed to microsphere surface, to red blood cell occur in the clustering phenomena of microsphere surface.
Cytotoxicity experiment
Experimental cell uses the eugonic L929 cell line cell (commercially available) of 48h~72h.Culture medium is to be added 10%
(V/V) RAPI1640 of fetal calf serum.
Negative control group (the fresh sterile RAPI1640 culture medium containing 10% fetal calf serum)；
Experimental group (takes the 0.5g degradable medicine hemostatic microsphere that carries described in embodiment 1 to contain 10% fetal calf serum with 10mL
Fresh sterile RAPI1640 culture for 24 hours, obtains leaching liquor based on 37 DEG C of extractions)；
Positive controls (phenol solution that mass fraction is 5%)；
Test carries out on 96 orifice plates.The cell density of initial incubation liquid is about 50,000/mL, and the training of 200 μ L cells is added in every hole
Nutrient solution makes number of cells about 10000 in every hole.Every hole in triplicate, in the constant temperature of 37 DEG C of 5% (V/V) carbon dioxide/air
Culture for 24 hours, then discards former culture medium in incubator.
In negative control group plus 200 μ L contain the fresh sterile RAPI1640 culture medium of 10% fetal calf serum；
Experimental group adds 10 μ L, 20 μ L, 30 μ L, 40 μ L, 50 μ L leaching liquors respectively, add negative controls make it is molten in every hole
Liquid product is 200 μ L；
Positive controls add respectively 10 μ L, 20 μ L, 30 μ L, 40 μ L, 50 μ L mass fractions be 5% phenol solution, then plus
Entering negative controls makes 200 μ L of liquor capacity in every hole.
Then, which is put into after being further cultured for 48h in 37 DEG C of constant incubators and takes out culture plate, discarded in culture plate
20 μ L MTT solution are added in solution, every hole, continue to cultivate 4h, then suck stoste, 150 μ L dimethyl sulfoxides are added, concussion is very
Clock measures absorbance value (ABS) at 570nm wavelength in immune microplate reader.
Versus cell activity (%)=ABS570 experimental groups/ABS570 negative controls× 100%
According to GB/T16886.5-2003 vitro cytotoxicity judgment criteria, degradable load medicine described in embodiment 1 stops
Blood microballoon leaching liquor has 0 grade of cytotoxicity in 2.5~12.5 μ g/mL, shows good biocompatibility.As a result such as Fig. 7
It is shown.
The cytotoxicity for carrying medicine hemostatic microsphere is investigated, 10% tire ox is being contained with the logarithmic phase cell of normal growth
Culture is negative control, the benzene with the logarithmic phase cell of normal growth 6% in the fresh sterile RAPI1640 culture medium of serum
Culture is positive control in phenol solution, is cultivated in degradable load medicine hemostatic microsphere leaching liquor with the logarithmic phase cell of normal growth
For experimental group.Under current experiment condition, the cytotoxicity for carrying medicine hemostatic microsphere is all larger than 70%, does not show apparent
Cytotoxicity.
Liver hemostasis experiment
Abdominal cavity is opened after SD rat (weight is close) anesthesia, manufactures long 0.5cm depth 0.2cm with scalpel in liver right middle lobe
Oozing of blood wound, uniformly spray the degradable load medicine hemostatic microsphere of minimum dose 20mg, do not deal with it is (blank control) and commercially available
Gold wound haemostatic powder (positive control) starts timing afterwards, bleeding is observed every 20s, until liver surface does not have extra blood
Exudation is used as the bleeding time.Experimental result shows have by load medicine hemostatic microsphere degradable prepared by embodiment 1 good
Hemostasia effect, bleeding stopping period are about 20s, and the bleeding stopping period of corresponding blank control is about 220s, and commercially available gold wound styptic powder
Bleeding stopping period be about 180s.As a result as shown in Figure 8.Wherein, A figure is blank control group, and B figure is to be added to gold in the bleeding surface of a wound
It creates styptic powder (commercial product), C figure is the haemostatic effect figure being added after hemostatic microsphere prepared by embodiment 1.
Using body surface hemostasis model, the characterization of system is carried out to the anthemorrhagic performance for carrying medicine hemostatic microsphere, has passed through SD rat
Liver bleeding hemostasis model, to prove that the hemostasia effect of material of the present invention has the effect of quick-acting haemostatic powder.As a result as shown in figure 8,
After bleeding part applies and carries medicine hemostatic microsphere, the bleeding surface of a wound in a short period of time (< 5s), just completes hemostasis.
Embodiment 2
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
The spinning solution that degree is 12%, using electrostatic spinning process, under the conditions of positive electricity 25KV, negative voltage (- 2) KV, by the spinning solution system
The standby medical high molecular compounds spinning film artificial synthesized at hydrophobicity；The artificial synthesized medical high polymer chemical combination of the hydrophobicity
Object is the polylactic acid of number-average molecular weight 250000；The first described polar organic solvent is tetrahydrofuran/N, N- dimethyl formyl
Amine (4:1, v/v) composite solution；
(2) the spinning film for taking 10g step (1) to obtain is placed in the ammonolysis solution that 50g mass concentration is 50%, in 60 DEG C
Ammonolysis 72h is centrifuged 5min with 500rpm, abandons supernatant, collects solid, dry, obtains ammonia products；The ammonolysis solution is 1,
3- propane diamine aqueous solution；
(3) 10g ammonia products are taken to be dissolved in second of polar organic solvent, the ammonia products that preparation mass concentration is 10%
Solution, into ammonia products solution, successively plus 1g coupling agent, the hydrophilic natural high molecular compound water of 5g mass concentration 10%
Solution, in 80 DEG C of reaction 48h；
Second of polar organic solvent is N,N-dimethylformamide；
The coupling agent is N, N'- diisopropylcarbodiimide；
The hydrophilic natural high molecular compound is chondroitin sulfate；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 10000, is dialysed in aqueous solution
After 7d, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 20g mass concentration is that 15% vancomycin hydrochloride aqueous solution is sprayed onto 800g step
Suddenly on the microballoon that (4) obtain, 80 DEG C of dry 48h obtain degradable load medicine hemostatic microsphere.
It is demonstrated experimentally that poly- (lactic acid-ethanol) that is 100000 with number-average molecular weight, with number-average molecular weight be 250000
Poly- (lactic acid-ethanol), intrinsic viscosity are 1.5dL/g polydioxanone or intrinsic viscosity is the poly- to dioxy of 2.2dL/g
Cyclohexanone substitutes the polylactic acid of the number-average molecular weight 250000 of the present embodiment respectively, and other same the present embodiment, prepared drops
The property and effect of the load medicine hemostatic microsphere of solution, it is similar to degradable load medicine hemostatic microsphere manufactured in the present embodiment.
It is demonstrated experimentally that having with the first polarity that dimethyl sulfoxide, acetone, isopropanol or toluene substitute the present embodiment respectively
Solvent (tetrahydrofuran/n,N-Dimethylformamide (4:1, v/v) composite solution), other same the present embodiment, prepared can
The property and effect of the load medicine hemostatic microsphere of degradation, it is similar to degradable load medicine hemostatic microsphere manufactured in the present embodiment.
It is demonstrated experimentally that with 1,7- heptamethylene diamine aqueous solution or 1, the ammonolysis that 9- nonamethylene diamine aqueous solution substitutes the present embodiment respectively is molten
Liquid (1,3- propane diamine aqueous solution) other same the present embodiment, the property and effect of prepared degradable load medicine hemostatic microsphere,
It is similar to degradable load medicine hemostatic microsphere manufactured in the present embodiment.
It is demonstrated experimentally that the n,N-Dimethylformamide for substituting the present embodiment respectively with hexamethylene or pyridine is other with this implementation
Example, the property and effect of prepared degradable load medicine hemostatic microsphere, stops blooding with degradable load medicine manufactured in the present embodiment
Microballoon is similar.
It is demonstrated experimentally that the chondroitin sulfate for substituting the present embodiment respectively with glucan or hyaluronic acid is other with this implementation
Example, the property and effect of prepared degradable load medicine hemostatic microsphere, stops blooding with degradable load medicine manufactured in the present embodiment
Microballoon is similar.
It is demonstrated experimentally that with gentamicin sulphate, aclarubicin hydrochloride, erythromycin lactobionate, hydrochloric acid Epirubicin or first
Nitre azoles substitutes the vancomycin hydrochloride aqueous solution of the present embodiment, other same the present embodiment, prepared degradable load medicine respectively
The property and effect of hemostatic microsphere, it is similar to degradable load medicine hemostatic microsphere manufactured in the present embodiment.
Embodiment 3
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
The spinning solution that degree is 8%, using electrostatic spinning process, under the conditions of positive voltage 18KV, negative voltage (- 1.2) KV, by the spinning solution
It is prepared into the artificial synthesized medical high molecular compounds spinning film of hydrophobicity；The artificial synthesized medical high polymer of the hydrophobicity
Close the polylactic acid that object is number-average molecular weight 150000；The first described polar organic solvent is chloroform；
(2) the spinning film for taking 6g step (1) to obtain is placed in the ammonolysis solution that 30g mass concentration is 10%, in 20 DEG C of ammonia
Solution is centrifuged 40min for 24 hours, with 3000rpm, abandons supernatant, collects solid, dry, obtains ammonia products；The ammonolysis solution is 1,
8- octamethylenediamine aqueous solution.
(3) 5g ammonia products are taken to be dissolved in second of polar organic solvent, the ammonia products that preparation mass concentration is 6% are molten
Liquid sequentially adds 0.5g coupling agent, the hydrophilic natural macromolecule of 2g mass concentration 6% into the ammonia products solution
Object aqueous solution is closed, for 24 hours in 40 DEG C of reactions；
Second of polar organic solvent is trifluoroacetic acid；
Coupling agent is n-hydroxysuccinimide；
Hydrophilic natural high molecular compound is heparin；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 5000, dialyse 3d in aqueous solution
Afterwards, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 10g mass concentration is that 5% Ciprofloxacin Lactate aqueous solution is sprayed onto 400g step
Suddenly on the microballoon that (4) obtain, 50 DEG C of dry 12h obtain degradable load medicine hemostatic microsphere.
Embodiment 4
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
The spinning solution that degree is 12%, using electrostatic spinning process, under the conditions of positive voltage 22KV, negative voltage (- 2) KV, by the spinning solution
It is prepared into the artificial synthesized medical high molecular compounds spinning film of hydrophobicity；
The artificial synthesized medical high molecular compounds of the hydrophobicity are the polycaprolactone that intrinsic viscosity is 2.7dL/g；Institute
Stating the first polar organic solvent is methylene chloride；
(2) the spinning film for taking 5g step (1) to obtain is placed in the ammonolysis solution that 10g mass concentration is 10%, in 25 DEG C of ammonia
36h is solved, 15min is centrifuged with 1000rpm, abandons supernatant, collects solid, it is dry, obtain ammonia products；The ammonolysis solution is 1,
6- hexamethylene diamine aqueous solution；
(3) 3g ammonia products are taken to be dissolved in second of polar organic solvent, the ammonia products that preparation mass concentration is 5% are molten
Liquid sequentially adds 0.6g coupling agent, the hydrophilic natural macromolecule of 4g mass concentration 5% into the ammonia products solution
Object aqueous solution is closed, in 35 DEG C of reaction 12h；
Second of polar organic solvent is dimethyl sulfoxide；
Coupling agent is dicyclohexylcarbodiimide；
Hydrophilic natural high molecular compound is carboxymethyl chitosan；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 6000, dialyse 2d in aqueous solution
Afterwards, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 5g mass concentration is that 5% pharmaceutical aqueous solution is sprayed onto 100g step (4) acquisition
Microballoon on, 40 DEG C of dry 18h obtain degradable load medicine hemostatic microsphere.That is mould for Ceftriaxone Sodium/sulfuric acid card for the drug
Plain (1:1, m/m).
Embodiment 5
A kind of preparation method of degradable load medicine hemostatic microsphere, includes the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in the first polar organic solvent be prepared into it is dense
The spinning solution that degree is 6%, using electrostatic spinning process, under the conditions of positive voltage 15KV, negative voltage (- 1.2) KV, by the spinning solution
It is prepared into the artificial synthesized medical high molecular compounds spinning film of hydrophobicity；The artificial synthesized medical high polymer of the hydrophobicity
Closing object is the polycaprolactone that intrinsic viscosity is 0.40dL/g；The first described polar organic solvent is methylene chloride；
(2) the spinning film for taking 4g step (1) to obtain is placed in the ammonolysis solution that 10g mass concentration is 20%, in 30 DEG C of ammonia
22h is solved, 5min is centrifuged with 5000rpm, abandons supernatant, collects solid, it is dry, obtain ammonia products；The ammonolysis solution is second
Two amine aqueous solutions；
(3) 8g ammonia products are taken to be dissolved in second of polar organic solvent, the ammonia products that preparation mass concentration is 8% are molten
Liquid, into the ammonia products solution, 1g coupling agent, the hydrophilic natural high molecular compound aqueous solution of 5g mass concentration 6%,
In 40 DEG C of reaction 28h；
Second of polar organic solvent is paraxylene；
Coupling agent is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；
Hydrophilic natural high molecular compound is starch；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 5000, dialyse 5d in aqueous solution
Afterwards, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 10g mass concentration is that 8% ceftriaxone sodium water solution is sprayed onto 50g step
(4) on the microballoon obtained, 50 DEG C of dry 48h obtain degradable load medicine hemostatic microsphere.
It is demonstrated experimentally that the ammonia products entirety pattern that 5 step (2) of embodiment 2- embodiment obtains is " corynebacterium ", step
Suddenly the pattern for the microballoon that (4) obtain is micron order bead, and surface is smooth, and particle diameter distribution is uniform.Degradable load medicine hemostatic microsphere
Pattern observed through scanning electron microscope, keep spherical morphology.Experiments have shown that prepared by each embodiment of embodiment 2- embodiment 5
Degradable load medicine hemostatic microsphere to prolonged drug slow-release function, antibacterial functions, hemadsorption effect, biocompatibility and
Hemostasia effect is similar to degradable load medicine hemostatic microsphere prepared by embodiment 1.
Claims (9)
1. a kind of preparation method of degradable load medicine hemostatic microsphere, it is characterized in that including the following steps:
(1) the artificial synthesized medical high molecular compounds of hydrophobicity are dissolved in and are prepared into concentration in the first polar organic solvent and are
The spinning solution is prepared into the artificial synthesized medical high score of hydrophobicity using electrostatic spinning process by the spinning solution of 5%-12%
Sub- compound spinning film；
(2) press mass parts, take 0.1~10 part of step (1) obtain spinning film, be placed in 5~50 parts of mass concentrations be 0.1%~
In 50% ammonolysis solution, in 4 DEG C~60 DEG C 0.5~72h of ammonolysis, 5min~60min is centrifuged with 500rpm~5000rpm, is abandoned
Supernatant collects solid, dry, obtains ammonia products；
(3) 0.1~10 part of ammonia products is taken to be dissolved in second of polar organic solvent, preparation mass concentration is 0.01%~10%
Ammonia products solution sequentially add 0.01 part~1 part coupling agent, 0.5 part~5 parts quality into the ammonia products solution
The hydrophilic natural high molecular compound aqueous solution of concentration 0.01%~10%, in 4 DEG C~80 DEG C 0.5~48h of reaction；
(4) product that step (3) obtain is fitted into the bag filter that molecular cut off is 2000~10000, in aqueous solution thoroughly
After analysing 1d~7d, vacuum freeze drying；Obtain microballoon；
(5) solvent evaporation method is utilized, taking 1~20 part of mass concentration is that 1%~15% pharmaceutical aqueous solution is sprayed onto 20~800 parts
On the microballoon that step (4) obtains, 25 DEG C~80 DEG C dry 0.5h~48h obtain degradable load medicine hemostatic microsphere.
2. preparation method according to claim 1, it is characterised in that the artificial synthesized medical high polymer of the hydrophobicity
Close the polylactic acid that object is number-average molecular weight 100000~250000, the poly- (lactic acid-second that number-average molecular weight is 100000~250000
Alkyd), the polycaprolactone and intrinsic viscosity that intrinsic viscosity is 0.40dL/g~2.7dL/g are poly- pair of 1.5dL/g~2.2dL/g
At least one of dioxanone.
3. preparation method according to claim 1, it is characterised in that the first described polar organic solvent be chloroform,
At least one in methanol, dimethyl sulfoxide, methylene chloride, acetone, isopropanol, toluene, tetrahydrofuran and N,N-dimethylformamide
Kind.
4. preparation method according to claim 1, it is characterised in that the ammonolysis solution is ethylenediamine solution, 1,3- third
Two amine aqueous solutions, 1,6- hexamethylene diamine aqueous solution, 1,7- heptamethylene diamine aqueous solution, 1,8- octamethylenediamine aqueous solution and 1,9-nonamethylene diamine are water-soluble
At least one of liquid.
5. preparation method according to claim 1, it is characterised in that second of polar organic solvent is that dimethyl is sub-
At least one of sulfone, N,N-dimethylformamide, trifluoroacetic acid, hexamethylene, paraxylene and pyridine.
6. preparation method according to claim 1, it is characterised in that the coupling agent is 1- (3- dimethylamino-propyl) -3-
Ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, in N'- diisopropylcarbodiimide and n-hydroxysuccinimide
It is at least one.
7. preparation method according to claim 1, it is characterised in that the hydrophilic natural high molecular compound be starch,
At least one of sodium alginate, carboxymethyl chitosan, glucan, hyaluronic acid, chondroitin sulfate and heparin.
8. preparation method according to claim 1, it is characterised in that the drug is Amoxicillin Sodium, Benzylpenicillin sodium salt, head
Spore Qusong sodium, kanamycin sulfate, vancomycin hydrochloride, gentamicin sulphate, aclarubicin hydrochloride, erythromycin lactobionate,
At least one of hydrochloric acid Epirubicin, metronidazole or Ciprofloxacin Lactate.
9. degradable load medicine hemostatic microsphere prepared by the method for one of claim 1-8.
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