CN108721690A - A kind of preparation method and products thereof of medicament slow release type antiseptic dressing - Google Patents
A kind of preparation method and products thereof of medicament slow release type antiseptic dressing Download PDFInfo
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- 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
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- 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
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- 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
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0033—Collagen
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- 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
- A61L26/0085—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0095—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
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- A—HUMAN NECESSITIES
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- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
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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
- 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
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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
- 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
- A61L2300/604—Biodegradation
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Abstract
The invention discloses a kind of preparation methods and products thereof of medicament slow release type antiseptic dressing, and preparation method includes the following steps：（1）Carboxymethyl chitosan, macromolecular collagen protein, aminoglycoside antibiotics are mixed；（2）Mixed liquor is poured into mold, is stood, it is dry, obtain uncrosslinked spongy material；（3）Uncrosslinked spongy material is soaked in the ethanol solution containing EDC/NHS, is crosslinked, obtains composite crosslinking sponge dressing, i.e. antiseptic dressing.The mode that amino on antibiotic of the present invention is covalently bonded to form amido bond with the carboxyl in carboxymethyl chitosan and collagen realizes that antibiotic grafts in dressing matrix, and by amido bond on polymer backbone slow fracture realize the slow release of antibiotic in dressing, to be made with compared with high-biocompatibility, long-term antimicrobial activity, the antiseptic dressing product for promoting wound healing.
Description
Technical field
The present invention relates to wound dressing, especially a kind of preparation method and products thereof of medicament slow release type antiseptic dressing.
Background technology
In order to avoid wound infection, wound dressing should have good antibacterial activity.Ideal antiseptic dressing can be effective
The bacterium or fungi in wound infection are killed, prevents bacterial biof iotalm from being formed, and prevent wound in healing, wound examination, surgery
Infecting again during operation or dressing.However, currently used antiseptic dressing preparation method is by physical mixed small molecule
Drug is in the material（Such as the Chinese patent that Authorization Notice No. is CN201337582 discloses and a kind of Ciprofloxacin is passed through object
The mixed mode of reason is added to the method that chitosan disinfectant dressing is prepared in chitosan glue）, it is the treatment of wound infection
Provide a kind of feasible selection.However, since the antibacterials on this kind of antiseptic dressing will usually discharge within 48 hours
It is complete, cause antibacterials excessive concentration in the short time of wound tissue position, antibacterials to travel further into vivo, to vitals
It adversely affects；Also, since the antibacterial efficacy of these antiseptic dressings was held time no more than 48 hours, it is necessary to pass through frequency
Numerous more change dressings maintain, to the antibacterial efficacy of wound location, to increase nursing cost and patient suffering.Therefore active demand is opened
Sending out a kind of having the wound dressing of long-term antimicrobial activity.
In recent years, the antiseptic dressing with long-term antimicrobial activity prepared using nano-scale anti-biotic material is also obtained more
Carry out more concerns.For example, being had using the combine dressing of the preparations such as nano silver, nano-metal-oxide, carbon nanotube notable
Antibacterial and anti-inflammatory effect, and have long-term antibacterial activity（Particular reference is：Mosselhy D A, Granbohm
H, Hynönen U, et al. Nanosilver-silica composite: Prolonged antibacterial
effects and bacterial interaction mechanisms for wound dressings [J].
Nanomaterials, 2017, 7(9)；Díezpascual A M, Díezvicente A L. Wound healing
bionanocomposites based on castor oil polymeric films reinforced with
chitosan-modified zno nanoparticles [J]. Biomacromolecules, 2015, 16(9):
2631-2644；Chen Y, Xu P, Wu M, et al. Colloidal rbc-shaped, hydrophilic, and
hollow mesoporous carbon nanocapsules for highly efficient biomedical
engineering [J]. Advanced Materials, 2014, 26(25): 4294）.However, these nano materials
Toxicity can not be ignored, research shows that nano silver has significantly damages to a variety of organs such as spleen, liver and kidney.Nano metal
Oxide can cause organ damage, osmotic adjustment change and immunologic derangement.In addition, it was reported that carbon nanotube can be easily
Cell is pierced through, and can induce the release of proinflammatory cytokine.
Therefore, prepare the wound dressing with high-biocompatibility and long-term antimicrobial activity be still clinical application it is urgent highly necessary
It asks.
Invention content
One of the objects of the present invention is to provide a kind of preparation methods of medicament slow release type antiseptic dressing, pass through the preparation side
Antiseptic dressing product made from method not only has higher biocompatibility, but also is provided simultaneously with long-term antimicrobial activity and promotes to hinder
The function of mouth healing.
To achieve the above object, the present invention uses following technological means：
A kind of preparation method of medicament slow release type antiseptic dressing, includes the following steps：
（1）Carboxymethyl chitosan, macromolecular collagen protein, aminoglycoside antibiotics are dissolved in deionized water, stirred evenly,
Mixed liquor is obtained, the mass ratio of carboxymethyl chitosan and macromolecular collagen protein is 0.75~2.5 in mixed liquor:1, amino sugar
A concentration of 0.5~1 mmol/L of tobramycin antibiotic；
（2）Again by step（1）Obtained mixed liquor pours into mold, stands de-soak, and freeze-drying obtains uncrosslinked after dry
Spongy material；
（3）By step（2）Obtained uncrosslinked spongy material is soaked in the ethanol solution containing EDC/NHS, EDC's
Dosage is subject to integral molar quantity excess of the mole relative to carboxyl in mixture of EDC, under room temperature cross-linking reaction 18-
For 24 hours, extra crosslinker solution is discarded, cleans 3 ~ 5 times, removes extra crosslinking agent, composite crosslinking is obtained after being freeze-dried again
Sponge dressing, i.e., the described medicament slow release type antiseptic dressing.
The macromolecular collagen protein uses molecular weight for the collagen of 80-100 KDa.
The aminoglycoside antibiotics preferably sulfuric acid gentamicin.Gentamicin sulphate is aminoglycoside wide spectrum antibiosis
Element has broad spectrum antibiotic activity to gram-positive bacteria and Gram-negative bacteria in vitro.And generating bacterial drug resistance side
Face, gentamicin sulphate is also below other glucoside-containing components.
Step（3）Described in the dosage of EDC be preferably that the mass ratio of EDC and carboxymethyl chitosan is：1.6~2.88:
1；At this point, the stability of cross-linking agent is good.
Step（3）Described in EDC and the molar ratio of NHS be preferably 4:1.
The step（2）Mixed liquor after middle standing de-soak, is sealed, and carries out pre-freeze to mixed liquor and be allowed to solid
Change；Then it is freeze-dried again.Before being freeze-dried to mixed liquor, first by mixed liquor sealing, slow pre-freeze, can have
Effect avoids the dehydration of mixed liquor surface too fast and ice crystal largely generates, and causes surface cracked, to influence the flat of product surface
Whole degree.
The mold preferably uses the mold of polyvinyl fluoride material.Adhesion is not susceptible between this mold and product, profit
In demoulding the rate of output is improved simultaneously because product edge and bottom are more smooth；In addition, under equal conditions, with iron mold
Or glass mold is compared, the hole using the product of the Mold Making of polyvinyl fluoride material is larger, more advantageous to wound healing.
The present invention is using natural macromolecular material --- and carboxymethyl chitosan and macromolecular collagen protein pass through as host material
EDC/NHS makes the carboxyl on carboxymethyl chitosan and macromolecular collagen protein carry out covalent bonding with amino, realizes the friendship of the two
Connection is to form compound dressing matrix；Meanwhile keeping the amino on aminoglycoside antibiotics compound with this by EDC/NHS
Carboxyl in dressing matrix is covalently bonded to form amido bond and realizes that antibiotic grafts in compound dressing matrix, is made a kind of new
Type antiseptic dressing；The novel antibacterial dressing has the following advantages that：
（1）The present invention it is crosslinked after dressing formed it is not soluble in water but can the big quantity of fluid of swellable absorbent three-dimensional netted polymerization knot
Structure；It is with good water absorption rate, moisture-vapor transmission and mechanical strength；
（2）Host material-the carboxymethyl chitosan and macromolecular collagen protein of antiseptic dressing obtained by the present invention are to have
The natural macromolecular material of good biocompatibility so that the novel antibacterial dressing no cytotoxicity obtained by the present invention, biology
Compatibility is preferable, and also found in test：Antiseptic dressing obtained by the present invention can effectively improve cell adhesion and proliferation；
（3）Antiseptic dressing obtained by the present invention realizes antibiotic in compound dressing base by the slow fracture of amido bond
Release in matter has achieved the effect that long-term antibacterial, and it is unfavorable caused by wound healing to avoid frequently replacement wound dressing
It influences, meanwhile, and prevent the explosion of drug in antiseptic dressing to discharge and have an adverse effect to body；
（4）The present invention establishes SD rat full skin wound models, in SD rat full skin wound infection models, incite somebody to action this
Antiseptic dressing prepared by invention is in the reparative experiment of rat wound, finding：The antiseptic dressing of the present invention shows good
The feature of re-epithelialization, dense collagenous deposition and angiogenesis.
Another object of the present invention is to provide a kind of preparation methods according to said medicine slowly released type antibiotic dressing to be made
Antiseptic dressing.
Description of the drawings
Fig. 1 is step of the present invention（2）The cross-cutting fault microscopic appearance of obtained uncrosslinked spongy material；
Fig. 2 is the cross-cutting fault microscopic appearance of the antiseptic dressing obtained by the present invention；
Fig. 3 is step of the present invention（2）The longitudinal sectional section microscopic appearance of obtained uncrosslinked spongy material；
Fig. 4 is the longitudinal sectional section microscopic appearance of the antiseptic dressing obtained by the present invention；
Fig. 5 is the product picture of the antiseptic dressing obtained by the present invention.
Specific implementation mode
Below in conjunction with specific embodiment, the present invention will be further described, but the present invention is not limited only to these embodiments.
Embodiment
A kind of preparation method of medicament slow release type antiseptic dressing, includes the following steps：
（1）Carboxymethyl chitosan, macromolecular collagen protein, aminoglycoside antibiotics are dissolved in deionized water, stirred evenly,
Mixed liquor is obtained, the mass ratio of carboxymethyl chitosan and macromolecular collagen protein is 0.75~2.5 in mixed liquor: 1；Amino sugar
A concentration of 0.5~1 mmol/L of tobramycin antibiotic；
（2）Again by step（1）Obtained mixed liquor pours into mold, stands de-soak, and freeze-drying obtains uncrosslinked after dry
Spongy material；
（3）By step（2）Obtained uncrosslinked spongy material is soaked in the ethanol solution containing EDC/NHS, EDC's
Dosage be subject to EDC mole relative to the carboxyl integral molar quantity excess in mixed liquor, the molar ratio of EDC and NHS are 4:1,
20 h of cross-linking reaction under room temperature discards extra crosslinker solution, cleans 5 times, removes extra crosslinking agent, and freezing is dry again
Composite crosslinking sponge dressing is obtained after dry, i.e., the described medicament slow release type antiseptic dressing.
4 embodiments have been carried out according to the preparation method of said medicine slowly released type antibiotic dressing（That is 1~embodiment of embodiment
4）, wherein carboxymethyl chitosan in 1~embodiment of embodiment 4, macromolecular collagen protein, aminoglycoside antibiotics, EDC,
The dosage of NHS is shown in Table 1, the water absorption rate of the antiseptic dressing obtained by embodiment 1- embodiments 4, porosity, moisture-vapor transmission, drawing
The test data for stretching intensity is shown in Table 2.
The deacetylation of carboxymethyl chitosan employed in embodiment 1- embodiments 4 is 91.6%, molecular weight 20
KDa is purchased from Nantong Lv Shen bioengineering Co., Ltd；Macromolecular collagen protein uses molecular weight for the collagen egg of 80-100 KDa
In vain, it is purchased from Fujian sea God Bioisystech Co., Ltd；Antibiotic containing amino selects gentamicin sulphate, is purchased from Beijing Suo Laibaoke
Skill Co., Ltd；EDC（1-（3- dimethylamino-propyls）- 3- ethyl-carbodiimide hydrochlorides）And NHS（N- hydroxysuccinimidyls acyl is sub-
Amine）It is purchased from the Shanghai bio tech ltd Yuan Ye.
Table 1
Table 2
The test method difference of water absorption rate, moisture-vapor transmission, tensile strength in embodiment 1- embodiments 4 is as follows：
（1）The test method of water absorption rate is specially：Drying sample is cut into the square dressing of the mm of 20 mm × 20, is weighed in the balance
The weight for measuring dressing, is denoted as Mo, sample dressing is placed in PBS（10 mmol/L, pH=7.4）In solution, after 30 min quickly
The moisture that surface is sucked with filter paper, record sample quality of weighing is Mw.Each sample is parallel to do five experiments, is averaged,
Sample water absorption rate is according to formula（2-1）It calculates：
Wherein, MoFor the weight of dry dressing（g）；MwFor the weight of dressing after water suction（g）；X is the water absorption rate of dressing（%）；
（2）Moisture-vapor transmission is measured according to the ASTM E96-00 methods of American Bureau of Standards (ABS), is as follows：First, it will apply
Material is cut into suitable size and is placed in the bottle bottleneck for having been loaded with 10 mL deionized waters（13 mm of diameter）Place seals dressing with rubber band
Gap between bottleneck prevents steam loss, weighs its initial weight.Secondly, the sample bottle for covering dressing is put into constant temperature
Constant humidity incubator（Temperature is 37 DEG C, relative humidity 79%）In, to be only equipped with the sample bottle of 10 mL deionized waters as blank pair
According to group.It is taken out after 24 h, claims its weight.Moisture-vapor transmission is according to following formula（2-2）It is calculated：
Wherein,For 24 hours moisture loss weight（g/day）, A is the surface area of bottleneck（mm2）；
（3）Tensile strength is carried out with reference to the test method of pharmaceuticals industry standard YY/T 0471.4-2004, is tried using electronics pulling force
The tensile strength of machine test dressing is tested, bearing capacity is 500 N, and efficiency is within ± 1%.It is as follows：Sample is cut out
It is cut into a length of 90 mm, width is the strip sample of 25 mm.With its thickness of vernier caliper measurement and record.In constant temperature and humidity condition
（Temperature is 25 DEG C, relative humidity 70%）Under stretched, the clamp distance of sample is 50 mm when test, and rate of extension is
300 mm/min.Setting program is provided according to test method, is detected, 5 groups of valid data of each experimental test, takes it average
Value.The tensile strength of dressing（TS）It is calculated according to following formula:
Tensile strength calculation formula（2-3）：
Wherein, TS is tensile strength（MPa）, Fmax is the maximum pull born when sample fracture（N）, L is the thickness of dressing
（mm）, W is the width of dressing（mm）.
It can be seen that from Tables 1 and 2：The water absorption rate of antiseptic dressing obtained by the present invention 2200% or more, has good
Water absorbing properties.This high water absorption rate is mainly due to the high-hydrophilic of carboxymethyl chitosan and the holey of antiseptic dressing
Caused by structure.From application angle of the dressing on wound, water absorption rate is bigger, is more conducive to quickly absorb wound exudation
Liquid, and keep the healing environment of moistening appropriate.And the step of the present invention（2）Obtained uncrosslinked spongy material is in water
In degrade soon, its water absorption rate can not be surveyed.Meanwhile the moisture-vapor transmission of antiseptic dressing obtained by the present invention exists
1912.70 g/m2G/m for 24 hours~3541.152•24h.With control group（No dressing covering）Experimental data（12705.90 g/
m2•24h）It compares, low-moisture evaporation can drop in the antiseptic dressing obtained by the present invention.Therefore, compared with blank control group, this
The obtained antiseptic dressing of invention can effectively reduce the loss of vapor, to promote epidermal cell and fibroblastic increasing
It grows；Also, the tensile strength of antiseptic dressing obtained by the present invention in 0.12 MPa or more, has good tensile resistance.
In addition, the present inventor has also carried out the measurement of elongation at break, measurement side to antiseptic dressing made from embodiment 4
Method is specially：90 mm are grown into sample cutting, width is the strip sample of 25 mm.With its thickness of vernier caliper measurement and remember
Record.In constant temperature and humidity condition（Temperature is 25 DEG C, relative humidity 70%）Under stretched, the clamp distance of sample is when test
50 mm, rate of extension are 300 mm/min.Setting program is provided according to test method, is detected, 5 groups of each experimental test
Valid data take its average value.Elongation at break calculation formula（2-4）：
Wherein, EB is elongation at break（%）, L0It is the distance between sample stretching front jig（mm）, L1Fixture when being sample fracture
Length（mm）.As a result it is：Antiseptic dressing made from embodiments herein 4 is in the elongation of incision position 12% or so.Fracture
Elongation indicates the flexibility of material, and therefore, the antiseptic dressing obtained by the present invention has good flexibility, can protect wound
Mouth is from external collision.
The present invention also cultivates HSF cells by the antiseptic dressing surface obtained by embodiment 4（Application on human skin is at fiber finer
Born of the same parents are purchased from Beijing bio tech ltd Ding Guo）, and use live/dead staining kit（Purchased from the rich limited public affairs of biology of upper sea cowry
Department）Cell activity is detected, the cell for the fluoresced green observed under fluorescence microscope is living cells, sends out the cell of red fluorescence
For dead cell, the growing state of the HSF cells of different time is observed, cell is carried out to the antiseptic dressing obtained by the application
As a result toxotest is shown：Antiseptic dressing group obtained by embodiment 4（I.e. by HSF cell inoculations obtained by embodiment 4
On antiseptic dressing surface）In visible cell largely survive, with the control group for being directly inoculated in tissue polystyrene culture dish
Compared to no significant difference；At first day of inoculation, only a small amount of cell adherence and proliferation were in antiseptic dressing group and control group；
At second day, cell started largely to migrate proliferation；In third day, with the extension of incubation time, it can be seen that a large amount of cells are close
Collection is grown on antiseptic dressing, and cell is saturated already close to proliferation, and cell arrangement is intensive, is paved with entire bottom surface substantially.These realities
It tests phenomenon and shows antiseptic dressing no cytotoxicity prepared by the present invention, biocompatibility is preferable, and can effectively improve cell
Stick and is proliferated.
Wherein, step of the present invention（2）The cross-cutting fault microscopic appearance of obtained uncrosslinked spongy material such as 1 institute of attached drawing
Show, longitudinal sectional section microscopic appearance it is as shown in Figure 3；The cross-cutting fault microscopic appearance of the antiseptic dressing after crosslinking obtained by the present invention
As shown in Figure 2, longitudinal sectional section microscopic appearance is as shown in Fig. 4.It can be seen that from attached drawing 2：Antiseptic dressing obtained by the present invention is in
Even porous reticular structure；It can be seen that from attached drawing 4：Antiseptic dressing obtained by the present invention has the pore structure of stratiform, and this
The structure of stratiform between the carboxyl and amino in carboxymethyl chitosan and macromolecular collagen protein mainly due to that can form interpenetrating
Network structure.This lamellar structure of antiseptic dressing of the present invention can better absorbing wound exudate, keep suitable moisture
Environment increases the contact area of wound and extraneous oxygen, promotes wound healing.In addition, be interconnected between Kong Yukong, cell energy
Enough migration growths inside it, are conducive to the conveying of nutriment, the dressing that different wound conditions are adapted to for preparation creates
Condition.
The present invention has also carried out anti-microbial property test to antiseptic dressing made from embodiment 4, specially：
（1）Culture medium is prepared
LB liquid medium：Weigh 10 g tryptones, 5 g yeast extracts, 10 g sodium chloride be dissolved in 1000 mL go from
In sub- water, stirs to being completely dissolved, be used in combination 1 mol/L NaOH to debug pH value between 7.0~7.4, high pressure sterilization（120
DEG C, 20 min）Obtain LB liquid medium；
Solid LB media：The agar powder of 17 g is added in the fluid nutrient medium of 1000 mL, high pressure sterilization waits for that it is cooled to
At 50~60 DEG C, sterile glass culture dish is poured into（90 mm of diameter）, it is cooled to room temperature to obtain the solid LB cultures of 3 mm thickness
Base.
（2）The recovery of strain and the preparation of bacteria suspension
Take the gram-positive bacteria frozen（S. aureus, staphylococcus aureus）And Gram-negative bacteria（E. coli, large intestine
Bacillus；P. aeruginosa, pseudomonas aeruginosa）Strain carries out recovery culture on solid LB media after defrosting.Every other day
Well-grown single bacterium colony after picking recovery uses physiological saline dilute respectively after being inoculated in 37 DEG C of 24 h of culture of LB liquid medium
It releases, is counted by the method for plate culture count, it is 1 × 10 to be made into bacterial concentration8The laboratory bacteria suspension of CFU/mL.
（3）Inhibition zone test
Antiseptic dressing made from embodiment 4 is cut into the round sample of 10 mm of diameter, in 30 min of superclean bench ultraviolet irradiation
Sterilizing.Drop takes the 100 above-mentioned bacteria suspensions of μ L on solid LB media, sticks sample to be tested with spreading rod even spread, just sets 15
Culture dish is positioned over to be inverted in 37 DEG C of biochemical cultivation cases after min and is cultivated.The bacterium observed on culture medium is taken out after cultivating 24 h
Growing state simultaneously records antibacterial circle diameter（D）, every group of three Duplicate Samples；
As a result it shows：Antiseptic dressing made from embodiment 4 is straight to E. coli, S. aureus, the inhibition zone of P. aeruginosa
Diameter be 17.8 ± 1.6 mm, 15.6 ± 0.9 mm, 12.0 ± 0.8 mm, and antibiotic-free load, only by carboxymethyl
Antiseptic dressing does not have E. coli, S. aureus, P. aeruginosa made of chitosan-macromolecular collagen protein crosslinking
There is apparent inhibition zone.
In order to determine that can the antiseptic dressing obtained by the present invention maintain long-term anti-microbial property, it is made to select embodiment 4
The antiseptic dressing obtained has carried out long-term anti-microbial property and has measured.The specific method is as follows：Antiseptic dressing obtained by embodiment 4 is cut into
The round sample of 10 mm of diameter, is immersed in the PBS buffer solutions of 10 mL, and sealing is placed on 37 DEG C, the constant temperature of 100 rpm shakes
Release in vitro is simulated in bed.Point takes out sample at the appointed time, and sterile water wash sample is commented by inhibition zone method
Valence, 3 Duplicate Samples of every group of setting.As a result it shows：Antiseptic dressing obtained by embodiment 4 is at the 11st day to E. coli, S.
Aureus, P. aeruginosa maintain original inhibition zone size substantially, and inhibition zone size is 16.5 ± 0.1
Mm, 16.0 ± 0.1 mm and 14.8 ± 0.0 mm, it was demonstrated that the antiseptic dressing prepared by the application has durable antibiotic.
Meanwhile present invention is alternatively directed to obtained antiseptic dressings to have carried out vitro drug release studies, be as follows：
1, pharmaceutical standards curvilinear equation
Gentamicin sulphate standard curve：O-phthalaldehyde solution allocation：The o-phthalaldehyde of 2.5 g is weighed, 62.5 mL are added
Methanol and 3 mL 2 mercapto ethanols, are finally settled to 560 mL with the dobell's solution of 0.04 mol/L.Solution is stored in palm fibre
It in color bottle, is placed in dark room, and is at least placed 24 hours before.Take 150 μ L gentamicin sulfate solutions
（50 mg/mL）It is dissolved in PBS buffer solution, is configured to the storing solution of 150 mg/L concentration.Storing solution is carried out a series of dilute
It releases, is configured to the solution of 100 mg/L, 80 mg/mL, 60 mg/mL, 40 mg/mL, 20 mg/mL, 10 mg/mL.It takes on 1 mL
It states solution, 1 mL isopropanols and 1 mL o-phthalaldehyde solution mixings is added, reacts 30 min at room temperature, from reacted molten
It takes 1 mL in quartz colorimetric utensil in liquid, measures it in 332 nm absorbance values with ultraviolet specrophotometer, draw standard curve；
2, vitro drug release is tested
Antiseptic dressing obtained by embodiment 4 is cut into the square of the mm of 30 mm × 30, the PBS bufferings for being immersed in 100 mL are molten
In liquid, sealing is placed on 37 DEG C, simulates release in vitro in the constant-temperature table of 100 rpm.Point takes out 1 mL and releases at the appointed time
Tapping, while adding the synthermal fresh PBS solutions of 1 mL.Sulfuric acid in release liquid is determined using Indirect Ultraviolet spectrometry to celebrate
The content of big mycin, calculates drug（Gentamicin sulphate）Cumulative release amount, 3 Duplicate Samples of every group of setting；
3, test result
（1）Gentamicin sulphate is since without UV absorption, gentamicin sulphate is measured using derivatization method under ultraviolet light
Content.Gentamicin sulphate calibration curve equation is：Y=0.046x+0.1729, in formula：X is Ciprofloxacin Hydrochloride concentration（mg/
mL）；Y is that be measured under 332 nm wavelength be light absorption value, R2=0.9977, linear relationship is preferable；
（2）The present invention determines the OD of PBS solution in 24 hours332Value, and the accumulative of drug is calculated by calibration curve equation and is released
Concentration is put, and further calculates the drug release rate in 24 hours（As shown in table 3）With the drug release rate in 11 days（Such as table
Shown in 4）；
Table 3
Table 4
As can be seen from Table 3：Antiseptic dressing obtained by the present invention releases 46.59 ± 3.61% sulphur in 12 initial h
Sour gentamicin.The increase of the accumulative drug release of early stage is that release due to the antibiotic on antiseptic dressing surface and antibacterial are applied
Expect the release of the physical bond antibiotic on surface.As seen from Table 4：Nearly 20% gentamicin sulphate does not discharge yet after 11 days.
The sustained release of antibiotic is due to caused by the slow fracture of amido bond between antibiotic and polymer.
The present invention has also set up SD rat full skin wound models, and in wound ehec infection and golden yellow Portugal
Grape coccus, by antiseptic dressing made from embodiment 4 in the reparative experiment of rat wound, macroscopic evaluation wound healing situation
And healing rate, and histology and immunohistochemical staining are carried out to it, as a result show:
（1）In wound healing rate, dressing group（Wound covers antiseptic dressing made from embodiment 4）Wound area percentage
Substantially less than gauze group（Wound covers common gauze）, with business antiseptic dressing Aquacel Ag groups（Wound covering business
Antiseptic dressing Aquacel Ag）Quite；
（2）In histological observation, compared with gauze group, dressing group wound starts epithelialization, lymphocyte and red blood cell on the 3rd day
Number is obviously less, and is basically completed in the 6th day epithelialization.Dressing group is 49.99 ± 9.46% in the 6th day collagen deposition, glue
Former synthesis and deposition is apparently higher than business Aquacel Ag groups（33.63±7.98%）With gauze group（26.73±7.46%）.Together
When, dressing group is 158.6 ± 47.9/mm in the 6th day vessel density2, vessel density is significantly higher than gauze group (83.4 ± 36.8/
mm2), slightly it is better than business Aquacel Ag groups (128.1 ± 54.6/mm2).It follows that dressing group shows good epithelium again
Change, dense collagenous deposits and the features such as angiogenesis.
The source of above-mentioned strain and SD rats see the table below 5：
Table 5
The aminoglycoside antibiotics of the present invention is not limited to the gentamicin sulphate of 1~embodiment of embodiment 4, may be
Streptomysin, gentamicin, tobramycin, neomycinsulphate, sulfamethoxazole, ampicillin, vancomycin, minocycline
Deng all antibiotic containing amino available amino thereon and the carboxylic on carboxymethyl chitosan or macromolecular collagen protein
Base crosslinks to form amido bond to make corresponding antiseptic dressing.
The dosage of the EDC of the present invention is also not limited to the specific dosage in embodiment 1- embodiments 3（Embodiment 1~implementation
The mass ratio of EDC and carboxymethyl chitosan is respectively in example 4：2.88:1,2.4:1,1.6:1,2.4:1）, EDC is a kind of chemistry
The extremely active crosslinking agent of property, it has through activated carboxyl, and carboxyl is promoted to form the effect of amido bond with amino covalence, and
Its own is simultaneously not involved in reaction, therefore, extra chemical group will not be introduced after the completion of crosslinking, and therefore, the dosage of EDC is not
It is changeless, usually, as long as the mole of EDC is excessive relative to the integral molar quantity of the carboxyl of mixture, so that it may to reach
To catalytic mixing object（Carboxymethyl chitosan, macromolecular collagen protein, antibiotic containing amino）Upper carboxyl forms acyl with amino covalence
The purpose of amine key.
The molar ratio of the EDC and NHS of the present invention are also not necessarily limited to 4 in embodiment 1- embodiments 4:1, can also be 1:1,
2:1, it is more than 4:Common ratio value in 1 equal EDC/NHS cross-linking reactions.
The step（2）Mixed liquor after middle standing de-soak, is sealed, and carries out pre-freeze to mixed liquor and be allowed to solid
Change；Then it is freeze-dried again（Usually, the temperature of the temperature > freeze-dryings of temperature >=pre-freeze of de-soak, example are stood
Such as：The temperature for standing de-soak is 4 DEG C, and the temperature of pre-freeze is 4 DEG C or -20 DEG C, and the temperature of freeze-drying is -50 DEG C or so, but, it is quiet
It sets the temperature of de-soak, the temperature of pre-freeze, the temperature of freeze-drying and is not limited to this）.Before being freeze-dried to mixed liquor,
First by mixed liquor sealing, pre-freeze, it can effectively avoid the too fast and a large amount of ice crystal of mixed liquor surface dehydration and generate, surface is caused to be split
Line, to influence the flatness of product surface.
The mold preferably uses the mold of polyvinyl fluoride material.Adhesion is not susceptible between this mold and product, profit
In demoulding the rate of output is improved simultaneously because product edge and bottom are more smooth；In addition, under equal conditions, with iron mold
Or glass mold is compared, the hole using the product of the Mold Making of polyvinyl fluoride material is larger, more advantageous to wound healing.
Another object of the present invention is to provide a kind of preparation methods according to said medicine slowly released type antibiotic dressing to be made
Antiseptic dressing, as shown in Figure 5.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification should all belong to the covering scope of the present invention.
Claims (9)
1. a kind of preparation method of medicament slow release type antiseptic dressing, it is characterised in that：Include the following steps：
（1）Carboxymethyl chitosan, macromolecular collagen protein and aminoglycoside antibiotics are dissolved in deionized water, stirring is equal
It is even, mixed liquor is obtained, the mass ratio of carboxymethyl chitosan and macromolecular collagen protein is 0.75~2.5 in mixed liquor:1, amino
A concentration of 0.5~1 mmol/L of glycoside antibiotic；
（2）Again by step（1）Obtained mixed liquor pours into mold, stands de-soak, and freeze-drying obtains uncrosslinked after dry
Spongy material；
（3）By step（2）Obtained uncrosslinked spongy material is soaked in the ethanol solution containing EDC/NHS, room temperature
Under the conditions of cross-linking reaction 18-24h, discard extra crosslinker solution, clean 3 ~ 5 times, remove extra crosslinking agent, freezing is dry again
Composite crosslinking sponge dressing is obtained after dry, i.e., the described medicament slow release type antiseptic dressing.
2. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：Described big point
Sub- collagen uses molecular weight for the collagen of 80-100 KDa.
3. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：The ammonia
Base glycoside antibiotic uses gentamicin sulphate.
4. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：Step（3）
Described in the dosage of EDC be subject to integral molar quantity excess of the mole relative to carboxyl in mixture of EDC.
5. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 4, it is characterised in that：Described
The dosage of EDC is preferably：The mass ratio of EDC and carboxymethyl chitosan is 1.6~2.88:1.
6. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：Step（3）
Described in EDC and NHS molar ratio be 4:1.
7. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：The step
Suddenly（2）Mixed liquor after middle standing de-soak, is sealed, and carries out pre-freeze to mixed liquor and be allowed to cure；Then it is freezed again
It is dry.
8. a kind of preparation method of medicament slow release type antiseptic dressing according to claim 1, it is characterised in that：Step（2）
Described in the preferred polyvinyl fluoride material of mold mold.
9. a kind of preparation method system of medicament slow release type antiseptic dressing according to any one of the claims 1~8
The antiseptic dressing obtained.
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| CN113797381A (en) * | 2021-09-22 | 2021-12-17 | 佛山湘潭大学绿色智造研究院 | Biological dressing and preparation method thereof |
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| CN116236611A (en) * | 2023-05-09 | 2023-06-09 | 天津包钢稀土研究院有限责任公司 | Rare earth metal-based functional interactive dressing and preparation method thereof |
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