CN105778126A - Genipin cross-linked biogel as well as preparation method and application thereof - Google Patents

Genipin cross-linked biogel as well as preparation method and application thereof Download PDF

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Publication number
CN105778126A
CN105778126A CN201610202049.4A CN201610202049A CN105778126A CN 105778126 A CN105778126 A CN 105778126A CN 201610202049 A CN201610202049 A CN 201610202049A CN 105778126 A CN105778126 A CN 105778126A
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genipin
gel
solution
biogel
crosslinked bio
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CN105778126B (en
Inventor
窦桂芳
高磊
甘慧
孟志云
孙涛
朱晓霞
顾若兰
吴卓娜
孙文种
李俭
郑颖
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Institute of Field Blood Transfusion Chinese Academy of Military Medical Sciences
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Institute of Field Blood Transfusion Chinese Academy of Military Medical Sciences
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    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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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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    • A61L26/0061—Use of materials characterised by their function or physical properties
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • 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
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Abstract

The invention discloses genipin cross-linked biogel as well as a preparation method and application thereof. The genipin cross-linked biogel comprises the following raw materials in percentage by weight: 0.05wt%-0.2wt% of genipin, 1wt%-10wt% of matrix and the balance of water. By carrying out crosslinking by virtue of optimized genipin concentration, the obtained biogel has the properties of low toxicity, good water-absorbing property and mechanical property and the like. The biogel can be directly used for protecting and isolating the surfaces of various wounds, bedsores and ulcers, can be used as a dressing carrier to load antibacterial drugs, paregorics, growth factors and the like, and can be applied to the treatment of wound infection, wound analgesia or promotion of wound healing and the like. According to the genipin cross-linked biogel, the matrix, a crosslinking agent and the components are all derived from natural organisms, so that the biogel is safe and non-toxic and can be widely applied to the treatment and repair of clinical acute and chronic wounds.

Description

A kind of genipin crosslinked bio gel and preparation method and application
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to the biology that a kind of genipin obtains as cross-linking agents and coagulate Glue and preparation method and application.
Background technology
Wound refers to the skin injury that any physical factor, chemical factor or disease infection etc. are caused, including anatomy and The destruction of two aspects of function.According to normal healing process after wound, wound can be divided into acute injury and chronic trauma.Anxious Sexual trauma refers to the wound that typically can heal within 8-12 week, and great majority are that the mechanical wounding caused due to physical factor draws Rise, such as scratch, knife injury etc., also include some radiate or chemical substances etc. cause burn or caustic trauma.Chronic trauma Refer generally to heal relatively slower, usually more than 1 year, and the wound that may recur.Healing delay be probably not Cause with factor, such as the existence of the complication such as diabetes, disturbance of blood circulation, persistent infection.Chronic trauma is common Decubital ulcer, traumatic ulcer etc., be often accompanied by excessive transudate, causes wound surface dipping to delay a series of physiological healing mistake Journey, even has the risk causing systemic infection.Additionally, according to the degree of depth of wound and size, shallow table also can be divided into Wound (wound is to epidermis), II degree wound (hindering to corium, as deep as blood vessel, sweat gland and hair follicle) and III degree wound (wound To subcutaneous tissue).
Wound healing is extremely complex physiological process.Although skin has himself intrinsic wound repair mechanisms, but creates Hinder agglutination and still can there is many obstacles, as wound surface contacts cause with the microorganism in air or water or other pollutant Infecting, the latter then can be deep into surrounding normal tissue and cause tissue damage etc..Wound surface under natural open state is especially Be deep wounds indolence and more difficult and functionally reaching from structure recovered completely, finally cause patient physiology, The burden of psychological two aspects.Therefore, reduce tissue necrosis and the risk of loss function for improving wound healing degree, On wound surface, use in time suitable dressing protection timely to wound surface after wound and to accelerate wound healing the most necessary.
In recent years, many naturally occurring or synthetic macromolecular material such as chitosan, gelatin, collagen, polyacrylamide, ammonia Base Polyethylene Glycol etc., because having good biocompatibility, obtain at the biomedical sector including wound dressing Extensively application, the chitosan gel rubber made such as above material, gelfoam, collagen sponge, polyacrylamide gel etc..
If but these naturally occurring or synthetic macromolecular materials directly apply its mechanical performance often not reach requirement.Then, For increasing the mechanical performance of gel rubber material, many scholars use cross-linking method to process, mainly have crosslinking with radiation, from Son crosslinking and chemical crosslinking etc..Crosslinking with radiation needs specific plant equipment, and the gel that ionomer obtains is more crisp easily Broken.Chemical crosslinking makes cross-linking process controlled, obtains product stable homogeneous.Conventional chemical cross-linking agent has glutaraldehyde, first The aldehyde material such as aldehyde, Biformyl, although this type of cross-linking agent can obtain the gel of satisfactory mechanical property, but has bigger thin Cellular toxicity, causes the biomaterial of gained can affect the growth of normal structure after wound tissue is applied on the contrary.In recent years Successively multiple safer cross-linking agent is had to be attempted in biomaterial cross-linking reaction by people to improve biomaterial Biocompatibility.
Genipin is to separate from natural plants cape jasmine fruit, purify and the compound of iridoids that obtains, has Many active functional group group, and crosslinking can be carried out instead with unimolecule and polymolecular form with the macromolecular material containing amido Should.Compared with conventional cross-linking agent, natural biological cross-linking agent genipin has good biocompatibility, and has certain Anti-inflammatory activity, the release of inflammatory factor and metallo-matrix proteases can be suppressed, thus be accordingly used in trauma care material have There is unique advantage.But, the crosslinked bio gel fragility obtained by reacting with macromolecular material with genipin is higher, stretches Malleability is poor with elasticity, is still not used as wound dressing.
Summary of the invention
It is an object of the invention to for technological deficiency present in prior art, it is provided that wound surface can be carried out effectively by one Isolation, protection genipin crosslinked bio gel, its raw material composition include 0.05wt%-0.2wt% genipin, 1wt%-10wt% substrate and the water of surplus；The wherein preferred 0.05wt%-0.1wt% of the content of genipin, most preferably 0.075 Wt%.
Described substrate can be chitosan, carboxymethyl chitosan, carboxyetbyl chitosan, collagen, gelatin, polyacrylamide One or more in the macromolecular compound containing amido such as amine and amino-polyethyleneglycols.
Described substrate also includes alginate, starch, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose The mixture of arbitrarily composition such as one or more in element, carbomer etc..
Also include carrying medicament, one in the preferred antibacterials of described carrying medicament, analgesic drug product and somatomedin or Several.
The weight/mass percentage composition of described antibacterials is 0.001%-10%, can be penicillins, cephalosporins, ammonia Base glucosides class, quinolones, Macrolide, many peptides, sulfonamides, Tetracyclines, chloromycetin, silver salt class A class in (containing nanometer silver), zincum salts (containing Nano-Zinc) medicine or classes of combination in any.
The weight/mass percentage composition of described analgesic drug product is 0.001%-10%, can be procaine, tetracaine, benefit card Cause, bupivacaine, etidocaine, ropivacaine, dyclonine, indomethacin, ibuprofen, diclofenac diethyl The combination in any of one or more in amine, diclofenac sodium etc..
The weight/mass percentage composition of described somatomedin is 0.001%-10%, can be recombinant human epidermal growth factor, Mus table Skin growth factor, recombination human basic fibroblast growth factor, recombination human acidic mechanocyte growth factor, weight The combination in any of one or more in group human/bovine basic fibroblast growth factor etc..
Second aspect, the invention reside in a kind of method preparing above-mentioned genipin crosslinked bio gel of offer, preparation process Including: the genipin solution of preparation 5wt%；The 1wt% aqueous acetic acid of preparation substrate；By the genipin solution of 5wt% Mix homogeneously with the 1wt% aqueous acetic acid of substrate and use deionized water constant volume, obtain gel solution；It is sub-packed in mould and puts In 37 DEG C of isothermal reaction 24h, to obtain final product.
Comprise the following steps:
(1), the preparation of genipin solution:
Take 5g genipin to be dissolved in the deionized water of 95g, after mix homogeneously, obtain the capital that weight/mass percentage composition is 5wt% The flat solution of Buddhist nun；
(2), the preparation of gel solution:
Substrate is scattered in the aqueous acetic acid of 1wt%, the most swelling after, add 5wt% genipin solution, stirring Using deionized water constant volume after uniformly, obtain gel solution, genipin ultimate density in gel solution is 0.05%-0.2%, substrate ultimate density in gel solution is 1%-10%；Preferably, 5wt% genipin solution is added While, it is also possible to add carrying medicament (solid or solution)；
(3), the molding of genipin crosslinked bio gel:
The gel solution of step (2) gained is sub-packed in mould, mould is positioned over 37 DEG C of isothermal reaction 24h, i.e. Obtain described genipin crosslinked bio gel.
The third aspect, the invention reside in the above-mentioned genipin crosslinked bio gel of offer at preparation treatment traumatic infection, wound surface Application in pain relieving or wound healing medicine.
The genipin crosslinked bio gel that the present invention provides uses the genipin concentration optimized to cross-link, and is that one can Being applied to acute, chronic wound treatment and the biological gel nursed, the substrate and the crosslinker component that form it are all Natural biological sources, safe and nontoxic.This genipin crosslinked bio gel can be spread evenly across wound surface, has water absorption Well, the character such as satisfactory mechanical property, all kinds of wounds, decubital ulcer and skin surface can be effectively isolated, protect, Reparation for wound surface provides absorbable exogenous substrates support；It is also used as dressing carrier load antimicrobial drug, pain relieving Medicine and somatomedin etc., treat for traumatic infection, wound surface pain relieving or wound healing etc..
Accompanying drawing explanation
Fig. 1 show the micro-structure diagram of the genipin crosslinked bio gel of the present invention；
Fig. 2 show the micro-structure diagram after the genipin crosslinked bio gel load antibacterials of the present invention；
Fig. 3 show the drug release profiles figure after the genipin crosslinked bio gel load antibacterials of the present invention.
Detailed description of the invention
In the genipin crosslinked bio gel that the present invention proposes, genipin is as cross-linking agent, is a kind of from natural plants Fructus Gardeniae The macromolecular compound extracted in fruit, amido therein can react with himself, be cross-linked with each other into tridimensional network. The cytotoxicity of genipin be only glutaraldehyde ten thousand/, and the cross-linking products obtained has and aldehydes cross-linking products phase When mechanical strength.In addition, genipin is proven to have antiinflammatory action, can suppress inflammatory factor and metal matrix The release of protease.
The crosslinked polymeric gel dressing of genipin has been reported both at home and abroad at present, and wherein genipin is as cross-linking agent Concentration is many between 0.5wt%-2wt%, but inventor finds to react with macromolecular material with this concentration genipin through test Obtained crosslinked bio gel fragility is higher, and extensibility is poor with elasticity, it is impossible to as Wound dressing.Then, send out A person of good sense wishes to search out the crosslinking technological of mechanical performance and the ductility that can take into account material, makes the biogel of acquisition make More preferable by property.Find through repetition test: when genipin crosslinker concentration is less than 0.05wt%, gel becomes pasty state, it is difficult to Obtain enough mechanical strengths, and the cross-linked gel fragility obtained higher than during 0.2wt% is too high, touches frangible.Cause This most at last genipin crosslinker concentration optimize between 0.05wt%-0.2wt%.
The raw material composition of genipin crosslinked bio gel of the present invention includes genipin and for forming the substrate of gel, wherein The weight/mass percentage composition of genipin is 0.05%-0.2%, and the weight/mass percentage composition of substrate is 1%-10%；Substrate can be shell Polysaccharide, carboxymethyl chitosan, carboxyetbyl chitosan, collagen, gelatin, polyacrylamide, amino-polyethyleneglycols etc. contain There are one or more combination in any in the macromolecular compound of amido, it is also possible to be these producing high-moleculars containing amido After compound combination in any, more same alginate, starch, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl are fine The mixture of arbitrarily composition such as one or more in dimension element, carbomer (Carbopol) etc., combination matching does not limit. These substrate are in field of medicaments conventional adjuvant, safety non-toxic.
The biogel that the present invention relates to can be free from the gel rubber material of any medicine, it is also possible to is to be loaded with different pharmaceutical Gel rubber material.Its carrying medicament can be antibacterials, analgesic drug product, a class of somatomedin or classes of arbitrarily Combination, is used for controlling traumatic infection, wound surface pain relieving and wound healing etc..
When wound exists some complication, such as infection, excessive inflammation and diabetic ulcer etc., common gel dressing can Can be difficult to resist more obstinate complication.As a example by infecting, due to battalion such as the transudate rich in proteins that wound surface exists Supporting material, provide good condition of culture for microbial growth, therefore wound surface is easy to accompanying infection.Infect and occur Time microorganism can decompose wound surface collagen and granulation tissue, destroy newborn substrate, and cause macrophage, inflammatory cell Excessively assembling Deng lasting, these all can cause delaying of wound healing, and even wound surface deteriorates or even causes whole body sepsis. For controlling traumatic infection, topical application antibacterials are particularly significant in time, especially downright bad when wound tissue, lack blood Liquid circulates, and when systemic administration is unable to reach wound tissue, for reply topical wound infections, can be arrived by Antibiotics usage In the genipin crosslinked bio gel of the present invention, to reverse local infection and accelerate infect wound healing have particularly significant Meaning.Additionally, also have some analgesics, somatomedin etc. to also apply be applicable to the genipin crosslinked bio gel of the present invention In, for wound surface pain relieving, accelerate wound healing etc..
The weight/mass percentage composition of antibacterials is 0.001%-10%, can be penicillins, cephalosporins, amino sugar Glycoside, quinolones, Macrolide, many peptides, sulfonamides, Tetracyclines, chloromycetin, silver salt class (contain Nanometer silver), a class in zincum salts (containing Nano-Zinc) medicine or classes of combination in any.The application of antibacterials is controlled System or prevention traumatic infection, be decreased or even eliminated wound surface microbial growth, it is to avoid wound surface is newly granulated group by microorganism The destruction knitted, accelerates wound healing.
The weight/mass percentage composition of analgesic drug product is 0.001%-10%, can be procaine, tetracaine, lignocaine, Bupivacaine, etidocaine, ropivacaine, dyclonine, indomethacin, ibuprofen, diclofenac diethylammonium, The combination in any of one or more in diclofenac sodium etc..The application of analgesic drug product can alleviate the making patient of deep wounds The pain become, especially can reduce the misery of patient's more change dressings.
The weight/mass percentage composition of somatomedin is 0.001%-10%, can be recombinant human epidermal growth factor, the life of Mus epidermis The long factor, recombination human basic fibroblast growth factor, recombination human acidic mechanocyte growth factor, recombinant bovine The combination in any of one or more in basic fibroblast growth factor etc..The application of somatomedin can accelerate into fiber Cell migration, propagation, accelerate collagen fiber synthesis and granulation tissue is formed, and finally accelerates wound healing.
The method preparing genipin crosslinked bio gel of the present invention, comprises the following steps:
(1), the preparation of genipin solution:
Weighing 5g genipin to be dissolved in the deionized water of 95g, obtaining weight/mass percentage composition after mix homogeneously is 5wt%'s Genipin solution.
(2), the preparation of gel solution:
Substrate is scattered in the aqueous acetic acid of 1wt%, the most swelling after, add appropriate 5wt% genipin solution, stir Using deionized water constant volume after mixing uniformly, obtain gel solution, genipin ultimate density in gel solution is 0.05wt%-0.2wt%, substrate ultimate density in gel solution is 1wt%-10wt%；Add 5wt% genipin solution While, it is also possible to adding carrying medicament, carrying medicament can be solid drugs itself or the solution dissolved with medicine.
(3), the molding of genipin crosslinked bio gel:
The gel solution of step (2) gained is sub-packed in 50mm × 30mm × 2mm mould of plastics, mould is positioned over 37 DEG C of calorstats react 24h, obtains the genipin crosslinked bio gel of the present invention.
Below in conjunction with specific embodiment, further illustrate present disclosure, and the present invention is further elaborated, But these embodiments limit the invention absolutely not.
Embodiment 1-8:
Preparing a series of genipin crosslinked bio gel without any medicine as stated above, its raw material composition is shown in Table 1.
The raw material composition of table 1 genipin crosslinked bio gel
Meanwhile, being prepared for the biogel without any medicine of two comparative examples the most as stated above, its raw material forms Consistent with embodiment 4, it is only that genipin ultimate density in gel solution is respectively 0.01wt% (comparative example 1) With 0.5wt% (comparative example 2).
The performance of the genipin crosslinked bio gel prepared in mensuration table 1
1, microstructure:
The genipin crosslinked bio gel prepared by table 1 raw material is placed in-80 DEG C of refrigerator pre-freeze 24h, lyophilization 48h, uses SEM to investigate its tangent plane internal microstructure.As a example by embodiment 1-4, its microstructure such as Fig. 1, F1 Shown in width-F4 width is the microstructure of the genipin crosslinked bio gel of embodiment 1-4 respectively.
As seen from Figure 1, genipin cross-linked chitosan biogel microstructure is porous spongy, along with cross-linking agent is used The increase of amount, crosslinking degree increases, and microstructure is the finest and close, is conducive to increasing gel mechanical strength, and is cell Growth migrates provides more attachment points.
Other embodiments effect duplicates, and repeats the most one by one.
2, physicochemical property:
Investigate storage modulu, contact angle and the water suction of the genipin crosslinked bio gel prepared by table 1 raw material respectively Swelling ratio, concrete method of testing is as follows:
Storage modulu: use parallel-plate rheometer to investigate storage (elastic) mould of genipin crosslinked bio gel of the present invention Amount G '.Being transferred to bottom parallel-plate rheometer specimen disc set level by biogel before Ce Shi, temperature is set to 37 DEG C, flat The plate test degree of depth is set to 1.5mm, performs a scan respectively and scans with deformation.The compressive deformation of frequency scanning is set to 1.0%, range of scanned frequencies is 0.1-10Hz；The frequency of vibration of deformation scanning is set to 5.0Hz, scans deformation range For 0.1-10%.
Contact angle: by the hydrophilic of static contact angle test evaluation genipin of the present invention crosslinked bio gel surface.10 μ l pure water drops to biogel surface by tapping method, test droplets both sides contact angle after 5s.Each biogel Also average in 6 regions of sample test.
Swelling ratio: use weight method to test genipin crosslinked bio gel of the present invention in the PBS solution that pH is 7.4 Water absorption and swelling rate.It is that to immerse appropriate pH after the biogel precise weighing of 3mm be 7.4 by a diameter of 20mm, thickness PBS solution in, after the most swelling 24h, take out sample, suck excessive moisture with filter paper, be again precisely weighed. Water absorption and swelling rate is calculated by below equation: water absorption and swelling rate %=(WSwelling rear weight-WInitial weight)/WInitial weight× 100%. Each biogel sample is repeated 3 times test.
As a example by the genipin crosslinked bio gel of embodiment 1-4, its storage modulu, contact angle and water absorption and swelling rate are shown in Table 2.
Storage modulu, contact angle and the water absorption and swelling rate of table 2 embodiment 1-4 genipin crosslinked bio gel
As can be seen from Table 2, along with the increase (embodiment 1-4) of genipin consumption, crosslinking compactness increases, elastic Modulus is gradually increased, and illustrates that mechanical strength gradually strengthens, and the biogel obtained can meet the machine of wound dressing simultaneously Tool intensity and extensibility are with elastic.Also knowing that from table 2, the biogel surface nature of embodiment 1-4 is by slightly dredging Water (contact angle 103.6 °) gradually becomes neutral hydrophilic (contact angle 71.0 °), shows gel internal structure compactness Raising add its hydrophilic.Gel also show appropriateness water absorption and swelling, water absorption and swelling rate also with crosslinking degree Relevant, along with crosslinking degree increases, its swelling ratio reduces, and can make the viscoelasticity that gel maintenance is certain, be more beneficial for coagulating Glue is in the attaching of wound surface.And when genipin consumption too low (such as comparative example 1), gel becomes pasty state, its elastic modelling quantity It is only 560Pa, it is difficult to obtain enough mechanical strengths, and (such as comparative example 2) time too high, obtained gel elastomer Modulus ＞ 3000Pa, fragility is higher, and extensibility is poor with elasticity, touches frangible, it is impossible to as wound dressing.
Other embodiments effect duplicates, and repeats the most one by one.
3, Cytotoxic evaluation
By genipin crosslinked bio gel radiosterilization 30min under uviol lamp of embodiment 1-8, immerse the most respectively 37 DEG C of extraction 24h in aseptic DMEM culture fluid, extraction ratio is 1.25cm2/ml.L929 cell is inoculated in 96 holes In plate, every hole 5 × 103Individual, then 96 orifice plates are positioned in 37 DEG C of cell culture incubators and hatch 24h.Take out 96 holes Plate, discards old liquid, is separately added into the lixiviating solution of collection, and every hole adds 100 μ l, continues to place in incubator and cultivates. After 48h, taking out, every hole adds 5mg/ml MTT solution 20 μ l, continues to place in incubator and reacts 4h.Finally Taking out 96 orifice plates, carefully the exhaustion of old liquid discarded, every hole adds DMSO 150 μ l, after concussion 10min, places enzyme Mark instrument reads OD value.Test wavelength 490nm, reference wavelength 630nm.Every kind of sample sets 6 multiple holes, blank Culture fluid (DMSO) and 0.5wt% phenol solution are respectively as negative control and positive control.Relative growth rate The computing formula of (Relative growth rate, RGR%) is: RGR%=ODSample/ODNegative control× 100%.With reality As a example by executing the genipin crosslinked bio gel of example 1-4, it is shown in Table 3 to the relative growth rate of cell.
The cell relative growth rate of the genipin crosslinked bio gel of table 3 embodiment 1-4
Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Positive control Negative control
OD 0.445 0.433 0.418 0.425 0.010 0.361
RGR/% 123.27 119.94 115.79 117.73 2.77 100.00
SD 2.70 2.52 3.00 4.28 0.00 4.46
P value 0.0001 0.0008 0.0024 0.0075 0.0000 -
From the relative growth rate RGR% of table 3: compared with negative control, the biogel of the present invention can remarkably promote L929 cell proliferation, wherein the gel of embodiment 1-4 shows notable proliferation (P ＜ compared with positive control 0.05), wound surface sticks and uses the propagation that can may advantageously facilitate Wound fibroblasts, endotheliocyte, and then accelerates wound surface Healing.
Embodiment 9: the genipin crosslinked bio gel of load antibacterials
The method of the genipin crosslinked bio gel of preparation load antibacterials, comprises the following steps:
(1), the preparation of genipin solution:
Weighing 5g genipin to be dissolved in the deionized water of 95g, obtaining weight/mass percentage composition after mix homogeneously is 5wt%'s Genipin solution.
(2), the preparation of gel solution:
Substrate is scattered in the aqueous acetic acid of 1wt%, the most swelling after, add appropriate 5wt% genipin solution and 20wt% gentamicin sulfate solution, uses deionized water constant volume after stirring, obtain gel solution, and genipin is at gel Ultimate density in solution is 0.05wt%-0.2wt%, and substrate ultimate density in gel solution is 1wt%-10wt%, Gentamycin sulfate ultimate density in gel solution is 0.001wt%-10wt%.
(3), the molding of genipin crosslinked bio gel:
The gel solution of step (2) gained is sub-packed in 50mm × 30mm × 2mm mould of plastics, mould is positioned over 37 DEG C of calorstats react 24h, obtains the genipin crosslinked bio gel of the load antibacterials of the present invention.
Embodiment 10-13: the genipin crosslinked bio gel of load antibacterials
Preparation method, with embodiment 9, is only that the gentamicin sulfate solution in step (2) changes nanometer silver sulfadiazine into Suspension, nanometer silver sulfadiazine ultimate density in gel solution is 0.001wt%-10wt%.
Wherein being formulated as of the nanometer silver sulfadiazine suspension of 20wt%: 2.5ml Tween 80 is dissolved and is scattered in 50g In deionized water, obtain Tween 80 solution, 10g silver sulfadiazine be scattered in Tween 80 solution shearing uniformly, Adding in ball mill, regulation rotating speed processes 10min to 1500rpm, and then 2000rpm processes 50min, obtains nanometer Silver sulfadiazine suspension.
Prepare the genipin crosslinked bio Gel Examples of a series of load antibacterials as described in Example 9 10-13, its gel material consists of embodiment 1-4, silver sulfadiazine Buddhist nun in Beijing usual friendship connection biogel in the denseest Degree is 1mg/g.
Microscopic feature
1, microstructure:
The genipin crosslinked bio Gel Examples 10-13 of the load silver sulfadiazine prepared is placed in-80 DEG C of ice Case pre-freeze 24h, lyophilization 48h, use silver sulfadiazine form and the particle diameter of encapsulating in scanning electron microscopic observation gel, Form is shown in Fig. 2.
From Figure 2 it can be seen that load silver sulfadiazine genipin crosslinked bio gel in silver sulfadiazine diameter of particle about At about 100-400nm.According to Ostwald-Freundlich equation and Noyes-Whitney equation, when When drug microparticles particle diameter is less than 1 μM, the least saturation solubility of particle diameter is the highest with rate of dissolution.Thus, it can be known that this In bright biogel, the dissolubility of silver sulfadiazine substantially increases, beneficially the release of medicine and playing a role；In addition medicine Thing particle diameter is reduced to nanometer and is caused its specific surface area to dramatically increase, and then considerably increases the contact area of medicine and antibacterial, Be conducive to improving antimicrobial effect.
2, release Mechanisms:
The genipin crosslinked bio Gel Examples 10-13 of the load silver sulfadiazine prepared is placed in 250ml cone In shape bottle, it is fixed in 37 DEG C of isothermal vibration devices, adds 100ml PBS solution, regulation concussion speed to 100rpm. From every conical flask, 50 μ l are sampled in 5,20,40min and 1,2,3,6,12,24,36,48h Add blank EP pipe, and supplement the PBS solution of same volume at once in conical flask.Each sample adds the phase that flows in right amount After (0.1% phosphoric acid solution: acetonitrile=94ml:6ml) dilution, at 14000rpm high speed centrifugation 10min, take supernatant 20 μ l, use UHPLC to measure sulfadiazine silver content, calculate each time point silver sulfadiazine and add up rate of release, Make drug release profiles such as Fig. 3, the biogel of the most corresponding embodiment 10-13 of D1-D4 in figure.Carry as shown in Figure 3 The genipin crosslinked bio gel having silver sulfadiazine has slow-release function, and its drug release time is more than 48h, is conducive to long Effect controls traumatic infection.
3, fungistatic effect is investigated
Take activation and be diluted to 1.5 × 108Staphylococcus aureus (S.aureus) the 100 μ l of individual/ml, adds to solid-state LB agar media surface, touches and smoothens, with basic noresidue bacterium solution as standard.With a spacing on agar plates Punch into the cavity of diameter about 3mm from arrangement, be separately added into the 50 dual anti-solution of μ l (containing 5U/ml penicillin and 5 μ g/ml streptomycins), commercially available Sulfadiazine Silver Cream (AgSD emulsifiable paste), Blank gel (embodiment 1 not negative The biogel of medicine carrying thing) and the genipin crosslinked bio Gel Examples 10-13 loading silver sulfadiazine of the present invention (AgSD/NCT gel), all samples LB agar culture medium is diluted to sulfadiazine silver concentration 10 μ g/ml.Will training It is inverted in 37 DEG C of incubators after supporting ware lid lid, cultivates 12h.Inoculate as stated above escherichia coli (E.coli), Pseudomonas aeruginosa (P.aeruginosa), and press same method addition sample.Every kind of bacterium solution is parallel does 3 cultivations Ware.As a example by the genipin crosslinked bio gel of the load silver sulfadiazine of embodiment 10, above each group to golden yellow Portugal Grape coccus, escherichia coli, the average result of Bactericidal test of Pseudomonas aeruginosa are shown in Table 4.
The different AgSD formulation against S staphylococcus of table 4, escherichia coli and the inhibition zone footpath (mm) of Pseudomonas aeruginosa
S.aureus E.coli P.aeruginosa
Dual anti-solution 13.7±0.9 12.8±1.9 10.2±0.6
AgSD emulsifiable paste 14.6±1.5 11.5±0.6 13.4±0.9
Blank gel 4.9±0.5 4.5±0.5 4.3±0.2
AgSD/NCT gel 17.2±0.8*# 12.7±1.1* 14.7±0.3*#
Note:*, P ＜ 0.05, vs AgSD emulsifiable paste；#, the dual anti-solution of P ＜ 0.05, vs；
As seen from the results in Table 4, except Blank gel, three kinds of antibacterials are all shown and significantly press down by other three kinds of products Bacterium effect.The genipin crosslinked bio gel of the load silver sulfadiazine of the present invention is the most aobvious to the inhibition zone footpath of three kinds of antibacterials Write more than commercially available Sulfadiazine Silver Cream, and golden yellow Portugal coccus is significantly higher than dual anti-with the inhibition of Pseudomonas aeruginosa Solution, this may with the rate of dissolution improving medicine and in gel slow release effect relevant.
Embodiment 14: the biogel of load analgesic drug product
Preparation method, comprises the following steps:
The preparation of step (1) genipin solution and the molding of step (3) genipin crosslinked bio gel and embodiment 9 Identical, it is only in the preparation of step (2) gel solution, substrate is scattered in the aqueous acetic acid of 1wt%, fully After swelling, add 5wt% genipin solution and the lidocaine hydrochloride solution of 20wt%, after stirring, use deionized water Constant volume, obtains gel solution, and lidocaine hydrochloride ultimate density in gel solution is 0.001wt%-10wt%.
Embodiment 15: prepared by growth factor-loaded biogel
Preparation method, comprises the following steps:
The preparation of step (1) genipin solution and the molding of step (3) genipin crosslinked bio gel and embodiment 9 Identical, it is only that substrate is scattered in the aqueous acetic acid of 1wt% by the preparation of step (2) gel solution, the most molten After swollen, add 5wt% genipin solution and the recombinant human epidermal growth factor solution of 20wt%, spend after stirring from Sub-water constant volume, obtains gel solution, and recombinant human epidermal growth factor ultimate density in gel solution is 0.001wt%-10wt%.
The above is only the preferred embodiment of the present invention, it is noted that for the common skill of the art For art personnel, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improve Also present disclosure is should be regarded as with retouching.

Claims (10)

1. a genipin crosslinked bio gel, it is characterised in that its raw material composition includes 0.05wt%-0.2wt%'s Genipin, 1wt%-10wt% substrate and the water of surplus；The wherein preferred 0.05wt%-0.1wt% of the content of genipin, optimum Select 0.075wt%.
Genipin crosslinked bio gel the most according to claim 1, it is characterised in that described substrate can be that shell gathers Sugar, carboxymethyl chitosan, carboxyetbyl chitosan, collagen, gelatin, polyacrylamide and amino-polyethyleneglycols etc. contain One or more in the macromolecular compound of amido.
Genipin crosslinked bio gel the most according to claim 2, it is characterised in that described substrate also includes Sargassum One in hydrochlorate, starch, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, carbomer etc. or The mixture of several any compositions.
4. according to the arbitrary described genipin crosslinked bio gel of claim 1-3, it is characterised in that also include loading medicine Thing, one or more in the preferred antibacterials of described carrying medicament, analgesic drug product and somatomedin.
Genipin crosslinked bio gel the most according to claim 4, it is characterised in that the quality of described antibacterials Percentage composition is 0.001%-10%, can be penicillins, cephalosporins, aminoglycoside, quinolones, big Cyclic lactone class, many peptides, sulfonamides, Tetracyclines, chloromycetin, silver salt class (containing nanometer silver), zincum salts (contain Nano-Zinc) class in medicine or classes of combination in any.
6. according to genipin crosslinked bio gel described in claim 4 or 5, it is characterised in that described analgesic drug product Weight/mass percentage composition is 0.001%-10%, can be procaine, tetracaine, lignocaine, bupivacaine, depend on and replace In caine, ropivacaine, dyclonine, indomethacin, ibuprofen, diclofenac diethylammonium, diclofenac sodium etc. The combination in any of one or more.
7. according to the arbitrary described genipin crosslinked bio gel of claim 4-6, it is characterised in that described somatomedin Weight/mass percentage composition be 0.001%-10%, can be recombinant human epidermal growth factor, M-EGF, restructuring Human alkaline fibroblast growth factor, recombination human acidic mechanocyte growth factor, recombinant bovine basic fibroblast are thin The combination in any of one or more in the intracellular growth factor etc..
8. the method preparing the arbitrary described genipin crosslinked bio gel of claim 1-7, it is characterised in that system Standby process includes: the genipin solution of preparation 5wt%；The 1wt% aqueous acetic acid of preparation substrate；By the capital Buddhist nun of 5wt% Flat solution is mixed homogeneously with the 1wt% aqueous acetic acid of substrate and is used deionized water constant volume, obtains gel solution；It is sub-packed in mould Tool is placed in 37 DEG C of isothermal reaction 24h, to obtain final product.
Method the most according to claim 8, it is characterised in that comprise the following steps:
(1), the preparation of genipin solution:
Take 5g genipin to be dissolved in the deionized water of 95g, after mix homogeneously, obtain the capital that weight/mass percentage composition is 5wt% The flat solution of Buddhist nun；
(2), the preparation of gel solution:
Substrate is scattered in the aqueous acetic acid of 1wt%, the most swelling after, add 5wt% genipin solution, stirring Using deionized water constant volume after uniformly, obtain gel solution, genipin ultimate density in gel solution is 0.05%-0.2%, substrate ultimate density in gel solution is 1%-10%；Preferably, 5wt% genipin solution is added While, it is also possible to add carrying medicament (solid or solution)；
(3), the molding of genipin crosslinked bio gel:
The gel solution of step (2) gained is sub-packed in mould, mould is positioned over 37 DEG C of isothermal reaction 24h, i.e. Obtain described genipin crosslinked bio gel.
10. the arbitrary described genipin crosslinked bio gel of claim 1-7 is in preparation treatment traumatic infection, wound surface pain relieving Or the application in wound healing medicine.
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