WO2017197542A1 - 一种抑菌敷料及其制备方法与应用 - Google Patents

一种抑菌敷料及其制备方法与应用 Download PDF

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Publication number
WO2017197542A1
WO2017197542A1 PCT/CN2016/000269 CN2016000269W WO2017197542A1 WO 2017197542 A1 WO2017197542 A1 WO 2017197542A1 CN 2016000269 W CN2016000269 W CN 2016000269W WO 2017197542 A1 WO2017197542 A1 WO 2017197542A1
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Prior art keywords
dressing
bacteriostatic
ammonium salt
dressings
solution
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PCT/CN2016/000269
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English (en)
French (fr)
Inventor
曾菊红
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浙江红雨医药用品有限公司
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Application filed by 浙江红雨医药用品有限公司 filed Critical 浙江红雨医药用品有限公司
Priority to CN201680079420.0A priority Critical patent/CN109069687A/zh
Priority to PCT/CN2016/000269 priority patent/WO2017197542A1/zh
Publication of WO2017197542A1 publication Critical patent/WO2017197542A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/07—Stiffening bandages
    • A61L15/14—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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds

Definitions

  • the invention relates to a dressing, in particular to a bacteriostatic dressing, and a preparation method and application of the dressing. It belongs to the field of medical dressing technology.
  • the pathogenic bacteria are mainly Gram-positive bacteria (G+), including group B hemolytic streptococcus, staphylococcus, and drug-resistant Staphylococcus.
  • G+ Gram-positive bacteria
  • the blood routine is mainly to look at white blood cells. If the number and proportion increase, it can be considered as a bacterial infection.
  • Local wound infection leads to a pathological time for the increase of whole blood leukocytes, and it is only after the pathogenic bacteria infecting the wound reaches a certain amount that the infection can be diagnosed by blood routine examination. But the rate of pathogen reproduction is very fast, such as a Staphylococcus aureus can multiply into 17 million in 24 hours.
  • the reproductive conditions of most pathogens are closely related to the pH of the environment.
  • the most suitable pH value for most pathogens to propagate and exist is 7.2-7.6.
  • the optimum pH value for streptococci is 7.4-7.6; the optimum pH for Staphylococcus is 7.4.
  • the traditional dressing mainly refers to skin substitutes for hemostasis and healing of wounds in wounds, burns and skin ulcers; mainly including ordinary cotton gauze, bandages, cotton gauze, cotton pads and Vaseline gauze, etc.
  • These dressings are clinical
  • the most widely used dressing has the advantage of low production costs. However, its water absorption performance is poor, and it can adhere to the wound. The process of wound healing will be crusted and need to be replaced frequently, which will easily lead to newly formed tissue. It is easy to damage, and the wound is prone to secondary damage when the gauze is removed, and the wound is at risk of dehydration.
  • dry gauze although it can play a role in supervising the covering of wounds, can not be used for infectious wounds, has no promoting effect on wound healing, limited ability of exudate management, adhesion of wounds, re-injury to new epithelial tissue and bleeding, patient replacement Pain after dressing.
  • Oil yarn containing petrolatum or triglyceride, can play a role of non-adhesive wounds; but it does not promote the entire healing process of the wound, is ineffective for infected wounds, can drain fluid to two layers of dressing, and has limited fluid management capabilities.
  • Traditional ordinary cellulose soluble gauze has no antibacterial property, needs to be coated with antibiotics every day, and it is easy to cause secondary damage to the skin by renewing the gauze.
  • Natural dressings mainly include chitosan dressings, alginate dressings, animal dressings and collagen dressings.
  • chitosan has a series of biological effects that activate the body system and mediate the body system, improve the system function of phagocytic cells, and also have antibacterial effects.
  • the price of chitosan gauze is high, and its preparation has the disadvantage of serious environmental pollution.
  • Seaweed salt medical dressings are mainly dressings made of sodium alginate, zinc alginate or calcium alginate, which are hydrophilic and biocompatible.
  • Collagen dressings are made by using natural proteins extracted from animals. These dressings are biodegradable and resorbable, non-toxic, and provide a nutritional basis for wound healing.
  • problems of high price and serious contamination of collagen are also problems of high price and serious contamination of collagen.
  • Pharmaceutical dressings include interactive wound dressings, silver dressings, calcium alginate dressings, and the like.
  • General drug-based dressings refer to the addition of antibacterial agents, such as silver sulfapyridine, ciprofloxacin, etc., to increase the antibacterial properties of the dressing.
  • the silver ion in the silver dressing can directly bind the cell wall to kill the bacteria, control the wound infection, accelerate the wound healing, and remove the odor caused by the bacteria. It is an ideal anti-infective dressing; its disadvantage is that it is expensive, and the metal ion is used by the patient. Certain health risks. Because most of the raw materials of pharmaceutical dressings are synthetic raw materials, which are not biodegradable, and synthetic antibiotics are prone to drug resistance, the excessive use of antibiotics and increased bacterial resistance affect the efficacy of antibiotics in the treatment of wound infections.
  • wet wound healing theory that is, the wound is more conducive to wound healing while maintaining the wet state, helping the cells to swim and make the skin grow smoothly; let people have a breakthrough in the healing process of the wound understanding. Therefore, a series of wet wound synthetic dressing products with better healing properties have been developed, mainly including film type dressings, foam dressing, hydrogel dressing, hydrocolloid dressing. )Wait.
  • This type of synthetic dressing can replace damaged skin and always act until wound healing and skin healing; such as resisting external mechanical factors (such as dirt, collision, inflammation, etc.), resisting pollution and chemical stimulation, preventing secondary infection, and preventing Dryness and loss of body fluids (electrolyte loss), prevention of heat loss, etc.
  • it can also actively influence the wound healing process through debridement, creating a micro-environment that promotes wound healing.
  • Hydrogel medical dressings are prepared by using polyurethane polymer compounds with strong water-absorbent structure. These polymer structures can form a three-dimensional network structure by cross-linking; and they have hydrophilic groups and can absorb them.
  • the exudate covers the surface of the wound to form a layer of hydrogel to protect the wound; it can automatically adjust the wetness of the wound, has a small amount of ability to absorb exudate, is non-sticky, and is easy to remove.
  • the hydrocolloid dressing with higher water absorption ratio adopts the principle of airtight moisturizing, and the hydrophilic carboxymethyl cellulose sodium (CMC) particles are in contact with the wound exudation, and the wound surface A moist gel forms on the surface to create a moist environment that does not stick to the wound. It can absorb physiological saline equivalent to 20 times its own weight, but it is still slightly insufficient when it encounters the initial stage of wound or large and deep wound, and the wet wound dressing absorbs moisture and affects its viscosity, making it easy to fall off to the maximum. Disadvantages.
  • the wound when there is too much exudate in the wound, the wound is too humid for too long, it is prone to skin ulceration and even cause bacterial infection, which leads to secondary injury. At this time, the absorption rate of the dressing for the exudate is also limited.
  • the dressings currently used on the market do not have any warning function, and can not remind the wound infection to change the dressing, and can only be replaced according to the length of time.
  • bacteriostatic dressing may also have a degree of warning of wound infection.
  • the technical problem to be solved by the present invention is to provide a bacteriostatic dressing having a better inhibitory effect on bacterial growth, and the bacteriostatic dressing does not contain any antibacterial agent or bactericide such as antibiotics or metal ions. .
  • the present invention provides a novel bacteriostatic dressing which has a function of inhibiting bacterial growth comparable to a pharmaceutical dressing, and particularly inhibits the growth of infectious bacteria.
  • a bacteriostatic dressing comprising a bacteriostatic dressing component
  • the pH of the bacteriostatic dressing component is 3.5-6.5
  • the required pH can be passed through the bacteriostatic dressing
  • a buffer is added to the components to obtain.
  • the bacteriostatic dressing component has a pH of from 4.4 to 5.5.
  • the buffer is preferably glycine-hydrochloric acid buffer, citric acid/disodium hydrogen phosphate buffer, citric acid/sodium citrate buffer, citric acid-sodium hydroxide-hydrochloric acid buffer or acetic acid. / Sodium acetate buffer, etc. More preferred is a citric acid containing buffer system.
  • the buffer may be present in an amount from about 0.3% to 2% by weight of the bacteriostatic dressing component in order to maintain the desired stable pH system.
  • the present invention allows any form of wound or wound to be applied to the dressing and its surroundings (in the absence of strong acid and alkali contact) by controlling the pH environment of the dressing, particularly the slightly acidic environment in which the dressing component (core) is controlled.
  • the pH remains unchanged for at least 36 hours, thereby destroying the absorption of nutrients of most pathogenic bacteria around the wound, thereby achieving a stable inhibition of the growth of pathogenic bacteria.
  • the dressing containing the slightly acidic dressing component of the present invention is particularly suitable for inhibiting the growth of infectious pathogens such as Staphylococcus aureus, Escherichia coli, and Helicobacter.
  • the inventors have surprisingly found that when the bacteriostatic dressing contains a silicon component, the pH of the dressing component can be stably present, so that the bacteriostatic effect can be maintained for a longer period of time.
  • the inventors estimated that the principle is that when the organosilicon compound is contained, the synergistic effect between the silicon component and the quaternary ammonium salt ion can stably support the pH of the attached material to have a buffering elasticity, thereby achieving a relatively constant slightly acidic pH value.
  • the dressing component can be in the form of a solution that can be used as a spray or a solution dipping solution for the dressing that can be applied to the dressing.
  • the bacteriostatic dressing component of the present invention comprises a silicone antibacterial agent, a buffer stabilizer, a solvent.
  • the silicone antibacterial agent is 0.01% to 3% by mass percentage, It is more preferably 0.01% to 1.5%, still more preferably 0.01% to 1%.
  • the buffer stabilizer content is from 0.001% to 3%, preferably from 0.01% to 1.5%, more preferably from 0.01% to 1%.
  • the silicone antimicrobial agent comprises predominantly a silicone quaternary ammonium salt compound and/or silica.
  • the silicone antibacterial agent is a silicone quaternary ammonium salt compound and silica, and the ratio of the silica to the organosilicon quaternary ammonium salt compound is preferably 1:30 to 10:by mass percent. 1.
  • organosilicon quaternary ammonium salts have excellent antibacterial and antibacterial properties, especially against Staphylococcus aureus, Escherichia coli and Candida albicans after 24h, the inhibition rate can be as high as 95% or more, and it is safe and non-toxic. No enzyme reaction.
  • polysiloxanes with pendant benzyldimethylsilylpropylammonium chloride on pure cotton sheets and their strong bactericidal activity against Escherichia coli and Staphylococcus aureus. .
  • silicone quaternary ammonium salts for dressings has not been reported.
  • silicone quaternary ammonium salt as an antibacterial agent is that it is environmentally safe, non-toxic, non-irritating to the skin, and has good antibacterial effect, long-lasting and washable.
  • silicon When using silicon as a medium, it can strongly adsorb the ammonium cationic group with antibacterial properties on the surface of the bacteria, thereby changing the permeability of the bacterial cell wall, causing the enzyme, coenzyme and metabolic intermediates in the bacteria to overflow. It causes the bacterial microbes to dehydrate and die, thereby achieving the antibacterial effect.
  • the organosilicon quaternary ammonium salt compound may be selected as a silicone quaternary ammonium salt compound which is commonly used in the art as an antibacterial agent, and the present invention is not particularly limited thereto, and those skilled in the art may select a configuration or purchase according to actual needs. Commercially known compounds.
  • the organosilicon quaternary ammonium salt compound is preferably a monoquaternary ammonium salt, a diquaternary ammonium salt, a triquaternary ammonium salt, a polyquaternary ammonium salt, a hyperbranched quaternary ammonium salt of an organosilicon compound; for example, a monoalkyltrimethylammonium salt, a dialkyl group a dimethylammonium salt, or a monoalkylmonobenzyldimethylammonium salt, a quaternary ammonium salt of a trialkoxysilane, or the like; wherein the alkyl group is a hydrocarbon group having 1 to 20 carbon atoms.
  • the organosilicon compound is an organosilicon compound which is formed by substitution of four hydrogen atoms in an ammonium ion by a hydrocarbon group.
  • the organosilicon compound is preferably tetraethyl orthosilicate, 3-chloropropyltriethoxysilane or the like.
  • the organosilicon quaternary ammonium salt compound is N,N-dimethyl-N-octadecylaminopropyltrimethoxysilane quaternary ammonium salt (DC-5700) developed by Dow Corn-ing, USA.
  • an organotitanium compound can also be used in place of the organosilicon quaternary ammonium salt compound, and the bacteriostatic effect is similar, but in terms of production cost, the organic titanium compound is more remarkable than the organosilicon quaternary ammonium salt compound.
  • the silica is preferably SiO 2 pore mesoporous 2nm 50nm-range; more preferably 20nm-50nm pore size of mesoporous SiO 2, for example, mesoporous molecular sieves (MCM41).
  • the buffer stabilizer (pH stabilizer) of the present invention functions to provide pH buffering to the bacteriostatic dressing of the present invention, so that the bacteriostatic dressing can maintain a stable pH of 3.5-6.5.
  • the buffer stabilizer is preferably triethanolamine.
  • the solvent of the present invention is preferably deionized water.
  • the buffer system is a citric acid containing buffer system and the pH stabilizer is triethanolamine.
  • citric acid is a compound in which the cation generated when ionized in the solution is completely hydrogen ion; in synthesizing with the molecular sieve, a long-chain alkyl quaternary ammonium salt and a hydrolyzed matching organosilicon source of tetraethyl orthosilicate, inorganic silicon are used.
  • the source silica sol forms an effective and stable carrier.
  • the bacteriostatic dressing of the present invention further has a warning function, and is a color-changing bacteriostatic dressing, which is a sensing type wound dressing which can be used to remind wound infection.
  • the bacteriostatic dressing further comprises an acid-base indicating component, and when the bacteriostatic dressing having the warning function is applied to the wound surface of the skin, the action of the component can be indicated by the acid-base.
  • the acid-base indicating component of the present invention can be specifically selected depending on the practical application, and is not particularly limited.
  • the acid-base indicating component may be one of litmus, methyl orange, phenolphthalein, or other natural acid-base indicator or the like. Since the amount of the indicator used in the dressing is small in practical applications, the indicator selection range is wide, and is not limited.
  • it may also be methyl violet, picric acid, methyl chloride, malachite green, cresol red, thymol blue, cillin yellow, dimethyl yellow, methyl orange, bromophenol blue, litmus, Congo red, One or more of bromocresol green, methyl red, bromophenol red, bromocresol purple, bromothymol blue, neutral red, phenol red, cresol red, phenolphthalein, thymolphthalein and dadan yellow; Or choose from sugar radish, blueberry, carrot, cherry, curry powder, delphinium petals, geranium petals, grapes, horse chestnut leaves, hydrangea, onion, morning glory petals, European primrose, poppy petals, purple peony One or more of red cabbage, carrot, rhubarb, rose petals, strawberry, tea, thyme, turmeric, tulip petals, violet rose petals, and purple cabbage juice.
  • the color-changing bacteriostatic dressing of the present invention is not particularly limited in its content of the acid-base indicating component.
  • the acid-base indicator component has a weight content of from 0.001% to 10%, more preferably from 0.001% to 1%; the amount is less favorable for cost control.
  • the present invention also provides a preparation method of a color-changing bacteriostatic dressing, which comprises the following steps:
  • the silica after the amination treatment in the second step refers to the amination modification of the nano SiO 2 , and the functionalized mesoporous material of the amino functionalized SiO 2 has a larger specific surface area than the SiO 2 and a controlled pore diameter. Size and pore size distribution, good thermal stability and mechanical properties.
  • each group in the preparation of the dressing can be calculated by calculating the pH of the immersion dressing substrate. Dosage.
  • the present invention also provides an application of a color-changing bacteriostatic dressing in the preparation of a medical dressing device.
  • the general dressing contains an absorbent cushion (also a core), an adhesive layer (some special dressings do not contain this layer, such as a hydrocolloid dressing), and a substrate layer (fixed core and contact surface).
  • an absorbent cushion also a core
  • an adhesive layer some special dressings do not contain this layer, such as a hydrocolloid dressing
  • a substrate layer fixed core and contact surface.
  • the dressing substrate is selected from the group consisting of cotton, cellulose derivatives, polysulfones, polyamides, polyimides, polyesters, polyolefins, vinyl polymers, One of a silicon-containing polymer, a fluoropolymer or a chitin. More preferably, the dressing substrate is one of a nonwoven fabric, a polyurethane film, and a polyethylene film.
  • the medical dressing device is selected from the group consisting of self-adhesive stickers, non-woven dressings, gauze dressings, oil gauze dressings, non-adhesive dressings, transparent film dressings, hydrogels, hydrocolloid dressings, alginate dressings, hydrophilic fibers, A superabsorbent wound pad, a collagen-containing dressing, a hypertonic saline dressing, a foam dressing, a carbonaceous dressing, a silver-containing dressing, a soft silicone dressing, or a liquid dressing. More preferably, the medical dressing device is one of a self-adhesive sticker, a bandage, a hydrocolloid, a hydrogel, and a scar sticker.
  • the color-changing bacteriostatic dressing of the present invention also includes applications in sanitary articles and daily necessities. Such as the use on sanitary napkins, as well as the use of special purpose fabrics.
  • Sanitary napkins generally consist of a surface layer, an absorbent layer and a bottom layer.
  • the bacteriostatic dressing of the invention can be used for the absorption layer of the sanitary napkin to achieve the function of inhibiting bacteria, and at the same time, the replacement time can be judged according to the color change of the sanitary napkin during use, and the growth of some germs can be suppressed in time and effectively. It has great significance for women's health.
  • the bacteriostatic dressing of the invention can also be applied to daily necessities such as clothes, and the textile fabric composed of fibers has microbes (such as bacteria decomposing human sweat, due to the shape of the multi-space object and the chemical structure of the polymer to facilitate microbial adhesion, A good parasite that survives and breeds by the intrinsic odor of the stench, spoilage, and chemicals produced by the skin. In addition to harm to the human body, the parasitic body can also contaminate the fiber.
  • the textile fabric immersed in the bacteriostatic dressing of the invention can greatly eliminate these adverse effects, and can make people play an antibacterial role in daily wear, especially It is an antibacterial effect by inhibiting the increase in bacteria.
  • the invention has the advantages that the bacteriostatic dressing of the invention has superior absorption and exudate Performance, keep the wound moist, promote wound healing, reduce pain, reduce the number of dressing changes, apply for a long time, waterproof, breathable, inhibit pathogens, especially inhibit the growth of streptococcus and staphylococcus; have better antibacterial / antibacterial
  • the effect can detect the wound environment in time, which is convenient for observation, and can promptly change the time according to the color change of the product.
  • the bacteriostatic dressing of the invention can achieve the same antibacterial effect as the dressing using nano silver as a bacteriostatic agent, because the silver-containing dressing will continuously release silver ions during use, and the water body is regulated by countries such as Europe and the United States.
  • the ppm of BOC should not exceed 0.5 PPM, otherwise it will cause heavy metal pollution and cause great damage to the water body.
  • the nano-silver antibacterial agent is absorbed by the human body, it will accumulate and cause lesions, which endanger human health. Therefore, the bacteriostatic dressing of the invention has no pollution, is harmless to the human body, has no cytotoxicity, is non-irritating, and has extremely low sensitization; and has good commercial prospects for replacing silver dressings.
  • an embodiment or “an embodiment” as used herein refers to a specific feature, structure, or characteristic that can be included in at least one implementation of the invention.
  • Immobilization of amino group There is a large amount of Si-OH bond on the surface of SiO 2 skeleton formed by TEOS hydrolysis.
  • ATES ethoxy group in ATS is condensed with the hydroxyl group on the surface of SiO 2 , and the amino group can be grafted onto the surface of SiO 2 . .
  • E. coli E. coli (ATCC 25922) and S. aureus (ATCC 6538) were used as test strains. Antibacterial tests were carried out on samples that were not washed and washed differently, in accordance with ASTME 2149:2001 "Dynamic Test Method for Antibacterial Activity of Fixative Antimicrobial Agents". The sample was placed in a bacterial suspension of CFU 105-106, and cultured at 37 ° C for 4-12 hours. The suspension was diluted to a certain number of coated agar plates, and the antibacterial effect was calculated according to the formula.
  • the antibacterial rate of the antibacterial rate of the obtained non-woven fabric color-changing antibacterial dressing was 90%, Staphylococcus aureus: 92%, and Escherichia coli: 90%.
  • the obtained solution was added to 1000 mL of deionized water to form an infusion solution.
  • Add in the soaking solution The polyurethane film non-woven fabric (pH ⁇ 7.4) with the initial pollution bacteria meets the standard, soak the whole volume until the pH value of the soaking solution is 4.0-4.5, then soak for 30min, then take out and drain, and dry the film at low temperature drying;
  • the bacteriostatic rate of the obtained color-changing bacteriostatic dressing was 93% for Staphylococcus aureus, 91% for Escherichia coli, and 89% for Helicobacter.
  • the bacteriostatic rate of the obtained color-changing bacteriostatic dressing was: Staphylococcus aureus: 94%, Escherichia coli: 93%, and Helicobacter: 91%.
  • the bacteriostatic rate of the obtained color-changing bacteriostatic dressing was: Staphylococcus aureus: 94%, Escherichia coli: 92%, and Helicobacter: 95%.
  • the bacteriostatic rate of the obtained color-changing bacteriostatic dressing was 92% for Staphylococcus aureus, 94% for Escherichia coli, and 95% for Helicobacter.
  • a polyvinyl alcohol solution (10 g) was added to the pre-formed acidic solution at room temperature, and magnetically stirred for 1 hour.
  • the mixed solution was cast in a mold and frozen for 12 hours, and the freezing temperature was -20 °C. Then thawing for 2 hours at room temperature; freezing at -20 ° C for 12 hours, then thawing for 2 hours at room temperature; third time -20 ° C frozen for 12 hours, third room temperature thawing for 2 hours; fourth -20 ° C freezing for 12 hours The fourth time was thawed at room temperature for 2 hours.
  • the pH of the solution and the polyvinyl alcohol solution, and the pH of the citric acid mixture are adjusted to 3.5-6.5. That is, the color-changing bacteriostatic hydrogel dressing is obtained.
  • the bacteriostatic rate of the obtained color-changing bacteriostatic dressing was: Staphylococcus aureus: 95%, Escherichia coli: 94%, and Helicobacter: 92%.

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Abstract

一种抑菌敷料及其制备方法与应用。该抑菌敷料组分包括有机硅抗菌剂、缓冲液稳定剂和溶剂。该抑菌敷料组分的pH值为3.5-6.5。该抑菌敷料的制备方法包括：向有机硅季铵盐化合物溶液中加入缓冲剂稳定剂调节pH值为3.0-6.9，加入氨基化处理的二氧化硅并用缓冲剂稳定剂调节pH值为3.5-6.5，在溶液中加入水形成浸泡液，在浸泡液中加入敷芯，并调节浸泡液pH值为3.5-6.5。该pH值能够控制敷料组分的微酸性环境，使得贴附该敷料的创面或伤口维持弱酸性，从而达到稳定抑制病原菌生长的作用。

Description

一种抑菌敷料及其制备方法与应用 技术领域
本发明涉及一种敷料，尤其涉及一种抑菌敷料，以及该敷料的制备方法与应用。属于医用敷料技术领域。
背景技术
现有伤口和创面诊断方法的缺陷：
致病菌以革兰氏阳性菌(G+)为主，包括B群溶血性链球菌、葡萄球菌、耐药金葡萄球菌。目前临床常用诊断感染的方式为血常规检查。血常规主要是看白细胞，如果数量、比例增多升高，可认为是细菌感染。而局部的伤口感染导致全血白细胞增高需要一个病理时间，并且是在感染伤口的致病菌达到一定数量后，才能通过血常规检查诊断其发生了感染。但是病菌繁殖速度是非常之快，如一个金黄色葡萄球菌能在24小时内繁殖成1700万个。
由于氢离子影响代谢过程酶活性，从而影响多数病原菌营养物质吸收，因此，多数病原菌的繁殖条件与环境pH值息息相关。例如：多数病原菌繁殖与存在的最适宜pH值为7.2-7.6，如：链球菌最适宜pH值为7.4-7.6；葡萄球菌最适宜pH值为7.4。经反复试验得知，链球菌与葡萄球菌随着酸性的增高pH下降，pH下降至5.5以下时，89％的链球菌与葡萄球菌繁殖受到了抑制并死亡(此时的环境已经不适合这些病菌的生长)；pH下降至4.5以下时，链球菌与葡萄球菌不能生长而死亡。由此可见，弱酸的环境可以破坏致病菌代谢，可见维持弱酸环境尤为重要，由于氢离子影响代谢过程酶活性，从而影响多数病原菌营养物质吸收，因此多数病原菌的繁殖条件与环境pH值息息相关。
当人体皮肤受到擦伤、刀伤、烧烫伤、撕裂外伤等，需于创伤处使用医疗等级敷料进行保护，避免伤口感染，加快伤口愈合。当皮肤受损后，通常会引发大量渗液的渗出，且易受细菌病毒的感染，导致产生炎症甚至组织坏死，进而严重影响皮肤的正常运行，此时，伤口敷料的作用就显得十分突出。现有的医用敷料依照敷料的材料可分为传统型敷料和新型敷料。其中，新型敷料主要有四类，天然型敷料、药用型敷料、合成型敷料、敷料组织工程类敷料。
其中，传统型敷料主要指在创伤、烧伤及皮肤溃烂时对伤口进行止血、复愈的皮肤替代品；主要包括普通棉纱布、绷带、脱脂棉纱布、棉垫和凡士林纱布等，这类敷料是临床上应用最广的敷料，其的优点是生产成本低。但是，其吸水性能较差，并且能与伤口产生粘连，伤口愈合的过程会结痂，且需要经常更换，容易导致新形成的组织 易于损伤，在揭除纱布时伤口易产生二次伤害，同时伤口有脱水的风险。例如干纱布，虽然可以起到监督覆盖伤口的作用，但是不能用于感染性伤口，对伤口愈合没有促进作用，渗液管理能力有限，粘连伤口，对新生上皮组织再损伤和导致出血，病人更换敷料后疼痛。油纱，含有凡士林或者甘油三酯，可以起到不粘连伤口的作用；但对伤口的整个愈合过程没有促进作用，对感染伤口无效，可以引流渗液到两层敷料，渗液管理能力有限。传统普通纤维素可溶纱布无抗菌性、需要每天涂抹抗生素，再更新换纱布也易对皮肤造成二次伤害。
天然型敷料主要包括壳聚糖敷料、海藻酸盐敷料、动物类敷料和胶原敷料。其中，壳聚糖具有激活机体系统、介导机体系统的系列生物学效应，提高吞噬细胞的系统功能，还有抑菌的作用。但壳聚糖纱布价格高，且其制备有严重环境污染的弊端。海藻盐类医用敷料主要是由海藻酸钠、海藻酸锌或海藻酸钙等制成的敷料，这类敷料具有亲水性和生物相容性。胶原型敷料是利用从动物中提取的天然蛋白质制备敷料，这类敷料可生物降解和重吸收，无毒性，并且能够为伤口愈合提供营养基础。但同样存在价格昂贵、胶原提纯污染严重问题。
药物类敷料包括交互式伤口敷料、银敷料、藻酸钙敷料等。一般药物类敷料是指添加抗菌剂，如磺胺吡啶银、环丙沙星等，以增加敷料的抗菌性。银敷料中银离子可以直接结合细胞壁杀死细菌，控制伤口感染，加速伤口愈合，去除因细菌而产生的异味，是一种理想的抗感染敷料；其缺点是价格昂贵，且金属离子对使用患者有一定的健康风险。由于药物类敷料大多原料为合成原料，不能生物降解，而且合成抗生素易产生耐药性等问题，抗生素的过度使用和细菌耐药性增加影响了抗生素在伤口感染治疗中的功效。
上世纪60年代，英国人Winter提出“湿润伤口愈合理论”，即伤口在保持湿润状态下更有利于伤口愈合，帮助细胞游动使皮肤顺利生长；让人们对于创伤的愈合过程有了突破性的认识。因此发展出一系列具有更好的愈合性能的湿性伤口合成型敷料产品，主要包括薄膜型敷料、泡沫类敷料(foam dressing)、水凝胶类敷料(hydrogel dressing)、水胶体类敷料(hydrocolloid dressing)等。该类合成型敷料能取代受损皮肤，并一直作用至伤口愈合及皮损愈合；如抵御外界机械因素(如脏物、碰撞、发炎等)、抵御污染和化学刺激、防止二度感染、防止干燥和体液丢失(电解质丢失)、防止热量丢失等。并且，除了对伤口实行全面保护外，还能通过清创主动影响伤口愈合过程，创造促进伤口愈合的微环境。
水凝胶医用敷料利用一些具有强吸水性结构的聚氨酯聚合物高分子化合物制备而成，这类高分子结构通过交联可以形成三维网状结构；并且自身带有亲水性基团，能够吸收渗液覆于伤口表面成为一层水凝胶以保护伤口；能自动调节伤口的湿润度，有少量吸收渗液的能力，不粘伤口，容易去除。而具有较高吸水倍率的水胶体敷料采用密闭保湿原理，亲水羧甲基纤维素钠(CMC)颗粒与伤口渗出相接触作用，创面 表面形成一层湿润的凝胶体，持续营造湿润环境，不与创面粘连。其可以吸收相当于自身重量20倍的生理食盐水，但当遇到伤口初期或较大较深伤口而言仍略显不足，且湿性伤口敷料吸湿后影响其黏性，使其容易脱落为最大缺点。其次，当遇到伤口产生渗出液过多时，伤口因处于过度湿润环境太久，容易产生皮肤溃烂，甚至引起细菌感染，进而导致伤口二次伤害，此时敷料对于渗出液的吸收倍率也是有限。再次，目前市面上所用的敷料起不到任何警示作用，并不能提醒伤口的感染情况来更换敷料，只能根据时间长短来进行人为更换。
因此，本领域的技术人员致力于开发一种新的不含抗生素、抗菌剂、杀菌剂或金属离子，具有较好抑菌效果的敷料；尤其是一种不含化学抗菌剂/杀菌剂的抑菌敷料，该抑菌敷料还可具有警示伤口感染程度。
发明内容
有鉴于现有技术的上述缺陷，本发明所要解决的技术问题是提供一种具有较好抑制细菌生长效果的抑菌敷料，该抑菌敷料不含任何抗生素、金属离子等抑菌剂或杀菌剂。
为实现上述目的，本发明提供了一种新型的抑菌敷料，该敷料具备与药物类敷料媲美的抑制细菌生长功能，尤其是可抑制感染性细菌的生长。
本发明解决上述技术问题所采用的技术方案为：一种抑菌敷料，包括抑菌敷料组分，该抑菌敷料组分的pH值为3.5-6.5，所需要的pH可以通过在抑菌敷料组分中加入缓冲剂来获得。在本发明的较佳实施方式中，抑菌敷料组分的pH值为4.4-5.5。
在本发明的具体实施例中，缓冲剂优选为甘氨酸-盐酸缓冲液、柠檬酸/磷酸氢二钠缓冲液、柠檬酸/柠檬酸钠缓冲液、柠檬酸-氢氧化钠-盐酸缓冲液或乙酸/乙酸钠缓冲液等。更优选为含柠檬酸的缓冲液体系。缓冲剂可以约0.3％-2％抑菌敷料组分重量的量存在，以便保持所需稳定的pH体系。
本发明通过控制敷料的pH值环境，尤其是控制敷料组分(敷芯)的微酸性环境，使得贴覆该敷料的任何形式的创面或伤口及其周围(在无强酸强碱接触情况下)至少36小时内pH维持该弱酸性不变，从而破坏伤口周围多数致病菌的营养物质吸收，从而达到稳定的抑制病原菌生长的作用。本发明含微酸性敷料组分的敷料尤其适宜抑制金黄色葡萄球菌、大肠杆菌、螺旋杆菌等感染性病菌的生长。
发明人惊奇的发现，当抑菌敷料含有硅组分时，敷料组分的pH能稳定的存在，使得抑菌效果能维持更长的时间。发明人估测其原理是含有有机硅化合物时，通过硅组分与季铵盐离子之间的协同作用可以稳定支撑所附着物的酸碱度富有缓冲弹性，从而实现保持相对恒定的微酸性pH值。
敷料组分可以为溶液形式存在，该溶液可用作应用于敷料的喷雾或可浸泡敷料的溶液浸渍液。在本发明的具体实施例中，本发明的抑菌敷料组分包括有机硅抗菌剂、缓冲液稳定剂、溶剂。按质量百分比计，优选地，有机硅抗菌剂含量为0.01％-3％， 较优选为0.01％-1.5％，更优选为0.01％-1％。当有机硅抗菌剂含量高于3％时，本发明的抑菌敷料更为稳定，但其成本也大大增加。缓冲液稳定剂含量为0.001％-3％，优选为0.01％-1.5％，更优选为0.01％-1％。
在本发明的具体实施例中，所述的有机硅抗菌剂主要包含有机硅季铵盐化合物和/或二氧化硅。在本发明的优选实施例中，有机硅抗菌剂为有机硅季铵盐化合物和二氧化硅，按质量百分比计，二氧化硅和有机硅季铵盐化合物的比例优选为1∶30-10∶1。
虽然已有文献报道有机硅季铵盐具有优良的抗菌抑菌性能，尤其是对金黄色葡萄球菌、大肠杆菌和白色念珠球菌24h后的抑菌率都可高达95％以上，且安全无毒、无致酶反应。例如有专利报道带有苄基二甲基硅丙基氯化铵侧基的聚硅氧烷在纯棉床单布上的吸附性能及其对大肠杆菌与金黄色葡萄球菌有较强的的杀菌活性。因而在诸如棉、涤纶、锦纶等材质高档织物抗菌防霉上也可得到广泛应用，如贴身内衣内裤、毛巾、鞋垫、袜子抗菌。但是，将有机硅季铵盐用于敷料尚未有报道。并且，使用有机硅季铵盐为抗菌剂的最大优点是环保安全无毒，对皮肤无刺激性而且抗菌效果好、持久、耐洗。当以硅作为媒介时，其能将具有抑菌性能的铵阳离子基团强有力地吸附于细菌的表面，从而改变细菌细胞壁的通透性，使得菌体内的酶、辅酶和代谢中间产物溢出，致使细菌微生物脱水死亡，从而达到抑菌的作用。
在本发明中，有机硅季铵盐化合物可选为本领域常用的用作抗菌剂的有机硅季铵盐化合物，本发明对此没有特别限制，本领域技术人员可以根据实际需求选用配置或购买商用已知化合物。有机硅季铵盐化合物优选为有机硅化合物的单季铵盐、双季铵盐、三季铵盐、多季铵盐、超支化季铵盐；例如单烷基三甲基铵盐、二烷基二甲基铵盐、或单烷基单苄基二甲基铵盐、三烷氧基硅烷的季铵盐等；其中烷基为含碳原子1～20个的烃基。更优选为包含铵离子中的四个氢原子都被烃基取代而生成的有机硅化合物。有机硅化合物优选为正硅酸乙酯、3-氯丙基三乙氧基硅烷等。更优选地，有机硅季铵盐化合物为美国Dow Corn-ing公司研制出的N，N-二甲基-N-十八烷基氨基丙基三甲氧基硅烷季铵盐(DC-5700)。在本发明中，也可用有机钛化合物来替代有机硅季铵盐化合物，两者抑菌效果差不多，但从制作成本上看，明显有机钛化合物高于有机硅季铵盐化合物。
在本发明中，二氧化硅优选为孔径在2nm-50nm范围的介孔SiO2；更优选孔径为20nm-50nm的介孔SiO2，例如介孔分子筛(MCM41)。
本发明的缓冲液稳定剂(pH值稳定剂)所起的作用是为本发明的抑菌敷料提供pH值缓冲，使得该抑菌敷料能稳定持久的保持pH 3.5-6.5。缓冲液稳定剂优选为三乙醇胺。本发明的溶剂优选为去离子水。
在本发明的一个具体实施例中，缓冲液体系为含柠檬酸的缓冲体系，pH值稳定剂为三乙醇胺。其中，柠檬酸为在溶液中电离时产生的阳离子完全是氢离子的化合物；在与分子筛合成中，采用长链烷基季铵盐和水解匹配的有机硅源正硅酸乙酯，无机硅 源的硅溶胶，形成有效稳定的载体。
优选地，本发明的抑菌敷料还具有警示功能，为一种变色抑菌敷料，即可用来提醒伤口感染的感测型伤口敷料。
在本发明的另一较佳实施方式中，抑菌敷料还含有酸碱指示组分，当将该具备警示功能的抑菌敷料运用于皮肤的伤口表面时，可通过酸碱指示组分的作用，利用敷料吸收渗出液后的颜色变化，提醒使用者进行敷料的更换。
本发明的酸碱指示组分可根据实际应用进行具体选择，没有特别限制。例如酸碱指示组分可为石蕊、甲基橙、酚酞中的一种，或其他天然酸碱指示剂等。由于敷料在实际应用中对指示剂的使用量很小，因此指示剂选择范围广，具体不限。例如也可为甲基紫、苦味酸、甲基氯、孔雀绿、甲酚红、百里酚蓝、西素黄、二甲基黄、甲基橙、溴酚蓝、石蕊、刚果红、溴甲酚绿、甲基红、溴酚红、溴甲酚紫、溴百里酚蓝、中性红、酚红、甲酚红、酚酞、百里酚酞和达旦黄的一种或多种；或者选自糖萝卜、蓝莓、胡萝卜、樱桃、咖哩粉、飞燕草花瓣、天竺葵花瓣、葡萄、七叶树的叶、绣球花、洋葱、牵牛花花瓣、欧洲樱草、罂粟花瓣、紫牡丹、红叶卷心菜、红萝卜、大黄、玫瑰花瓣、草莓、茶、百里香、姜黄、郁金香花瓣、紫萝兰花瓣和紫色高丽菜汁中的一种或者多种。
由于酸碱指示组分自身的特点，本领域技术人员根据本领域的公知常识可知，即使是微量含量的酸碱指示组分也会根据溶液pH变化而变化。因此，本发明的变色抑菌敷料对酸碱指示组分的含量没有特别限制。优选地，酸碱指示组分的重量含量为0.001％-10％，更优选为0.001％-1％；含量少利于成本控制。
作为本发明的另一目的，本发明还提供一种变色抑菌敷料的制备方法，具体包括以下步骤：
(1)向有机硅季铵盐化合物溶液(20-100mL)中加入去离子水(1000mL)；同时加入缓冲剂调至pH 3.0-6.9，在室温条件下，将该混合溶液置于磁力搅拌器搅拌，得到预制酸性溶液；
(2)在预制酸性溶液中加入的氨基化处理后的二氧化硅，继续搅拌后置于离心机离心，过滤滤去不溶物，向滤液中再加入酸碱指示剂，用缓冲液稳定剂调节pH3.5-6.5；
(3)将制得的溶液加入去离子水，形成浸泡液，在浸泡液中加入初始污染菌达标的敷芯，调节浸泡液pH值维持至3.5-6.5，浸泡；沥干、低温烘干；即得所述的变色抑菌敷料。
其中步骤二中所述氨基化处理后的二氧化硅是指纳米SiO2氨基化改性，氨基功能化的SiO2即功能化介孔材料具有比SiO2更大的比表面积、可控的孔径大小和孔径分布、良好的热稳定性和机械性。
在具体实施例中，可通过计算浸入物敷料基材的酸碱度来计算敷料制备中的各组 分用量。
另一方面，本发明还提供一种变色抑菌敷料在制备医疗敷料器材的应用。
在医疗敷料器材的实际应用中，一般敷料含有吸收垫层(也为敷芯)、粘附层(有些特殊敷料不含此层，如水胶体敷料)、基材层(固定敷芯与接触面)。上述由浸泡液浸泡形成的变色抑菌敷料即为应用中的敷芯，将浸泡后的敷芯分切后并粘附在敷料基材上形成敷料。
在优选的具体实施例中，敷料基材为选自棉质、纤维素衍生物类、聚砜类、聚酰胺类、聚酰亚胺类、聚酯类、聚烯烃类、乙烯类聚合物、含硅聚合物、含氟聚合物或甲壳素类)中的一种。更优选地，敷料基材为无纺布、聚氨酯膜、聚乙烯膜中的一种。
优选地，医疗敷料器材为选自创口贴、无纺布敷料、纱布敷料、油纱敷料、无粘性敷料、透明膜敷料、水凝胶、水胶体敷料、藻酸盐敷料、亲水性纤维、超吸收性伤口垫、含胶原蛋白敷料、高渗盐敷料、泡沫敷料、含碳敷料、含银敷料、软聚硅酮敷料或液体敷料中的一种。更优选地，医疗敷料器材为选自创口贴、绷带、水胶体、水凝胶、疤痕贴中的一种。
在实际应用中，本发明的变色抑菌敷料还包括在卫生用品和日用品上的应用。如在卫生巾上的用途，以及在特种用途的面料上的用途。
女性在经期，敏感部位的皮肤最易受损伤或感染。调查表明，有38％的人会患上严重的妇科疾病；73％的女性会在经期感到局部皮肤瘙痒、灼痛；80％左右的女性还会出现高烧、头痛、腹痛等症状；这多是由于使用的卫生巾造成的。其原因是女性盆腔、子宫、宫颈体外环境都是相通的，这样的结构使女性的生殖系统容易遭受外界致病物的侵袭。尤其月经期间，生殖器官的抵抗力下降，比平时更加脆弱，如果使用了不合标准的卫生巾，就容易发生感染。经血中有丰富的营养物质，也因此成为细菌大肆滋生的“培养基”。一项实验表明，普通卫生巾连续使用2小时后，表层细菌总数可达每平方厘米107个。因此，要安度经期，选择合适的卫生巾至关重要。卫生巾一般由表面层、吸收层和底层三部分构成。将本发明的抑菌敷料用于卫生巾的吸收层即可达到抑制细菌的作用，同时，在使用时还可根据卫生巾颜色变化来判断更换时间，能及时、有效地抑制一些病菌的生长，对于女性健康有着重大的意义。
本发明的抑菌敷料还可应用于日用品如衣服上，由纤维组成的纺织品面料，由于其多空式物体形状和高分子聚合物的化学结构利于微生物附着，成为微生物(如细菌分解人体汗液、皮肤所生成的恶臭、腐败物质、化学物质等固有的气味)生存、繁殖的良好寄生体。寄生体除了对人体的危害之外还会污染纤维，经本发明的抑菌敷料浸泡处理后的纺织品面料可大大消除这些不利影响，能够使人们在日常穿着过程中起到抑菌的作用，尤其是可通过抑制细菌增值而达到抗菌的效果。
技术效果
与现有技术相比，本发明的优点在于：本发明的抑菌敷料具有优越的吸收渗出液 性能，保持伤口湿润，促进创面愈合，减轻疼痛，减少换药次数，可长时间敷贴，防水、透气，抑制病原菌，尤其是抑制链球菌与葡萄球菌的生长；具有较好的抑菌/抗菌效果，可及时检测伤口环境，方便观察，可根据产品颜色变化及时提示更换时间。经试验证明，本发明的抑菌敷料能达到与使用纳米银为抑菌剂的敷料同样的抑菌效果，由于含银敷料在使用过程中会不断释放出银离子，而欧美等国家规定，水体中银的ppm不能超过0.5PPM，否则会造成重金属污染，对水体造成巨大的破坏。并且，如果纳米银抗菌剂被人体内脏吸收，会累积而发生病变，危害人体健康。因此，本发明的抑菌敷料无污染，对人体无害，无细胞毒性、无刺激性、极低致敏性；对替代银敷料有良好商业前景。
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明，以充分地了解本发明的目的、特征和效果。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但本发明也可采取其他方式来实施，本技术领域人员可在不违背本发明内涵的条件下做类似推广，因此本发明不受下面公开的具体实施例的限制。
其次，此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非指同一个实施例，也不是单独的或选择性的与其他实施例相互排斥的实施例。
实施例1
一种无纺布(为基材)伤口敷料的制备
(1)有机硅季铵盐化合物的制备
在四口烧瓶中，加入N，N-二乙基氨丙基甲基二甲氧基硅烷与有机溶剂的混合物(质量比为3∶5)；升温至45℃，缓慢滴加环氧氯丙烷与溶剂的混合物(质量比为1∶2)，滴加完毕，反应一段时间；降至室温，旋转蒸发掉绝大部分溶剂；用乙醚洗涤3次，真空干燥5h，得环氧型有机硅季铵盐。
(2)氨基化处理二氧化硅
SiO2材料制备：称取2g CTAB溶于盐酸溶液(1.6mol/L，75mL)中，加入4mL TMB搅拌均匀作为油相。缓慢滴加一定量正硅酸乙酯(TEOS)水浴(40℃)反应24h，再置于高压反应釜内(110℃)反应24h，所得产物经抽滤、洗涤数次后，放在空气中自然干燥2天，所得白色粉末在马弗炉内550℃下有氧煅烧5h以去除表面活性剂，即可得介孔SiO2材料。
氨基的固定化：TEOS水解生成的SiO2骨架表面存在大量的Si-OH键，当加入 ATES时，ATES中的乙氧基与SiO2表面的羟基发生缩合反应，氨基就可嫁接到SiO2表面。
(3)将制备得到的有机硅季铵盐溶液(0.12g，50mL)，加入500mL的去离子水中；同时加入柠檬酸-柠檬酸钠缓冲液(0.2mol/L，3.4mL)，三乙醇胺(1.5mL)调pH至3.0；在室温条件下，将该混合溶液置于磁力搅拌器搅拌4h，得到预制酸性溶液；
(4)在预制酸性溶液中加入氨基化处理后的二氧化硅(1g，pH≤4.5，孔径为20nm)，继续搅拌1h后置于2000转速的离心机进行离心，过滤滤出不溶物，在离心后得到的溶液中加入石蕊(0.01g，pH≥6.1)；此时所得溶液pH为3.5；
(5)将制得的上述溶液加入去离子水1200mL，形成浸泡液。在浸泡液中加入初始污染菌达标的无纺布敷芯(pH为8.8)，整卷浸泡至浸泡液pH值约为3.5，再浸泡30min后取出沥干，低温烘道烘干覆卷；
(6)根据制备要求将制得的无纺布敷芯分切后，采用胶黏剂(pH＝5.2)将其粘附在无纺布(pH＝8.8)基材上形成变色抑菌敷料。
(7)抗菌性能测试
以E.coli(ATCC25922)和S.aureus(ATCC6538)作为供试菌株。参照ASTME2149：2001《固着性抗菌剂抗菌活性的动态测试法》对未经洗涤和洗涤不同次数的样品进行抗菌测试。即将样品置于CFU105～106的菌悬液中，37℃振荡培养4～12h后，将悬液稀释一定倍数涂布琼脂培养板上，按公式计算其抗菌效果。
P(％)＝[(Co-C)/Co]×100％
式中：P-细菌抑制百分率；Co-未抗菌处理物共培养后的菌落数；C-抗菌物共培养后的菌落数。
经检测，所得无纺布变色抑菌敷料敷芯抑菌率的抑菌率为，金黄色葡萄球菌：90％，大肠杆菌：92％，螺旋杆菌：90％。
实施例2
一种聚氨酯(为基材)伤口敷料的制备
(1)有机硅季铵盐化合物与二氧化硅的氨基化处理同实施例1；
(2)将制备得到的有机硅季铵盐DC-5700溶液(0.5g，30mL)，加入500mL的去离子水中；同时加入柠檬酸-柠檬酸钠缓冲液(0.2mol/L，2.6mL)，三乙醇胺(1mL)调pH至4.4；在室温条件下，将该混合溶液置于磁力搅拌器搅拌2h，得到预制酸性溶液；
(4)在预制酸性溶液中加入氨基化处理后的二氧化硅(0.6g，pH≤4.5，孔径为2nm)，继续搅拌1h后置于2000转速的离心机进行离心，过滤滤出不溶物，在离心后得到的溶液中加入石蕊(0.01g，pH≥6.1)；此时所得溶液pH为4.4；
(5)将制得的上述溶液加入去离子水1000mL，形成浸泡液。在浸泡液中加入 初始污染菌达标的聚氨酯膜无纺布(pH≥7.4)敷芯，整卷浸泡至浸泡液pH值为4.0-4.5，再浸泡30min后取出沥干，低温烘道烘干覆卷；
(6)根据制备要求将制得的无纺布敷芯分切后，采用胶黏剂(pH＝5.2)将其粘附在聚氨酯膜(pH≥7.4)基材上形成变色抑菌敷料。
经检测，所得变色抑菌敷料的抑菌率为，金黄色葡萄球菌：93％，大肠杆菌：91％，螺旋杆菌：89％。
实施例3
一种聚乙烯(为基材)伤口敷料的制备
(1)有机硅季铵盐化合物与二氧化硅的氨基化处理同实施例1；
(2)将制备得到的有机硅季铵盐DC-5700溶液(3.5g，60mL)，加入500mL的去离子水中；同时加入柠檬酸-氢氧化钠-盐酸缓冲液(0.05mol/L，1.6mL)，三乙醇胺(1mL)调pH至6.5；在室温条件下，将该混合溶液置于磁力搅拌器搅拌2h，得到预制酸性溶液；
(4)在预制酸性溶液中加入氨基化处理后的二氧化硅(1.2g，pH≤4.5，孔径为50nm)，继续搅拌1h后置于2000转速的离心机进行离心，过滤滤出不溶物，在离心后得到的溶液中加入石蕊(0.01g，pH≥6.1)；此时所得溶液pH为6.5；
(5)将制得的上述溶液加入去离子水1000mL，形成浸泡液。在浸泡液中加入初始污染菌达标的聚乙烯膜无纺布(pH≥8.0)敷芯，整卷浸泡至浸泡液pH值为6.0-6.5，再浸泡30min后取出沥干，低温烘道烘干覆卷；
(6)根据制备要求将制得的无纺布敷芯分切后，采用胶黏剂(pH＝5.2)将其粘附在聚乙烯膜(pH≥8.0)基材上形成变色抑菌敷料。
经检测，所得变色抑菌敷料的抑菌率为，金黄色葡萄球菌：94％，大肠杆菌：93％，螺旋杆菌：91％。
实施例4
一种聚氨酯(为基材)伤口敷料的制备
(1)二氧化硅的氨基化处理同实施例1；
(2)向500mL的去离子水中加入柠檬酸-氢氧化钠-盐酸缓冲液(0.05mol/L，1.5mL)，三乙醇胺(0.8mL)调pH至5.5；在室温条件下，将该混合溶液置于磁力搅拌器搅拌2h，得到预制酸性溶液；
(4)在预制酸性溶液中加入氨基化处理后的二氧化硅(2g，pH≤4.5，孔径为10nm)，继续搅拌2h后置于5000转速的离心机进行离心，过滤滤出不溶物，在离心后得到的溶液中加入石蕊(0.01g，pH≥6.1)；此时所得溶液pH为5.5；
(5)将制得的上述溶液加入去离子水1000mL，形成浸泡液。在浸泡液中加入初始污染菌达标的聚氨酯膜无纺布(pH≥7.4)敷芯，整卷浸泡至浸泡液pH值为5.0-5.5，再浸泡30min后取出沥干，低温烘道烘干覆卷；
(6)根据制备要求将制得的无纺布敷芯分切后，采用胶黏剂(pH＝5.2)将其粘附在聚氨酯膜(pH≥7.4)基材上形成变色抑菌敷料。
经检测，所得变色抑菌敷料的抑菌率为，金黄色葡萄球菌：94％，大肠杆菌：92％，螺旋杆菌：95％。
实施例5
变色抑菌水胶体敷料
(1)将有机硅季铵盐DC-5700溶液(0.12g，4mL，加入90mL的去离子水中。同时加入柠檬酸(3.4g)，三乙醇胺(1.5mL)调pH至3.0-6.9，在室温条件下，将该混合溶液置于磁力搅拌器搅拌4h，得到预制酸性溶液；
(2)在预制酸性溶液中加入的氨基化处理后的二氧化硅(1g，pH≤4.5，孔径为30nm)，继续搅拌1h后离心机3000转速离心，过滤，滤液中加入酸碱指示剂(0.01g)；
(3)称取1.5kg苯乙烯-异戊二烯嵌段共聚物、2.3kg聚异丁烯、1.0kg松香季戊四醇酯、和1.2kg医用级白油放入真空捏合机内正常捏合1-2小时，然后再抽真空(真空度0.07MPa)捏合1小时。投入反应釜温度升至140～170℃，待完全溶化后，加入37.65kg羧甲基纤维素钠，然后缓慢加入到反应釜中，不断搅拌，待完全混合均匀后，降温脱泡，备用；
(4)将上述水胶体胶浆于密炼机中于80℃搅拌30min，温度降至45℃时，加入(1)所得溶液，与胶浆搅拌20min。通过计算(1)溶液与水胶体胶浆的酸碱度，柠檬酸(3g)调节混合后pH值至3.5-6.5。与胶浆搅拌20min。完毕后，将混合物从密炼机中移出，进入低温烘道去除水份，再涂布在防粘纸上，均速涂布，冲压出不同规格的变色抑菌水胶体敷料。
经检测，所得变色抑菌敷料的抑菌率为，金黄色葡萄球菌：92％，大肠杆菌：94％，螺旋杆菌：95％。
实施例6
变色抑菌水凝胶敷料
(1)将环氧基团与有机胺反应合成季铵盐结构的季铵盐溶液(0.12g，10mL)，加入80mL的去离子水中。同时加入缓冲剂柠檬酸3.4g调至pH 3.0-6.9，在室温条件下，将该混合溶液置于磁力搅拌器搅拌3h，得到预制酸性溶液；
(2)将1kg聚乙烯醇放入8.9L无离子水中溶解20分钟；再放入90℃水中溶解；磁力搅拌1小时。该步骤不能接触金属。
(3)聚乙烯醇溶液(10g)室温后加入预制酸性溶液，磁力搅拌1小时。将混合溶液浇注于模具冷冻12小时成型，冷冻温度在-20℃。然后室温下解冻2小时；再-20℃冷冻12小时，再室温解冻2小时；第三次置于-20℃冷冻12小时，第三次室温解冻2小时；第四次-20℃冷冻12小时，第四次室温解冻2小时。通过计算预制酸性 溶液与聚乙烯醇溶液的酸碱度，柠檬酸调节混合后pH值至3.5-6.5。即得变色抑菌水凝胶敷料。
经检测，所得变色抑菌敷料的抑菌率为，金黄色葡萄球菌：95％，大肠杆菌：94％，螺旋杆菌：92％。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。

Claims (16)

  1. 一种抑菌敷料，其特征在于，包括抑菌敷料组分，所述的抑菌敷料组分位于pH值为3.5-6.5的缓冲液体系中。
  2. 根据权利要求1所述的抑菌敷料，其特征在于：所述的抑菌敷料组分包括有机硅抗菌剂、缓冲液稳定剂、溶剂。
  3. 根据权利要求2所述的抑菌敷料，其特征在于，按质量百分比计，有机硅抗菌剂含量为0.01％-3％，缓冲液稳定剂含量为0.001％-3％；优选地，有机硅抗菌剂含量为0.01％-1.5％，更优选地，有机硅抗菌剂含量为0.01％-1％。
  4. 根据权利要求1-3任一所述的抑菌敷料，其特征在于：所述的缓冲液体系为柠檬酸/磷酸氢二钠、柠檬酸/柠檬酸钠、或乙酸/乙酸钠缓冲体系。
  5. 根据权利要求2所述的抑菌敷料，其特征在于：所述的有机硅抗菌剂为有机硅季铵盐化合物和/或二氧化硅。
  6. 根据权利要求1所述的抑菌敷料，其特征在于：所述的缓冲液的pH值为4.4-5.5。
  7. 根据权利要求5所述的抑菌敷料，其特征在于：所述二氧化硅优选为孔径在2nm-50nm范围的介孔SiO2；更优选孔径为20nm-50nm的介孔SiO2。
  8. 根据权利要求5所述的抑菌敷料，其特征在于：所述有机硅抗菌剂为有机硅季铵盐化合物和二氧化硅；按质量百分比计，所述二氧化硅和有机硅季铵盐化合物的比例为1∶30-10∶1。
  9. 根据权利要求5所述的抑菌敷料，其特征在于：所述有机硅季铵盐化合物为有机硅化合物的单季铵盐、双季铵盐、三季铵盐、多季铵盐、超支化季铵盐；所述铵盐为单烷基三甲基铵盐、二烷基二甲基铵盐、或单烷基单苄基二甲基铵盐；其中硅化合物为正硅酸乙酯、或3-氯丙基三乙氧基硅烷。
  10. 根据权利要求2所述的抑菌敷料，其特征在于：所述的缓冲液稳定剂为三乙醇胺。
  11. 根据权利要求1-6任一所述的抑菌敷料，其特征在于：所述的变色抑菌敷料还含有酸碱指示组分。
  12. 一种制备如权利要求1-6任一所述的抑菌敷料的方法，其特征在于，包括以下步骤：
    (1)在室温条件下，向有机硅季铵盐化合物的水溶液中加入缓冲液调至pH3.0-6.9，搅拌得到预制酸性溶液；
    (2)在预制酸性溶液中加入氨基化处理后的二氧化硅，继续搅拌1-4h，离心，过滤，向滤液加入酸碱指示剂；
    (3)将制得的溶液加入去离子水，形成浸泡液，在浸泡液中加入敷料基材，调 节浸泡液pH值至3.5-6.5，即得所述的变色抑菌敷料。
  13. 根据权利要求12所述的抑菌敷料的制备方法，其特征在于，所述的敷料基材为无纺布、聚氨酯膜、聚乙烯膜、棉质、纤维素衍生物类、聚砜类、聚酰胺类、聚酰亚胺类、聚酯类、聚烯烃类、乙烯类聚合物、含硅聚合物、含氟聚合物或甲壳素类中的一种。
  14. 一种权利要求1-11任一项所述的抑菌敷料在制备医疗敷料器材中的应用。
  15. 一种权利要求1-11任一项所述的抑菌敷料在卫生用品、日用品中的应用。
  16. 根据权利要求14所述的抑菌敷料在制备医疗敷料器材的应用，其特征在于，所述的医疗敷料器材为创口贴、绷带、水胶体、水凝胶、疤痕贴、无纺布敷料、纱布敷料、油纱敷料、无粘性敷料、透明膜敷料、水凝胶、水胶体敷料、藻酸盐敷料、亲水性纤维、超吸收性伤口垫、含胶原蛋白敷料、高渗盐敷料、泡沫敷料、含碳敷料、含银敷料、软聚硅酮敷料或液体敷料中的一种。
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109550076A (zh) * 2018-12-08 2019-04-02 郑州和济生物科技股份有限公司 医用聚硅酮臭氧油凡士林敷料及基于该敷料的创面护理贴
CN111012736A (zh) * 2020-02-11 2020-04-17 福建蓝昊肽生物科技发展有限公司 一种阻断新型冠状病毒2019-nCov的无菌喷剂敷料的应用
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CN113773525A (zh) * 2021-09-18 2021-12-10 安徽大学 一种二硫化钼负载纳米银抗菌水凝胶的制备方法及其应用
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CN114432485A (zh) * 2022-02-15 2022-05-06 周建大 一种pH响应季铵盐抗菌敷料及其制备方法
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CN115006583B (zh) * 2022-07-04 2023-05-12 温州医科大学附属口腔医院 一种医用敷料、制备方法及应用
CN116285096A (zh) * 2022-12-16 2023-06-23 沪金(苏州)实业有限公司 一种长效抗菌聚丙烯盛装容器及制造方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004073566A1 (ja) * 2003-02-21 2004-09-02 Menicon Co., Ltd. 医療用被覆材
UA34086U (uk) * 2008-03-13 2008-07-25 Институт химии высокомолекулярных соединений НАН Украины Бактерицидний перев'язувальний пінополіуретановий матеріал "смс - пур - ан" для медичних цілей
CN103285028A (zh) * 2013-05-14 2013-09-11 陈美儿 一种壳聚糖和有机硅季铵盐复合抗菌剂及制备方法
CN104220043A (zh) * 2012-04-30 2014-12-17 金伯利-克拉克环球有限公司 包含硅氧烷聚酯的发泡制剂和清洁产品
CN105343926A (zh) * 2015-11-09 2016-02-24 广东泰宝医疗科技股份有限公司 一种含有纳米二氧化硅的疤痕贴及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681802A (en) * 1994-06-01 1997-10-28 Lever Brothers Company, Division Of Conopco, Inc. Mild antimicrobial liquid cleansing formulations comprising buffering compound or compounds as potentiator of antimicrobial effectiveness
CN1235597C (zh) * 2003-11-21 2006-01-11 凌沛学 用于创伤护理的药物组合物
US8388992B2 (en) * 2006-03-28 2013-03-05 Georgia-Pacific Consumer Products Lp Anti-microbial hand towel with time-delay chromatic transfer indicator and absorbency rate delay
WO2009089346A2 (en) * 2008-01-08 2009-07-16 Quick-Med Technologies, Inc. Disinfectant alcohol-soluble quaternary ammonium polymers

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004073566A1 (ja) * 2003-02-21 2004-09-02 Menicon Co., Ltd. 医療用被覆材
UA34086U (uk) * 2008-03-13 2008-07-25 Институт химии высокомолекулярных соединений НАН Украины Бактерицидний перев'язувальний пінополіуретановий матеріал "смс - пур - ан" для медичних цілей
CN104220043A (zh) * 2012-04-30 2014-12-17 金伯利-克拉克环球有限公司 包含硅氧烷聚酯的发泡制剂和清洁产品
CN103285028A (zh) * 2013-05-14 2013-09-11 陈美儿 一种壳聚糖和有机硅季铵盐复合抗菌剂及制备方法
CN105343926A (zh) * 2015-11-09 2016-02-24 广东泰宝医疗科技股份有限公司 一种含有纳米二氧化硅的疤痕贴及其制备方法

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CN114432485A (zh) * 2022-02-15 2022-05-06 周建大 一种pH响应季铵盐抗菌敷料及其制备方法
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CN115414523B (zh) * 2022-08-31 2023-09-12 五邑大学 一种水凝胶敷料及其制备方法
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