WO2021179611A1 - 一种银离子控释的抗菌敷料及其制备方法与应用 - Google Patents

一种银离子控释的抗菌敷料及其制备方法与应用 Download PDF

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WO2021179611A1
WO2021179611A1 PCT/CN2020/122385 CN2020122385W WO2021179611A1 WO 2021179611 A1 WO2021179611 A1 WO 2021179611A1 CN 2020122385 W CN2020122385 W CN 2020122385W WO 2021179611 A1 WO2021179611 A1 WO 2021179611A1
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silver ions
water
controlled release
polyvinyl alcohol
agp
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French (fr)
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陈坤
殷盼超
许哲玮
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华南理工大学
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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
    • 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
    • A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • 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
    • 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
    • A61L15/18—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing inorganic materials
    • 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
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/45—Phosphates containing plural metal, or metal and ammonium
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G41/00—Compounds of tungsten
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G41/00—Compounds of tungsten
    • C01G41/006—Compounds containing, besides tungsten, two or more other elements, with the exception of oxygen or hydrogen
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of biomedical materials, and specifically relates to a silver ion controlled release antibacterial dressing and a preparation method and application thereof.
  • antibacterial wound dressing can prevent mechanical factors and pollutants from adversely affecting wound healing.
  • the exudation of serotonin, prostaglandin, histamine and blood and tissue fluid from the injured area requires antibacterial Wound dressings have a certain ability to absorb exudate.
  • Traditional dry gauze loaded with silver salt or nano-silver as an antibacterial wound dressing is very easy to adhere to the wound, and subsequent cleaning is more likely to cause secondary damage, which brings pain and risks to the patient.
  • the ideal antibacterial wound dressing should not only have good antibacterial activity and effectively prevent wound infection, but also have strong drug-carrying capacity and sustained release performance. At the same time, it should also take into account the problem of adhesion to the wound to shorten the wound healing period.
  • Polyoxometalate (abbreviated as polyacid) is a sub-nano-scale monodisperse metal oxide cluster. Past studies have proved the direct antibacterial effect of this material and its synergy with other antibacterial agents. In addition, some polyacid structures have cavities that can accommodate guests. This feature makes polyacids have potential applications in the field of controlled release.
  • Polyvinyl alcohol is the alcoholysis product of polyvinyl acetate.
  • PVA can be added to the cell culture medium in an appropriate amount to support cell growth.
  • the PVA molecular chain contains a large number of hydroxyl groups, which can easily absorb water to form a hydrogel.
  • PVA also shows better compatibility with inorganic materials such as polyacids. This feature makes PVA-inorganic composite materials have good mechanical properties.
  • the primary purpose of the present invention is to provide an antibacterial dressing with controlled release of silver ions.
  • the antibacterial dressing is composed of polyvinyl alcohol and polyacid K 13 Na[AgP 5 W 30 O 110 ], has good antibacterial and mechanical properties, has good exudate absorption capacity, and has a simple preparation method.
  • Another object of the present invention is to provide a method for preparing the above-mentioned silver ion controlled release antibacterial dressing.
  • the preparation method is simple, and the production scale can be scaled up.
  • Another object of the present invention is to provide an application of the aforementioned antibacterial dressing with controlled release of silver ions.
  • An antibacterial dressing with controlled release of silver ions prepared from polyvinyl alcohol (PVA), polyacid K 13 Na[AgP 5 W 30 O 110 ] and water, of which polyacid K 13 Na[AgP 5 W 30 O 110 ]Accounting for 0.5-3% of the dry weight of PVA, the mass ratio of polyvinyl alcohol to water is 1:99-30:70.
  • PVA polyvinyl alcohol
  • the degree of polymerization of the polyvinyl alcohol is 300-2400, and the degree of alcoholysis is 88-99%.
  • the polyvinyl alcohol is at least one of polyvinyl alcohol 124 and polyvinyl alcohol 1799.
  • the mass ratio of the polyvinyl alcohol to water is 12:88-30:70, more preferably 12:88.
  • the polyacid K 13 Na[AgP 5 W 30 O 110 ] is prepared by the following method:
  • the concentration of the solution obtained by dissolving the Na 2 WO 4 ⁇ H 2 O in water in step (1) is 1.1 g/mL; the H 3 PO 4 is added in the form of an H 3 PO 4 aqueous solution, and the H The mass concentration of the 3 PO 4 aqueous solution is 85%, and the ratio of the Na 2 WO 4 ⁇ H 2 O to the H 3 PO 4 aqueous solution is 33 g: 26.5 mL.
  • the ratio of the volume of water added after cooling in step (1) to the volume of water used to dissolve Na 2 WO 4 ⁇ H 2 O in water is 1:2; the ratio of Na 2 WO 4 ⁇ H 2 O to The mass ratio of KCl is 33:10.
  • the washing in step (1) refers to washing the precipitate with 2 mol/L potassium acetate and methanol respectively; the number of recrystallization is 1 to 3 times.
  • the concentration of the solution obtained by dissolving K 13 Na[NaP 5 W 30 O 110 ] in water in step (2) is 0.1 g/mL; the K 13 Na[NaP 5 W 30 O 110 ] and silver nitrate The mass ratio is 30:1.
  • the mass ratio of K 13 Na[NaP 5 W 30 O 110 ] to potassium nitrate in step (2) is 1:4.5.
  • the preparation method of the aforementioned silver ion controlled release antibacterial dressing includes the following steps:
  • the temperature for heating, stirring and dissolving is from room temperature to 95° C., and the time is from 2 to 10 hours.
  • the temperature at which the polyacid K 13 Na[AgP 5 W 30 O 110 ] is added is 30-50°C.
  • the standing time is 12-24h.
  • the substrate is a glass plate; the drying is natural air drying or heat drying; the temperature of the heat drying is 40 to 80° C., and the time is 1 to 6 hours.
  • the application refers to an application in the field of biomedical materials.
  • the present invention has the following advantages and beneficial effects:
  • the antibacterial dressing for the controlled release of silver ions of the present invention realizes the protection of silver ions through a specific polyacid structure, realizes the controlled release of silver ions, and avoids excessive consumption of silver ions caused by substances such as chloride ions, and realizes Long-acting antibacterial.
  • PVA has good water absorption capacity, can effectively absorb wound exudate, while maintaining a certain degree of moisture on the wound surface, avoiding adhesion with the wound surface, and will not cause wound bleeding and granulation tissue damage due to adhesion during dressing change, so as to maintain Good healing environment;
  • PVA is water-soluble. After the wound is healed, the material can be removed by washing with plenty of warm water.
  • the preparation of the antibacterial dressing with controlled release of silver ions of the present invention is simple and easy. It can be prepared only by solution casting method. PVA has good compatibility with polyacids, and the prepared material has good mechanical properties. It can be prepared according to the wound The size can be adjusted, and it can also be used as a wound filler. It can be shaped arbitrarily after absorbing moisture to adapt to wounds of different depths. In addition, the active ingredients in the material are continuously released to achieve long-term antibacterial effects.
  • the current treatment of post-traumatic infection is facing a very important problem is how to deal with the emergence of multi-drug resistant bacteria.
  • Local wound infection not only affects wound healing, but may also cause systemic bacteremia and sepsis.
  • the antibacterial wound dressing of the present invention can directly contact the wound, can absorb wound exudate to maintain a moist environment conducive to wound healing, and release broad-spectrum antibacterial active substances, reduce the frequency of dressing changes, reduce the probability of wound infection, and promote wounds heal.
  • Fig. 1 is a schematic diagram of the structure of the Preyssler type polyoxometalate (K 13 Na[AgP 5 W 30 O 110 ]) used in the present invention.
  • Figure 2 is the infrared spectra of Preyssler type polyoxometalates K 13 Na[NaP 5 W 30 O 110 ] and K 13 Na[AgP 5 W 30 O 110 ] used in the present invention.
  • Figure 3A is the 31 P NMR spectrum of the intermediate product K 13 Na[NaP 5 W 30 O 110 ] and the final product K 13 Na[AgP 5 W 30 O 110 ], and B is the K 13 Na[AgP 5 W 30 O 110 ] 31 P NMR monitoring results of Ag + controlled release.
  • Figure 4 shows the Preyssler type polyoxometalate K 13 Na[AgP 5 W 30 O 110 ] of the present invention in a D 2 O solution containing 1 wt% NaCl, 5 ⁇ mol/L transferrin, and 5 mmol/L bovine serum albumin, respectively 31 P NMR monitoring results 7 days after Ag + controlled release.
  • Figure 5 is a scanning electron micrograph of the antibacterial dressings obtained in Comparative Examples 1 and 4 and Examples 1 to 3.
  • Figure 6 shows the bacteriostatic zone of the antibacterial dressings obtained in Comparative Examples 1 to 3 and Examples 1 to 3, wherein the bacteria used in A is Escherichia coli, and the bacteria used in B is Staphylococcus aureus.
  • Fig. 7 is the release curve of Ag + in the antibacterial dressings obtained in Examples 1 to 3 and Comparative Example 3.
  • the controlled release of Ag + in K 13 Na[AgP 5 W 30 O 110 ] prepared by the present invention is monitored by 31 P nuclear magnetic resonance, the final product is dissolved in NaCl D 2 O, and the change of the nuclear magnetic spectrum is monitored.
  • the tensile strength test of the film in the examples and comparative examples refers to GB/T 1040.3-2006.
  • the zone of inhibition was obtained by agar diffusion experiment.
  • the K 13 Na[AgP 5 W 30 O 110 ] mentioned in this application is prepared by the following method:
  • the 31 P NMR spectra of the intermediate product K 13 Na[NaP 5 W 30 O 110 ] and the final product K 13 Na[AgP 5 W 30 O 110 ] are obviously different (as shown in Figure 3A), and -10.1 ppm corresponds to In the intermediate product K 13 Na[NaP 5 W 30 O 110 ] central phosphorus peak, -10.4 corresponds to the final product K 13 Na[AgP 5 W 30 O 110 ] central phosphorus peak.
  • the central metal ion is replaced by sodium ion to silver ion, the chemical shift of the central phosphorus has undergone a significant migration.
  • Comparative Example 4 In contrast, the elongation at break of Comparative Example 4 is reduced by 14%, and if it is used for wounds in joints, etc., it is difficult to provide a good protective effect. Especially after dry heat sterilization (160°C, 2h), the physical properties of the antibacterial wound dressing prepared in Comparative Example 4 are easily broken due to the excessive amount of inorganic ingredients in it (160°C, 2h), the color turns yellow, the brittleness increases, and high temperature treatment Reduce its tensile strength, and some adhesion fractures.
  • the antibacterial dressings prepared in Comparative Examples 1 to 3 and Examples 1 to 3 were cut out and placed on the surface of the agar medium coated with Escherichia coli (or Staphylococcus aureus). After 24 hours of incubation at 37°C, no zone of inhibition was formed around the dressings prepared in Comparative Examples 1 and 2, and a zone of inhibition was formed around the antibacterial dressings made in Comparative Example 3 and Examples 1 to 3 (as shown in Figure 6). ), indicating that dressings without silver ions have no antibacterial activity, and only dressings with a certain amount of silver ions have antibacterial activity.
  • the antibacterial dressing prepared in Comparative Example 3 is directly mixed with silver ions at the same molar concentration as in Example 1. By comparing the size of the inhibition zone, it can be found that the antibacterial dressings prepared in Examples 1 to 3 have short-term antibacterial properties. The activity is almost equivalent to the antibacterial activity of dressings directly incorporated with silver ions.
  • Figure 7 is an in vitro release curve of silver ions contained in the polyacid K 13 Na[AgP 5 W 30 O 110 ] and the comparative example 3AgNO 3 in the antibacterial dressings obtained in Examples 1 to 3.
  • the antibacterial dressings obtained in Comparative Examples 1 and 2 did not contain silver ions, and the release of silver ions was zero.
  • the antibacterial dressing obtained in Comparative Example 3 is mixed with silver nitrate. Because PVA gradually adsorbs water to form a gel, the silver ions are released in a large amount within the first 2 hours under the action of free diffusion, and the release rate within 2 hours reaches 61.3%. , The release amount dropped sharply afterwards, and it was difficult to produce long-term antibacterial protection to the wound. In Examples 1 to 3, the release of silver ions gradually increased within the first 2 days, and after 6 days, the release of silver ions showed a plateau, which can produce long-term antibacterial effects.
  • Wound dressing change test 30 male BALB/C mice aged 8 weeks were used to make a circular full-thickness skin defect with a diameter of 5mm on the back of the mice using sterilized ophthalmic scissors.
  • the wound size of mice was basically the same, and there was no obvious difference in depth to ensure comparability.
  • the mice were randomly divided into 2 groups, 15 mice in the control group and 15 mice in the observation group.
  • Two groups of injured mice cut out the POM-PVA antibacterial dressing or Vaseline gauze dressing (Zhende Demeisha sterilized Vaseline gauze 5cm ⁇ 5cm spun yarn) prepared in Example 3 of suitable size according to the wound condition.
  • the observation group used POM-PVA antibacterial dressing to cover the wound
  • the control group used Vaseline gauze dressing to cover the wound.
  • the wounds of all mice were located on the outermost layer and covered with a polymembrane (BIOCLUSIVE, Johnson & Johnson) and fixed. The number of dressing changes is determined according to the wound condition. The results showed that the wound adhesion of the observation group was significantly better than that of the control group (see Table 2).
  • the number of dressing changes in the observation group (referring to the average number of dressing changes per mouse) is less than that of the control group (as shown in Table 3).
  • Each dressing change shows that the wound is in a moist state, and there is no adhesion during dressing change. Wound hemorrhage and granulation tissue damage are caused, indicating that the POM-PVA antibacterial dressing prepared in Example 3 can maintain the moist healing environment of the wound, the wound healing time is relatively short (as shown in Table 3), and there is no infection in the wound-infected mice.

Abstract

一种银离子控释的抗菌敷料及其制备方法与应用。所述抗菌敷料由聚乙烯醇、多酸K 13Na[AgP 5W 30O 110]和水制备而成，其中多酸K 13Na[AgP 5W 30O 110]占PVA干重的0.5-3％，聚乙烯醇和水的质量比为1:99～30:70。所述抗菌敷料的抗菌性能以及力学性能良好，具有良好的渗出液吸收能力，同时实现银离子的控释，避免氯离子等物质造成银离子浓度的过快消耗，实现长效抑菌，且制备方式简单，可按比例扩大制作规模。

Description

一种银离子控释的抗菌敷料及其制备方法与应用 技术领域
本发明属于生物医用材料技术领域，具体涉及一种银离子控释的抗菌敷料及其制备方法与应用。
背景技术
抗菌伤口敷料对伤口的覆盖可一定程度上避免机械因素以及污染物对伤口愈合产生不良影响，然而创伤处血清素、前列腺素、组胺及受损处流出的血液和组织液的渗出，要求抗菌伤口敷料对渗出液具有一定的吸收能力。传统的负载银盐或纳米银的干纱布作为抗菌伤口敷料极易与伤口粘连，后续的清理较易产生二次损伤，给患者带来疼痛和风险。理想的抗菌伤口敷料，不但要具有良好的抗菌活性，有效预防伤口感染，还应具有较强的载药能力和持续释放性能，同时也要兼顾与伤口粘连的问题，以缩短伤口愈合期。
由于耐药性细菌的出现，抗生素的抑菌效果受到了极大的削弱，而银作为一种具有悠久使用历史的抗菌剂在伤口敷料中逐渐得到普及。目前硝酸银以及磺胺嘧啶银常作为抗菌剂递送银离子，然而银离子的抗菌效果具有很强的浓度依赖性。事实上，真实生理环境中含有大量的Cl -、S 2-以及与金属离子具有强烈螯合作用的蛋白质，这些物质的存在会导致银离子被大量消耗，从而降低其抑菌效率。因此需要实现银离子的控释以实现长效的抑菌效果。
多金属氧酸盐(简称多酸)是一种亚纳米尺度的单分散金属氧化物团簇。过去的研究证明了该材料的直接抗菌效果以及与其他抗菌剂的协同作用。此外，一些多酸结构中具有可容纳客体的空穴，这一特点使得多酸在控释领域具有潜在的应用价值。
聚乙烯醇(PVA)为聚醋酸乙烯的醇解产物。作为一种生物相容性良好的高分子材料，PVA可在细胞培养基中适量加入以支持细胞生长。此外，PVA分子链上含有大量羟基，易吸收水分形成水凝胶。与非极性高分子相比，PVA还与多酸等无机材料体现出了更好的相容性，这一特性使得PVA-无机复合材料具有良好的力学性能。
发明内容
为解决现有技术的缺点和不足之处，本发明的首要目的在于提供一种银离子控释的抗菌敷料。该抗菌敷料由聚乙烯醇以及多酸K 13Na[AgP 5W 30O 110]组成，抗菌性能以及力学性能良好，具有良好的渗出液吸收能力，且制备方式简单。
本发明的另一目的在于提供上述一种银离子控释的抗菌敷料的制备方法。该制备方法简单，且可按比例扩大制作规模。
本发明的再一目的在于提供上述一种银离子控释的抗菌敷料的应用。
本发明目的通过以下技术方案实现：
一种银离子控释的抗菌敷料，由聚乙烯醇(PVA)、多酸K 13Na[AgP 5W 30O 110]和水制备而成，其中多酸K 13Na[AgP 5W 30O 110]占PVA干重的0.5-3％，聚乙烯醇和水的质量比为1:99～30:70。
优选的，所述聚乙烯醇的聚合度为300～2400，醇解度为88～99％。
更优选的，所述聚乙烯醇为聚乙烯醇124和聚乙烯醇1799中的至少一种。
优选的，所述聚乙烯醇和水的质量比为12：88～30：70，更优选为12：88。
优选的，所述多酸K 13Na[AgP 5W 30O 110]由以下方法制备得到：
(1)将Na 2WO 4·H 2O溶于水中，加入H 3PO 4，在110～160℃水热反应10～24小时，冷却后，加入水和KCl，搅拌5～20min，过滤取沉淀，洗涤，重结晶，得到K 13Na[NaP 5W 30O 110]；
(2)将K 13Na[NaP 5W 30O 110]溶于水中，加入硝酸银，在150～200℃水热反应20～30小时，冷却后，加入硝酸钾，搅拌5～20min，过滤取沉淀，重结晶，得 到K 13Na[AgP 5W 30O 110]。
更优选的，步骤(1)所述Na 2WO 4·H 2O溶于水所得溶液的浓度为1.1g/mL；所述H 3PO 4以H 3PO 4水溶液的形式加入，所述H 3PO 4水溶液的质量浓度为85％，所述Na 2WO 4·H 2O与H 3PO 4水溶液的比例为33g：26.5mL。
更优选的，步骤(1)所述冷却后加入水的体积与Na 2WO 4·H 2O溶于水所用水的体积之比为1：2；所述Na 2WO 4·H 2O与KCl的质量比为33：10。
更优选的，步骤(1)所述洗涤指分别用2mol/L的醋酸钾和甲醇洗涤沉淀；所述重结晶的次数为1～3次。
更优选的，步骤(2)所述K 13Na[NaP 5W 30O 110]溶于水中所得溶液的浓度为0.1g/mL；所述K 13Na[NaP 5W 30O 110]与硝酸银的质量比为30：1。
更优选的，步骤(2)所述K 13Na[NaP 5W 30O 110]与硝酸钾的质量比为1：4.5。
上述一种银离子控释的抗菌敷料的制备方法，包括以下步骤：
将聚乙烯醇和水混合，加热搅拌溶解后，加入多酸K 13Na[AgP 5W 30O 110]，继续搅拌3～4小时，静置，得成膜液，平铺于基底上，干燥，得到银离子控释的抗菌敷料。
优选的，所述加热搅拌溶解的温度为常温～95℃，时间为2～10h。
优选的，所述加入多酸K 13Na[AgP 5W 30O 110]的温度为30～50℃。
优选的，所述静置的时间为12～24h。
优选的，所述基底为玻璃板；所述干燥为自然风干或加热干燥；所述加热干燥的温度为40～80℃，时间为1～6小时。
上述一种银离子控释的抗菌敷料的应用。
优选的，所述应用指在生物医用材料领域中的应用。
与现有技术相比，本发明具有以下优点及有益效果：
(1)本发明所述银离子控释的抗菌敷料通过特定的多酸结构实现了对银离子的保护，实现银离子的控释，避免氯离子等物质造成银离子浓度的过快消耗，实现长效抑菌。
(2)PVA具有良好的吸水能力，能有效吸收伤口渗出液，同时维持创面一定的润湿度，避免与创面粘连，在换药时不会因粘连而引起创面出血、肉芽组织损伤，以保持良好愈合环境；此外，PVA具有水溶性，伤口愈合后，材料可通过大量温水冲洗除去。
(3)本发明所述银离子控释的抗菌敷料的制备简便易行，仅需通过溶液浇铸法即可制备，PVA与多酸相容性良好，制得的材料力学性能良好，可以根据伤口大小调节尺寸，也可作为伤口填充物，在吸湿后能够任意成型，适应不同深度的伤口。此外，该材料中活性成分可持续性地释放出来，以实现长效抑菌效果。
(4)当前创伤后感染的治疗面临一个非常重要的问题就是如何应对多重耐药菌的出现。局部创面感染不仅影响创面愈合，还可能引起全身性的菌血症和脓毒血症。本发明所述抗菌伤口敷料能直接接触伤口，可吸收伤口渗液维持有利于伤口愈合的微湿环境，并释放广谱性的抑菌活性物质，减少换药次数，降低伤口感染几率，促进伤口愈合。
附图说明
图1为本发明所使用Preyssler型多金属氧酸盐(K 13Na[AgP 5W 30O 110])的结构示意图。
图2为本发明所使用Preyssler型多金属氧酸盐K 13Na[NaP 5W 30O 110]和K 13Na[AgP 5W 30O 110]的红外光谱图。
图3A为中间产物K 13Na[NaP 5W 30O 110]以及最终产物K 13Na[AgP 5W 30O 110]的 31P核磁共振谱图，B为K 13Na[AgP 5W 30O 110]中Ag +控释的 31P核磁共振监控结果。
图4为本发明Preyssler型多金属氧酸盐K 13Na[AgP 5W 30O 110]分别在含1wt％NaCl、5μmol/L转铁蛋白和5mmol/L牛血清白蛋白的D 2O溶液中Ag +控释7天后的 31P核磁共振监控结果。
图5为对比例1和4以及实施例1～3所得抗菌敷料的扫描电镜图。
图6为对比例1～3和实施例1～3所得抗菌敷料的抑菌圈，其中A所用细菌为大肠杆菌，B所用细菌为金黄葡萄球菌。
图7为实施例1～3和对比例3所得抗菌敷料中Ag +的释放曲线。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
本发明实施例中未注明具体条件者，按照常规条件或者制造商建议的条件进行。所用未注明生产厂商者的原料、试剂等，均为可以通过市售购买获得的常规产品。
本发明制得的K 13Na[AgP 5W 30O 110]中Ag +的控释通过 31P核磁共振监控，将最终产物溶于NaCl的D 2O中，并监控核磁谱图的变化。实施例和对比例中薄膜抗拉强度测试参照GB/T 1040.3-2006。抑菌圈通过琼脂扩散实验获得，将0.2mL浓度为10 8CFU/mL的大肠杆菌(ATCC 8739)与金黄葡萄球菌(ATCC 6538)分别涂布于不同组的琼脂表面，然后将制得的薄膜放置于琼脂表面，37℃孵育24h后，测量抑菌带宽度。抗菌敷料中K 13Na[AgP 5W 30O 110]向水中的释放实验参考GB 31604.1-2015进行，并通过电感耦合等离子体发射光谱测定模拟物中Ag的浓度。
本申请所述K 13Na[AgP 5W 30O 110]由以下方法制得：
(1)将33g Na 2WO 4·H 2O溶于30mL水中，并加入26.5mL质量浓度为85％的H 3PO 4水溶液，置于聚四氟乙烯内衬的水热反应釜中，120℃反应12小时。待冷却后，加入15mL水以及10g固体KCl，搅拌10分钟后，过滤得沉淀，并分别用2mol/L醋酸钾以及甲醇洗涤沉淀，重结晶2次得中间产物K 13Na[NaP 5W 30O 110]。
(2)取1.2g中间产物K 13Na[NaP 5W 30O 110]，溶于12mL水，加入40mg 硝酸银，置于聚四氟乙烯内衬的水热反应釜中，160℃反应24小时。待冷却后，加入5.4g固体硝酸钾，搅拌10分钟后，过滤得沉淀，重结晶后得最终产物K 13Na[AgP 5W 30O 110](其结构图如图1所示)。
中间产物K 13Na[NaP 5W 30O 110]及最终产物K 13Na[AgP 5W 30O 110]的红外光谱图如图2所示，通过对比骨架峰，说明所得无机化合物为最终产物K 13Na[AgP 5W 30O 110]。另外，中间产物K 13Na[NaP 5W 30O 110]以及最终产物K 13Na[AgP 5W 30O 110]的 31P核磁共振谱图明显不同(如图3A所示)，-10.1ppm对应于中间产物K 13Na[NaP 5W 30O 110]中心磷的峰，-10.4对应于最终产物K 13Na[AgP 5W 30O 110]中心磷的峰。由于中心金属离子由钠离子换成了银离子，中心磷的化学位移发生了明显的迁移。通过监控中心磷化K 13Na[AgP 5W 30O 110]学位移的迁移，可监测室温条件下，生理盐水(0.9wt％NaCl)氘代水溶液中K 13Na[AgP 5W 30O 110]中银离子被钠离子逐渐替换的过程(如图3B所示)。 31P核磁共振谱图的结果说明，银离子在Preyssler型多酸骨架的保护下，可以持久性地释放出来。已有研究发现，有些负载了银离子的抗菌辅料只有一小部分银出现在伤口部位，发挥抗菌作用(J Wound Care 2004；13(4):131)，其中相当大一部分银与伤口处的蛋白质结合而丧失抗菌活性。本发明中，所使用的K 13Na[AgP 5W 30O 110]与氘代水溶液中5μmol/L转铁蛋白或5mmol/L牛血清白蛋白作用7天后的 31P核磁共振谱几乎没有发生明显变化(如图4所示)，监控结果说明银离子在Preyssler型多酸骨架的保护下，有效避免了被蛋白质的消耗，从而保证银离子最大程度上发挥抗菌作用。
对比例1
称取12g聚乙烯醇1799于烧杯中，加入88mL去离子水，于95℃下搅拌5小时。将溶液温度降至50℃后，继续搅拌4小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得抗菌敷料。
对比例2
称取12g聚乙烯醇1799于烧杯中，加入88mL去离子水，于95℃下搅拌5 小时。将溶液温度降至50℃后，加入0.36g K 13Na[NaP 5W 30O 110]，继续搅拌4小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得抗菌敷料。
对比例3
称取12g聚乙烯醇1799于烧杯中，加入88mL去离子水，于95℃下搅拌5小时。将溶液温度降至50℃后，加入0.0006gAgNO 3，继续搅拌4小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得抗菌敷料。
对比例4
称取12g聚乙烯醇1799于烧杯中，加入88mL去离子水，于95℃下搅拌5小时。将溶液温度降至50℃后，加入0.72g K 13Na[AgP 5W 30O 110]，继续搅拌4小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得抗菌敷料。
实施例1
称取12g聚乙烯醇124于烧杯中，加入88mL去离子水，于95℃下搅拌5小时。将溶液温度降至45℃后，加入0.06g K 13Na[AgP 5W 30O 110]，继续搅拌4小时。停止搅拌及加热，静置16小时后铺于玻璃板上，55℃条件下干燥3小时，制得该抗菌敷料。
实施例2
称取12g聚乙烯醇1799于烧杯中，加入28mL去离子水，于95℃下搅拌5小时。将溶液温度降至50℃后，加入0.12g K 13Na[AgP 5W 30O 110]，继续搅拌4小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得该抗菌敷料。
实施例3
称取12g聚乙烯醇1799于烧杯中，加入88mL去离子水，于95℃下搅拌5小时。将溶液温度降至50℃后，加入0.36g K 13Na[AgP 5W 30O 110]，继续搅拌4 小时。停止搅拌及加热，静置12小时后铺于玻璃板上，50℃条件下干燥3小时，制得该抗菌敷料。
实施例1～3所制得的抗菌敷料与不含多酸的对比例1所得抗菌敷料的扫描电镜图几乎一样(如图5所示)，可以看出制得的抗菌敷料表面及截面都十分光滑、均匀。而对比例4所制得的抗菌伤口敷料表面出现了颗粒状的斑点，断面出现裂纹，说明多酸添加量达到6％以上时，所制得的抗菌敷料中多酸分布的均匀度下降。结合表1，与对比例1相比，多酸掺入后，实施例1～3的抗拉强度都有明显提升，断裂伸长率略微下降，最多下降6％。相比之下，对比例4的断裂伸长率下降了14％，如果用于关节等处的伤口，则难以起到良好的保护作用。尤其在干热灭菌后(160℃，2h)，由于其中的无机成分多酸过量，对比例4所制得的抗菌伤口敷料的物理性状易被破环，颜色变黄，脆性增加，高温处理降低其抗拉强度，还有部分粘连断裂。
表1抗菌伤口敷料力学性能
Figure PCTCN2020122385-appb-000001
对比例1～3和实施例1～3所制得的抗菌敷料剪下一小块置于涂布了大肠杆菌(或金黄葡萄球菌)的琼脂培养基表面。37℃孵育24h后，对比例1和2所制得的敷料周围没有形成抑菌圈，对比例3和实施例1～3所制得的抗菌敷料周围形成了抑菌圈(如图6所示)，说明不含银离子的敷料没有抑菌活性，只有含有一定量的银离子的敷料才具备抑菌活性。对比例3所制得的抗菌敷料中直接掺入的是与实施例1相同摩尔浓度的银离子，通过对比抑菌圈大小，可以发现实施例1～3所制得的抗菌敷料的短期抑菌活性几乎与直接掺入银离子的敷料的抑菌活性相当。
图7为实施例1～3所得抗菌敷料中多酸K 13Na[AgP 5W 30O 110]及对比例3AgNO 3所含银离子的体外释放曲线图。对比例1和2所得抗菌敷料中不含银离子，银离子释放结果为零。对比例3所得抗菌敷料中掺入的是硝酸银，由于PVA逐渐吸附水分形成凝胶，因而银离子在自由扩散作用下在初始2小时内被大量释放出来，2小时的释放率即达到61.3％，随后释放量急剧下降，难以对伤口产生长久的抑菌保护。实施例1～3在初始的2天内，银离子释放量逐渐增加，在6天后，银离子的释放才出现平台期，可以产生长效抑菌作用。
伤口换药试验：8周龄雄性BALB/C小鼠30只，使用灭菌眼科剪刀于小鼠背部制作直径为5mm的圆形全层皮肤缺损。小鼠伤口大小基本一致、深浅无明显差异，以确保具有可比性。小鼠随机分为2组，对照组小鼠15只，观察组小鼠共15只。两组受伤小鼠根据创面情况，剪下合适尺寸实施例3所制备的POM-PVA抗菌敷料或凡士林油纱敷料(振德德美纱灭菌凡士林纱布5cm×5cm细纱)。伤口周围使用碘伏消毒，再用生理盐水棉球清洗伤口，彻底清创，去除坏死组织及分泌物。观察组使用POM-PVA抗菌敷料覆盖创面，对照组使用凡士林油纱敷料覆盖创面。所有小鼠的伤口部位于最外层使用多聚膜(BIOCLUSIVE，强生)覆盖，并固定。根据伤口情况决定换药次数。结果显示，观察组小鼠创面粘连情况明显优于对照组小鼠(如表2)。观察组小鼠的换药次数(指平均每只小鼠的换药次数)少于对照组小鼠(如表3)，每次换药可见伤口处于湿润状态，在换药时不会因粘连而引起创面出血、肉芽组织损伤，说明实施例3所制备的POM-PVA抗菌敷料可保持伤口的湿性愈合环境，伤口愈合时间比较短(如表3)，并且伤口感染小鼠没有感染情况。
表2两组小鼠创面粘连情况比较
Figure PCTCN2020122385-appb-000002
表3两组小鼠换药次数、伤口愈合时间比较
Figure PCTCN2020122385-appb-000003
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种银离子控释的抗菌敷料，其特征在于，由聚乙烯醇、多酸K 13Na[AgP 5W 30O 110]和水制备而成，其中多酸K 13Na[AgP 5W 30O 110]占PVA干重的0.5-3％，聚乙烯醇和水的质量比为1:99～30:70。
  2. 根据权利要求1所述一种银离子控释的抗菌敷料，其特征在于，所述聚乙烯醇的聚合度为300～2400，醇解度为88～99％。
  3. 根据权利要求2所述一种银离子控释的抗菌敷料，其特征在于，所述聚乙烯醇为聚乙烯醇124和聚乙烯醇1799中的至少一种。
  4. 根据权利要求1或2所述一种银离子控释的抗菌敷料，其特征在于，所述聚乙烯醇和水的质量比为12：88～30：70。
  5. 根据权利要求1或2所述一种银离子控释的抗菌敷料，其特征在于，所述多酸K 13Na[AgP 5W 30O 110]由以下方法制备得到：
    (1)将Na 2WO 4·H 2O溶于水中，加入H 3PO 4，在110～160℃水热反应10～24小时，冷却后，加入水和KCl，搅拌5～20min，过滤取沉淀，洗涤，重结晶，得到K 13Na[NaP 5W 30O 110]；
    (2)将K 13Na[NaP 5W 30O 110]溶于水中，加入硝酸银，在150～200℃水热反应20～30小时，冷却后，加入硝酸钾，搅拌5～20min，过滤取沉淀，重结晶，得到K 13Na[AgP 5W 30O 110]。
  6. 根据权利要求5所述一种银离子控释的抗菌敷料，其特征在于，步骤(1)所述冷却后加入水的体积与Na 2WO 4·H 2O溶于水所用水的体积之比为1：2；所述Na 2WO 4·H 2O与KCl的质量比为33：10；所述H 3PO 4以H 3PO 4水溶液的形式加入，所述H 3PO 4水溶液的质量浓度为85％，所述Na 2WO 4·H 2O与H 3PO 4水溶液的比例为33g：26.5mL；所述Na 2WO 4·H 2O溶于水所得溶液的浓度为1.1g/mL；
    步骤(2)所述K 13Na[NaP 5W 30O 110]与硝酸银的质量比为30：1；所述 K 13Na[NaP 5W 30O 110]与硝酸钾的质量比为1：4.5；所述K 13Na[NaP 5W 30O 110]溶于水中所得溶液的浓度为0.1g/mL。
  7. 权利要求1～6任一项所述一种银离子控释的抗菌敷料的制备方法，其特征在于，包括以下步骤：将聚乙烯醇和水混合，加热搅拌溶解后，加入多酸K 13Na[AgP 5W 30O 110]，继续搅拌3～4小时，静置，得成膜液，平铺于基底上，干燥，得到银离子控释的抗菌敷料。
  8. 根据权利要求7所述一种银离子控释的抗菌敷料的制备方法，其特征在于，所述加热搅拌溶解的温度为常温～95℃，时间为2～10h；所述加入多酸K 13Na[AgP 5W 30O 110]的温度为30～50℃；所述静置的时间为12～24h。
  9. 权利要求1～6任一项所述一种银离子控释的抗菌敷料的应用。
  10. 根据权利要求9所述一种银离子控释的抗菌敷料的应用，其特征在于，所述应用指在生物医用材料领域中的应用。
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