WO2010069152A1 - 形成多效抗微生物表面涂层的材料及其制备方法 - Google Patents

形成多效抗微生物表面涂层的材料及其制备方法 Download PDF

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Publication number
WO2010069152A1
WO2010069152A1 PCT/CN2009/001503 CN2009001503W WO2010069152A1 WO 2010069152 A1 WO2010069152 A1 WO 2010069152A1 CN 2009001503 W CN2009001503 W CN 2009001503W WO 2010069152 A1 WO2010069152 A1 WO 2010069152A1
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volatile
antimicrobial
antimicrobial agent
coating
polymer
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PCT/CN2009/001503
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English (en)
French (fr)
Inventor
杨经伦
梁伟健
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Hong Kong University of Science and Technology
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Hong Kong University of Science and Technology
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Priority to KR1020117006570A priority Critical patent/KR101308261B1/ko
Priority to CN200980135845.9A priority patent/CN102149278B/zh
Priority to AU2009327015A priority patent/AU2009327015B8/en
Priority to HK11113066.9A priority patent/HK1158452B/zh
Priority to EP09832834.7A priority patent/EP2359691A4/en
Priority to MX2011006630A priority patent/MX2011006630A/es
Priority to JP2011541063A priority patent/JP5638536B2/ja
Priority to CA2736575A priority patent/CA2736575C/en
Publication of WO2010069152A1 publication Critical patent/WO2010069152A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/14—Paints containing biocides, e.g. fungicides, insecticides or pesticides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • A01N25/28—Microcapsules or nanocapsules
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A01N59/20—Copper

Definitions

  • the present invention relates to a multi-effect antimicrobial material.
  • Microbes are ubiquitous in our environment. Although many of them have no harmful effects, some are still beneficial to the human body. But some of the microbes can still be used as unknown maps.
  • Ho et al. (Ho, CH et al., Adv. Mater. 2004, 16, 957-961) use a multi-polymer film to encapsulate nano-silver ions to achieve both release and contact sterilization methods.
  • Ethylene glycol prevents bacteria from adsorbing on their surface.
  • pathogenic bacteria eg, microorganisms
  • dust, and/or contaminants to the surface can affect their release and contact bactericidal effects, which is a problem for antimicrobial coatings. Therefore, there is still a need for a material that forms a multi-effect antimicrobial surface coating.
  • SUMMARY OF THE INVENTION The present invention provides a solution to the problems encountered in the current development of antimicrobial surface coatings.
  • One aspect of the present invention provides a material for forming a multi-effect antimicrobial surface coating comprising one or more volatile or gaseous antimicrobial agents, one or more non-volatile antimicrobial agents, And one or more polymers, wherein the volatile or gaseous antimicrobial agent is encapsulated in the polymer to provide a slow release effect.
  • Another aspect of the invention provides a material for forming a multi-effect antimicrobial surface coating a method of preparing, comprising: coating one or more volatile or gaseous antimicrobial agents in one or more polymers such that the volatile or gaseous antimicrobial agent is slowly released, and Mixed with one or more non-volatile antimicrobial agents.
  • Another aspect of the invention provides a method of sterilizing an article or device, wherein the method comprises: providing a material that forms a multi-effect antimicrobial surface coating comprising one or more volatile or gaseous resistant a microbial agent, one or more non-volatile antimicrobial agents, and one or more polymers, wherein the volatile or gaseous antimicrobial agent is encapsulated in the polymer to provide a slow release effect; And applying the material to the surface of the article or device to form an antimicrobial surface coating having a release killing, contact killing and anti-sticking effect.
  • Figure 1 is a photograph showing (a) a state in which the water-in-oil-in-water emulsion of polymer-coated chlorine dioxide is stored for one month, and (b) an optical micrograph, and (c) an antimicrobial water-in-oil package prepared.
  • Water emulsified composition B (C10 2 + ZnCl 2 ), zinc-free composition A (wrapped) and pure, uncoated Ultraviolet analysis of the chlorine dioxide solution (cio 2 ).
  • Figure 2 is a photograph showing a (a) coated chlorine dioxide coated glass slide with (: left) or no (right) polymer, (b) optical and (c) and (d) scanning electron microscope The photograph, in which the coated glass shows a uniform surface coating (b), has a spherical morphology of microparticles (Fig. 2c) containing smaller particles of 0.5-1 micron (Fig. 2d).
  • Figure 3 is a schematic view showing the coated surface of Composition B with a high-resolution transmission electron microscope, the inset shows a zinc-containing rod-like nanostructure (about 20 nm X 1000 nm) self-polymer coated The surface is prominent.
  • Figure 4 is a graph showing (a) release of chlorine dioxide on the surface of the coating within 7 days at 25 °C ( ⁇ ) and 35 °C (mouth) (relative humidity is 60-80%) (b) ) Release within 28 days (temperature is maintained at 20-26 ° C, relative humidity is 60-90%).
  • Figure 5 is a graph showing the average release of chlorine dioxide gas from the coating on the glass within 7 days.
  • Figure 6 is a graph showing the log reduction of (a) Bacillus subtilis and (b) Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, and ( c ) with a polymer package of 1 mg/cm 2 After 10, 30 and 60 minutes of contact with the glass coating of chlorine dioxide, (1) Staphylococcus aureus; (2) Staphylococcus epidermidis; (3) E. coli and (4) survival of Pseudomonas aeruginosa.
  • Figure 7 is a diagram showing the application of an antimicrobial water-in-oil double-layer emulsified composition B (coating) containing 30 ppm of zinc chloride salt in contact for 10 minutes, chlorine dioxide (solution) and coated water (pseudogroup) The log reduction of surviving Gram-positive and Gram-negative bacteria after the surface coating (log reduction)
  • Figure 8 shows bacteria (a) Bacillus subtilis (b) Staphylococcus aureus and (c) bacteria that survived contact with the glass surface of a 1 mg/cm 2 multi-effect antimicrobial coating at 1, 5, 10 and 30 minutes. number. The error value represents the standard deviation of 5 samples.
  • Figure 9 shows (a) Staphylococcus aureus and (b) E. coli with 1 mg/cm 2 of antimicrobial composition A (filled symbol) coating, and composition of 30 ppm of zinc chloride (open symbol) The number of bacteria that the coating contacted for 30 minutes (neutral pH) and died after different days. Each data was obtained from at least five samples, and part of the data was repeated more than once.
  • Figure 10 is a graph showing the continuous monitoring of the release of the antimicrobial coated chlorine dioxide from the zinc dioxide-coated chlorine dioxide and testing at room temperature for more than thirty days. After 10 minutes of contact with the coating, Staphylococcus aureus can still be used. Maintain a reduction in the number of viable Staphylococcus aureus greater than 99.9%.
  • Figure 11 shows the amount of Staphylococcus aureus survival after 1, 5, 10 and 30 minutes of contact with 1 mg/cm 2 of the antimicrobial composition B coating containing 0, 10 and 30 ppm of zinc chloride.
  • the error value represents the standard deviation of 5 samples.
  • Figure 12 shows the amount of malondialdehyde produced by the surviving Bacillus subtilis after contact with the glass coating of the antimicrobial composition A and the glass coating of the chlorine dioxide (open symbols) for different lengths of time.
  • Fig. 13 is an optical photograph magnified 1000 times showing Escherichia coli attached to (a) coated sterilized water (pseudo group:) and (b) uncoated glass.
  • Figure 14 is an optical photograph magnified 1000 times showing Staphylococcus aureus attached to (a) coated sterilized water (pseudo-group) and (b) uncoated glass.
  • Figure 15 shows a glass coated with a 1 mg/cm 3 antimicrobial water-in-oil double-layer emulsified composition A (filled with a symbol), and a Bacillus subtilis spore after contact with an uncoated glass (open symbol). Reduce the number.
  • DETAILED DESCRIPTION OF THE INVENTION All technical and scientific terms used herein have the technical field of the art unless otherwise defined. The same meaning is usually understood by the technicians.
  • the article “a” refers to one or more (i.e., at least one) of the grammatical objects of the article.
  • a component means one component or more than one component.
  • the present invention provides a material for forming a multi-effect antimicrobial surface coating comprising one or more volatile or gaseous antimicrobial agents, one or more non-volatile antimicrobial agents, and one or A plurality of polymers, wherein the volatile or gaseous antimicrobial agent is encapsulated in the polymer to provide a slow release effect.
  • the volatile or gaseous antimicrobial agent includes, but is not limited to, soluble chlorine dioxide, soluble chlorine, chlorinated mixtures, ethanol or phenolic compounds and solid or liquid precursors thereof, or combinations thereof.
  • the volatile antimicrobial agent is soluble chlorine dioxide or a precursor thereof.
  • the volatile antimicrobial agent is a combination of chlorine dioxide, chloride salts and chlorine.
  • Non-volatile antimicrobial agents in accordance with the present invention include, but are not limited to, metal-containing antimicrobial agents, triclosan, carboxylic acids, sugar acids, or combinations thereof.
  • An example of a carboxylic acid is citric acid, and one example of a sugar acid is a vitamin (:.
  • the non-volatile antimicrobial agent is a metal-containing antimicrobial agent.
  • any metal-containing agent The antimicrobial agent is selected from the group consisting of one or more antimicrobial agents comprising Group VII, IB, IIB, IVA and IVB metals and related salts thereof, and combinations thereof.
  • Metallic antimicrobial agents include transition metal containing compounds or related salts thereof, such as compounds containing silver, copper, or zinc.
  • the term "polymer” as used herein means “polymer”, “copolymer” or a combination of the above, which polymer constitutes an emulsion-encapsulating antimicrobial agent, thus making the antimicrobial agent Can be released slowly, gradually and continuously into the surrounding environment.
  • the polymer and/or copolymer surfactant forms a two-layered emulsion, such as a water-in-oil water-in-oil.
  • any polymer is selected from a bis-block copolymer
  • amphiphilic block copolymer and a combination of the same.
  • the amphiphilic block copolymer is a bimodal double or triple embedded copolymer, such as a polyxamers (e.g., commercially available Pluronics® or Tetronics®), or a combination thereof.
  • the coating formed from the material has multi-functional antimicrobial functions, including release killing, contact killing, and anti-adhesion, etc., which are achieved by: (1) slow release of sufficient amount Volatile antimicrobial agent to kill or inhibit microbial growth; (2) accelerate the release of antimicrobial agents when in contact with infectious droplets; and (3) non-volatile antimicrobial agents can be applied to the surface of the coating A nanostructure is formed to prevent adhesion of microorganisms and to inactivate microorganisms.
  • the material or composition forming the antimicrobial surface coating comprises a volatile oxidizing antimicrobial agent and a non-volatile antimicrobial agent, for example: a VII, IB, a compound of Group IIB, Group IVA and Group IVB, and one or more polymers to form a water-in-oil-in-water double emulsion which encapsulates the two antimicrobial agents, wherein the polymer is oxidizable with volatiles
  • the antimicrobial agent and the non-volatile antimicrobial agent react with each other to form a metal-containing nanostructure and are present on the outer surface of the water-in-oil-in-water double emulsion.
  • the metal-containing nanostructure is confirmed to be related to the redox reaction between the oxidized antimicrobial agent and the metal-containing compound (for example, a metal salt), and metal or metal oxidation can be formed according to the individual oxidation-reduction potential.
  • the structure of the nano The polymer functions as a general surfactant and controls the growth of the nanostructure to avoid the formation of large substances. Therefore, the nanostructure Can be formed and stored in situ on the surface of the emulsion.
  • the water-in-oil-in-water double-layer emulsion comprises a first water layer, an oil layer, and a second water layer, which is composed of a polymer of 1:0.5-2:2-20 The volume ratio is formed.
  • the first aqueous layer comprises from about 10 ppm to about 70 volume percent of a volatile antimicrobial agent, the amount of which depends on the efficacy and time of use and the use of more than one antimicrobial agent;
  • the oil layer comprises low volatility oils that are compatible with the antimicrobial agent and are denatured by mutual reaction, and may comprise a second antimicrobial agent, such as a non-volatile carboxylic acid or sugar acid, and an aroma to provide The purpose of the olfactory cues and aesthetics; and the second aqueous layer, which is coated with the outermost polymer, comprising one or more non-volatile metal-containing antimicrobial agents to provide contact killing efficacy
  • the non-volatile antimicrobial agent comprises a metal of about 5,000 ppm or less, preferably less than about 100 ppm.
  • the second aqueous layer comprises a non-volatile antimicrobial agent, triclosan, which is about 3% by weight of the total material.
  • the first aqueous layer, the oil layer and the second aqueous layer are separated by a polymer or polymer interface active agent.
  • the outermost polymer zone oil barrier layer and the second water layer also provide antimicrobial adhesion, wherein the lowest concentration of the polymer or polymer surfactant depends on their primary microgel The concentration of the micelle and the characteristics of the surfactant.
  • the material of the present invention is applied to an article to form a surface coating which provides multiple effects, including a "release killing” effect, wherein the volatile resistance
  • the biological agent is slowly released from a water-in-oil-in-water emulsion prepared from a polymer or a polymer surfactant at room temperature to achieve sterilization and inhibit microbial growth; and a "contact killing” effect, when When the surface coating is in contact with or contaminated by infectious droplets, this effect is achieved by increasing the release of non-volatile metal-containing antimicrobial agents; and the "anti-sticking" function, which is through metal-containing antimicrobials.
  • the formed metal-containing nanostructure is formed to achieve this function.
  • the invention further provides a method of preparing a material for forming a multi-effect antimicrobial surface coating, wherein the method comprises: coating one or more volatile or gaseous antimicrobial agents to one or more polymers The volatile or gaseous antimicrobial agent is slowly released and mixed with one or more non-volatile antimicrobial agents.
  • the non-volatile antimicrobial agent can be encapsulated in the polymer with the volatile or gaseous antimicrobial agent.
  • the present invention provides a method of sterilizing an article or device, wherein the method comprises: providing a material for forming a multi-effect antimicrobial surface coating comprising one or more volatile or gaseous antimicrobial agents One or more non-volatile antimicrobial agents, and one or more polymers, wherein the volatile or gaseous antimicrobial agent is encapsulated in the polymer to provide a slow release effect;
  • the material is applied to the surface of the article or device to form an antimicrobial surface coating having a slow release, contact sterilization and anti-sticking effect.
  • Example 1 Preparation of an antimicrobial water-in-oil-in-water double-layer emulsified composition A
  • Example 2 Preparation of an antimicrobial, water-in-oil-in-water double-layer emulsified composition B
  • the resulting water-in-oil emulsion was then added to 2.5 g of Pluronic F127 aqueous solution (EO 106 PO 70 EO 106 , MW 12600 g/mol, HLB value 22, purchased from BASF, Germany), and finally dissolved in 50 ml. Ionized water was stirred at 200 rpm to obtain a 1:1:2 water-in-oil double emulsion. 0.25 ml of 50 mM ZnCl 2 (99%, Aldrich) was added to the final emulsion. In other preparations, CuCl 2 (99%, Aldrich), AgN 0 3 (99%, Aldrich) or metal salts (for example, Zn 2+ , Cu 2+ and Ag+) may be used in place of ZnCl 2 .
  • Pluronic F127 aqueous solution EO 106 PO 70 EO 106 , MW 12600 g/mol, HLB value 22, purchased from BASF, Germany
  • Ionized water was stirred at 200 r
  • Example 2 Preparation of an antimicrobial, water-in-oil-in-water double-layer emulsified composition C
  • the resulting water-in-oil emulsion was then added to 2.5 g of Pluronic F127 aqueous solution (EO l06 PO 70 EO l 06 , MW 12600 g/mol, HLB value For 22, purchased from BASF, Germany), finally dissolved in 50 ml of deionized water and stirred at 200 rpm to obtain a 1:1:2 water-in-water double emulsion.
  • 500 ppm CuCl 2 (99%, Aldrich) and 100 ppm vitamin C (99%, Aldrich) were added.
  • Example 4 Characteristics of an antimicrobial, water-in-oil-in-water double emulsion
  • the water-in-oil double-layer emulsion of the present invention may be a white opaque body to a transparent body and is stable in long-term storage (see Fig. la);
  • Figure lb is a photograph of the polymer encapsulated chlorine dioxide of the present invention. Microemulsion particles measuring about 10-20 microns in diameter were observed under a microscope, and the blurring of smaller micron-sized oil-in-water emulsions was observed in the particles;
  • the storage amount of chlorine dioxide is determined by iodometric titration using 0.1 M sodium thiosulfate (Na 2 S 2 O 3 , RDH) and a starch indicator (starch indicator);
  • the water-in-oil double-layer emulsion forming the coating is transparent, and as shown in Figure 2a, it forms a smooth-touch coating on the surface of the article. Colloidal syneresis problems common in colloids and hydrogels are not observed here.
  • the coating of the oil-in-water double-layer emulsion was irradiated with an optical microscope (Olympus BH2-MJLT) and a JEOL 6300 scanning electron microscope (accelerated at 10-15 kV) Press down) to observe.
  • Figure 2b shows the surface observed with an optical microscope at 100X magnification, the coating being very uniform and similar to deposited microcapsules. Further observation by a scanning electron microscope at a higher resolution revealed a spherical shape of the particles (Fig. 2c) containing smaller particles of 0.5-1 micron (Fig. 2d).
  • composition B containing zinc chloride salts
  • FIG. 3 is a schematic diagram illustrating the detailed coating structure.
  • the transition zinc chloride salt added to the composition forms a zinc-containing nanorod in situ with chlorine dioxide and is embedded in the outermost surface of the particle. Additional transition metal salts including zinc, copper and silver greatly increase the effectiveness of the antibacterial (eg, an increase of 10-100 times).
  • the surface of the coating was wiped 30 times with a clean cotton cloth applied to the surface for 20 Newtons to simulate the lossy condition. As shown in Table 1, after a severe wiping, the coating remained intact and could be wiped off with an aqueous detergent solution. Table 1
  • the chlorine dioxide release of the surface coating is measured at 25 ° C and 35 ° (:, relative humidity of 60-80%, the chlorine dioxide content is measured at different time points.
  • the coated sample was dissolved in 20 ml of deionized distilled water by ultrasonic vibration. Add excess potassium iodide (KI, BDH), and titrated by iodine in an acidic solution. Free iodide (1 2 ) 0.1 M sodium thiosulfate was titrated with a starch indicator.
  • Figure 4a shows the chlorine dioxide content remaining in the coating at 25 ° C for a period of continuous volatilization. About 15,000 micrograms of chlorine dioxide per day is released from each gram of coating material at 25 ° C and 60-80% relative humidity. At 35 ° C, the rate of diffusion of chlorine dioxide is 11 mg / g / day.
  • the release of chlorine dioxide from the surface coating in the ventilated layer flow ventilator is measured, and the ambient conditions are, for example, a temperature of 20-26 ° C and a relative humidity of 60-90%.
  • the coating samples were removed at regular intervals and the coating was dissolved by ultrasonic vibration in 20 mL of deionized distilled water.
  • An excess of potassium iodide (KI, BDH) was added and the quantitative titration of iodine was carried out in an acidic solution.
  • Figure 4b shows the chlorine dioxide content remaining in the coating at 25 ° C for 28 days. About 1300 micrograms of chlorine dioxide per day is released from each gram of coating material at 25 ° C and 60-80% relative humidity.
  • the chlorine dioxide release of the surface coating is measured at 25 ° C, 30 ° C and 35 ° (:, relative humidity of 60-80%, the chlorine dioxide content is measured at different time points.
  • the coating sample was removed at regular intervals and the coating was dissolved by ultrasonic vibration in 20 ml of deionized distilled water. Excess potassium iodide (KI, BDH) was added and the iodine quantitative titration was carried out in an acidic solution. The iodide was titrated with 0.1 M sodium thiosulfate in combination with a starch indicator.
  • Figure 5 shows the average release of chlorine dioxide at 25 ° C, 30 ° C and 35 ° C.
  • the increase in temperature increases the rate of diffusion, and at the interface of the oil-in-water emulsion, the P123 film becomes unstable and fuses with the coated F123 film, causing a combined effect that the antimicrobial agent is quickly released.
  • the antimicrobial efficacy of Composition A against S. aureus cells was investigated by chlorine dioxide gas released from the glass coating.
  • the sterilized agarose plate (TSA plate) was inoculated on average by a loop (about 100 ⁇ l) of the imre inoculum cultured in broth (ca. 10 6 /cm 3 ).
  • the coated 1 mg/cm 2 coated chlorine dioxide glass was fixed to a distance of 0.6, 3 and 10 mm from the surface of the agarose plate by a sterilized U-shaped fixed thickness paper mold.
  • the agarose plate was cultured in inverted at 37 ⁇ 0.1 ° C for one night, and the acacia gum under the coated glass was used to detect the growth of the bacteria.
  • the coating of the polymer A coated with chlorine dioxide provides the function of "contact killing" Effective.
  • the observed bacterial activity was consistent with the mass measurement data.
  • a concentration of about 80 ppm chlorine dioxide gas near the coating was observed in this test, which is sufficient to prevent bacteria from growing on the vegetable gum located 0.6 mm outside the glass coating. No growth of bacteria was observed in the vegetable gum placed 3 mm from the surface of the glass coating. However, at a distance of 10 mm, no antibacterial activity was observed due to a decrease in the concentration of chlorine dioxide.
  • Preparation of sterilized neutralizing solution 1% (v/v) 0.1 M sodium thiosulfate is added to 600 ml of 0.85% (w/v) sodium chloride solution (containing 0 ⁇ 1% ( ⁇ / ⁇ ) of Tween 80), followed by autoclaving at 121 °C for 20 minutes. Take 100 ⁇ l of the solution from the neutralized culture tube and apply agarose plate, 37 ⁇ 0. 1 °C After 24 hours of culture, the number of colonies on the agar plates was counted. After the samples were taken out, they were dripped and transferred to a second culture tube containing 20 ml of sterile broth no. 2 (Oxoid) for 10 minutes. 100 ⁇ l of the solution was taken out from the culture tube, and the number of colonies on the agar plate was calculated after culturing for 24 hours at 37 ° C.
  • Table 2 provides the survival of the glass coating (1 mg/cm 2 ) after exposure to bacteria for 1 or 7 days, respectively, for 10 and 30 minutes.
  • the tested bacteria were two Gram-positive bacteria (Bacillus subtilis ( A subtilis), Staphylococcus aureus and two Gram-negative bacteria (E. coli, P aeruginosa)) Table 2 Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa in contact coating The number of kills after the layer (unit: log)
  • Figure 6 shows (a) Bacillus subtilis and (b) E. coli, Pseudomonas aeruginosa and Staphylococcus aureus log reduction (log reduction), and (c) with coating 1 mg after contact at fixed time. /cm 2 polymer coated chlorine dioxide after contact with the glass coating for 10, 30 and 60 minutes, (1) Staphylococcus aureus; (2) Staphylococcus epidermidis; (3) Escherichia coli and (4) green The amount of survival of Pseudomonas. The percentage reduction is provided at each contact time point in the figure. Each data is the average of five replicates of five samples.
  • the antimicrobial, water-in-oil-in-water double emulsion composition B contains 30 ppm zinc chloride salt which is used to test the bactericidal ability against Gram-positive and Gram-negative bacteria.
  • Composition B for different time periods of Gram-negative and positive bacteria in a sterilized biosafety cabinet (NuAire, Nu-425-400E) with 100 ⁇ l of 10 7 /cm 3 bacterial suspension droplets Coating surface (23 ⁇ 2 ° C, relative humidity 70%). 5 samples were taken at each action time point and the test was repeated 3 times. The action time is 1, 5, 10 and 30 minutes respectively. The treated sample was transferred to a culture tube, and 20 ml of the neutralizing solution was added for 30 minutes to stabilize and restore the surviving bacteria.
  • Figure 7 shows the application of an antimicrobial, water-in-oil double-layer emulsified composition B (coating) containing 30 ppm of zinc chloride salt, chlorine dioxide (solution) and coated water (pseudogroup) with contact for 10 minutes. After the surface of the coating, the log reduction of the surviving Gram-positive and Gram-negative bacteria (log reduction) 0
  • the composition B coating containing 30 ppm of zinc chloride salt can be contacted with the bacteria for 10 minutes. Provides greater than 99% reduction in viable bacteria.
  • the icon also clearly shows that uncoated chlorine dioxide is not active after volatilization, and only polymer surfactants do not provide high antimicrobial efficacy.
  • Figure 8 shows the number of bacteria surviving after exposure to the glass surface coating of Composition B containing 1 mg/cm 2 of 30 ppm zinc chloride salt for 1, 5, 10 and 30 minutes. The results showed that after exposure for 10 minutes or less, the coating had excellent bactericidal effect and a five-log reduction in viable cells (for example: 99.999% sterilization).
  • compositions A and B for different durations of action of Gram-negative and positive bacteria
  • the antimicrobial properties of the glass plates were tested at different time points after application of the antimicrobial compositions A and B.
  • a sterilized biosafety cabinet (NuAire, Nu-425-400E)
  • 5 samples were taken at each action time point and the test was repeated 3 times.
  • the action time is 30 minutes.
  • the treated sample was transferred to a culture tube, and 20 ml of the neutralizing solution was added for 30 minutes to stabilize and restore the surviving bacteria.
  • Figure 9 is a comparison of the antibacterial ability of glass plates coated with multi-effect antimicrobial compositions A and B after 28 days.
  • the icon shows the log reduction in Staphylococcus aureus (Figure 9a) and E. coli ( Figure 9b) that survived 30 minutes after exposure to the coated glass plate. After more than 28 days, the glass plate coated with the antimicrobial composition B maintained a five-log reduction in the number of viable bacteria and provided an effective long-term bactericidal effect.
  • Example 8 Kirby-Bauer disk-diffusion test of Staphylococcus aureus
  • the standard Kirby-Bauer disc diffusion method was tested using Staphylococcus aureus.
  • the sterilized agarose plate was inoculated on average by a loop (about 100 ⁇ l) of aureus inoculum cultured in broth (ca. 10 6 /cm 3 ).
  • the sterilized filter paper was coated with 100 microliters of sterile deionized water, 70% ethanol and antimicrobial composition B. After drying, the filter paper was placed on an agarose plate and cultured upside down overnight at a temperature of 37 ⁇ 0.1 °C:. A filter paper that was not dried and coated with 100 microliters of 70% ethanol was used as a positive control group.
  • Kirby-Bauer disc diffusion method is a standard anti-microbial susceptibility test method that uses drugs on filter paper to spread onto the medium and identify areas where bacteria do not grow (called zone of inhibition). The susceptibility of a particular bacterium to a drug.
  • the antimicrobial composition B is coated and the dried filter paper has the largest inhibition ring, the next is the filter paper coated with 70% ethanol, while at the same time the filter paper coated with 70% ethanol (dry) and sterilized water (dry) A ring of inhibition was observed.
  • Example 9 Composition with Zinc Chloride Release of Chlorine Dioxide and Antimicrobial Capacity of Surface Coating of B
  • Figure 10 shows that the amount of chlorine dioxide persisted in the coating for 28 days at 25 °C. About 1600 micrograms of gaseous chlorine dioxide is released per gram of coating surface per day.
  • the glass plate was coated with the antimicrobial composition B, its antibacterial ability was examined at different action times.
  • a sterilized biosafety cabinet (NuAire, Nu-425-400E)
  • use 100 ⁇ l of 10 7 /cm 3 bacterial suspension droplets on the surface of the coating 23 ⁇ 2 ° C, 70% relative humidity.
  • 5 samples were taken at each action time point and the test was repeated 3 times.
  • the action time is 10 minutes.
  • the treated sample was transferred to a culture tube, and 20 ml of the neutralizing solution was added for 30 minutes to stabilize and restore the surviving bacteria.
  • the glass coated with the antimicrobial composition B containing zinc chloride provided antibacterial efficacy for 28 days.
  • the icon shows the log reduction in S. aureus after 10 minutes of contact with the coated glass. After more than 28 days, the number of viable bacteria in the glass plate coated with the antimicrobial composition B maintained a 4-5 log reduction, and provided an effective long-term bactericidal effect.
  • Example 10 Antimicrobial Composition B Additional Transitional Zinc Chloride Improves Bactericidal Ability The glass plate was coated with the antimicrobial composition B and tested for antimicrobial activity at different time points.
  • the transitional zinc chloride added to the antimicrobial composition B substantially increased the bactericidal ability of the coating. After contact with the coated glass surface for 10 minutes, it observed antimicrobial composition containing 30 ppm of zinc chloride reduced the number of viable bacteria 105.
  • Example 11 Antimicrobial efficacy of Composition B containing transition zinc, copper and silver salts
  • Antimicrobial water-in-water double emulsion composition B containing 30 ppm copper chloride and 30 ppm silver nitrate was according to Example 2 Prepared by the preparation method.
  • This experiment shows that after contact with the glass surface of the antimicrobial composition B containing 30 ppm of copper chloride for 10 minutes, it can reduce 10 7 E. coli (99%) and 10 7 Bacillus subtilis (greater than 99.999%) and after the antimicrobial composition containing the coated surface of the glass B 30 ppm of silver nitrate into contact for 10 minutes to reduce subtilis 107 107 E. coli and Bacillus (greater than 99.999%).
  • MDA malondialdehyde
  • lipid peroxidation occurs in the cell membrane, which is an indicator of the oxidative stress of the cell membrane caused by chlorine dioxide, which causes damage to the cell membrane.
  • Malondialdehyde is tested by the thiobarbital kit test (Esterbauer, H. & Cheeseman, ⁇ . ⁇ ; Methods Enzymol. 1990, 186, 407-421).
  • Observation of bacterial cell membrane damage by atomic force microscopy 100 microliters of antimicrobial water-in-water double emulsion composition B containing 30 ppm zinc chloride was applied to 1 square inch of clean and sterilized Silicon wafer. 100 microliters of 10 cm 3 E. coli was coated on the coated chip and observed by atomic force microscopy (Nanoscope ⁇ ) in a trapping mode.
  • Example 13 Anti-adhesion efficacy of an antimicrobial water-in-oil-in-water double emulsion
  • This test is to identify E. coli K12 (Carolina 15-5065A) and Staphylococcus aureus adhered to clean glass or coated with an antimicrobial water-in-oil emulsified composition A (0 ppm zinc chloride, eg pseudo-group)
  • the situation of the glass 200 ml of 10 8 /cm 3 suspension was uniformly applied to the surface of the coated or uncoated glass, and cultured at 37 ° C for 4 hours without shaking. Gently wash away the unadsorbed bacteria with sterile water. After Gram staining, the bacteria were observed under a microscope (magnification 1000 times) and the bacteria were separately adhered to clean glass or coated glass.
  • the amount of Staphylococcus aureus adhered to the coated glass was significantly less than that of the uncoated glass.
  • the results of the pseudo-group coating showed that the polymer used for coating enhanced the resistance to adhesion.
  • Example 14 Spore killing of antimicrobial water-in-water double-layer emulsified compositions A and C Efficacy
  • Bacillus subtilis (Carolina 15-4921A) was cultured on an agarose plate for 3 days to obtain a large amount of spores (37:). Pick up 1-2 colonies into a centrifuge tube containing 5 ml of sterile water, mix the sterile water containing the colonies, and mix the bacteria and spores evenly. Take 2 ml of the bacterial suspension into another centrifuge tube and obtain pure spores by centrifugation and washing. The centrifugation conditions were ⁇ ⁇ g, 20 minutes (4 ° C). After centrifugation, the supernatant was removed, and 1 ml of sterile water (4 ° C) was added to resuspend the sample.
  • Sterilized biosafety cabinet (NuAire, Nu-425-400E), with 100 ⁇ l of 10 5 /cm 3 spore suspension droplets on coated or uncoated glass (23 ⁇ 2 ° C, relative Humidity 70%).
  • the action time was 0.5, 2, 8, 24, 48 and 72 hours, respectively, and five samples were taken at each time point.
  • the sample was transferred to a solution containing 20 ml of neutralizing solution and allowed to act for 30 minutes so that the spores that had not been killed could be resuscitated, and then the glass piece was transferred to 10 ml of broth medium for another 10 minutes.
  • the number of surviving spores was calculated by applying an agarose plate (overnight culture at 37 ° C).
  • Figure 15 shows the log reduction in the viability of the viable Bacillus subtilis cells after contact with the glass coated with the antimicrobial water-in-water-in-water double emulsion composition A.

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Description

形成多效抗微生物表面涂层的材料及其制备方法 技术领域 本发明系有关于一种提供多效的抗微生物剂材料。
说 背景技术
书
微生物在我们所处的环境中无处不在。 虽然它们的中很多并无有害作 用， 甚至有些对人体还是有益的。但是其中一些的微生物仍可以作为未知 图
的致病原， 并会引起人体过敏反应。 世界卫生组织报导， 传染病最广泛的 传播途径是人群接触带有病毒或者细菌的物体，而这些带菌物通常是由传 染病患者通过咳嗽， 打喷嚏或讲话留下的。 很多微生物， 如病毒， 可以在 沾粘附的物体表面存活数天的久， 其中流感病毒可以存活 24至 48小时， 而副流感病毒和 SARS 病毒则在多数情况下可以存活数小时或者数天的 久。 许多致病菌已知通过接触带菌物体的表面 （如污染物） 而传播。 当接 触到这些带菌物体的污染物， 致病菌将通过接触传播。 因此， 常规的清洁 和灭菌是阻止传染疾病连锁爆发的重要手段， 而在物体表面加上抗微生物 材料涂层则为阻止疾病传播提供了新的安全保护。 很多金属， 如银、 铜和黄铜都具有杀菌的功效， 其系通过与微生物接 触来杀死许多致病性微生物 (Fang, H.P., Pure & Appl Chem. 1997, 69, 2425-2429) 奈米银、光催化型的二氧化钛和表面抗菌物 (：例如:四级胺化合 物或鳞盐)是近年来发展的表面抗菌物质。 但是， 当这些抗菌物质的表面 被污染源所弄脏时， 它们的抗菌效应就会急速减小或消失。 因此， 需要经 常性的清洁其表面， 以保持其杀菌效用。
目前也发展出将抗生素、 抗微生物剂 (例如:酚类、 卤素)和金属 (：例如:银离 子)包裹在其它材料中， 让其杀菌物质缓释， 从而让该材料长期地具有这 种释放性的杀菌能力， 直到其内部物质释放完为止。 Cohen等 (Li, Z. e^/.， Langmuir 2006, 22, 9820-9823)是采取迭层 (layer-by-layer)自我组装的方式 (self-assembly method)制成双层杀菌材料， 其系将银包裹在材料里面， 强 碱性季胺离子在其表面， 使其具有 「释放型杀灭 (release-killing)」 和 「接 触性杀灭 (contact-killing)」。 Ho等 (Ho， C. H. et al.， Adv. Mater. 2004, 16, 957-961) 则利用多聚物膜来包裹奈米银离子来达到释放型和接触型两种 杀菌方式， 同时材料使用聚乙二醇防止细菌吸附在其表面。 然而， 致病菌 (例如：微生物)、灰尘及 /或污染物于表面的沾附会影响其释放及接触型杀菌 效果， 这对于抗微生物剂涂层来说是个问题。 因此， 针对一种形成多效抗 微生物表面涂层的材料仍有需求。 发明内容 本发明针对目前发展抗微生物表面涂层所遇到的问题， 提供了一种解 决方法。
本发明的一个态样是提供一种形成多效抗微生物表面涂层的材料，其 中包括一种或多种易挥发或气态的抗微生物剂， 一种或多种不具挥发性的 抗微生物剂， 以及一种或多种聚合物， 其中该易挥发或气态的抗微生物剂 系包裹于该聚合物中， 以得到缓慢释放的效果。
本发明的另一个态样是提供一种形成多效抗微生物表面涂层的材料 的制备方法，其中该方法包括:包覆一种或多种易挥发或气态的抗微生物剂 于一种或多种聚合物的中， 使得该易挥发或气态的抗微生物剂能缓慢释 放， 以及与一种或多种不具挥发性的抗微生物剂混合。
本发明的另一个态样是提供将物品或装置灭菌的方法，其中该方法包 括:提供一种形成多效抗微生物表面涂层的材料，其中包括一种或多种易挥 发或气态的抗微生物剂， 一种或多种不具挥发性的抗微生物剂， 以及一种 或多种聚合物， 其中该易挥发或气态的抗微生物剂系包裹于该聚合物中， 以得到缓慢释放的效果;以及将该材料涂在该物品或该装置表面以形成一 抗微生物表面涂层，该涂层具有释放性杀灭、接触性杀灭及抗沾附的效果。
本发明的其它特色和优点将在下列说明中分别提出， 且可从说明中分 别显见， 或可通过本发明的实施而得知， 而通过所述的要素和组合将能了 解并达成本发明的特色和优点。
应了解前述的发明内容和下列实施方式仅为示例和解释， 并非为本发 明的限制。 附图说明 前文所述以及实施方式可通过附图达到更好的说明效果。为了加强本 发明的说明， 将适当的实施例的附图列举于此。 要注意的是， 本发明并不 受限于列举于此的说明。
图 1 是一相片显示 (a) 聚合物包裹二氧化氯的水包油包水乳化物储存 一个月后的状态， 以及 (b)光学显微镜照片， 以及 (c)制备的抗微生物水包油 包水乳化组合物 B (C102 + ZnCl2)、 无锌的组合物 A (包裹)以及纯的、 无包 覆二氧化氯溶液 (cio2)的紫外线分析图。
图 2是显示 (a)有 (：左边)或无 (右边)聚合物的包裹二氧化氯涂层的玻璃 玻片的照片， （b)光学及 (c)和 (d)扫瞄式电子显微镜照片， 其中具有涂层的 玻璃显示出均匀的表面涂层 (b)， 具有微颗粒的球状型态 (图 2c)， 其中包含 更小的 0.5- 1微米的颗粒 (图 2d)。
图 3 是一示意图显示以高分辨率的穿透式电子显微镜观察组合物 B 的包覆表面的情况， 其插图显示含锌棒状奈米结构 (约 20 nm X 1000 nm) 自聚合物包覆的表面突出。
图 4是一图表显示 (a)分别在 25 °C (〇)和 35 °C (口)的情况下， 涂层表 面二氧化氯 7天内的释放情况 (相对湿度为 60-80 %) (b) 28天内释放的情况 (温度保持在 20-26°C， 相对湿度为 60-90 %)。
图 5是显示二氧化氯气体在 7天内自玻璃上的涂层平均释放的量。 图 6系显示存活的 (a)枯草芽孢杆菌及 (b)大肠杆菌、 绿脓杆菌及金黄 葡萄球菌的对数降低量 (log reduction) , 以及 (c)与具有 1 mg/cm2聚合物包 裹二氧化氯的玻璃涂层接触 10、 30及 60分钟后， （1 )金黄葡萄球菌；（2)表 皮葡萄球菌 OS. epidermidis); (3)大肠杆菌及 (4)绿脓杆菌的存活量。
图 7系显示在接触 10分钟涂覆含有 30 ppm氯化锌盐的抗微生物的水 包油包水双层乳化组合物 B (涂层)， 二氧化氯 (溶液)及包覆水 (伪组)的表面 涂层后， 存活的革兰氏阳性及革兰氏阴性细菌的对数降低量 (log reduction)
图 8 系显示 (a)枯草芽孢杆菌 (b)金黄葡萄球菌及 (c)大肠杆菌 与 1 mg/cm2多效抗微生物涂层的玻璃表面接触 1、 5、 10及 30分钟后存活的细 菌数。 误差值代表 5个样本的标准差值。 图 9系显示 (a)金黄葡萄球菌及 (b)大肠杆菌分别与 1 mg/cm2抗微生物 组合物 A (填满符号)涂层， 及含有 30 ppm氯化锌的组合物 B (空心符号)涂 层接触 30分钟 (中性 pH)， 在不同天数后死亡的细菌数。 每个数据系得自 至少五个样本， 且部分数据系重复试验超过一次。
图 10系显示持续监测自包覆二氧化氯含锌的抗微生物涂层二氧化氯 的释放含量， 并在室温下超过三十天后测试， 金黄葡萄球菌与该涂层接触 10分钟后， 仍可维持降低大于 99.9%的存活金黄葡萄球菌的数目。
图 11系显示在与 1 mg/cm2含有 0、 10及 30 ppm氯化锌的抗微生物 组合物 B涂层接触 1、 5、 10及 30分钟后金黄葡萄球菌存活的数量。误差 值代表 5个样本的标准差值。
图 12系显示经与抗微生物组合物 A 真满符号)及喷洒二氧化氯 (空心 符号)的玻璃涂层接触不同时间长度后， 存活的枯草芽孢杆菌产生的丙二 醛量。
图 13是放大 1000倍的光学照片， 显示附着于 (a)涂覆包裹灭菌水 (伪 组：)及 (b)无涂覆的玻璃的大肠杆菌。
图 14是放大 1000倍的光学照片， 显示附着于 (a)涂覆包裹灭菌水 (伪 组)及 (b)无涂覆的玻璃的金黄葡萄球菌。 图 15系显示接触涂覆有 1 mg/cm3抗微生物水包油包水双层乳化组合 物 A (填满符号)的玻璃， 与接触无涂层的玻璃 (空心符号)后枯草芽孢杆菌 孢子的降低数量。 具体实施方式 除非另外定义，本文中所用的所有技术及科学词汇具有所属技术领域 的技术人员所通常明了的相同意义。
在本文中， 冠词 "一"是指一个或一个以上 （亦即， 至少一个） 的该 冠词的文法客体。 举例而言， "一组件"意谓一个组件或一个以上的组件。
本发明系提供一种形成多效抗微生物表面涂层的材料，其中包括一种 或多种易挥发或气态的抗微生物剂， 一种或多种不具挥发性的抗微生物 剂， 以及一种或多种聚合物， 其中该易挥发或气态的抗微生物剂系包裹于 该聚合物中， 以得到缓慢释放的效果。
根据本发明， 易挥发或气态的抗微生物剂包括， 但不限于， 可溶性二 氧化氯， 可溶性氯气， 氯化混合物， 乙醇或酚类化合物及其固态或液态前 驱物， 或上述的组合。 根据本发明的一个实施例， 易挥发的抗微生物剂为 可溶性二氧化氯或其前驱物。 根据本发明的另一个实施例， 易挥发的抗微 生物剂为二氧化氯、 氯盐及氯气的组合。
根据本发明， 不具挥发性的抗微生物剂包括， 但不限于， 含金属抗微 生物剂， 三氯沙 (triclosan), 羧酸， 糖酸 (sugar acid)或上述的组合。 羧酸的 一个例示是柠檬酸， 及糖酸的一个例示是维生素 (：。 根据本发明的一个实 施例， 不具挥发性的抗微生物剂是含金属抗微生物剂。 根据本发明， 任一 个含金属抗微生物剂系选自由一或多个含第 VII， IB, IIB, IVA及 IVB族金 属及其相关盐类的抗微生物剂， 及其组合所组成的群。 根据本发明的一些 实施例， 含金属抗微生物剂包括含过渡金属的化合物或其相关盐类， 例如 含银， 铜， 或锌的化合物。
根据本发明， 术语 「聚合物」 在此意指 「聚合物」、 「共聚物」 或上述 的组合， 该聚合物系组成一乳化物包裹抗微生物剂， 因而使得抗微生物剂 能缓慢地、逐渐地及持续地释放至周围环境中。根据本发明的一个实施例， 该聚合物及 /或共聚物界面活性剂形成一双层的乳化物， 例如水包油包水
(W/0/W)双层乳化物， 其中包裹易挥发的抗微生物剂， 以提供抗微生物剂 的持续释放。 根据本发明， 任一聚合物系选自由一双性嵌段共聚物
(amphiphilic block copolymer)及其组合所组成的群。 根据本发明的一些实 施例， 该双性嵌段共聚物是一双性双嵌式或三嵌式共聚物， 例如 polyxamers (例如：市售 Pluronics®或 Tetronics®), 或其组合。
根据本发明， 由该材料所形成的涂层具有多效抗微生物的功能，包括 释放型杀灭、 接触性杀灭及抗沾附等， 其系通过以下方式达成：（1)缓慢释 放足量的挥发性抗微生物剂以杀死或抑制微生物生长；（2)当接触具传染性 的液滴时能加速抗微生物剂的释放；以及 (3)不具挥发性的抗微生物剂可在 涂层表面形成奈米结构， 以防止微生物的沾附及使微生物失去活性。
根据本发明一个具体的实施例，该形成抗微生物剂表面涂层的材料或 组合物包含一易挥发性的氧化的抗微生物剂及不具挥发性的抗微生物剂， 例如： 一个第 VII, IB, IIB, IVA及 IVB族金属的化合物， 以及一种或多种 聚合物以形成一水包油包水双层乳化物， 其系包裹上述两种抗微生物剂， 其中聚合物与易挥发性的氧化的抗微生物剂及不具挥发性的抗微生物剂 互相反应后形成含金属的奈米结构， 并存在于该水包油包水双层乳化物的 外层表面。
根据本发明，含金属的奈米结构确认为与氧化的抗微生物剂及含金属 的化合物 (例如金属盐类)的间的氧化还原反应有关， 根据个别的氧化还原 电位， 可形成金属或金属氧化的奈米结构。 聚合物的功能如同一般界面活 性剂， 以及控制奈米结构的成长， 以避免大物质的产生， 因此， 奈米结构 能在乳化物表面原位形成及储存。
根据本发明的一个实施例，该水包油包水双层乳化物包含一个第一水 层， 一油层， 以及一第二水层， 其系由聚合物以 1 :0.5-2:2-20的体积比所 形成。 根据本发明的一个实施例， 该第一水层包含约 10 ppm至约 70体积 百分比的易挥发性抗微生物剂，其含量取决于功效及使用的时间和使用超 过一种抗微生物剂等情况;该油层包含低挥发性的油类，其系与抗微生物剂 兼容且相互反应而变性， 且可能包含第二种抗微生物剂， 例如不具挥发性 的羧酸或糖酸， 以及一种香气以提供嗅觉线索和美感的目的； 以及该第二 水层， 其系由最外层聚合物包覆， 包含一种或多种不具挥发性的含金属的 抗微生物剂， 以提供接触性杀灭的功效， 其中该不具挥发性的抗微生物剂 包含的金属约相当于或少于 5000 ppm， 较佳为少于约 100 ppm。根据一个 实施例， 该第二水层所包含的不具挥发性的抗微生物剂为三氯沙， 约为总 材料重量的 3%。 第一水层， 油层及第二水层系由聚合物或聚合物界面活 性剂所区隔。 根据本发明， 最外层的聚合物区隔油层和第二水层， 同时亦 提供抗微生物沾附的功效，其中该聚合物或聚合物界面活性剂最低的浓度 系取决于它们主要的微胶粒 (micelle)浓度和界面活性剂的特性。
根据本发明的一个实施例，本发明的材料系涂覆在一物品上以形成一 表面涂层， 该涂层可提供多效， 包括 「释放性杀灭」 效果， 其中该易挥发 性的抗生物剂系由来自于在室温下由聚合物或聚合物界面活性剂所制备 的水包油包水乳化物中缓慢释放，以达到杀菌和抑制微生物生长； 以及「接 触性杀灭」 效果， 当表面涂层接触或遭具传染性的液滴污染时， 系通过增 加不具挥发性含金属的抗微生物剂的释放以达到该效果；以及「抗沾附」功 能， 其系通过含金属的抗微生物剂与最外层的聚合物交互作用后， 在表面 形成的含金属奈米结构以达成该功能。
本发明进一步地提供一种该形成多效抗微生物表面涂层的材料的制 备方法，其中该方法包括:包覆一种或多种易挥发或气态的抗微生物剂于一 种或多种聚合物的中， 使得该易挥发或气态的抗微生物剂能缓慢释放， 以 及与一种或多种不具挥发性的抗微生物剂混合。 根据本发明的一个实施 例， 该不具挥发性的抗微生物剂可与该易挥发或气态的抗微生物剂一起包 裹于该聚合物中。
此外， 本发明提供一种将物品或装置灭菌的方法， 其中该方法包括: 提供一种形成多效抗微生物表面涂层的材料，其中包括一种或多种易挥发 或气态的抗微生物剂， 一种或多种不具挥发性的抗微生物剂， 以及一种或 多种聚合物， 其中该易挥发或气态的抗微生物剂系包裹于该聚合物中， 以 得到缓慢释放的效果；以及将该材料涂在该物品或该装置表面以形成一抗 微生物表面涂层， 该涂层具有缓慢释放、 接触杀菌及抗沾附的效果。
本发明的各个具体实施例的细节说明如后，下述具体实施例仅用以说 明而非作为本发明的限制。
实施例 1 : 抗微生物的水包油包水双层乳化组合物 A的制备
二氧化氯的水溶液先以氢氯酸 (0.45 mol/L)活化，两者莫耳数比为 1 : 1。 将 25 毫升上述溶液悬浮于柠檬油 (10% (v/v)天然萃取的精油溶解于石蜡 溶剂， 其具有低蒸发率 0.1相对于 BuAc =l (注： 水为 0.3))中后， 加入 25 毫升 5% (w/v) Pluronic P123 (E02。P07QE02。， MW 5750 g/mol, HLB 值 (hydrophilic lipophilic balance)为 8， 购自 BASF, 德国)界面活性剂溶液， 并予以适当地搅拌 (例如： 400 rpm) o接着把生成的油包水乳化物加入到 2.5 克 Pluronic F127水溶液中 (EO,06PO70EO106， MW 12600 g/mol, HLB值为 22， 购自 BASF, 德国）， 最后溶于 50毫升去离子水， 以 200 rpm的速度 搅拌得到 1 : 1 :2的水包油包水双层乳化物。
实施例 2: 抗微生物的水包油包水双层乳化组合物 B的制备
二氧化氯的水溶液先以氢氯酸 (0.45 mol/L)活化，两者莫耳数比为 1 : 1。 将 25 毫升上述溶液悬浮于柠檬油 (10% (v/v)天然萃取的精油溶解于石蜡 溶剂， 其具有低蒸发率 0.1相对于 BuAc =l (注： 水为 0.3))中后， 加入 25 毫升 5% (w/v) Pluronic PI 23 (E02。P07。E02。， MW 5750 g/mol, HLB 值 (hydrophilic lipophilic balance)为 8， 购自 BASF, 德国)界面活性剂溶液， 并予以适当地搅拌 (例如： 400 rpm)。 接着把生成的油包水的乳化物加入到 2.5克 Pluronic F127水溶液中 (EO106PO70EO106, MW 12600 g/mol, HLB值 为 22， 购自 BASF, 德国）， 最后溶于 50毫升去离子水， 以 200 rpm的速 度搅拌得到 1 : 1 :2的水包油包水双层乳化物。 加入 0.25毫升 50 mM ZnCl2 (99%, Aldrich)于该最终乳化物中。在其它制备例中， CuCl2 (99%, Aldrich)、 AgN03 (99%， Aldrich)或金属盐类 (例如，合并 Zn2+, Cu2+及 Ag+)可用于取代 ZnCl2。
实施例 2: 抗微生物的水包油包水双层乳化组合物 C的制备
二氧化氯的水溶液先以氢氯酸 (0.45 mol/L)活化，两者莫耳数比为 1 : 1。 将 25 毫升上述溶液悬浮于柠檬油 (10% (v/v)天然萃取的精油溶解于石蜡 溶剂， 其具有低蒸发率 0.1相对于 BuAc =l (注： 水为 0.3))中后， 加入 25 毫升 5% (w/v) Pluronic P123 (EO20PO70EO20， MW 5750 g/mol, HLB 值 (hydrophilic lipophilic balance)为 8， 购自 BASF, 德国）界面活性剂溶液， 并予以适当地搅拌 (例如： 400 rpm)。接着把生成的油包水的乳化物加入到 2.5克 Pluronic F127水溶液中 (EOl06PO70EOl 06, MW 12600 g/mol, HLB值 为 22， 购自 BASF, 德国）， 最后溶于 50毫升去离子水， 以 200 rpm的速 度搅拌得到 1 : 1 :2的水包油包水双层乳化物。 加入 500 ppm CuCl2 (99%, Aldrich)以及 100 ppm 维生素 C (99%, Aldrich)。
实施例 4: 抗微生物的水包油包水双层乳化物的特性
(1) 本发明的水包油包水双层乳化物可为白色不透明体至透明体， 且 在长期保存中稳定 (请参图 la);
(2) 在光学显微镜下观察该水包油包水双层乳化物中聚合物包裹二 氧化氯的情形。 图 lb是本发明的聚合物包裹二氧化氯的照片。 在显微镜 下观察到直径测量约 10-20 微米的微小乳化物颗粒，且能够在颗粒中看见 更小微米尺寸的水包油乳化物的模糊痕迹；
(3) 二氧化氯的储存量系由碘定量滴定 (iodometric titration)测定， 其 系使用 0.1 M 硫代硫酸钠 （Na2S203, RDH)以及淀粉指示剂 （starch indicator);
(4) 二氧化氯的储存量亦由紫外光光谱仪 (Ultrospec 4300 pro)检验以 表现其它氧氯化物种类， 例如： 亚氯酸盐（chlorite)及氢溴化物 (hydrochlorite 图 lc是波长设定在 200至 600 nm的间， 分辨率为 0.5 nm 的图谱。 紫外光光谱仪可在 340 nm的波长下在双层乳化物中侦测到二氧 化氯。
以显微镜分析组合物 A
形成涂层的水包油包水双层乳化物为透明状， 且如图 2a所示， 其能 在物品表面形成触感平滑的涂层。在胶体及水凝胶中常见的胶体脱水收缩 问题在此并未观察到。 形成涂层的水包油包水双层乳化物以光学显微镜 (Olympus BH2-MJLT)及 JEOL 6300扫瞄式电子显微镜 (在 10-15 kV加速电 压下)观察。 图 2b显示在 100倍放大倍数下以光学显微镜观察的表面， 该 涂层非常均匀， 且类似沉积的微胶囊。 由扫瞄式电子显微镜在更高分辨率 下做进一步地观察， 显示出颗粒的球状型态 (图 2c)， 其中包含更小的 0.5-1 微米的颗粒 (图 2d)。
包含氯化锌盐类的组合物 B的断面图
含有 30 ppm 氯化锌盐的抗微生物水包油包水双层乳化组合物 B涂 覆在穿透式电子显微镜的格子 (grid)中。该涂层系由 JEOL JEM2010高分辨 率穿透式电子显微镜观察，加速电压为 200 kV，离子束电流为 100 pA.cm-2 0 图 3是一示意图说明详细的涂层结构。加入组合物中的过渡氯化锌盐 类， 如图 3的插图所示， 与二氧化氯在原位形成含锌的奈米棒并嵌于颗粒 的最外层表面。 附加的过渡金属盐类包括锌、 铜及银大幅增加抗菌的效用 (例如： 增加 10-100倍)。
擦拭试验
涂层表面以干净的棉布施予表面 20牛顿正向力擦拭 30次，以模拟耗 损的状况。 如表 1所示， 在经过剧烈的擦拭后， 涂层持续保持完整无缺的 状态， 但能以清洁剂水溶液擦拭掉。 表 1
玻璃 不锈钢
元素 无涂层 涂层 擦拭 元素 无涂层 涂层 擦拭
a a
Si(2p) 20.7 0.5 4.8 Fe(2p) 24.6 1.2 0.6
Al(2p) 0.6 0.0 0.0 Cr(2p) 6.6 0.7 0.7 Mg(ls) 5.1 0.0 0.0 Ni(LMM) 1.9 0.0 0.0
O(ls) 54.0 29.0 39.6 O(ls) 47.2 34.6 34.6
Na(ls) 6.9 0.5 5.9 Na(ls) 0.0 10.5 9.2
C(ls) 12.7 69.5 48.6 C(ls) 19.4 49.2 54.3 a.以干净的棉布施予表面 20牛顿正向力重复擦拭 30次 实施例 5: 组合物 A表面涂层的二氧化氯释放情况
短期二氧化氯的释放
在温箱中， 表面涂层的二氧化氯释放情况系于 25°C及 35° (：、 相对湿 度 60-80%的条件下， 于不同时间点测量二氧化氯的含量。 在固定时间拿 出涂层样本， 在 20 毫升去离子蒸馏水中以超音波震荡溶解涂层。 加入过 量的碘化钾 (KI, BDH), 碘定量滴定测定进行于一酸性溶液中。 游离的碘 化物 (12)以 0.1 M硫代硫酸钠配合淀粉指示剂滴定。
图 4a标示在 25°C下、持续挥发 Ί天而残留于涂层中的二氧化氯含量。 在 25°C、 相对湿度 60-80%的环境下， 每日约有 15000 微克的二氧化氯自 每克的涂层材料中释放出来。在 35°C下，二氧化氯释放的扩散速率为 11 毫 克 /克 /日。
长期二氧化氯的释放
在不同作用时间点中，测量通风的层面流通气柜中二氧化氯自表面涂 层的释放情况，周围环境条件为，例如：温度为 20-26°C及相对湿度 60-90%。 在固定的时间间隔里移除涂层样本， 在 20 毫升去离子蒸馏水中以超音波 震荡溶解涂层。 加入过量的碘化钾 (KI, BDH), 碘定量滴定测定进行于一 酸性溶液中。 游离的碘化物 (12)以 0.1 M硫代硫酸钠配合淀粉指示剂滴定。 图 4b标示在 25°C下、 持续挥发 28天而残留于涂层中的二氧化氯含 量。 在 25°C、 相对湿度 60-80%的环境下， 每日约有 1300 微克的二氧化 氯自每克的涂层材料中释放出来。
在不同温度下二氧化氯的释放情况
在温箱中， 表面涂层的二氧化氯释放情况系于 25°C、 30°C及 35° (：、 相对湿度 60-80%的条件下， 于不同时间点测量二氧化氯的含量。 在固定 的时间间隔里移除涂层样本， 在 20 毫升去离子蒸馏水中以超音波震荡溶 解涂层。 加入过量的碘化钾 (KI, BDH), 碘定量滴定测定进行于一酸性溶 液中。 游离的碘化物 以 0.1 M硫代硫酸钠配合淀粉指示剂滴定。
图 5标示在 25°C、 30°C及 35°C下二氧化氯平均释放的量。 温度的提 升会增加扩散速率， 且接近人体温度时水包油乳化物的界面 P123膜会变 得不稳定而与包覆的 F123膜融合， 产生联合效应使得抗微生物剂快速被 释放。
实施例 6: 组合物 A表面涂层的抗菌功效
组合物 A针对金黄色葡萄球菌 (S. aureus cells)的抗菌功效
组合物 A针对金黄色葡萄球菌 OS. aureus cells)的抗菌功效， 系由自玻 璃涂层上释放的二氧化氯气体进行调查。 灭菌的琼脂糖平板 (TSA plate)平 均地接种一环 (约 100 微升)培养于肉汤 (ca. 106/cm3)的 imre 接种物。 通过灭菌的 U型固定厚度纸模， 将涂覆 l mg/cm2 经包覆二氧化氯的玻璃 固定于距离琼脂糖平板表面 0.6、 3及 10 毫米的位置。 琼脂糖平板倒置地 在 37±0.1°C中培养一个晚上，位于经涂覆玻璃下方的洋菜胶系用于检测细 菌的生长情形。
经聚合物包覆二氧化氯的组合物 A涂层提供了 「接触型杀灭」 的功 效。 观察到的细菌活性与质量量测数据一致。 在此试验中观察到在涂层附 近约 80 ppm二氧化氯气体浓度，即足以防止细菌在位于玻璃涂层 0.6毫米 外的洋菜胶上生长。置于距离玻璃涂层表面 3毫米的的洋菜胶亦未观察到 细菌的生长。 但是， 位于 10毫米的距离， 因二氧化氯浓度的下降而观察 不到抗菌的活性。
组合物 A针对革兰氏阴性及阳性细菌的抗菌功效 (1)
在灭菌的生物安全柜内 (NuAire, Nu-425-400E) , 用 100微升 107/cm3 细菌悬液滴在涂层表面 （23 ± 2° (：， 相对湿度 70 %)。 每个作用时间点 5个 样品， 重复试验 3次。 作用时间为分别为 5、 10、 20、 30和 60分钟。 将 作用后的样品转入培养管内， 加入 20毫升的中和液作用 30分钟， 使得还 存活的细菌得以稳定和恢复。 灭菌的中和液的配制： 1 % (v/v) 0.1 M硫代 硫酸钠加入 600毫升 0.85% (w/v) 的氯化钠溶液中 （含有 0· 1% (ν/ν) 的吐 温 80)， 接着 121 °C高温灭菌 20分钟。 从中和完毕的培养管中取出 100微 升溶液涂琼脂糖平板， 37±0. 1 °C下培养 24小时后计算琼脂板上的菌落数。 将样品取出后， 滴干并转入第二个装有 20 毫升无菌肉汤培养基 (Nutrient broth no. 2, Oxoid)培养管作用 10分钟。培养管中取出 100微升溶液涂平板， 37士 0.1 °C下培养 24小时后计算琼脂板上的菌落数。
表 2提供细菌分别接触放置 1天或者 7天的玻璃涂层 ( 1 mg/cm2), 作 用 10和 30分钟后的存活情况， 受试细菌为两种革兰氏阳性菌 (枯草芽孢 杆菌 (A subtilis) , 金黄葡萄球菌)及两种革兰氏阴性菌 (大肠杆菌 coli) , 绿脓杆菌 P aeruginosa)) 表 2 枯草芽孢杆菌、 金黄葡萄球菌、 大肠杆菌及绿脓杆菌在接触涂 层后被杀死的数目 (单位： log)
细菌品种 被杀死的细胞数目 （单位： log)
[死亡百分比]
第 0天 第 0天 第 7天
(t = 10 min) (t = 30 min) (t = 10 min)
B. subtili 0.66±0.07 2.70±0.85 0.60±0.13
[78.1 %] [98.8%] [74.2%]
E. coli 2.16±0.76 5.10±0.66 2.40±1 .76
[96.6%] [99.9%] [97.7%]
P. aeruginosa 0.61±0.17 2.00+0.30 0.83±0· 12
[73.6%] [99.2%] [84.6%]
S. aureus 0.46±0.03 0.80±0.20 --
[65.1 %] [83.1%] 组合物 Α针对革兰氏阴性及阳性细菌的抗菌功效 (2)
在灭菌的生物安全柜内 (NuAire, Nu-425-400E) , 用 100微升 107/cm3 细菌悬液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个 样品， 重复试验 3次。 作用时间为分别为 5、 10、 20、 30和 60分钟。 将 作用后的样品转入培养管内， 加入 20毫升的中和液作用 30分钟， 使得还 存活的细菌得以稳定和恢复。 灭菌的中和液的配制： 1 % (v/v) 0.1 M硫代 硫酸钠加入 600毫升 0.85% (w/v) 的氯化钠溶液中 （含有 0.1% (v/v) 的吐 温 80)， 接着 121 °C高温灭菌 20分钟。 从中和完毕的培养管中取出 100微 升溶液涂琼脂糖平板， 37±0.1 °C下培养 24小时后计算琼脂板上的菌落数。 将样品取出后， 滴干并转入第二个装有 20 毫升无菌肉汤培养基 (Nutrient broth no. 2, Oxoid)培养管作用 10分钟。培养管中取出 100微升溶液涂平板， 37±0.1°C下培养 24小时后计算琼脂板上的菌落数。
图 6显示在固定时间接触后存活的 (a)枯草芽孢杆菌及 (b)大肠杆菌、 绿脓杆菌及金黄葡萄球菌的对数降低量 (log reduction), 以及 (c)与具有涂覆 1 mg/cm2聚合物包裹二氧化氯的玻璃涂层接触 10、 30及 60分钟后， （1) 金黄葡萄球菌； （2)表皮葡萄球菌 O . epidermidis); (3)大肠杆菌及 (4)绿脓杆 菌的存活量。 在图中每个接触时间点提供减少百分比。 每个数据皆为五个 样本三重复的平均值。
实施例 7: 组合物 B涂层的抗微生物功效
抗微生物的水包油包水双层乳化组合物 B含有 30 ppm氯化锌盐， 其 系用来测试对于革兰氏阳性及革兰氏阴性细菌的杀菌能力。
组合物 B针对革兰氏阴性及阳性细菌的不同作用时间的抗菌能力 在灭菌的生物安全柜内 (NuAire, Nu-425-400E), 用 100微升 107/cm3 细菌悬液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个 样品， 重复试验 3次。 作用时间为分别为 1、 5、 10和 30分钟。 将作用后 的样品转入培养管内， 加入 20毫升的中和液作用 30分钟， 使得还存活的 细菌得以稳定和恢复。 灭菌的中和液的配制： 1% (v/v) 0.1 M硫代硫酸钠 加入 600毫升 0.85% (w/v) 的氯化钠溶液中（含有 0.1% (v/v) 的吐温 80)， 接着 121°C高温灭菌 20分钟。从中和完毕的培养管中取出 100微升溶液涂 琼脂糖平板， 37±0.1°C下培养 24 小时后计算琼脂板上的菌落数。 将样品 取出后，滴千并转入第二个装有 20毫升无菌肉汤培养基 (Nutrient broth no. 2, Oxoid)培养管作用 10分钟。培养管中取出 100微升溶液涂平板， 37±0.1°C 下培养 24小时后计算琼脂板上的菌落数。
图 7显示在接触 10分钟涂覆含有 30 ppm氯化锌盐的抗微生物的水包 油包水双层乳化组合物 B (涂层)， 二氧化氯 (溶液)及包覆水 (伪组)的涂层表 面后， 存活的革兰氏阳性及革兰氏阴性细菌的对数降低量 (log reduction) 0 含有 30 ppm氯化锌盐的组合物 B涂层在与细菌接触 10分钟后，可提供大 于 99%的存活细菌降低量。图标中亦清楚地显示无包覆的二氧化氯挥发后 不具活性， 而仅有聚合物界面活性剂亦无法提供高的抗微生物功效。
图 8标示在与涂覆 1 mg/cm2含有 30 ppm氯化锌盐的组合物 B的玻璃 表面涂层接触 1、 5、 10及 30分钟后存活的细菌数。 结果显示在接触 10 分钟或更短的时间后，涂层具有极佳的杀菌效果及存活细胞的 5对数降低 量 (例如： 99.999%的杀菌)。
组合物 A及 B针对革兰氏阴性及阳性细菌的不同作用时间的抗菌能 力
玻璃平板涂覆抗微生物组合物 A及 B后在不同作用时间检测其抗菌 能力。在灭菌的生物安全柜内 (NuAire, Nu-425-400E)， 用 100微升 107/cm3 细菌悬液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个 样品， 重复试验 3次。 作用时间为 30分钟。 将作用后的样品转入培养管 内， 加入 20毫升的中和液作用 30分钟， 使得还存活的细菌得以稳定和恢 复。灭菌的中和液的配制： 1% (v/v) 0.1 M硫代硫酸钠加入 600毫升 0.85% (w/v) 的氯化钠溶液中（含有 0.1% (v/v) 的吐温 80)，接着 121°C高温灭菌 20分钟。从中和完毕的培养管中取出 100微升溶液涂琼脂糖平板， 37±0.1 °C 下培养 24小时后计算琼脂板上的菌落数。 将样品取出后， 滴干并转入第 二个装有 20毫升无菌肉汤培养基 (Nutrient broth no. 2, Oxoid)培养管作用 10分钟。 培养管中取出 100微升溶液涂平板， 37±0.1 °C下培养 24小时后 计算琼脂板上的菌落数。
图 9是比较涂覆多效抗微生物组合物 A及 B的玻璃平板在 28天后的 抗菌能力。 图标中显示在接触该经涂覆的玻璃平板 30分钟后存活的金黄 葡萄球菌 (图 9a)及大肠杆菌 (图 9b)的对数降低量。超过 28天后，涂覆抗微 生物组合物 B的玻璃平板维持存活细菌数的 5对数降低量，且提供有效的 长期杀菌效果。
实施例 8: 金黄葡萄球菌的 Kirby-Bauer纸片扩散法 (disk-diffusion test)
标准 Kirby-Bauer纸片扩散法使用金黄葡萄球菌进行试验。 灭菌的琼 脂糖平板平均地接种一环（约 100 微升）培养于肉汤 (ca. 106/cm3)的 aureus接种物。 灭菌的滤纸涂覆 100微升灭菌去离子水， 70% 乙醇及抗 微生物组合物 B。 干燥后， 滤纸置于琼脂糖平板上并倒置培养隔夜， 温度 为 37±0.1 °C：。 未干燥且涂覆有 100 微升 70%乙醇的滤纸作为正控制组。
Kirby-Bauer纸片扩散法是一种标准的抗微生物感受性测试法， 其系 利用滤纸上的药物扩散至培养基上， 通过观察细菌不生长的区域 (称为抑 制环 (zone of inhibition))鉴定特定细菌对药物的感受性。涂覆抗微生物组合 物 B且干燥的滤纸有最大的抑制环， 次大的是涂覆 70% 乙醇的滤纸， 然 而同时在涂覆 70%乙醇 (干燥)及灭菌水 (干燥)的滤纸未观察到抑制环。
实施例 9:具有氯化锌的组合物 B表面涂层的二氧化氯释放情况及抗 微生物能力
自组合物 B中释放经包覆二氧化氯
在不同作用时间点中测量通风的层面流通气柜中二氧化氯自表面涂 层的释放情况，周围环境条件为，例如：温度为 20-26°C及相对湿度 60-90%。 在固定的时间间隔里移除涂层样本， 在 20 毫升去离子蒸馏水中以超音波 震荡溶解涂层。 加入过量的碘化钾 (KI, BDH), 碘定量滴定测定进行于一 酸性溶液中。 游离的碘化物 (12： (以 0.1 M硫代硫酸钠配合淀粉指示剂滴定。
图 10显示在 25°C下二氧化氯的量持续存在于涂层中 28天。 每日约 自每克的涂层表面释放 1600 微克气态的二氧化氯。
组合物 B的抗沾附功效
玻璃平板涂覆抗微生物组合物 B后在不同作用时间检测其抗菌能力。 在灭菌的生物安全柜内 (NuAire, Nu-425-400E)，用 100微升 107/cm3细菌悬 液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个样品， 重复试验 3次。 作用时间为 10分钟。 将作用后的样品转入培养管内， 加 入 20毫升的中和液作用 30分钟， 使得还存活的细菌得以稳定和恢复。 灭 菌的中和液的配制： 1% (v/v) 0.1 M硫代硫酸钠加入 600毫升 0.85% (w/v) 的氯化钠溶液中 （含有 0.1% (v/v) 的吐温 80)， 接着 121°C高温灭菌 20分 钟。 从中和完毕的培养管中取出 100微升溶液涂琼脂糖平板， 37±0.1 °C下 培养 24小时后计算琼脂板上的菌落数。 将样品取出后， 滴干并转入第二 个装有 20毫升无菌肉汤培养基 (Nutrient broth no. 2, Oxoid)培养管作用 10 分钟。 培养管中取出 100微升溶液涂平板， 37士 0.1°C下培养 24小时后计 算琼脂板上的菌落数。
如图 10所示， 涂覆含有氯化锌的抗微生物组合物 B的玻璃可提供抗 菌功效 28天。图标中显示与经涂覆玻璃接触 10分钟后金黄葡萄球菌的对 数降低量。 超过 28天后， 涂覆抗微生物组合物 B的玻璃平板的存活细菌 数维持 4-5对数降低量， 且提供有效的长期杀菌效果。 实施例 10: 抗微生物组合物 B附加的过渡氯化锌可增进杀菌能力 玻璃平板涂覆抗微生物组合物 B后在不同作用时间检测其抗菌能力。 在灭菌的生物安全柜内 (NuAire，Nu-425-400E)，用 100微升 107/cm3细菌悬 液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个样品， 重复试验 3次。 作用时间分别为 1、 5、 10、 20、 30及 60分钟。 将作用后 的样品转入培养管内， 加入 20毫升的中和液作用 30分钟， 使得还存活的 细菌得以稳定和恢复。 灭菌的中和液的配制： 1% (v/v) 0.1 M硫代硫酸钠 加入 600毫升 0.85% (w/v) 的氯化钠溶液中（含有 0.1% (v/v) 的吐温 80)， 接着 121°C高温灭菌 20分钟。从中和完毕的培养管中取出 100微升溶液涂 琼脂糖平板， 37±0.1°C下培养 24 小时后计算琼脂板上的菌落数。 将样品 取出后，滴干并转入第二个装有 20毫升无菌肉汤培养基 (Nutrient broth no. 2， Oxoid)培养管作用 10分钟。培养管中取出 100微升溶液涂平板， 37±0.1 °C 下培养 24小时后计算琼脂板上的菌落数。
如图 11所示， 附加于抗微生物组合物 B中的过渡氯化锌大幅增加涂 层的杀菌能力。 与该经涂覆的玻璃表面接触 10分钟后， 可观察到含有 30 ppm氯化锌的抗微生物组合物降低 105的存活细菌数。
实施例 11: 含过渡锌、 铜及银盐的组合物 B的抗微生物功效 含有 30 ppm氯化铜及 30 ppm硝酸银的抗微生物水包油包水双层乳 化组合物 B系根据实施例 2的制备方法而制备。
灭菌的生物安全柜内 (NuAire, Nu-425-400E), 用 100微升 108/cm3细 菌悬液滴在涂层表面 （23 ± 2°C , 相对湿度 70 %)。 每个作用时间点 5个样 品， 重复试验 3次。 作用时间为 10分钟。 将作用后的样品转入培养管内， 加入 20毫升的中和液作用 30分钟， 使得还存活的细菌得以稳定和恢复。 灭菌的中和液的配制： 1% (v/v) 0.1 M硫代硫酸钠加入 600毫升 0.85% (w/v) 的氯化钠溶液中 （含有 0.1% (v/v) 的吐温 80)， 接着 121 °C高温灭菌 20分 钟。 从中和完毕的培养管中取出 100微升溶液涂琼脂糖平板， 37士 0.1 °C下 培养 24小时后计算琼脂板上的菌落数。 将样品取出后， 滴干并转入第二 个装有 20毫升无菌肉汤培养基 (Nutrient broth no. 2， Oxoid)培养管作用 10 分钟。 培养管中取出 100微升溶液涂平板， 37±0.1 °C下培养 24小时后计 算琼脂板上的菌落数。
本实验显示与经涂覆含 30 ppm氯化铜的抗微生物组合物 B的玻璃表 面接触 10分钟后， 能降低 107大肠杆菌 (99% )及 107枯草芽孢杆菌 (大于 99.999%) 与经涂覆含 30 ppm硝酸银的抗微生物组合物 B的玻璃表面接 触 10分钟后，能降低 107大肠杆菌及 107的枯草芽孢杆菌 (大于 99.999%)。
实施例 12: 细胞膜损伤实验分析
丙二酸 (Malondialdehyde)试验
细胞膜发生脂质过氧化反应时会产生过量的丙二醛 (MDA)，是二氧化 氯造成细胞膜发生氧化压力从而造成细胞膜损伤的指标。丙二醛系由硫代 巴比妥试剂盒测试检测（Esterbauer, H. & Cheeseman, Κ. Η·; Methods Enzymol. 1990, 186, 407-421)。
100微升 107/cm3枯草芽孢杆菌滴到涂有抗微生物组合物 A的玻璃片 上作用 10分钟。 在加入 0.6 % 2-硫代巴比妥酸的前 (98 %, Sigma), 先加入 5%的三氯乙酸 (99.0 %, Sigma-Aldrich)与搜集至微量离心管内的菌液混合。 混合的溶液加热至 95°C反应 15分钟， 然后让其降到室温并离心 10分钟 (lOOO rpm, Eppendorf 5415C)。 在 534和 600 nm下， 用分光光度计检测上 清液的透光度 (ICN Biomedicals, 156812)。MDA浓度则由标准曲线中推算。 如图 12所示， MDA含量的增加和细菌的死亡有紧密的关系， 这说 明细胞膜损伤是涂层减活和杀死微生物的可能机制的一。
通过原子力显微镜 (Atomic Force Microscopy)观察细菌细胞膜的损伤 将 100微升含有 30 ppm氯化锌的抗微生物水包油包水双层乳化组合 物 B涂覆于 1 平方英吋的干净且灭菌的硅芯片 (silicon wafer)。 100微升 10 cm3大肠杆菌涂覆于形成涂层的芯片上， 并在设陷模态 (trapping mode) 下通过原子力显微镜 (Nanoscope ΙΠα)观察。
本实验中观察到， 当与干净且无菌的硅芯片上的健康大肠杆菌比较 时， 与涂覆抗微生物组合物 Β 的硅芯片接触的大肠杆菌及其细胞膜已受 损。 这进一步地证实抗微生物组合物会损伤细菌细胞。
实施例 13: 抗微生物水包油包水双层乳化物的抗沾附功效
本试验系以鉴定大肠杆菌 K12(Carolina 15-5065A)及金黄葡萄球菌沾 附于干净玻璃或涂覆有抗微生物水包油包水乳化组合物 A (0 ppm氯化锌， 例如： 伪组)的玻璃的情况。 200毫升 108/cm3的悬浮菌液均匀地涂在有涂 层或无涂层的玻璃表面， 并在 37°C不摇晃地培养 4小时。用无菌水轻轻冲 掉未吸附上的细菌。革兰氏染色后， 在显微镜下 (放大 1000倍)观察并将分 别沾附在干净玻璃或者具有涂层的玻璃上的细菌定量。
如图 13所示， 沾附于具有涂层的玻璃上的大肠杆菌的数量显著性地 少于无涂层的玻璃。 此一结果显示涂层能预防细菌的沾附。
如图 14所示， 沾附于具有涂层的玻璃上的金黄葡萄球菌的数量显著 性地少于无涂层的玻璃。伪组涂层的结果显示包覆所使用的聚合物能加强 抗沾附的能力。
实施例 14:抗微生物水包油包水双层乳化组合物 A及 C的孢子杀灭 功效
孢子的制备 (枯草芽抱杆菌)
枯草芽抱杆菌 (Carolina 15-4921A)在琼脂糖板上培养 3天， 从而得到 大量的孢子 （37 ：)。 挑取 1-2个菌落到含有 5毫升无菌水的离心管里， 将含有菌落的无菌水混匀， 使细菌和孢子混合均匀。 取 2毫升的细菌悬液 到另外一个离心管中， 通过离心和洗涤得到纯的孢子。 离心条件为 ΙΟΟΟ χ g, 20分钟（4°C )。 离心后移除上清液， 再加入 1毫升的无菌水（4°C )重 新悬浮样品。 取出一点悬液到显微镜下检验观察， 并继续离心和洗涤， 直 到在相差显微镜下观察到样品里的游离孢子达到 99%。将所得到的孢子转 入磷酸缓冲液中 （pH 7.4)， 在 4°C里保存 （不超过 7天）。 阶段性稀释孢 子悬液后分别涂琼脂糖板， 记录菌落数并计算相应孢子悬液浓度。
孢子的杀灭试验
灭菌的生物安全柜内 (NuAire, Nu-425-400E), 用 100微升 105/cm3孢 子悬液滴在具有涂层或无涂层的玻璃材料上 （23 ± 2°C , 相对湿度 70 %)。 作用时间分别为 0.5、 2、 8、 24、 48及 72小时， 每个时间点进行五个样本。 将样本转入含有 20毫升中和液并再与其作用 30分钟，使得尚未杀死的孢 子可以复苏， 然后将玻璃片转入 10毫升肉汤培养基中再作用 10分钟。 通 过涂琼脂糖板的方法来计算存活的孢子数量 (37°C下隔夜培养)。
图 15显示出在接触涂覆有抗微生物水包油包水双层乳化组合物 A的 玻璃后， 存活的枯草芽孢杆菌其具有生长力的细胞的对数降低量。
在接触 30分钟后， 涂覆抗微生物水包油包水双层乳化组合物 C的玻 璃呈现大于 90%的孢子降低量。其提高的功效来自于含金属奈米结构的形 成以及铜-维生素 C氧化二联反应造成孢子的损伤。 所属技术领域的技术人员将可明了，可对上述的具体实例进行变化而 不偏离其广泛的发明概念。 因此， 应明了本发明并不限于所揭示的特定具 体实例， 其欲涵括由权利要求所定义的本发明精神及范围中的修饰。 所属技术领域的技术人员应了解， 在不悖离其广泛的发明概念下， 上 述具体实例可做改变。 因此应了解， 本发明并不受限于本文中所揭示的特 定具体实例，但希望将上述这些修正涵盖在如权利要求定义的本发明的精 神和范畴内。

Claims

权 利 要 求 书
1. 一种形成多效抗微生物表面涂层的材料， 其系一种或多种易挥发 或气态的抗微生物剂， 一种或多种不具挥发性的抗微生物剂， 以及一种或 多种聚合物， 其中该易挥发或气态的抗微生物剂系包裹于该聚合物中， 以 得到缓慢释放的效果。
2. 如权利请求项 1所述的材料， 其中任一易挥发或气态的抗微生物 剂系选自由可溶性二氧化氯， 可溶性氯气， 氯化混合物， 乙醇或酚类化合 物及其固态或液态前驱物， 及上述的组合所组成的群。
3. 如权利请求项 1所述的材料， 其中该易挥发抗微生物剂为可溶性 二氧化氯及其前驱物。
4. 如权利请求项 1所述的材料， 其中该易挥发抗微生物剂为可溶性 二氧化氯、 可溶性亚氯酸盐及可溶性氯气的组合。
5. 如权利请求项 1所述的材料， 其中该不具挥发性的抗微生物剂系 自由含金属抗微生物剂， 三氯沙 (triclosan), 羧酸， 糖酸 (sugar acid)及上述 的组合所组成的群。
6. 如权利请求项 5所述的材料， 其中该羧酸为柠檬酸。
7. 如权利请求项 5所述的材料， 其中该糖酸为维生素 C。
8. 如权利请求项 1所述的材料， 其中该不具挥发性的抗微生物剂为 含金属抗微生物剂。
9. 如权利请求项 8所述的材料， 其中该任一含金属抗微生物剂系选 自由由一或多个含第 VII, IB, IIB, IVA及 IVB族金属及其相关盐类的抗微 生物剂， 及上述组合所组成的群。
10. 如权利请求项 9所述的材料，其中该含金属抗微生物剂为含过渡 金属化合物或其相关盐类。 .
11. 如权利请求项 10所述的材料， 其中该含金属抗微生物剂包括含 银、 铜或锌的化合物。
12. 如权利请求项 1 所述的材料， 其中该聚合物为一种或多种聚合 物， 一种或多种聚合物界面活性剂或其相关组合。
13. 如权利请求项 1所述的材料，其中该聚合物形成乳化物包裹该抗 微生物剂， 因而使得该抗微生物剂能缓慢地、 逐渐次地及持续地释放至周 围环境中。
14. 如权利请求项 13所述的材料，其中该聚合物形成一双层乳化物。
15. 如权利请求项 14所述的材料， 其中该聚合物形成一水包油包水 (w/o/vv)双层乳化物， 其中该乳化物包裹易挥发或气态的抗微生物剂， 以提 供抗微生物剂的持续释放。
16. 如权利请求项 1所述的材料，其中该任一聚合物系选自由双性嵌 段共聚物 (amphiphilic block copolymer)及其组合所组成的群。
17. 如权利请求项 16所述的材料， 其中该双性嵌段共聚物是双性双 嵌式或三嵌式共聚物。
18. 如权利请求项 17 所述的材料， 其中该双性嵌段共聚物为 Polyxamers或其组合。
19. 如权利请求项 1所述的材料，其中该材料形成的涂层表现出多种 抗菌功效， 包括释放型杀灭 (release-killing)、 接触性杀灭 (contact-killing)及 抗沾附 (anti-adhesion)等功效， 其系通过以下方式达成：（1 )缓慢释放足量的 挥发性抗微生物剂以杀死或抑制微生物生长；（2)当接触具传染性的液滴时 能加速抗微生物剂的释放;以及 (3)不具挥发性的抗微生物剂可在涂层表面 形成奈米结构， 以防止微生物的沾附和使微生物失去活性。
20. 一种制备一形成多效抗微生物表面涂层的材料的方法， 其中该方 法包括：包覆一种或多种易挥发或气态的抗微生物剂于一种或多种聚合物 的中， 使得该易挥发或气态的抗微生物剂能缓慢释放， 以及与一种或多种 不具挥发性的抗微生物剂混合。
21. 根据权利请求项 20所述的方法， 其中该不具挥发性的抗微生物 剂可与该易挥发或气态的抗微生物剂一起包裹于该聚合物中。
22. 一种提供物品或装置灭菌的方法， 其中该方法包括:提供一种形 成多效抗微生物表面涂层的材料，其中包括一种或多种易挥发或气态的抗 微生物剂，一种或多种不具挥发性的抗微生物剂，以及一种或多种聚合物， 其中该易挥发或气态的抗微生物剂系包裹于该聚合物中， 以得到缓慢释放 的效果；以及将该材料涂覆在该物品或该装置表面以形成一抗微生物表面 涂层， 该涂层具有释放性杀灭、 接触性杀灭及抗沾附的效果。
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