WO2014059738A1

WO2014059738A1 - Anti-microbial catheter and preparation method for same

Info

Publication number: WO2014059738A1
Application number: PCT/CN2012/087954
Authority: WO
Inventors: 蔡文胜; 吴晓迪
Original assignee: Cai Wensheng
Priority date: 2012-10-19
Filing date: 2012-12-30
Publication date: 2014-04-24
Also published as: CN102886077A; CN102886077B

Abstract

Disclosed are an anti-microbial catheter and preparation method for same. The anti-microbial catheter comprises a catheter and an anti-microbial layer coating the catheter surface. The anti-microbial layer is composed of a polymer and nanometal micro-particles having anti-microbial properties contained in said polymer. The preparation method comprises: preparing a nanometal solution; adding a polymer solution to the nanometal solution, and performing nanometal polymer coating modification or preparing a nanometal-polymer compound to obtain a solution of polymer-coated nanometal micro-particles; coating the catheter surface with said solution of polymer-coated nanometal micro-particles; cleaning and drying to finally obtain the anti-microbial catheter. The product and method provided in the invention are easy and inexpensive to develop, and produce stable and long-acting, and controllable anti-microbial effects.

Description

Antibacterial catheter and preparation method thereof

Technical field

The invention belongs to the field of medical instruments and preparation methods thereof.

Background technique

The catheter is mainly used for clinical stroke, fracture and severe patient retention. It is one of the most commonly used medical devices in hospitals. About 25% of inpatients use catheters during their stay. During use, urinary tract infections are often associated with catheters due to various factors. It has been reported that CAUTI accounts for 30% of all clinical bacterial infections. As the retention time increases, the catheter infection rate increases. During the use of the catheter, usually the bacterial infection rate after a simple catheterization is about 1 to 5 %, 25% of the catheter with a retention period of more than 7 days can cause bacterial infection, catheterization time is more than 14 days, urinary tract infection The incidence is between 90 and 100%, and CAUTI is the most common type of clinical bacterial infection.

In order to reduce and control the incidence of CAUTI, various management and technical strategies have been adopted in the clinic, including strict aseptic procedures, reduction of unnecessary catheter use, and use of catheters with antibacterial properties. Among them, anti-bacterial catheters are a more effective means than clinical use of antibiotics. According to clinical data (Franken et al., 2007), antibacterial catheters can reduce the incidence of blood infections by 15 times in central venous catheter use and reduce the incidence of bacterial infections in the urinary catheter by 3 times. Therefore, the development of a medical catheter with antibacterial function is of great significance in reducing the occurrence of CAUTI and reducing the cost of clinical treatment.

A wide variety of antimicrobial techniques are applied to medical catheters to develop antimicrobial medical catheters. Chinese Patent Publication No. CN2529660 describes the preparation of a dosing zone below the catheter balloon, which is used to add various antibiotics depending on the situation. Chinese invention patent application 200810200169. 6 Silver-based inorganic antibacterial agent using zirconium phosphate as a carrier is incorporated into a catheter material to prepare a sustained-release antibacterial medical catheter. Chinese invention patent application 200810203587. 0 discloses a preparation method of an organic/inorganic composite antibacterial catheter, which is mixed with a high-speed stirring of an inorganic antibacterial agent and a silicone emulsion, mixed into a raw material of a catheter, and coated on the surface after molding. Antibacterial coating of quaternary ammonium salts. Chinese invention patent application 200810200169. 6 discloses a silver-based inorganic antibacterial agent which is doped with zirconium phosphate as a carrier in a medical catheter material, which is characterized in that an antibacterial masterbatch is prepared by using a silver-based inorganic antibacterial agent and a small amount of medical catheter material, and then The antibacterial masterbatch and the remainder of the catheter material are extruded to prepare an antibacterial catheter.

In general, antibacterial medical catheters that have been introduced at home and abroad mainly have the following categories:

1 ; Direct incorporation of antibacterial agents: As shown in several patent applications in the above several aspects, silver-based antibacterial agents or other broad-spectrum antibiotics are incorporated into the catheter material. This method incorporates a large antibacterial dose and is costly, and the antibacterial agent incorporated only has an antibacterial effect on the surface which penetrates the surface, and the incorporated antibacterial material may affect other properties of the catheter.

2; surface coating antibacterial reagent: the surface of the catheter is coated with various antibiotics, the antibiotics coated on the surface of the catheter are generally used Compound antibiotics or broad-spectrum antibiotics, such as minocycline/rifampicin.

Nano-metals use nanotechnology to nano-metalize them to produce antibacterial effects. For example, nano-silver makes a qualitative leap in the bactericidal ability of silver, and only a very small amount of nano-silver can produce a strong bactericidal effect. The antibacterial effect of nano-silver, its bactericidal mechanism and catalyst reaction are similar, that is, when the nano-silver is close to viruses, fungi, bacteria or phage, it produces active silver cation (Ag+) substances and oxygen metabolism on the surface of bacteria. The enzyme (a SH) binds, destroys the activity of the bacterial cell synthetase, blocks the metabolism of the bacteria and causes it to suffocate and die.

Therefore, the sustained and slow release of metal cations in nano-metal particles is the root cause of their long-lasting sterilization and antibacterial effects. Ordinary nano metal particles are unstable, easy to aggregate, and more difficult to apply directly on the surface of various urinary catheters. Therefore, they are generally mixed in the urinary catheter material, as described in Chinese Patent No. 200510041228. This technique is costly, and a large amount of silver ions that are directly mixed may also affect other properties of the catheter material, while the antibacterial effect of the catheter is determined only by a small amount of nano-silver coating on the surface.

Another nano-silver coating method is to electroplate metal silver or vacuum silver plating on the metal or plastic surface through the surface of the catheter. The secondary coating method requires high equipment and increases the cost of the process.

Summary of the invention

SUMMARY OF THE INVENTION The object of the present invention is to provide an antibacterial catheter which is simple, low in cost, durable in antibacterial, effective in effect, and controllable in effect.

Another object of the present invention is to provide a method for preparing the above urinary catheter. The method is simple and easy, and the cost is low, and the antibacterial property of the final product is stable and effective, and the effect can be controlled.

The object of the present invention is achieved by the following technical solutions:

An antibacterial catheter, comprising a catheter, further comprising an antibacterial layer disposed on a surface of the catheter, the antibacterial layer being composed of polymer-coated nano metal particles aggregated, the nano metal being an antibacterial nanometer metal.

In the above solution, the polymer-coated nano metal particles can form a chemical bond or an ionic bond with the surface of the catheter through the surface active group of the polymer, so that the polymer-coated nano metal particles directly adhere to the surface of the medical catheter, and firmly adhere. , so that the nano metal particles are not easy to elute, achieving long-lasting, effective, and stable antibacterial effects. The antibacterial layer can control the amount, speed and duration of the slow release of metal cations by the nano metal particles through different polymers and coating thicknesses to achieve a sustained, stable and long-lasting antibacterial effect on the surface.

The nano metal having antibacterial property refers to metal particles having a particle diameter generally less than 100 nm, and has a killing effect on bacteria, viruses, yeasts, fungi, etc., and inhibits growth functions such as silver, copper, zinc or titanium, and most preferably silver. .

Preferably, the polymer is a functional group of fluorenyl silicon germanium (preferably one or more of an amine group, a carboxyl group, a hydroxyl group, a thiol group, a cyclopropenyl group or an aldehyde group functional group), There are ion-charged polymer electrolytes (preferably polyacrylic acid, polyallylamine salt), polyvinylpyrrolidone, polyethylene oxide or polyethylene glycol. Preferably, the polymer-coated nano-metal particles have a particle diameter of 2 to 150 nm, preferably 5 to 100 nm, more preferably 30 to 100 nm, and most preferably 30 to 50 nm.

A method for preparing the aforementioned antibacterial catheter comprises the following steps in sequence:

A, preparing a nano metal solution;

B. adding a polymer solution to the nano metal solution, modifying the nano metal polymer or preparing the nano metal-polymer composite to obtain a polymer-coated nano metal particle solution; as a preferred mode, the polymer encapsulates the nano metal The particle diameter of the fine particles is 2 to 150 nm, preferably 5 to 100 nm, more preferably 30 to 100 nm, and most preferably 30 to 50 nm.

C. The polymer-coated nano metal particle solution is attached to the surface of the catheter, and the antibacterial catheter is obtained by washing and drying. In the above scheme, the method of encapsulating the nano metal by the polymer increases the solution stability of the nano metal particles without aggregation. At the same time, the polymer encapsulates the nano-metal, so that the nano-metal is firmly bonded to the surface of the catheter through chemical bonds, so that the anti-bacterial catheter is resistant to rinsing and immersion, and the polymer coating also increases the time for the slow release of the nano-metal to maintain the long-term antibacterial effect of the surface. The nano-metal particles are slowly controlled to release the amount, speed and duration of the metal cations by different polymers and adjusting the polymer-coated nano-metal concentration or coating thickness to achieve a sustained, stable and long-lasting antibacterial effect on the surface.

Preferably, the nano metal is silver, and the step of adding a polymer solution to the nano silver solution to modify the nano silver polymer package comprises:

1-1. The weight of the solution is 100 parts by weight of 100-300 PPM of the nano-silver solution, 100 parts by weight of 100-1000 parts of ethanol (preferably 300 parts), stirred for 15 minutes, the pH of the solution is adjusted to alkaline, adding parts by weight 0. 1-1 Parts (preferably 1 part) tetraethylsilane and 3-aminopropyltriethoxysilane mixed in a weight ratio of 1:1, stirring is continued at room temperature, and the product is purified by centrifugation to obtain a silicone-coated surface aminated. Nano silver particles.

Preferably, the step of preparing the nano metal-polymer composite by adding the polymer solution to the nano silver solution is as follows:

An aqueous solution of PVP is added to the nanosilver solution to form a complex. Preferably, the PVP aqueous solution has a mass concentration of 1 to 10%, the nano silver solution concentration is 100-300 PPM, and the PVP aqueous solution and the nano silver solution are mixed at a weight ratio of 1:1 -1 :10.

Preferably, in the step C, the polymer-coated nano-metal particle solution is attached to the surface of the catheter by dipping or coating. Preferably, the soaking is a soaking in heat.

Preferably, before the step C, the catheter is pretreated, the pretreatment is to soak the catheter with a surface void enlargement agent, or the surface of the catheter is modified by a silicon germanium coupling reagent.

In the above solution, the urinary catheter is immersed by heating, the surface void enlargement agent is used, or the surface of the urinary catheter is modified by the silicon germanium coupling reagent, thereby further enhancing the bonding force between the antibacterial layer and the surface of the catheter, so that The combination is stronger. Advantageous Effects of Invention The antibacterial catheter provided by the present invention and the preparation method thereof are simple and easy to operate, and the cost is low. Adopt The method for preparing polymer-coated nano-silver overcomes the instability of ordinary nano-silver colloidal particles, is easy to aggregate, and is more difficult to be directly applied uniformly on the surface of various urinary catheters. After application, the antibacterial layer is easy to elute and is not resistant to soaking. Disadvantages; the polymer-coated nano-silver prepared by the invention can be directly and uniformly coated on the surface of the catheter (see FIG. 5), and the polymer coating layer delays the release rate of silver ions from the nano silver particles, and increases the surface antibacterial time. The polymer-coated nano-silver antibacterial catheter remained immersed in physiological saline for 15 days and remained antibacterial. It overcomes the common antibacterial agent directly doped in the catheter and has a large antibacterial dose and high cost, and the antibacterial agent incorporated only has an antibacterial effect on the surface penetrated into the surface, and the antibacterial material is incorporated at the same time. Defects that may affect other properties of the catheter. DRAWINGS

1 is a TEM image of a nano silver solution according to an embodiment of the present invention;

2 is a UV/VIS spectrum diagram of a nano silver solution according to an embodiment of the present invention;

Figure 3 is a TEM image of a nano silver solution of Example 2 of the present invention;

4 is a UV/VIS spectrum diagram of a nano silver solution of Example 2 of the present invention;

Figure 5 is a TEM image of a silicone-coated nanosilver solution of Example 3 of the present invention;

Figure 6 is an SEM image of an antibacterial catheter of Example 6 of the present invention;

Fig. 7 is a view showing the antibacterial effect of the antibacterial catheter of the tenth embodiment of the present invention. detailed description

The following non-limiting examples are illustrative of the invention.

One: Antibacterial catheter:

An antibacterial catheter, comprising a catheter, further comprising an antibacterial layer disposed on a surface of the catheter; the antibacterial layer is composed of polymer-coated nano metal particles, and the particle size of the polymer-coated nano metal particles is 2 to 150 nm. It is preferably 5 to 100 nm, more preferably 30 to 100 calendars, and most preferably 30 to 50 nm. The nanometal is a nanometal having antibacterial properties such as silver, copper, zinc or titanium, and most preferably silver. The polymer is a functional group of fluorenyl silicon germanium (preferably one or more of an amine group, a carboxyl group, a hydroxyl group, a thiol group, a cyclopropenyl group or an aldehyde group), and an ion-charged polymer electrolyte (preferably polyacrylic acid, polyallylamine salt), polyvinylpyrrolidone, polyethylene oxide or polyethylene glycol.

Two: Preparation of antibacterial catheter:

A, preparing a nano metal solution (the present invention does not limit how to prepare a nano metal solution, various preparation methods are available, and the following examples are merely examples);

B. adding a polymer solution in the nano metal solution, modifying the nano metal polymer or preparing the nano metal-polymer composite to obtain a polymer-coated nano metal particle solution; c. Attaching the polymer-coated nano metal particle solution to the surface of the catheter, and drying and drying to obtain an antibacterial catheter <Example 1:

Preparation of nano silver particles:

The benzoyl sulfonimide solution is prepared by using o-benzoyl sulfonimide as a stabilizer and tetramethylethylenediamine as a reducing agent. Add 10ml 0. 1~0. 5 mol/L AgN0 ₃ solution to mix well, add 2ml mass concentration of 1~10% TMEDA (tetramethylethylenediamine), and react for 1h with stirring. Thus, a nanosilver solution having a turbid yellow color was prepared. The supernatant was centrifuged to obtain a yellow-brown transparent nanosilver solution.

The particle diameter distribution and particle shape of the nanosilver solution were synthesized by TEM observation, and as a result, the nanosilver solution having an average particle diameter of less than 10 nm as shown in Fig. 1 was spherical in shape.

The nanosilver solution was determined by UV/VIS spectroscopy. As a result, as shown in Fig. 2, the absorption peak of the nanosilver solution was 418 nm. Example 2:

Synthesis of nanosilver by using NaBH ₄ as a reducing agent and stabilizer:

10 ml 0. l~2 m mol / L NaBH ₄ solution was added to the flask, and 10 ml of 0. l~ ₂ m mol/L AgN0 _{3 was added} thereto with stirring, and the reaction was further stirred for 20 min. Thus, a nanosilver solution having a yellow color was prepared.

The particle diameter distribution and particle shape of the nanosilver solution were synthesized by TEM observation. As a result, a nanosilver solution having a uniform particle size of 12 to 15 nm was obtained as shown in Fig. 3, and the shape was spherical particles.

The nanosilver solution was determined by UV/VIS spectroscopy. As a result, as shown in Fig. 4, the absorption peak of the nanosilver particles was 390 nm. Example 3:

Preparation of polymer modified nanosilver:

The nano silver prepared in the above Examples 1 and 2 can be modified by polymer encapsulation.

100 parts of the nano silver solution having a concentration of 100-300 ppm obtained by weight, 300 parts of ethanol was added, and stirred at 100 to 400 rpm for 15 minutes, and the pH of the solution was adjusted to be alkaline with ammonia water, and 1 part by weight was added: 1 mixed tetraethylsilane and 3-aminopropyltriethoxysilane, stirring at room temperature for 18 to 24 hours, and the product is purified by centrifugation at 2000~10000 rpm to obtain a silicone-coated surface aminated. The new nano-silver particles, as shown in Figure 5, have a UV absorption peak of 399 nm with a particle size of 100 nm. Example 4:

Preparation of nanosilver-polymer composites: Adding a polymer PVP (polyvinylpyrrolidone), PEG (polyethylene glycol) or PVA (polyvinyl alcohol) aqueous solution to a concentration of 100-300 PPM nano silver solution prepared in Example 1-2 to form a nanometer Silver-polymer composite. For preparing a mass percentage of 1~10% PVP aqueous solution, the PVP aqueous solution is mixed at a weight ratio of 1:1 -1 : 10 and the nano silver having a concentration of 100-300 PPM prepared in Example 2 is obtained to obtain a polymer-coated nano silver fine particle solution. Wherein the polymer-coated nanosilver particles have a particle size of 30 nm. Example 5:

Nanosilver-polymer composite coated catheter:

40 ml of the Example 4 nanosilver-polymer composite solution was added to a 35 cm long test tube, and the catheter was immersed therein for several hours, and the catheter was taken out and rinsed with water to dry. A catheter with a yellow-green coating is obtained. Example 6:

Coating the nanosilver by soaking:

The polymer-coated nanosilver microparticle solutions prepared in the above Examples 3 and 4 can be subjected to dip coating.

40 ml of the polymer-coated nanosilver microparticle solution prepared in Example 3 was placed in a test tube having a length of 35 cm, and the catheter was immersed therein for several hours, and the catheter was taken out and rinsed with water to dry. A catheter with a brown-yellow coating is obtained.

The SEM scan is shown in Figure 6. The white color in the figure is about 12~20nm. Example 7

Coating nanosilver by heat soaking:

40 ml of the polymer-coated nanosilver particle solution of Example 3 was placed in a test tube of 35 cm in length, and the catheter was immersed therein for several hours under heating, and the catheter was taken out and rinsed with water to dry. A catheter with a dark brown coating is obtained. Example 8

Increase the amount of nano-silver adsorption by temporarily increasing the void on the surface of the catheter:

The polymer-coated nanosilver microparticle solutions prepared in Examples 3 and 4 can be subjected to dip coating.

40 ml of the polymer-coated nano-silver particle solution of Example 3 was added to a test tube of 35 cm in length, and the catheter was soaked with a surface void enlargement agent (such as methanol), and then immersed in a nanosilver solution for several hours to take out the guide. Rinse the tube with water and dry it. A catheter with a dark brown coating is obtained. Example 9 Adding appropriate functional groups to the surface of the catheter through a silicon germanium coupling reagent increases the affinity of the catheter for nanosilver: with a certain concentration of r-aminopropyltrimethoxysilane (or maleic acid propyl triethoxylate) Silicon germanium, 3-thiopropyltriethoxysilane, 3-glycidoxypropyl-dimethylethoxysilane, etc.), soak the catheter under heating for several hours, take out the lead The urinary tube was rinsed and air-dried. 40 ml of the polymer-coated nano-silver particle solution prepared in Example 3, 4 was added to a test tube of 35 cm in length, and the catheter was immersed therein for several hours. The catheter was taken out and rinsed with water. . A catheter with a bright yellow coating is obtained. Experimental Example 10:

In vitro antibacterial performance test of polymer-coated nano-silver coated catheter:

The catheter was coated with the catheter of Example 6 and cut into 2 cm long sections. Escherichia col i ATCC 25922 strain was used for the antibacterial experiment. The size of the antibacterial ring region is measured (the shortest distance between the outermost edge of the material and the innermost edge of the bacterial growth).

The antibacterial area of E. coli is l ± 0. 2cm. As shown in Fig. 7, a large number of bacteria grow around the uncoated catheter on the right side, whereas the left side uses a nanosilver-coated catheter to form a distinct antibacterial area. It can be seen that the nano silver coated catheter has good antibacterial properties.

The 5 bis bacteriostatic zone is formed by the in vitro antibacterial property of the urinary tube. There are differences in the methods of different sizes of bacteriostatic areas. Experimental Example 11:

Antibacterial experiment on the surface of nano silver coated silica gel sheet:

A 5 _cm X 5 _Cm silica gel sheet conforming to the material of the catheter was coated with the nano silver of Example 2 in the same manner as in Example 6. Escherichia col i ATCC 25922 strain was used for the antibacterial experiment. According to the filming method in GB/T 21510-2008, the antibacterial rate is 100%. Experimental Example 12:

5cm。 The size of the antibacterial properties of the E. coli and the Staphylococcus aureus were respectively tested. The antibacterial ring shows that the catheter has a strong antibacterial effect on both bacteria. The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope.

Claims

WO 2014/059738 Claim PCT/CN2012/087954

An antibacterial catheter comprising a catheter, further comprising: an antibacterial layer disposed on a surface of the catheter, the antibacterial layer being composed of a polymer-coated nano metal particle aggregate, the nano metal It is a nano metal with antibacterial properties.

2. The antibacterial catheter according to claim 1, wherein: the polymer is a functional group of fluorenyl silicon germanium, an ion-charged polymer electrolyte, polyvinylpyrrolidone, polyethylene oxide垸 or polyethylene glycol.

The antibacterial catheter according to claim 1, wherein the polymer-coated nano metal particles have a particle diameter of 2 to 150 nm.

A method of producing an antibacterial catheter according to any one of claims 1 to 3, which comprises the steps of:

A, preparing a nano metal solution;

B. adding a polymer solution to the nano metal solution, modifying the nano metal polymer or preparing the nano metal-polymer composite to obtain a polymer-coated nano metal particle solution;

C, the polymer-coated nano metal particle solution is attached to the surface of the catheter, and the antibacterial catheter is obtained by washing and drying.

The method for preparing an antibacterial catheter according to claim 4, wherein: the nano metal is silver, and the step of adding a polymer solution to the nano silver solution to modify the nano silver polymer package comprises: :

1-1份重量比1 : The weight ratio of the solution is 100 parts by weight of 100-300 PPM, 100 parts by weight of 100-1000 parts of ethanol, and the mixture is stirred for 15 minutes, and the pH of the solution is adjusted to be alkaline. 1 mixed tetraethylsilane and 3-aminopropyltriethoxysilane, stirring was continued at room temperature, and the product was centrifugally purified to obtain a silicone-coated surface-aminated nanosilver particle.

The method for preparing an antibacterial catheter according to claim 4, wherein: the nano metal is silver, and the step of preparing a nano metal-polymer composite by adding a polymer solution to the nano silver solution comprises: :

An aqueous solution of PVP is added to the nanosilver solution to form a complex.

The method for preparing an antibacterial catheter according to claim 6, wherein: the PVP aqueous solution has a mass concentration of 1 to 10%, and the nano silver solution has a concentration of 100 to 300 PPM, and the weight ratio is 1: 1 _1: 10 ratio of PVP aqueous solution and nano silver solution.

The method of preparing an antibacterial catheter according to claim 4, wherein in the step C, the polymer-coated nano metal particle solution is attached to the surface of the catheter by dipping or coating.

9. The method of preparing an antibacterial catheter according to claim 8, wherein: the soaking is a heating soak.

The method for preparing an antibacterial catheter according to claim 4, wherein: before the step C, the catheter is pretreated, and the pretreatment is to soak the catheter with a surface void enlargement agent. , or modify the surface of the catheter by a silicon germanium coupling reagent.