Preparation method of dual-pH intelligent response drug-loaded ureteral stent

Abstract

The invention discloses a preparation method of a dual-pH intelligent response drug-loaded ureteral stent, which belongs to the technical field of medical instruments, and is characterized in that the dual-pH intelligent response drug-loaded ureteral stent comprises a dual-pH intelligent response drug-loaded coating and a bare stent; wherein the dual pH intelligent response drug-loading coating contains polymer-modified porous silicon dioxide drug-loading particles, and the main effect of the drug-loading coating is that after the pH of the internal environment of the ureteral stent is changed due to bacterial infection, the antibacterial agent is controllably released through the structural change of the drug-loading particles or the property of the surface polymer is changed, so that the bactericidal ability is improved; and a complex infection environment can be accurately dealt with.

Description

Technical Field

[0001] The invention relates to a preparation method of a dual pH intelligent response drug-loaded ureteral stent, belonging to the technical field of medical devices. Background Art

[0002] As a foreign body in the human body, ureteral stents are usually severely attacked by bacteria, among which the most common bacteria are Escherichia coli, followed by Proteus, Pseudomonas, Klebsiella, Enterococcus, Candida, Serratia, etc. When bacterial infection occurs, bacterial metabolic activities will cause changes in the pH of the environment in the human ureter. For example, many bacteria that cause ureteral infection, such as Proteus and certain Escherichia coli, can produce urease. Urease can decompose urea, and urea decomposition will produce ammonia and carbon dioxide. Ammonia will form ammonium ions and hydroxide ions in aqueous solution, which increases the concentration of hydroxide ions in urine, thereby increasing the pH value of urine and making urine alkaline. Abnormal urine pH will in turn affect the progress of ureteral infection. Alkaline urine environment is conducive to the growth of certain bacteria, such as bacteria that can produce urease, because the alkaline environment produced by their decomposition of urea is beneficial to their own growth and reproduction. Moreover, the alkaline environment is prone to the formation of crystals such as calcium phosphate and ammonium magnesium phosphate. These crystals may adhere to the ureteral stent or ureteral wall, further causing complications such as stones. If the infected bacteria are acid-producing bacteria, they will produce acidic metabolites during metabolism, causing the pH value of the infected site to drop. The acidic environment may aggravate the irritation and damage to the urinary tract mucosa, leading to aggravation of symptoms such as hematuria and dysuria, and the damaged mucosa is more susceptible to bacterial adhesion and invasion, thereby aggravating the infection.

[0003] Bacterial infection after long-term implantation of ureteral stents has become a difficult problem for clinical and engineering researchers. Traditional antibiotic therapy and materials coated with antibiotic drugs are often greatly reduced due to drug resistance and drug burst release. Researchers have also actively explored material improvements.

[0004] Patent CN114504719A discloses an antibacterial ureteral stent tube with an analgesic function, wherein the two ends of the stent body are respectively connected with a first annular bend and a second bend, and a plurality of accommodating chambers are evenly distributed in the tube walls of the stent body, the first bend and the second bend, and the antibacterial components and the analgesic components are arranged in the accommodating chambers in the tube wall and are slowly released through capillaries, so that the ureteral stent tube has both antibacterial and analgesic effects.

[0005] Patent CN107261294A discloses a double-layer antibacterial urinary catheter, comprising a urinary catheter body and a functional layer arranged on the outer surface of the urinary catheter body, wherein the functional layer comprises a hydrophilic super-slip coating and an antibacterial coating. The urinary catheter uses a double-layer extrusion technology to co-extrude the hydrophilic super-slip coating and the antibacterial coating on the outer surface of the urinary catheter body, thereby preventing the hydrophilic super-slip coating and the antibacterial coating from falling off and maintaining the long-term effectiveness of the super-slip function and the antibacterial function.

[0006] Faced with the complex and changeable environment of the urinary system after infection, there is an urgent need to develop a pH-intelligent responsive drug-loaded ureteral stent that can accurately respond to complex infection environments and achieve efficient and controllable release of antibacterial drugs, thereby reducing the risk of infection and improving treatment effects. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a preparation method of a dual pH intelligent response drug-loaded ureteral stent, comprising: a dual pH intelligent response drug-loaded coating and a bare stent; wherein the dual pH intelligent response drug-loaded coating contains polymer-modified porous silica drug-loaded particles, and the polymer-modified porous silica drug-loaded particles are composed of porous silica with polydimethylaminoethyl methacrylate grafted on the surface and loaded with antibacterial agents inside, and polydimethylaminoethyl methacrylate has a certain bactericidal ability under neutral conditions, and the antibacterial ability is significantly enhanced under acidic conditions; the porous silica particles undergo structural collapse in an alkaline environment, accelerating the release of antibacterial agents; the synergistic effect of the two enables the nanoparticles to effectively control drug release under specific environments and exert antibacterial effects, thereby providing an innovative solution to problems such as bacterial infections.

[0008] To achieve the above object, the present invention provides the following technical solutions: A preparation method of a dual pH intelligent response drug-loaded ureteral stent, the specific preparation steps are as follows: (1) Preparation of porous silica particles: preparing a solution of tetraethyl orthosilicate, ammonium hydroxide and a template agent in a certain proportion, carrying out a polymerization reaction, filtering and washing after the reaction, adding acidic ethanol to remove the template agent, and obtaining a porous silica particle precipitate; purifying and setting aside; (2) Preparation of polymer-modified porous silica particles: The porous silica particles are dispersed in a solution containing a surface modifier to modify the silica surface, and dimethylaminoethyl methacrylate monomer is used as a raw material to carry out an atom transfer radical polymerization reaction under the action of a catalyst. During the reaction, the monomer molecules polymerize one by one at the initiator sites on the surface of the mesoporous silica, gradually forming polydimethylaminoethyl methacrylate chains grafted on the surface. After the reaction is completed, the porous silica particles modified by the polymer are obtained after washing and drying; (3) Preparation of polymer-modified porous silica drug-loaded particles: The antibacterial agent and the zwitterionic polymer-modified porous silica particles are prepared into a mixed solution, stirred at room temperature for 24 hours to fully mix, precipitated, and washed to obtain polymer-modified porous silica drug-loaded particles; (4) dispersing polymer-modified porous silica drug-loaded particles in the coating material to form a uniform solution, which is then coated on the surface of the bare stent by spraying, dipping, etc.;

[0009] Furthermore, the antibacterial agent in step (3) is any one or more combinations of silver ions, copper ions, chlorhexidine, penicillin, quaternary ammonium salts, isothiazolone derivatives, and phenol.

[0010] Furthermore, the coating material in step (4) is a combination of one or more of polylactic acid and its copolymers, polycaprolactone and its copolymers, polytrimethylene carbonate and its copolymers.

[0011] Furthermore, the bare stent is one of a degradable stent and a non-degradable stent.

[0012] The present invention has the following beneficial effects: 1. When the ureteral stent is implanted in the body and is not attacked by a large number of bacteria, the polymer-modified porous silica drug-loaded particles can slowly release the antibacterial agent in the pores, and the surface-modified polymer-modified porous silica drug-loaded particles also have a certain antibacterial ability under a normal relatively neutral pH environment. The two work synergistically to maintain a relatively stable environment inside the stent.

[0013] 2. When bacteria produce urease, the concentration of hydroxide ions in urine increases, causing the urine to become alkaline. The polymer-modified porous silica drug-loaded particles collapse in structure, accelerating the release of antibacterial agents, which can quickly kill bacteria.

[0014] 3. When certain bacterial infections cause the environment inside the stent to become acidic, the tertiary amine groups in polydimethylaminoethyl methacrylate will be protonated, making the polymer positively charged, which can interact with the negative charge on the surface of the bacterial cell membrane, destroying the integrity of the bacterial cell membrane and causing bacterial death.

[0015] Therefore, the porous silica drug-loaded particles and the surface-modified polydimethylaminoethyl methacrylate work synergistically. When bacterial infection causes changes in the environment inside the stent, they can respond intelligently and sterilize, accurately coping with complex infection environments. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Schematic diagram of polymer-modified porous silica drug-loaded particles; 1: poly (dimethylaminoethyl methacrylate) chain, 2: porous silica drug-loaded particles, 3: antibacterial agent. DETAILED DESCRIPTION

[0017] The following is a more specific description of the present invention in conjunction with specific embodiments, and further elaboration of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0018] Example 1 (1) Preparation of porous silica particles: 1 g of template agent hexadecyltrimethylammonium bromide, 240 mL of purified water and 10 mL of ammonium hydroxide were stirred at 80°C for 30 min, 5 mL of tetraethyl orthosilicate (TEOS) was added, stirred for 3 h and filtered. The precipitate was washed thoroughly with ethanol and deionized water, and then stirred in an ethanol solution of ammonium nitrate for 24 h to remove hexadecyltrimethylammonium bromide, thereby obtaining porous silica particles; (2) Preparation of polymer-modified porous silica particles: The porous silica particles are dispersed in a solution containing a surface modifier to modify the surface of the silica particles. 0.2 g of the surface-modified silica particles are added with 3 ml of dimethylaminoethyl methacrylate monomer, and an atom transfer radical polymerization reaction is carried out under the action of a catalyst of 10 mg of cuprous bromide and 20 ml of pentamethyldiethylenetriamine. The polydimethylaminoethyl methacrylate chain 1 is grafted on the surface of the porous silica. After the reaction is completed, the porous silica particles modified by the polymer are obtained after washing and drying. (3) Preparation of polymer-modified porous silica drug-loaded particles: silver ion antibacterial agent 3 and polymer-modified porous silica particles are prepared into a mixed solution, stirred at room temperature for 24 hours to fully mix, precipitated, and washed to obtain polymer-modified porous silica drug-loaded particles; (4) The polymer-modified porous silica drug-loaded particles are dispersed in polycaprolactone to form a uniform solution, which is then spray-coated onto the surface of the bare stent.

[0019] Example 2 The operation of each step is the same as that of Example 1, except that the antibacterial agent 3 is chlorhexidine.

[0020] Comparative Example 1 (1) Preparation of porous silica particles: 1 g of template agent hexadecyltrimethylammonium bromide, 240 mL of purified water and 10 mL of ammonium hydroxide were stirred at 80°C for 30 min, 5 mL of tetraethyl orthosilicate (TEOS) was added, stirred for 3 h and filtered. The precipitate was washed thoroughly with ethanol and deionized water, and then stirred in an ethanol solution of ammonium nitrate for 24 h to remove hexadecyltrimethylammonium bromide, thereby obtaining porous silica particles; (2) The porous silica particles are dispersed in a polycaprolactone solvent to form a uniform solution, which is then sprayed onto the surface of the bare stent.

[0021] Comparative Example 2 The operation of each step is the same as that of Example 1, except that the surface of the porous silica particles is not polymer-modified, but is treated with drug loading.

[0022] Comparative Example 3 The operations of each step are the same as those of Example 1, except that the polymer-modified porous silica particles are not subjected to drug loading treatment.

[0023] 1. Cytotoxicity test: Before the cytotoxicity test, the scaffold was sterilized. This study tested the potential cytotoxicity of the sample in accordance with the method requirements of GB / T 16886.5-2017. The example scaffold and the comparative example scaffold were placed in MEM culture medium containing 10% fetal bovine serum and extracted in a 37°C incubator for 24 hours. After the extraction, the cell culture medium in the 96-well plate cultured for 24 hours was removed and replaced with the corresponding extract, and cultured in a cell culture incubator (37°C, 5% CO2, >90% humidity) for 24 hours. After the culture was completed, the cell morphology and cell lysis were observed under a microscope, and the cytotoxicity value of the sample was determined by the MTT method. The results showed that the cells were morphologically intact and normal throughout the experiment, and no cytotoxic reaction was shown.

[0024] 2. Antibacterial test: Escherichia coli and Staphylococcus aureus are common Gram-negative bacteria and Gram-positive bacteria, respectively. These two bacteria are used as representatives, and the stent prepared in Comparative Example 1 is used as a blank control group to study the antibacterial function of the stents in different comparative examples under different pH conditions. As shown in Table 2, the sterilization rate of the embodiment in acidic and alkaline environments is more than 80%, and the sterilization rate in a neutral environment also reaches 50%; the porous silica drug-loaded particles 2 without surface modification in Comparative Example 2 have a higher sterilization rate in an alkaline environment, but a lower sterilization rate in an acidic and neutral environment; the porous silica particles without drug-loaded surface modification in Comparative Example 3 have a higher sterilization rate in an acidic environment, but a lower sterilization rate in an alkaline environment.

[0025] The specific implementation methods pointed out above have made a detailed description of the present invention, so that people in this field can have a more comprehensive understanding of the present innovative invention. It is self-evident for those skilled in the art to make some adjustments or improvements on the basis of the present invention. Adjustments or improvements that do not depart from the spirit and scope of the claims defined in the present innovative invention are all within the scope of protection of the present innovative invention.

Claims

1. A method for preparing a dual pH intelligent response drug-loaded ureteral stent, comprising: The dual pH intelligent response drug-loaded coating and bare stent, wherein the dual pH intelligent response drug-loaded coating contains polymer-modified porous silica drug-loaded particles, and the specific preparation steps are as follows: (1) Preparation of porous silica particles: tetraethyl orthosilicate, ammonium hydroxide and a template agent are prepared into a solution in proportion, and a polymerization reaction is carried out. After the reaction is completed, the solution is filtered, washed and acidic ethanol is added to remove the template agent to obtain a porous silica particle precipitate; Purify and set aside; (2) Preparation of polymer-modified porous silica particles: The porous silica particles are dispersed in a solution containing a surface modifier to modify the surface of the silica. The dimethylaminoethyl methacrylate monomer is used as a raw material and reacts under the action of a catalyst to form polydimethylaminoethyl methacrylate chains grafted on the surface of the porous silica particles. After the reaction is completed, the polymer-modified porous silica particles are obtained by washing and drying. (3) Preparing polymer-modified porous silica drug-carrying particles: preparing a mixed solution of the antibacterial agent and the polymer-modified porous silica particles, stirring and fully mixing at room temperature, precipitating, and washing to obtain polymer-modified porous silica drug-carrying particles; (4) The polymer-modified porous silica drug-loaded particles are dispersed in the coating material to form a uniform solution, which is then coated on the surface of the bare stent by spraying, dipping, etc.

2. The method for preparing the dual pH intelligent response drug-loaded ureteral stent according to claim 1, characterized in that The antibacterial agent in step (3) is any one or more of silver ions, copper ions, chlorhexidine, penicillin, quaternary ammonium salts, isothiazolone derivatives, and phenol.

3. The method for preparing the dual pH intelligent response drug-loaded ureteral stent according to claim 1, characterized in that The coating material in step (4) is any one or more of polylactic acid and its copolymers, polycaprolactone and its copolymers, polytrimethylene carbonate and its copolymers.

4. The method for preparing the dual pH intelligent response drug-loaded ureteral stent according to claim 1, characterized in that Bare stent is one of the degradable stent and non-degradable stent.

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