CN114432504B

CN114432504B - Surface treatment composition, balloon microcatheter with composition and preparation method

Info

Publication number: CN114432504B
Application number: CN202210114462.0A
Authority: CN
Inventors: 郭平; 张伟; 卫泽宇; 陈艳
Original assignee: Suzhou Hao Microbial Medical Technology Co ltd
Current assignee: Suzhou Hao Microbial Medical Technology Co ltd
Priority date: 2022-01-30
Filing date: 2022-01-30
Publication date: 2023-06-20
Anticipated expiration: 2042-01-30
Also published as: CN117159811A; CN114432504A

Abstract

The invention discloses a surface treatment composition, a balloon microcatheter with the composition and a preparation method of the balloon microcatheter. One end of the balloon microcatheter with the surface treatment composition is provided with the surface treatment composition, and the surface treatment composition at least comprises a material compounded by a hydrophilic material and an anticoagulant material, wherein the anticoagulant material is any one or more of heparin, hirudin, sodium citrate and potassium fluoride; the hydrophilic material is polyvinylpyrrolidone or any one or more of polycarboxylic acid, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, methyl vinyl ether/maleic anhydride copolymer, polyvinyl alcohol and polyethylene glycol. The balloon microcatheter with the composition has stable hydrophilicity and anticoagulation performance, and the duration is more than 4 hours and can even reach more than 24 hours.

Description

Surface treatment composition, balloon microcatheter with composition and preparation method

Technical Field

The invention relates to a surface treatment composition, a balloon microcatheter with the composition and a preparation method of the balloon microcatheter, and belongs to the technical field of medical appliances.

Background

Chinese patent publication CN 103533967A describes medical devices having a lubricious coating applied over a primer coating applied directly to the medical device and a method of coating the medical device. The coating may include one or more agents that provide enhanced adhesion of the coating on the device. The lubricious coating may be a network of hydrophilic compounds crosslinked to itself and interlocked with a network of crosslinked polymeric polyfunctional monomers or polymers. Further, the lubricious coating may have one or more therapeutic or diagnostic agents, and in one embodiment, the agent is eluted relatively rapidly from the lubricious coating at a high concentration release after hydration of the coating.

Chinese patent publication CN 108939257a describes a balloon microcatheter with a releasable head end, comprising a microcatheter body, wherein one end of the microcatheter body is communicated with a catheter holder, and the other end of the microcatheter body is also connected with the releasable microcatheter head end; the microcatheter is characterized in that a sleeve is coaxially arranged outside the microcatheter body, and two ends of the sleeve are respectively communicated with the catheter seat and the inflatable saccule on the microcatheter body. The inflatable balloon and the outer surface of the sleeve are both covered with a hydrophilic coating.

The catheter for endovascular intervention is one of the main instruments of endovascular intervention. Since all interventional catheters must be in contact with blood and reach the distal lesion along the curved vessel, the catheters should have good blood compatibility, a degree of flexibility and surface lubricity for the purpose of reducing damage to the vessel wall and blood cells, while the catheters should also have X-ray or fluorescence detectability.

The common high molecular material Pebax of the catheter has excellent physical and mechanical properties and relatively good biocompatibility, but the surface of the medical Pebax material has no lubricity and the anticoagulation performance is not durable enough. The catheter needs to be contacted with blood during the use process, so thrombus and infection are main problems affecting the indwelling use of the catheter. When blood contacts with foreign matters such as polymer materials, a plurality of adverse reactions can be caused, so that a good blood compatibility material is constructed, the anticoagulation property of the interventional catheter is endowed, and the clinical use value is great.

However, many interventional catheters used in the market have been modified by coating the outer surface of the catheter with a hydrophilic coating. However, since the catheter commonly used in intravascular interventional procedures has a short period of time, the catheter is withdrawn from the vessel at the end of the surgical procedure, and thus the immersion time of the catheter in blood is not long, and an anticoagulant coating is not required.

For perfusion chemotherapy, especially hepatic artery perfusion chemotherapy, the catheter needs to be left in hepatic artery for a long time, the outer surface of the catheter can be contacted with blood for a long time, and when the blood is contacted with foreign matters such as high polymer materials, various adverse reactions can be caused, and thrombus and infection caused by the inner surface and the outer surface of the catheter are important reasons for influencing the use of the catheter. With the deep use of interventional catheters, the single-coated catheters are insufficient to meet the requirements of clinical use on instruments, and in order to reduce the risk of treatment processes and reduce the economic burden of patients, the construction of multifunctional coatings on the outer surfaces is an important direction of future development of interventional catheters.

Disclosure of Invention

One technical problem to be solved by the present invention is to provide a balloon microcatheter with a surface treatment composition.

Another technical problem to be solved by the present invention is to provide a surface treatment composition.

Another technical problem to be solved by the present invention is to provide a method for preparing a balloon microcatheter with a surface treatment composition.

In order to achieve the technical purpose, the invention adopts the following technical scheme:

according to a first aspect of embodiments of the present invention there is provided a balloon microcatheter having a surface treatment composition comprising at least one end having a surface treatment composition comprising at least a material compounded from a hydrophilic material and an anticoagulant material, wherein the anticoagulant material is any one or more of heparin, hirudin, sodium citrate, potassium fluoride; the hydrophilic material is polyvinylpyrrolidone or any one or more of polycarboxylic acid, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, methyl vinyl ether/maleic anhydride copolymer, polyvinyl alcohol and polyethylene glycol.

Wherein preferably, the pipe body comprises an inner pipe and an outer pipe, and a through cavity is formed in the inner pipe and the outer pipe; the inner tube is positioned at the distal end of the outer tube and a balloon is provided at the junction of the inner tube and the outer tube, and the surface treatment composition is formed on the outer surfaces of the inner tube and the balloon.

Wherein preferably, the microcatheter is provided with a balloon developing ring at the middle or two end positions of the balloon and a distal developing ring at the distal end, and the surface treatment composition is further arranged on the outer surface of the outer tube and the outer surface of the developing ring.

Wherein preferably the polyvinylpyrrolidone has an average molecular weight of 30000-130000.

According to a second aspect of embodiments of the present invention, there is provided a surface treatment composition for an outer surface of a medical device for use in blood, the surface treatment composition comprising at least a material composited from a hydrophilic material and an anticoagulant material, wherein the anticoagulant material is any one or more of heparin, hirudin, sodium citrate, potassium fluoride; the hydrophilic material is polyvinylpyrrolidone or any one or more of polycarboxylic acid, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, methyl vinyl ether/maleic anhydride copolymer, polyvinyl alcohol and polyethylene glycol.

According to a third aspect of embodiments of the present invention, there is provided a method of preparing a balloon microcatheter with a surface treatment composition comprising the steps of:

step A: cleaning the tube body of the balloon microcatheter, and drying;

and (B) step (B): placing the tube body into 1-20wt% polyethylenimine or benzalkonium chloride water solution, soaking in 37 deg.C water bath for 0.5-1 hr, and vacuum drying; repeating the operation for 0-2 times;

step C: placing the dried tube body into heparin water solution, soaking in 37 ℃ water bath for 1h, and vacuum drying; repeating the operation for 0-2 times;

step D: and C, preparing a hydrophilic coating solution, immersing the tube body subjected to vacuum drying in the step C into the hydrophilic coating solution, and performing ultraviolet curing treatment to obtain the balloon microcatheter with the surface treatment composition.

Wherein preferably, ethanol is used for cleaning the pipe body in the step A; washing with distilled water after the ethanol is washed; and then placing the pipe body into a vacuum dryer for full drying.

Wherein preferably, the aqueous solution of polyethylenimine or benzalkonium chloride in the step B contains glutaraldehyde or aldehyde sodium alginate.

Wherein preferably, the concentration of the heparin aqueous solution in the step C is 1-5wt%.

Wherein preferably, the hydrophilic coating solution in the step D is an ethanol solution containing PVP.

Wherein preferably, the hydrophilic coating solution in the step D comprises the following components in parts by weight:

the invention has the following technical effects: the balloon microcatheter prepared by the surface treatment composition has good hydrophilicity and anticoagulation performance, stable hydrophilicity and anticoagulation performance, and lasting time exceeding 4 hours and even reaching more than 24 hours when being used in blood for a long time.

Drawings

FIG. 1 is a schematic view of a balloon microcatheter according to one embodiment of the invention;

FIG. 2 is a schematic molecular structure of an anticoagulant component and a hydrophilic gel component of the surface treatment composition of the present invention;

FIG. 3 is a heparin concentration versus time diffusion profile for a surface treatment composition of the present invention.

Detailed Description

The technical contents of the present invention will be described in detail with reference to the accompanying drawings and specific examples.

< first embodiment >

As shown in fig. 1, the balloon micro-catheter of the present invention comprises a catheter base 5, a stress diffusion tube 4 and a catheter body. The tube body comprises an inner tube 1, an outer tube 2 and a balloon 3. A cavity (not shown) is formed in the inner tube 1 and the outer tube 2; the inner tube 1 is formed at the distal end of the outer tube 2 and a balloon 3 is provided at the junction of the inner tube 1 and the outer tube 2, and the surface treatment composition is formed on the outer surfaces of the inner tube 1, the outer tube 2 and the balloon 3. The balloon 3 is fixed on the inner tube by bonding. The outer surface of balloon 3 may or may not have a surface treatment composition.

In the interventional operation, the balloon catheter is sequentially delivered into the blood vessel from the distal end to the proximal end, and the balloon 3 is expanded to form a closed channel in the blood vessel. Finally, according to the requirement of interventional operation, embolic agent, chemotherapeutics or contrast agent and the like are delivered through the cavity.

The proximal end of the balloon micro-catheter is provided with a Y-shaped handle 6, and the handle 6 of the balloon micro-catheter is used for connecting an external instrument. The handle 6 of the balloon microcatheter is in line with the tube body and is inclined at an acute angle relative to the axis of the tube body. The balloon microcatheter not only can temporarily change the blood flow direction (stay blood at a desired position to ensure targeted therapy) and prevent the drifting of the embolic agent, but also can be used for infusion chemotherapy such as Hepatic Artery Infusion Chemotherapy (HAIC) in a human body for a long time of 24 hours.

The outer tube of the micro-catheter is made of a high polymer material pebax, the inner tube is a braided tube, the micro-catheter is composed of a high polymer material pebax, stainless steel wires braided or wound springs and a high polymer material Polytetrafluoroethylene (PTFE), and the catheter seat is composed of a high polymer material polycarbonate. The inner tube and the outer tube form a cavity for delivering drugs, such as embolic agents, chemotherapeutic agents or contrast agents.

The surface treatment composition is applied in two passes, an anticoagulant coating (also referred to as anticoagulant material) and then a hydrophilic coating (also referred to as hydrophilic material). The hydrophilic material adopts polyvinylpyrrolidone (PVP), and the material has no toxicity and excellent biocompatibility. Once in an aqueous environment, such as after contact with body fluids or blood, the hydrophilic material surface absorbs water rapidly to form a hydration layer, significantly reducing the frictional resistance of the device during exercise. And the hydrophilic lubricating coating does not fall off during intubation. The anticoagulation coating is one or more of heparin, hirudin, sodium citrate and potassium fluoride, and has anticoagulation effect in vivo. Heparin is selected over heparin compounds because heparin has better anticoagulant effects than heparin compounds.

PVP is a water-soluble polymer catalyzed by N-vinyl-2-pyrrolidone monomer, and is easy to dissolve in polar organic solvents such as water, ethanol and the like. PVP has hydrophilic effect, and has no influence on physiological coagulation process, and is not influenced by human coagulation factors, and has no influence on the coagulation factors. PVP thus acts as a hydrophilic coating in the surface treatment composition of the present invention, PVPK30-PVPK120 can be selected, with an average molecular weight of 30000-130000.

As shown in fig. 2, the PVP latticed molecular structure facilitates the permeation of heparin molecules, and allows the heparin molecules to be modified on the PVP molecules. Thus, the surface treatment composition of the present invention is a composite material resulting from the combination of hydrophilic and anticoagulant materials. The hydrophilic material has high hydrophilicity and certain viscosity, so that the release of heparin is controllable. In a preferred embodiment, PVP has a solids content of 0.5-5% (mass ratio) and a viscosity of 5-50 mPa.s-25 ℃/aq.

It will also be appreciated by those of ordinary skill in the art that instead of PVP, polycarboxylic acids, polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides, methyl vinyl ether/maleic anhydride copolymers (CAS number: 9011-16-9), polyglycols such as polyethylene glycol (PEG), and the like may be used as hydrophilic materials.

The hydrophilic material of the surface treatment composition adopts PVP ethanol solution or PVP ethanol solution prepared from PVP and propanol, isopropanol, butanol, etc

It is known that grafting heparin onto the surface of a polymeric material prevents the adsorption of thrombin, thereby avoiding coagulation. The data show that the blood coagulation time and the partial thromboplastin (APTT) time are obviously prolonged within 10 minutes of intravenous heparin injection, and the effect of 3-4 hours can be maintained. Therefore, in the case where long-term anticoagulation (more than 4 hours) is required, it is necessary to keep heparin molecules in blood. In the surface treatment composition, gel formed by PVP plays a role of a controlled release agent, forms a composite coating with an anticoagulant function with heparin molecules, and regulates the diffusion speed of the heparin molecules in blood.

Example 1

And (3) cleaning the balloon microcatheter body with ethanol for 1h, cleaning with distilled water for 1h, and fully drying in a vacuum dryer for 12h.

Preparing a 5wt% polyethyleneimine water solution, putting the catheter body into 100ml polyethyleneimine water solution, and soaking in a water bath at 37 ℃ for 1h; and taking out the catheter body after the soaking is finished, and fully drying the catheter body in a vacuum dryer for 12 hours. After drying, the catheter body is put into 100ml of polyethyleneimine water solution again, and soaked in water bath at 37 ℃ for 1h; and taking out the catheter body after the soaking is finished, and fully drying the catheter body in a vacuum dryer for 12 hours. After drying, the catheter body is put into 100ml of polyethyleneimine water solution for the third time, and soaked in water bath at 37 ℃ for 1h; and taking out the catheter body after the soaking is finished, and fully drying the catheter body in a vacuum dryer for 12 hours.

An aqueous solution containing 5wt% heparin was prepared, and the dried catheter body was placed in 100mL of the aqueous solution of heparin and immersed in a water bath at 37℃for 1 hour. And taking out the catheter body after the soaking is finished, and fully drying in a vacuum dryer. The dried heparin-coated catheter body was again placed in 100mL of heparin in water (5 wt%) and immersed in a 37 ℃ water bath for 1h. And taking out the catheter body after the soaking is finished, and fully drying in a vacuum dryer. After drying, the heparin-coated catheter body was again placed in 100mL of heparin in water (5 wt%) and immersed in a 37 ℃ water bath for 1h. And taking out the catheter body after soaking, and fully drying in a vacuum dryer to obtain the dried catheter body coated with the tertiary heparin.

Wherein, step C: placing the tube body into heparin water solution, soaking in 37 ℃ water bath for 1h, and vacuum drying; step D: preparing hydrophilic coating solution, immersing the catheter body subjected to vacuum drying in the hydrophilic coating solution, and then performing ultraviolet curing treatment to obtain the balloon microcatheter with the surface treatment composition, wherein the two steps can be repeated for a plurality of times according to the required dosage. For example, step C may be repeated twice, followed by two more steps D; for example, the step C is performed once again, the step D is performed once again, the step C is performed once again, and the step D is performed once again.

Alternatively, the heparin aqueous solution and the PVP alcoholic solution are mixed to prepare a mixed solution, and then the tube body after vacuum drying in the step B is immersed into the mixed solution, and is taken out for ultraviolet curing treatment.

The following components are respectively taken to prepare hydrophilic coating solution:

5 grams PVP K90;

0.5g of crosslinker PEGDA1000;

0.2g of initiator Irgacure2959;

0.1g of leveling agent WX6214;

sequentially dissolving in 94.2g of absolute ethyl alcohol, and uniformly stirring to obtain a hydrophilic coating solution with the mass of 100 g.

And (3) completely immersing the dried catheter body coated with the tertiary heparin into a hydrophilic coating solution, and then performing ultraviolet curing treatment for 60 seconds to obtain the balloon microcatheter with the composite coating having the hydrophilic property and the anticoagulation property.

The diffusion concentration curve diagram of heparin molecules of the obtained balloon microcatheter under the use environment is shown in figure 3. In the experiment shown in fig. 3, a surface treatment composition (a surface treatment composition prepared with a hydrophilic coating solution having PVP solid content of 5%) was formed outside the catheter, and the concentration of the resulting heparin molecules diffused into the outer layer physiological saline was measured by methylene blue fading photometry using an ultraviolet-visible spectrophotometer. As can be seen, after 6 hours, heparin concentration was maintained at a steady level and the duration was maintained above 72 hours. The specific data are shown in Table 1:

table 1: heparin concentration diffusion schedule

The balloon microcatheter prepared by the embodiment and the surface treatment composition comprising the anticoagulation layer with the inner layer and the hydrophilic layer with the outer layer are arranged on the outer surface of the balloon, and the hydrophilic material in the hydrophilic coating and the network structure are entangled to absorb water to form hydrogel in the long-time blood contacting process, so that the friction force on the surface of the catheter can be remarkably reduced. The friction force was found to be 4.4g. The friction test experimental conditions are as follows: the water bath temperature is 37 ℃, the hardness of the silica gel sheet is 55, the lifting speed is 10mm/s, the clamping force is 300g, the outer diameter of the catheter is 1mm, the test length is 100mm, and the cycle times are 25 times.

Example 2

A method for preparing a balloon microcatheter with a surface treatment composition that is a composite coating having hydrophilic and anticoagulant properties. The method comprises the following steps:

step A: cleaning the tube body of the balloon microcatheter, and drying;

step D: preparing a hydrophilic coating solution, immersing the tube body subjected to vacuum drying in the step C into the hydrophilic coating solution, and then performing ultraviolet light curing treatment; the operation was repeated 0-2 times.

The balloon microcatheter with the surface treatment composition was obtained by the above procedure. When the steps B-D are repeatedly executed, the step B can be repeatedly executed first, then the step C can be repeatedly executed, and finally the step D can be repeatedly executed; steps B-D may also be performed first and then steps B-D may be performed.

The 5wt% aqueous polyethyleneimine solution described in this example contains 5% sodium alginate aldehyde.

Example 3-example 8

A balloon microcatheter with a composite layer having hydrophilic and anticoagulant properties was prepared with reference to example 1.

Except that the components were present in the proportions shown in the following tables, respectively.

The reagents and raw material sources in the above examples were as follows:

polyethyleneimine: shanghai Bike New Material technology Co.Ltd

Benzalkonium chloride: shanghai Ala Biochemical technology Co.Ltd

Glutaraldehyde: shanghai Ala Biochemical technology Co.Ltd

Sodium alginate: shanghai Ala Biochemical technology Co.Ltd

Heparin sodium: shenzhen Haiepren pharmaceutical Co.Ltd

PVP K90: shanghai Bike New Material technology Co.Ltd

Crosslinking agent PEGDA1000: shanghai Ala Biochemical technology Co.Ltd

Initiator Irgacure2959: basiff (China Co., ltd.)

Leveling agent WX6214: sea name, si modesty (Shanghai) chemical industry Co., ltd

Absolute ethyl alcohol: shanghai Ala Biochemical technology Co.Ltd

The balloon microcatheter of the present invention is suitable for prolonged use in blood in vivo, such as prolonged infusion chemotherapy, for example, 12-72 hours of placement in blood, due to the surface treatment composition. According to the coagulation mechanism, the surface of the saccule micro-catheter made of the blood compatible polymer material needs to inhibit the activation of the coagulation factors and can prevent the adhesion, release and aggregation of the platelets, which are indispensable. The initiator forms a network, and the PVP is crosslinked by a crosslinking agent and then is embedded with heparin to form the surface treatment composition.

The balloon microcatheter and the surface treatment composition of the balloon outer surface provided with the anticoagulation layer of the inner layer and the hydrophilic layer of the outer layer can obviously reduce the friction force on the surface of the catheter to below 4.5g when the hydrophilic material in the hydrophilic coating is entangled with the network structure to absorb water in the long-time blood contacting process. The modified heparin molecules are immersed into the hydrogel after the surface of the catheter is soaked by blood, penetrate into the hydrogel network structure, and play a role in anticoagulation on the surface of the catheter.

The present invention has been described in detail. Any obvious modifications to the present invention, without departing from the spirit thereof, would constitute an infringement of the patent rights of the invention and would take on corresponding legal liabilities.

Claims

1. A balloon microcatheter having a surface treatment composition comprising at least a material compounded from a hydrophilic material and an anticoagulant material, wherein the anticoagulant material is heparin, wherein at least one end of the balloon microcatheter has a surface treatment composition; the hydrophilic material is polyvinylpyrrolidone; the surface treatment composition comprises an anticoagulation coating which is pretreated by polyethyleneimine or benzalkonium chloride aqueous solution and dried, and a hydrophilic coating which is formed after the anticoagulation coating is dried;

the balloon microcatheter is obtained by immersing a heparin-coated tube body subjected to vacuum drying in a hydrophilic coating solution and performing ultraviolet light curing treatment;

the hydrophilic coating solution further includes a crosslinking agent and an initiator.

2. The balloon microcatheter of claim 1, wherein the tube body comprises an inner tube and an outer tube, the inner tube and the outer tube forming a lumen therethrough; the inner tube is positioned at the distal end of the outer tube and a balloon is provided at the junction of the inner tube and the outer tube, and the surface treatment composition is formed on the outer surfaces of the inner tube and the balloon.

3. The balloon microcatheter of claim 2 wherein the microcatheter is provided with balloon development rings at intermediate or both end positions of the balloon and distal development rings at the distal ends, the surface treatment composition being further provided on the outer surface of the outer tube and on the outer surface of the development rings.

4. A balloon microcatheter according to claim 3 wherein the polyvinylpyrrolidone has an average molecular weight of 30000-130000 and the heparin molecule is modified on the polyvinylpyrrolidone molecule.

5. A method of preparing a balloon microcatheter with a surface treatment composition as in any of claims 1-4, comprising the steps of: step A: cleaning the tube body of the balloon microcatheter, and drying; and (B) step (B): placing the tube body into 1-20wt% polyethylenimine or benzalkonium chloride water solution, soaking in 37 deg.C water bath for 0.5-1 hr, and vacuum drying; repeating the operation for 0-2 times; step C: placing the dried tube body into heparin water solution, soaking in 37 ℃ water bath for 1h, and vacuum drying; repeating the operation for 0-2 times; step D: preparing a hydrophilic coating solution, immersing the heparin-coated tube body subjected to vacuum drying in the step C into the hydrophilic coating solution, and then performing ultraviolet curing treatment to obtain the balloon microcatheter with the surface treatment composition.

6. The method according to claim 5, wherein the pipe body is washed with ethanol in the step A; washing with distilled water after the ethanol is washed; and then placing the pipe body into a vacuum dryer for full drying.

7. The method according to claim 5, wherein the aqueous solution of polyethylenimine or benzalkonium chloride in step B contains glutaraldehyde or aldehyde sodium alginate.

8. The preparation method according to claim 5, wherein the concentration of the heparin aqueous solution in the step C is 1-5wt%, and the crosslinking agent is PEGDA1000.

9. The method according to claim 5, wherein the hydrophilic coating solution in step D is an ethanol solution containing PVP.

10. The method according to claim 5, wherein the hydrophilic coating solution in the step D comprises the following components in parts by weight: PVP 0.5-5; 89.4 to 99.2 portions of absolute ethyl alcohol; 0.2-5 parts of cross-linking agent; 0.05 to 0.5 of initiator; 0.05 to 0.1 portion of leveling agent.