CN108261569B - Preparation method of medicine balloon - Google Patents

Preparation method of medicine balloon Download PDF

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Publication number
CN108261569B
CN108261569B CN201611267439.6A CN201611267439A CN108261569B CN 108261569 B CN108261569 B CN 108261569B CN 201611267439 A CN201611267439 A CN 201611267439A CN 108261569 B CN108261569 B CN 108261569B
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drug
balloon
temperature
solvent
medicine
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CN108261569A (en
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谢琦宗
曹明芳
宋精忠
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Lifetech Scientific Shenzhen Co Ltd
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Lifetech Scientific Shenzhen Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices

Abstract

The invention relates to a preparation method of a medicine balloon, which comprises the following steps: uniformly coating a mixed solution containing a medicine, a polymer and a solvent on the surface of the balloon; carrying out low-temperature freezing treatment on the coated balloon; carrying out vacuum drying treatment on the saccule subjected to the low-temperature freezing treatment to obtain a medicinal saccule; wherein the temperature of the low-temperature freezing treatment is not higher than the freezing point of the solvent, and the temperature of the vacuum drying treatment is lower than the freezing point of the solvent and lower than the glass transition temperature of the polymer. According to the preparation method of the drug balloon, a uniform porous structure is formed on the surface of the balloon, and the drug is uniformly distributed in the porous structure, so that the specific surface area of drug particles can be increased, the drug can be fully contacted with target cell sites during balloon expansion, and is uniformly released to a lesion part and absorbed by cells, and the treatment effect of the drug balloon on preventing restenosis and intimal hyperplasia is improved.

Description

Preparation method of medicine balloon
Technical Field
The invention relates to the technical field of medical instruments, in particular to a preparation method of a medicine balloon.
Background
In recent years, drug-coated stents have had great success in treating vascular stenosis. However, long-term clinical test results show that the drug-coated stent can generate side reactions caused by metal frameworks and polymer carriers and risks of late thrombus in blood vessels to human bodies, and postoperative in-stent restenosis also becomes another troublesome problem. In the subsequent study of new devices and therapeutic techniques, Drug Coated balloons (hereinafter "DCB" or "Drug Balloon") have become an emerging tool for the treatment of restenosis within stents, and have found widespread use due to their unique advantages.
The DCB has the action mechanism that the anti-cell proliferation medicine is uniformly coated on the surface of the balloon, and after the DCB is conveyed to a blood vessel pathological change part, the blood vessel is torn and extruded through the short-time expansion of the balloon, so that the medicine is quickly released and adhered to the blood vessel wall and is withdrawn from the balloon, and the purpose of long-time treatment effect can be achieved through the short-time exposure of the medicine. The unique construction of DCB avoids side reactions caused by the metal framework and the polymeric carrier. The DCB has the advantages that the medicine is uniformly coated on the surface of the balloon, and is uniformly released on the blood vessel wall in the expansion process, so that the toxic and side effects of the whole body of a human body caused by the enrichment of the medicine in a part of the blood vessel wall area are avoided. The treatment effect of the drug-coated balloon depends not only on the uniformity of the drug coating on the surface of the balloon, but also on the uniform release of the drug on the surface of the balloon during the expansion process and the uniformity of the drug adhered on the vessel wall. How to achieve uniform coating of the drug balloon surface coating and uniform distribution of the drug in the target tissue after expansion release is therefore a key factor in determining its ultimate therapeutic effect.
The earliest preparation method of the drug balloon is a manual coating technology, the preparation technology is greatly influenced by human factors, and the drug coating is unevenly distributed on the surface of the balloon, so that the aims of uniformly releasing the drug, uniformly adhering the drug to a target vascular tissue and fully adhering and combining lipophilic sites of the vascular tissue cannot be fulfilled in the expansion process. Systemic toxicity may also be caused by the release of more drugs at individual sites of blood vessels.
Currently, uniformity issues can be addressed for different types of drug balloons by applying a vibrator during the coating process. According to the technology, centrifugal force or vibration is adopted to coat the bioactive liquid on the surface of the balloon, and certain centrifugal force is achieved through rotation to achieve uniform coating.
The method also comprises a technology for solving the problem of uniformity of paclitaxel coating on the surface of the balloon, wherein the technology comprises the steps of firstly carrying out abrasion shot blasting on the surface of the balloon or processing the surface of the balloon by sodium bicarbonate to form certain roughness on the surface of the balloon or enable the surface of the balloon to have certain textures, and then coating active drugs on the surface of the balloon. Treatments such as abrasion also have a certain effect on the performance of the balloon.
Another preparation method of the medicinal coating of the balloon dilatation catheter for treatment comprises preparing the medicinal solution from the medicinal materials; then mixing the medicine solution with the medicine incompatible interference solvent, and then feeding the mixture into a double-channel ultrasonic spray head to coat the balloon dilatation catheter. The method is mainly characterized in that a medicine solution is mixed with another incompatible interference solvent before ultrasonic spraying, medicine molecules are separated out from the mixed solution in a crystal form, and then the medicine molecules enter an ultrasonic spray head for ultrasonic spraying. The method improves the uniformity of the coating by controlling the uniformity of the grain size. The method has the disadvantages that the medicine crystals and the smooth surface of the saccule are adsorbed on the surface of the saccule by virtue of physical action, the medicine in the form of crystals precipitated from the solution can block the spray head, so that the ultrasonic spray head cannot be sprayed or blocked, and the formed coating is uneven, thereby affecting the treatment effect.
Disclosure of Invention
Based on this, in order to solve the above problems, it is necessary to provide a method for preparing a drug balloon, so as to achieve uniform distribution of the drug on the surface of the balloon.
A preparation method of a drug balloon comprises the following steps:
uniformly coating a mixed solution containing a medicine, a polymer and a solvent on the surface of the balloon;
freezing the coated saccule at low temperature to enable the mixed solution to form a layer of crystalline film on the surface of the saccule;
carrying out vacuum drying treatment on the saccule subjected to the low-temperature freezing treatment to obtain a medicinal saccule;
wherein the temperature of the low-temperature freezing treatment is not higher than the freezing point of the solvent, and the temperature of the vacuum drying treatment is lower than the freezing point of the solvent and lower than the glass transition temperature of the polymer.
In one embodiment, the polymer is a homopolymer or copolymer of poly L-lactic acid, poly DL-lactic acid, polyglycolic acid, polyvinyl alcohol, polyethylene oxide.
In one embodiment, the solvent is a polar volatile solvent.
In one embodiment, the solvent is at least one of water, dioxane, acetic acid, acetone, pyridine, acetonitrile, isopropanol, formic acid, and dimethylacetamide.
In one embodiment, the temperature of the low-temperature freezing treatment is-100 ℃ to-20 ℃, and the time of the low-temperature freezing treatment is 0.5h to 5 h.
In one embodiment, the temperature of the vacuum drying treatment is-110 ℃ to 10 ℃, and the time of the vacuum drying treatment is 2h to 48 h.
In one embodiment, the mass ratio of the drug to the polymer in the mixed solution is 1 to 10.
In one embodiment, the concentration of the drug in the mixed solution is 5-20 mg/mL.
In one embodiment, the drug is at least one of paclitaxel, docetaxel, tacrolimus, phosphorylcholine, CD34 antibodies, rapamycin, or derivatives thereof.
In one embodiment, the mixed solution is applied to the balloon surface using a spray, drip, or dip method.
According to the preparation method of the medicine balloon, the mixed solution coated on the surface of the balloon is subjected to low-temperature freezing treatment, the medicine and the polymer are frozen in the solidified solvent on the surface of the balloon, the solvent is sublimated during vacuum drying treatment, a uniform porous structure is formed on the surface of the balloon, and the medicine is uniformly distributed in the porous structure, so that the specific surface area of medicine particles can be increased, the medicine can be fully contacted with a target cell site during expansion of the balloon, and is uniformly released to a lesion part and absorbed by cells, and the treatment effect of the medicine balloon on preventing restenosis and intimal hyperplasia is improved;
the porous structure of the invention enables the drug molecules to generate tiny intervals, reduces the possibility of drug molecule agglomeration, prevents the drug from agglomerating in a large area, and reduces the occurrence probability of the phenomenon of blood vessel blockage and even thrombus. In addition, in the sacculus expansion process, the porous structure makes the scouring action of the blood flow that the medicine received weaken to reduce the probability that the medicine is washed to the low reaches blood vessel, and then not only help the medicine evenly to shift and bond on the vascular wall in shorter time, also play the guard action to the medicine moreover. In addition, the preparation process of the drug balloon does not need to carry out physical or chemical modification on the balloon, so that the mechanical property and the service life of the balloon are effectively maintained, the operation is simple, special processing equipment is not needed, and the production cost is greatly reduced compared with other similar technologies.
Drawings
Fig. 1 is an SEM (100 x) photograph of a drug balloon obtained in example 1 of the present invention;
fig. 2 is a 3D microscope (50 x) photograph of the drug balloon obtained in example 1 of the present invention;
FIG. 3 is an SEM (100X) photograph of a drug balloon obtained in comparative example 1 of the present invention;
FIG. 4 is a 3D microscope (50X) photograph of the drug balloon obtained in comparative example 1 of the present invention;
FIG. 5 is a graph showing the planar fluorescence distribution of the drug balloon on the vessel wall of the fluorescently-labeled paclitaxel obtained according to the procedure in example 3;
fig. 6 is a fluorescence distribution diagram of a transverse section of a drug balloon on a blood vessel wall, which is obtained by the steps of example 3, of paclitaxel after fluorescent labeling.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The invention provides a preparation method of a medicine balloon, which comprises the following steps:
s110, uniformly coating a mixed solution containing a medicine, a polymer and a solvent on the surface of the balloon;
s120, performing low-temperature freezing treatment on the coated saccule to enable the mixed solution to form a layer of crystalline film on the surface of the saccule;
s130, carrying out vacuum drying treatment on the saccule subjected to the low-temperature freezing treatment to obtain a medicine saccule;
wherein the temperature of the low-temperature freezing treatment is not higher than the freezing point of the solvent, and the temperature of the vacuum drying treatment is lower than the freezing point of the solvent and lower than the glass transition temperature of the polymer.
The preparation method of the medicine balloon comprises the steps of coating a mixed solution containing medicines on the surface of the balloon, then carrying out low-temperature freezing treatment on the coated balloon, enabling the mixed solution to form a layer of compact crystalline film on the surface of the balloon, namely enabling the solvent to be solidified into a solid state in the low-temperature freezing process, enabling the medicines and the polymer to be crystallized and frozen in the solvent in the low-temperature freezing process, finally carrying out vacuum drying treatment, enabling the solvent to be sublimated in the vacuum drying process to form pores on the surface of the balloon, and enabling the medicines to be loaded in the pores.
Specifically, step S110 includes the following steps:
s111, preparing a mixed solution;
for example, after the drug and the polymer are weighed in proportion, a solvent is added to completely dissolve the drug and the polymer in the solvent to form a mixed solution. Specifically, a certain amount of medicine and polymer are weighed according to a proportion, the medicine and the polymer are placed in a volumetric flask, then a solvent is added into the volumetric flask, and ultrasonic vibration is carried out to completely dissolve the medicine and the polymer to form a mixed solution. For another example, the mass ratio of the drug to the polymer in the mixed solution is 1 to 10. In the mixed solution, the concentration of the medicine is 5-20 mg/mL.
The drug may be at least one of paclitaxel, docetaxel, tacrolimus, phosphorylcholine, CD34 antibody, rapamycin, or a derivative thereof.
The polymer forms a crystalline state in the low-temperature freezing treatment process, in other words, the polymer shows crystalline state properties after the low-temperature freezing treatment. The polymer may be a homopolymer or copolymer of poly L-lactic acid (PLA), poly DL-lactic acid (PDLLA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), polyethylene oxide (PEO), and easily forms a crystalline state during low temperature freezing.
The solvent is a polar volatile solvent, has high solubility to drugs and polymers, is easy to form a uniform solution, and is easy to sublimate and volatilize in the vacuum drying process. For example, the solvent may be at least one of water, dioxane, chloroform, acetic acid, acetone, pyridine, acetonitrile, isopropanol, formic acid, and dimethylacetamide.
And S112, uniformly coating the mixed solution on the surface of the balloon.
For example, the mixed solution is applied to the balloon surface by a coating method such as a spray coating method, a drop coating method, or a dip coating method. Specifically, a layer of mixed solution with the thickness of 6-10 microns is coated on the surface of the balloon. The concentration of the medicine on the surface of the saccule is 1-5 mu m/mm2。
Preferably, in S120, the low-temperature freezing process is performed in a vacuum environment. The temperature range of the low-temperature freezing treatment is-100 ℃ to-20 ℃, for example, the temperature of the low-temperature freezing treatment is-90 ℃ to-30 ℃, and for example, the temperature of the low-temperature freezing treatment is-80 ℃ to-40 ℃, and for example, the temperature of the low-temperature freezing treatment is-70 ℃ to-50 ℃, so that the solvent is solidified into a solid state in the process, and the medicine is uniformly frozen in the solid solvent. More specifically, the time of the low-temperature freezing treatment is 0.5h to 5h, for example, the time of the low-temperature freezing treatment is 1h to 4h, and for example, the time of the low-temperature freezing treatment is 2h to 3h, so that the drug and the polymer are completely crystallized in the low-temperature freezing process, and meanwhile, the production cost is reduced as much as possible, and the production efficiency is improved.
Specifically, in S130, the temperature of the vacuum drying process is not higher than the freezing point of the solvent and is lower than the glass transition temperature of the polymer. So that the solvent forms an even porous structure on the surface of the balloon after sublimation and volatilization in the vacuum drying process, and the phenomenon that the polymer flows due to the melting of the polymer in the vacuum drying process so that the medicine is unevenly distributed can be avoided, the medicine is evenly distributed, and the medicine is evenly released. The temperature range of the vacuum drying treatment is-110 to 0 ℃, for example, the temperature of the vacuum drying treatment is-100 to 0 ℃, further for example, the temperature of the vacuum drying treatment is-90 to-10 ℃, further for example, the temperature of the vacuum drying treatment is-80 to-20 ℃, further for example, the temperature of the vacuum drying treatment is-70 to-30 ℃, more specifically, the time of the vacuum drying treatment is 2 to 48 hours, for example, the time of the vacuum drying treatment is 4 to 40 hours, further for example, the time of the vacuum drying treatment is 8 to 36 hours, further for example, the time of the vacuum drying treatment is 12 to 28 hours, further for example, the time of the vacuum drying treatment is 16 to 24 hours, so that the solvent is completely sublimated and volatilized, and the production cost is reduced as much as possible, the production efficiency is improved.
The preparation method of the medicine balloon comprises the steps of carrying out low-temperature freezing treatment on a mixed solution coated on the surface of the balloon, freezing the medicine and the polymer in a solidified solvent on the surface of the balloon, carrying out vacuum drying treatment, sublimating the solvent to form a uniform porous structure on the surface of the balloon, and uniformly distributing the medicine in the porous structure, so that the specific surface area of medicine particles can be increased, the medicine can be fully contacted with a target cell site when the balloon is expanded, and can be uniformly released to a lesion part and absorbed by cells, and the treatment effect of the medicine balloon on preventing restenosis and intimal hyperplasia is improved.
It should be noted that, because the drug has strong lipophilicity and is easy to agglomerate, the drug can cause blood vessel blockage and even thrombus after being washed into the downstream blood vessel. The porous structure of the invention ensures that micro intervals are generated between the drug molecules, reduces the possibility of drug molecule agglomeration, prevents large-area agglomeration of the drug, and reduces the occurrence probability of vascular occlusion and even thrombosis. In addition, in the sacculus expansion process, the porous structure makes the scouring action of the blood flow that the medicine received weaken to reduce the probability that the medicine is washed to the low reaches blood vessel, and then not only help the medicine evenly to shift and bond on the vascular wall in shorter time, also play the guard action to the medicine moreover.
In addition, the preparation process of the drug balloon does not need to carry out physical or chemical modification on the balloon, so that the mechanical property and the service life of the balloon are effectively maintained, the operation is simple, special processing equipment is not needed, and the production cost is greatly reduced compared with other similar technologies.
In order to more clearly illustrate the technical solution of the present invention, the present invention is further illustrated by a plurality of specific examples.
Example 1
Step 1, paclitaxel solution: 50mg of paclitaxel and 10mg of PLA are weighed and put into a 10mL volumetric flask, 10mL of water/dioxane 1:1(V: V) mixed solution is added into the volumetric flask, and the medicine is completely dissolved after 5 minutes of ultrasonic oscillation to form a uniform mixed solution.
Step 2, spraying the mixed solution on the surface of the polyester balloon with the flap by using spraying equipment in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2。
And 3, putting the saccule into a vacuum box for low-temperature freezing treatment for 2 hours at the temperature of-90 ℃.
And 4, putting the saccule after low-temperature freezing into a vacuum drying oven for vacuum drying for 2 hours at the temperature of-95 ℃.
Example 2
Step 1, paclitaxel solution: 75mg of paclitaxel and 25mg of PDLLA are weighed and put into a 10mL volumetric flask, 10mL of a mixed solution of water/chloroform 2:1(V: V) is added into the volumetric flask, and the medicine is completely dissolved after 3min of ultrasonic oscillation to form a uniform mixed solution.
Step 2, coating the mixed solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2。
And 3, putting the saccule into a vacuum box for low-temperature freezing treatment for 0.5h at-100 ℃.
And 4, putting the saccule after low-temperature freezing into a vacuum drying oven for drying for 12 hours, wherein the drying temperature is-90 ℃.
Example 3
Step 1, paclitaxel solution: 100mg of paclitaxel and 10mg of PGA are weighed and put into a 10mL volumetric flask, 10mL of a mixed solution of water/acetone 3:1(V: V) is added into the volumetric flask, and the drug is completely dissolved after 3min of ultrasonic oscillation to form a uniform mixed solution.
Step 2, uniformly coating the mixed solution on the surface of the balloon by adopting a dip coating method in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2。
And 3, putting the saccule into a vacuum box for low-temperature freezing treatment for 5 hours at the temperature of-60 ℃.
And 4, putting the sacculus frozen at the low temperature into a vacuum drying oven for vacuum drying for 24 hours at the temperature of-70 ℃.
Example 4
Step 1, rapamycin solution: 150mg of rapamycin and 15mg of PEO were weighed and placed in a 10mL volumetric flask, 10mL of a mixed solution of acetone/dioxane 3:2(V: V) was added to the volumetric flask, and the drug was completely dissolved after 3 minutes of ultrasonic oscillation to form a uniform mixed solution.
Step 2, uniformly coating the mixed solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment by adopting a dripping method to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2。
And 3, putting the saccule into a vacuum box for low-temperature freezing treatment for 0.5h at the temperature of-93 ℃.
And 4, putting the saccule after low-temperature freezing into a vacuum drying oven for vacuum drying for 48 hours at the temperature of minus 80 ℃.
Example 5
Step 1, rapamycin solution: 200mg of rapamycin and 30mg of PVA were weighed and placed in a 10mL volumetric flask, and 10mL of a mixed solution of pyridine/formic acid 5:2(V: V) was added to the volumetric flask, and the drug was completely dissolved after 5 minutes of ultrasonic shaking to form a uniformly mixed solution.
Step 2, coating the mixed solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2。
And 3, putting the saccule into a vacuum box for low-temperature freezing treatment for 3 hours at the temperature of-20 ℃.
And 4, putting the saccule after low-temperature freezing into a vacuum drying oven for vacuum drying for 36 hours at the temperature of-10 ℃.
Comparative example 1
Step 1, paclitaxel solution: weighing 50mg of paclitaxel and 10mg of PLA, and putting into a 10mL volumetric flask; 10mL of a water/dioxane 1:1(V: V) mixed solution is added into a volumetric flask, and the drug is completely dissolved after 5 minutes of ultrasonic oscillation to form a uniform mixed solution.
Step 2, spraying a coating solution on the surface of the polyester balloon behind the flap by using spraying equipment in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2And naturally drying.
Comparative example 2
Step 1, paclitaxel solution: 75mg of paclitaxel and 25mg of PDLLA are weighed and put into a 10mL volumetric flask, 10mL of a mixed solution of water/chloroform 2:1(V: V) is added into the volumetric flask, and the medicine is completely dissolved after 3min of ultrasonic oscillation to form a uniform mixed solution.
Step 2, coating the mixed solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2And naturally drying.
Comparative example 3
Step 1, paclitaxel solution: 100mg of paclitaxel and 10mg of PGA are weighed and put into a 10mL volumetric flask, 10mL of a mixed solution of water/acetone 3:1(V: V) is added into the volumetric flask, and the drug is completely dissolved after 3min of ultrasonic oscillation to form a uniform mixed solution.
Step 2, mining under hundred-grade clean environmentThe mixture solution is evenly coated on the surface of the balloon by a dip coating method, so that the drug concentration on the surface of the balloon reaches 3 mu g/mm2And naturally drying.
Comparative example 4
Step 1, rapamycin solution: 150mg of rapamycin and 15mg of PEO were weighed and placed in a 10mL volumetric flask, 10mL of a mixed solution of acetone/dioxane 3:2(V: V) was added to the volumetric flask, and the drug was completely dissolved after 3 minutes of ultrasonic oscillation to form a uniform mixed solution.
Step 2, uniformly coating the mixture solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment by adopting a dripping method to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2And naturally drying.
Comparative example 5
Step 1, rapamycin solution: weighing 200mg of rapamycin and 30mg of PVA, and putting into a 10mL volumetric flask; 10mL of a mixed solution of pyridine/formic acid 5:2(V: V) was added to the volumetric flask, and the drug was completely dissolved after 5 minutes of ultrasonic shaking to form a uniformly mixed solution.
Step 2, coating the mixed solution on the surface of the balloon by using a precision injector in a hundred-grade clean environment to ensure that the drug concentration on the surface of the balloon reaches 3 mu g/mm2And naturally drying.
Please refer to fig. 1 and 2, which are SEM photographs and 3D microscope photographs of the drug balloon obtained in example 1 of the present invention. Please refer to fig. 3 and 4, which are SEM photographs and 3D microscope photographs of the drug balloon obtained in comparative example 1 of the present invention. As can be seen from the figure, the distribution of the drug on the balloon surface is more uniform in example 1 compared to the drug balloon obtained in comparative example 1.
Transport process loss simulation test
A delivery process loss simulation test was performed with porcine coronary vessels to simulate the target vessels of the coronary artery system to test the amount of drug lost prior to balloon filling, i.e., during insertion and movement of the drug coated balloon to the target site.
The porous drug-coated balloons prepared in examples 1 to 5 and comparative examples 1 to 5 were inserted into an in vitro simulated blood vessel model, the drug balloon was floated in the simulated blood vessel system for 120 seconds, and then the balloon was taken out. The residual drug content on the balloon surface was measured using High Performance Liquid Chromatography (HPLC). The condition parameters of HPLC test are: a chromatographic column: waters symmetry, C18, 5 μm, 25 cm. times.4.6 mm, mobile phase: methanol acetonitrile: water 70:20:10, uv detector, flow rate: 0.8mL/min, detection wavelength: 227 nm.
The HPLC measurement results are shown in table 1:
table 1 results of transportation loss simulation test
Figure BDA0001200885760000101
As can be seen from table 1, compared to the drug-coated balloons of comparative examples 1 to 5, which do not employ the low-temperature freezing and vacuum freeze-drying techniques, the drug-coated balloons prepared in the embodiments 1 to 5 of the present invention have a reduced percentage of drug loss in the vascular system during the transfer to the therapeutic intervention site, indicating that the balloon of the present invention has a greater adhesion to the drug coating.
In vitro simulated reprint release test
The release amount of the drugs was detected in the in vitro simulation environment using the porous drug-coated balloons prepared in examples 1 to 5 and comparative examples 1 to 5, respectively, and the release was simulated using the porcine coronary vessels as the target vessels. After the saccule is transported to the simulated blood vessel, the saccule is inflated by air pressure to expand the saccule, and the medicine is released to the blood vessel wall for 1 min. After release, the drug balloon is removed, the blood vessel is cut into 5 sections, and the drug concentration in the 5 sections of blood vessel is measured respectively. The results are shown in table 2:
table 2 in vitro simulated release test results
Figure BDA0001200885760000111
As can be seen from table 2, the drug content distribution in 5 sections of blood vessels of the porous drug-coated balloons prepared in examples 1 to 5 is more uniform than that of the porous drug-coated balloons prepared in comparative examples 1 to 5 in the in vitro simulated release result, which indicates that the porous drug-coated balloons prepared in examples 1 to 5 can be uniformly released and bonded in the blood vessel wall during the expansion release. As can be seen from fig. 1 to 4 and table 2, the drug coating on the surface of the porous drug balloon prepared in examples 1 to 5 is uniformly distributed and released.
Particle shedding test
The porous drug-coated balloons prepared in examples 1 to 5 and comparative examples 1 to 5 were subjected to simulation of their delivery process in an in vitro simulation test (purified water, 37 ℃, 300mL/min) environment, and after reaching the delivery site, the balloons were expanded, the balloon surface was eluted, and the particles falling off from the drug coating were detected, and the size and number of the falling particles were detected by a particle detector. And observing and measuring the specific size and shape of the large-size particles (more than 100 mu m) by a microscope method. The results of the in vitro simulated microparticle tests obtained are shown in table 3:
TABLE 3 in vitro simulated microparticle test results
Figure BDA0001200885760000112
Figure BDA0001200885760000121
As can be seen from table 3, compared to the drug-coated balloons of comparative examples 1 to 5, the drug balloons of examples 1 to 5 had a smaller maximum size of particle diameter and a smaller number of particles falling off within each size range during the course of the catheter simulated path expansion, that is, the particle falling-off level was far lower than that of the drug-coated balloons of comparative examples 1 to 5. Therefore, in embodiments 1 to 5 of the present invention, a smaller drug particle size and a smaller number of particles falling off can be obtained, the bonding force between the drug and the balloon surface is better, and the drug loss is less during the balloon delivery process.
Drug release fluorescence labeling assay
To paclitaxel, imidazole and CH2Cl2Et was slowly added to the mixture3SiCl and subjecting it to nitrogenAnd after reacting for 30 minutes at room temperature in the atmosphere, adding water for extraction, drying an extracted oil layer, and concentrating under reduced pressure to obtain a product 2. Dissolve product 2 and dimethylaminopyridine to CH at room temperature2Cl2Then, 6-N-tert-butoxycarbonylaminocaproic acid and DCC were added successively under a nitrogen atmosphere to obtain a first mixture. The first mixture was stirred at room temperature for 20h and then with CH2Cl2Diluting, filtering, refining the filtered residue with silica gel desiccant, and taking ethyl acetate and n-hexane as eluent in the refining process to obtain a product 3. After stirring the mixture of product 3 and 99% formic acid at room temperature under nitrogen, 10% NaHCO was used first3Dissolving the aqueous solution, extracting with ethyl acetate, collecting ethyl acetate layer, vacuum drying, and refining by thin layer chromatography to obtain product 4. The product 4 was dissolved in dioxane and NaHCO3Adding lissamine rhodamine B sulfonyl chloride into the mixed solution at room temperature under the protection of inert gas, reacting under stirring, diluting with sodium chloride aqueous solution after the reaction is finished, extracting with ethyl acetate, drying the extracted ethyl acetate layer under reduced pressure, refining the dried product by thin-layer chromatography, and taking ethyl acetate as an eluent in the refining process to obtain a purple part, wherein the purple part is the fluorescence-labeled taxol medicament.
The paclitaxel after fluorescent labeling is prepared into the porous drug coating saccule containing the fluorescent label according to the steps in the embodiment 3. The pig coronary blood vessel is used as a target blood vessel to simulate the in-vitro release of the pig coronary blood vessel, after the saccule is transported to the simulated blood vessel, the saccule is inflated by air pressure to expand the saccule, and the medicine is released to the blood vessel wall, wherein the release time is 1 min. And after releasing, withdrawing the drug balloon, and observing the distribution condition of the drugs in the blood vessel by using a fluorescence microscope to obtain the fluorescence distribution map of the paclitaxel on the blood vessel wall.
As can be seen from fig. 5 and 6, paclitaxel can be uniformly adhered to the vessel wall by using the fluorescence labeled paclitaxel and the drug balloon prepared by the steps in example 3, so as to achieve uniform release of the drug.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The preparation method of the medicine balloon is characterized by comprising the following steps:
uniformly coating a mixed solution containing a medicine, a polymer and a solvent on the surface of the balloon;
freezing the coated saccule at low temperature to enable the mixed solution to form a layer of crystalline film on the surface of the saccule;
carrying out vacuum drying treatment on the saccule subjected to the low-temperature freezing treatment, wherein the solvent is sublimated during the vacuum drying treatment, a uniform porous structure is formed on the surface of the saccule, and the medicine is uniformly distributed in the porous structure to obtain a medicine saccule;
wherein the temperature of the low-temperature freezing treatment is not higher than the freezing point of the solvent, and the temperature of the vacuum drying treatment is lower than the freezing point of the solvent and lower than the glass transition temperature of the polymer.
2. The method for manufacturing a drug balloon according to claim 1, wherein the polymer is a homopolymer or copolymer of poly-L-lactic acid, poly-DL-lactic acid, polyglycolic acid, polyvinyl alcohol, polyethylene oxide.
3. The method of manufacturing a drug balloon of claim 1, wherein the solvent is a polar volatile solvent.
4. The method for preparing a drug balloon according to claim 3, wherein the solvent is at least one of water, dioxane, acetic acid, acetone, pyridine, acetonitrile, isopropanol, formic acid, and dimethylacetamide.
5. The preparation method of the drug balloon according to claim 1, wherein the temperature of the cryogenic freezing treatment is-100 ℃ to-20 ℃, and the time of the cryogenic freezing treatment is 0.5h to 5 h.
6. The preparation method of the drug balloon according to claim 1, wherein the temperature of the vacuum drying treatment is-110 ℃ to 10 ℃, and the time of the vacuum drying treatment is 2h to 48 h.
7. The method for manufacturing a drug balloon according to claim 1, wherein the mass ratio of the drug to the polymer in the mixed solution is 1 to 10.
8. The preparation method of the drug balloon according to claim 7, wherein the concentration of the drug in the mixed solution is 5-20 mg/mL.
9. The method of manufacturing a drug balloon according to claim 1, wherein the drug is at least one of paclitaxel, docetaxel, tacrolimus, phosphocholine, CD34 antibody, rapamycin, or a derivative thereof.
10. The method for preparing a drug balloon according to claim 1, wherein the mixed solution is applied to the balloon surface by a spray coating method, a drop coating method or a dip coating method.
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CN109091748A (en) * 2018-08-15 2018-12-28 山东吉威医疗制品有限公司 A kind of medicine-coated balloon and preparation method thereof
CN111035813B (en) * 2018-10-15 2022-02-18 复旦大学附属中山医院 Liquid band-aid type coronary artery membrane stent and manufacturing method thereof
CN114788898A (en) * 2022-04-15 2022-07-26 杭州巴泰医疗器械有限公司 Preparation method of coronary sacculus surface crystallization drug coating
CN114832214A (en) * 2022-04-25 2022-08-02 上海畅德医疗科技有限公司 Medicinal balloon catheter and preparation method and application thereof

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