CN114748701B - Drug coating, drug balloon, preparation method and application of drug balloon - Google Patents

Drug coating, drug balloon, preparation method and application of drug balloon Download PDF

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CN114748701B
CN114748701B CN202210288855.3A CN202210288855A CN114748701B CN 114748701 B CN114748701 B CN 114748701B CN 202210288855 A CN202210288855 A CN 202210288855A CN 114748701 B CN114748701 B CN 114748701B
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drug
balloon
coating
carrier
preparing
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CN114748701A (en
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马翠杰
赵丽晓
刘扬扬
何智浩
王哲
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Lepu Medical Technology Beijing 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
    • A61L29/08—Materials for 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
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • 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
    • A61L2420/06—Coatings containing a mixture of two or more compounds

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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Materials For Medical Uses (AREA)
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Abstract

The invention provides a drug coating, a drug balloon and a preparation method and application of the drug balloon. The drug coating for the drug balloon comprises a drug and a carrier, wherein the carrier is a phenolic compound or a pyrone compound, and the mass ratio of the drug to the carrier is 1 (0.01-10). The medicine balloon is obtained by coating the surface of the balloon with the medicine coating. The invention takes the phenolic compound or the pyrone compound as a novel carrier, improves the carrier selection efficiency of the drug coating, can obtain ideal crystal forms, obviously improves the quality of the drug coating, prolongs the retention time of the drug in treating vascular or other lumen stenosis diseases, and further ensures that the drug balloon catheter can better inhibit restenosis of lumen in treating vascular, urethra or ureter stenosis.

Description

Drug coating, drug balloon, preparation method and application of drug balloon
Technical Field
The invention relates to the technical field of medicine balloons, in particular to a medicine coating, a medicine balloon, a preparation method of the medicine balloon and application of the medicine balloon.
Background
The medicine saccule catheter is one kind of interventional medical instrument comprising catheter and medicine saccule. The medicine balloon consists of a balloon and a medicine coating coated on the surface of the balloon. The medicine saccule catheter is mainly used for dilating a narrow part of a blood vessel, and can release medicine to an intima of the blood vessel while dilating the blood vessel, thereby playing a role in inhibiting restenosis of the blood vessel.
The formulation of the drug coating generally comprises a drug and a carrier, and the drug balloon can be obtained by dissolving the drug and the carrier in a solvent and coating the solvent on the surface of the balloon. At present, in the technology at home and abroad, the carrier used for obtaining the medicine saccule is generally contrast medium, ester compound, heparin, castor oil or hydrophilic dye, sugar derivative, polymer and the like, and the medicine is generally paclitaxel, rapamycin and the like. In short, the formulation of the drug coating is more selected, however, the crystallization state of the drug coating obtained by the current formulation is mostly difficult to control, and the retention time of the drug in treating vascular or other lumen stenosis diseases is difficult to ensure.
Disclosure of Invention
Therefore, the invention aims to overcome the defects that most of the drug coatings obtained by the formulas in the prior art are difficult to control the crystallization state and the retention time of the drug balloon in treating vascular or other lumen stenosis diseases is difficult to ensure.
Therefore, the invention provides a drug coating, which comprises a drug and a carrier, wherein the carrier is a phenolic compound or a pyrone compound, and the mass ratio of the drug to the carrier is 1 (0.01-10).
Further, the phenolic compound is selected from at least one of eugenol, thymol, grape polyphenol, tea polyphenol and thymol; the pyrone compound is at least one selected from maltol, ethyl maltol, coumarin, vinic acid, flavone and flavonoid compounds;
optionally, the carrier is preferably one or more of eugenol, tea polyphenol, thymol, maltol, ethyl maltol and vinic acid.
Further, the drug is selected from at least one of paclitaxel, rapamycin, a paclitaxel derivative, and a rapamycin derivative.
The invention provides a medicine balloon, which is obtained by coating the surface of the balloon with the medicine coating.
The invention provides a preparation method of a medicine balloon, which comprises the following steps:
dissolving the medicine and the carrier into a solvent to obtain a solution;
the solution is coated onto the balloon surface to form a drug coating.
Further, the solvent is at least one selected from water, alcohol compounds, aliphatic hydrocarbon compounds, ether compounds, halogenated hydrocarbon compounds, ketone compounds, tetrahydrofuran and acetonitrile; the aliphatic hydrocarbon compound comprises n-hexane and/or n-butane; the ether compound comprises diethyl ether and/or propylene oxide; the halogenated hydrocarbon compound comprises chloroform; the ketone compounds include acetone and/or methyl butanone.
Further, the mass ratio of the medicine to the solvent is 1 (0.002-50).
Further, the alcohol compound is a compound with the carbon number less than or equal to 15; the alcohol compound is at least one selected from ethanol, methanol, isopropanol, propanol, n-butanol, isobutanol and sec-butanol.
Further, in the dissolving step, after the drug and the carrier are added to the solvent, stirring, ultrasonic vibration and standing are performed.
Further, the standing time is 0.5-1.5h.
Further, the coating mode comprises spray coating, dip coating or dripping coating.
The medicine saccule prepared by the preparation method is applied to the narrow expansion and restenosis inhibition of the vascular, urethral or ureteral lumen; the blood vessels include coronary vessels, peripheral vessels, intracranial vessels, and arteriovenous fistula vessels; the urethra comprises a prostatic urethra, a bulbar urethra, a membranous urethra and a penile urethra.
The technical scheme of the invention has the following advantages:
1. the medicine coating provided by the invention takes the phenolic compound or the pyrone compound as a new carrier, improves the carrier selection efficiency of the medicine coating, can obtain ideal needle-shaped or columnar crystals, obviously improves the quality of the medicine coating, prolongs the retention time of the medicine in treating vascular or other lumen stenosis diseases, and further ensures that the medicine balloon catheter can better inhibit restenosis of blood vessels in treating vascular stenosis.
2. The drug coating provided by the invention reduces the selection range of the drug coating formula, simplifies the formula selection process, has a simple coating preparation method, and greatly improves the firmness of the drug coating.
3. The medicine saccule is applied to the stricture expansion and restenosis inhibition of blood vessels, urethra and ureteral lumens.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a scanning electron microscope image of a drug coating of example 1 provided by the present invention; the scale bar in the figure is 5 μm;
FIG. 2 is a scanning electron microscope image of the drug coating of comparative example 1 provided by the present invention; the scale in the figure is 10. Mu.m.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
The balloon material used in the embodiment of the invention is a self-made balloon made of nylon material, and the specific preparation method comprises the following steps:
preforming: the two ends of the balloon material pipe are thinned, and a certain proportion of bubble length is reserved in the middle of the balloon material pipe, so that a preformed balloon is obtained;
and (3) mold forming: and (3) placing the preformed balloon into a balloon mold for blow molding, and charging nitrogen into the preformed balloon, wherein the temperature of the balloon mold is controlled to be 110-120 ℃, and the pressure of the nitrogen in the preformed balloon is 300-400psi.
The tea polyphenol used in the examples of the invention has the product number T821916 and is purchased from microphone;
the maltol used in the examples of the present invention was purchased from microphone under the number M813318;
the eugenol used in the examples of the present invention was purchased from microphone under the product number E809010;
the ethyl maltol used in the examples of the present invention was commercially available from microphone under the accession number E824420.
Example 1
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is paclitaxel, the carrier is tea polyphenol, the solvent is acetone, the mass ratio of the drug to the carrier is 25:1, and the mass ratio of the drug to the solvent is 30:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the specific preparation method comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 0.5h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 2
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is taxol, the carrier is maltol, the solvent is acetone, the mass ratio of the drug to the carrier is 20:1, and the mass ratio of the drug to the solvent is 30:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the specific preparation method comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 3
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is taxol, the carrier is eugenol, the solvent is acetonitrile, the mass ratio of the drug to the carrier is 1:10, and the mass ratio of the drug to the solvent is 500:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the specific preparation method comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 4
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is paclitaxel, the carrier is ethyl maltol, the solvent is isopropanol, the mass ratio of the drug to the carrier is 100:1, and the mass ratio of the drug to the solvent is 1:50.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 5
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is a paclitaxel derivative, the paclitaxel derivative is docetaxel (specific product number is D807092, purchased from microphone), the carrier is maltol, the solvent is acetone, the mass ratio of the drug to the carrier is 20:1, and the mass ratio of the drug to the solvent is 30:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 6
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is rapamycin, the carrier is maltol, the solvent is acetone, the mass ratio of the drug to the carrier is 20:1, and the mass ratio of the drug to the solvent is 30:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1.5h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Example 7
The embodiment provides a drug coating, which comprises a drug and a carrier, wherein the drug is a rapamycin derivative, the rapamycin derivative is zotarolimus (product number is Z872686, purchased from microphone), the carrier is maltol, the solvent is acetone, the mass ratio of the drug to the carrier is 20:1, and the mass ratio of the drug to the solvent is 30:1.
the embodiment provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic oscillation for 15min, wherein the ultrasonic frequency is 100Hz, the temperature is 30 ℃, and standing the oscillated solution for 1.5h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Comparative example 1
The present comparative example provides a drug coating comprising a drug and a carrier, the drug being paclitaxel, the carrier being sorbitol (sorbitol is available as D817607 from microphone), the solvent being acetone, the mass ratio of drug to carrier being 25:1, the mass ratio of drug to solvent being 30:1.
the comparative example provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic vibration for 15min, and standing the vibrated solution for 0.5h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; the spraying pressure is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Comparative example 2
The comparative example provides a drug coating comprising a drug and a carrier, wherein the drug is paclitaxel, the carrier is ethyl maltol, the solvent is propanol, the mass ratio of the drug to the carrier is 110:1, and the mass ratio of the drug to the solvent is 1:50.
the comparative example provides a drug balloon, which is obtained by coating the surface of the balloon with the drug coating, and the preparation method of the drug coating comprises the following steps:
s1, dissolving a medicine and a carrier into a solvent, stirring for 3min, performing ultrasonic vibration for 15min, and standing the vibrated solution for 1h;
s2, spraying the solution on the surface of the saccule by an ultrasonic spraying method; spraying pressThe force is 0.01MPa, the spraying flow rate is 0.03mL/min, and the nominal drug quantity of the balloon obtained by spraying is 1 mug/mm 2 。
Test example 1
The morphology of the drug coating obtained in the example 1 and the comparative example 1 is respectively observed by using a Scanning Electron Microscope (SEM), the morphology diagrams are shown in the figures 1 and 2, as shown in the figures 1 and 2, the drug coating in the figure 1 forms crystals with crystal morphology which grow vertically, the crystal size is uniform, and the size is mainly distributed at about 5 mu m, so that when the drug coating expands in a blood vessel, a urethra or a ureter, the drug coating can be better attached to the wall of a tube cavity, more crystals can be attached to the wall of the tube cavity, and meanwhile, the metabolism time of the crystals in tissues is longer; in FIG. 2, the crystals formed are not ideal, mostly crystalline grains, less than 1 μm in size, and have a short metabolism time in the tissue.
Test example 2
The method comprises the steps of selecting a balloon with the size of 2.75 x 12mm, respectively obtaining the drug balloon according to the methods of examples 1-7 and comparative examples 1-2, and testing the retention time of the drug balloon in a blood vessel, wherein the specific test method comprises the following steps: the method comprises the steps of performing in-vivo animal testing on a drug balloon, wherein the selected animal is a white pig with the weight of about 30kg, the tested blood vessel part is a coronary blood vessel, the drug coated balloon is conveyed to the coronary blood vessel position of the animal, the drug balloon is taken out after 30s expansion, the drug content of the blood vessel tissue of the expansion section is tested at 30 days, and the residual drug content ratio is calculated. Residual drug content ratio = tissue drug content/balloon surface nominal drug amount x 100%, test results are shown in table 1;
the method for testing the drug content of the vascular tissue of the expansion section comprises the following steps: vascular tissue was obtained, the support tissue homogenate was ground at 1000r/min using a tissue triturator, the tissue homogenate was added to 5mL of a mixed solution of methanol and acetonitrile (wherein the volume ratio of methanol to acetonitrile was 1:1), then 200 μg of an internal standard drug (the internal standard drug was the drug used in the corresponding example or comparative example), vortexed for 1min, centrifuged at 4000r/min for 15min to obtain a supernatant, the supernatant was diluted with a 1:1 solvent (volume ratio) of methanol to water, and after twice the dilution, the tissue drug concentration data was tested by liquid chromatography-mass spectrometry.
TABLE 1 intravascular test results for examples 1-7, comparative examples 1-2
Sample group 30 days tissue drug content (μg/g) Content ratio of residual medicine (mill)
Example 1 10.2 9.8
Example 2 7.8 7.5
Example 3 8.5 8.2
Example 4 14.0 13.5
Example 5 6.9 6.7
Example 6 9.2 8.9
Example 7 7.8 6.9
Comparative example 1 0.6 0.6
Comparative example 2 0.3 0.3
As shown in Table 1, the 30-day storage amount of the drugs in examples 1 to 7 in the coronary blood vessel was 10.45.+ -. 3.55. Mu.g/g, and the remaining drug content ratio was 10.1.+ -. 3.4%. The medicine in comparative examples 1-2 had a 30-day storage of 0.45.+ -. 0.15. Mu.g/g in coronary vessels, and the remaining medicine content ratio was 0.45%o.+ -. 0.15%o. It can be seen that the residence time of the drug in the tissue is higher in the present invention than in the comparative example.
Test example 3
The method for preparing the medicine balloon comprises the steps of selecting a balloon with the size of 8.0 mm by 40mm, respectively obtaining the medicine balloon according to the methods of examples 1-7 and comparative examples 1-2, and testing the retention time of the medicine balloon in the urethra, wherein the specific test method comprises the following steps: expanding the medicine saccule in the urethra of a dog (about 15kg beagle) for 3min, taking out the medicine saccule, testing the medicine content in the urethra of the expanded section at 30 days, and calculating the content ratio of the residual medicine; residual drug content ratio = tissue drug content/balloon surface nominal drug amount x 100%, test results are shown in table 2;
the method for testing the drug content in the urethra of the expansion section comprises the following steps: the method comprises the steps of obtaining urethral tissue vascular tissue, grinding support tissue homogenate at 1000r/min by using a tissue triturator, adding the tissue homogenate into 5mL of a mixed solution of methanol and acetonitrile (wherein the volume ratio of the methanol to the acetonitrile is 1:1), then adding 200 mug of an internal standard drug (the internal standard drug is used in a corresponding example or a comparative example), carrying out vortex for 1min, centrifuging for 15min at 4000r/min to obtain supernatant, diluting the supernatant by using a 1:1 solvent (volume ratio) of the methanol and water, diluting the supernatant twice, and testing by using liquid chromatography-mass spectrometry to obtain tissue drug concentration data.
TABLE 2 results of intra-urethral experiments for examples 1-7, comparative examples 1-2
Sample group 30 days tissue drug content (μg/g) Content ratio of residual medicine (mill)
Example 1 16.2 8.1
Example 2 18.3 9.1
Example 3 19.2 9.6
Example 4 18.1 9.0
Example 5 18.6 9.3
Example 6 15.6 7.8
Example 7 16.1 8.0
Comparative example 1 0.8 0.4
Comparative example 2 0.5 0.5
As shown in Table 2, the drugs in examples 1 to 7 had a tissue retention amount of 17.4.+ -. 1.8. Mu.g/g in the urethra for 30 days, and the remaining drug content ratio was 8.6%.+ -. 0.9%; the drug of comparative examples 1-2 had a tissue retention of 0.65.+ -. 0.15. Mu.g/g in the urethra for 30 days, and the remaining drug content ratio was 0.45%.+ -. 0.05%. It can be seen that the residence time of the drug in the tissue is higher in the present invention than in the comparative example.
Test example 4
The method for preparing the drug balloon comprises the steps of selecting a balloon with the size of 4.0 multiplied by 20mm, respectively obtaining the drug balloon according to the methods of examples 1-7 and comparative examples 1-2, and testing the drug release rate of the drug balloon, wherein the specific test method comprises the following steps: immersing a simulated blood vessel with a proper size into a bovine serum albumin PBS simulated solution, respectively extending the medicine saccule into the simulated blood vessel and expanding to burst pressure (12 atm), maintaining the pressure for 60s, releasing the pressure, taking out the expanded medicine saccule from the solution, putting the solution into a 5mL brown volumetric flask, adding 5mL methanol, and standing for half an hour to obtain an elution solution of the medicine. The eluted solution was then subjected to drug content measurement using a high performance liquid chromatograph, and the residual drug rate was calculated, and the test results are shown in table 3.
The preparation method of the bovine serum albumin PBS simulated solution comprises the following steps: 10g of bovine serum albumin was weighed and added to 100mL of PBS buffer,a0.1 g/mL bovine serum albumin solution was prepared. The preparation method of the PBS buffer solution comprises the following steps: 8g of NaCl, 0.2g of KCl and 1.44g of Na are weighed 2 HPO 4 And 0.24g KH 2 PO 4 Dissolving in 800ml distilled water, adjusting pH to 7.4 with HCl, and adding distilled water to volume to 1L.
Residual drug rate = 1-drug content detected/drug balloon nominal drug content.
By the same method, the simulated blood vessel after the expansion of the medicine saccule is subjected to medicine content measurement, so that the medicine release rate is obtained, and the specific calculation formula is as follows:
drug release rate = drug content detected/drug balloon nominal drug content
Drug loss = 1-residual drug rate-drug release rate
TABLE 3 in vitro drug release simulation test results
Sample group Drug release rate (%) Residual drug content (%) Loss of drug (%)
Example 1 98.1 1.4 0.5
Example 2 97.5 2.0 0.5
Example 3 99.2 0.4 0.4
Example 4 98.3 1.3 0.4
Example 5 97.8 1.6 0.6
Example 6 99.0 0.3 0.7
Example 7 98.7 1.0 1.3
Comparative example 1 78.2 10.4 11.4
Comparative example 2 81.1 9.6 9.3
As shown in Table 3, the in vitro drug release rate of examples 1 to 7 was 98.35% + -0.85%, the residual drug rate was 1.15% + -0.85%, and the drug loss was 0.85% + -0.45%; the in vitro drug release rate of comparative examples 1-2 was 79.65% + -1.45%, the residual drug rate was 10% + -0.4%, and the drug loss was 10.35% + -1.05%. It can be seen that the drug release rate of the present invention is higher than that of the comparative example, and the residual drug amount rate and the drug loss are lower than those of the comparative example.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims (13)

1. The drug coating comprises a drug and a carrier, and is characterized in that the carrier is a phenolic compound or a pyrone compound, and the mass ratio of the drug to the carrier is 1 (0.01-10);
the medicine is selected from at least one of paclitaxel, rapamycin, paclitaxel derivatives and rapamycin derivatives;
the phenolic compound is at least one selected from eugenol, thymol, grape polyphenol, tea polyphenol and thymol; the pyrone compound is selected from at least one of maltol and ethyl maltol.
2. A pharmaceutical coating according to claim 1, wherein the carrier is selected from at least one of eugenol, tea polyphenol, thymol, maltol and ethyl maltol.
3. A drug balloon obtained by applying the drug coating according to any one of claims 1-2 to the surface of the balloon.
4. A method for preparing a drug balloon, which is characterized in that the drug balloon is the drug balloon of claim 3, and the method comprises the following steps:
dissolving the medicine and the carrier into a solvent to obtain a solution;
the solution is coated onto the balloon surface to form a drug coating.
5. The method for preparing a pharmaceutical balloon according to claim 4, wherein the solvent is at least one selected from the group consisting of water, alcohol compounds, aliphatic hydrocarbon compounds, ether compounds, halogenated hydrocarbon compounds, ketone compounds, tetrahydrofuran and acetonitrile.
6. The method for preparing a drug balloon as claimed in claim 5, wherein,
the aliphatic hydrocarbon compound comprises n-hexane and/or n-butane; the ether compound comprises diethyl ether and/or propylene oxide; the halogenated hydrocarbon compound comprises chloroform; the ketone compounds include acetone and/or methyl butanone.
7. The method for preparing a drug balloon according to any one of claims 4 to 6, wherein the mass ratio of the drug to the solvent is 1 (0.002 to 50).
8. The method for preparing a drug balloon according to any one of claims 5 to 6, wherein the alcohol compound is a compound having carbon number of 15 or less.
9. A method of preparing a pharmaceutical balloon according to any one of claims 5-6,
the alcohol compound is at least one selected from ethanol, methanol, isopropanol, propanol, n-butanol, isobutanol and sec-butanol.
10. A method of preparing a drug balloon according to any of claims 4-6 wherein in the dissolving step, the drug and carrier are added to the solvent followed by stirring, ultrasonic agitation and standing.
11. The method of claim 10, wherein the resting time is 0.5-1.5 hours.
12. A method of preparing a pharmaceutical balloon according to any of claims 4-6, wherein the coating means comprises spray coating, dip coating or drop coating.
13. Use of a pharmaceutical balloon prepared by the method for preparing a pharmaceutical balloon according to any one of claims 4-12 for preparing a product for stenotic dilation and restenosis inhibition of a vessel, urethra or ureteral lumen; the blood vessels include coronary vessels, peripheral vessels, intracranial vessels, and arteriovenous fistula vessels; the urethra comprises a prostatic urethra, a bulbar urethra, a membranous urethra and a penile urethra.
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DE102007036685A1 (en) * 2007-08-03 2009-02-05 Innora Gmbh Improved drug-coated medical devices their manufacture and use
CN101239216A (en) * 2008-02-20 2008-08-13 上海赢生医疗科技有限公司 Novel sacculus dilating catheter
DE202009017490U1 (en) * 2009-12-22 2010-04-08 Sellin, Lothar Frankincense and / or boswellic acid coating
WO2014008875A1 (en) * 2012-07-12 2014-01-16 Cardionovum Gmbh Catheter balloon, method for producing a coated catheter balloon and use of the pharmacological active ingredient
DE102013104029A1 (en) * 2013-04-22 2014-10-23 Innora Gmbh balloon catheter
CN209713964U (en) * 2018-04-12 2019-12-03 中国医学科学院阜外医院 A kind of sacculus for biological body vessel bifurcated lesions

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