CN114870096B - Balloon catheter coating, preparation method thereof and balloon catheter - Google Patents
Balloon catheter coating, preparation method thereof and balloon catheter Download PDFInfo
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- CN114870096B CN114870096B CN202210797063.9A CN202210797063A CN114870096B CN 114870096 B CN114870096 B CN 114870096B CN 202210797063 A CN202210797063 A CN 202210797063A CN 114870096 B CN114870096 B CN 114870096B
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- balloon catheter
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- sirolimus
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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
- A61L29/085—Macromolecular materials
-
- 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
- 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
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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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
- 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
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
- A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention provides a balloon catheter coating, a preparation method thereof and a balloon catheter. The balloon catheter coating comprises drug-loaded microspheres and a lipophilic material, wherein the drug-loaded microspheres are dispersed in the lipophilic material; the drug-loaded microspheres comprise sirolimus drugs and shells wrapping the drugs, and the shells comprise polylactic acid-glycolic acid copolymers; the lipophilic material comprises phospholipid compounds with phase transition temperature above 40 ℃. The coating of the invention is stable, less lost during delivery, and more uniform and robust.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a balloon catheter coating, a preparation method thereof and a balloon catheter.
Background
With the aging population and the change of dietary structure, arterial occlusive diseases (cardiovascular and cerebrovascular diseases) caused by Atherosclerosis (AS) become the leading cause of human death. Currently, percutaneous transluminal angioplasty and endovascular stent placement have become the primary means for treating vascular stenosis. The high pressure dilation of the balloon into the lesion site causes some physical damage to the vessel, such as endothelial cell destruction, rupture of the internal elastic lamina, and stripping of the media of the vessel, which often also extends into the adventitia of the external artery. Although implantation of the balloon restores the vascular access to normal, restenosis is difficult to avoid due to mechanical injury.
Currently, one strategy to reduce the restenosis response is to release drugs into the blood vessel in conjunction with balloon dilation therapy to counteract the inflammatory and healing responses, such as with a rapamycin drug balloon catheter. Rapamycin and its analogs have both antiproliferative and anti-inflammatory activity and are of greater biological safety. However, the drug release of the existing rapamycin drug balloon catheter is too fast, and the vascular thrombosis and restenosis can not be effectively inhibited; the non-lipophilic rapamycin coating is difficult to adhere to the surface of the balloon and absorb by vascular tissues; moreover, the coating is easily washed away by blood, and even if a small amount of rapamycin is absorbed, the therapeutic effect can be maintained for only a few days.
Therefore, it is a focus of research in the art to develop a new drug balloon catheter and simultaneously solve the problem of adsorption and absorption of non-lipophilic drugs to blood vessels.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a balloon catheter coating, a preparation method thereof and a balloon catheter. The balloon catheter coating solves the problems of stability of the coating of the non-lipophilic drug balloon catheter and adsorption and absorption of non-lipophilic substances and blood vessels, and realizes controllable drug release period, so that the drug can exert efficacy in vivo for a long time.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a balloon catheter coating, which comprises drug-loaded microspheres and a lipophilic material, wherein the drug-loaded microspheres are dispersed in the lipophilic material;
the drug-loaded microspheres comprise sirolimus drugs and shells wrapping the drugs, and the shells comprise polylactic acid-glycolic acid copolymers;
the lipophilic material includes phospholipid compounds with phase transition temperature above 25 deg.C (such as 25 deg.C, 26 deg.C, 28 deg.C, 30 deg.C, 32 deg.C, 34 deg.C, 36 deg.C, 38 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 80 deg.C, 100 deg.C, etc.).
In the invention, sirolimus (also named as rapamycin) drugs are selected, and the drugs of sirolimus and analogs thereof have antiproliferative activity, anti-inflammatory activity and better biological safety, but the drugs of sirolimus and analogs thereof are released too fast and are easily washed by blood, and even if a small amount of drugs are absorbed, the treatment effect can only be maintained for several days. Therefore, the invention selects polylactic acid-glycolic acid copolymer (PLGA for short) to coat the drug-loaded microspheres, the drug-loaded microspheres with different sizes prepared from PLGAs with different molecular weights have different release periods, and the release period of the drug in the balloon catheter coating can be controlled by controlling the release period of the microspheres.
In the invention, the lipophilic material comprises phospholipid compounds with the phase transition temperature of more than 25 ℃, and on one hand, the lipophilic material can help the drug to be absorbed by walls better; on the other hand, under the storage condition of normal temperature or higher temperature, the phospholipid compound with the phase transition temperature of more than 25 ℃ can exist in a solid state form, the coating is more stable, the drug-loaded microspheres are dispersed in the lipophilic material, and the loss in the delivery process is less.
In the present invention, the sirolimus drug includes sirolimus and/or a sirolimus derivative.
In the present invention, the sirolimus derivative includes everolimus and/or zotemsirolimus.
In the present invention, the polylactic acid-glycolic acid copolymer has a relative molecular mass of 30000 to 140000, and may be, for example, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 110000, 120000, 130000, 140000, or the like.
In the present invention, the polylactic acid-glycolic acid copolymer has a relative molecular mass of 30000-50000, such as 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000, 50000, etc., and the drug-loaded microspheres have an in vitro release half-life of 30-100 days, such as 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, etc.;
alternatively, the polylactic acid-glycolic acid copolymer has a relative molecular mass of 50000-100000, such as 50000, 60000, 70000, 80000, 90000, 100000, etc., and the drug-loaded microspheres have an in vitro release half-life of 100-300 days, such as 100 days, 120 days, 140 days, 160 days, 180 days, 200 days, 220 days, 240 days, 260 days, 280 days, 300 days, etc.;
or the relative molecular mass of the polylactic acid-glycolic acid copolymer is 100000-140000, such as 100000, 110000, 120000, 130000, 140000 and the like, and the in vitro release half-life of the drug-loaded microsphere is 300-1000 days, such as 300 days, 400 days, 500 days, 600 days, 700 days, 800 days, 900 days and 1000 days.
In the present invention, the particle size of the drug-loaded microspheres is 100 nm to 10 μm, and may be, for example, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, or the like.
In the present invention, the mass ratio of the polylactic acid-glycolic acid copolymer to the sirolimus drug is (0.5-5) from 1, for example, from 0.5; and/or the mass ratio of the sirolimus drug to the lipophilic material is (0.1-5): 1, for example, 0.1 2 For example, it may be 0.1. Mu.g/mm 2 、0.2 μg/mm 2 、0.4 μg/mm 2 、0.6 μg/mm 2 、0.8 μg/mm 2 、1 μg/mm 2 、1.5 μg/mm 2 、2 μg/mm 2 、2.5 μg/mm 2 、3 μg/mm 2 、3.5 μg/mm 2 、4 μg/mm 2 And so on.
If the proportion of the lipophilic material is further increased, the medicinal auxiliary materials are excessive, adverse reactions are caused, and if the proportion of the lipophilic material is further reduced, the hardness of the coating is changed, and the coating cannot help the adherent absorption of the medicine.
In the present invention, the lipophilic material further comprises cholesterol and/or fatty acid.
In the present invention, the lipophilic material is a combination of a phospholipid compound having a phase transition temperature of 25 ℃ or higher and cholesterol, and the mass ratio of the phospholipid compound to the cholesterol is (0.2-5): 1, 0.5.
In the present invention, the lipophilic material is a combination of a phospholipid compound having a phase transition temperature of 25 ℃ or higher and a fatty acid, and the mass ratio of the phospholipid compound to the fatty acid is (0.2 to 5): 1, 0.5.
In the present invention, the cholesterol includes DC-cholesterol and/or cholesterol.
In the present invention, the fatty acid includes any one of palmitic acid, stearic acid, lauric acid, myristic acid or arachidic acid, or a combination of at least two thereof.
In the present invention, the phospholipid compound is an amphiphilic phospholipid compound.
In the present invention, the phospholipid compound includes any one of or a combination of at least two of phosphatidylcholine dipalmitoyl, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine and distearoylphosphatidylethanolamine.
In the present invention, in the lipophilic material, the dispersion density of the drug-loaded microspheres is 10 3 -10 5 Per mm 2 May be, for example, 10 3 Per mm 2 、5×10 3 Per mm 2 、10 4 Per mm 2 、5×10 4 Per mm 2 、10 5 Per mm 2 And so on.
In the invention, the balloon catheter coating further comprises PEG-lipid and/or hydrophilic pharmaceutic adjuvant.
In the present invention, the addition of a small amount of PEG-lipid can increase coating firmness and biocompatibility.
In the invention, a small amount of hydrophilic pharmaceutic adjuvants are added, so that the coating of the balloon can be more easily dissolved in the expansion process, and the drug absorption rate of blood vessels is increased.
In the present invention, the PEG-lipid comprises 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-NMethoxy (polyethylene glycol) and/or 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol).
In the present invention, the number average molecular weight of the polyethylene glycol is 300 to 5000, and may be, for example, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or the like.
In the present invention, the mass ratio of the PEG-lipid and the phospholipid compound is (1-20): 100, e.g. can be 1.
In the present invention, the hydrophilic pharmaceutical excipients include any one of hyaluronic acid, mannitol, or water-soluble crystalline sugar, or a combination of at least two thereof.
The invention also provides a preparation method of the balloon catheter coating, which comprises the following steps:
(1) Preparing a coating solution: mixing the drug-loaded microspheres, the lipophilic material and a solvent to obtain a coating solution;
(2) Spraying: and (2) spraying the coating solution obtained in the step (1) on the surface of the balloon body of the balloon catheter under a stirring state to form the balloon catheter coating.
In the present invention, in the step (1), the mixing temperature is 0 to 37 ℃, for example, 0 ℃, 5 ℃,10 ℃, 15 ℃, 20 ℃, 25 ℃,30 ℃, 35 ℃, 37 ℃ and the like, and the mixing time is 1 to 10 min, for example, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min and the like.
In the invention, in the coating solution in step (1), the concentration of the drug-loaded microspheres is 10-30 g/L, such as 10 g/L, 12 g/L, 14 g/L, 16 g/L, 18 g/L, 20 g/L, 22 g/L, 24 g/L, 26 g/L, 28 g/L, 30 g/L, etc., and the concentration of the lipophilic material is 10-30 g/L, such as 10 g/L, 12 g/L, 14 g/L, 16 g/L, 18 g/L, 20 g/L, 22 g/L, 24 g/L, 26 g/L, 28 g/L, 30 g/L, etc.
In the present invention, in the step (1), the solvent includes any one of methanol, ethanol, acetone, isopropanol, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, n-heptane, n-hexane, cyclohexane or water or a combination of at least two thereof.
In the present invention, in step (1), each raw material for preparing the balloon catheter coating layer is dried before the coating solution is prepared.
In the present invention, in the step (2), the rotation speed of the stirring is 500 to 10000 rpm, and may be, for example, 500 rpm, 1000 rpm, 2000 rpm, 3000 rpm, 4000 rpm, 5000 rpm, 6000 rpm, 7000 rpm, 8000 rpm, 9000 rpm, 10000 rpm, or the like.
In the present invention, in the step (2), the spraying is ultrasonic atomization spraying.
In the present invention, in the step (2), the power of the spraying is 0.2 to 5W, for example, 0.2W, 0.5W, 0.8W, 1W, 1.5W, 2W, 2.5W, 3W, 5W, etc., the temperature is 20 to 50 ℃, for example, 20 ℃, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃, etc., and the gas pressure is 0.01 to 0.3 MPa, for example, 0.01 MPa, 0.05 MPa, 0.1 MPa, 0.15 MPa, 0.2 MPa, 0.25 MPa, 0.3 MPa, etc.
In the present invention, in the step (2), the spraying is in the range of 10 to 300 mm, for example, 10 mm, 20 mm, 30 mm, 40 mm, 50 mm, 300 mm, etc.
In the present invention, in step (2), the flow rate of the sprayed pharmaceutical solution is preferably 0.1 to 1.0 mL/min, and may be, for example, 0.1 mL/min, 0.2 mL/min, 0.5 mL/min, 0.8 mL/min, 1.0 mL/min, or the like.
In the present invention, in step (2), the relative humidity of the environment for spraying is 45-60%, for example, 45%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, etc.
In the invention, in the step (2), after the balloon catheter coating is formed, the balloon catheter coating is dried, and the balloon body part of the balloon is compressed by a folding winder to obtain the size of the blood vessel entering the human body.
In the present invention, the size of the blood vessel entering the human body is 0.1-2.0 mm, and may be, for example, 0.1 mm, 0.2 mm, 0.4 mm, 0.6mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm, 1.8 mm, 2.0 mm, etc.
In the present invention, the coating solution further comprises PEG-lipid and/or hydrophilic pharmaceutical excipients.
The invention also provides a balloon catheter which comprises the balloon catheter coating.
Compared with the prior art, the invention has the following beneficial effects:
(1) The balloon catheter coating can control the release period of the drug in vivo by controlling the molecular weight and the diameter of the drug-coated microspheres;
(2) According to the invention, the coating is constructed by combining the amphiphilic phospholipid with the phase transition temperature of more than 25 ℃, so that the phospholipid exists in a solid state under the condition of normal-temperature storage, the coating is more stable, the loss in the delivery process is less, the suspension used in spraying needs to be continuously stirred, and the spraying is more uniform and firmer;
(3) The invention adds a small amount of hydrophilic pharmaceutic adjuvant excipient, so that the coating is easier to dissolve in the expansion process of the balloon, thereby increasing the drug absorption rate of blood vessels.
Drawings
Fig. 1 is an appearance diagram of the drug balloon provided in example 1.
Fig. 2 is an appearance diagram of the drug balloon provided in comparative example 1.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
All of the starting materials in the following examples and comparative examples are commercially available.
Example 1
The embodiment provides a sacculus pipe coating, sacculus pipe coating includes medicine carrying microsphere and lipophilic material, medicine carrying microsphere disperses in lipophilic material, the dispersion density of medicine carrying microsphereIs 1 mu g/mm 2 ；
The drug-loaded microsphere comprises a core and a shell, wherein the core is sirolimus, and the shell is a polylactic acid-glycolic acid copolymer (the relative molecular weight is 40000); the particle size of the drug-loaded microspheres is 5 μm; the lipophilic material is dimyristoyl phosphatidylcholine;
the balloon catheter coating further comprises DSPE-mPEG 650 accounting for 10% of the mass of dimyristoyl phosphatidylcholine, and hyaluronic acid accounting for 25% of the mass of dimyristoyl phosphatidylcholine;
the balloon catheter coating described in this example was prepared by the following method:
(a) Pretreatment: respectively drying the drug-loaded microspheres, dimyristoyl phosphatidylcholine, DSPE-mPEG 650 and hyaluronic acid;
(b) Preparing a coating solution: mixing 150 mg of drug-loaded microspheres, 80mg of dimyristoyl phosphatidylcholine, 8 mg of DSPE-mPEG 650 and 20 mg of hyaluronic acid in 10 mg of n-heptane at 25 ℃ and performing ultrasonic treatment for 10 min to obtain a coating solution;
(c) Spraying: stirring the coating solution at the rotating speed of 2000 rpm, performing the spraying operation by using ultrasonic atomization spraying equipment, and spraying the coating solution on the surface of the balloon body of the balloon catheter to form the balloon catheter coating;
wherein the spraying power is 2W, the temperature is 30 ℃, and the air pressure is 0.1 MPa; the spraying range is 40 mm; the flow rate of the sprayed medicinal solution is preferably 0.5 mL/min; the relative humidity of the spraying environment is 50%;
(d) And (3) post-treatment: after the balloon catheter coating is formed, the balloon catheter is dried, and the balloon body part of the balloon is compressed by a folding winder to obtain the size (the specific size is 0.6 mm) of the blood vessel entering the human body.
Example 2
The embodiment provides a sacculus pipe coating, sacculus pipe coating includes medicine carrying microsphere and lipophilic material, medicine carrying microsphere disperses in lipophilic material, medicine carrying microsphere's dispersion density is 1 microgram/mm 2 ；
The inner core of the drug-loaded microsphere is sirolimus, and the outer shell is polylactic acid-glycolic acid copolymer (the relative molecular weight is 40000); the particle size of the drug-loaded microspheres is 2 μm; the lipophilic material is phosphatidylcholine dipalmitate;
the balloon catheter coating further comprises DSPE-mPEG 5000 accounting for 5% of the mass of the phosphatidylcholine dipalmitate, and hyaluronic acid accounting for 15% of the mass of the phosphatidylcholine dipalmitate;
the balloon catheter coating is prepared by the following preparation method:
(a) Pretreatment: respectively drying the drug-loaded microspheres, the phosphatidylcholine dipalmitate, the DSPE-mPEG 5000 and the hyaluronic acid;
(b) Preparing a coating solution: mixing 150 mg of drug-loaded microspheres, 80mg of phosphatidylcholine dipalmitate, 4 mg of DSPE-mPEG 5000 and 12 mg of hyaluronic acid in 10 mg of n-heptane at 25 ℃ and carrying out ultrasonic treatment for 10 min to obtain a coating solution;
(c) Spraying: stirring the coating solution at the rotating speed of 1000 rpm, performing the spraying operation by using ultrasonic atomization spraying equipment, and spraying the coating solution onto the surface of the balloon catheter balloon to form the balloon catheter coating;
wherein the spraying power is 3W, the temperature is 40 ℃, and the air pressure is 0.2 MPa; the spraying range is 40 mm; the flow rate of the sprayed medicinal solution is preferably 0.6 mL/min; the relative humidity of the spraying environment is 45 percent;
(d) And (3) post-treatment: after the balloon catheter coating is formed, the balloon catheter coating needs to be dried, and the balloon body part of the balloon is compressed by a folding winder to obtain the size (the specific size diameter is 0.6 mm) of the blood vessel entering the human body.
Example 3
The embodiment provides a sacculus pipe coating, sacculus pipe coating includes medicine carrying microsphere and lipophilic material, medicine carrying microsphere disperses in lipophilic material, medicine carrying microsphere's dispersion density is 1 microgram/mm 2 ；
The drug-loaded microsphere has a kernel of zothamus and a shell of polylactic acid-glycolic acid copolymer (the relative molecular weight is 40000); the particle size of the drug-loaded microspheres is 8 μm; the lipophilic material is phosphatidylcholine dipalmitate;
the balloon catheter coating further comprises DOPE-mPEG 2000 at 3% by mass of the phosphatidylcholine dipalmitate, and mannitol at 10% by mass of the phosphatidylcholine dipalmitate;
the balloon catheter coating is prepared by the following preparation method:
(a) Pretreatment: respectively drying the drug-loaded microspheres, the phosphatidylcholine dipalmitate, the DOPE-mPEG 2000 and the mannitol;
(b) Preparing a coating solution: mixing 150 mg of drug-loaded microspheres, 80mg of phosphatidylcholine dipalmitate, 2.4 mg of DOPE-mPEG 2000 and 8 mg of mannitol in 10 mg of n-heptane at 25 ℃ and carrying out ultrasonic treatment for 10 min to obtain a coating solution;
(c) Spraying: stirring the coating solution at the rotating speed of 3000 rpm, performing the spraying operation by using ultrasonic atomization spraying equipment, and spraying the coating solution on the surface of the balloon body of the balloon catheter to form the balloon catheter coating;
wherein the spraying power is 4W, the temperature is 20 ℃, and the air pressure is 0.3 MPa; the spraying range is 40 mm; the flow rate of the sprayed medicinal solution is preferably 0.8 mL/min; the relative humidity of the spraying environment is 60%;
(d) And (3) post-treatment: after the balloon catheter coating is formed, the balloon catheter coating needs to be dried, and the balloon body part of the balloon is compressed by a folding winder to obtain the size (the specific size is that of the blood vessel entering the human body)0.6mm）。
Example 4
This example provides a balloon catheter coating that differs from example 1 only in that the polylactic acid-glycolic acid copolymer of the outer shell of the drug-loaded microspheres has a relative molecular weight of 45000.
Example 5
This example provides a balloon catheter coating differing from example 1 only in that the polylactic acid-glycolic acid copolymer of the outer shell of the drug-loaded microspheres has a relative molecular weight of 90000.
Example 6
This example provides a balloon catheter coating differing from example 1 only in that the polylactic acid-glycolic acid copolymer of the outer shell of the drug-loaded microspheres has a relative molecular weight of 15000.
Example 7
This example provides a balloon catheter coating differing from example 1 only in that the polylactic acid-glycolic acid copolymer of the outer shell of the drug-loaded microspheres has a relative molecular weight of 120000.
Example 8
This example provides a balloon catheter coating differing from example 1 only in that the lipophilic material is a combination of dimyristoylphosphatidylcholine and DC-cholesterol in a mass ratio of 1.
Example 9
This example provides a balloon catheter coating differing from example 1 only in that the lipophilic material is a combination of dimyristoylphosphatidylcholine and palmitic acid in a mass ratio of 2.5.
Example 10
This example provides a balloon catheter coating that differs from example 1 only in that no DSPE-mPEG 650 was added and dimyristoylphosphatidylcholine was supplemented to 88 mg.
Example 11
This example provides a balloon catheter coating differing from example 1 only in that, without the addition of hyaluronic acid, dimyristoyl phosphatidylcholine supplemented to 100 mg.
Example 12
This example provides a balloon catheter coating that differs from example 1 only in that step (a) is not dried, and the other steps are the same as example 1.
Comparative example 1
This comparative example provides a balloon catheter coating, which differs from example 1 only in that dimyristoyl phosphatidylcholine is replaced with equal mass of egg yolk lecithin (PC-98T, phase transition temperature-8 ℃), and the other steps are the same as example 1.
Comparative example 2
This comparative example provides a balloon catheter coating differing from example 1 only in that dimyristoyl phosphatidylcholine was replaced with equal mass of 1-stearoyl-2-oleoyl lecithin (SOPC, phase transition temperature 6 ℃), and the other steps were the same as example 1.
Test example 1
Folding winding compression stability test
Test samples: the balloon catheter coatings provided in examples 1-12, the balloon catheter coatings provided in comparative examples 1-2;
the test method comprises the following steps: folding and winding the sprayed saccule, testing the drug-loading rate on the saccule surface before and after folding, calculating the shedding percentage in the process,
the specific test results are shown in table 1 below:
TABLE 1
The test results in table 1 show that the balloon catheter coating of the invention has excellent performance in the folding, winding and falling-off experiment, and the falling-off percentage is below 10%; the results show that the phospholipid exists in a solid state under the condition of normal-temperature storage, the coating is more stable, the loss in the delivery process is less, the suspension used for spraying needs to be continuously stirred, and the spraying is more uniform and firmer.
In particular, fig. 1 is the drug balloon appearance (unfolded after folding and winding) of phospholipids with a phase transition temperature above 25 ℃ provided in example 1; fig. 2 shows the appearance of the drug balloon (folded and wound and then unfolded) of the phospholipid of which the phase transition temperature is below 25 ℃ in comparative example 1, and as is clear from comparison between fig. 1 and fig. 2, the phospholipid of which the phase transition temperature is above 25 ℃ in example 1 can further ensure that the phospholipid exists in a solid state and the coating is more stable under the storage condition of normal temperature or higher temperature, while the phospholipid of which the phase transition temperature is below 25 ℃ in comparative example 1 shows that the coating falls off at a plurality of positions on the appearance of the drug balloon.
Test example 2
Drug absorption test
Test samples: the balloon catheter coatings provided in examples 1-12, the balloon catheter coatings provided in comparative examples 1-2;
the test method comprises the following steps: implanting each group of samples into rabbit blood vessels with corresponding animal numbers by a liquid chromatography (HPLC) detection method, and detecting the drugs detected in tissues 1 hour after the group of samples are implanted into the domestic pigs;
the specific test results are shown in table 2 below:
TABLE 2
As can be seen from the test results in Table 2, the more the drug is detected in the blood vessel after 1 h, the more the microspheres are transferred to the blood vessel wall by the balloon, and the better the absorption is. Wherein, the coating of medicine sacculus is comparatively stable in the embodiment, has stable medicine carrying microballon to transfer to the vascular wall. The results of the comparative examples show that: the drug-loaded microspheres transferred to the blood vessels by using the phospholipid coating with the phase transition temperature lower than 25 ℃ have less amount and larger data fluctuation. This may be due to the coating being unstable and the majority of the drug loaded microspheres having been lost during the delivery process.
Test example 3
Microsphere in vitro release assay
Microspheres prepared from PLGA of different molecular weights were subjected to a simulated in vitro release experiment by the following method:
10 mg of drug-loaded microspheres (all microspheres are made by the same department, wherein the molecular weight of PLGA in microsphere 1 is 40000, that of PLGA in microsphere 2 is 60000, that of PLGA in microsphere 3 is 75000, and that of PLGA in microsphere 4 is 120000) were weighed and placed in a 10 mL centrifuge tube, and 6.0 mL of PBS-0.1% SDS (pH 7.4, 37 ℃) was added thereto. Placing in a constant temperature oscillator, controlling the temperature at 37 + -0.5 deg.C, rotating at 200 r/min, taking out centrifuge tube at different time points, centrifuging at 3000 r for 10 min, taking supernatant 5 mL, supplementing constant temperature release medium with equal amount, measuring release amount at 279 nm by ultraviolet spectrophotometry, and calculating cumulative release percentage for 7 days. The release results for 7 days for microspheres prepared from PLGA of different viscosities were fitted to Higuchi equation using Origin software and the half-lives of the microspheres of different molecular weights were calculated.
The specific results are shown in table 3 below:
TABLE 3
The single rapamycin is proved to be capable of maintaining effective concentration in vivo for only a few days, and cannot meet the long-acting treatment effect of the drug balloon, so that the long-acting slow release effect is required to be achieved by coating with high polymers.
The release process of the microspheres was simulated by in vitro tests, and the results in table 3 show that: the release rate of the microspheres can be effectively controlled by controlling the molecular weight of the PLGA microspheres and the size of the prepared microspheres, so that the rapamycin microspheres transferred to the vessel wall have a slow-release effect.
The applicant states that the invention is described by the above embodiments of the balloon catheter coating, the preparation method thereof and the balloon catheter, but the invention is not limited to the above process steps, i.e. the invention does not depend on the above process steps to be implemented. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Claims (9)
1. The balloon catheter coating is characterized by comprising drug-loaded microspheres, a lipophilic material, PEG-lipid and a hydrophilic pharmaceutic adjuvant, wherein the drug-loaded microspheres are dispersed in the lipophilic material, and the lipophilic material comprises a phospholipid compound;
the drug-loaded microsphere comprises a sirolimus drug and a shell wrapping the drug, wherein the shell comprises a polylactic acid-glycolic acid copolymer;
the phospholipid compound is any one of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine and distearoyl phosphatidylethanolamine;
the relative molecular mass of the polylactic acid-glycolic acid copolymer is 30000-50000, and the in vitro release half-life period of the drug-loaded microsphere is 30-100 days;
or the polylactic acid-glycolic acid copolymer has the relative molecular weight of 50000-100000, and the in-vitro release half-life period of the drug-loaded microsphere is 100-300 days;
or the relative molecular weight of the polylactic acid-glycolic acid copolymer is 100000-140000, and the in vitro release half-life of the drug-loaded microsphere is 300-1000 days;
the hydrophilic pharmaceutic adjuvant comprises hyaluronic acid and/or mannitol;
the PEG-lipid comprises 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine-NMethoxy (polyethylene glycol) and/or 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol);
the particle size of the drug-loaded microspheres is 100 nm-10 μm;
the preparation method of the balloon catheter coating comprises the following steps:
(1) Preparing a coating solution: mixing the drug-loaded microspheres, lipophilic materials, PEG-lipid, hydrophilic pharmaceutic adjuvants and a solvent to obtain a coating solution;
(2) Spraying: spraying the coating solution obtained in the step (1) on the surface of the balloon body of the balloon catheter under a stirring state to form a balloon catheter coating;
in the step (1), before the coating solution is prepared, all preparation raw materials of the balloon catheter coating are required to be dried.
2. A balloon catheter coating according to claim 1, wherein the sirolimus drug comprises sirolimus and/or a sirolimus derivative.
3. A balloon catheter coating according to claim 1, wherein the polylactic-co-glycolic acid isThe mass ratio of the copolymer to the sirolimus medicament is (0.5-5) to 1; and/or the mass ratio of the sirolimus medicament to the lipophilic material is (0.1-5): 1, and the medicament loading rate of the sirolimus medicament in the coating is 0.1-4 mu g/mm 2 。
4. The balloon catheter coating of claim 1 wherein the lipophilic material further comprises cholesterol and/or fatty acid.
5. A balloon catheter coating according to claim 1, wherein the phospholipid compound is an amphiphilic phospholipid compound.
6. The balloon catheter coating of claim 1, wherein the drug-loaded microspheres have a dispersion density of 10 in the lipophilic material 3 -10 5 Per mm 2 。
7. The balloon catheter coating of claim 1, wherein the mass ratio of the PEG-lipid to the phospholipid compound is (1-20): 100, and/or the mass ratio of the hydrophilic pharmaceutical excipient to the phospholipid compound is (5-40): 100.
8. A method of making a balloon catheter coating according to any one of claims 1-7, comprising the steps of:
(1) Preparing a coating solution: mixing the drug-loaded microspheres, lipophilic materials, PEG-lipid, hydrophilic pharmaceutic adjuvants and a solvent to obtain a coating solution;
(2) Spraying: and (2) spraying the coating solution obtained in the step (1) on the surface of the balloon body of the balloon catheter under a stirring state to form the balloon catheter coating.
9. A balloon catheter comprising a balloon catheter coating according to any one of claims 1-7.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211090040.0A CN116271254B (en) | 2022-07-08 | 2022-07-08 | Balloon catheter coating, preparation method thereof and balloon catheter |
| CN202210797063.9A CN114870096B (en) | 2022-07-08 | 2022-07-08 | Balloon catheter coating, preparation method thereof and balloon catheter |
| PCT/CN2023/100094 WO2024007830A1 (en) | 2022-07-08 | 2023-06-14 | Balloon catheter coating, method for preparing same, and balloon catheter |
Applications Claiming Priority (1)
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| CN115957383A (en) * | 2021-10-12 | 2023-04-14 | 凯诺威医疗科技(武汉)有限公司 | Interventional medical instrument |
| CN116271254B (en) * | 2022-07-08 | 2024-04-02 | 上海申淇医疗科技有限公司 | Balloon catheter coating, preparation method thereof and balloon catheter |
| CN115501395B (en) * | 2022-09-22 | 2023-11-03 | 广东博迈医疗科技股份有限公司 | Medicine carrying saccule and preparation method thereof |
| CN115581848B (en) * | 2022-10-17 | 2024-05-24 | 上海申淇医疗科技有限公司 | Preparation method of medicine saccule |
| CN116172980A (en) * | 2022-12-28 | 2023-05-30 | 上海百心安生物技术股份有限公司 | Micelle microsphere with core-shell structure and preparation method and application thereof |
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- 2022-07-08 CN CN202210797063.9A patent/CN114870096B/en active Active
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| WO2024007830A1 (en) | 2024-01-11 |
| CN114870096A (en) | 2022-08-09 |
| CN116271254B (en) | 2024-04-02 |
| CN116271254A (en) | 2023-06-23 |
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