CN110201243B - Composite drug coating balloon catheter and preparation method thereof - Google Patents
Composite drug coating balloon catheter and preparation method thereof Download PDFInfo
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- CN110201243B CN110201243B CN201910613891.0A CN201910613891A CN110201243B CN 110201243 B CN110201243 B CN 110201243B CN 201910613891 A CN201910613891 A CN 201910613891A CN 110201243 B CN110201243 B CN 110201243B
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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
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- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1002—Balloon catheters characterised by balloon shape
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1036—Making parts for balloon catheter systems, e.g. shafts or distal ends
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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
- A61L2300/40—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61L2300/43—Hormones, e.g. dexamethasone
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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
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
- A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/02—General characteristics of the apparatus characterised by a particular materials
- A61M2205/0238—General characteristics of the apparatus characterised by a particular materials the material being a coating or protective layer
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Abstract
The invention relates to a composite drug coating balloon catheter and a preparation method thereof, belonging to the technical field of medical instruments. A composite drug-coated balloon catheter comprises a balloon and a drug coating covering the surface of the balloon; the drug coating comprises an active drug and a carrier; the carrier comprises a low molecular weight carrier and a high molecular weight carrier, the mass ratio of the active drug in the drug coating to the high molecular weight carrier is 0.2-20, the mass ratio of the low molecular weight carrier to the high molecular weight carrier is 0.5-10, and the drug loading is 0.5-10 ug/mm2. The invention can quickly transfer the medicine and reduce the loss in the conveying process. The integrity of the coating of the drug balloon is ensured; after the drug is transferred to the vascular tissue, part of the drug is temporarily fixed in the carrier and can not be released, and the drug is gradually released along with the degradation and/or dissolution of the high molecular weight carrier, so that the duration of the drug in the tissue is prolonged, the tissue hyperplasia is inhibited for a longer time, and the restenosis rate in the blood vessel is reduced.
Description
Technical Field
The invention relates to a composite drug coating balloon catheter and a preparation method thereof, belonging to the technical field of medical instruments.
Background
Percutaneous Transluminal Angioplasty (PTA) has gone through the stages of bare balloons, bare metal stents, drug eluting stents, drug coated balloons since the last 70 s. The Drug Coated Balloon (DCB) can effectively inhibit smooth muscle cell hyperproliferation so as to reduce restenosis incidence on one hand, and does not need to be placed into a stent on the other hand, thereby reducing inflammation reaction of blood vessel intima, reducing thrombosis risk in the stent, shortening duplex antiplatelet time and reducing bleeding risk. In addition, in clinical studies of coronary artery disease, DCB shows better efficacy and safety in treating in-stent restenosis, small vessel lesions, bifurcation lesions, and also is suitable for patients at high risk of bleeding, patients who are taking oral anticoagulation drugs, or patients who have recently undergone surgical operations. DCB also achieves better therapeutic effects in the treatment of primary stenosis of peripheral vessels and in-stent restenosis. DCB is becoming a hotspot for research with its "interventional non-implantation" advantage.
Braun corporation, b.germany, introduced the first generation of drug balloons to date, and drug balloons from several companies were marketed at home and abroad. The drug balloon of Braun company utilizes iopromide as a contrast agent as a carrier and paclitaxel as a drug coating to be coated on a balloon catheter for treating coronary restenosis, the hydrophilic property of iopromide can improve the transfer rate of lipid-soluble drug paclitaxel to vascular tissues, and the effectiveness of the product in clinical use is ensured. Therefore, improvements to excipients in subsequent DCB development are still in need of continuing, balancing the risk of drug delivery with excessive drug delivery losses and particle size.
Patent application No. CN200880001141.8, relates to a medical device for delivering a therapeutic agent to tissue. The medical device has a layer overlying an outer surface of the medical device. The layer contains a therapeutic agent and an additive. In certain embodiments, the additive has a hydrophilic portion and a drug affinity portion, wherein the drug affinity portion is at least one of the following: a hydrophobic moiety, a moiety that has an affinity to the therapeutic agent through hydrogen bonding, and a moiety that has an affinity to the therapeutic agent through van der Waals interactions. In embodiments, the additive is water soluble. In other embodiments, the additive is at least one of a surfactant and a compound, and the compound has a molecular weight of 80 to 750 or has four or more hydroxyl groups. The patent adopts hydrophilic and lipophilic amphiphilic substances as carriers, can realize transition balance between fat-soluble medicines and the hydrophilicity of vascular tissues, and enables lipophilic medicines to be better contacted and transloaded with the vascular tissues, but the patent adopts a single carrier, so that the contradiction between quick release transloading of medicines, overlarge medicine conveying loss and particles cannot be solved.
Patent application No. CN201310732989.0 relates to a drug-coated balloon catheter including a balloon and a drug coating covering the surface of the balloon. The drug coating comprises an active drug and a carrier; the active drug is paclitaxel, rapamycin, a paclitaxel derivative or a rapamycin derivative; the carrier comprises organic acid salt and polyhydric alcohol, the mass ratio of the active drug in the drug coating to the carrier is 0.2-100, and the mass ratio of the organic acid to the polyhydric alcohol is (0.2-5) to 1. The organic acid salt and the polyhydric alcohol in the drug coating play a role together, so that the premature release of the drug before the balloon catheter is placed into a target site is prevented, the rapid release of the drug from the surface of the balloon and the absorption of the drug by a target tissue are promoted, the drug loss in the conveying process can be reduced, and a better drug transferring effect is achieved.
Patent application number CN201510124482.6 relates to a medicine elution sacculus pipe, including pipe, sacculus body and sacculus surface, still includes hydrophilic lipophilic bottom and medicine carrying coating, hydrophilic lipophilic bottom is located the sacculus on the surface, and medicine carrying coating is located hydrophilic lipophilic bottom above, medicine carrying coating comprises polymer and medicine. The drug eluting balloon catheter has the characteristics of simple structure, simple production process, less drug loss in the conveying process and less drug residue on the balloon after interventional operation. This patent describes a composite coating structure that is divided into a hydrophilic and lipophilic bottom layer and a drug coating, the hydrophilic and lipophilic bottom layer coating can help the drug-loaded coating to load on the balloon surface to form a stable coating, reducing the loss during the delivery process, but the drug carrier of the coating is a polymer, which is prone to form larger particles and risks causing downstream vascular embolization.
The key difficulty of drug balloon coating is how to achieve a balance between the bonding of the drug coating to the balloon surface and the drug release into the vascular tissue. The stable combination between the drug coating and the surface of the balloon can realize less loss of the drug coating in the balloon catheter conveying process and reduce the influence on downstream blood vessels; meanwhile, the rapid release of the drug to the vascular tissue can realize the drug transfer and adsorption of more proportion to the target blood vessel, so as to achieve the purpose of effectively inhibiting the smooth muscle cell hyperproliferation, and the coating structure and the patent coating technology of the products on the market at present are difficult to realize the two key performances, so that a novel composite coating needs to be researched and developed to realize the balance of conveying loss and rapid release. In addition, the prior art controls the drug release by depending on the tissue absorption characteristics and crystallinity of the drug, and compared with a drug stent, the drug release period of the drug balloon is shorter, which is one of the reasons for the defect of the drug balloon in inhibiting restenosis.
Disclosure of Invention
Aiming at the defects that the prior art can not give consideration to the rapid drug transfer and the reduction of the loss in the conveying process, the invention provides a novel composite coating, and the composite coating takes the combination of a high molecular weight carrier and a low molecular weight carrier as a drug carrier and forms a uniformly dispersed coating with a drug for inhibiting tissue hyperplasia.
In order to achieve the purpose, the invention adopts the following technical scheme.
A composite drug coating balloon catheter is characterized by comprising a balloon and a drug coating covering the surface of the balloon; the drug coating comprises an active drug and a carrier; the active medicine is one or more of rapamycin, zotarolimus, paclitaxel, dexamethasone and derivatives thereof; the carrier comprises a low molecular weight carrier and a high molecular weight carrier, the molecular weight of the low molecular weight carrier is 50-2000 Da, the molecular weight of the high molecular weight carrier is 400-40000 Da, the mass ratio of the active drug in the drug coating to the high molecular weight carrier is 0.2-20, the mass ratio of the low molecular weight carrier to the high molecular weight carrier is 0.5-10, and the drug loading rate of the active drug on the surface of the balloon in unit area is 0.5-10 ug/mm2。
The low molecular weight carrier is selected from one or more of polyalcohol, phospholipid, organic acid salt, laurocapram and urea.
The polyalcohol comprises one or more selected from polyethylene glycol, xylitol, mannitol, sorbitol and amino alcohol; the phospholipid is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol; the organic acid salt is selected from one or more of stearate, benzoate, oxalate, aspartate, and nicotinate.
The molecular weight of the low molecular weight carrier is 50-200 Da or 200-2000 Da.
The high molecular weight carrier is selected from one or more of polyalcohol, polyester substances, poloxamer, iopromide, polyvinylpyrrolidone and tween, and has a molecular weight of 400-20000 Da or 5000-40000 Da.
The polyalcohol is one or more of polyethylene glycol and polysorbate; the polyester material is selected from one or more of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate or polyhydroxybutyrate valerate copolymer.
The active drug and the high molecular weight carrier exist in the composite drug coating in the form of composite particles, and the discrete island phase structures are provided, and the particle size of each island phase structure is less than or equal to 20 mu m.
The mass ratio of the active drug in the island phase structure to the high molecular weight carrier is 0.2-20, and above the mass ratio, the amount of the drug encapsulated by the high molecular weight carrier is less, so that the tissue drug concentration in a longer period cannot be maintained; below this ratio, the drug is encapsulated by a large number of high molecular weight carriers, the drug release rate is slow, and the drug does not reach effective tissue drug concentrations in the short term.
The mass ratio of the active drug to the high molecular weight carrier in the drug coating is 0.5-2, the ratio influences the release of the drug in the island phase structure, and further influences the tissue drug concentration, and the mass ratio of the drug to the high molecular weight carrier is lower than 0.5, which may cause slow drug releaseSlow, higher doses may be required to achieve effective tissue drug concentrations; a ratio higher than 2 may result in less encapsulated drug, resulting in a large fraction of drug being released initially and not being able to sustain tissue drug concentrations for a longer period of time (e.g., 60 days). The mass ratio of the low-molecular-weight carrier to the high-molecular-weight carrier is 1-5, the low-molecular-weight carrier aims to form a continuous phase, the ratio is too low, and the high-molecular-weight carrier cannot form a dispersed island phase, so that the drug unloading is difficult; too high a ratio will make the drug/high molecular weight carrier deeply embedded in the low molecular weight carrier less prone to rapid drug transfer to the tissue. The preferable unit area drug loading rate of the active drug on the surface of the balloon is 0.5-4 ug/mm2Under the proper drug/carrier ratio and process conditions, the drug loading rate and the drug slow-release effect are improved, and the dosage of the drug can be further reduced to 0.5-4 ug/mm2。
The high molecular weight carrier is tightly combined with the medicine and uniformly dispersed into the low molecular weight carrier to form an island phase structure, which is beneficial to the unloading of the medicine from the saccule.
The combination of high molecular weight carrier and drug is mixed into the low molecular weight carrier to form a heterogeneous system, and the combination of high molecular weight carrier and drug is dispersed in the continuous low molecular weight carrier, just like the islets are dispersed in the sea, and is called an "island phase" structure. After the coating reaches the target position, the saccule expands, and the sea phase structure of the low molecular weight carrier is easily dissolved in water, so that the island phase can be quickly unloaded from the saccule and transferred into the vascular tissue. On the other hand, the smaller the size of the "island phase", the larger the specific surface area thereof, the larger the surface area per unit mass, and the larger the contact area with the tissue, thereby accelerating the adsorption of the vascular tissue; and when the size of the island phase is smaller than the intimal space of the blood vessel, the island phase substance can penetrate the intima or/and the media of the blood vessel and is deeply buried in the blood vessel, so that the loss of the medicament caused by the flushing of the blood is avoided.
The invention provides a preparation method of three drug-coated balloons, which comprises the following steps:
the method comprises the following steps: a preparation method of a drug-coated balloon comprises the following steps:
1) preparing a solution 1 of a high molecular weight carrier and a medicament, and fully mixing;
2) preparing a solution 2 of a low molecular weight carrier, and fully mixing;
3) mixing the solution 1 and the solution 2 to obtain a coating solution;
4) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5) and drying the coating to obtain the drug-coated balloon catheter.
The preparation method is simple, easy to operate and good in process stability.
The second method comprises the following steps: a preparation method of a drug-coated balloon comprises the following steps:
1) dissolving a high molecular weight carrier and a drug into an organic solvent, and fully mixing to obtain a solution 3; wherein the solvent is one or more selected from chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and acetonitrile.
2) Dissolving a low molecular weight carrier in a solvent, and fully mixing to obtain a solution 4; wherein the solvent is selected from one or more of methanol, ethanol, isopropanol and water;
3) dissolving polyvinylpyrrolidone or polyvinyl alcohol in an aqueous solution to obtain a solution 5;
4) spraying the solution 3 to the solution 5 or water stirred at a high speed by ultrasonic atomization, stirring for more than 1h, and performing suction filtration, cleaning and drying to obtain drug-loaded microspheres with the particle size of not more than 20 um;
5) mixing the drug-loaded microspheres obtained in the step 4) into the solution 4 to obtain a coating solution;
6) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
7) and drying the coating to obtain the drug-coated balloon catheter.
The drug-loaded microspheres prepared by the preparation method can effectively encapsulate drugs and can maintain drug release for a longer time.
The third method comprises the following steps: a preparation method of a drug-coated balloon comprises the following steps:
1) dissolving a high molecular weight carrier and a drug into an organic solvent, and fully mixing to obtain a solution 6; wherein the solvent is selected from one or more of chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and acetonitrile, and the polymer carrier is insoluble in methanol, ethanol, isopropanol and water.
2) Dissolving a low molecular weight carrier in a solvent, and fully mixing to obtain a solution 7; wherein the solvent is selected from one or more of methanol, ethanol, isopropanol and water;
3) spraying the solution 6 into the solution 7 which is stirred at a high speed through ultrasonic atomization to obtain suspension with drug-loaded microspheres, wherein the solution is a coating solution;
4) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5) and drying the coating to obtain the drug-coated balloon catheter.
The third method is the optimization of the first 2 methods, not only the preparation method is simple, but also the high molecular weight carrier can better encapsulate the drug, and the drug release in a longer period is maintained.
The principle of the invention is as follows:
the invention adopts the mixing of a high molecular weight carrier and a low molecular weight carrier, wherein the high molecular weight carrier is characterized in that: the drug coated inside the carrier is gradually dissolved or degraded and gradually released along with the high molecular weight carrier, so that the effect of drug slow release is achieved, and the phenomenon that the drug concentration of local tissues exceeds the toxic concentration due to drug burst release can be avoided.
The low molecular weight carrier is characterized in that: the micromolecule compound can form a uniformly dispersed coating structure with drug molecules and/or drug compounds; secondly, the water solubility is good, the medicine can be dissolved quickly, and the aim of quickly unloading the medicine from the saccule is achieved; and affinity with tissues is good, and transfer of the medicine can be promoted.
The composite coating structure formed by combining the carriers with the two characteristics has the following advantages:
firstly, the drug coating is dispersed uniformly and stably;
under the protection of the high molecular weight carrier, the coating is stable, and the loss of the medicine is less in the process of conveying the catheter to the target lesion position;
thirdly, the high molecular weight carrier is tightly combined with the drug and uniformly dispersed into the low molecular weight carrier to form an island phase structure, which is beneficial to the unloading of the drug from the balloon.
The low molecular weight carrier and the medicament for inhibiting the tissue hyperplasia and/or the medicament compound form a uniformly dispersed coating structure, and the dissolution of the low molecular weight carrier is beneficial to the disintegration of the coating, so that the medicament is quickly transferred to the tissue from the balloon;
the encapsulation effect of the high molecular weight carrier on the drug ensures that the drug release period is longer and the drug concentration maintenance time in tissues is long.
The patents in the background section and the existing drug balloons on the market have two problems:
firstly, the drug transfer rate is low and is not higher than 5%, more drugs are lost in the balloon delivery process, and a large amount of drugs are flushed to downstream blood vessels or organs; therefore, the drug transfer rate is improved, on one hand, the hyperplasia can be effectively inhibited, on the other hand, the initial drug-loading rate of the drug balloon can be reduced, the drug quantity flushed to downstream tissues is reduced, and the toxic and side effects of the drug on downstream blood vessels or organs are reduced.
Second, the effective drug concentration in the tissue is maintained for a short time, not longer than 30 days, because the prior art depends on the tissue absorption property and crystallinity of the drug itself to control the drug release, and the drug release period of the drug balloon is shorter compared with that of the drug stent, which is one of the reasons for the insufficiency of the drug balloon in inhibiting restenosis.
The invention has the following advantages:
the carriers designed by the invention comprise high molecular weight carriers and low molecular weight carriers. The low molecular weight carrier can be embedded between drug molecules in the coating solution, so that the dispersion of the drug in the drug coating can be promoted to be more uniform, the vascular tissue is fully contacted with the drug, and the drug transfer rate is increased; after the low molecular weight carrier is dissolved in the implantation process, the drug is easy to separate from the saccule and is transferred to the blood vessel, so that the transfer rate is improved; however, if the mass fraction of the low molecular weight carrier in the coating is too high, a large amount of drug is lost during delivery, and the molecular weight range and the proportion of the low molecular weight carrier in the drug coating carrier are preferred.
The high molecular weight carrier can be fully combined with the drug, so that the combination of the drug and the balloon is facilitated, and the integrity of the coating of the drug-coated balloon is ensured; in addition, after the drug is transferred to the vascular tissue, part of the drug is temporarily fixed in the high molecular weight carrier and can not be released, and the drug is gradually released along with the degradation and/or dissolution of the high molecular weight carrier, so that the duration of the drug in the tissue is prolonged, the tissue proliferation is inhibited for a longer time, and the restenosis rate in the blood vessel is reduced.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a photograph showing an island phase structure
Detailed Description
Example 1:
firstly, raw materials:
1. medicine preparation: paclitaxel;
2. low molecular weight carrier: mannitol, molecular weight 182;
3. high molecular weight carrier: PEG600, molecular weight 600;
4. purified water, medical grade ethanol.
Second, preparation method
1. Preparing ethanol solution of high molecular weight carrier PEG600 and paclitaxel with concentration of 21mg/ml, wherein the mass ratio of paclitaxel to PEG600 is 20: 1, and mixing thoroughly to obtain solution 1;
2. preparing a low molecular weight carrier mannitol aqueous solution with the concentration of 10mg/ml, and fully mixing to obtain a solution 2;
3. mixing 10ml of solution 1 and 1ml of solution 2 to obtain a coating solution, wherein the mass ratio of the paclitaxel to the high molecular weight carrier to the low molecular weight carrier is 20: 1;
4. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5. drying the coating to obtain the drug-coated balloon catheter and the balloonThe drug loading per unit external surface area is 2.5ug/mm2。
Example 2:
firstly, raw materials:
1. medicine preparation: rapamycin;
2. low molecular weight carrier: phosphatidylcholine, molecular weight 759;
3. high molecular weight carrier: polylactic-co-glycolic acid (PLGA), molecular weight 20000;
4. purified water, medical grade ethyl acetate, medical grade ethanol.
Second, preparation method
1. Dissolving high molecular weight carrier PLGA and rapamycin into ethyl acetate, wherein the concentration is 20mg/ml, the mass ratio of the rapamycin to the PLGA is 1: 1, and fully mixing to obtain a solution 3;
2. dissolving low molecular weight carrier phosphatidylcholine into ethanol, wherein the concentration of the low molecular weight carrier phosphatidylcholine is 10mg/ml, and fully mixing to obtain a solution 4;
3. dissolving polyvinyl alcohol in water to obtain 1mg/ml polyvinyl alcohol solution 5;
4. spraying the solution 3 into the solution 5 which is stirred at a high speed through ultrasonic atomization, continuously stirring for 2 hours, and then performing suction filtration, cleaning and drying to obtain PLGA/rapamycin drug-loaded microspheres with the particle size not more than 20 um;
5. mixing the drug-loaded microspheres obtained in the step 4 into a solution 4 to obtain a coating solution with rapamycin concentration of 10mg/ml, wherein the mass ratio of rapamycin to the high molecular weight carrier to the low molecular weight carrier is 1: 1;
6. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
7. drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 2.5ug/mm2。
Example 3:
firstly, raw materials:
1. medicine preparation: zotarolimus;
2. low molecular weight carrier: PEG400, molecular weight 400;
3. high molecular weight carrier: poloxamer, molecular weight 3000;
4. medical grade ethanol.
Second, preparation method
1. Preparing ethanol solution of poloxamer and zotarolimus as high molecular weight carriers, wherein the concentration of the ethanol solution is 12mg/ml, the mass ratio of the zotarolimus to the poloxamer is 1: 5, and fully mixing to obtain solution 1;
2. preparing ethanol solution of low molecular weight carrier PEG400 with the concentration of 10mg/ml, and fully mixing to obtain solution 2;
3. mixing 10ml of solution 1 and 5ml of solution 2 to obtain a coating solution, wherein the mass ratio of the zotarolimus to the high molecular weight carrier to the low molecular weight carrier is 2: 10: 5;
4. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5. drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 10ug/mm2。
Example 4:
firstly, raw materials:
1. medicine preparation: dexamethasone;
2. low molecular weight carrier: xylitol, molecular weight 152;
3. high molecular weight carrier: iopromide, molecular weight 791;
4. medical grade ethanol.
Second, preparation method
1. Preparing ethanol solution of high molecular weight carrier iopromide and dexamethasone with the concentration of 15mg/ml, wherein the mass ratio of dexamethasone to iopromide is 1: 2, and fully mixing to obtain solution 1;
2. preparing an ethanol solution of a low molecular weight carrier xylitol with the concentration of 50mg/ml, and fully mixing to obtain a solution 2;
3. mixing 10ml of solution 1 and 10ml of solution 2 to obtain a coating solution, wherein the mass ratio of dexamethasone to the high molecular weight carrier to the low molecular weight carrier is 1: 2: 10;
4. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5. drying the coating to obtain the drug-coated balloon catheter with the unit outer surface of the balloonThe drug loading rate of the area is 4ug/mm2。
Example 5:
firstly, raw materials:
1. medicine preparation: paclitaxel;
2. low molecular weight carrier: sodium stearate, molecular weight 306;
3. high molecular weight carrier: polyvinylpyrrolidone, molecular weight 10000;
4. purified water, medical grade ethanol.
Second, preparation method
1. Preparing ethanol solution of high molecular weight carrier polyvinylpyrrolidone and paclitaxel with concentration of 15mg/ml, wherein the mass ratio of paclitaxel to polyvinylpyrrolidone is 2: 1, and mixing thoroughly to obtain solution 1;
2. preparing a low molecular weight carrier sodium stearate aqueous solution with the concentration of 40mg/ml, and fully mixing to obtain a solution 2;
3. mixing 10ml of solution 1 and 2.5ml of solution 2 to obtain a coating solution, wherein the mass ratio of the paclitaxel to the high molecular weight carrier to the low molecular weight carrier is 2: 1: 2;
4. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5. drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 1.5ug/mm2。
Example 6:
firstly, raw materials:
1. medicine preparation: paclitaxel;
2. low molecular weight carrier: mannitol, molecular weight 182;
3. high molecular weight carrier: tween 20, molecular weight 1228;
4. medical grade ethanol.
Second, preparation method
1. Preparing ethanol solution of high molecular weight carrier Tween 20 and paclitaxel with concentration of 12mg/ml, wherein the mass ratio of paclitaxel to Tween 20 is 5: 1, and mixing thoroughly to obtain solution 1;
2. preparing an ethanol solution of a low molecular weight carrier PEG400 with the concentration of 30mg/ml, and fully mixing to obtain a solution 2;
3. mixing 10ml of solution 1 and 1ml of solution 2 to obtain a coating solution, wherein the mass ratio of the paclitaxel to the high molecular weight carrier to the low molecular weight carrier is 10: 2: 3;
4. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5. drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 1ug/mm2。
Example 7:
firstly, raw materials:
1. medicine preparation: paclitaxel;
2. low molecular weight carrier: PEG2000, molecular weight 2000;
3. high molecular weight carrier: poly-racemic lactic acid (PDLLA), molecular weight 40000;
4. medical grade ethanol, medical grade acetone.
Second, preparation method
1) Dissolving high molecular weight carrier poly-dl-lactic acid and paclitaxel into acetone with concentration of 30mg/ml, wherein the mass ratio of paclitaxel to PDLLA is 2: 1, and mixing thoroughly to obtain solution 6;
2) dissolving a low molecular weight carrier PEG2000 in ethanol, and fully mixing the solution with the concentration of 2mg/ml to obtain a solution 7;
3) spraying 2ml of solution 6 into 10ml of solution 7 which is stirred at a high speed through ultrasonic atomization to obtain suspension with drug-loaded microspheres, wherein the solution is a coating solution, and the mass ratio of paclitaxel to high molecular weight carriers to low molecular weight carriers is 10: 5;
4) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5) drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 0.5ug/mm2。
Comparative example:
firstly, raw materials:
1. medicine preparation: paclitaxel;
2. low molecular weight carrier: mannitol, molecular weight 182;
3. medical grade ethanol
Second, preparation method
1. Preparing an ethanol solution of paclitaxel and mannitol with the concentration of 9mg/ml, wherein the mass ratio of the rapamycin to the mannitol is 8: 1, and fully mixing to obtain a coating solution;
2. spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
3. drying the coating to obtain a drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 5ug/mm2。
Example 8: in vitro and in vivo testing
Materials (I) and (II)
The drug-coated balloon catheters prepared in examples 1 to 7 and comparative example were subjected to the test of the drug residue rate and the drug delivery rate.
Secondly, the method comprises the following steps:
1. method for testing drug residue rate and drug loading rate in vitro simulation manner
Pig coronary artery blood vessel is used for simulating target blood vessel for in vitro simulation test. Selecting a proper simulated blood vessel according to the over-expansion ratio of 1.10-1.20, placing the simulated path in a water bath at 37 ℃ for constant temperature, keeping the flow rate of purified water in the path at 300ml/min, inserting the prepared balloon catheter into a simulated target blood vessel (a pig coronary artery blood vessel obtained by dissection) through the simulated path, pressurizing the balloon to about 12atm, maintaining the pressure for 1min, then releasing the pressure of the balloon catheter, taking out the balloon catheter from an in-vitro simulation test system, continuously flushing the target blood vessel for 2min, and collecting target blood vessel tissues and a withdrawn balloon. And respectively testing the content of the residual medicine on the target blood vessel and the saccule by using High Performance Liquid Chromatography (HPLC), and comparing the content with the initial medicine amount of the medicine saccule to obtain the in vitro transfer rate and the in vitro medicine residual rate.
Chromatographic conditions are as follows:
an Agilent 1260 high performance liquid testing system;
a chromatographic column: agilent ZORBAX SB-C184.6X 250mm, 5 μm;
mobile phase, methanol, water and acetonitrile are 23: 41: 36;
column temperature: 30 ℃;
the pump flow rate: 1.0 ml/min;
detection wavelength: 227nm ultraviolet detector.
2. Method for testing tissue drug concentration
The drug-coated saccules are respectively placed in superficial femoral arteries of a healthy miniature pig and marked, the animal is killed at a preset follow-up time point, the target blood vessel at the expansion part of the drug-coated saccule is obtained by dissection, and the target blood vessel is slowly washed for 3 times by using 0.1mol/L PBS solution containing heparin (25000 units of heparin per 1000ml of PBS).
Sucking water on the surface of the target blood vessel, and then weighing the target blood vessel; and measuring the content of the drug in the target blood vessel by using a liquid chromatography-mass spectrometer (LC-MS).
The test conditions for LC-MS were:
liquid chromatography instrument: agilent model 1200 liquid chromatography system;
mass spectrometer: API4000 QTRAP type triple quadrupole tandem mass spectrometer from AB Sciex corporation;
a chromatographic column: venusil XBP C8 chromatography column by bornaegel, size: 2.1X 50mm, 5 μm;
mobile phase conditions: carrying out gradient elution on a phase A (containing 0.1% formic acid aqueous solution) and a phase B (containing 0.1% formic acid acetonitrile solution); column temperature: 30 ℃;
mass spectrum conditions: ESI positive ion detection mode.
Third, experimental results
As can be seen from table 1, compared with the comparative example, the in vitro transfer rate of the drug-coated balloon using the high molecular weight carrier and the low molecular weight carrier composite carrier is significantly improved; the effective tissue drug concentration is also maintained for a longer time, and is expected to have a better effect of inhibiting hyperplasia for a long time.
TABLE 1 in vitro transfer and in vivo tissue drug concentration test Experimental results
The above listing of a series of detailed descriptions is merely a detailed description of possible embodiments of the present invention and is not intended to limit the scope of the invention, and one skilled in the art may devise many other modifications and embodiments that will fall within the spirit and scope of the principles disclosed herein. More specifically, various variations and modifications are possible in the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure, the drawings and the appended claims. In addition to variations and modifications in the component parts and/or arrangements, other uses will also be apparent to those skilled in the art.
Claims (9)
1. A composite drug coating balloon catheter is characterized by comprising a balloon and a drug coating covering the surface of the balloon; the drug coating comprises an active drug and a carrier; the active medicine is one or more of rapamycin, zotarolimus, paclitaxel, dexamethasone and derivatives thereof; the carrier comprises a low molecular weight carrier and a high molecular weight carrier, the molecular weight of the low molecular weight carrier is 50-2000 Da, the molecular weight of the high molecular weight carrier is 5000-40000 Da, the mass ratio of the active drug in the drug coating to the high molecular weight carrier is 0.2-20, the mass ratio of the low molecular weight carrier to the high molecular weight carrier is 0.5-10, and the drug loading rate of the active drug on the surface of the balloon in unit area is 0.5-10 ug/mm2(ii) a The active drug and the high molecular weight carrier exist in the composite drug coating in the form of composite particles, discontinuous island phase structures are formed, and the particle size of each island phase structure is less than or equal to 20 microns.
2. The composite drug-coated balloon catheter as claimed in claim 1, wherein the low molecular weight carrier is selected from the group consisting of polyhydric alcohols, phospholipids, organic acid salts, and azone
One or more of ketone and urea.
3. The composite drug-coated balloon catheter as claimed in claim 2, wherein the polyol comprises one or more selected from polyethylene glycol, xylitol, mannitol, sorbitol, and amino alcohol; the phospholipid is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol; the organic acid salt is selected from one or more of stearate, benzoate, oxalate, aspartate, and nicotinate.
4. The composite drug-coated balloon catheter as claimed in claim 1, wherein the low molecular weight carrier has a molecular weight of 50-200 Da or 200-2000 Da.
5. The balloon catheter with composite drug coating according to claim 1, wherein the high molecular weight carrier is one or more selected from the group consisting of polyol, polyester, poloxamer, iopromide, polyvinylpyrrolidone and tween.
6. The composite drug-coated balloon catheter as claimed in claim 5, wherein the polyol is one or more of polyethylene glycol and polysorbate; the polyester material is selected from one or more of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polybutylene succinate, polyhydroxyalkanoate, polycaprolactone, polyethylene adipate or polyhydroxybutyrate valerate copolymer.
7. The balloon catheter with composite drug coating according to claim 1, wherein the mass ratio of the active drug to the high molecular weight carrier in the island phase structure is 0.2-20.
8. The balloon catheter with a composite drug coating according to any one of claims 1 to 7, wherein the mass ratio of the active drug to the high molecular weight carrier in the drug coating is 0.5 to 2, the mass ratio of the low molecular weight carrier to the high molecular weight carrier is 1 to 5, and the drug loading rate of the active drug on the balloon surface per unit area is 0.5～4ug/mm2。
9. The method for preparing a balloon catheter with a composite drug coating according to any one of claims 1 to 8, which is characterized by comprising any one of the following steps:
the method comprises the following steps: a preparation method of a drug-coated balloon catheter comprises the following steps:
1) preparing a solution 1 of a high molecular weight carrier and a medicament, and fully mixing;
2) preparing a solution 2 of a low molecular weight carrier, and fully mixing;
3) mixing the solution 1 and the solution 2 to obtain a coating solution;
4) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5) drying the coating to obtain a drug-coated balloon catheter;
the second method comprises the following steps: a preparation method of a drug-coated balloon catheter comprises the following steps:
1) dissolving a high molecular weight carrier and a drug into an organic solvent, and fully mixing to obtain a solution 3; wherein the solvent is one or more of chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and acetonitrile;
2) dissolving a low molecular weight carrier in a solvent, and fully mixing to obtain a solution 4; wherein the solvent is selected from one or more of methanol, ethanol, isopropanol and water;
3) dissolving polyvinylpyrrolidone or polyvinyl alcohol in an aqueous solution to obtain a solution 5;
4) spraying the solution 3 to the solution 5 or water stirred at a high speed by ultrasonic atomization, stirring for more than 1h, and performing suction filtration, cleaning and drying to obtain drug-loaded microspheres with the particle size of not more than 20 um;
5) mixing the drug-loaded microspheres obtained in the step 4) into the solution 4 to obtain a coating solution;
6) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
7) drying the coating to obtain a drug-coated balloon catheter;
the third method comprises the following steps: a preparation method of a drug-coated balloon catheter comprises the following steps:
1) dissolving a high molecular weight carrier and a drug into an organic solvent, and fully mixing to obtain a solution 6; wherein the solvent is selected from one or more of chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and acetonitrile, and the high molecular weight carrier is insoluble in methanol, ethanol, isopropanol and water;
2) dissolving a low molecular weight carrier in a solvent, and fully mixing to obtain a solution 7; wherein the solvent is selected from one or more of methanol, ethanol, isopropanol and water;
3) spraying the solution 6 into the solution 7 which is stirred at a high speed through ultrasonic atomization to obtain suspension with drug-loaded microspheres, wherein the suspension is a coating solution;
4) spraying the coating solution to the outer surface of the balloon through ultrasonic atomization;
5) and drying the coating to obtain the drug-coated balloon catheter.
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| CN110882473B (en) * | 2019-12-26 | 2022-04-15 | 科睿驰（深圳）医疗科技发展有限公司 | Medicinal balloon catheter and preparation method thereof |
| CN111035815A (en) * | 2020-01-10 | 2020-04-21 | 卢静 | Medical tracheal catheter, tracheal catheter coating and preparation method thereof |
| CN111298272A (en) * | 2020-03-11 | 2020-06-19 | 科塞尔医疗科技（苏州）有限公司 | Drug-coated balloon, preparation method thereof and drug-coated balloon dilatation catheter |
| CN111671982A (en) * | 2020-05-08 | 2020-09-18 | 北京永益润成科技有限公司 | Medicinal coating composition and preparation method thereof |
| CN113117220B (en) * | 2021-04-14 | 2023-03-21 | 深圳市赛禾医疗技术有限公司 | Medicine balloon catheter, medicine balloon catheter system and control method thereof |
| CN113546286A (en) * | 2021-08-12 | 2021-10-26 | 安徽通灵仿生科技有限公司 | Multi-balloon catheter assembly for interventional treatment of coronary bifurcation lesions |
| CN113813449A (en) * | 2021-08-30 | 2021-12-21 | 孟繁宇 | Preparation method of nanoparticle rapamycin drug-loaded coating balloon |
| CN115957383A (en) * | 2021-10-12 | 2023-04-14 | 凯诺威医疗科技(武汉)有限公司 | Interventional medical instrument |
| CN114377278A (en) * | 2022-01-14 | 2022-04-22 | 浙江介尔欣医疗科技有限公司 | Medicine balloon and preparation method thereof |
| CN116889651A (en) * | 2023-09-11 | 2023-10-17 | 苏州中天医疗器械科技有限公司 | Drug coating for drug coating balloon, and preparation method and application thereof |
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| CN106267377A (en) * | 2015-05-26 | 2017-01-04 | 先健科技(深圳)有限公司 | Drug coated balloon catheter |
| CN108295359A (en) * | 2016-12-30 | 2018-07-20 | 先健科技(深圳)有限公司 | Carry medicine instrument and preparation method thereof |
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| CN106267377A (en) * | 2015-05-26 | 2017-01-04 | 先健科技(深圳)有限公司 | Drug coated balloon catheter |
| CN108295359A (en) * | 2016-12-30 | 2018-07-20 | 先健科技(深圳)有限公司 | Carry medicine instrument and preparation method thereof |
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