CN116585602A - Method for improving utilization rate of medicine on surface of balloon and prepared balloon - Google Patents
Method for improving utilization rate of medicine on surface of balloon and prepared balloon Download PDFInfo
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- CN116585602A CN116585602A CN202310879684.6A CN202310879684A CN116585602A CN 116585602 A CN116585602 A CN 116585602A CN 202310879684 A CN202310879684 A CN 202310879684A CN 116585602 A CN116585602 A CN 116585602A
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- 239000003814 drug Substances 0.000 title claims abstract description 150
- 238000000034 method Methods 0.000 title claims abstract description 51
- 229940079593 drug Drugs 0.000 claims abstract description 102
- 239000002904 solvent Substances 0.000 claims abstract description 101
- 239000011248 coating agent Substances 0.000 claims abstract description 53
- 238000000576 coating method Methods 0.000 claims abstract description 53
- 210000005077 saccule Anatomy 0.000 claims abstract description 24
- 238000001035 drying Methods 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000005507 spraying Methods 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004744 fabric Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000000861 blow drying Methods 0.000 claims description 3
- 238000003618 dip coating Methods 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 238000002791 soaking Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 25
- 230000008569 process Effects 0.000 abstract description 14
- 238000002425 crystallisation Methods 0.000 abstract description 6
- 230000008025 crystallization Effects 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 19
- 239000013078 crystal Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 15
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical class O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 15
- 229930012538 Paclitaxel Natural products 0.000 description 14
- 229960001592 paclitaxel Drugs 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000002245 particle Substances 0.000 description 13
- 210000004204 blood vessel Anatomy 0.000 description 8
- 238000002399 angioplasty Methods 0.000 description 7
- 238000004080 punching Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 6
- 238000004088 simulation Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 208000037803 restenosis Diseases 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
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- 238000004440 column chromatography Methods 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
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Classifications
-
- 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
- A61M25/104—Balloon catheters used for angioplasty
-
- 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
-
- 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
-
- 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
-
- 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
- A61M2025/1075—Balloon catheters with special features or adapted for special applications having a balloon composed of several layers, e.g. by coating or embedding
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Biophysics (AREA)
- Pulmonology (AREA)
- Child & Adolescent Psychology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Vascular Medicine (AREA)
- Manufacturing & Machinery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for improving the utilization rate of drugs on the surface of a balloon, which comprises the following steps: s1) treating the surface of the saccule by adopting a solvent and drying; s2) contacting the dried saccule with a drug-containing solution to form a drug coating on the surface of the saccule; s3) performing solvent vapor treatment on the balloon after the drug coating is formed. The invention changes the physical and chemical properties of the saccule and improves the crystallization property of the drug coating by ingenious solvent pretreatment, so that the saccule and the drug coating have proper binding force, the drug absorption rate is greatly improved, and the firmness and the absorption rate of the coating reach better balance points. In the intravascular conveying process, the balloon expanding process and the balloon retracting process, the sufficient firmness of the drug coating on the balloon is ensured, and the drug loss is low; meanwhile, in the expanding process, the medicine after the crystallization is improved to be beneficial to tissue absorption. The method is simple and easy to operate, is easy to realize actual mass production, and can greatly improve the drug absorption rate of the drug-coated medical instrument.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for improving the utilization rate of medicines on the surface of a balloon and the prepared balloon.
Background
Along with the development of economy and society, the medicine industry is also rapidly developed, and the requirements and requirements of people on medical equipment are also higher and higher, in particular to medical equipment combination products. The medical instrument combination product (the guiding principle is called as medical instrument combination medical instrument) mainly used for medical instrument action is expected to be safer and more effective in the processes of disease prevention, treatment and the like. Minimally invasive interventional procedures provide an alternative method for treating atherosclerosis, and because of fewer complications they typically cause, can heal faster, are relatively inexpensive compared to open procedures, and are becoming the first choice for patients and doctors.
In conventional Percutaneous Transluminal Angioplasty (PTA) treatment, a physician treats a stenosis or blockage of a blood vessel with a PTA balloon. The main disadvantage of PTA balloons is the high probability of short-term restenosis. Although the long-term patency of stent implantation is higher than that of PTA balloons, patients suffer from common complications such as thrombosis, stent fracture, and in-stent restenosis (ISR) due to neointimal hyperplasia. Drug-coated balloon therapy is an innovative treatment approach, using an angioplasty balloon coated with an antiproliferative drug. Compared with PTA balloon, the medicine coated on the balloon can effectively inhibit neointimal hyperplasia, thereby reducing late lumen loss and restenosis. Compared with stent implantation, the drug-coated balloon treatment can remarkably reduce the risk of thrombosis, avoid stent fracture and restenosis in the stent, and more importantly, realize the value proposition of no implantation of intervention in human body.
The surface of the drug-coated saccule is generally coated with endothelial cell antiproliferation drugs and a coating, and the coating can reduce the drug loss in the delivery process, assist the drugs to be rapidly and effectively released into the blood vessel wall, continuously inhibit intimal hyperplasia and avoid restenosis of the blood vessel.
The drug coating balloon in the current market can lose 25% -35% of the drug in the balloon conveying process, the drug is lost about 20% when the balloon is expanded, the drug is lost about 10% -20% when the balloon is retracted, the drug contacted with the blood vessel is lost about 10% -20%, and the drug which is expanded into the blood vessel tissue is only about 5% -15%. The large number of shed drug particles may lead downstream to embolism, leading to downstream vascular atrophy, and even more likely to slow blood flow or perioperative myocardial infarction following interventional therapy.
In addition, the current drug balloons generally have the problem of low drug utilization, and the simulated absorption in vitro silica gel is only 3.15% ± 0.78% (in vitro evaluation method of drug release and particle shedding of drug coated balloons [ J ]. Journal of chinese medical instruments, 2017, 41 (2): 4).
The problems to be solved are to improve the utilization rate of the medicine and reduce the medicine falling into the blood vessel in the processes of expanding and withdrawing.
Currently, there are two main methods for improving the drug utilization rate: one is to treat the drug coating, because the surface of the saccule is coated with the drug, the direct contact with the drug coating is avoided during treatment; because the balloon is relatively slender, the balloon part is easy to shake, the wet coating is easy to collide with the wall, and the coating is damaged, and the coating treatment method has high operation requirements and is not easy to realize; and secondly, preparing supersaturated medicine solution and spraying for multiple times, wherein the supersaturated medicine solution is an unstable state solution, the medicine is easy to crystallize and separate out, the supersaturated state of the solution is difficult to maintain, and the supersaturated taxol solution is very easy to block a pipeline in the spraying process, so that the practical operation difficulty is very high.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a method for improving the utilization rate of the drugs on the surface of the balloon and the prepared balloon.
In order to achieve the above purpose, the invention provides a method for improving the utilization rate of drugs on the surface of a balloon, which comprises the following steps:
s1) treating the surface of the saccule by adopting a solvent and drying;
s2) contacting the dried saccule with a drug-containing solution to form a drug coating on the surface of the saccule;
s3) performing solvent vapor treatment on the balloon after the drug coating is formed.
According to the invention, the bare saccule is subjected to solvent treatment before the drug coating is formed, so that the drug absorption rate can be greatly improved, the in-vitro simulated absorption rate is improved from about 3% to 30%, and the absorption rate is improved by about 10 times. The phenomenon is that after the solvent surface is used for treating the bare balloon, a trace amount of solvent is remained on the surface of the original dry bare balloon, and after the medicine is sprayed, the solvent is covered below the medicine coating, so that the time for volatilizing the solvent is prolonged, the medicine is crystallized for a longer time, the crystallization structure is more perfect, the binding force between the original balloon and the coating is reduced, and the medicine absorptivity is greatly improved; after solvent vapor treatment, the formed crystals have smaller size, and the small-particle-diameter drug particles generated by expansion have larger ratio and smaller size, thus being more beneficial to absorption and improving the drug absorption rate.
Preferably, the solvent in the step S1) is selected from any one or more of methanol, ethanol, propanol, butanol, acetone, ethyl acetate and tetrahydrofuran, more preferably any one or more of methanol, ethanol, propanol and butanol, and especially the alcohol solvent does not damage the surface of the balloon, does not affect the physicochemical properties of the balloon, and does not change burst pressure and fatigue properties.
Preferably, the solvent may further contain a certain amount of water, and the water content is preferably 0-20%. The addition of moisture can further reduce the coating firmness.
Preferably, the temperature for treating the surface of the balloon by adopting the solvent is-10-40 ℃, and more preferably 20-25 ℃; the time is preferably 1s to 24 hours, more preferably 5s to 1 hour.
The method for treating the surface of the balloon by adopting the solvent is not particularly limited, and the solvent can be contacted with the surface of the balloon, and the preferable mode is any one or more of spraying, liquid drop, soaking and wet cloth wiping.
The surface of the balloon is treated by the solvent and then is dried.
The method for drying is not particularly limited, and the solvent on the surface of the balloon is removed, and the preferable drying mode is any one or more of vacuum drying, natural drying, blow drying and wiping.
The temperature of the vacuum drying is preferably-10 to 40 ℃, more preferably 20 to 25 ℃.
The temperature of the drying is preferably-10-40 ℃, more preferably 20-25 ℃.
Naturally airing, drying and wiping at room temperature.
The drying time is preferably 1s to 1h, more preferably 10s to 1h.
The dried balloon is then contacted with a drug-containing solution to form a drug coating on the balloon surface. The method of contacting the dried balloon with the drug-containing solution is not particularly limited, and the method can be any one or more of ultrasonic spraying, micro-droplet spraying and dip coating, more preferably ultrasonic spraying, which is well known to those skilled in the art, so that the coating formed by ultrasonic spraying is more uniform and the coating firmness is higher.
The invention is not particularly limited to the types of the drugs, and the drugs which are suitable for spraying on the surface of the balloon can be all the drugs in the prior art, and in some specific embodiments of the invention, the drugs are paclitaxel drugs, and the drug concentration is preferably 1-3 wt%. The solvent can be one or more selected from ethanol, methanol, isopropanol, acetone, etc.
And then, carrying out solvent vapor treatment on the balloon with the formed drug coating to dissolve and precipitate the drug to form new drug crystals.
The device used for solvent vapor treatment according to the present invention is an incompletely sealed device, preferably provided with an opening.
In some embodiments of the invention, the apparatus used is shown in FIG. 1. It includes a container provided with an opening, the shape of the container is not limited, including but not limited to cubes, cuboid, cylinders, etc. The container is provided with an open solvent holding means, such as a beaker, flask, etc., for volatilizing the solvent. During specific operations, it is preferred to place the balloon over the solvent containing means without contact.
The invention puts the medicine saccule after spraying into the unsealed container containing solvent for solvent vapor treatment, the vapor generated by the solvent volatilization can redissolve the medicine coating, the solvent gradually volatilizes from the unsealed container, the solvent content in the container gradually decreases, and the dissolved medicine coating gradually separates out to form new medicine crystal. The newly formed medicine crystals are more fully crystallized, a double-crystal structure is formed, the crystal structure is more perfect, the metabolism time of the medicine can be prolonged, and the medicine effect is more durable. Meanwhile, the treatment device is simple and convenient, convenient to process and easy to operate.
The pore size of the open cell container affects the rate of change of solvent content and thus the drug coating structure, preferably the ratio of the total area of the pores to the volume of the device is 1cm 2 :（5~1000）cm 3 More preferably 1cm 2 :（50~1000）cm 3 . The number of the openings is not limited, and may be 1, 2, 3, 4 or more, and the total area may satisfy the above ratio. The shape of the aperture is not limited and includes, but is not limited to, circular, oval, triangular, quadrilateral, other polygonal, etc. The location of the openings need not be limited and may be located at the top of the container, on any side wall or distributed over multiple side walls, etc.
In another embodiment of the present invention, the opening is configured as an openable and closable opening, and when the solvent vapor treatment is performed, the opening is closed to seal the container for a period of time, and then the opening is opened to volatilize the solvent to perform the solvent vapor treatment, and the sealing time is optionally 0-4h.
The solvent for the solvent vapor treatment is preferably one or a mixture of several of methanol, ethanol, propanol, isopropanol, butanol, etc.
The solvent may further contain a certain amount of water, and the water content is preferably 0.01% to 60% (by mass), more preferably 1% to 20%. The addition of water helps to form new drug crystals, such as paclitaxel 2H 2 And O crystal.
The time of the solvent steam treatment is preferably 1-48 h, 1-24 h.
The temperature of the solvent vapor treatment is preferably-10 to 40 ℃, more preferably 20 to 40 ℃.
The invention also provides the medicine coating saccule prepared by the method.
The balloon surface coated drug has a high degree of crystallization with an enthalpy value of greater than 7J/g, more preferably greater than 9J/g at 166 ℃.
Compared with the prior art, the invention provides a method for improving the utilization rate of drugs on the surface of a balloon, which comprises the following steps: s1) treating the surface of the saccule by adopting a solvent and drying; s2) contacting the dried saccule with a drug-containing solution to form a drug coating on the surface of the saccule; s3) performing solvent vapor treatment on the balloon after the drug coating is formed. The invention changes the physical and chemical properties of the saccule and improves the crystallization property of the drug coating by ingenious solvent pretreatment, so that the saccule and the drug coating have proper binding force, the drug absorption rate is greatly improved, and the firmness and the absorption rate of the coating reach better balance points. In the intravascular conveying process, the balloon expanding process and the balloon retracting process, the sufficient firmness of the drug coating on the balloon is ensured, and the drug loss is low; meanwhile, in the expanding process, the medicine after the crystallization is improved to be beneficial to tissue absorption. The method is simple and easy to operate, is easy to realize actual mass production, and can greatly improve the drug absorption rate of the drug-coated medical instrument.
Drawings
FIG. 1 is a schematic view of a solvent vapor treatment apparatus of the present invention;
FIG. 2 is a microstructure of a drug coating of example 1 of the present invention being crystallized;
FIG. 3 is the DSC test result of the drug coating of example 1 of the present invention;
FIG. 4 is the DSC test result of the drug coating of example 2 of the present invention;
FIG. 5 is the DSC test result of the drug coating of comparative example 1 of the present invention;
FIG. 6 is a microstructure of a drug coating of comparative example 1 of the present invention.
Detailed Description
In order to further illustrate the present invention, the method for improving the drug utilization rate on the surface of the balloon and the prepared balloon provided by the present invention are described in detail below with reference to examples.
The balloon specifications used for all examples and comparative examples were the same: the balloon diameter was 7mm and the balloon length was 100mm.
Example 1
Bare balloon solvent treatment: methanol is sprayed on the surface of a bare balloon by using an ultrasonic spraying machine, after standing for 5 seconds, the bare balloon is wiped by dust-free cloth, after the balloon is further stood for 10 seconds, the balloon is mounted to another ultrasonic spraying machine, compressed air is used for punching the balloon to inflate the balloon, the balloon is straightened, and then medicine spraying is carried out on the balloon (the mass concentration of taxol medicine is 1%). In a solvent vapor treatment device (as shown in fig. 1), 10ml of methanol is added, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the air hole area is: device volume = 1cm 2 :10 cm 3 The device is put into an oven, the temperature is set to 30 ℃, and the balloon is taken out after the device is kept at the constant temperature for 12 hours.
Fig. 2 is a microstructure of a drug coating being crystallized, and it can be seen that crystals are growing progressively.
FIG. 3 is a DSC test of a drug coating showing enthalpy values of crystals of 7.84J/g (139.3 ℃) and 2.04J/g (164.2 ℃), respectively.
Example 2
Bare balloon solvent treatment: ethanol is sprayed on the surface of a bare balloon by using an ultrasonic spraying machine, after standing for 30 minutes, the bare balloon is wiped by dust-free cloth, after standing for 1 hour, the balloon is mounted to the ultrasonic spraying machine, the balloon is inflated by using compressed air to press, the balloon is straightened, and then the balloon is sprayed with medicine (the mass concentration of taxol medicine is 3%). In the solvent vapor treatment device, 10ml of ethanol is added, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the area of the ventilation holes is as follows: device volume = 1cm 2 :20 cm 3 The device is put into an oven, the temperature is set at 26 ℃, and the balloon is taken out after the device is kept at the constant temperature for 24 hours.
FIG. 4 is a DSC test of a drug coating showing an enthalpy of crystal of 13.82J/g (166.8 ℃).
Example 3
Bare balloon solvent treatment: placing the bare saccule in ethanol solution, standing for 10 seconds, taking out, wiping with dust-free cloth, standing for 30 minutes, and collecting sacculeThe balloon was inflated with compressed air, straightened, and then drug sprayed (paclitaxel drug mass concentration 3%) using an ultrasonic applicator. In the solvent vapor treatment device, 10ml of butanol is added, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, and the area of the ventilation holes is that: device volume = 1cm 2 :30 cm 3 The device is put into an oven, the temperature is set to 28 ℃, and the balloon is taken out after the device is kept at the constant temperature for 24 hours.
Example 4
Bare balloon solvent treatment: the bare balloon is placed in ethanol solution, is taken out after standing for 5 seconds, is naturally dried, is mounted to an ultrasonic spraying machine after standing for 5 minutes, is inflated by punching with compressed air, is straightened, and is sprayed with medicine (the mass concentration of taxol medicine is 1%). 5ml of ethanol (containing 1% of water) is added into a solvent vapor treatment device, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the air hole area is: device volume = 1cm 2 :50 cm 3 The device is put into an oven, the temperature is set to 28 ℃, and the balloon is taken out after the device is kept at the constant temperature for 12 hours.
Example 5
Bare balloon solvent treatment: acetone is sprayed on the surface of the bare balloon by using an ultrasonic spraying machine, the balloon is stood for 10 minutes and naturally dried, the balloon is installed to the ultrasonic spraying machine, the balloon is inflated by punching by using compressed air, the balloon is straightened, and then the balloon is sprayed with medicine (the mass concentration of paclitaxel medicine is 3%). 5ml of ethanol (containing 20% of water) is added into a solvent vapor treatment device, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the air hole area is: device volume = 1cm 2 :300 cm 3 The device is put into an oven, the temperature is set to 28 ℃, and the balloon is taken out after the device is kept at the constant temperature for 24 hours.
Example 6
Bare balloon solvent treatment: spraying ethyl acetate onto the surface of a bare balloon, standing for 10 minutes, naturally airing the balloon, mounting the balloon to an ultrasonic spraying machine, punching the balloon by using compressed air to inflate the balloon, straightening, and then carrying out balloon inflationMedicine spraying (paclitaxel medicine mass concentration 1%). 5ml of isopropanol (containing 10% water) was added to the solvent vapor treatment apparatus, and the sprayed drug balloon was transferred into the solvent vapor treatment apparatus, with the vent area: device volume = 1cm 2 :1000 cm 3 The device is put into an oven, the temperature is set to 28 ℃, and the balloon is taken out after the device is kept at the constant temperature for 24 hours.
Comparative example 1
The bare balloon was not solvent treated, mounted to an ultrasonic applicator, punched with compressed air to inflate the balloon, straightened, and then drug sprayed (paclitaxel drug mass concentration 1%). The drug coating was not subjected to a vapor treatment.
FIG. 5 is a DSC test of a drug coating showing an enthalpy of crystal of 1.61J/g (158.6 ℃ C.).
Fig. 6 is a microstructure of a drug coating, and it can be seen that the coating exhibits a network shape, without the typical crystal structure, and with a relatively low degree of crystallinity.
Comparative example 2
Bare balloon solvent treatment: the bare balloon is placed in ethanol solution, is taken out after standing for 5 seconds, is wiped by dust-free cloth, is mounted to an ultrasonic spraying machine after standing for 30 minutes, is inflated by punching by using compressed air, is straightened, is sprayed with medicine (the mass concentration of taxol medicine is 3%), and is not subjected to vapor treatment after being sprayed.
Comparative example 3
The bare balloon was not solvent treated, mounted to an ultrasonic applicator, punched with compressed air to inflate the balloon, straightened, and then drug sprayed (paclitaxel drug mass concentration 1%). 5ml of ethanol (containing 20% of water) is added into a solvent vapor treatment device, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the air hole area is: device volume = 1:300, the device was placed in an oven, the temperature was set at 28 ℃, and after 24 hours of constant temperature the balloon was removed.
Comparative example 4
Bare balloon solvent treatment: the bare balloon is placed in ethanol solution, is taken out after standing for 5 seconds, is naturally dried, is mounted to an ultrasonic spraying machine after standing for 5 minutes, is inflated by punching with compressed air, is straightened, and is sprayed with medicine (the mass concentration of taxol medicine is 1%). 5ml of ethanol (containing 1% of water) is added into a solvent vapor treatment device, and the sprayed medicine balloon is transferred into the solvent vapor treatment device, so that the air hole area is: device volume = 1:50, the device was placed in an oven, the temperature was set at 28 ℃, and after 30 minutes of constant temperature, the balloon was removed.
Comparative example 5
Bare balloon solvent treatment: the bare balloon is placed in ethanol solution, is taken out after standing for 5 seconds, is naturally dried, is mounted to an ultrasonic spraying machine after standing for 5 minutes, is inflated by punching with compressed air, is straightened, and is sprayed with medicine (the mass concentration of taxol medicine is 3%). In a solvent vapor treatment device, 5ml of ethanol (containing 1% of water) is added, the sprayed medicine saccule is transferred into the solvent vapor treatment device, the device is a closed device, the device is placed into an oven, the temperature is set to 28 ℃, and the saccule is taken out after the temperature is kept constant for 3 hours.
Test of influence of bare balloon solvent treatment and solvent vapor treatment on balloon burst pressure
The test was performed according to the method given in YY0285.4-2017 appendix A, the test equipment Confluent HPT-1000, the water bath temperature was set to 37 ℃, the pressure was first increased to 4atm, then the balloon was pressurized in 1atm increments for 5 seconds until the balloon burst, and the pressure at burst was recorded. The test was conducted before, 2 days after, 5 days, and 7 days, and the results are shown in table 1.
TABLE 1 Effect of naked balloon solvent treatment and solvent vapor treatment on balloon burst pressure results
The data in table 1 shows that the bare balloon solvent treatment and solvent vapor treatment do not affect the burst pressure of the balloon, do not affect the physical properties of the balloon, and the solvent used for the treatment does not damage the balloon.
Simulation of transport experiments
A 7Fr guide catheter was passed through the simulated vessel (YY/T0807-2010, figure a.4) and the distal end of the guide catheter was extended approximately 15mm. The simulated blood vessel is placed in a water bath at 37+/-1 ℃ and the two ends of the guiding catheter are exposed out of the water surface. The normal saline is injected into the guide catheter by a syringe, so that the guide catheter is filled with the normal saline. The balloon catheter is passed through the guide catheter, the entire balloon portion is leaked out, and the balloon catheter is then withdrawn from the guide catheter. The guide catheter was rinsed with 300ml of physiological saline, the rinse was collected, and the microparticles were tested, and the results are shown in Table 2.
Table 2 simulation of the number of particles in the delivery of experimental rinse
The data in table 2 shows that the number of particles produced by the drug balloon catheter after both the bare balloon solvent treatment and the solvent vapor treatment increased to some extent, and more particles were produced, reducing the drug coating firmness, compared to the non-treated group.
In vitro simulation test using silica gel to simulate target blood vessel
The simulated vessel of silica gel was placed in 37 ℃ water, the drug eluting balloon catheters prepared in examples 1 to 4 and comparative example 1 were inserted into the simulated target vessel, the balloon fluid was inflated to about 9atm, and the ratio of balloon diameter to vessel diameter was 1:1, the expansion maintenance time was 60 seconds. After 60 seconds, the balloon was depressurized, removed from the silicone tube and the residual drug on the balloon was tested using HPLC. And taking out the silica gel tube, and testing the absorption medicine in the silica gel tube. The number of particles in the water was tested.
HPLC test conditions were for a Shimadzu LC-20A high performance liquid chromatograph, column chromatography, shim-pack VP-ODS 5 μm (4.6 mm. Times.25 cm), mobile phase: methanol/water/acetonitrile=23/41/36 (volume ratio), detection wavelength: 227 nm, column temperature: 30 ℃, flow rate: 1.0 ml/min.
The HPLC measurement results are shown in Table 3.
TABLE 3 in vitro simulation test results
The results in table 3 show that the absorption rate of the medicine can be greatly improved by the methods of bare saccule solvent treatment and solvent steam treatment, the absorption rate is improved from 3.14% to more than 30%, and the simulated absorption rate can reach 34.53%. The simulated absorption of comparative example 2 and comparative example 3 was also improved to some extent compared to comparative example 1, indicating that both balloon pretreatment and coating solvent vapor treatment can improve drug absorption.
Particle testing
The drug microparticle suspensions generated during the above simulation were measured using a microparticle tester (photoresist method), and the channel settings were 5 μm, 15 μm, 25 μm, and 100 μm, and the results are shown in Table 4.
Table 4 in vitro simulation test of particle count in drug particle suspensions
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As can be seen from the number of particles produced, the number of particles produced after treatment increases sharply from 162 of comparative example 1 to about 12 ten thousand, the firmness of the treated drug is significantly reduced, and conditions are created for greatly improving the absorption rate; the particle count of comparative examples 2 and 3 was also greatly increased as compared with comparative example 1. Indicating that both balloon pretreatment and coating solvent vapor treatment can reduce coating firmness.
Crystallinity test
TABLE 5 DSC test data
The DSC test data show that the enthalpy value of the drug coating after the solvent treatment and the solvent vapor treatment of the bare balloon is greatly improved from 1.001J/g to 9.8895J/g, and the crystallinity is greatly improved, thus indicating that the crystal structure is more perfect. Compared to the absorption peaks of the conventional taxol crystal structure of 166 ℃ (Pyo S H, et al Drying Technology, 2007, 25 (10): 1759-1767.) (2 absorption peaks at 139 ℃, 164 ℃ respectively) were present in example 1, the 139 ℃ absorption peak was due to the reduction in crystal size, the shift phenomenon was present, the crystal size was reduced, and the temperature of the absorption peak was also reduced; the article also shows an enthalpy at 166℃of 7.637J/g, above which the enthalpy of the examples is all greater, indicating an increase in crystallinity. High crystallinity is also beneficial for prolonging the drug metabolism cycle and prolonging the action time (JK Harper, et al Crystal Growth & Design, 2005, 5 (5): 1737-1742.).
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (13)
1. A method for improving the utilization rate of drugs on the surface of a balloon, comprising the following steps:
s1) treating the surface of the balloon with a solvent and drying to enable a trace of treatment solvent to remain on the surface of the balloon;
s2) contacting the dried saccule with a drug-containing solution to form a drug coating on the surface of the saccule;
s3) performing solvent vapor treatment on the balloon after the drug coating is formed;
the drying mode in the step S1) is selected from any one or more of vacuum drying, natural airing, blow drying and wiping;
the drying time is 1 s-1 h;
the device for treating the solvent vapor in the step S3) is provided with an opening;
the ratio of the total area of the openings to the volume of the device is 1cm 2 :（5~1000）cm 3 ；
The enthalpy value of the balloon after the solvent steam treatment at 166 ℃ is more than 7J/g.
2. The method according to claim 1, wherein the solvent in step S1) is selected from any one or more of methanol, ethanol, propanol, butanol, acetone, ethyl acetate, tetrahydrofuran.
3. The method according to claim 1, wherein the temperature of the balloon surface treated with the solvent in step S1) is-10 to 40 ℃ for 1S to 24 hours.
4. The method according to claim 1, wherein the treatment of the balloon surface with the solvent in step S1) is selected from any one or more of spraying, dripping, soaking, and wiping with a wet cloth.
5. The method according to claim 1, wherein the vacuum drying temperature in step S1) is-10 to 40 ℃;
the temperature of the drying is-10-40 ℃;
the temperature of natural airing, blow-drying and wiping is room temperature;
and the drying time is 10 s-1 h.
6. The method according to claim 5, wherein the vacuum drying temperature in the step S1) is 20-25 ℃;
the temperature of the drying is 20-25 ℃.
7. The method according to claim 1, wherein the method of contacting the dried balloon with the drug-containing solution in step S2) is selected from any one or more of ultrasonic spraying, micro-droplet, dip-coating.
8. The method according to claim 1, wherein the solvent vapor-treated solvent in step S3) is selected from any one or more of methanol, ethanol, propanol, isopropanol, butanol.
9. The method according to claim 1, wherein the solvent vapor treatment in step S3) is performed at a temperature of-10 to 40 ℃ for a time of 1 to 48 hours.
10. The method according to claim 9, wherein the temperature of the solvent vapor treatment in step S3) is 20 to 40 ℃.
11. The method of claim 1, wherein the openings are openable and closable openings, and wherein the solvent vapor treatment is performed by closing the openings to close the container for a period of time and then opening the openings to evaporate the solvent.
12. The method of claim 11, wherein the sealing is for a period of 0-4 hours.
13. A drug-coated balloon prepared by the method of any one of claims 1-12.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020098278A1 (en) * | 2000-10-31 | 2002-07-25 | Cook Incorporated | Coated implantable medical device |
| CN102307602A (en) * | 2009-01-09 | 2012-01-04 | 因瓦泰克技术中心有限公司 | Drug-eluting medical device |
| CN103611212A (en) * | 2013-11-21 | 2014-03-05 | 先健科技(深圳)有限公司 | Drug balloon preparation method |
| CN104511084A (en) * | 2014-12-30 | 2015-04-15 | 深圳市信立泰生物医疗工程有限公司 | Balloon catheter |
| CN106237485A (en) * | 2016-08-29 | 2016-12-21 | 恒壹（北京）医疗科技有限公司 | A kind of medicine-coated balloon dilating catheter and preparation method thereof |
| CN106334220A (en) * | 2016-10-20 | 2017-01-18 | 浙江归创医疗器械有限公司 | Process for coating medicine coating on medical apparatus |
| US20170080191A1 (en) * | 2008-07-17 | 2017-03-23 | Micell Technologies, Inc. | Drug delivery medical device |
| CN106620887A (en) * | 2016-11-03 | 2017-05-10 | 上海申淇医疗科技有限公司 | Production method for drug balloon |
| KR20180012885A (en) * | 2016-07-27 | 2018-02-07 | 주식회사 바이오알파 | Drug eluting balloon catheter |
| JP2019092810A (en) * | 2017-11-22 | 2019-06-20 | テルモ株式会社 | Forming method of medicament coat layer |
| CN111032103A (en) * | 2017-09-21 | 2020-04-17 | 泰尔茂株式会社 | Method and apparatus for forming drug coating |
| CN112535793A (en) * | 2020-11-19 | 2021-03-23 | 融冲(深圳)生物医疗科技有限责任公司 | Preparation method and application of drug-coated balloon catheter |
| US20210154372A1 (en) * | 2017-05-15 | 2021-05-27 | C.R. Bard, Inc. | Medical device with drug-eluting coating and intermediate layer |
-
2023
- 2023-07-18 CN CN202310879684.6A patent/CN116585602B/en active Active
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020098278A1 (en) * | 2000-10-31 | 2002-07-25 | Cook Incorporated | Coated implantable medical device |
| US20170080191A1 (en) * | 2008-07-17 | 2017-03-23 | Micell Technologies, Inc. | Drug delivery medical device |
| CN102307602A (en) * | 2009-01-09 | 2012-01-04 | 因瓦泰克技术中心有限公司 | Drug-eluting medical device |
| CN103611212A (en) * | 2013-11-21 | 2014-03-05 | 先健科技(深圳)有限公司 | Drug balloon preparation method |
| CN104511084A (en) * | 2014-12-30 | 2015-04-15 | 深圳市信立泰生物医疗工程有限公司 | Balloon catheter |
| KR20180012885A (en) * | 2016-07-27 | 2018-02-07 | 주식회사 바이오알파 | Drug eluting balloon catheter |
| CN106237485A (en) * | 2016-08-29 | 2016-12-21 | 恒壹（北京）医疗科技有限公司 | A kind of medicine-coated balloon dilating catheter and preparation method thereof |
| CN106334220A (en) * | 2016-10-20 | 2017-01-18 | 浙江归创医疗器械有限公司 | Process for coating medicine coating on medical apparatus |
| CN106620887A (en) * | 2016-11-03 | 2017-05-10 | 上海申淇医疗科技有限公司 | Production method for drug balloon |
| US20210154372A1 (en) * | 2017-05-15 | 2021-05-27 | C.R. Bard, Inc. | Medical device with drug-eluting coating and intermediate layer |
| CN111032103A (en) * | 2017-09-21 | 2020-04-17 | 泰尔茂株式会社 | Method and apparatus for forming drug coating |
| JP2019092810A (en) * | 2017-11-22 | 2019-06-20 | テルモ株式会社 | Forming method of medicament coat layer |
| CN112535793A (en) * | 2020-11-19 | 2021-03-23 | 融冲(深圳)生物医疗科技有限责任公司 | Preparation method and application of drug-coated balloon catheter |
Non-Patent Citations (1)
| Title |
|---|
| 刘艳等: "医用导管亲水涂层的制备", 应用化工, vol. 42, no. 1, pages 182 - 185 * |
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