CN104841060B - A kind of ultrasonically controlled-release medicine eluting balloon catheter and preparation method thereof - Google Patents
A kind of ultrasonically controlled-release medicine eluting balloon catheter and preparation method thereof Download PDFInfo
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- CN104841060B CN104841060B CN201410049782.8A CN201410049782A CN104841060B CN 104841060 B CN104841060 B CN 104841060B CN 201410049782 A CN201410049782 A CN 201410049782A CN 104841060 B CN104841060 B CN 104841060B
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Landscapes
- Media Introduction/Drainage Providing Device (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of ultrasonically controlled-release medicine eluting balloon catheters and preparation method thereof.The medicine eluting balloon catheter balloon surface is coated with medication coat, and the medication coat is by the fat-soluble medicine carrying microcapsule with ultrasonic response characteristic and there is water-soluble adhesive to constitute.The drug of medicament elution sacculus is wrapped in in lipophilic medicine carrying microcapsule, thus it is more difficult be dissolved in blood, reduce loss caused by washing away as blood.When use, medicine eluting balloon catheter is sent to diseased region rear distraction, sacculus to contact with pathological tissues, diseased region is imposed in vitro supersonic induced, under ultrasonication, medicine carrying microcapsule is accelerated to be detached from hydrophilic adhesive, it is spread in fat-soluble pathological tissues, while there is the medicine carrying microcapsule of ultrasonic response characteristic rupture, release drug to occur under ultrasonication, drug will be greatly improved by the efficiency that target lesion tissue resorption utilizes.By adjusting medicine carrying microcapsule characteristic, ultrasonic characteristic, it can be achieved that control to release amount of medicine, release time, improves the validity and safety of medicine eluting balloon catheter.
Description
Technical field
The present invention relates to medical instruments fields.More particularly to a kind of ultrasonically controlled-release medicine eluting balloon catheter and its preparation side
Method.
Background technique
Coronary heart disease is to threaten the principal disease of human health, and treating the disease at present, the most safely and effectively means are painstaking effort
Pipe interventional therapeutic technique (PCI).
Cardio-vascular interventional therapeutic occurred so far, experienced the development course of three phases from the last century 70's:
One, the mankind in 1977 use sacculus coronary artery stenosis lesion for the first time.Although sacculus can eliminate coronary stenosis,
But the elastical retraction due to vascular wall, neointimal hyperplasia and the tearing of tube wall inner membrance etc. can inspire reangiostenosis, target vessel
A postoperative 3-6 month restenosis rates are up to 30%-50%；
Two, bare mental stents (BMS) appearance in 1986, it can not only eliminate hemadostewnosis at once, substantially reduce simultaneously
The incidence of acute reocclusion.But the incidence of target vessel restenosis is still up to 30%；
Three, bracket for eluting medicament (DES) appearance in 2001, makes target vessel restenosis rate be down to 3% hereinafter, being so far
Maximally efficient Cardiac interventional therapy.
Although the restenosis rate of DES is reduced to 3% hereinafter, but rising year by year due to receiving the patient populations that PCI is treated, hair
The absolute quantity of the patient of raw stent restenosis is considerable.The method used at present for restenosis includes: simple sacculus
Expansion again, orientation patch rotary-cut art, turnery art, intravascular brachytherapy and repeat stenter to implant etc. and fail to show its reason
The validity or safety thought, there is presently no ideal countermeasures.It is implanted into medicine again after restenosis in studies have shown that drug stent
The probability that restenosis occurs for object bracket is 43%.The effect of simple common sacculus also allows of no optimist, the incidence of restenosis compared with
Stenter to implant is higher again.
Medicament elution sacculus (DEB) is to solve restenosis to bring new hope.Ideal of the sacculus as anti-proliferative drugs
Carrier wraps up anti-proliferative drug, and drug is played prevention again in process of expansion by rapid, Targeting delivery to local vascular tissue
Narrow effect.The high local concentrations sustained drug time as needed for antiproliferative effect is shorter, so be conducive in vascular wall
The quick progress of skin, to avoid the generation of thrombus.
Medicament elution sacculus needs exposure for a period of time, easily to cause sacculus in blood before reaching diseased region
The mass loss of surface anti-proliferative drug；Further, since balloon expandable process cannot be too long, sacculus and lesion are directly limited
The time of position contact and drug release.Therefore, the good therapeutic effect of sacculus is realized, it is necessary to overcome following technical bottleneck:
(1) when drug passes through in the blood vessel, excessively high mass loss is avoided；
(2) after drug reaches site of action, it can discharge rapidly, reach medicine effective concentration, and absorbed by vascular tissue；
(3) drug the release of diseased region should accomplish it is controllable, can quantify；
(4) drug dose of vascular tissue's intake interior in short-term, the anti-proliferate effect that can preferably play.
Existing patent CN101239216A discloses a kind of medicament elution sacculus dilating catheter, and carrying prescription formula is directly to apply
Fixation is covered, not can avoid foley's tube by the loss of surface drug when blood, drug-loading efficiency reduces, and therapeutic effect is not achieved.
Meanwhile after reaching diseased region sacculus and strutting, contained drug is merely by physical contact or similar compatibility principle Passive diffusion
Into tissue, drug absorption is slow, and utilization rate is low.Drug does not have " controlled release " " quantitative release " in the release of diseased region
The characteristics of.In the direct coated medicament of balloon surface diseased region can only be improved to drug by improving the drugloading rate of balloon surface
Absorption, drug release targeting is poor, drug release can not be carried out quantization and effectively control, there are security risks.
CN1124165A discloses a kind of liposome foley's tube for carrying gene and therapeutic agent, and the patent is using liposome as medicine
Object inclusion enclave reduces the loss of drug in blood to a certain extent, but still relies on physical contact or similar compatibility
Principle passively diffuses into tissue, do not solve the problems, such as drug diseased region it is controllable, quantitatively discharge.
Summary of the invention
The invention reside in a kind of ultrasonically controlled-release medicine eluting balloon catheter and preparation method thereof is provided, ultrasonically controlled-release drug is washed
De- foley's tube includes medicine eluting balloon catheter, and medicament elution sacculus and sacculus appearance are coated with the load with ultrasonic response characteristic
Medicine coating, drug-carried coat include two parts: the medicine carrying microcapsule with hydrophilic adhesive and with ultrasonic response characteristic.
Ultrasonically controlled-release medicine eluting balloon catheter provided by the invention, it is characterised in that:
Contained drug is wrapped in in lipophilic medicine carrying microcapsule blister cavities.Medicine carrying microcapsule passes through hydrophilic adhesive
It is fixed on the balloon portion outer surface of foley's tube.Medicine carrying microcapsule has a ultrasonic response characteristic, i.e., in some strength, frequency, no
Under the ultrasonic wave effect of same mode (pulse/continuous), medicine carrying microcapsule is rupturable, releases the drug in blister cavities.
Medicine eluting balloon catheter, since medicine carrying microcapsule has lipophilicity, glues before entering diseased region by blood vessel
Mixture has hydrophily, makes drug coated by its surface during being washed away by blood, drug loss is smaller, can be used for office
Portion conveys various therapeutic agents to using any intracavitary point or position in the accessibility human body of seal wire/guiding catheter.Such as heart coronaries
Artery, liver portal vein etc., increase the efficiency that drug is sent to diseased region.
When sacculus, which reaches diseased region, to be strutted, ultrasound is applied to diseased region, at this time:
1, under ultrasonication, there is the acceleration of fat-soluble medicine carrying microcapsule to leave water-soluble binder, to equally with rouge
It is spread in the pathological tissues of dissolubility, increases the absorption efficiency of drug.；
2, under ultrasonication, part or the close medicine carrying microcapsule all with ultrasonic response characteristic rupture, and discharge
Drug in blister cavities out, and accelerate to spread into pathological tissues, increase diseased region absorption of drugs efficiency.
3, by controlling the material and physical structure of medicine carrying microcapsule, the different medicine carrying microcapsule of ultrasonic sensitive can be prepared.
Wherein more easily rupturable medicine carrying microcapsule can be used for being administered immediately；When the medicine carrying microcapsule of more difficult rupture will be left in one section of diseased region
Between, with microencapsulated material degradation slow release drug, or giving different ultrasounds as required: when ultrasound as biggish such as energy
Release drug.There is the medicine carrying microcapsule of ultrasonic response sensibility difference can mix coated on foley's tube surface for these,
It can be used alone, provide more abundant treatment means for clinic.
The present invention provide it is a kind of prepare it is above-mentioned can be in the side of the medicament elution sacculus of targeted release anti-proliferative drug under ultrasound
Method.
1. the preparation with the medicine carrying microcapsule of ultrasonic response characteristic.Medicine carrying microcapsule is by microencapsulated material and the drug of internal package
It constitutes.Medicine carrying microcapsule material be good biocompatibility high molecular material or can be degradable high molecular material, the object of micro-capsule
Reason structure design should have ultrasonic responsiveness, and the wall thickness of medicine carrying microcapsule should be 10 ~ 10,000nm；The medicine carrying microcapsule of relatively thin wall thickness,
The response rdativery sensitive of ultrasound is easy to rupture, can be used for instant-free drug by when ultrasonication.Compared with thick wall
Medicine carrying microcapsule, be not easy to rupture when by same ultrasonication, can be used for drug in the slow release of diseased region.
Micro-capsule 100-1000nm of wall thickness range, be single-chamber room, the partial size of medicine carrying microcapsule should control at 8 μm hereinafter, it is preferred that
It is integrated distribution at 3 μm, to prevent it into the generation of embolism after capillary.
After medicine carrying microcapsule is made, it is distributed in the water soluble dispersing agent with special formulation, drug-carried coat material is made.It will
Drug-carried coat material is fixed on balloon surface by way of impregnating or spraying, dry through certain condition, makes in dispersing agent
After liquid component volatilization, medicine carrying microcapsule is bonded in balloon surface as adhesive and forms drug-carried coat by the solute in dispersing agent.
In conclusion the invention and advance are:
The medicine eluting balloon catheter with ultrasonic response characteristic provided by the present invention, load drug effect big with drugloading rate
The feature that rate is high, drug absorption rate is high.Even more important, medicine eluting balloon catheter provided by the present invention, medicine
Object release process is controllable, orientation: by the control of microcapsule structure and in conjunction with ultrasonic characteristic, the time of drug release, position
Set, burst size can be controlled, while improving medicine eluting balloon catheter therapeutic effect, more ensure that its safety
Property.
1, using medicine carrying microcapsule packaging medicine, the drugloading rate of balloon surface is improved, and reduces sacculus and reaches diseased region
Preceding blood washes away the loss for causing drug, improves utilization ratio of drug；
2, medicine carrying microcapsule has ultrasonic response characteristic, accelerates to spread to target lesion vascular tissue under ultrasonication, and break
It splits and releases drug, improve the speed that drug is spread to diseased region, there is certain targeting, overcome medicament elution ball
The problem that capsule causes utilization ratio of drug low since the expansion time is short；
3, pass through control ultrasonic characteristic: frequency, intensity, continuous/pulse, microencapsulated material and physical structure: wall thickness, chamber number
Amount can realize quantified controlling to the drug for entering vascular lesion position, it is ensured that the safety and validity for the treatment of；
4, by controlling the ratio and ultrasonic characteristic of the medicine carrying microcapsule of different structure, when the amount and release of Drug controlled release
Between, selection space bigger on pharmaceutical release time is provided to clinic；
5, the preferred anti-proliferative drug Docetaxel of institute in the present invention, it is similar that drug effect is better than taxol and rapamycin etc.
Anti-proliferative drug, particularly suitable for needing smaller medication amount to play the medicine eluting balloon catheter of anti-proliferative effect.
Detailed description of the invention:
Fig. 1 is ultrasonically controlled-release medicine eluting balloon catheter structural schematic diagram
1. ultrasonically controlled-release medicament elution sacculus；2. drug；3. the medicine carrying microcapsule with ultrasonic responsiveness；4. sacculus.
Embodiment:
The present invention provides the controllable medicine eluting balloon catheters in a kind of drug release position and release amount of medicine, and provide
Preparation method.Wherein:
One, the surface of common foley's tube is modified
Foley's tube surface drug coating firmness and drug lift-launch amount, but simultaneously non-drug eluting sacculus can be improved in the step
The necessary step of conduit preparation.
Plasma immersion processing is carried out in the sacculus section of common foley's tube, promotes the adherency of anti-proliferative drug coating.Tool
Body step are as follows: place a catheter in plasma immersion and ion implantation device, after vacuumizing, be passed through hydrogen, nitrogen, water vapour or
Ammonia, gas pressure 0,05~50 pa；200~1200W of radio frequency discharge power；The pulsed high voltage generator amplitude 1KV of load~
100KV, 50~40000 hertz of frequency or 10-20 megahertzs of AC power source, duty ratio 3%~80%；20~200 DEG C of heating temperature
The processing time 0,1~5 hour.
Two, the preparation of drug-carried coat material
1. preparing drug bearing microsphere using fast film emulsifying technology
By a certain amount of membrane material: polylactic acid (PLA), poly lactic-co-glycolic acid (PLGA) or polylactic acid-polyglycol
(PELA) it is dissolved in methylene chloride with anti-proliferative drug (preferably mostly dilute taxol) as oily phase, certain density polyvinyl alcohol
(PVA) aqueous solution is as water phase, and emulsifying (24000 r/min, 2 min) prepares oil/water (O/W) pre-emulsion, by pre- cream
Liquid pours into fast film emulsifier unit, the fenestra that aperture is 2,8 μm is pressed through repeatedly with certain nitrogen pressure, by gained lotion normal
The lower magnetic agitation volatilization removal organic solvent of temperature makes it be solidified into medicine carrying microcapsule, and with deionized water centrifuge washing 5 times, freezing is dry
It is dry that finished product is made.
2, the medicine carrying microcapsule as made from the above method is distributed to formation drug-carried coat material in water soluble dispersing agent.
The drug-carried coat material has following three features:
1. medicine carrying microcapsule has lipophilicity, not readily dissolves, discharges when contacting blood；
After 2. coating is contacted with diseased region, due to similar compatibility principle, the lipophilicity medicine carrying microcapsule in coating be easy to from
Boiled water phase dispersing agent is to equally with the diffusion of lipophilic vascular wall tissue；
3. ultrasound can speed up diffusion of the medicine carrying microcapsule from Aqueous dispersions agent into vascular wall tissue；
4. ultrasound can promote medicine carrying microcapsule to rupture, drug is released.
Three, the coating of drug-carried coat
1, by the sacculus of plasma immersion treated foley's tube with nominal pressure it is full after, be soaked at room temperature as above
5-60min in the medicine coating material；Or by above-mentioned medicine coating material according to 1mm2Sacculus area 0,1-50ug active drug
Dosage, be sprayed at balloon portion surface；
2, controlled at 10-80 DEG C, it is dried in vacuo 30min；
3, gas in sacculus is excluded, roll film is carried out.
With reference to embodiments, the present invention is further elaborated
Embodiment 1
At room temperature, the PEG2000 aqueous solution of 5mg/ml is prepared as dispersing agent.By the PLGA medicine carrying microcapsule of certain wall thickness
Above-mentioned aqueous dispersion is added according to PEG2000 mass ratio 1:1 in dispersing agent in (PLGA: mostly dilute taxol=1:1), rock to
It is uniformly dispersed, drug-carried coat material is made.It is prepared using above-mentioned spraying/immersion way on common foley's tube surface and carries medicine painting
Layer；
Embodiment 2
Dispersing agent is the ethanol solution of 5mg/mlPEG2000, and other conditions are the same as embodiment 1；
Embodiment 3
General sieve of 10ml Ultravist 370(iodine is added in the PLGA medicine carrying microcapsule (PLGA: taxol=1:1) of the certain wall thickness of 50mg
Amine aqueous solution) in drug-carried coat material is made, other conditions are the same as embodiment 1；
Embodiment 4
Preparing medicine carrying microcapsule wall thickness is 20nm, and other conditions are the same as embodiment 1；
Embodiment 5
Preparing medicine carrying microcapsule wall thickness is 100nm, and other conditions are the same as embodiment 1；
Embodiment 6
Preparing wall thickness is respectively the medicine carrying microcapsule that 20nm and 100nm ratio is 8:2, and other conditions are the same as embodiment 1.
Claims (11)
1. a kind of ultrasonically controlled-release medicine eluting balloon catheter, including medicine eluting balloon catheter and medicament elution sacculus, outside sacculus
Table is coated with the drug-carried coat with ultrasonic response characteristic；It is characterized by:
The drug-carried coat includes two parts: the medicine carrying microcapsule with hydrophilic adhesive and with ultrasonic response characteristic；
The physical design of the medicine carrying microcapsule has ultrasonic responsiveness, by microencapsulated material and the medicine being wrapped in micro-capsule chamber
Object composition, micro-capsule part there is the medicine carrying microcapsule of varying sensitivity to constitute certain characteristic ultrasound by being mixed into specific proportions, i.e.,
Under the action of the ultrasonic wave of pulse mode or continuation mode is with some strength and frequency, reach or sustained release instant to drug or choosing
Selecting property discharges the purpose controlled；
Medicine carrying microcapsule is fixed on the balloon portion appearance of the ultrasonically controlled-release medicine eluting balloon catheter by hydrophilic adhesive
Face；The medicine carrying microcapsule is single-chamber room, and micro-capsule wall thickness range is 20-100nm, and the size controlling of medicine carrying microcapsule is at 8 μm or less；
The medicine carrying microcapsule is mixed to get for the medicine carrying microcapsule that wall thickness is respectively 20nm and 100nm by 8:2.
2. ultrasonically controlled-release medicine eluting balloon catheter as described in claim 1, it is characterised in that: convey various control for part
Agent is treated to using any intracavitary point or position in the accessibility human body of seal wire/guiding catheter.
3. ultrasonically controlled-release medicine eluting balloon catheter as claimed in claim 2, it is characterised in that: any intracavitary in the human body
Point or position include heart coronary artery or liver portal vein.
4. ultrasonically controlled-release medicine eluting balloon catheter as described in claim 1, it is characterised in that: the microencapsulated material is
PLGA。
5. the ultrasonically controlled-release medicine eluting balloon catheter as described in claim 1-4 is any, it is characterised in that: its ultrasound response is special
Property specifically includes:
1. under ultrasound condition, medicine carrying microcapsule can be accelerated to release from the hydrophilic adhesive of balloon surface into lipophilic diseased region
It puts；
2. ultrasound promotes micro-capsule wall broken, wrapped up drug is released.
6. ultrasonically controlled-release medicine eluting balloon catheter as claimed in claim 5, it is characterised in that: the diseased region is blood vessel
Or tissue.
7. ultrasonically controlled-release medicine eluting balloon catheter as described in claim 1, it is characterised in that: its partial size integrated distribution is in 3 μ
m。
8. the ultrasonically controlled-release medicine eluting balloon catheter as described in claim 1-4 is any, it is characterised in that: the drug is more
Dilute taxol.
9. ultrasonically controlled-release medicine eluting balloon catheter as claimed in claim 5, it is characterised in that: the drug is mostly dilute Japanese yew
Alcohol.
10. ultrasonically controlled-release medicine eluting balloon catheter as claimed in claim 6, it is characterised in that: the drug is mostly dilute purple
China fir alcohol.
11. ultrasonically controlled-release medicine eluting balloon catheter as claimed in claim 7, it is characterised in that: the drug is mostly dilute purple
China fir alcohol.
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| CN201410049782.8A CN104841060B (en) | 2014-02-13 | 2014-02-13 | A kind of ultrasonically controlled-release medicine eluting balloon catheter and preparation method thereof |
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| CN104841060B true CN104841060B (en) | 2019-02-01 |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109985280B (en) * | 2017-12-29 | 2022-06-21 | 先健科技(深圳)有限公司 | Drug balloon and preparation method thereof |
| CN108371745B (en) * | 2018-03-16 | 2025-07-25 | 上海心至医疗科技有限公司 | Drug eluting balloon catheter system with vibration |
| CN109045446B (en) * | 2018-06-15 | 2021-07-20 | 重庆医科大学 | A method and system for controlling drug release |
| CN110339494B (en) * | 2019-07-22 | 2020-10-16 | 山东大学齐鲁医院 | Device and method for in-vivo microbubble manipulation and imaging |
| CN110584851A (en) * | 2019-09-21 | 2019-12-20 | 山东百多安医疗器械有限公司 | Ultrasonic controlled-release grooved degradable microsphere drug-loaded stent and preparation method thereof |
| CN111249536A (en) * | 2020-01-15 | 2020-06-09 | 山东瑞安泰医疗技术有限公司 | Novel drug eluting balloon catheter 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 |
| US20250025607A1 (en) * | 2022-02-23 | 2025-01-23 | Sino Medical Sciences Technology, Inc. | Method for preparing drug eluting balloons without coating |
| CN115501395B (en) * | 2022-09-22 | 2023-11-03 | 广东博迈医疗科技股份有限公司 | Medicine carrying saccule and preparation method thereof |
| CN116712615B (en) * | 2022-12-29 | 2024-05-24 | 微创优通医疗科技（上海）有限公司 | Preparation method of coating solution, medicine balloon for non-vascular intervention and preparation method |
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| CN101653420A (en) * | 2009-09-08 | 2010-02-24 | 中国科学院化学研究所 | Ultrasonically controlled-release target medicinal preparation and production method thereof |
| CN102271750A (en) * | 2008-11-14 | 2011-12-07 | 明诺医学股份有限公司 | Selective drug delivery in a lumen |
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| US20110160647A1 (en) * | 2009-12-30 | 2011-06-30 | Ross Tsukashima | Angioplasty Balloon Catheter with Active Delivery Medicament(s) Using Ultrasonic Means |
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| CN102271750A (en) * | 2008-11-14 | 2011-12-07 | 明诺医学股份有限公司 | Selective drug delivery in a lumen |
| CN101653420A (en) * | 2009-09-08 | 2010-02-24 | 中国科学院化学研究所 | Ultrasonically controlled-release target medicinal preparation and production method thereof |
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