CN108057168A - A kind of preparation method of medicinal balloon - Google Patents

A kind of preparation method of medicinal balloon Download PDF

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Publication number
CN108057168A
CN108057168A CN201711092572.7A CN201711092572A CN108057168A CN 108057168 A CN108057168 A CN 108057168A CN 201711092572 A CN201711092572 A CN 201711092572A CN 108057168 A CN108057168 A CN 108057168A
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sacculus
balloon
middle level
solution
drying
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CN108057168B (en
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韩晓阳
曾毅
杨大川
彭海成
杜玲
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Princeton Medical Science & Technology (guangzhou) Co Ltd
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Princeton Medical Science & Technology (guangzhou) Co Ltd
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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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Abstract

The invention discloses a kind of preparation method of medicinal balloon, drug used in the medicinal balloon in the present invention reprints the method that layer uses layered coating, is coated on bottom, is known as middle level.Drug, which reprints catalyst, in coating procedure is superimposed upon on bottom, is not mixed with bottom.Medicinal balloon of the present invention promotes drug from balloon surface in a short time, the maximum amount of to reprint to vascular wall.Medication coat is the process for discharging rapidly, quickly absorbing and slowly eliminating at target vessel position, i.e., peripheral blood vessel medicine balloon dilating catheter can play the role of active drug, the good potential applicability in clinical practice of tool.

Description

A kind of preparation method of medicinal balloon
Technical field
The present invention relates to a kind of preparation methods of medicinal balloon.
Background technology
The global burden of peripheral arterial disease (PAD) is being continuously increased, and has within 2000 1.64 hundred million people to suffer from peripheral arterial Disease, and increase within 2010 2.02 hundred million, illness rate adds nearly a quarter (23.5%).With the increasing of the population ages Long, the incidence of peripheral arterial disease is greatly improved with the growth at age；Within the coming years, patients with peripheral arterial disease people Number will continue to increase.
Lower limb peripheral arterial disease (PAD) is a kind of important behaviour of generalized atherosclerosis.The disease is by lower limb One or more arteriosclerotic lesions (limitation blocks blood stream to lower limb) of artery cause.
Artery of lower extremity obstruction causes some clinical manifestations, from asymptomatic to Charcot's syndrome (IC), ultimately results under severe Limb ischemic (CLI), makes artery blood flow degradation occur and jeopardizes lower limb.
About 30%~50% PAD patient will proceed to severe lower limb ischemia in the course of disease from Charcot's syndrome.Severe The prognosis mala of lower limb ischemia, the death rate are higher.After severe lower limb ischemia starts in 1 year, 25% patient separately has death 30% patient needs big amputation.Diabetes, smoking, lipodogramme exception, hypertension or patients with renal failure are suffered from periphery and are moved The risk of arteries and veins disease is higher.High mortality is caused by the angiocardiopathy coexisted.
Therefore, the purpose of peripheral arterial disease treatment is to protect limb, relief of symptoms, improve functional status and prevent painstaking effort It runs affairs part (acute myocardial infarction AMI [MI], palsy and vascular death).The treatment of peripheral arterial disease is alleviated including risk factors (smoking cessation, kinesiatrics etc.), drug therapy and final lower limb revascularization.
For a long time, operation is considered as the goldstandard of revascularization treatment always.But with the release of new instrument, Endovascular treatment is considered as now the first-line treatment of limping patient and critical extremity ischemia patient.
Medicinal balloon be by drug (such as：Taxol) apply and invest balloon surface, taxol be one kind can specificity tie Merge the anti-proliferative drug for stablizing micro-pipe.By preventing microtubule depolymerization, taxol can inhibit smooth muscle cell and into fiber finer The multiplication of born of the same parents and migration and the secretion of extracellular matrix.These effects can generate inhibition to the hyperplasia of endangium, so as to press down Reangiostenosis processed.
When carrying out peripheral blood vessel operation, especially during balloon expandable is carried out, medicine eluting balloon catheter surface Drug (such as：Taxol) it can be extruded in narrow vascular wall so that there are enough drugs to dissolve and penetrate into blood vessel Wall, so as to inhibit because balloon expandable in lesion vessels, middle film tear due to caused by endo cell hyperplasia, reach it is anti-angiogenic in, The purpose of middle film hyperplasia improves operation late period target vessel patency rate.
The content of the invention
It is an object of the invention to provide a kind of preparation methods of medicinal balloon.
The technical solution used in the present invention is：
A kind of preparation method of medicinal balloon, comprises the following steps：
1) access drop bottom solution is coated uniformly on balloon surface, and it is 0.5~5 μ g/ to make balloon surface bottom material concentration mm2, bottom solution is dried up, after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes the sacculus for scribbling bottom The middle level material concentration on surface is 4~30 μ g/mm2, middle level solution is dried up, after room temperature dries at least 30min, middle level must be scribbled Sacculus；
3) drug solution of suitable concentration is dropped in the balloon surface for scribbling middle level, sacculus is rotated in drop, makes drug equal Even to overlay on sacculus, drying, after room temperature dries 20~50min, drying obtains medicinal balloon；
The bottom material is selected from least one of polyethylene glycol oxide, polyvinyl acetate, polyvinylpyrrolidone；
The middle level substance is selected from acetate, benzoate, maleate, succinate, ascorbate, citric acid Salt, tartrate, lactate, oxalates, aspartate, nicotinate, gluconate, glutamate, vanillate, lactose At least one of hydrochlorate, polyethylene glycol, tromethamine, xylitol, sorbierite, mannitol, amino alcohol.
Further, in step 1), the concentration of the bottom solution is 1mg/ml~50mg/ml.
Further, in step 2), the concentration of the middle level solution is 10mg/ml~1000mg/ml.
Further, in step 1) and step 2), the concrete operations of the drying are：Under the conditions of 22~28 DEG C, wind is used Bottom solution or middle level solution are dried up in 80~110s.
Further, in step 1) and step 2), sacculus is rotated back and forth during drying.
Further, in step 3), the concentration of the drug solution is 8.0mg/ml~11.5mg/ml
Further, in step 3), drug solution coating at twice, and in coating procedure in drop rotating ball Capsule.
Further, in step 3), the concrete operations of the drying are：10 are blown with room temperature cold wind during the first secondary coating~ 60s, when the second secondary coating, are blown with fan middle-grade hot wind, and object is finally blown, rotating ball away from 45~60cm of fan with room temperature cold wind Capsule, evenly drying.
Further, the material of the sacculus is in polyethylene, Pebax, nylon, nylon elastomer, PET, polyurethane One kind.
Further, the drug is selected from taxol, everolimus, tacrolimus, phosphocholine, CD34 antibody and its spreads out One or more of biology.
A kind of medicinal balloon, its preparation method are method described in any one of the above embodiments.
The beneficial effects of the invention are as follows：
(1) in medicinal balloon made from the method for the present invention, the attachment force of coating and balloon surface is enhanced, and is strengthened Coat fastness, middle level will not fall off, visually will not peeling.
(2) drug used in the medicinal balloon in the present invention reprints the method that layer uses layered coating, is coated on bottom On, it is known as middle level.Drug, which reprints catalyst, in coating procedure is superimposed upon on bottom, is not mixed with bottom.Drug of the present invention Sacculus promotes drug from balloon surface in a short time (1-10 minutes), the maximum amount of to reprint to vascular wall.
(3) the method for the present invention realizes the purpose of protection sacculus self character without being surface-treated to sacculus.
(4) the method for the present invention can general accurate titration method by drug accurately " storing " in the middle level of medication coat In.The advantages of accurate coating is to realize to efficiently control drug load, reaches good clinical efficacy.
(5) after medicinal balloon of the present invention enters pig asrteriectasia, medication coat can discharge rapidly on sacculus, be inhaled by target vessel It receives, 0 moment is with regard to that can reach the peak value of absorption, and target vessel fraction medicine content is also far above minimum effective dose after 28 days 47ng/g(0.047μg/g)；The result shows that medication coat is discharged rapidly at target vessel position, quickly absorbs and slowly eliminated Process, i.e. peripheral blood vessel medicine balloon dilating catheter can play the role of active drug.
Description of the drawings
Fig. 1 is blood taxol medicine-time plot in pig body after medicinal balloon of the present invention expansion；
Fig. 2 is target vessel paclitaxel concentration-time plot in medicine balloon dilating catheter pig body of the present invention.
Specific embodiment
A kind of preparation method of medicinal balloon, comprises the following steps：
1) access drop bottom solution is coated uniformly on balloon surface, and it is 0.5~5 μ g/ to make balloon surface bottom material concentration mm2, bottom solution is dried up, after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes the sacculus for scribbling bottom The middle level material concentration on surface is 4~30 μ g/mm2, middle level solution is dried up, after room temperature dries at least 20min, middle level must be scribbled Sacculus；
3) drug solution of suitable concentration is dropped in the balloon surface for scribbling middle level, sacculus is rotated in drop, makes drug equal Even to overlay on sacculus, drying, after room temperature dries 20~50min, drying obtains medicinal balloon；
The bottom material is selected from least one of polyethylene glycol oxide, polyvinyl acetate, polyvinylpyrrolidone；
The middle level substance is selected from acetate, benzoate, maleate, succinate, ascorbate, citric acid Salt, tartrate, lactate, oxalates, aspartate, nicotinate, gluconate, glutamate, vanillate, lactose At least one of hydrochlorate, polyethylene glycol, tromethamine, xylitol, sorbierite, mannitol, amino alcohol.
Preferably, in step 1), the concentration of the bottom solution is 1mg/ml~50mg/ml.
Preferably, in step 1) and step 2), the concrete operations of the drying are：It, will with wind under the conditions of 22~28 DEG C Bottom solution or middle level solution dry up in 80~110s.
Preferably, in step 1) and step 2), sacculus is rotated back and forth during drying.
Preferably, in step 2), the concentration of the middle level solution is 10mg/ml~1000mg/ml.
Preferably, in step 3), the concentration of the drug solution is 8.0mg/ml~11.5mg/ml.
Preferably, in step 3), drug solution coating at twice, and in coating procedure in drop rotating ball Capsule.
Preferably, in step 3), the concrete operations of the drying are：10~60s is blown with room temperature cold wind during the first secondary coating, It is blown during the second secondary coating with fan hot wind, object is finally blown with room temperature cold wind away from 45~60cm of fan, rotates sacculus, uniformly It is dry.
It is furthermore preferred that in step 3), coating, first time first take the drug solution of half amount to drip to the drug solution at twice Scribbling the balloon surface in middle level, rotating sacculus in drop, medicaments uniformity is made to overlay on sacculus, at the same room temperature cold wind blow 10~ 60s；Open fan middle-grade, hot wind；The drug solution of other half amount is taken for the second time, makes sacculus left away from 45~60cm of fan The right side rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, after hot wind blows 10~60s, closes hot wind, opens cold wind, rotates Sacculus makes its evenly drying.
Preferably, the temperature of the hot wind is 35~50 DEG C.
Preferably, in step 3), the temperature of drying is 35~38 DEG C, and drying time is at least for 24 hours.
Preferably, the material of the sacculus is in polyethylene, Pebax, nylon, nylon elastomer, PET, polyurethane It is a kind of.
Preferably, the drug is selected from taxol, everolimus, tacrolimus, phosphocholine, CD34 antibody and its derivative One or more of object.
A kind of medicinal balloon, its preparation method are method described in any one of the above embodiments.
With reference to specific embodiment, the present invention is further illustrated.
Embodiment 1
1. sacculus is handled
The polyethylene balloon that coating uses first passes around following processing：Trimming → inflation → sealing → cleans → dries → It dries → weighs.
2. coat bottom
2.1 priming operation：Appropriate bottom solution (i.e. polyethylene oxide solutions) is taken, concentration 20.1mg/ml is poured into dedicated In glassware, two drop bottom solutions are dipped every time with coating brush and are coated uniformly on balloon surface, make balloon surface bottom material Concentration is 3 μ g/mm2.Open fan (low-grade wind speed, do not heat), 45~60cm of distance or so.Ball is coated back and forth with coating brush Capsule, general 90s bottom solutions parch completely, and environment temperature needs to control between 22~25 DEG C.
2.2 weigh the sacculus weight after priming operation：The sacculus of bottom will be coated, dried at ambient temperature at least 30min weighs, and records data；
3. coat middle level
3.1 apply middle level：Appropriate middle level solution, (i.e. xylitol solution) are taken, concentration 375mg/ml pours into dedicated glass In vessel, two drop middle level solution are dipped every time coated in above sacculus with coating brush, make the middle level for the balloon surface for scribbling bottom Material concentration is 15 μ g/mm2.Open fan (low-grade wind speed, do not heat), 45~60cm of distance or so.Sacculus is rotated back and forth, greatly General 80~110s, before middle level soon all parches, with coating brush gently coat it is several under, make coating surface uniform.Environment during coating Temperature needs to control at 22~28 DEG C.
3.2 weigh the sacculus weight after applying middle level：The sacculus in middle level will be coated, dried at ambient temperature at least 30min weighs, and records data；
4. coat drug-loaded layer
4.1 apply medicine layer：The sacculus for scribbling middle level solution is lain on special glass shallow bid, is drawn with liquid-transfering gun appropriate Prepared paclitaxel solution (paclitaxel concentration is between 8.0mg/ml~11.5mg/ml herein).
It takes(herein because each specification sacculus medicine taking amount is different, Therefore the calculation formula after simplifying has been write out), ensure that content of taxol is 3 μ g/mm on sacculus2.Open fan (low-grade, cold wind) The drug solution of half amount is taken to drop in the balloon surface for scribbling middle level, sacculus is rotated in drop, medicaments uniformity is made to overlay on sacculus, Blow 10-60S；The drug solution that fan (middle-grade, hot wind (35~50 DEG C)) takes other half amount is opened, makes sacculus away from fan 45 ~60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened Cold wind, mobile sacculus, makes its evenly drying.After room temperature dries 20~50min, in 35~38 DEG C of oven for drying at least for 24 hours, medicine is obtained Object sacculus
4.2 weigh sacculus weight after load medicine：After coated sacculus room temperature is dried 20~50min, in 35~38 DEG C of bakings Case is dried at least for 24 hours, is obtained medicinal balloon, is weighed, and records data；
5. sacculus stores：It is stored under the conditions of drying, shading etc..
A kind of preparation method of 2 medicinal balloon of embodiment,
1) access drop bottom solution (25mg/ml) is coated uniformly on balloon surface (balloon material is polyethylene), makes sacculus Surface bottom material concentration is 1.32 μ g/mm2, under the conditions of 28 DEG C, bottom solution is dried up to (drying process in 110s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (100mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 4.82 μ g/mm2, middle level solution is dried up in 80s (during drying with wind Sacculus is rotated back and forth), after room temperature dries at least 30min, 45 DEG C of drying 2.5h after room temperature dries at least 30min, must scribble middle level Sacculus；
3) taxol drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes half The drug solution of amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, blows 10- 60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 50min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 3 medicinal balloon of embodiment,
1) access drop bottom solution (30mg/ml) is coated uniformly on balloon surface (balloon material Pebax), makes sacculus table Face bottom material concentration is 2 μ g/mm2, under the conditions of 25 DEG C, bottom solution is dried up in 100s with wind (during drying come Back rotation sacculus), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (400mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 8.26 μ g/mm2, middle level solution is dried up to (drying process in 110s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, 55 DEG C drying 2.5h, after room temperature dries at least 30min, in must scribbling The sacculus of layer；
3) taxol drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes half The drug solution of amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, blows 10- 60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 20min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 4 medicinal balloon of embodiment,
1) access drop bottom solution (50mg/ml) is coated uniformly on balloon surface (balloon material is nylon), makes sacculus table Face bottom material concentration is 2.07 μ g/mm2, under the conditions of 22~28 DEG C, bottom solution in 80s is dried up with wind and (was dried up Sacculus is rotated in journey back and forth), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (10mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 4.85 μ g/mm2, middle level solution is dried up to (drying process in 110s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, 45 DEG C drying 1.5h, after room temperature dries at least 30min, in must scribbling The sacculus of layer；
3) taxol drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes half The drug solution of amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, blows 10- 60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 200min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 5 medicinal balloon of embodiment,
1) access drop bottom solution (50mg/ml) is coated uniformly on balloon surface (balloon material is nylon elastomer), makes Balloon surface bottom material concentration is 2.09 μ g/mm2, under the conditions of 22 DEG C, bottom solution is dried up to (drying in 80s with wind Rotate sacculus back and forth in the process), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (10mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 7.56 μ g/mm2, middle level solution is dried up in 80s (during drying with wind Sacculus is rotated back and forth), after room temperature dries at least 30min, 55 DEG C of drying 2.5h after room temperature dries at least 30min, must scribble middle level Sacculus；
3) taxol drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes half The drug solution of amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, blows 10- 60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 50min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 6 medicinal balloon of embodiment,
1) access drop bottom solution (1mg/ml) is coated uniformly on balloon surface (balloon material PET), makes balloon surface Bottom material concentration is 1.04 μ g/mm2, under the conditions of 28 DEG C, bottom solution is dried up in 110s with wind (during drying come Back rotation sacculus), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (1000mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes painting The middle level material concentration for having the balloon surface of bottom is 8.92 μ g/mm2, middle level solution is dried up to (drying process in 80s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, 55 DEG C drying 1.5h, after room temperature dries at least 30min, in must scribbling The sacculus of layer；
3) everolimus drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes one The drug solution of half amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, is blown 10-60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 20min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 7 medicinal balloon of embodiment,
1) access drop bottom solution (40mg/ml) is coated uniformly on balloon surface (balloon material is polyurethane), makes sacculus Surface bottom material concentration is 1.17 μ g/mm2, under the conditions of 26 DEG C, bottom solution is dried up to (drying process in 110s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (500mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 6.79 μ g/mm2, middle level solution is dried up in 90s (during drying with wind Sacculus is rotated back and forth), after room temperature dries at least 30min, 55 DEG C of drying 2.5h after room temperature dries at least 30min, must scribble middle level Sacculus；
3) tacrolimus drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes one The drug solution of half amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, is blown 10-60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 40min, 38 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 8 medicinal balloon of embodiment,
1) access drop bottom solution (30mg/ml) is coated uniformly on balloon surface (balloon material is polyethylene), makes sacculus Surface bottom material concentration is 0.89 μ g/mm2, under the conditions of 22~28 DEG C, bottom solution is dried up in 80~110s with wind (rotating sacculus back and forth during drying), after room temperature dries at least 30min, must scribble the sacculus of bottom；
2) access drop middle level solution (600mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 8.23 μ g/mm2, middle level solution is dried up to (drying process in 110s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, 55 DEG C drying 2.5h, after room temperature dries at least 30min, in must scribbling The sacculus of layer；
3) phosphocholine drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes one The drug solution of half amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, is blown 10-60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 50min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
A kind of preparation method of 9 medicinal balloon of embodiment,
1) access drop bottom solution (45mg/ml) is coated uniformly on balloon surface (balloon material is polyurethane), makes sacculus Surface bottom material concentration is 0.77 μ g/mm2, under the conditions of 27 DEG C, bottom solution is dried up to (drying process in 80s with wind In rotate sacculus back and forth), after room temperature dries at least 30min, the sacculus of bottom must be scribbled；
2) access drop middle level solution (700mg/ml) is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes to scribble The middle level material concentration of the balloon surface of bottom is 5.53 μ g/mm2, middle level solution is dried up in 80s (during drying with wind Sacculus is rotated back and forth), after room temperature dries at least 30min, 45 DEG C of drying 1.5h after room temperature dries at least 30min, must scribble middle level Sacculus；
3) CD34 antibody drug solution is dropped in the balloon surface for scribbling middle level, fan (low-grade, cold wind) is opened and first takes one The drug solution of half amount drops in the balloon surface for scribbling middle level, rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus, is blown 10-60S；Open fan (middle-grade, hot wind (35~50 DEG C)) and take the drug solution of other half amount, make sacculus away from fan 45~ 60cm or so rotates sacculus in drop, medicaments uniformity is made to overlay on sacculus.When drug solution quick-drying, hot wind is closed, is opened cold Wind, mobile sacculus, makes its evenly drying.After room temperature dries 20min, 35 DEG C of drying at least for 24 hours, obtain medicinal balloon.
The medicinal balloon prepared below to embodiment makees further effect detection.
First, bottom, middle level and the detection of medicine layer data
Following table 1 lists bottom, middle level and the medicine layer data of the medicinal balloon of the method for the present invention preparation.
1 medicinal balloon coating data of table is analyzed
2nd, drug release effect detection
Method：Medicinal balloon prepared by the present invention is used in the animal experiment of pig, expands pig with medicinal balloon of the present invention Femoral artery after 2 minutes, detect the medicament contg situation on sacculus, while detect the medicament contg in target vessel.
As a result：The testing result of medicament contg is as shown in table 2 on sacculus, there it can be seen that the medicinal balloon after expansion, Drug entrained by coating has largely discharged (70%), also retains on a small quantity in the coating.
The front and rear medicament contg situation of 2 medicinal balloon of the present invention of table expansion
3rd, the drug release effect that medicinal balloon is answered in animal body
(1) by after the femoral artery of medicinal balloon of the present invention expansion pig, the testing result of blood plasma drug content is such as in pig body Shown in Fig. 1, there it can be seen that the medicament contg in blood plasma reaches top at once in release, then decrease.24 it is small when Afterwards, drug disappears from blood plasma substantially.
(2) after the femoral artery that medicinal balloon of the present invention is expanded to pig, testing result such as Fig. 2 institutes of target vessel drug content Show.In balloon expandable at once, the medicament contg in target vessel has reached 1.5mg/g.Although target vessel fraction medicine after 28 days Content is decreased very much, but is also far above minimum effective dose 47ng/g (0.047 μ g/g).
(3) after medicinal balloon of the present invention being expanded pig blood pipe, the medicament contg in each tissue is as shown in table 3.From data In it can be seen that, drug be mostly reprint into vascular wall.The drug of (such as liver) in blood and its hetero-organization Content is relatively low.
Medicament contg of 3 medicinal balloon of the present invention of table after animal body expansion in each tissue
Using medicinal balloon catheter of the present invention in the in vivo experiment of pig, it can be deduced that such as draw a conclusion：
1) the total AUClast values of taxol in the blood vessel are 167264263.0ng*hr/g, the AUClast in liver organization It is worth for 63351ng*hr/g, the total distributed amount in target vessel is far more than abundance in liver organization, and main distribution is presented；
2) target vessel position is in 0h, medicament contg to peaking, up to 1.4 × 106ng/g(1.4×103μ g/g) more than, 7 It when content be 1.16 × 105ng/g(116μg/g).Hereafter content gently reduces, and is still 1.28 × 10 at 28 days4ng/g(12.8 μg/g)。
3) after peripheral blood vessel medicine balloon dilating catheter enters pig asrteriectasia, taxol contains in blood during T=0.083h Amount reaches peak value, after 28 days, fails to detect taxol in blood, i.e., taxol can be basic into after spending 28 days in blood It is eliminated.
4) after peripheral blood vessel medicine balloon dilating catheter enters pig asrteriectasia, medication coat can discharge rapidly on sacculus, Absorbed by target vessel, 0 moment just can reach the peak value of absorption, and after 28 days target vessel fraction medicine content also far above most Low effective dose 47ng/g (0.047 μ g/g)；The result shows that medication coat at target vessel position be discharge rapidly, quickly absorb and The process slowly eliminated, i.e. peripheral blood vessel medicine balloon dilating catheter can play the role of active drug.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention and from above-described embodiment Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification, Equivalent substitute mode is should be, is included within protection scope of the present invention.

Claims (10)

1. a kind of preparation method of medicinal balloon, which is characterized in that comprise the following steps：
1) access drop bottom solution is coated uniformly on balloon surface, and it is 0.5~5 μ g/mm to make balloon surface bottom material concentration2, will Bottom solution dries up, and after room temperature dries at least 30min, must scribble the sacculus of bottom；
2) access drop middle level solution is coated uniformly on the balloon surface that bottom is scribbled obtained by step, makes the balloon surface for scribbling bottom Middle level material concentration be 4~30 μ g/mm2, middle level solution is dried up, after room temperature dries at least 20min, the ball in middle level must be scribbled Capsule；
3) drug solution of suitable concentration is dropped in the balloon surface for scribbling middle level, sacculus is rotated in drop, covers medicaments uniformity On sacculus, drying, after room temperature dries 20~50min, drying obtains medicinal balloon；
The bottom material is selected from least one of polyethylene glycol oxide, polyvinyl acetate, polyvinylpyrrolidone；
The middle level substance is selected from acetate, benzoate, maleate, succinate, ascorbate, citrate, wine Stone hydrochlorate, lactate, oxalates, aspartate, nicotinate, gluconate, glutamate, vanillate, Lactobionate, At least one of polyethylene glycol, tromethamine, xylitol, sorbierite, mannitol, amino alcohol.
2. according to the method described in claim 1, it is characterized in that, in step 1), the concentration of the bottom solution is 1mg/ml ~50mg/ml.
3. according to the method described in claim 1, it is characterized in that, in step 1) and step 2), the concrete operations of the drying For：Under the conditions of 22~28 DEG C, bottom solution or middle level solution are dried up in 80~110s with wind.
4. according to the method described in claim 1, it is characterized in that, in step 1) and step 2), carry out back rotation during drying Sacculus.
5. according to the method described in claim 1, it is characterized in that, in step 3), the concentration of the drug solution is 8.0mg/ Ml~11.5mg/ml.
6. according to the method described in claim 1, it is characterized in that, in step 3), drug solution coating at twice, and In coating procedure sacculus is rotated in drop.
7. the method according to claim 1 or 6, which is characterized in that in step 3), the concrete operations of the drying are：The Blow 10~60s with room temperature cold wind during primary coating, when the second secondary coating, is blown with fan middle-grade hot wind, object away from fan 45~ 60cm is finally blown with room temperature cold wind, rotates sacculus, evenly drying.
8. according to the method described in claim 1, it is characterized in that, the material of the sacculus be selected from polyethylene, Pebax, nylon, One kind in nylon elastomer, PET, polyurethane.
9. according to the method described in claim 1,5 or 8, which is characterized in that the drug be selected from taxol, everolimus, he One or more of Ke Mosi, phosphocholine, CD34 antibody and its derivative.
10. a kind of medicinal balloon, its preparation method is claim 1~9 any one of them method.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514096A (en) * 1993-12-28 1996-05-07 Nissho Corporation Apparatus and balloon for dosing a liquid medicine
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
CN104623740A (en) * 2013-11-15 2015-05-20 微创心脉医疗科技（上海）有限公司 Medicine balloon and preparation method thereof
CN204932563U (en) * 2015-09-22 2016-01-06 傅国胜 A kind of dabbling drug sacculus
CN107206129A (en) * 2015-07-09 2017-09-26 上海脉科医疗科技有限公司 Medication coat medicine equipment
WO2017164278A1 (en) * 2016-03-23 2017-09-28 テルモ株式会社 Balloon catheter, method for producing same, and treatment method
CN107261300A (en) * 2016-04-04 2017-10-20 美敦力心血管股份有限公司 Foley's tube and the method for covering medical sacculus

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514096A (en) * 1993-12-28 1996-05-07 Nissho Corporation Apparatus and balloon for dosing a liquid medicine
CN104623740A (en) * 2013-11-15 2015-05-20 微创心脉医疗科技（上海）有限公司 Medicine balloon and preparation method thereof
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
CN107206129A (en) * 2015-07-09 2017-09-26 上海脉科医疗科技有限公司 Medication coat medicine equipment
CN204932563U (en) * 2015-09-22 2016-01-06 傅国胜 A kind of dabbling drug sacculus
WO2017164278A1 (en) * 2016-03-23 2017-09-28 テルモ株式会社 Balloon catheter, method for producing same, and treatment method
CN107261300A (en) * 2016-04-04 2017-10-20 美敦力心血管股份有限公司 Foley's tube and the method for covering medical sacculus

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