CN107362439A - A kind of preparation method of drug coated balloon catheter, the drug coated balloon catheter being prepared and its application - Google Patents
A kind of preparation method of drug coated balloon catheter, the drug coated balloon catheter being prepared and its application Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/63—Crystals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
- A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
-
- 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
- A61M2205/00—General characteristics of the apparatus
- A61M2205/02—General characteristics of the apparatus characterised by a particular materials
- A61M2205/0238—General characteristics of the apparatus characterised by a particular materials the material being a coating or protective layer
-
- 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
- A61M2207/00—Methods of manufacture, assembly or production
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Abstract
The present invention, which provides a kind of preparation method of drug coated balloon catheter, obtained drug coated balloon catheter and its application, methods described, to be included：Active medicine crystal seed is prepared, it is 1~3 μm of crystal seed to filter out length, and active medicine crystal seed suspension is made；It is separately added into the different passages of flush coater from active agent solution and additive solution, the mixed aerosol at the nozzle tip of the ultrasonic nozzle of the flush coater, spray to sacculus dilating catheter surface, obtain the suitable medication coat of crystalline size, homogenization post processing is carried out, obtains the more homogeneous drug coated balloon catheter of crystal.Be firmly combined with the invention enables medication coat with sacculus, medicine crystal it is uniformly complete；It can guarantee that and prepared in sacculus and drug loss is smaller in conveying in vivo; the active drug concentration that diseased region vascular wall enters is bigger, and carrier medicine carrying efficiency is higher, effectively treats that intravascular original position be narrow or ISR; reduces advanced thrombus, ISR equivalent risk, while the positivity that can form blood vessel reconstructs.
Description
Technical field
The invention belongs to medical instruments field, and in particular to a kind of preparation method of drug coated balloon catheter, be prepared into
The drug coated balloon catheter arrived and its application.
Background technology
Medicinal balloon be balloon dilatation or Balloon Angioplasty etc. intervention medical treatment on the basis of grow up it is therapeutic
Sacculus drug delivery technologies, it is that active medicine is coated on into balloon surface, expands blood vessel when sacculus reaches diseased region, and
Active medicine is discharged when being contacted with vascular endothelial tissue, to play a part of prevention and treatment.
Increasing people is directed to the research of medicinal balloon at present, and increasing medicinal balloon and carrier technique are public
Open, but not all medicinal balloon can reach good effect, and the factor for influenceing medicinal balloon validity mainly has
Below some：1) firmness of medication coat, human vas is entered because medicinal balloon will pass through intervention operation, it reaches lesion
To be washed away before position by blood flow, the challenge such as friction of conduit, seal wire, stenotic lesion, just because of it is such the reason for, many medicines
Thing sacculus does not reach obvious therapeutic effect；2) carrier or matrix, the medicine used in many medicinal balloons are fat-soluble medicines, single
Only fat-soluble medicine coating biology utilization rate is low, absorption difference, and carrier or matrix are usually water-soluble strong material, can be improved
The availability of medicine, 3) crystal habit of active medicine has a significant impact for tools such as its absorption in vivo, retention times, from
And influence its therapeutic effect.
When preparing medicinal balloon catheter, different coating technologies and its preparation technology may be to the firm of medication coat
The crystal habit of degree, fat-soluble medicine coating biology utilization rate and active medicine produces a very large impact, preparation main at present
Method is infusion process, microinjection and spraying process.
CN103611212A discloses a kind of preparation method of medicinal balloon, sacculus is carried out into hydrophilic treated first, then
Taxol is brushed on sacculus or the direct roll-in taxol drug of sacculus obtains medication coat, its medicine crystal size is 20
- 40 microns of micron, is prepared obtained medicine-coated balloon, and the combination of its medication coat and balloon surface is not firm enough,
Serious medicine can be caused to rush in internal course of conveying de-, drug loss is big, and has that medicine crystal size is larger, and medicine applies
The problems such as layer is not uniform enough.
CN104922735A discloses a kind of preparation method of medicinal balloon, and its method includes：(1) prepared in balloon surface
Particulate coatings, the particulate coatings are made up of sodium chloride, calcium chloride or urea, and the sacculus with particulate coatings is placed in medicine by (2)
In thing solution, make medicine in particulate coatings surface crystallization, form medication coat, sacculus is taken out from drug solution, dry, obtain
To the medicinal balloon.The inorganic salts of the invention are coated on balloon surface by the way of dip-coating, can cause this layer it is uneven,
Inorganic salts easily dissolve when entering in blood of human body simultaneously, so as to cause medicine layer thereon easily to come off；And due to nothing
Machine salt deposit first coats one layer, rather than is dissolved each other with active agent solution, the nucleation deficiency that only contact surface plays, causes its work
The crystallization effect of property medicine is limited.
CN106620887A discloses a kind of production method of medicinal balloon, and it uses multiple spraying technology, and medicine is molten
Liquid sprays to balloon surface from level to level, and the solvent vapo(u)r carried out to medication coat at 76 DEG C is handled.Although multilayer spraying is favourable
In the degree of supersaturation and its solvent evaporation rate of control drug solution, there is certain side hence for the Crystallization of active medicine
Help, but the overall firmness of medication coat can be reduced；And the solvent vapo(u)r processing under heating, balloon surface medicine are decrystallized
After recrystallize precipitation, the adhesion of former medication coat and sacculus utricule can be destroyed completely, so that medication coat is firm
Spend worse.
Therefore, in this area, it is expected to develop a kind of active drug particles size small and uniform, while coating firmness is good,
The medicinal balloon catheter for avoiding active constituents of medicine from being taken off in course of conveying by punching.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of preparation side of drug coated balloon catheter
Method, the drug coated balloon catheter being prepared and its application, the drug coated balloon catheter active drug that the present invention is prepared
Thing crystal size is small and homogeneous, and medication coat and sacculus are firmly combined with, are uniformly complete, can ensure in sacculus preparation process and
Drug loss in human body in course of conveying is smaller, and the active drug concentration that diseased region vascular wall enters is bigger, carries drug effect
Rate is higher, can effectively treat that intravascular original position is narrow or ISR, and reduces the security risks such as advanced thrombus, ISR, together
When can be formed blood vessel positivity reconstruct.
To reach this goal of the invention, the present invention uses following technical scheme：
On the one hand, the present invention provides a kind of preparation method of drug coated balloon catheter, the described method comprises the following steps：
(1) crystal seed of active medicine is prepared, and filters out the crystal seed that length is 1 μm~3 μm, prepares active drugs crystal seed
Suspension；
(2) active medicine crystal seed suspension and active agent solution and additive solution are separately added into the difference of flush coater
In passage, mix and be atomized at the nozzle tip of the ultrasonic nozzle of the flush coater, spray to balloon surface, obtain surface tool
There is the sacculus dilating catheter of medication coat；
(3) sacculus dilating catheter that the surface that step (2) obtains is had into medication coat carries out homogenization post processing, obtains
The drug coated balloon catheter.
In the present invention, by the preparation method, medication coat can be caused to be firmly bonded to sacculus dilating catheter
Surface, and medicine crystal is small and homogeneous in obtained drug coated balloon catheter.
In the present invention, using the ultrasonic spraying coating process using compressed gas to the decoction line after atomization, so as to
Enough so that liquor granule arrives balloon surface with certain speed " punching ", therefore the adhesion of medication coat and utricule is more preferable, relative to
Other drugs coating method more can guarantee that the firmness of medication coat.
The crystal seed for needing to use active medicine in the present invention reaches in sacculus so that induced activity drug crystallization separates out
Dilating catheter surface obtains small and homogeneous medicine crystallite, and uses additive in the preparation process in accordance with the present invention, itself and work
The crystal seed of property medicine strengthens the crystallization of active medicine together so that the crystal grain of active medicine is more uniform, and can also increase
The fastness that strong medication coat is combined with sacculus.
The size (i.e. length) of the crystal seed of step (1) described active medicine is selected as 1 μm~3 μm in the present invention, such as 1
μm, 1.3 μm, 1.5 μm, 1.8 μm, 2 μm, 2.2 μm, 2.4 μm, 2.6 μm, 2.8 μm or 3 μm.The present invention screens by lot of experiments
The optimal section of the seed sized of active medicine, this section match with technical scheme：If crystal seed length is less than 1
μm it is possible that active pharmaceutical crystals crystallization is incomplete, and the partial crystals advantages life that active medicine occurs higher than 3 μm
It is long, the situation that crystal size differs.
Preferably, the preparation method of the crystal seed of step (1) described active medicine is：Active medicine is added into organic solvent a
In, medicine is dissolved using ultrasound or mode of heating, obtains the supersaturated solution of active medicine；The supersaturated solution is used
Evaporative crystallization, decrease temperature crystalline add the mode that frozen water is cooled down rapidly and quickly stirred, and obtain the crystal seed of the active medicine.
Preferably, the concentration of the supersaturated solution is 30mg/mL~65mg/mL, such as 30mg/mL, 33mg/mL,
35mg/mL、38mg/mL、40mg/mL、45mg/mL、48mg/mL、50mg/mL、53mg/mL、55mg/mL、58mg/mL、60mg/
ML or 65mg/mL.
Preferably, the preparation method of step (1) the active medicine crystal seed suspension is：The crystal seed of active medicine is added
Disperse into solvent b, obtain the active medicine crystal seed suspension.
Preferably, the concentration of the active medicine crystal seed suspension is 0.1mg/mL~1mg/mL, such as 0.1mg/mL,
0.3mg/mL, 0.5mg/mL, 0.8mg/mL or 1mg/mL, preferably 0.6mg/mL.
Preferably, the solvent b is but is not limited to purified water and/or deionized water.
Preferably, suspending agent is added in the crystal seed suspension；
Preferably, the suspending agent be but be not limited to glycerine, syrup, sorbierite, natural gum, sodium alginate, methylcellulose,
Sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, sodium cellulose sulfate, sodium hydroxyethyl cellulose, aluminum stearate or colloidal silicon
In sour magnalium any one or at least two combination.
Preferably, step (1) method for filtering out the crystal seed that length is 1 μm~3 μm is sieve method, sedimentation or electricity
Mirror method.
In the present invention, step (2) is described by active medicine crystal seed suspension and active agent solution and additive solution
Be separately added into the different passages of flush coater, wherein can be active medicine and additive are prepared the two mixing it is molten
Liquid, i.e., active medicine and additive are dissolved in organic solvent c, obtain the mixed solution of active medicine and additive, then
It is separately added into the different passages of flush coater or is dissolved in active medicine organic molten from active medicine crystal seed suspension
Active agent solution is prepared in agent d, additive is dissolved in organic solvent e additive solution is prepared, then will
Both solution are separately added into the different passages of flush coater from active agent solution.
Preferably, the active medicine is taxol.
Preferably, the weight ratio of step (2) active medicine and additive is 1:0.1~20, such as 1:0.1、1:
0.3、1:0.5、1:1、1:3、1:5、1:8、1:10、1:13、1:15、1:18 or 1:20, preferably 1:0.3~1.
Preferably, the concentration of step (2) described active agent solution is 1mg/mL~50mg/mL, such as 1mg/mL, 3mg/
mL、5mg/mL、8mg/mL、10mg/mL、15mg/mL、18mg/mL、20mg/mL、25mg/mL、28mg/mL、30mg/mL、
35mg/mL, 38mg/mL, 40mg/mL, 45mg/mL, 48mg/mL or 50mg/mL, preferably 15mg/mL~35mg/mL.
Preferably, the concentration of step (2) described additive solution is 1mg/mL~20mg/mL, such as 1mg/mL, 3mg/
ML, 5mg/mL, 8mg/mL, 10mg/mL, 12mg/mL, 15mg/mL, 18mg/mL or 20mg/mL, preferably 5mg/mL~15mg/
mL。
Preferably, the additive is urea, Iopromide, polysorbate, polyethylene glycol, glycol glucoside, alkyl
In glucosides, meglumine, pectin, mannitol, methylcellulose, vinyl cellulose, hydroxypropyl cellulose, mannitol or acetamide
Any one or at least two combination.
Preferably, the material for preparing of the sacculus dilating catheter is appointing in nylon, nylon elastomer Pebax or polyethylene
Anticipate a kind of or at least two combinations.
Preferably, the organic solvent a, organic solvent c, organic solvent d and organic solvent e independently are but are not limited to first
Alcohol, ethanol, ethyl acetate, ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, Ethyl formate or acetic acid
In methyl esters any one or at least two combination.
Preferably, it is 10 μm~20 μm (examples by mixed solution atomization at the nozzle of step (2) ultrasonic nozzle
Such as 10 μm, 12 μm, 14 μm, 16 μm, 18 μm or 20 μm) decoction little particle.In the decoction little particle, active medicine crystallite is made
For crystal seed, in supersaturation separates out crystallization process, induced activity drug crystallization separates out.
In the present invention, step (2) is described by active medicine crystal seed suspension, active agent solution and additive solution,
It is injected separately into medicinal balloon ultrasound spraying equipment, active agent solution/additive solution is at nozzle tip by ultrasonic atomizatio
For 10 μm~20 μm of decoction little particle, drug ingedient mixes with active medicine crystallite in these decoction little particles, active medicine
Crystallite separates out as the crystal seed in decoction, the crystallization of induced activity medicine, and it is small and equal finally to prepare active pharmaceutical crystals granularity
One medication coat.
Preferably, step (2) described ultrasonic nozzle has the nozzle of more than 3, wherein a centrally located nozzle
For 99.99% high pure nitrogen passage/filtering compressed air passage.
Preferably, the pressure of the high pure nitrogen or filtering compressed air is 0.01MPa~0.20MPa, such as
0.01MPa, 0.02MPa, 0.04MPa, 0.06MPa, 0.08MPa, 0.1MPa, 0.13MPa, 0.15MPa, 0.18MPa or
0.2MPa。
Preferably, the ultrasonic generator power of step (2) described flush coater is 0.8W~5.0W, such as 0.8W, 1W,
1.3W, 1.5W, 1.8W, 2W, 2.5W, 2.8W, 3W, 3.5W, 3.8W, 4W, 4.5W, 4.8W or 5W.
Preferably, the fltting speed of active agent solution and additive solution independently is in step (2) described flush coater
0.01mL/min~0.50mL/min, such as 0.01mL/min, 0.03mL/min, 0.05mL/min, 0.08mL/min, 0.1mL/
min、0.15mL/min、0.18mL/min、0.2mL/min、0.25mL/min、0.3mL/min、0.35mL/min、0.4mL/
Min, 0.45mL/min or 0.5mL/min.
In the present invention, when active medicine and additive are prepared into active agent solution and addition respectively as described above
During agent solution, then active agent solution and additive solution are added in the different passages of flush coater, control its fltting speed respectively
0.01mL/min~0.50mL/min independently is, and works as and the mixed of the two is prepared in active medicine and additive as described above
When closing solution, then it is added into the different passages of flush coater, the fltting speed for controlling the mixed solution is 0.01mL/min
~0.50mL/min.
Preferably, the fltting speed of crystal seed suspension is 0.03mL/min~0.20mL/ in step (2) described flush coater
Min, for example, 0.03mL/min, 0.05mL/min, 0.08mL/min, 0.1mL/min, 0.15mL/min, 0.18mL/min or
0.2mL/min。
Preferably, step (2) it is described ultrasound spraying when, sacculus dilating catheter be longitudinally travelled speed for 1mm/s~
20mm/s (such as 1mm/s, 3mm/s, 5mm/s, 8mm/s, 10mm/s, 13mm/s, 15mm/s, 18mm/s or 20mm/s), axially
Rotary speed be 1 turn/s~20 turn/s (such as 1 turn/s, 3 turns/s, 5 turns/s, 8 turns/s, 10 turns/s, 13 turns/s, 15 turns/s, 18
Turn/s or 20 turn/s).
Preferably, distance of step (2) ultrasonic nozzle apart from sacculus dilating catheter surface is 0.5cm~3cm, such as
0.5cm, 0.8cm, 1cm, 1.3cm, 1.5cm, 1.8cm, 2cm, 2.3cm, 2.5cm, 2.8cm or 3cm.
Preferably, step (3) the homogenization post processing is the sacculus dilating catheter for having the surface medication coat
In the post-treatment tool of flush coater using organic solvent carry out 0.5~2h of steam treatment, such as 0.5h, 0.8h, 1h, 1.2h,
1.4h, 1.6h, 1.8h or 2h.Then take out, carry out the production processes such as follow-up conduit welding, packing box sterilizing.
In the present invention, the homogenization post processing is handled for normal temperature, it is not necessary to is heated；The mistake of the homogenization post processing
Medicine coated crystal continued growth in journey, but do not allow to recrystallize, it can be reached not by the control of condition as described above
The purpose recrystallized.
Preferably, the organic solvent used in the homogenization post processing is methanol, ethanol, ethyl acetate, ether, second
Any one in nitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, Ethyl formate or methyl acetate or at least two
The combination of kind.
On the other hand, the invention provides the drug coated balloon catheter that preparation method as described above is prepared, institute
Stating drug coated balloon catheter includes sacculus dilating catheter and the medication coat coated on sacculus dilating catheter surface, the medicine
Coating includes active pharmaceutical crystals and the additive.
The active pharmaceutical crystals granularity for the drug coated balloon catheter that the present invention is prepared by methods described is small and equal
One, it is not easy to be rushed in course of conveying de-, the active drug concentration that diseased region vascular wall enters is bigger, and carrier medicine carrying efficiency is higher.
Preferably, the length of the active pharmaceutical crystals is 50nm~20 μm, for example, 50nm, 60nm, 80nm, 100nm,
300nm, 500nm, 800nm, 1 μm, 3 μm, 5 μm, 8 μm, 10 μm, 13 μm, 15 μm, 18 μm or 20 μm.It is preferred that 500nm~10 μm.
In the present invention, the crystal length of active medicine can not be too big, and otherwise its combination on sacculus dilating catheter surface is not firm enough,
Preparing and easily causing drug loss in transportation in vivo, can not only make it that the dose into diseased region is reduced, and
And excessive crystal also results in the bioavilability reduction of active medicine, the validity of medicinal balloon catheter is reduced.
Preferably, the thickness of the medication coat be 0.5 μm~15 μm, such as 0.5 μm, 1 μm, 3 μm, 5 μm, 7 μm, 9 μm,
10 μm, 12 μm, 14 μm or 15 μm, preferably 2~10 μm.Effective tissue of active medicine is not reached if medication coat is too thin
Drug concentration；It is easier to wash away loss by blood flow if medication coat is too thick, can not equally ensures " effective " load medicine of conduit
Concentration.
Preferably, the load pharmaceutical quantities on the sacculus dilating catheter surface are 1~6 μ g/mm2, such as 1 μ g/mm2、1.5μg/
mm2、1.8μg/mm2、2μg/mm2、2.3μg/mm2、2.5μg/mm2、2.8μg/mm2、3μg/mm2、3.5μg/mm2、3.8μg/mm2、
4μg/mm2、4.5μg/mm2、4.8μg/mm2、5μg/mm2、5.3μg/mm2、5.5μg/mm2、5.8μg/mm2Or 6 μ g/mm2。
The drug coated balloon catheter being prepared by preparation method of the present invention can strengthen medication coat with
The being firmly combined with property on foley's tube surface, medication coat is uniformly complete, the load pharmaceutical quantities on increase sacculus dilating catheter surface, relatively
In conventional medicament coating sacculus, it can ensure drug loss in sacculus preparation process and in human body in course of conveying more
Small, the active drug concentration that diseased region vascular wall enters is bigger, higher from carrier medicine carrying efficiency, and it is narrow can effectively to treat intravascular original position
Narrow or ISR, and the security risks such as advanced thrombus, ISR are reduced, while the positivity reconstruct of blood vessel can be formed.
On the other hand, it is used as the invention provides drug coated balloon catheter as described above and is used to treat intravascular original position
The application of narrow or ISR apparatus.
Relative to prior art, the invention has the advantages that：
Preparation method using the present invention can cause medication coat to be firmly bonded to sacculus dilating catheter surface, and
So that medicine crystal is small and homogeneous in obtained drug coated balloon catheter, ensure the medication coat on foley's tube surface in human body
It is not easy to be rushed de- in interior course of conveying, carrier medicine carrying efficiency is higher so that the active drug concentration that diseased region vascular wall enters is bigger,
Drug availability is improved, reduces toxic side effect, it is narrow that drug coated balloon catheter of the invention can effectively treat intravascular original position
Or ISR, and the security risks such as advanced thrombus, ISR are reduced, while the positivity reconstruct of blood vessel can be formed, in medical treatment
Instrument field tool has been widely used, and preparation method of the present invention is simple, is easily used to industrialized production.
Brief description of the drawings
Fig. 1 is the ultrasonic spraying process schematic diagram of the present invention；
Fig. 2 is the scanning electron microscope (SEM) photograph of medication coat in the drug coated balloon catheter that the present invention is prepared, and its scale is
20μm；
Fig. 3 is the schematic diagram of present invention homogenization post processing；
The Pulsating Flow analog machine overall structure signal that Fig. 4 is used when being external pulsed analog testing drug coating firmness
Figure；Wherein 1 is plunger pump, and 2,9 and 10 be check valve, and 3 and 8 be fluid path buffer unit, and 4 be proportioning valve, and 5 be flowmeter, and 6 be blood
Pipe holder test model, 7 be pressure sensor.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In the present embodiment, drug coated balloon catheter is prepared by following preparation method：
(1) active medicine taxol is added in organic solvent ethanol, dissolves medicine using ultrasound or mode of heating, obtain
To the supersaturated solution of active medicine, the concentration of supersaturated solution is 30mg/mL；The supersaturated solution is used into evaporative crystallization
Mode, the crystal seed of the active medicine is obtained, and use sieve method to filter out length as 1 μm~3 μm of crystal seed, by active drug
The crystal seed and suspending agent glycerine of thing, which are added in purified water and/or physiological saline, to be disperseed, and is prepared active drugs crystal seed and is hanged
Supernatant liquid, the concentration of the active medicine crystal seed suspension is 0.6mg/mL；
(2) by active medicine crystal seed suspension and active agent solution (active medicine dissolving obtains in ethanol) and addition
Agent polysorbate solution (dissolving of additive polysorbate obtains in ethanol) is separately added into the different passages of flush coater, in institute
Mixed aerosol at the nozzle tip of the ultrasonic nozzle of flush coater is stated, sprays to the sacculus dilating catheter (preparation of sacculus dilating catheter
Material is nylon) surface, obtaining surface has the sacculus dilating catheter of medication coat；Wherein described active medicine and additive
Weight ratio is 1:1, the concentration of the active agent solution is 15mg/mL, and the concentration of step (2) described additive solution is
10mg/mL；
If Fig. 1 is ultrasonic spraying process schematic diagram, wherein by the mixed solution mist at the nozzle of the ultrasonic nozzle
10 μm~20 μm of decoction little particle is turned to, the ultrasonic nozzle has the nozzle of more than 3, wherein centrally located one
Nozzle is 99.99% high pure nitrogen passage/filtering compressed air passage, and the pressure of the high pure nitrogen or filtering compressed air is
0.01MPa, the ultrasonic generator power of flush coater are 1.0W, and active agent solution and additive solution pushes away in the flush coater
It is 0.03mL/min to enter speed, and the fltting speed of active medicine crystal seed suspension is 0.03mL/min, in the ultrasound spraying
When, the speed that is longitudinally travelled of sacculus dilating catheter is 5mm/s, and axial-rotation speed is 10 turns/s.
(3) surface that step (2) obtains is had to post-treatment tool of the sacculus dilating catheter in flush coater of medication coat
It is middle to carry out steam treatment 1h using organic solvent, obtain the drug coated balloon catheter.
As shown in figure 3, only handling sacculus utricule part, the process is at normal temperatures for post processing after uniformly
Can, it is simple and easy.But it should be noted to ensure that the organic solvent amount in frock is consistent, the stabilization of sacculus medication coat prepared by guarantee
Property.
The drug coated balloon catheter being prepared by method as described above includes sacculus dilating catheter and coated on sacculus
The medication coat on dilating catheter surface, the medication coat include active pharmaceutical crystals and additive, the active pharmaceutical crystals
Length be 500nm~5 μm, the thickness of the medication coat is 2~10 μm, the sacculus dilating catheter surface being prepared
Load pharmaceutical quantities be 3 μ g/mm2。
Utricule is carried out to the sacculus dilating catheter that is prepared using above method divides valve, folding, then suppresses to leading
The nominal pressure of pipe, ESEM carry out morphology characterization to the medication coat on its surface, as shown in Figure 2.Its medication coat is firm
Spend good, complete uniform, uncoated chap and obscission；Crystal length scope is 4 μm~9 μm in medication coat, very
It is even consistent.2 points can fully ensure that its clinical safety and validity more than.
Embodiment 2
In the present embodiment, drug coated balloon catheter is prepared by following preparation method：
(1) active medicine taxol is added in organic solvent ethanol, dissolves medicine using ultrasound or mode of heating, obtain
To the supersaturated solution of active medicine, the concentration of supersaturated solution is 40mg/mL；The supersaturated solution is tied using evaporation
Brilliant, decrease temperature crystalline adds the mode that frozen water is cooled down rapidly and quickly stirred, and obtains the crystal seed of the active medicine, and using sieve
It is 1 μm~3 μm of crystal seed that point-score, which filters out length, by the crystal seed of active medicine and suspending agent sorbierite be added to purified water and/
Or disperseed in physiological saline, active drugs crystal seed suspension is prepared, the concentration of the active medicine crystal seed suspension is
1mg/mL；
(2) by active medicine crystal seed suspension and active agent solution (active medicine dissolving obtains in ethanol) and addition
Agent urea liquid (dissolving of additive urea obtains in ethanol) is separately added into the different passages of flush coater, in the flush coater
Ultrasonic nozzle nozzle tip at mixed aerosol, spraying to sacculus dilating catheter, (material for preparing of sacculus dilating catheter is Buddhist nun
Dragon) surface, obtaining surface has the sacculus dilating catheter of medication coat；The weight ratio of wherein described active medicine and additive is
1:0.1, the concentration of the active agent solution is 10mg/mL, and the concentration of step (2) described additive solution is 5mg/mL；
As shown in figure 1, it is ultrasonic spraying process schematic diagram, wherein at the nozzle of the ultrasonic nozzle that the mixing is molten
Liquid mist turns to 10 μm~20 μm of decoction little particle, and the ultrasonic nozzle has the nozzle of more than 3, wherein centrally located
One nozzle is 99.99% high pure nitrogen passage or filtering compressed air passage, the high pure nitrogen or filtering compressed air
Pressure is 0.20MPa, and the ultrasonic generator power of flush coater is 3.0W, and active agent solution and additive are molten in the flush coater
The fltting speed of liquid is 0.5mL/min, and the fltting speed of active medicine crystal seed suspension is 0.1mL/min, in the ultrasound
During spraying, the speed that is longitudinally travelled of sacculus dilating catheter is 1mm/s, and axial-rotation speed is 20 turns/s.
(3) surface that step (2) obtains is had to post-treatment tool of the sacculus dilating catheter in flush coater of medication coat
It is middle to carry out steam treatment 1h using organic solvent, obtain the drug coated balloon catheter.
The drug coated balloon catheter being prepared by method produced above includes sacculus dilating catheter and coated on sacculus
The medication coat on dilating catheter surface, the medication coat include active medicine paclitaxel crystal and the additive, the work
Property medicine crystal length be 5 μm~10 μm, the thickness of the medication coat is 0.5 μm~5 μm, the sacculus being prepared
The load pharmaceutical quantities on dilating catheter surface are 5 μ g/mm2。
Embodiment 3
In the present embodiment, drug coated balloon catheter is prepared by following preparation method：
(1) active medicine is added in organic solvent a, dissolves medicine using ultrasound or mode of heating, obtain active drug
The supersaturated solution of thing, the concentration of supersaturated solution is 65mg/mL；By the supersaturated solution using evaporative crystallization, cooling knot
Mode that is brilliant or adding the rapid cooling of frozen water and quickly stir, obtains the crystal seed of the active medicine, and screen using sieve method
It is 1 μm~3 μm of crystal seed to go out length, by the crystal seed of active medicine and suspending agent sodium cellulose sulfate be added to purified water and/or
Disperseed in physiological saline, prepare active drugs crystal seed suspension, the concentration of the active medicine crystal seed suspension is
0.1mg/mL；
(2) by active medicine crystal seed suspension and active agent solution (active medicine dissolving obtains in organic solvent) and
Additive solution (additive dissolving obtains in organic solvent) is separately added into the different passages of flush coater, in the flush coater
Ultrasonic nozzle nozzle tip at mixed aerosol, spraying to sacculus dilating catheter, (material for preparing of sacculus dilating catheter is Buddhist nun
Imperial elastomer Pebax) surface, obtaining surface has the sacculus dilating catheter of medication coat；Wherein described active medicine and addition
The weight ratio of agent is 1:20, the concentration of the active agent solution is 1mg/mL, and the concentration of step (2) described additive solution is
1mg/mL；
As shown in figure 1, it is ultrasonic spraying process schematic diagram, wherein at the nozzle of the ultrasonic nozzle that the mixing is molten
Liquid mist turns to 10 μm~20 μm of decoction little particle, and the ultrasonic nozzle has the nozzle of more than 3, wherein centrally located
One nozzle is 99.99% high pure nitrogen passage or filtering compressed air passage, the high pure nitrogen or filtering compressed air
Pressure is 0.1MPa, and the ultrasonic generator power of flush coater is 0.8W, and active agent solution and additive are molten in the flush coater
The fltting speed of liquid is 0.01mL/min, and the fltting speed of active medicine crystal seed suspension is 0.05mL/min, described super
When sound sprays, the speed that is longitudinally travelled of sacculus dilating catheter is 1mm/s, and axial-rotation speed is 1 turn/s.
(3) surface that step (2) obtains is had to post-treatment tool of the sacculus dilating catheter in flush coater of medication coat
It is middle to carry out steam treatment 1h using organic solvent, obtain the drug coated balloon catheter.
Drug coated balloon catheter includes sacculus dilating catheter and the medication coat coated on sacculus dilating catheter surface, institute
Stating medication coat includes active medicine crystallite and additive, and the length of the active pharmaceutical crystals is 50nm~3 μm, the medicine
The thickness of coating is 3 μm~10 μm, and the load pharmaceutical quantities on the sacculus dilating catheter surface being prepared are 6 μ g/mm2。
Embodiment 4
In the present embodiment, the drug coated balloon catheter is prepared by following preparation method：
(1) active medicine taxol is added in organic solvent-acetone, dissolves medicine using ultrasound or mode of heating, obtain
To the supersaturated solution of active medicine, the concentration of supersaturated solution is 50mg/mL；The supersaturated solution is tied using evaporation
Brilliant, decrease temperature crystalline adds the mode that frozen water is cooled down rapidly and quickly stirred, and obtains the crystal seed of the active medicine, and using sieve
Point-score filters out the crystal seed that length is 1 μm~3 μm, the crystal seed of active medicine and suspending agent sodium carboxymethylcellulose is added to pure
Change and disperseed in water and/or physiological saline, prepare active drugs crystal seed suspension, the active medicine crystal seed suspension
Concentration is 0.5mg/mL；
(2) by active medicine crystal seed suspension and active agent solution (active medicine dissolving obtains in acetone) and addition
Agent solution (additives polyethylene glycol dissolving obtains in acetone) is separately added into the different passages of flush coater, in the flush coater
Ultrasonic nozzle nozzle tip at mixed aerosol, spray to sacculus dilating catheter surface, obtaining surface has medication coat
Sacculus dilating catheter (material for preparing of sacculus dilating catheter is polyethylene)；The weight ratio of wherein described active medicine and additive
For 1:10, the concentration of the active agent solution is 40mg/mL, and the concentration of step (2) described additive solution is 20mg/mL；
As shown in figure 1, it is ultrasonic spraying process schematic diagram, wherein at the nozzle of the ultrasonic nozzle that the mixing is molten
Liquid mist turns to 10 μm~20 μm of decoction little particle, and the ultrasonic nozzle has the nozzle of more than 3, wherein centrally located
One nozzle is 99.99% high pure nitrogen passage or filtering compressed air passage, the high pure nitrogen or filtering compressed air
Pressure is 0.20MPa, and the ultrasonic generator power of flush coater is 5.0W, and active agent solution and additive are molten in the flush coater
The fltting speed of liquid is 0.50mL/min, and the fltting speed of active medicine crystal seed suspension is 0.2mL/min, in the ultrasound
During spraying, the speed that is longitudinally travelled of sacculus dilating catheter is 20mm/s, and axial-rotation speed is 20 turns/s.
(3) surface that step (2) obtains is had to post-treatment tool of the sacculus dilating catheter in flush coater of medication coat
It is middle to carry out 0.5~2h of steam treatment using organic solvent, obtain the drug coated balloon catheter.
Drug coated balloon catheter includes sacculus dilating catheter and the medication coat coated on sacculus dilating catheter surface, institute
Stating medication coat includes active medicine crystallite and additive, and the length of the active medicine crystallite is 10~20 μm, the medicine
The thickness of coating is 10~15 μm, and the load pharmaceutical quantities on the sacculus dilating catheter surface being prepared are 1 μ g/mm2。
Embodiment 5
In the present embodiment, the drug coated balloon catheter is prepared by following preparation method：
(1) active medicine taxol is added in organic solvent acetonitrile, dissolves medicine using ultrasound or mode of heating, obtain
To the supersaturated solution of active medicine, the concentration of supersaturated solution is 30mg/mL mg/mL；By the supersaturated solution using steaming
Hair crystallization, decrease temperature crystalline add the mode that frozen water is cooled down rapidly and quickly stirred, and obtain the crystal seed of the active medicine, and adopt
The crystal seed that length is 1 μm~3 μm is filtered out with sieve method, by the crystal seed of active medicine and suspending agent sodium cellulose sulfate and hydroxyl second
Base sodium cellulosate, which is added in purified water and/or physiological saline, to be disperseed, and prepares active drugs crystal seed suspension, the work
The concentration of property medicine crystal seed suspension is 0.6mg/mL；
(2) by active medicine crystal seed suspension and active agent solution (active medicine is dissolved in acetonitrile and obtained) and addition
The difference that agent solution (additive methylcellulose and hydroxypropyl cellulose are dissolved in acetonitrile and obtained) is separately added into flush coater is led to
In road, the mixed aerosol at the nozzle tip of the ultrasonic nozzle of the flush coater, sacculus dilating catheter surface is sprayed to, obtains table
Face has the sacculus dilating catheter of medication coat (material for preparing of sacculus dilating catheter is nylon)；Wherein described active medicine with
The weight ratio of additive is 1:3, the concentration of the active agent solution is 15mg/mL, step (2) described additive solution it is dense
Spend for 8mg/mL；
As shown in figure 1, it is ultrasonic spraying process schematic diagram, wherein at the nozzle of the ultrasonic nozzle that the mixing is molten
Liquid mist turns to 10 μm~20 μm of decoction little particle, and the ultrasonic nozzle has the nozzle of more than 3, wherein centrally located
One nozzle is 99.99% high pure nitrogen passage or filtering compressed air passage, the high pure nitrogen or filtering compressed air
Pressure is 0.08MPa, and the ultrasonic generator power of flush coater is 1.0W, and active agent solution and additive are molten in the flush coater
The fltting speed of liquid is 0.2mL/min, and the fltting speed of active medicine crystal seed suspension is 0.15mL/min, described super
When sound sprays, the speed that is longitudinally travelled of sacculus dilating catheter is 15mm/s, and axial-rotation speed is 8 turns/s.
(3) surface that step (2) obtains is had to post-treatment tool of the sacculus dilating catheter in flush coater of medication coat
It is middle to carry out 0.5~2h of steam treatment using organic solvent, obtain the drug coated balloon catheter.
Drug coated balloon catheter includes sacculus dilating catheter and the medication coat coated on sacculus dilating catheter surface, institute
Stating medication coat includes active medicine crystallite and additive, and the length of the active medicine crystallite is 50nm~3 μm, the medicine
The thickness of coating is 0.5 μm~8 μm, and the load pharmaceutical quantities on the sacculus dilating catheter surface being prepared are 2 μ g/mm2。
Comparative example 1
Be added without the crystal seed of active medicine as different from Example 1, i.e., it is directly that active medicine is molten in preparation process
Liquid and additive solution mixing, resulting mixed solution ultrasound is then sprayed to by sacculus using the ultrasonic nozzle of flush coater and expanded
Catheter surface is opened, obtaining surface has the sacculus dilating catheter of medication coat；Obtained surface is had to the sacculus of medication coat
Dilating catheter carries out homogenization post processing, obtains the drug coated balloon catheter.In addition the selection of remaining condition with
Embodiment 1 is identical.
Comparative example 2
Difference from Example 1 is, without using additive solution, the selection of remaining preparation method and condition with reality
It is identical to apply example 1.
Test 1：External pulsed analog testing drug coating firmness
Body is carried out to the coating firmness of embodiment 1-5 and comparative example the 1-2 drug coated balloon catheter being prepared
Outer simulation is assessed, and method is：Embodiment 1-5 and comparative example 1-2 are prepared into each 10 of drug coated balloon catheter, specification is
3.0 × 35mm, after dividing it to valve and folding according to same process parameter, protecting pipe is put, it is stand-by.
Using Pulsating Flow analog machine, in-vitro simulated medicine-coated balloon is subjected to the effect of blood vessel Pulsating Flow, and (equipment is with 75
Beat/min frequency, control systolic pressure 130mmHg, diastolic pressure 80mmHg), afterwards using high performance liquid chromatograph test (HPLC)
Medicine-coated balloon remained on surface medicament contg；And the solution in collecting device, particle test experiment is carried out, detection is by simulation
The firmness situation of balloon surface medicine delamination after Pulsating Flow effect.If Fig. 4 is whole using Pulsating Flow analog machine in experiment
Body structural representation.
Wherein, pulsation flow field simulation is carried out on laminar flow station in vitro, glass apparatus and other required samples be it is clean,
Without particulate；Wherein, the method for medicine-coated balloon remained on surface medicament contg is：By high performance liquid chromatography HPLC (middle Chinese
(2010 editions) the annex V of people republic pharmacopeia second D) sample introduction need testing solution and reference substance solution are calculated in test sample respectively
The medicament contg of taxol.Wherein, the test of Microne experiment with reference to Pharmacopoeia of People's Republic of China 2005 edition two annex Ⅸ " no
Relevant regulations in molten microparticles method " are carried out.
Tested according to above method, obtained result is as shown in table 1.
The external Pulsating Flow simulation test result of table 1
Test 2：Testing drug sacculus validity in animal body
Each 10 of the drug coated balloon catheter that embodiment 1-5 and comparative example 1-2 are prepared, specification is 3.0
× 35mm, after dividing it to valve and folding according to same process parameter, protecting pipe is put, it is stand-by., carry out small test pig coronary blood
Intervention Experiment in pipe, study security and validity inside each group.Specific zoopery experimental method is as follows：Every pig is led to
Cross intervention means respectively coronary artery blood vessel right hat, descending anterior branch, Circumflex branch carry out medicinal balloon expansion, divergence ratio be 1.1~
1.2:1 (sacculus/artery), expansion time are 60s.Determine medicinal balloon course of conveying (HPLC), into coronary artery vascular tissue
(HPLC-MS) and open after balloon surface drug residue (HPLC).
Experimental result in the animal body of table 2
As it can be seen from table 1 the drug coated balloon catheter of the present invention, average after external Pulsating Flow simulated experiment
Dose loss embodiment 1-5 (average 2.5%) is substantially less than comparative example 1-2 (average 22.0%)；The drug particles to come off are more
It is few, show that the bond strength of medication coat and sacculus of the present invention is very high.From table 2 it can be seen that in animal body in surgical procedure, put down
Equal dose loss embodiment 1-5 (average 4.3%) is substantially less than comparative example 1-2 (average 22.3%).
Comprehensive analysis above experimental result (Tables 1 and 2), it can be seen that medicinal balloon of the invention is pulsed flow field simulation in vitro
It is consistent with animal vivo results to prove that it washes away loss dose less (within 10%) relative to comparative example, and surveyed from graininess
Try out, its particulate to come off is less and without bulky grain, it was demonstrated that medication coat firmness of the present invention is more preferable；Meanwhile internal
Tissue CmaxAlso the checking present invention has more medicines to enter in tissue, and less medicine remains in ball on sacculus
On capsule, can ensure more medicines enter lesion locations vascular tissue in, so as to ensure clinical safety (reduce at once and
Advanced thrombus risk) and validity (effectively suppressing ISR).
Applicant states that the present invention illustrates the drug coated balloon catheter of the present invention and its preparation by above-described embodiment
Methods and applications, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention has to rely on above-described embodiment
It can implement.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to raw material selected by the present invention
The addition of equivalence replacement and auxiliary element, selection of concrete mode etc., all fall within protection scope of the present invention and open scope it
It is interior.
Claims (10)
1. a kind of preparation method of drug coated balloon catheter, it is characterised in that the described method comprises the following steps：
(1) crystal seed of active medicine is prepared, and filters out the crystal seed that length is 1 μm~3 μm, prepares the suspension of active drugs crystal seed
Liquid；
(2) active medicine crystal seed suspension is separately added into the different passages of flush coater from active agent solution and additive solution
In, mix and be atomized at the nozzle tip of the ultrasonic nozzle of the flush coater, spray to balloon surface, obtaining surface has medicine
The sacculus dilating catheter of thing coating；
(3) there is the sacculus of medication coat to carry out the homogenization of surface crystal the surface that step (2) obtains to post-process, obtain institute
State drug coated balloon catheter.
2. preparation method according to claim 1, it is characterised in that the preparation of the crystal seed of step (1) described active medicine
Method is：Active medicine is added in organic solvent a, medicine is dissolved using ultrasound or mode of heating, obtains active medicine
Supersaturated solution；The supersaturated solution is cooled down rapidly using evaporative crystallization, decrease temperature crystalline or addition frozen water and quickly stirred
Mode, obtain the crystal seed of the active medicine；
Preferably, the active medicine is taxol；
Preferably, the concentration of the supersaturated solution is 30mg/mL~65mg/mL；
Preferably, the organic solvent a is methanol, ethanol, ethyl acetate, ether, acetonitrile, acetone, hexane, isopropanol, dichloro
In methane, tetrahydrofuran, Ethyl formate or methyl acetate any one or at least two combination.
3. preparation method according to claim 1 or 2, it is characterised in that step (1) the active medicine crystal seed suspension
Preparation method be：The crystal seed of active medicine is added in solvent b and disperseed, obtains the active medicine crystal seed suspension；
Preferably, the concentration of the active medicine crystal seed suspension is 0.1mg/mL~1mg/mL, preferably 0.6mg/mL；
Preferably, the solvent b is purified water and/or deionized water；
Preferably, suspending agent is added in the crystal seed suspension；
Preferably, the suspending agent is glycerine, syrup, sorbierite, natural gum, sodium alginate, methylcellulose, carboxymethyl cellulose
Appointing in sodium, hydroxypropyl methyl cellulose, sodium cellulose sulfate, sodium hydroxyethyl cellulose, aluminum stearate or veegum
Anticipate a kind of or at least two combinations；
Preferably, step (1) method for filtering out the crystal seed that length is 1 μm~3 μm is sieve method, sedimentation or Electronic Speculum
Method.
4. according to the preparation method any one of claim 1-3, it is characterised in that step (2) active medicine with
The weight ratio of additive is 1:0.1~20, preferably 1:0.3~1；
Preferably, the concentration of step (2) described active agent solution is 1mg/mL~50mg/mL, preferably 15mg/mL~
35mg/mL；
Preferably, the concentration of step (2) described additive solution is 1mg/mL~20mg/mL, preferably 5mg/mL~15mg/
mL。
5. according to the preparation method any one of claim 1-4, it is characterised in that the additive is urea, iodine is general
Sieve amine, polysorbate, polyethylene glycol, glycol glucoside, APG, meglumine, pectin, mannitol, methylcellulose, second
In alkenyl cellulose, hydroxypropyl cellulose, mannitol or acetamide any one or at least two combination.
6. according to the preparation method any one of claim 1-4, it is characterised in that exist in step (2) each solution
Mixed at the nozzle tip of ultrasonic nozzle and be atomized the decoction little particle for 10 μm~20 μm；
Preferably, step (2) described ultrasonic nozzle has the nozzle of more than 3, wherein a centrally located nozzle is
99.99% high pure nitrogen passage or filtering compressed air passage；
Preferably, the pressure of the high pure nitrogen or filtering compressed air is 0.01MPa~0.20MPa；
Preferably, the ultrasonic generator power of step (2) described flush coater is 0.8W~5.0W；
Preferably, the fltting speed of active agent solution and additive solution independently is in step (2) described flush coater
0.01mL/min~0.50mL/min；
Preferably, the fltting speed of crystal seed suspension is 0.03mL/min~0.20mL/min in step (2) described flush coater；
Preferably, in step (2) the ultrasound spraying, the speed that is longitudinally travelled of sacculus dilating catheter is 1mm/s~20mm/s,
Axial-rotation speed is 1 turn/s~20 turn/s；
Preferably, distance of step (2) ultrasonic nozzle apart from sacculus dilating catheter surface is 0.5cm~3cm.
7. according to the preparation method any one of claim 1-6, it is characterised in that locate after step (3) described homogenization
Manage to there is the surface sacculus dilating catheter of medication coat enter in the post-treatment tool of flush coater using organic solvent
Row steam treatment 0.5h~2h；
Preferably, the organic solvent is methanol, ethanol, ethyl acetate, ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane
In alkane, tetrahydrofuran, Ethyl formate or methyl acetate any one or at least two combination；Preferably methanol or ethanol.
8. the drug coated balloon catheter that the preparation method according to any one of claim 1-7 is prepared, its feature
It is, the drug coated balloon catheter includes sacculus dilating catheter and the medication coat coated on sacculus dilating catheter surface,
The medication coat includes active pharmaceutical crystals and additive.
9. drug coated balloon catheter according to claim 8, it is characterised in that the length of the active pharmaceutical crystals is
50nm~20 μm, preferably 500nm~10 μm；
Preferably, the thickness of the medication coat is 0.5 μm~15 μm, preferably 2~10 μm；
Preferably, the load pharmaceutical quantities on the sacculus dilating catheter surface are 1~6 μ g/mm2；
Preferably, the material for preparing of the sacculus dilating catheter is any one in nylon, nylon elastomer Pebax or polyethylene
Kind or at least two combination.
10. the drug coated balloon catheter according to claim 1-9 is used as narrow or narrow again for treating intravascular original position
The application of narrow apparatus.
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| CN109954198A (en) * | 2017-12-25 | 2019-07-02 | 先健科技(深圳)有限公司 | Medicinal balloon and preparation method thereof |
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