CN116712615A - Preparation method of coating solution, medicine balloon for non-vascular intervention and preparation method - Google Patents
Preparation method of coating solution, medicine balloon for non-vascular intervention and preparation method Download PDFInfo
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- CN116712615A CN116712615A CN202211708969.5A CN202211708969A CN116712615A CN 116712615 A CN116712615 A CN 116712615A CN 202211708969 A CN202211708969 A CN 202211708969A CN 116712615 A CN116712615 A CN 116712615A
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- carrier
- drug
- balloon
- coating solution
- medicine
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- 239000003814 drug Substances 0.000 title claims abstract description 160
- 239000011248 coating agent Substances 0.000 title claims abstract description 52
- 238000000576 coating method Methods 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 230000002792 vascular Effects 0.000 title claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 122
- 230000001028 anti-proliverative effect Effects 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 26
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims abstract description 10
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 0.000 claims abstract description 8
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- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims abstract description 8
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- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims abstract description 6
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims abstract description 6
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical group COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims abstract description 6
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- -1 preferably Lu Fen Chemical compound 0.000 claims abstract description 5
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- CSGQJHQYWJLPKY-UHFFFAOYSA-N CITRAZINIC ACID Chemical compound OC(=O)C=1C=C(O)NC(=O)C=1 CSGQJHQYWJLPKY-UHFFFAOYSA-N 0.000 claims abstract description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 4
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 claims abstract description 4
- 235000013793 astaxanthin Nutrition 0.000 claims abstract description 4
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 claims abstract description 4
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 4
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- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008103 glucose Substances 0.000 claims abstract description 4
- 229960002389 glycol salicylate Drugs 0.000 claims abstract description 4
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229960004359 iodixanol Drugs 0.000 claims abstract description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 4
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims abstract description 4
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 4
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 claims abstract description 4
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000005507 spraying Methods 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 3
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- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 claims description 2
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Classifications
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- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
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- A61L29/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—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
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- A—HUMAN NECESSITIES
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- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
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Abstract
The invention discloses a preparation method of a coating solution, a medicine balloon for non-vascular intervention and a preparation method thereof, wherein the outer surface of the balloon is coated with a medicine coating, the medicine coating comprises an antiproliferative medicine, a first carrier and a second carrier, the first carrier is a water-soluble compound, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups. The antiproliferative drug is paclitaxel, paclitaxel derivative, rapamycin or rapamycin derivative. The first carrier is diatrizosamine, iodixanol, preferably Lu Fen, sorbose, glucose or mannose. The second carrier is ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, glycol salicylate, resveratrol or astaxanthin. The medicine balloon provided by the invention can reduce the medicine loss in the process of reaching the target position, and simultaneously transfers more medicine to the pipe wall of the target position in the process of expanding the target position.
Description
Technical Field
The invention relates to the technical field of medical instruments, in particular to a preparation method of a coating solution, a medicine balloon for non-vascular intervention and a preparation method.
Background
The concept of a drug balloon starts with coronary interventions. Since the first report of the drug balloon in 2004 on prevention of restenosis in porcine coronary stents compared to the common balloon, it was shown that paclitaxel-coated balloons can significantly reduce the incidence of ISR (in-stent restenosis), and CE certification was obtained by the first drug balloon worldwide in 2009 and since it was marketed in europe. The medicine saccule is used as a new interventional treatment technology and is gradually and widely applied to the fields of coronary artery and peripheral interventional treatment in Europe and China. In addition, in the "2016 pharmaceutical coated balloon" national expert consensus for clinical applications, pharmaceutical balloons are recommended for applications in coronary stenting for restenosis, primary lesions of the coronary arteries, and bifurcation lesions. With the clinical characteristics and treatment concepts of 'interventional non-implantation', the importance and status of drug balloon interventional therapy are increasing in recent years.
However, the products on the market at present mainly focus on the medical balloon treatment of the intravascular stenosis, but few related medical balloon treatments are reported on the stenosis of the natural cavity of the human body, and the natural cavity of the human body mainly comprises a ureter, a urethra, a digestive tract, a biliary tract, a respiratory tract and the like. At present, the commonly used intra-cavity treatment method for the human body natural cavity stenosis mainly comprises the steps of expanding a bare saccule and using a bracket to treat the human body natural cavity. However, studies have shown that restenosis rates in patients after dilation with a bare balloon will be as high as 30% -50%. The use of the stent can damage the inner wall of the cavity, and the implantation time is long, the stent can cause stimulation, so that inflammation is caused, in addition, the implantation of the stent can also combine the stent with the inner wall of the cavity, and the subsequent extraction process is difficult. In the vascular field, under the concept of 'implantation without intervention', a drug balloon becomes a more common operation mode, and meanwhile, research shows that the drug balloon can prevent restenosis.
It is well known that the characteristics required of drug balloons include mainly lower drug loss during delivery and superior drug transfer rates when the lesion is dilated. The formulation of the drug balloon on the market at present mostly consists of an antiproliferative drug and a carrier. Among them, most of antiproliferative drugs are paclitaxel and its derivatives or rapamycin and its derivatives, which can prevent restenosis due to their characteristics of inhibiting cell division or proliferation.
For research on carriers, the most currently used carriers are nonionic contrast agents such as iopromide, iohexol and the like. The carrier has certain viscosity and can make the medicine possess certain adhesive force on the surface of saccule. However, experiments show that the carrier has larger dosage loss in the process of delivering the carrier to a lesion site, and the main reason is that the nonionic contrast agent has strong water solubility (the nonionic contrast agent introduces a plurality of hydrophilic side chains containing hydroxyl groups on a benzene ring, the spatial distribution of the hydrophilic side chains is symmetrical, the hydrophilic side chains are wrapped around iodine atoms, and the hydroxyl groups on the side chains also ensure the strong water solubility). In addition, it is not easily aggregated when dissolved in water, resulting in a decrease in viscosity. In the process of delivering the drug balloon, the carrier is dissolved in the aqueous solution to cause the viscosity to be reduced due to the fact that a large amount of aqueous solution continuously flows, so that the loss rate of the drug is relatively high.
There are also products using water-soluble binders such as urea as a carrier that have a certain viscosity when dissolved in water, so that during delivery, a large amount of drug is still delivered into the target site, although some of the carrier is washed out during the water flow. However, drug balloons using such carriers do not exhibit high drug transfer rates when the drug is transferred to the lesion. The main reason is that the carrier is easy to cause uneven grain size of the paclitaxel, and has lower efficiency when the drug is transferred to the pipe wall of the target position, so that a large amount of paclitaxel cannot be transferred to the lesion position.
In addition, there are also drug balloons using low hydrophilicity such as lac ammonium salt or lipophilic carriers such as magnesium stearate. Such carriers, when mixed with lipophilic drugs, can form liposomes, or polymer aggregates, which can exhibit higher drug transfer rates and maintain higher concentrations in the tissue when delivered to the target site. However, the poor hydrophilic carrier coating has poor adsorptivity, is easy to fall off, causes distal embolism, cannot obtain higher coating firmness, and has larger drug loss in the delivery process.
Two coronary drug balloons on the market have been used by scholars to perform in vitro crossing experiments to obtain loss rates of 26.+ -.3% (urea formulation) and 36.+ -.11% (iopromide formulation), and although the drug amount in the target vessel can also inhibit cell proliferation, a formulation that can achieve less sales loss and more drug transfer is still being explored. However, a carrier is not found yet, and the drug balloon delivery capacity and the drug absorptivity can be perfectly balanced. It has been reported that existing drug balloons use a drug balloon formulation composed of an antiproliferative drug and two carriers, wherein the carriers are two water-soluble carriers. The carrier has a water affinity part and a drug affinity part, is connected with the drug through hydrogen bond or Van der Waals force, and can rapidly release the drug when reaching a target position. However, both of these water-soluble carriers are not sufficiently viscous, and the problem of uneven particle size of paclitaxel is not solved because they are hydrophilic, and thus a large dose loss is exhibited before reaching the target site.
Similar to the vascular field, the main cause of the formation of stenosis in the natural lumen of the human body is also the thickening of the intima due to cell proliferation, thereby forming a stenosis. The main cause of the stenosis of the natural lumen of the human body is trauma, inflammation or other lesions. And the formed stenosis is mostly scar tissue, the hardness of the stenosis is much higher than that of atherosclerosis of blood vessels, and the medicine balloon is continuously contacted with the scar tissue when passing through the stenosis part, so that a part of medicine amount is lost. In addition, because the natural cavity of the human body is generally in a shrunken state, namely, under normal conditions, two sides of the inner wall of the cavity are closed, a great amount of physiological saline is required to be used for flushing in the operation process so as to keep the filling state of the cavity, and the loss rate of the drug amount is increased in the continuous flushing process. When the drug balloon reaches the lesion site to expand, the transfer rate of the drug is also reduced due to the presence of scar tissue. Thus, although the cause of the natural lumen stenosis in the human body is similar to vascular atherosclerosis, the requirements for the drug balloon are higher, and the drug balloon is required to have good drug transfer rate under the condition of very good coating firmness. This results in the inability of the vascular field drug formulation to be used in the natural lumen of the human body.
Therefore, for non-vascular interventional drug balloons, there is a need to develop a highly targeted drug coating for medical devices that minimizes drug loss during the target site, while transferring more drug to the wall of the target site during the target site expansion.
Disclosure of Invention
The invention aims to provide a preparation method of a coating solution, a medicine balloon for non-vascular intervention and a preparation method thereof, so that the medicine on the balloon reduces the medicine loss in the process of reaching a target position, and simultaneously more medicine is transferred to the pipe wall of the target position in the process of expanding the target position.
In order to achieve the above object, the present invention provides a method for preparing a coating solution, comprising the steps of: s1: weighing an antiproliferative drug, a first carrier and a second carrier according to a preset amount, wherein the first carrier is a water-soluble compound, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups; s2: organic solvent and water are prepared according to a preset proportion to form solvent; s3: pouring the first carrier, the second carrier and the antiproliferative drug into the solvent for dissolution to obtain a coating solution.
Preferably, in the step S1, the mass ratio of the antiproliferative drug to the second carrier is 10:1 to 1:1, a step of; the first carrier is an ionic contrast agent, and the ratio of the predetermined capacity of the coating solution to the capacity of the first carrier is 100:1 to 5:1 measuring the first carrier, or, the first carrier is monosaccharide, according to the mass ratio of the antiproliferation drug to the first carrier being 10:1 to 2:1 weighing the first carrier.
Preferably, in the step S3, the concentration of the antiproliferative drug in the coating solution is 5mg/ml to 50mg/ml.
Preferably, in the step S2, the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, isopropanol and diethyl ether.
In order to achieve the above purpose, the invention also provides a preparation method of the drug balloon for non-vascular intervention, wherein the coating solution is sprayed on the surface of the balloon to prepare the drug balloon.
Preferably, the coating solution is atomized by ultrasonic vibration, and then the atomized coating solution is sprayed on the surface of the balloon by a high-pressure nozzle.
In order to achieve the above object, the present invention further provides a drug balloon for non-vascular intervention, comprising a balloon, wherein the outer surface of the balloon is coated with a drug coating, the drug coating comprises an antiproliferative drug, a first carrier and a second carrier, the first carrier is a water-soluble compound, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups.
Preferably, the antiproliferative drug is paclitaxel, docetaxel, cabazitaxel, rapamycin, sirolimus, grace morse, everolimus, or zotarolimus; the first carrier is diatrizoic amine, iodixanol, preferably Lu Fen, sorbose, glucose or mannose; the second carrier is ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, glycol salicylate, resveratrol or astaxanthin.
Preferably, the drug loading rate of the antiproliferative drugs on the surface of the drug balloon is 1 mug/mm 2-10 mug/mm 2.
Preferably, the drug coating is formed by spraying the coating solution prepared by the preparation method on the surface of the balloon after ultrasonic vibration atomization.
Compared with the prior art, the invention has the following beneficial effects: according to the preparation method of the coating solution, the medicine balloon for non-vascular intervention and the preparation method, two carriers are added into the antiproliferation medicine coated on the surface of the balloon, the first carrier is a hydrophilic carrier, and the antiproliferation medicine can be fixed or attached on the surface of the balloon in the water flowing process; the second carrier is fat-soluble, can form liposome or polymer agglomeration with the drug, and meanwhile, the lipophilic carrier can also obtain drug particles with fine and uniform particle size, so that the release rate of the drug at the lesion position is finally ensured. Meanwhile, as the first carrier is a water-soluble carrier and has certain viscosity in water, part of water can be locked on the surface of the balloon, hydrophilic groups of the second carrier can be compatible with the part of water, the medicine is fixed on the surface of the balloon in the delivery process, and the medicine loss is lower. When the medicine contacts with the inner tube wall of the natural cavity of the human body, the second carrier has less hydroxyl groups and smaller affinity with water than that of the liposome when contacting with the inner tube wall, so that the second carrier can bring the medicine to be quickly separated from the first carrier and enter the inner tube wall of the natural cavity of the human body, thereby transferring a large amount of medicine to the lesion position. Therefore, the medicine balloon provided by the invention can reduce the medicine loss in the process of reaching the target position, and simultaneously transfer more medicine to the pipe wall of the target position in the process of expanding the target position.
Drawings
FIG. 1 is a flow chart of the preparation of a pharmaceutical solution according to an embodiment of the present invention.
Detailed Description
The invention is further described below with reference to the drawings and examples.
The drug balloon for non-vascular intervention comprises a balloon, wherein the outer surface of the balloon is coated with a drug coating, the drug coating comprises an antiproliferative drug, a first carrier and a second carrier, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups.
The drug coated on the surface of the balloon uses two carriers, and the coating solution is sprayed on the surface of the balloon preferably by an ultrasonic spraying mode to form a drug coating and is delivered to the narrow part of the natural cavity of the human body. Wherein the antiproliferative drug is selected from paclitaxel or paclitaxel derivatives, such as paclitaxel, docetaxel, etc., or the antiproliferative drug is selected from rapamycin or rapamycin derivatives, such as sirolimus, grace morse, everolimus, etc. Such antiproliferative agents can be absorbed by the inner tube wall of the human system due to their lipophilicity to inhibit the recurrence of stenosis.
In this embodiment, the first carrier is an ionic contrast agent or monosaccharide, and the ionic contrast agent mainly includes diatrizoic glucosamine, iodixanol or eulexin, preferably, eulexin, and the eulexin is compound diatrizoic glucosamine, and the main components are diatrizoic glucosamine and diatrizoic sodium. The monosaccharides mainly comprise sorbose, glucose or mannose, preferably mannose. The main reason for using an ionic contrast agent is that the ionic contrast agent is hydrophilic compared to the non-ionic contrast agent, but the viscosity does not decrease rapidly after being dissolved in water, but a certain viscosity is still maintained, so that the first carrier can still fix the antiproliferative drug on the surface of the balloon during the water flowing process. The monosaccharide is mainly used because the monosaccharide molecule contains a plurality of hydrophilic groups, is easy to dissolve in water, can generate certain viscosity, and can also attach the antiproliferative drug on the surface of the saccule. However, since the hydrophilic carrier may cause uneven particle size of the drug, the present invention introduces a second carrier in order to solve this problem.
The second carrier is a fat-soluble compound having two or three hydrophilic groups, such as: ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, glycol salicylate, resveratrol, astaxanthin, etc. Because the second carrier is fat-soluble, liposome or polymer agglomeration can be formed with the medicine, and meanwhile, the lipophilic carrier can also obtain medicine particles with fine and uniform particle size, so that the release rate of the medicine at a lesion position is finally ensured. Meanwhile, as the first carrier is a water-soluble carrier and has certain viscosity in water, part of water can be locked on the surface of the balloon, hydrophilic groups of the second carrier can be compatible with the part of water, the medicine is fixed on the surface of the balloon in the delivery process, and the medicine loss is lower. When the medicine contacts with the inner tube wall of the natural cavity of the human body, the second carrier has less hydroxyl groups and smaller affinity with water than that of the liposome when contacting with the inner tube wall, so that the second carrier can bring the medicine to be quickly separated from the first carrier and enter the inner tube wall of the natural cavity of the human body, thereby transferring a large amount of medicine to the lesion position.
Preferably, the drug loading rate of the surface of the drug balloon is 1 mug/mm 2 ～10μg/mm 2 . Referring to fig. 1, the preparation method of the coating solution is as follows:
s1: weighing an antiproliferative drug, a first carrier and a second carrier according to a preset amount, wherein the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups.
First, the volume of the coating solution to be formulated before spraying is determined, and the required weighed quantity of drug is calculated according to the required drug concentration of the solution. The concentration of the antiproliferative drug is generally controlled to be between 5mg/ml and 50mg/ml.
Next, the antiproliferative agent and the second carrier are weighed. Controlling the mass ratio of the antiproliferative drug to the second carrier to be 10:1 to 1:1;
then, if the first carrier selects an ionic contrast agent, the ratio of the required coating solution capacity to the first carrier capacity is 100:1 to 5:1, placing a first carrier into a reagent bottle; if the first carrier is selected from monosaccharides, the mass ratio of the antiproliferative drug to the first carrier is 10:1 to 2:1 weighing a first carrier.
S2: organic solvent and water are prepared according to a preset proportion to form solvent; wherein the organic solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran, isopropanol and diethyl ether.
S3: pouring the first carrier, the second carrier and the antiproliferative drug into the solvent for dissolution to obtain a coating solution. Specifically, the first carrier, the second carrier and the antiproliferative drug are gradually poured into a solvent and fully oscillated to obtain a coating solution before spraying.
After the coating solution is prepared, the coating solution can be sprayed on the surface of the balloon by using an ultrasonic spraying method to form a drug coating, and the coating of the drug on the balloon is completed to obtain the drug balloon. Specifically, the coating solution is atomized by ultrasonic vibration, and then the atomized coating solution is uniformly and stably sprayed on the surface of the balloon by a high-pressure nozzle to form a drug coating.
The medicine saccule is used in saccule dilating treatment of non-vascular (natural human cavity) stenosis, and the natural human cavity mainly includes ureter, urethra, digestive tract, biliary tract, respiratory tract, etc.
Example 1
In this embodiment, the antiproliferative agent used in the coating solution is paclitaxel, the first carrier is preferably Lu Fen, the second carrier is resveratrol, and the solvent is prepared from ethanol, acetone, tetrahydrofuran and water.
In the three comparative examples, the antiproliferative drug and the solvent are the same as in this example, except that: comparative example 1 was free of carrier; comparative example 2 with the addition of only the first carrier U Lu Fen; in comparative example 3, only resveratrol as the second carrier was added, and the rate of drug loss and the rate of drug transfer in this example and three comparative examples were compared, respectively.
From the above table, it can be seen that the drug balloon provided in this embodiment can greatly reduce the drug loss during the process of reaching the target position, and simultaneously transfer more drug to the wall of the target position during the process of expanding the target position.
Example 2
In this embodiment, the antiproliferative agent used in the coating solution is paclitaxel, the first carrier is mannose, the second carrier is ferulic acid, and the solvent is prepared from acetone, tetrahydrofuran and water.
In the three comparative examples, the antiproliferative drug and the solvent are the same as in this example, except that: comparative example 4 was free of carrier; comparative example 5 only the first carrier mannose was added; only the second carrier ferulic acid was added in comparative example 6, and the rate of drug loss and the rate of drug transfer in this example and three comparative examples were compared, respectively.
From the above table, it can be seen that the drug balloon provided in this embodiment can greatly reduce the drug loss during the process of reaching the target position, and simultaneously transfer more drug to the wall of the target position during the process of expanding the target position.
Experimental evaluation of the results of the present invention on paclitaxel pharmacokinetics at ureteral target sites was performed on female pigs weighing about 45 kg.
Pigs are anesthetized before operation, and all consumables and instruments needed in the operation are sterilized. When the operation starts, the pig is fixed on an operating table, skin around the operation part (pudendum) is disinfected by using an ambroxol conventional disinfectant, and a sterile operation film or a sterile operation towel can be stuck after the pig is dried.
In operation, a doctor finally reversely delivers four drug balloons with different formulas to a preset target position in the ureter from the urethral orifice of the pig through fixing the operation flow, expands for 1 time according to actual conditions and continues filling for 5 minutes. The balloon is withdrawn after aspiration by a pressure pump.
Double J-tubes were prevented post-operatively and removed at 8 days follow-up. The drug content of the expanded site was analyzed by dissecting the established pigs 1h,8d,28d and 60d after surgery, respectively, as follows:
as can be seen from the above table, both of example 1 and example 2 exhibited the results of longer residual time at the target site and more drug content, meaning that both formulations could act on the lesion site for a long period of time, exhibiting the excellent effects of the present invention.
While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, and it is to be understood that other modifications and improvements may be made by those skilled in the art without departing from the spirit and scope of the invention, which is therefore defined by the appended claims.
Claims (10)
1. A method for preparing a coating solution, comprising the steps of:
s1: weighing an antiproliferative drug, a first carrier and a second carrier according to a preset amount, wherein the first carrier is a water-soluble compound, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups;
s2: organic solvent and water are prepared according to a preset proportion to form solvent;
s3: pouring the first carrier, the second carrier and the antiproliferative drug into the solvent for dissolution to obtain a coating solution.
2. The method according to claim 1, wherein in the step S1, the mass ratio of the antiproliferative drug to the second carrier is 10:1 to 1:1, a step of; the first carrier is an ionic contrast agent, and the ratio of the predetermined capacity of the coating solution to the capacity of the first carrier is 100:1 to 5:1 measuring the first carrier, or, the first carrier is monosaccharide, according to the mass ratio of the antiproliferation drug to the first carrier being 10:1 to 2:1 weighing the first carrier.
3. The method according to claim 1, wherein in the step S3, the concentration of the antiproliferative agent in the coating solution is 5mg/ml to 50mg/ml.
4. The preparation method according to claim 1, wherein in the step S2, the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, isopropanol and diethyl ether.
5. A method for preparing a drug balloon for non-vascular intervention, which is characterized in that the drug balloon is prepared by spraying the coating solution of any one of claims 1-4 on the surface of the balloon.
6. The method according to claim 5, wherein the coating solution is atomized by ultrasonic vibration and then the atomized coating solution is sprayed on the surface of the balloon by a high-pressure nozzle.
7. The drug balloon for non-vascular intervention is characterized by comprising a balloon, wherein the outer surface of the balloon is coated with a drug coating, the drug coating comprises an antiproliferative drug, a first carrier and a second carrier, the first carrier is a water-soluble compound, the first carrier is an ionic contrast agent or monosaccharide, and the second carrier is a fat-soluble compound with two or three hydrophilic groups.
8. The drug balloon of claim 7, wherein the antiproliferative drug is paclitaxel, docetaxel, cabazitaxel, rapamycin, sirolimus, grace morse, everolimus, or zotarolimus; the first carrier is diatrizoic amine, iodixanol, preferably Lu Fen, sorbose, glucose or mannose; the second carrier is ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, glycol salicylate, resveratrol or astaxanthin.
9. The drug balloon of claim 7, wherein the drug loading of the antiproliferative drug on the surface of the drug balloon is 1 μg/mm 2 ～10μg/mm 2 。
10. The drug balloon of claim 7, wherein the drug coating is formed by spraying a coating solution prepared by the preparation method of any one of claims 1 to 5 on the surface of the balloon after ultrasonic vibration atomization.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211708969.5A CN116712615B (en) | 2022-12-29 | 2022-12-29 | Preparation method of coating solution, medicine balloon for non-vascular intervention and preparation method |
| PCT/CN2023/117591 WO2024139383A1 (en) | 2022-12-29 | 2023-09-08 | Preparation method for coating solution, and drug balloon for non-vascular intervention and preparation method therefor |
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| CN202211708969.5A CN116712615B (en) | 2022-12-29 | 2022-12-29 | Preparation method of coating solution, medicine balloon for non-vascular intervention and preparation method |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120036627A (en) * | 2010-10-08 | 2012-04-18 | 한국과학기술원 | Drug-eluting balloon catheter multilayer coating with drug-embeded nanoparticles and polymers and preparation method thereof |
| CN102883753A (en) * | 2010-03-25 | 2013-01-16 | 路通医疗股份有限公司 | Drug releasing coatings for medical devices |
| CN104841060A (en) * | 2014-02-13 | 2015-08-19 | 张海军 | Ultrasonic controlled release medicine elution balloon catheter and preparation method |
| CN107635593A (en) * | 2015-04-24 | 2018-01-26 | 优敦力公司 | The foley's tube of the coated with drug narrow for non-vascular |
| CN113117220A (en) * | 2021-04-14 | 2021-07-16 | 深圳市赛禾医疗技术有限公司 | Medicine balloon catheter, medicine balloon catheter system and control method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857573A (en) * | 2010-03-25 | 2015-08-26 | 路通医疗股份有限公司 | Drug releasing coating for medical device |
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2022
- 2022-12-29 CN CN202211708969.5A patent/CN116712615B/en active Active
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- 2023-09-08 WO PCT/CN2023/117591 patent/WO2024139383A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102883753A (en) * | 2010-03-25 | 2013-01-16 | 路通医疗股份有限公司 | Drug releasing coatings for medical devices |
| KR20120036627A (en) * | 2010-10-08 | 2012-04-18 | 한국과학기술원 | Drug-eluting balloon catheter multilayer coating with drug-embeded nanoparticles and polymers and preparation method thereof |
| CN104841060A (en) * | 2014-02-13 | 2015-08-19 | 张海军 | Ultrasonic controlled release medicine elution balloon catheter and preparation method |
| CN107635593A (en) * | 2015-04-24 | 2018-01-26 | 优敦力公司 | The foley's tube of the coated with drug narrow for non-vascular |
| CN113117220A (en) * | 2021-04-14 | 2021-07-16 | 深圳市赛禾医疗技术有限公司 | Medicine balloon catheter, medicine balloon catheter system and control method thereof |
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| CN116712615B (en) | 2024-05-24 |
| WO2024139383A1 (en) | 2024-07-04 |
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