CN115414538A - Lipid nanocapsule drug-loaded particles with uniform particle size, drug balloon, and preparation method and application thereof - Google Patents
Lipid nanocapsule drug-loaded particles with uniform particle size, drug balloon, and preparation method and application thereof Download PDFInfo
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- CN115414538A CN115414538A CN202211042550.0A CN202211042550A CN115414538A CN 115414538 A CN115414538 A CN 115414538A CN 202211042550 A CN202211042550 A CN 202211042550A CN 115414538 A CN115414538 A CN 115414538A
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- drug
- balloon
- particle size
- solution
- loaded particles
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
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Abstract
The invention provides lipoid nanocapsule drug-loaded particles with uniform particle size, a drug balloon, and preparation methods and applications thereof. The preparation method of the lipoid nano-capsule drug-loaded particles comprises the following steps: (1) Mixing a nonionic surfactant with water to obtain a first solution; mixing cholesterol, macrolide medicines and an organic solvent to obtain a solution II; (2) Dropwise adding the solution II into the solution I at a constant speed, and performing ultrasonic emulsification to obtain an emulsion; (3) Removing the organic solvent in the emulsion to obtain a nanoparticle suspension; (4) Filtering the nanoparticle suspension to obtain a nanoparticle filtrate; (5) Dialyzing the nano particle filtrate to obtain suspension with uniform particle size; (6) And centrifuging the suspension with uniform particle size, and collecting the precipitate to obtain the lipoid nanocapsule drug-loaded particles. The invention takes the lipoid nano-capsules with uniform grain diameter prepared by a specific process as a medicament carrier, and realizes the quick delivery of the medicament to tissues and the slow release in vivo by utilizing the high trafficability of the nano-carrier.
Description
Technical Field
The invention belongs to the field of interventional medical devices, and particularly relates to lipid nanocapsule drug-loaded particles with uniform particle size, a drug balloon, and preparation methods and applications thereof
Background
Ischemic stroke is one of the major diseases endangering human health at present, and one of the main causes of ischemic stroke is intracranial arterial stenosis caused by atherosclerosis and further insufficient blood supply to cause stroke. In the case of atherosclerosis, the implantation of a stent is the most common and the most main treatment means, so that the treatment efficiency is greatly improved, but problems of restenosis, thrombus formation in the later stage and the like exist after the operation.
Drug-coated balloons (DCB) are an emerging means of intraluminal treatment, whose principle is to avoid restenosis of the vessel by inhibiting the hyperproliferation of vascular smooth muscle cells in the lesion area by the active drug in the coating. Compared with a drug stent, the endothelial disorder caused by continuous contact of the drug is avoided. The technical key points are the selection of the medicine and the preparation of the coating, and the difficulty is to solve the problems of the controllable release of the medicine and the rapid absorption of the affected tissues to the medicine.
Controlled release of the drug requires a cohesive balance between the drug coating and the balloon surface. When the adhesive force is too small, the medicine is easy to fall off in the balloon folding process, or is washed away by high-speed flowing blood in the conveying process of placing the medicine into a pathological change part and the balloon expansion process; when the adhesive force is too large, the medicine is difficult to transfer to the affected tissue within the limited time of balloon expansion to achieve the treatment purpose.
In order to realize the controllable release of the medicine and the quick absorption of the medicine by the affected part tissues, the technical personnel in the field improve the structure of the medicine coating balloon, the composition of the coating, the micro morphology of the medicine and the like, for example, CN 208003247U discloses a manufacturing method of the medicine balloon, the medicine is coated on the surface of the balloon at 360 degrees, and a part of the medicine is wrapped inside the flap by a special folding method and is not contacted with the blood vessel wall in the conveying process, so that the medicine loss is reduced.
CN 103736154A discloses a drug-coated balloon catheter, which adds organic acid and polyol into the carrier to prevent the premature release of the drug before the balloon catheter is inserted into the target site, and after reaching the target site, the drug is rapidly released from the balloon surface and absorbed by the target tissue.
CN 113813449A discloses a method for preparing a nanoparticle rapamycin-loaded drug coating balloon, which comprises the step of wrapping rapamycin-loaded mesoporous silica nanoparticles on the surface of the balloon by polylactic acid-polyglycolic acid (PLGA), and the bioavailability of rapamycin is improved through the permeability and the slow release property of the nanoparticles. However, it is a problem whether the silica nanoparticles are completely degraded in the human body, and silica nanoparticles that are not completely degraded may cause some systemic toxicity.
CN 112546414A discloses a drug-loaded medical device and its preparation method, the active drug includes macrolide drug, the drug is prepared into long column crystal with more than three edges, which can effectively improve the transfer ability of the drug to the vessel wall and prolong the concentration of the tissue drug. At the same time, however, the sharp crystal itself will cause damage to the vessel wall, which will cause a new series of problems.
The technical personnel apply the nano particle drug-loading technology to the field of drug coating balloons, and the nano particles are a microcosmic colloid system, have the particle size of less than 1 mu m generally and can be divided into nano microspheres and nano microcapsules. Nanoparticles can pass through interstitial spaces, capillaries, across the blood-brain barrier and tissue endothelial cells, releasing drugs at the cellular or subcellular level.
Most cells take up exogenous nanoparticles mainly by endocytosis, which is mainly divided into clathrin-mediated endocytosis (clathrin-mediated endocytosis), caveolae-mediated endocytosis (caveolae-mediated endocytosis), macroendocytosis and 4 types of endocytosis that are not clathrin-caveolae-dependent.
CN 111973813A discloses a rapamycin nanoparticle for use in porous balloon angioplasty, wherein the rapamycin nanoparticle comprises a polymer core and a phospholipid shell, wherein the polymer core is composed of rapamycin and a biodegradable high-molecular polymer. Not only realizes the slow delivery of the insoluble drug in vivo, but also improves the affinity of the nanoparticles to the tissues of the pathological change part. The preparation method is simple and rapid, but the particle size of the formed nano particles is not uniform enough, the drug loading capacity is insufficient when the particle size is too small, and the particle size is too large and is not easy to be endocytosed by cells. Meanwhile, the type of the encapsulated medicine is single, and the medicine loading rate is limited. In addition, the domestic production process of the phospholipid is not mature enough, the batch repeatability is poor, and the price is higher, so that the large-scale production is still difficult.
Therefore, it is highly desirable to develop lipid nanocapsules with uniform particle size as drug carrier, which can realize rapid drug delivery to tissues and sustained release in vivo by utilizing high permeability of the nanocarrier, and the biodegradable material avoids the toxicity problem in the whole body.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the lipoid nano-capsule drug-loaded particles with uniform particle size, the drug balloon, and the preparation method and the application thereof. The lipoid nanocapsules with uniform particle size are prepared by a specific process and used as a drug carrier, the high permeability of the nanocarrier is utilized to realize the rapid delivery of the drug to tissues and the slow release in vivo, and the biodegradable material avoids the problem of toxicity in the whole body.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a preparation method of lipid nanocapsule drug-loaded particles with uniform particle size, wherein the preparation method comprises the following steps:
(1) Mixing a nonionic surfactant with water to obtain a first solution; mixing cholesterol, macrolide medicines and an organic solvent to obtain a solution II;
(2) Dropwise adding the solution II obtained in the step (1) into the solution I at a constant speed, and performing ultrasonic emulsification to obtain an emulsion;
(3) Removing the organic solvent in the emulsion obtained in the step (2) to obtain a nanoparticle suspension;
(4) Filtering the nanoparticle suspension obtained in the step (3) to obtain a nanoparticle filtrate;
(5) Dialyzing the nano particle filtrate obtained in the step (4) to obtain suspension with uniform particle size;
(6) And (4) centrifuging the suspension with uniform particle size obtained in the step (5), and collecting precipitates to obtain the lipoid nano-capsule drug-loaded particles with uniform particle size.
In the invention, the lipoid nano-capsule drug-loaded particles with uniform particle size are prepared by the specific process, and the lipoid nano-capsule is a nano-structure similar to a liposome and consists of an oil phase, a water phase and a nonionic surfactant. The active substance has a core-shell structure, and can be wrapped in an inner core formed by an oil phase; the lipoid nano-capsule drug-loaded particles prepared by the process have the following advantages: (1) the nonionic surfactant has good biocompatibility and stability, no toxicity, no immunogenicity and biodegradability; (2) the active substance is coated in a wide range, both hydrophilic and lipophilic substances can be coated, and the drug loading is larger than that of the liposome; (3) can be specifically phagocytized by certain cells, such as vascular endothelial cells, and has targeting effect; (4) the size and the structure of the device can be adjusted; (5) compared with the phospholipid used in the liposome, the cost is higher and the batch repeatability is poorer, and the lipid nanocapsule can effectively avoid the problems.
Preferably, in step (1), the concentration of the nonionic surfactant in the first solution is 1 to 15mg/mL, and may be, for example, 1mg/mL, 2mg/mL, 3mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 12mg/mL, 15mg/mL, or the like.
Preferably, in step (1), the concentration of cholesterol in the second solution is 5-20mg/mL, such as 5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, etc., and the concentration of macrolide in the second solution is 5-25mg/mL, such as 5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, etc.
Preferably, in step (1), the nonionic surfactant is selected from any one of tween 80, steareth-21, ceteth-25, laureth-23, S40, olivem 800, olivem 700, cetearyl alcohol and glucoside, sucrose fatty acid ester, poloxamer 407, poloxamer 188, glycerol hexametaphosphate, glycerol decamonomyristate, glycerol decamonolaurate or glycerol hexameric monomyristate, or a combination of at least two thereof.
Preferably, in step (1), the macrolide is selected from any one or a combination of at least two of rapamycin, everolimus, zotarolimus, dexamethasone, paclitaxel, docetaxel, probucol, colchicine, heparin, aspirin or doxorubicin, wherein typical but non-limiting combinations include: a combination of rapamycin and everolimus, a combination of zotarolimus, dexamethasone, paclitaxel and docetaxel, a combination of docetaxel, probucol, colchicine, heparin, aspirin and doxorubicin, and the like.
Preferably, in step (1), the organic solvent is selected from any one of dichloromethane, acetone, chloroform or tetrahydrofuran or a combination of at least two of the above.
Preferably, in the step (2), ultrasonic emulsification is simultaneously carried out in the process of uniform dropping.
Preferably, in step (2), the uniform dropping is performed by using a micro-syringe pump for sample injection, and the sample injection speed ranges from 0.01mL/min to 99.99mL/min, such as 0.01mL/min, 1mL/min, 2mL/min, 5mL/min, 10mL/min, 15mL/min, 20mL/min, 25mL/min, 30mL/min, 35mL/min, 40mL/min, 60mL/min, 80mL/min, 90mL/min, 99.99mL/min, and the like.
Preferably, in step (2), the power of the ultrasonic emulsification is 100-500W, such as 100W, 150W, 200W, 250W, 300W, 350W, 400W, 450W, 500W and the like, and the time of the ultrasonic emulsification is 20-100min, such as 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min and the like.
Preferably, in step (2), the particle size of the emulsion obtained after the ultrasonic emulsification is 600nm or less, for example, 600nm, 500nm, 400nm, 300nm, 200nm, etc.
Preferably, in the step (3), the method for removing the organic solvent is: and (3) evaporating the organic solvent in the emulsion obtained in the step (2) to dryness.
Preferably, the temperature for the evaporation is 30-50 deg.C, such as 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C.
Preferably, in step (4), the filtration is: filtering the nanoparticle suspension obtained in the step (3) by using a needle filter.
Preferably, the pore size of the filter membrane in the needle filter is any one of 0.22 μm, 0.45 μm or 0.88 μm.
Preferably, in step (5), the number of times of dialysis is 2 or more, for example, 2, 3, 4, etc.
Preferably, in the step (5), the dialysis membrane has a molecular weight cut-off of any one of 500, 1000, 3500 or 7000.
Preferably, in step (6), the rotation speed of the centrifugation is 10000-30000r/min, such as 10000r/min, 15000r/min, 20000r/min, 25000r/min, 30000r/min and the like, and the time of the centrifugation is 10-30min, such as 10min, 15min, 20min, 25min, 30min and the like.
Preferably, in step (6), the lipid nanocapsule drug-loaded particles have a particle size of 160-650nm, such as 160nm, 170nm, 180nm, 190nm, 200nm, 300nm, 400nm, 500nm, 600nm, 620nm, 650nm, etc.
In a second aspect, the invention provides lipid nanocapsule drug-loaded particles with uniform particle size, which are prepared by the preparation method in the first aspect.
In a third aspect, the invention provides a drug balloon, which sequentially comprises a balloon body, a hydrophilic coating and a drug-loaded coating from inside to outside; wherein the drug-loaded coating comprises the lipid nano-capsule drug-loaded particles with uniform particle size according to the second aspect.
Preferably, the balloon body comprises an intracranial balloon and/or a coronary balloon.
Preferably, the balloon body is made of a high molecular polymer material.
Preferably, the material of the balloon body is Pebax.
Preferably, the hydrophilic coating is a hydrophilic high molecular polymer.
Preferably, the hydrophilic high molecular polymer is selected from any one of polyacrylamide, polyvinylpyrrolidone or polymethyl vinyl ether-copolymerized maleic acid.
Preferably, the thickness of the hydrophilic coating is 0.05-0.2. Mu.m, and may be, for example, 0.05. Mu.m, 0.1. Mu.m, 0.15. Mu.m, 0.2. Mu.m, etc., preferably 0.1. Mu.m.
Preferably, the drug loading rate of the drug balloon per unit external surface area is 1-10 mug/mm 2 For example, it may be 1. Mu.g/mm 2 、2μg/mm 2 、4μg/mm 2 、6μg/mm 2 、8μg/mm 2 、10μg/mm 2 And the like.
Preferably, the drug-loaded coating comprises an additive with binding and shaping effects and the lipid nanocapsule drug-loaded particles with uniform particle size.
Preferably, the drug-loaded coating further comprises additives for binding and shaping.
Preferably, the additive is selected from any one of or a combination of at least two of dextran, polysorbate, sorbitol, fructose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, heptatol, isomalt, maltitol, lactitol, maltotriose, voglibose, xylitol or polyethylene glycol.
Preferably, the mass ratio of the additive to the lipid nanocapsule drug-loaded particles is (1-20) to 100, and can be, for example, 1.
In a fourth aspect, the invention provides a preparation method of the drug balloon, and the preparation method comprises the following steps:
(a) Dispersing the lipoid nanocapsule drug-loaded particles with uniform particle size in an ethanol water solution, and then carrying out ultrasonic dispersion on the lipoid nanocapsule drug-loaded particles and an additive with bonding and shaping effects to obtain a nanoparticle spraying suspension;
(b) Uniformly spraying the nano particle spraying suspension obtained in the step (a) on the surface of the balloon subjected to hydrophilic treatment by using ultrasonic spraying equipment, and then carrying out curing treatment to obtain the medicine balloon.
Preferably, in step (a), the volume ratio of ethanol to water in the ethanol aqueous solution is 1.
Preferably, in step (a), the concentration of the lipid nanocapsule-loaded particles in the nanoparticle spray suspension is 13-40mg/mL, such as 13mg/mL, 14mg/mL, 16mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, etc., and the concentration of the additive is 0.2-8mg/mL, such as 0.2mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, etc.
Preferably, in step (a), the power of the ultrasonic dispersion is 100-500W, such as 100W, 150W, 200W, 250W, 300W, 350W, 400W, 450W, 500W, etc., and the time of the ultrasonic dispersion is 20-100min, such as 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min, etc.
Preferably, in the step (b), the hydrophilic treatment comprises the following specific steps: uniformly spraying polyacrylamide with the mass concentration of 0.5-2% (for example, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, etc.) on the surface of the balloon by a spraying device, wherein the spraying amount is 15-25 mug/mm 2 (it may be, for example, 15. Mu.g/mm 2 、16μg/mm 2 、18μg/mm 2 、20μg/mm 2 、22μg/mm 2 、24μg/mm 2 、25μg/mm 2 Etc.), after the spraying is finished, drying in a vacuum drying oven for 20 hours or more (for example, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, etc.) under 0.1 to 1atm (for example, 0.1atm, 0.2atm, 0.4atm, 0.6atm, 0.8atm, 1atm, etc.) and 55 to 65 ℃ (for example, 55 ℃, 56 ℃, 58 ℃, 60 ℃, 62 ℃, 65 ℃, etc.).
Preferably, in step (b), the curing treatment is drying at a temperature of 40-70 ℃, for example, 40 ℃, 50 ℃, 60 ℃, 70 ℃ and the like.
In a fifth aspect, the invention provides lipid nanocapsule drug-loaded particles with uniform particle size, and application of the drug-loaded nanocapsule in drug delivery to tissues and sustained release in vivo.
Compared with the prior art, the invention has the following beneficial effects:
(1) The prepared nanoparticles have uniform particle size, and the particles can be quickly absorbed by cells while the drug loading is ensured;
(2) Before loading the drug, the surface of the balloon is coated with a hydrophilic coating, so that the drug-loaded layer can be uniformly dispersed on the surface of the balloon and has uniform thickness;
(3) The drug-coated balloon prepared by the invention has accurate and controllable drug-loading rate, avoids waste caused by insufficient drug-loading to reach a treatment target and excessive drug-loading and generates systemic toxicity in a human body;
(4) In the medicine coating prepared by the invention, all materials can be biodegraded, and the product is harmless to human body and cannot cause any damage to patients;
(5) Compared with pure water, the spray suspension prepared by the invention has lower boiling point, relatively lower required drying temperature and relatively shorter drying time;
(6) The preparation process is simple, efficient, stable and convenient to operate.
Drawings
FIG. 1 is a schematic view of a drug balloon according to the present invention;
wherein, 1 is a balloon body, 2 is a hydrophilic coating, and 3 is a drug-loaded coating.
FIG. 2 is a graph showing the distribution of the particle size of nanoparticles in the spray suspension provided in examples 1-3 of the present invention.
Detailed Description
The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The sources of the components in the following examples and comparative examples are as follows:
name (R) | Manufacturer of the product | Model and/or specification |
Balloon | Suzhou Zhongtian medical treatment | Pebax material |
Hydrophilic high molecular polymer | Science and chemical engineering of Xilonga | Polyacrylamide |
Additive agent | Science and chemical industry of west longu | Sucrose |
The drug balloon containing a hydrophilic coating in the following examples was prepared by the following method:
uniformly spraying polyacrylamide (MW 300 ten thousand) with the mass concentration of 1% on the surface of the balloon by spraying equipment, wherein the spraying amount is 20 mu g/mm 2 And after the spraying is finished, the mixture is placed in a vacuum drying oven to be dried for 24 hours under the conditions of 0.5atm and 60 ℃.
Example 1
The present embodiment provides a drug balloon, which is prepared by the following steps:
(1) Preparing 40mL of 3mg/mL tween 80 deionized water solution to obtain a first solution; dissolving 50mg of rapamycin and 50mg of cholesterol in 4mL of dichloromethane simultaneously to obtain a solution II;
(2) Transferring the second solution into a 5mL injector, and installing the injector on a micro injection pump, wherein the sample injection flow rate of the micro injection pump is set to be 0.5mL/min; putting the first solution into a 100mL beaker, inserting an ultrasonic emulsification probe into the first solution, setting the total ultrasonic time to be 60min, and setting the power to be 300W; opening the ultrasonic emulsification instrument to start working, simultaneously opening a micro-injection pump to dropwise add the solution II into the aqueous phase solution, and performing ultrasonic emulsification to obtain an emulsion;
(3) After the ultrasound is finished, transferring the beaker to a constant-temperature water bath magnetic stirring kettle at 40 ℃, and evaporating dichloromethane in the mixed solution while stirring until the dichloromethane is completely volatilized to preliminarily obtain a nano suspension;
(4) Filtering the nanometer suspension by a needle filter, wherein the aperture of the filter membrane is 0.8 mu m, and removing particles with overlarge particle size to obtain a nanometer particle filtrate;
(5) Dialyzing with dialysis membrane with molecular weight cutoff of 1000 for 2 times to remove free rapamycin and carrier molecule to obtain suspension with uniform particle diameter;
(6) Centrifuging at 20000r/min for 20min in a centrifuge, discarding supernatant, and collecting precipitate to obtain lipid nanometer capsule drug-loaded particles with uniform particle diameter (average particle diameter of 345.3 nm);
(7) Re-dispersing the lipoid nanocapsule drug-loaded particles in 10% ethanol solution by volume concentration, and mixing with 20mg/mL additive (sucrose) to prepare a spraying suspension;
(8) Uniformly spraying the spraying suspension on the surface of the balloon subjected to hydrophilic treatment by using ultrasonic spraying equipment, and drying to obtain the drug-coated balloon catheter, wherein the drug-loading rate of the balloon per unit external surface area is 2 mu g/mm 2 。
Example 2
The embodiment provides a medicine balloon, which is prepared by the following steps:
(1) Preparing 40mL of 3mg/mL deca-myristoyl glyceride deionized water solution to obtain a first solution; simultaneously dissolving 40mg of everolimus and 50mg of cholesterol in 4mL of dichloromethane to obtain a solution II;
(2) Transferring the second solution into a 5mL injector, and installing the injector on a micro injection pump, wherein the sample injection flow rate of the micro injection pump is set to be 0.5mL/min; putting the first solution into a 100mL beaker, then inserting an ultrasonic emulsification probe into the solution, setting the total ultrasonic time to be 60min, and setting the power to be 300W; turning on an ultrasonic emulsification instrument to start working, simultaneously turning on a micro-injection pump to dropwise add a solution II into the aqueous phase solution, and carrying out ultrasonic emulsification to obtain an emulsion;
(3) After the ultrasound is finished, transferring the beaker to a constant-temperature water bath magnetic stirring kettle at 40 ℃, and evaporating dichloromethane in the mixed solution while stirring until the dichloromethane is completely volatilized to preliminarily obtain a nano suspension;
(4) Filtering the nanometer suspension by a needle filter, wherein the aperture of the filter membrane is 0.8 mu m, and removing particles with overlarge particle size to obtain a nanometer particle filtrate;
(5) Dialyzing with dialysis membrane with molecular weight cutoff of 1000 for 2 times to remove free rapamycin and carrier molecule to obtain suspension with uniform particle diameter;
(6) Centrifuging at 23000r/min for 20min in a centrifuge, discarding supernatant, and collecting precipitate to obtain lipoid nanocapsule drug-loaded particles with uniform particle size (average particle size is 349.2 nm);
(7) Re-dispersing the lipoid nanocapsule drug-loaded particles in 12% ethanol solution by volume concentration, and mixing with 15mg/mL additive (sucrose) to prepare spraying suspension;
(8) Uniformly spraying the spraying suspension on the surface of the balloon subjected to hydrophilic treatment by using ultrasonic spraying equipment, and drying to obtain the drug-coated balloon catheter, wherein the drug-loading rate per unit external surface area of the balloon is 2 mu g/mm 2 。
Example 3
The embodiment provides a medicine balloon, which is prepared by the following steps:
(1) Preparing 40mL of 3mg/mL Tween 80 deionized water solution to obtain a first solution; taking 50mg of zotarolimus and 50mg of cholesterol, and simultaneously dissolving in 4mL of acetone to obtain a solution II;
(2) Transferring the solution II into a 5mL injector, and installing the injector on a micro injection pump, wherein the sample injection flow of the micro injection pump is set to be 0.5mL/min; putting the first solution into a 100mL beaker, then inserting an ultrasonic emulsification probe into the solution, setting the total ultrasonic time to be 60min, and setting the power to be 300W; opening the ultrasonic emulsification instrument to start working, simultaneously opening a micro-injection pump to dropwise add the solution II into the aqueous phase solution, and performing ultrasonic emulsification to obtain an emulsion;
(3) After the ultrasound is finished, transferring the beaker into a constant-temperature water bath magnetic stirring pot at 40 ℃, and evaporating acetone in the mixed solution while stirring until the acetone is completely volatilized to preliminarily obtain a nano suspension;
(4) Filtering the nano suspension by a needle filter, wherein the aperture of the filter membrane is 0.8 mu m, and removing particles with overlarge particle size to obtain nano particle filtrate;
(5) Dialyzing with dialysis membrane with molecular weight cutoff of 1000 for 2 times to remove free rapamycin and carrier molecule to obtain suspension with uniform particle diameter;
(6) Centrifuging at 23000r/min in a centrifuge for 20min, discarding supernatant, and collecting precipitate to obtain lipid nanometer capsule drug-loaded particles with uniform particle diameter (average particle diameter is 347.5 nm);
(7) Re-dispersing the lipoid nanocapsule drug-loaded particles in 15% ethanol solution by volume concentration, and mixing with 10mg/mL additive (sucrose) to prepare a spraying suspension;
(8) Uniformly spraying the spraying suspension on the surface of the balloon subjected to hydrophilic treatment by using ultrasonic spraying equipment, and drying to obtain the drug-coated balloon catheter, wherein the drug-loading rate of the balloon per unit external surface area is 2 mu g/mm 2 。
Example 4
This example provides a drug balloon that differs from example 1 only in that in step (7), the additive sucrose is replaced with dextran at the same concentration.
Example 5
This example provides a drug balloon that differs from example 1 only in that in step (7), the additive sucrose is replaced with mannitol at the same concentration.
Example 6
This example provides a drug balloon, which is different from example 1 only in that tween 80 is replaced by equal mass of steareth-21 in step (1).
Example 7
This example provides a drug balloon, which is different from example 1 only in that, in step (1), 40mL of tween 80 deionized water solution of 0.5mg/mL is prepared to obtain solution one; 10mg of rapamycin and 50mg of cholesterol were dissolved in 4mL of dichloromethane to obtain a second solution.
Example 8
The present embodiment provides a drug balloon, which is different from embodiment 1 only in that, in step (1), 40mL of tween 80 deionized water solution with a concentration of 5mg/mL is prepared to obtain a first solution; 50mg of rapamycin and 10mg of cholesterol were dissolved in 4mL of dichloromethane to obtain a second solution.
Example 9
This example provides a drug balloon, which is different from example 1 only in that, in step (2), the injection flow rate is set to 0.01mL/min.
Example 10
This example provides a drug balloon, which is different from example 1 only in that, in step (2), the injection flow rate is set to 10mL/min.
Example 11
This example provides a drug balloon that differs from example 1 only in that in step (4), the pore size of the filter membrane is 0.8 μm.
Example 12
This example provides a drug balloon that differs from example 1 only in that in step (5), dialysis is performed 2 times against a dialysis membrane with a molecular weight cutoff of 7000.
Comparative example 1
This comparative example provides a drug balloon, which is different from example 1 only in that tween 80 is replaced with sodium dodecylbenzenesulfonate (anionic surfactant) of an equal mass in step (1).
Comparative example 2
This comparative example provides a drug balloon that differs from example 1 only in that cholesterol is replaced with an equal mass of phospholipid in step (1).
Comparative example 3
The comparative example provides a drug balloon, which is different from the drug balloon in example 1 only in that in the step (2), a micro-syringe pump is not adopted for sample injection, but the solution I and the solution II are directly and uniformly mixed within 60min at the rotating speed of 50 rpm.
Comparative example 4
This comparative example provides a drug balloon that differs from example 1 only in that step (4) filtration is not performed, and step (5) dialysis is performed directly.
Comparative example 5
This comparative example provides a drug balloon that differs from example 1 only in that step (5) dialysis is not performed, but step (6) centrifugation is performed directly.
Test example 1
Particle size distribution test
Test samples: examples 1-3 the resulting spray suspensions were prepared;
the test method comprises the following steps: the measurement was carried out using a particle size distribution analyzer (manufacturer: masteriser model: 2000E)
The test results are shown in fig. 2, and the particle diameters of the nanoparticles prepared by the 3 schemes are all about 350nm, which indicates that the lipid nanocapsules with uniform particle diameters prepared by a specific process are used as drug carriers.
Test example 2
Transport loss rate and tissue absorption rate testing
Test samples: the drug balloons prepared in examples 1 to 12 and comparative examples 1 to 5;
the test method comprises the following steps: the balloon is divided into a group a, a group b and a group c, and the drug content m of the drug coating balloon is directly tested 1 And the group b simulates the use process of the drug balloon in a human body through an in-vitro test model, adopts a 1. b, conveying the group of drug-coated sacculus to the position of a coronary artery blood vessel of a pig through a guide wire, then cutting off the sacculus part from the tail end of a pipeline, drying, putting the sacculus part into a glass container, adding quantitative acetonitrile into the glass container, performing ultrasonic oscillation, and testing by using a high performance liquid chromatograph to obtain the content m of the drug on the drug-coated sacculus 2 . And c, the group C drug saccule reaches the position of the pig coronary artery through a guide wire, then the saccule is expanded, the pressure of 10atm is kept for 60s, and the drug saccule is withdrawn. Cutting off pig coronary artery blood vessel tissue, drying, soaking in acetonitrile, ultrasonically vibrating for 15min, testing the content of leaching solution medicine to obtain medicine amount m transferred from medicine saccule to blood vessel tissue 3 。
Measuring the content of the medicine by liquid chromatography: selecting an instrument: liquid chromatograph Waters 2695; and (3) chromatographic column: shimadzu, C18, 4.6X 250,5 μm; the working parameters of the instrument are as follows: detection wavelength: rapamycin drug 278nm, column temperature: 40 ℃, sample introduction: 10 μ L, flow rate: 1.2mL/min, setting according to the parameters, and after the instrument is stabilized, feeding the sample solution into a sample machine for testing. The balloon delivery loss rate is [ (m) 1 -m 2 )/m 1 ]The tissue absorption rate is (m) 3 /m 2 ) (ii) a The specific test results are shown in table 1 below:
TABLE 1
As can be seen from the test data in Table 1, the delivery loss rate of the drug balloon prepared by the invention is below 57%, and the tissue absorption rate is above 13%, so that the nano particles prepared by the invention have uniform particle size, and the drug-loading rate is ensured, and the particles can be rapidly absorbed by cells; according to the invention, before loading the medicine, the surface of the balloon is coated with a hydrophilic coating, so that the medicine-loading layer can be uniformly dispersed on the surface of the balloon and has uniform thickness; the drug-coated balloon prepared by the invention has accurate and controllable drug-loading rate, and avoids waste and systemic toxicity in human bodies caused by insufficient drug-loading to achieve the treatment target and excessive drug-loading.
The applicant states that the lipid nanocapsule drug-loaded particles with uniform particle size, the drug balloon and the preparation method and application thereof are illustrated by the above examples, but the invention is not limited to the above process steps, i.e. the invention does not mean that the invention is implemented only by relying on the above process steps. It will be apparent to those skilled in the art that any modifications to the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific forms, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of lipid nanocapsule drug-loaded particles with uniform particle size is characterized by comprising the following steps:
(1) Mixing a nonionic surfactant with water to obtain a first solution; mixing cholesterol, macrolide medicines and an organic solvent to obtain a second solution;
(2) Dropwise adding the solution II obtained in the step (1) into the solution I at a constant speed, and performing ultrasonic emulsification to obtain an emulsion;
(3) Removing the organic solvent in the emulsion obtained in the step (2) to obtain a nanoparticle suspension;
(4) Filtering the nanoparticle suspension obtained in the step (3) to obtain a nanoparticle filtrate;
(5) Dialyzing the nano particle filtrate obtained in the step (4) to obtain suspension with uniform particle size;
(6) And (4) centrifuging the suspension with uniform particle size obtained in the step (5), and collecting precipitates to obtain the lipoid nano capsule drug-loaded particles with uniform particle size.
2. The method for preparing lipid nanocapsule drug-loaded particles with uniform particle size according to claim 1, wherein in step (1), the concentration of the nonionic surfactant in the first solution is 1-15mg/mL;
preferably, in the step (1), the concentration of cholesterol in the second solution is 5-20mg/mL, and the concentration of macrolide drug is 5-25mg/mL;
preferably, in step (1), the nonionic surfactant is selected from any one of tween 80, steareth-21, ceteth-25, laureth-23, S40, olivem 800, olivem 700, cetearyl alcohol and glucoside, sucrose fatty acid ester, poloxamer 407, poloxamer 188, hexameric monolaurate glyceride, decapolymeric monomyristate glyceride, decapolymeric monolaurate glyceride or hexameric monomyristate glyceride, or a combination of at least two thereof;
preferably, in step (1), the macrolide includes any one or a combination of at least two of rapamycin, everolimus, zotarolimus, dexamethasone, paclitaxel, docetaxel, probucol, colchicine, heparin, aspirin, or doxorubicin;
preferably, in step (1), the organic solvent is selected from any one of dichloromethane, acetone, chloroform or tetrahydrofuran or a combination of at least two of the dichloromethane, the acetone, the chloroform and the tetrahydrofuran;
preferably, in the step (2), ultrasonic emulsification is simultaneously carried out in the uniform-speed dropwise adding process;
preferably, in the step (2), the uniform dropping adopts a micro-injection pump for sample injection, and the sample injection speed range is 0.01-99.99mL/min;
preferably, in the step (2), the power of the ultrasonic emulsification is 100-500W, and the time of the ultrasonic emulsification is 20-100min;
preferably, in step (2), the particle size of the emulsion obtained after ultrasonic emulsification is below 600 nm.
3. The method for preparing lipid nanocapsule drug-loaded particles having a uniform particle size according to claim 1 or 2, wherein the organic solvent is removed in step (3) by: evaporating the organic solvent in the emulsion obtained in the step (2) to dryness;
preferably, the temperature for evaporating to dryness is 30-50 ℃;
preferably, in step (4), the filtration is: filtering the nanoparticle suspension obtained in the step (3) by using a needle filter;
preferably, the pore size of the filter membrane in the needle filter is any one of 0.22 μm, 0.45 μm or 0.8 μm.
4. The method for preparing lipid nanocapsule drug-loaded particles having a uniform particle size according to any one of claims 1 to 3, wherein in the step (5), the dialysis is performed for 2 or more times;
preferably, in the step (5), the dialysis membrane has a molecular weight cut-off of any one of 500, 1000, 3500 or 7000;
preferably, in the step (6), the rotation speed of the centrifugation is 10000-30000r/min, and the time of the centrifugation is 10-30min;
preferably, in the step (6), the particle size of the lipid nano-capsule drug-loaded particle is 160-650nm.
5. The lipid nanocapsule drug-loaded particles with uniform particle size are prepared by the preparation method of any one of claims 1 to 4.
6. A drug balloon is characterized by sequentially comprising a balloon body, a hydrophilic coating and a drug-loading coating from inside to outside; wherein the drug-loaded coating layer comprises lipid nanocapsules drug-loaded particles of uniform size according to claim 5.
7. The drug balloon of claim 6, wherein the balloon body comprises an intracranial balloon and/or a coronary balloon;
preferably, the balloon body is made of a high molecular polymer material;
preferably, the balloon body is made of Pebax;
preferably, the hydrophilic coating is a hydrophilic high molecular polymer;
preferably, the hydrophilic high molecular polymer is selected from any one of polyacrylamide, polyvinylpyrrolidone or polymethyl vinyl ether copolymerized maleic acid;
preferably, the thickness of the hydrophilic coating is 0.05-0.2 μm, preferably 0.1 μm;
preferably, the drug loading rate of the drug balloon per unit external surface area is 1-10 mug/mm 2 ;
Preferably, the drug-loaded coating further comprises additives for binding and shaping;
preferably, the additive is selected from any one or a combination of at least two of dextran, polysorbate, sorbitol, fructose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, heptatol, isomalt, maltitol, lactitol, maltotriose, voglibose, xylitol or polyethylene glycol;
preferably, the mass ratio of the additive to the lipid nano-capsule drug-loaded particles is (1-20): 100.
8. A method for preparing a drug balloon according to claim 6 or 7, comprising the following steps:
(a) Dispersing the lipoid nanocapsule drug-loaded particles with uniform particle size in an ethanol water solution, and then carrying out ultrasonic dispersion with optional additives with bonding and shaping functions to obtain a nanoparticle spraying suspension;
(b) Uniformly spraying the nano particle spraying suspension obtained in the step (a) on the surface of the balloon subjected to hydrophilic treatment by using ultrasonic spraying equipment, and then carrying out curing treatment to obtain the medicine balloon.
9. The method for preparing a drug balloon according to claim 8, wherein in the ethanol aqueous solution in the step (a), the volume ratio of ethanol to water is 1;
preferably, in the step (a), in the nanoparticle spray suspension, the concentration of the lipid nanocapsule drug-loaded particles is 13-40mg/mL, and the concentration of the additive is 0.2-8mg/mL;
preferably, in the step (a), the power of the ultrasonic dispersion is 100-500W, and the time of the ultrasonic dispersion is 20-100min;
preferably, in the step (b), the hydrophilic treatment comprises the following specific steps: polyacrylamide with the mass concentration of 0.5-2 percent is evenly sprayed on the surface of the saccule by spraying equipment, and the spraying amount is 15-25 mug-mm 2 After the spraying is finished, the mixture is placed in a vacuum drying oven to be dried for more than 20 hours under the conditions of 0.1-1 atm and 55-65 ℃;
preferably, in step (b), the curing treatment is drying, and the temperature of drying is 40-70 ℃.
10. Use of the uniform sized lipid nanocapsule drug-loaded particles of claim 5, the drug balloon of claim 6 or 7 for delivery of a drug to a tissue and for sustained release in vivo.
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