CN111317907A - Composite drug coating balloon, preparation method thereof and composite drug coating balloon dilatation catheter - Google Patents
Composite drug coating balloon, preparation method thereof and composite drug coating balloon dilatation catheter Download PDFInfo
- Publication number
- CN111317907A CN111317907A CN202010166819.0A CN202010166819A CN111317907A CN 111317907 A CN111317907 A CN 111317907A CN 202010166819 A CN202010166819 A CN 202010166819A CN 111317907 A CN111317907 A CN 111317907A
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- Prior art keywords
- drug
- acid
- coating
- spraying
- solution
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- 229940079593 drug Drugs 0.000 title claims abstract description 244
- 239000011248 coating agent Substances 0.000 title claims abstract description 138
- 238000000576 coating method Methods 0.000 title claims abstract description 122
- 239000002131 composite material Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 37
- 230000008569 process Effects 0.000 claims abstract description 22
- 239000000243 solution Substances 0.000 claims description 103
- 238000005507 spraying Methods 0.000 claims description 102
- 239000002245 particle Substances 0.000 claims description 61
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
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- 238000001914 filtration Methods 0.000 claims description 20
- 239000000725 suspension Substances 0.000 claims description 19
- -1 tri-n-hexyl butyryl citrate Chemical compound 0.000 claims description 19
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a composite drug coating balloon, which comprises a balloon and a composite drug coating covering the surface of the balloon, wherein the composite drug coating comprises a bottom coating, a middle coating and an outer coating, the bottom coating is coated on the surface of the balloon and consists of a drug A and a hydrophilic excipient; the middle layer coating consists of a medicament B coated by a coating agent and hydrophilic excipient/lipophilic excipient/amphiphilic excipient; the outer coating consists of drug C and lipophilic/amphiphilic excipients. The invention also discloses a preparation method of the composite drug coating balloon and a composite drug coating balloon dilatation catheter. The composite drug coating balloon can reduce the loss of drugs in the balloon conveying process, can enable the vascular lesion position to have effective drug concentration in a short term, inhibit vascular restenosis, provide long-term drug release, keep longer drug action time and reduce restenosis rate.
Description
Technical Field
The invention relates to the technical field of medical instruments, in particular to a composite drug coating balloon, a preparation method of the composite drug coating balloon and a balloon dilatation catheter comprising the composite drug coating balloon.
Background
In recent years, with the rapid development of neurosmagraphy, catheter technology and materials, computers and other sciences, intravascular interventional techniques are becoming mature in the aspect of treating vascular diseases, and are determined by doctors and patients on the basis of the characteristics of minimal invasion, safety, effectiveness and the like, so that the intravascular interventional techniques are one of the important methods for treating vascular diseases at present.
Balloon angioplasty is an established method of treating vascular disease by physically dilating an area of reduced lumen diameter or stenosis in an atherosclerotic, diseased blood vessel. Typically, angioplasty is performed using a catheter that can be advanced within the circulatory system to the diseased area. The catheter has a balloon at the distal end that is inflated to inflate and expand the stricture. In many cases, such as in coronary arteries, the stent is also expanded over the outside of the balloon. After decompression and removal of the balloon, the stent remains in place to maintain patency of the expanded lumen.
Drug-coated stents have met with great success in the treatment of vascular stenosis. However, long-term clinical test results show that the drug-coated stent can generate side reactions caused by metal frameworks and polymer carriers and risks of late thrombus in blood vessels to human bodies, and postoperative in-stent restenosis also becomes another troublesome problem. In the subsequent study of new devices and therapeutic techniques, drug eluting balloons (hereinafter "DCB", "DEB" or "drug balloon") have become an emerging means of treating restenosis within stents, and have gained widespread use due to their unique advantages.
The medicine saccule is one new kind of medicine releasing saccule technology developed on the basis of saccule expanding operation, saccule forming operation and other intervention technology, and is one technology of coating antiproliferative medicine, such as taxol, onto the surface of saccule, spreading and expanding when reaching the pathological part and contacting with the inner membrane of blood vessel wall, so that the medicine is released fast and transferred to the local blood vessel wall to prevent blood vessel restenosis after blood vessel intervention. The drug coating balloon can effectively inhibit the excessive proliferation of smooth muscle cells so as to reduce the incidence rate of restenosis on one hand, and does not need to be placed into a stent on the other hand, thereby reducing the inflammatory reaction of intima of a blood vessel, reducing the risk of thrombosis in the stent, shortening the time of duplex antiplatelet and reducing the bleeding risk. In addition, in clinical studies of coronary artery disease, the drug balloon shows better effectiveness and safety in treating in-stent restenosis, small vessel lesions, bifurcation lesions, and is also suitable for patients at high risk of bleeding, patients who are taking oral anticoagulant drugs, or patients who have recently undergone surgical operations.
The basic principle of the drug-coated balloon dilatation catheter is local drug delivery, and the drug coating is important as an important technical index of the drug-coated balloon. The firmness of the drug coating in the blood vessel, the drug release capacity in the artery, and the drug absorption capacity by the blood vessel are all determined by the drug coating. It can also be seen from the presently published patents and literature that a consensus has been established that obtaining crystalline drug coatings is the primary prerequisite for a therapeutic effect of drug balloons. However, the paclitaxel crystal obtained by the current technology has larger size, loose crystallization, no firm combination between the crystal and the carrier, separation or carrier-free phenomenon, low coating fastness, great loss in the process of passing through and expanding the drug balloon and low drug utilization rate. Moreover, the larger crystal size means that the drug coating may generate drug particles during surgery, which are prone to thrombus blockage as blood circulates into the microcirculatory system or capillaries. Many coating techniques use a single carrier, and the contradiction between rapid release and transshipment of the drug, excessive drug delivery loss and particles cannot be solved. There is also coating technique to set up the protection film outside the coating to reduce the medicine loss of transportation process, but the protection film of design is too closed, and the medicine is kept apart and can't direct and vascular wall contact, and the too little area of contact causes adverse effect to the release of medicine equally.
When the drug coating is released quickly, more drugs can be washed away by blood in the conveying process, and the drugs acting on local parts are very few. The drug absorption amount can be locally increased by increasing the drug loading amount of the balloon coating, but a large amount of redundant drug flows to the far end of the blood vessel, so that the health of a patient is influenced. Because the common drug balloon dilatation catheter has short dilatation time and is not easy to release drugs, the problems and difficulties faced by the common drug balloon dilatation catheter at present are as follows: 1. when the drug coating is released quickly, more drugs can be flushed away by blood in the conveying process; 2. the drug adheres to the wall in a short time and is difficult to be absorbed by the vessel wall in a large amount, so that a better treatment effect cannot be achieved; 3. the drug coating is easy to fall off to generate particles and thrombus.
Disclosure of Invention
The invention aims to provide a composite drug coating balloon, which can reduce the loss of drugs in the balloon conveying process, can enable the vascular lesion position to have effective drug concentration in a short term, inhibit vascular restenosis, and can provide long-term drug release, keep longer drug action time and reduce restenosis rate.
In order to solve the technical problems, the invention provides the following technical scheme:
in a first aspect, the invention provides a composite drug coating balloon, which comprises a balloon and a composite drug coating covering the surface of the balloon, wherein the composite drug coating comprises a bottom coating, a middle coating and an outer coating, the bottom coating is coated on the surface of the balloon and consists of a drug A and a hydrophilic excipient; the middle layer coating consists of a medicament B coated by a coating agent and hydrophilic excipient/lipophilic excipient/amphiphilic excipient; the outer coating consists of drug C and lipophilic/amphiphilic excipients.
Further, the drug A, the drug B and the drug C are respectively and independently selected from one or more of macrolide immunosuppressant, macrolide antibiotic, rapamycin, structural derivative of rapamycin, everolimus, structural derivative of everolimus, zotarolimus, paclitaxel, structural derivative of paclitaxel, anti-hemagglutination drug, inhibitory RNA, inhibitory DNA, statins, traditional Chinese medicine ligustrazine, steroid, histone deacetylase inhibitor and complement inhibitor.
Further, the hydrophilic excipient is selected from one or more of iopromide, iohexol, ioversol, urea, polyethylene glycol, polysorbate, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide (PEO) and vitamins;
said lipophilic excipient is selected from the group consisting of tri-n-hexyl butyryl citrate, tributyl acetyl citrate, shellac, triglycerides triacetate, triglycerides capric acid, triglycerides caprylic acid, stearic acid, cholesterol, PEG-lipids, myristoleic acid laurate, caprylic acid, myristic acid, myristoleic acid, decenoic acid, capric acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, one or more of eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosadienoic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, nervonic acid, phytosterol, higher fatty alcohol, cetyl or stearyl alcohol, cholesterol, lanolin, lecithin, methylparaben, ethylparaben, and glyceryl stearate;
the amphiphilic excipient is selected from one or more of dextran, polysorbate, sorbitol, and ammonium shellac salt.
Further, the wrapping agent is phospholipid or/and degradable polymer;
preferably, the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidylinositol, sphingomyelin, phosphatidylcholine, amine derivatives of phosphatidylcholine, dioleoylphosphatidylethanolamine;
preferably, the degradable polymer is selected from one or more of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, poly-racemic lactide-glycolide (PDLGA), polylactide-caprolactone (placid), monomethoxypolyethylene glycol poly-racemic lactic acid-glycolic acid copolymer (MPEG-PDLGA), polyethylene glycol poly-racemic lactic acid-glycolic acid copolymer (PDLGA-PEG-PDLGA), polytrimethylene carbonate (PTMC).
Further, in the bottom coating, the mass ratio of the drug A to the hydrophilic excipient is 1: 0.01-1: 10; in the middle layer coating, the mass ratio of the medicine B to the wrapping agent is 1: 0.05-1: 10; in the outer coating, the mass ratio of the drug C to the lipophilic excipient/amphiphilic excipient is 1: 0.01-1: 20.
Further, the total concentration of the drug in the drug coating is 0.5 μ g/mm2～10μg/mm2。
In a second aspect, the present invention provides a method for preparing a composite drug-coated balloon, for preparing the composite drug-coated balloon according to the first aspect, comprising the following steps:
s1, respectively preparing a drug spraying solution A, a drug spraying solution B and a drug spraying solution C;
s2, uniformly spraying the medicine spraying solution A on the surface of a naked sacculus to obtain a bottom coating; then, uniformly spraying the drug spraying solution B on the bottom layer coating to obtain an intermediate layer coating; then uniformly spraying the medicine spraying solution C on the middle layer coating to obtain an outer layer coating;
s3, drying the saccule treated in the step S2 to obtain the composite medicine coating saccule;
wherein, the medicine spraying solution A is obtained by dissolving the medicine A and a hydrophilic excipient in a solvent and filtering; the drug spraying solution C is obtained by dissolving the drug C and lipophilic excipient/amphiphilic excipient in a solvent and filtering;
the preparation method of the drug spraying solution B comprises the following steps (i) or (ii):
(i) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; then ultrasonically spraying the medicine solution B, drying, collecting the medicine particles coated by the coating agent, and dispersing in an aqueous solution or an aqueous solution containing an emulsifying agent to obtain a medicine particle suspension solution; filtering to remove the drug particles with large particle size, and mixing the drug particles with the solution containing the excipient to obtain a drug spraying solution B;
(ii) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; dripping the medicine solution B into an aqueous solution containing an emulsifier, and forming to obtain a medicine particle suspension solution coated by a coating agent; filtering to remove the drug particles with large particle size, and mixing into the solution containing the excipient to obtain a drug spraying solution B.
Further, the solvent is selected from one or more of ethanol, methanol, acetone, isopropanol, methyl vinyl ketone, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform, n-heptane, methyl acetate and butyl acetate.
Further, in the medicine spraying solution A, the concentration of the medicine A is 0.5-300 mg/ml; in the medicine solution B, the concentration of the medicine B is 0.5-300 mg/ml; in the medicine spraying solution C, the concentration of the medicine C is 1-50 mg/ml.
Further, in step (i), the ultrasonic spraying conditions are as follows: the ultrasonic spraying power is 0.1-3W, and the flow of the drug solution conveyed by the injection pump is 0.01-10 ml/min; the particle size of the drug particles coated by the coating agent is 10 nm-8 μm.
Further, in the steps (i) and (ii), the emulsifier is selected from one or more of polyvinyl alcohol, polysorbate, vitamin, polyethylene glycol succinate and polyoxyethylene polyoxypropylene ether block copolymer, and the concentration of the emulsifier in the emulsifier-containing aqueous solution is 0.1-10 wt%.
Further, in the step (ii), the forming treatment comprises ultrasonic emulsification, high-speed dispersion homogenization, membrane emulsification and micelle forming; in the medicament particle suspension solution coated by the coating agent, the particle size of the medicament suspension particles is 10 nm-8 mu m.
Further, in the steps (i) and (ii), in the drug spraying solution B, the particle size of the drug particles is 10 nm-8 μm.
Further, in step S2, the spraying is performed by using an ultrasonic spraying process, and the process parameters of the ultrasonic spraying are as follows: the ultrasonic spraying power is 0.2-3W, the flow of the drug solution conveyed by the injection pump is 0.01-1.0 ml/min, the spraying temperature is 20-55 ℃, the spraying air pressure is 0.01-0.5 MPa, and the spraying height is 5-100 mm.
In a third aspect, the invention also provides a composite drug-coated balloon dilatation catheter, which comprises the composite drug-coated balloon as described in the first aspect.
Compared with the prior art, the invention has the beneficial effects that:
1. the drug coating of the drug balloon catheter consists of three parts, wherein the excipient in the bottom layer, namely the coating close to the balloon, is a hydrophilic excipient, and when the balloon is expanded, the hydrophilic excipient is quickly dissolved in blood, so that the coating is quickly transferred to the wall of a blood vessel from the surface of the balloon.
2. In the invention, the middle layer of the drug coating contains drug particles with different particle sizes, and the drug particles with different sizes penetrate and diffuse to different positions in the vascular tissue, thereby fully playing the drug effect and inhibiting intimal hyperplasia. The drug particles are coated by substances, which are equivalent to micro drug storage reservoirs, and can continuously release drugs into tissues to inhibit long-term restenosis.
3. In the invention, the intermediate layer of the drug coating is wrapped by phospholipid or contains lipophilic excipient, so that the drug can easily pass through endothelial cell plasma membrane, the drug is promoted to be absorbed by the vessel wall, and the defect that the drug is washed and lost by the blood flow flowing at high speed due to slow drug absorption of tissues is overcome.
4. In the invention, the outermost layer of the drug coating is composed of lipophilic excipient or amphiphilic excipient which is not easy to be dissolved by blood, thus being beneficial to maintaining the integrity of the coating and reducing the drug loss in the drug balloon conveying process.
5. In the invention, the bottom layer of the drug coating contains the drug and the hydrophilic excipient, and the hydrophilic excipient is quickly dissolved in the expansion process, so that the drug coating forms a porous loose structure, which is beneficial to increasing the surface area and improving the bioavailability of the drug.
6. In the invention, the bottom layer and the outermost layer of the coating both contain the drug, so that the short-term effective drug concentration can be provided, and the drug particles in the middle layer can continuously release the drug, so that the drug can be continuously effective.
Drawings
FIG. 1 is a schematic structural view of a drug-coated balloon dilation catheter in an embodiment of the present invention;
FIG. 2 is a schematic structural view of a composite drug coating according to the present invention;
FIG. 3 is a schematic illustration of an ultrasonic spray coating process;
wherein: 1-balloon, 2-developing marking ring, 3-pushing rod, 4-catheter seat, 5-composite drug coating, 6-ultrasonic nozzle, 7-atomized drug solution, 8-bottom coating, 9-middle coating and 10-outer coating.
Detailed Description
The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The key technical point of the drug balloon is how to realize the bonding balance between the drug coating and the balloon surface and increase the tissue absorption in a short time. If the adhesive force between the drug coating and the balloon is weak, the drug in the drug balloon delivery process is lost more, and the drug amount is less when the drug is delivered to the lesion position. If the combination of the drug coating and the balloon is too strong, the drug amount transferred to the vessel wall in a short time is too small in the process of drug balloon expansion and transfer, and most of the drug is still on the balloon. When the medicine coating of current medicine sacculus reprints the medicine, the tissue absorbs slowly, and the medicine of reprinting to the vascular wall is easily washed away by blood, leads to the medicine volume of pathological change position few, does not have the medicine sustained action.
In order to solve the technical problems, the invention provides a balloon dilatation catheter with a composite medicine coating, which has a typical structure shown in figure 1, and comprises a balloon 1, a push rod 3 and a catheter seat 4, wherein the balloon 1 partially contains a developing mark ring 2, and the surface of the balloon 1 is coated with the composite medicine coating 5. The invention defines the whole of the balloon 1 and the composite drug coating 5 as the composite drug coating balloon.
Fig. 2 shows a schematic structural diagram of the composite drug coating 5, which comprises a bottom coating, a middle coating and an outer coating. Wherein, the bottom layer coating is directly coated on the outer surface of the balloon and consists of a medicament A and a hydrophilic excipient; the middle layer coating consists of a medicament B coated by a coating agent and hydrophilic excipient/lipophilic excipient/amphiphilic excipient; the outer coating consists of drug C and lipophilic/amphiphilic excipients.
In the invention, the drug A, the drug B and the drug C can be independently selected from one or more of macrolide immunosuppressants, macrolide antibiotics, rapamycin, structural derivatives of rapamycin, everolimus, structural derivatives of everolimus, zotarolimus, paclitaxel, structural derivatives of paclitaxel, anti-hemagglutination drugs, inhibitory RNA, inhibitory DNA, statins, traditional Chinese medicines of ligustrazine, steroids, histone deacetylase inhibitors and complement inhibitors.
In the present invention, the drug coating is composed of three parts. The excipient in the coating close to the saccule is hydrophilic excipient, and when the saccule expands, the hydrophilic excipient is quickly dissolved in blood, so that the coating is quickly transferred; the outermost layer uses lipophilic or amphiphilic excipient to protect the drug coating from being damaged in the drug balloon delivery process, reduce the drug loss and enable the coating to be absorbed by vascular tissues more quickly; the drugs on the bottom layer and the outermost layer can enable the vascular lesion position to have effective drug concentration in a short time, and inhibit vascular restenosis. The middle layer medicine is wrapped by a wrapping agent which is phospholipid or degradable polymer, the sizes of the middle layer medicine particles are different, the medicine releasing speeds of different particles are different after the medicine is absorbed, and the medicine is wrapped, so that long-time medicine release can be provided, the longer medicine action time is kept, and the restenosis rate is reduced.
The hydrophilic excipient can be one or more selected from iopromide, iohexol, ioversol, urea, polyethylene glycol, polysorbate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, and vitamins;
the lipophilic excipient can be selected from butyrylcitrilic acid tri-n-hexyl citrate, acetyl tributyl citrate, shellac, triglyceride, triacetic acid triglyceride, capric acid triglyceride, caprylic acid triglyceride, stearic acid, cholesterol, PEG-lipid, lauric acid tetradecadienoic acid, caprylic acid, myristic acid, myristoleic acid, decenoic acid, capric acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, nervonic acid, phytosterol, higher fatty alcohol, cetyl alcohol or stearyl alcohol, cholesterol, lanolin, lecithin, methylparaben, ethylparaben, and mixtures thereof, One or more of glyceryl stearate;
the amphiphilic excipient may be one or more selected from dextran, polysorbate, sorbitol, and ammonium shellac salt.
The coating agent can be phospholipid or/and degradable polymer; wherein the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidylinositol, sphingomyelin, phosphatidylcholine, amine derivatives of phosphatidylcholine, and dioleoylphosphatidylethanolamine;
the degradable polymer may be one or more selected from polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, poly-racemic lactide-glycolide, polylactide-caprolactone, monomethoxypolyethylene glycol poly-racemic lactic acid-glycolic acid copolymer, polyethylene glycol poly-racemic lactic acid-glycolic acid copolymer, and polytrimethylene carbonate.
In the present invention, in the primer coating, the mass ratio of the drug a to the hydrophilic excipient is preferably 1: 0.01-1: 10; in the middle layer coating, the mass ratio of the medicament B to the wrapping agent is preferably 1: 0.05-1: 10; in the outer coating, the mass ratio of the drug C to the lipophilic excipient/amphiphilic excipient is preferably 1: 0.01-1: 20.
In the invention, the bottom layer coating, the middle layer coating and the outer layer coating are preferably prepared by adopting an ultrasonic spraying process, fig. 3 shows a schematic diagram of the ultrasonic spraying process, in the spraying process, the balloon rotates, and the medicine nozzle solution is coated on the surface of the balloon after ultrasonic atomization.
In the present invention, the total concentration of the drug in the drug coating layer is preferably 0.5. mu.g/mm2～10μg/mm2。
In addition, the invention also provides a method for preparing the composite drug coating balloon, which comprises the following steps:
s1, respectively preparing a drug spraying solution A, a drug spraying solution B and a drug spraying solution C;
s2, uniformly spraying the medicine spraying solution A on the surface of a naked sacculus to obtain a bottom coating; then, uniformly spraying the drug spraying solution B on the bottom layer coating to obtain an intermediate layer coating; then uniformly spraying the medicine spraying solution C on the middle layer coating to obtain an outer layer coating;
s3, drying the saccule treated in the step S2 to obtain the composite medicine coating saccule;
wherein, the medicine spraying solution A is obtained by dissolving the medicine A and a hydrophilic excipient in a solvent and filtering; the drug spraying solution C is obtained by dissolving the drug C and lipophilic excipient/amphiphilic excipient in a solvent and filtering;
the preparation method of the drug spraying solution B comprises the following steps (i) or (ii):
(i) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; then ultrasonically spraying the medicine solution B, drying, collecting the medicine particles coated by the coating agent, and dispersing in an aqueous solution or an aqueous solution containing an emulsifying agent to obtain a medicine particle suspension solution; filtering to remove the drug particles with large particle size, and mixing the drug particles with the solution containing the excipient to obtain a drug spraying solution B;
(ii) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; dripping the medicine solution B into an aqueous solution containing an emulsifier, and forming to obtain a medicine particle suspension solution coated by a coating agent; filtering to remove the drug particles with large particle size, and mixing into the solution containing the excipient to obtain a drug spraying solution B.
The solvent may be one or more selected from ethanol, methanol, acetone, isopropanol, methyl vinyl ketone, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform, n-heptane, methyl acetate, and butyl acetate.
Further, in the medicine spraying solution A, the concentration of the medicine A is 0.5-300 mg/ml; in the medicine solution B, the concentration of the medicine B is 0.5-300 mg/ml; in the medicine spraying solution C, the concentration of the medicine C is 1-50 mg/ml.
Further, in step (i), the ultrasonic spraying conditions are as follows: the ultrasonic spraying power is 0.1-3W, and the flow of the drug solution conveyed by the injection pump is 0.01-10 ml/min; the particle diameter of the obtained medicament particles coated by the coating agent is 10 nm-8 mu m. By controlling the ultrasonic conditions, drug particles of different particle sizes can be prepared.
Further, in the steps (i) and (ii), the emulsifier is selected from one or more of polyvinyl alcohol, polysorbate, vitamin, polyethylene glycol succinate and polyoxyethylene polyoxypropylene ether block copolymer, and the concentration of the emulsifier in the emulsifier-containing aqueous solution is 0.1-10 wt%.
Further, in the step (ii), the forming treatment comprises ultrasonic emulsification, high-speed dispersion homogenization, membrane emulsification and micelle forming; in the medicament particle suspension solution coated by the coating agent, the particle size of the medicament suspension particles is 10 nm-8 mu m. The forming method is controlled, and the medicine suspension particles with different particle sizes can be prepared.
Further, in the steps (i) and (ii), in the drug spraying solution B, the particle size of the drug particles is 10 nm-8 μm.
Further, in step S2, the spraying is preferably performed by using an ultrasonic spraying process, and the process parameters of the ultrasonic spraying are as follows: the ultrasonic spraying power is 0.2-3W, the flow of the drug solution conveyed by the injection pump is 0.01-1.0 ml/min, the spraying temperature is 20-55 ℃, the spraying air pressure is 0.01-0.5 MPa, and the spraying height is 5-100 mm.
Further, in step S3, a vacuum drying process is preferably employed.
Example 1
Weighing 50mg of paclitaxel and 50mg of PDLGA, dissolving in 10ml of mixed solvent (volume ratio is 1:3) of acetone and dichloromethane, adding the solution into 1 wt% polyvinyl alcohol aqueous solution after fully dissolving, ultrasonically emulsifying for 60min, stirring at high speed (1500rpm) for 60min, and filtering with a filter membrane with pores of 2um to obtain the drug suspension emulsion.
Example 2
Weighing 120mg of rapamycin and 100mg of lecithin, dissolving in 20ml of methanol, adding the solution into 100ml of 2 wt% polysorbate aqueous solution after full dissolution, dispersing and emulsifying by using a high-speed homogenizer at the rotating speed of 15000rpm for 5min, stirring the emulsion for 5h at the rotating speed of 1000rpm, centrifuging the emulsion at the rotating speed of 2000rpm, and taking the supernatant to obtain the drug particle suspension.
Example 3
150mg of paclitaxel and 100mg of PLA are weighed and dissolved in 12ml of mixed solvent of acetone and dichloromethane (volume ratio is 1:5), after the paclitaxel and the PLA are fully dissolved, the solution is sprayed into a heated container by ultrasonic, the ultrasonic spraying power is 1.5W, and the flow of the medicine solution conveyed by an injection pump is 1.0 ml/min. Collecting the dried medicine particle powder, dispersing in a 1 wt% polysorbate aqueous solution, ultrasonically shaking for 40min, and filtering to obtain a medicine suspension.
Example 4
Weighing 120mg of paclitaxel and 100mg of iopromide, dissolving in 10ml of ethanol, dissolving by ultrasonic wave until colorless and transparent, and filtering to obtain a spraying solution.
Example 5
100mg of rapamycin and 100mg of iohexol are weighed and dissolved in 10ml of ethanol, the mixture is dissolved by ultrasonic waves until the mixture is colorless and transparent, and the spraying solution is obtained by filtration.
Example 6
Weighing 50mg of paclitaxel and 100mg of butyryl tri-n-hexyl citrate, dissolving in 10ml of ethanol, sufficiently dissolving by ultrasonic waves, and filtering to obtain a spraying solution.
Example 7
Rapamycin 40mg and acetyl tributyl citrate 100mg are weighed and dissolved in ethanol 10ml, ultrasonic waves are fully dissolved, and the spraying solution is obtained by filtering.
Example 8
And (2) ultrasonically spraying the solution obtained in the embodiment 4 onto the surface of the balloon, then ultrasonically spraying the mixture of the drug suspension solution obtained in the embodiment 1 and a 1 wt% iopromide aqueous solution onto the balloon, finally ultrasonically spraying the spray solution obtained in the embodiment 6 onto the balloon, and drying to obtain the drug balloon. The drug concentration of the balloon catheter is 3 mug/mm2。
Example 9
And (2) ultrasonically spraying the solution obtained in the embodiment 5 onto the surface of the balloon, then ultrasonically spraying the mixture of the drug suspension solution obtained in the embodiment 2 and 1 wt% of iohexol aqueous solution onto the balloon, finally ultrasonically spraying the spray solution obtained in the embodiment 7 onto the balloon, and drying to obtain the drug balloon. The drug concentration of the balloon catheter is 3 mug/mm2。
Example 10
The solution obtained in example 4 is taken and ultrasonically sprayed on the surface of the balloon, and then the balloon is takenAnd mixing the drug suspension solution obtained in the embodiment 3 with a 1 wt% iopromide aqueous solution, performing ultrasonic spraying on the mixture, finally performing ultrasonic spraying on the balloon with the spray solution obtained in the embodiment 6, and drying to obtain the drug balloon. The drug concentration of the balloon catheter is 2 mug/mm2。
Comparative example 1
Dissolving 100mg of paclitaxel and 40mg of iopromide in 5ml of ethanol, dissolving by ultrasonic wave until colorless and transparent, and filtering to obtain a spraying solution. And ultrasonically spraying the solution on the saccule, and drying to obtain the medicinal saccule. The drug concentration of the balloon catheter is 3 mug/mm2。
Comparative example 2
Dissolving rapamycin 100mg and iohexol 50mg in ethanol 5ml, dissolving by ultrasonic wave until colorless and transparent, and filtering to obtain a spraying solution. And ultrasonically spraying the solution on the saccule, and drying to obtain the medicinal saccule. The drug concentration of the balloon catheter is 2 mug/mm2。
The drug-coated balloon samples (balloon with diameter of 3mm and length of 20mm, Pebax material) prepared in example 8, example 9, example 10, comparative example 1 and comparative example 2 were divided into a, b and c groups, the drug content m1 was directly measured by the drug-coated balloon in group a, and the drug content m1 was measured by the drug-coated balloon in group b by an in vitro test model, and the use of the drug-coated balloon in human was simulated by using a 1:1 human tube model, using a guide catheter as a delivery path, and using a peristaltic pump to control the water flow rate. And b, conveying the group b drug coating sacculus to the position of a pig coronary artery blood vessel through a guide wire, then cutting off the sacculus part from the tail end of the pipeline, drying, putting the sacculus part into a glass container, adding quantitative acetonitrile, performing ultrasonic oscillation, and testing by using a high performance liquid chromatograph to obtain the drug content m2 on the drug coating sacculus. And c, leading the group of medicine balloons to reach the position of the pig coronary artery through a guide wire, then expanding the balloons, keeping the pressure of 10atm for 60s, and withdrawing the medicine balloons. Cutting off the blood vessel tissue of the coronary artery of the pig, soaking the blood vessel tissue in acetonitrile after drying, and testing the drug content of a leaching solution after ultrasonic oscillation for 15min to obtain the drug amount m3 transferred by the drug saccule into the blood vessel tissue.
Measuring the content of the medicine by liquid chromatography:
selecting an instrument: liquid chromatograph Waters 2695; a chromatographic column: shimadzu, C18, 4.6X250, 5 μm
The working parameters of the instrument are as follows:
detection wavelength: 227nm of paclitaxel medicine, 278nm of rapamycin medicine,
column temperature: at a temperature of 40 c,
sample introduction amount: 10 mu L of the mixture is added into the solution,
flow rate: 1.2ml/min of the mixture is added,
paclitaxel drug detection mobile phase: methanol: water: acetonitrile 23:41:36
Rapamycin drug detection mobile phase: acetonitrile: water: methanol 45:19:36
And setting according to the parameters, and carrying out sample introduction and machine test on the sample solution after the instrument is stabilized. The balloon delivery loss rate is [ (m1-m2)/m1], the tissue absorption rate is (m3/m2), and the test results are shown in the following table.
The above test results show that the drug-coated balloon catheter of the present invention reduces drug loss during delivery, while delivering drug to tissue relatively more rapidly during expansion and with high tissue uptake.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (15)
1. A composite drug coating balloon comprises a balloon and a composite drug coating covering the surface of the balloon, and is characterized in that the composite drug coating comprises a bottom coating, a middle coating and an outer coating, wherein the bottom coating is coated on the surface of the balloon and consists of a drug A and a hydrophilic excipient; the middle layer coating consists of a medicament B coated by a coating agent and hydrophilic excipient/lipophilic excipient/amphiphilic excipient; the outer coating consists of drug C and lipophilic/amphiphilic excipients.
2. The composite drug-coated balloon according to claim 1, wherein each of the drug A, the drug B and the drug C is independently selected from one or more of macrolide immunosuppressants, macrolide antibiotics, rapamycin, structural derivatives of rapamycin, everolimus, structural derivatives of everolimus, zotarolimus, paclitaxel, structural derivatives of paclitaxel, anti-coagulants, inhibitory RNA, inhibitory DNA, statins, the traditional Chinese medicines ligustrazine, steroids, histone deacetylase inhibitors, and complement inhibitors.
3. The composite drug-coated balloon of claim 1, wherein the hydrophilic excipient is selected from one or more of iopromide, iohexol, ioversol, urea, polyethylene glycol, polysorbate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, vitamins;
said lipophilic excipient is selected from the group consisting of tri-n-hexyl butyryl citrate, tributyl acetyl citrate, shellac, triglycerides triacetate, triglycerides capric acid, triglycerides caprylic acid, stearic acid, cholesterol, PEG-lipids, myristoleic acid laurate, caprylic acid, myristic acid, myristoleic acid, decenoic acid, capric acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, one or more of eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosadienoic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, nervonic acid, phytosterol, higher fatty alcohol, cetyl or stearyl alcohol, cholesterol, lanolin, lecithin, methylparaben, ethylparaben, and glyceryl stearate;
the amphiphilic excipient is selected from one or more of dextran, polysorbate, sorbitol, and ammonium shellac salt.
4. The composite drug-coated balloon of claim 1, wherein the encapsulating agent is a phospholipid or/and a degradable polymer;
the phospholipid is selected from one or more of soybean lecithin, yolk lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, sphingomyelin, phosphatidylcholine, amine derivatives of phosphatidylcholine, and dioleoylphosphatidylethanolamine;
the degradable polymer is selected from one or more of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, poly-racemic lactide-glycolide, polylactide-caprolactone, monomethoxypolyethylene glycol poly-racemic lactic acid-glycolic acid copolymer, polyethylene glycol poly-racemic lactic acid-glycolic acid copolymer and polytrimethylene carbonate.
5. The composite drug-coated balloon of claim 1, wherein the mass ratio of drug A to hydrophilic excipient in the bottom coating is 1: 0.01-1: 10; in the middle layer coating, the mass ratio of the medicine B to the wrapping agent is 1: 0.05-1: 10; in the outer coating, the mass ratio of the drug C to the lipophilic excipient/amphiphilic excipient is 1: 0.01-1: 20.
6. The composite drug-coated balloon of claim 1, wherein the total concentration of drug in the drug coating is 0.5 μ g/mm2～10μg/mm2。
7. A preparation method of a composite drug-coated balloon, which is used for preparing the composite drug-coated balloon as described in any one of claims 1 to 6, and is characterized by comprising the following steps:
s1, respectively preparing a drug spraying solution A, a drug spraying solution B and a drug spraying solution C;
s2, uniformly spraying the medicine spraying solution A on the surface of a naked sacculus to obtain a bottom coating; then, uniformly spraying the drug spraying solution B on the bottom layer coating to obtain an intermediate layer coating; then uniformly spraying the medicine spraying solution C on the middle layer coating to obtain an outer layer coating;
s3, drying the saccule treated in the step S2 to obtain the composite medicine coating saccule;
wherein, the medicine spraying solution A is obtained by dissolving the medicine A and a hydrophilic excipient in a solvent and filtering; the drug spraying solution C is obtained by dissolving the drug C and lipophilic excipient/amphiphilic excipient in a solvent and filtering;
the preparation method of the drug spraying solution B comprises the following steps (i) or (ii):
(i) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; then ultrasonically spraying the medicine solution B, drying, collecting the medicine particles coated by the coating agent, and dispersing in an aqueous solution or an aqueous solution containing an emulsifying agent to obtain a medicine particle suspension solution; filtering to remove the drug particles with large particle size, and mixing the drug particles with the solution containing the excipient to obtain a drug spraying solution B;
(ii) dissolving the medicine B and the wrapping agent in a solvent to obtain a medicine solution B; dripping the medicine solution B into an aqueous solution containing an emulsifier, and forming to obtain a medicine particle suspension solution coated by a coating agent; filtering to remove the drug particles with large particle size, and mixing into the solution containing the excipient to obtain a drug spraying solution B.
8. The method for preparing a composite drug-coated balloon according to claim 7, wherein the solvent is selected from one or more of ethanol, methanol, acetone, isopropanol, methyl vinyl ketone, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform, n-heptane, methyl acetate, and butyl acetate.
9. The preparation method of the composite drug-coated balloon according to claim 7, wherein in the drug spraying solution A, the concentration of the drug A is 0.5-300 mg/ml; in the medicine solution B, the concentration of the medicine B is 0.5-300 mg/ml; in the medicine spraying solution C, the concentration of the medicine C is 1-50 mg/ml.
10. The preparation method of the composite drug-coated balloon according to claim 7, wherein in the step (i), the ultrasonic spraying conditions are as follows: the ultrasonic spraying power is 0.1-3W, and the flow of the drug solution conveyed by the injection pump is 0.01-10 ml/min; the particle size of the drug particles coated by the coating agent is 10 nm-8 μm.
11. The preparation method of the composite drug-coated balloon according to claim 7, wherein in the steps (i) and (ii), the emulsifier is selected from one or more of polyvinyl alcohol, polysorbate, vitamin, polyethylene glycol succinate and polyoxyethylene polyoxypropylene ether block copolymer, and the concentration of the emulsifier in the emulsifier-containing aqueous solution is 0.1-10 wt%.
12. The method for preparing the composite drug-coated balloon according to claim 7, wherein in the step (ii), the molding treatment comprises ultrasonic emulsification, high-speed dispersion homogenization, membrane emulsification and micelle molding; in the medicament particle suspension solution coated by the coating agent, the particle size of the medicament suspension particles is 10 nm-8 mu m.
13. The method for preparing a composite drug-coated balloon according to claim 7, wherein in the steps (i) and (ii), the particle size of the drug particles in the drug spraying solution B is 10 nm-8 μm.
14. The method for preparing a drug-coated balloon according to claim 7, wherein in step S2, the spraying is performed by an ultrasonic spraying process, and the ultrasonic spraying process parameters are as follows: the ultrasonic spraying power is 0.2-3W, the flow of the drug solution conveyed by the injection pump is 0.01-1.0 ml/min, the spraying temperature is 20-55 ℃, the spraying air pressure is 0.01-0.5 MPa, and the spraying height is 5-100 mm.
15. A composite drug-coated balloon dilatation catheter comprising the composite drug-coated balloon of any of claims 1-6.
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