CN118267534A

CN118267534A - Drug delivery device, therapeutic system, and method of administering drug into a blood vessel

Info

Publication number: CN118267534A
Application number: CN202211717150.5A
Authority: CN
Inventors: 请求不公布姓名
Original assignee: Hangzhou Juzheng Medical Technology Co ltd
Current assignee: Hangzhou Juzheng Medical Technology Co ltd
Priority date: 2022-12-29
Filing date: 2022-12-29
Publication date: 2024-07-02

Abstract

The application discloses a drug-carrying device, a treatment system and a method for administering drugs into blood vessels. The drug-carrying device comprises a deformation body, wherein a drug coating is arranged on the surface of the deformation body, and the drug coating comprises a first drug coating and a second drug coating; the first drug coating comprises a first agent which is riboflavin and/or a riboflavin salt; the second drug coating includes a second agent that is an inhibitor that inhibits intimal hyperplasia. The drug-carrying device can be used for applying the riboflavin which can generate the endogenous micro-stent in situ on the wall of the blood vessel and the inhibitor for inhibiting the proliferation of the intima of the blood vessel at the preset position in the blood vessel, so that the occurrence of restenosis of the blood vessel after operation can be effectively prevented, and the adverse reaction of treatment can be reduced.

Description

Drug delivery device, therapeutic system, and method of administering drug into a blood vessel

Technical Field

The application relates to the technical field of medical instruments, in particular to a drug carrying device, a treatment system and a method for applying drugs into blood vessels.

Background

Angioplasty balloons can be applied to open calcified lesions in the arterial wall, one of the main ways of arterial stenosis revascularization. However, vascular dilation can lead to injury to the vessel wall, thereby initiating thrombosis and release of growth factors, which can lead to restenosis or subsequent reclosing of the dilated vessel.

At present, the above problems are mainly solved by implanting a vascular stent in a blood vessel, and the existing vascular stent is mainly made of biocompatible metal, but implantation of the metallic stent may cause intimal hyperplasia in the blood vessel lumen, so that the lumen may be narrowed again despite placement of the stent. Because the sites of the intima where endothelial cells are less covered are more prone to thrombosis, antithrombotic drugs must be administered for a long period of time (i.e., about half a year) after surgery, and there is a risk of late thrombosis and restenosis after cessation of drug administration despite such antithrombotic drugs.

Disclosure of Invention

In view of the problems of the prior art, the present application provides a drug delivery device comprising a deformation body, the surface of the deformation body being provided with a drug coating, the drug coating comprising a first drug coating and a second drug coating;

the first drug coating comprises a first agent which is riboflavin and/or a riboflavin salt;

the second drug coating includes a second agent that is an inhibitor that inhibits intimal hyperplasia.

Optionally, the second agent is at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42- (dimethylphosphino) rapamycin (deforolimus), dipholimus, bimimus (biolimus), aconitimost (umirolimus), tacrolimus, paclitaxel, protamine (protaxel), and docetaxel.

Optionally, the second drug coating is disposed outside the first drug coating along a radial direction of the deformation body.

Optionally, the thickness of the first drug coating is 0.5-100 μm; preferably 1 to 50. Mu.m.

Optionally, the thickness of the second drug coating is 0.5-100 μm, preferably 1-30 μm.

Optionally, the total thickness of the drug coating is 1-200 μm; preferably 2 to 80. Mu.m.

Optionally, the first agent is used in an amount of 0.5 to 10 μg/mm ² per unit balloon surface area; preferably 1-5 mug/mm ²;

Optionally, the second agent is used in an amount of 0.5 to 10 μg/mm ² per unit balloon surface area; preferably 1 to 5. Mu.g/mm ².

Optionally, the loading method of each drug coating comprises the following steps:

Preparing the solution of each drug coating in advance by using a solvent, coating each solution on the surface of the deformed body according to a preset sequence, and drying.

Optionally, the solvent is at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane and n-heptane.

Alternatively, the coating is performed by spraying or dipping.

Optionally, each drug coating further comprises a carrier.

Optionally, the carrier is at least one of polyethylene glycol, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polysorbate, polyvinylpyrrolidone, magnesium stearate, urea, butyryl citrate tri-n-hexyl ester, iopromide, ethyl cellulose, methylparaben, ethylparaben, acetyl tributyl citrate, glyceryl stearate, diethyl pyrocarbonate (DEPC), distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG), cholesterol, phospholipid, polylactic acid-glycolic acid copolymer (PLGA), shellac, and pectin.

Optionally, the carrier is a micelle, liposome, microsphere or nanoparticle formed by the raw materials.

Optionally, the mass ratio of the first reagent, the carrier and the solvent (10-45): (10-45): (10-80). Preferably (30-45): (30-45): (10-40).

Optionally, the mass ratio of the second reagent, the carrier and the solvent (30-49): (30-49): (2-40). Preferably (45-49): (45-49): (2-10).

Optionally, the variant is a balloon.

Optionally, the drug delivery device comprises:

The deformation body is provided with opposite inflation states and contraction states suitable for interventional delivery;

A catheter having opposite distal and proximal ends, wherein the distal end is in communication with the deformed body for delivering a fluid into the deformed body.

The present application also provides a therapeutic system comprising:

A drug delivery device comprising a shape-changing body having an opposed, inflated state and a contracted state suitable for interventional delivery, the surface of the shape-changing body being provided with a first drug coating and a second drug coating, the first drug coating comprising a first agent which is riboflavin and/or a riboflavin salt, the second drug coating comprising a second agent which is an inhibitor of vascular intimal hyperplasia, the catheter having opposed distal and proximal ends, wherein the distal end is in communication with the shape-changing body for delivering a fluid into the shape-changing body;

One end of the light guide element extends to the light emitting end of the deformation body, and the other end of the light guide element is a light entering end extending to the proximal end through the catheter;

the light source device is connected with the light inlet end of the light guide element by adopting a light path.

The present application also provides a method of administering an agent intravascularly comprising:

Administering a first agent which is riboflavin and/or a riboflavin salt and a second agent which is an inhibitor for inhibiting vascular intimal hyperplasia to a predetermined location in a blood vessel;

After the first agent is administered, light is applied to the predetermined location, and the first agent is activated to cause the first agent to act on the predetermined location to form the vascular in-situ stent.

Alternatively, the method of administering each agent is: a coating is applied and delivered to the predetermined location by an interventional device.

Optionally, the second agent and the first agent are administered sequentially at predetermined locations.

Optionally, the wavelength of the applied light is 300-700 nm; preferably 400 to 500nm.

Optionally, the illumination intensity is 5-500 mW/cm ²; preferably 100-500 mW/cm ²;

optionally, the application time is 0.1-30 min; preferably 1 to 5 minutes.

Compared with the prior art, the drug-loading device can apply the riboflavin which can generate the endogenous micro-stent in situ on the vessel wall at the preset position in the vessel, and the inhibitor for inhibiting the proliferation of the intima of the vessel, and the combination of the riboflavin and the inhibitor can effectively prevent restenosis of the vessel and reduce adverse reaction of treatment.

Drawings

FIG. 1 is a schematic diagram of a drug delivery device according to an embodiment;

FIG. 2 is a schematic view of another embodiment of a drug delivery device;

FIG. 3 is a flow chart of a method of intravascularly administering an agent in one embodiment;

FIG. 4 is an artificial view of a preoperative peripheral blood vessel according to application example 1;

FIG. 5 is a view of a peripheral blood vessel after the operation of application example 1;

FIG. 6 is an artificial view of a peripheral blood vessel before operation in application example 2;

FIG. 7 is a view of a peripheral blood vessel after the operation of application example 2;

FIG. 8 is an ostomy of the peripheral blood vessel before the operation of comparative example 1;

FIG. 9 is a contrast map of the peripheral blood vessel after the operation of comparative example 1;

FIG. 10 is an ostomy of the peripheral blood vessel before the operation of comparative example 2;

FIG. 11 is a contrast map of the peripheral blood vessel after the operation of comparative example 2;

Reference numerals in the drawings are described as follows:

10. A variant;

20. A conduit;

30. A light guide element; 31. a light emitting end; 32. a light inlet end;

40. a light source device;

50. a drug coating; 51. a first drug coating; 52. a second drug coating;

60. A vessel wall.

Detailed Description

The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.

It will be understood that when an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present. When an element is referred to as being "disposed on" another element, it can be directly on the other element or intervening elements may also be present.

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 application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

As shown in fig. 1, a drug delivery device according to an embodiment of the present application includes a shape body 10, such as a balloon body, having a drug coating 50 on a surface thereof, wherein the drug coating 50 includes a first drug coating 51 and a second drug coating 52. Wherein the first drug coating 51 comprises a first agent, the first agent being riboflavin and/or a riboflavin salt; the second drug coating 52 includes a second agent that is an inhibitor of vascular intimal hyperplasia.

During the interventional procedure, the deformation body 10 is delivered to a predetermined location of the blood vessel and the deformation body 10 is driven to deform to expose each of the drug coatings 50, thereby releasing the first and second agents. Wherein, the first reagent is used for crosslinking proteins and polypeptides in the blood vessel wall 60, generating an endogenous micro-stent on the blood vessel wall 60 in situ, effectively inhibiting elastic retraction and preventing restenosis of the blood vessel after operation. The second agent can inhibit proliferation of intimal hyperplasia caused by smooth muscle cell hyperproliferation, thereby promoting proliferation of endothelial cells, and has effects of preventing and treating vascular restenosis.

In particular, the riboflavin salt may be riboflavin 5' - (dihydrogen phosphate) monosodium salt dihydrate, and the content of riboflavin (C17H 20N4O 6) should be 74.0% -79.0%.

The second agent may be at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42- (dimethylphosphino) rapamycin (deforolimus), dipholimus, bimolimus (biolimus), ulimoraxe (umirolimus), tacrolimus, paclitaxel, pramoxine (protaxel), and docetaxel. Wherein rapamycin, sirolimus, everolimus, zotarolimus, 42- (dimethylphosphino) rapamycin, diphospolimus, bimatose, ulimorelin and tacrolimus are cytostatic drugs, and paclitaxel, pramoxine and docetaxel are antiproliferative drugs.

The balloon can be a balloon commonly used in OTW (coaxial exchange) and RX (rapid exchange). The coverage of the drug coating 50 may be all or a partial surface of the balloon, e.g. the balloon has a folded-over configuration in which the drug coating 50 is only disposed.

The order in which the drug coatings 50 are disposed on the surface of the deformed body 10 affects the release of the drug and thus the final therapeutic effect. In one embodiment, the second drug coating 52 is disposed outside the first drug coating 51 in the radial direction of the deformed body 10. This arrangement reduces the loss of the first agent during intervention of the variant 10 into the blood vessel, ensuring a concentration of the first agent released at the predetermined location of the blood vessel.

In one embodiment, the thickness of the first drug coating 51 is 0.5-100 μm. Preferably 1 to 50. Mu.m. The thickness of the second drug coating layer 52 is 0.5 to 100 μm, preferably 1 to 30 μm.

The drug coatings 50 are generally arranged according to the expected drug loading, but the total thickness of the drug coatings 50 should not be too large, and the excessive thickness can significantly increase the compression size of the balloon body, so that not only is the intervention difficulty increased, but also the drug coatings 50 can fall off due to friction in the intervention process, so that the total thickness of the drug coatings 50 should be controlled to be 1-200 μm, preferably 2-80 μm.

The amount of each agent applied per unit balloon surface area affects the therapeutic effect, and in one embodiment the amount of the first agent is 0.5 to 10 μg/mm ², calculated as riboflavin, relative to the unit balloon surface area; preferably 1 to 5. Mu.g/mm ². The concentration in the range can ensure the formation of the vascular micro-stent with high bonding strength, effectively inhibit the elastic retraction of blood vessels and prevent the occurrence of restenosis of blood vessels after operation.

The second agent is used in an amount of 0.5 to 10 μg/mm ² per unit balloon surface area. Preferably 1 to 5. Mu.g/mm ².

In one embodiment, each drug coating 50 further comprises a carrier. The carrier may be at least one of polyethylene glycol, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polysorbate, polyvinylpyrrolidone, magnesium stearate, urea, butyryl tri-n-hexyl citrate, iopromide, ethyl cellulose, methylparaben, ethylparaben, acetyl tributyl citrate, glyceryl stearate, shellac, pectin, diethyl pyrocarbonate (DEPC), distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG), cholesterol, phospholipid, and polylactic acid-glycolic acid copolymer (PLGA).

The dose is usually determined according to the condition of the intravascular lesion, but the experimental process finds that the expected curative effect is not achieved after the administration according to the preset dose, and researches find that the reason is that the active drug is released from the surface of the deformed body 10 into blood quickly, and the concentration change trend of the free active drug in the body is not ideal, namely, the concentration decrease trend of the free active drug is faster than the utilization rate of the drug of tissues or cells. To solve this problem, in one embodiment, the carrier material is used to form micelles, liposomes, microspheres or nanoparticles to encapsulate the agent, so as to achieve a sustained release effect.

For example, in one embodiment, the carrier is a liposome, the liposome is a hollow sphere composed of phospholipids and other lipid compounds, and the specific type of liposome is a plurality of, for example, phospholipid-cholesterol liposome, which has good biocompatibility and can be successfully endocytosed by cells, so that the active drug can be smoothly transported into the cells. Depending on the structural choice, the liposomes may be unilamellar, multilamellar or multilamellar. Depending on the performance choice, the liposome may be a thermosensitive liposome, a pH-sensitive liposome, an ultrasound-sensitive liposome, or a magnetic liposome. From the standpoint of endocytosis, the liposome particle size is required to be 5 μm or less. The phospholipid for preparing liposome can be soybean lecithin, egg yolk lecithin, dipalmitoyl phosphatidylcholine or distearoyl phosphatidylcholine, etc.; other lipid compounds) are cholesterol, octadecylamine or phosphatidic acid.

There are many ways of loading each drug coating 50, and in one embodiment, each drug coating 50 is prepared in advance with a solvent, and each solution is applied to the surface of the deformed body 10 in a predetermined order and dried. For example, a solution containing a first agent is applied to the surface of the deformed body 10 and dried to form a first drug coating 51, and a solution containing a second agent is applied to the first drug coating 51 and dried to form a second drug coating 52.

The above solution may be at least one of water, methanol, ethanol, formic acid, acetic acid, acetonitrile, isopropanol, acetone, ethyl acetate, n-hexane, cyclohexane, dichloromethane, methyl acetate, butyl acetate, carbon tetrachloride, butanone, n-hexane, n-pentane and n-heptane.

The coating mode can be spray coating or dip coating.

Wherein, the concentration of the first reagent in the solution is 0.2-1.2 mg/mL based on riboflavin. The concentration of the second reagent in the solution is 0.5-60 mg/mL based on the inhibitor.

The mass ratio of the first reagent to the carrier to the solvent is (10-45): 10-80. Preferably (30-45): (30-45): (10-40).

The mass ratio of the second reagent to the carrier to the solvent is (30-49): 2-40. Preferably (45-49): (45-49): (2-10).

Specifically, for example, in one embodiment, DEPC, DSPE-mPEG2000 and cholesterol are dissolved in a solvent to obtain a dispersion A; the first agent or the second agent is dispersed in the dispersion a to prepare a corresponding solution of the drug coating 50. In this preparation, the first agent or the second agent is entrapped in the liposomes formed.

In another embodiment, the polylactic acid-glycolic acid copolymer and the first reagent or the second reagent are dispersed in a solvent to obtain a dispersion liquid B; preparing a polyvinyl alcohol aqueous solution; the dispersion B is mixed with an aqueous solution of polyvinyl alcohol, and the first reagent or the second reagent is encapsulated in the microspheres formed during the mixing process. These reagent-containing microspheres can be washed and dried to prepare a solution of the drug coating 50.

As shown in fig. 1, the drug delivery device of the present application further comprises a catheter 20 having opposite distal and proximal ends, wherein the distal end is in communication with the deformation body 10 for delivering a fluid, such as saline or the like, into the deformation body 10. In operation, the deformation body 10 has a relatively contracted state suitable for interventional delivery and an inflated state formed by the delivery fluid. In the inflated state, the agents of the coating are released in the blood.

As shown in fig. 2, the present application further provides a therapeutic system, which includes the above-mentioned drug delivery device, the light guiding element 30, and the light source device 40. One end of the light guiding element 30 extends to the light emitting end 31 of the deformable body 10, and the other end is a light incident end 32 extending proximally through the catheter 20. The light source device 40 is optically connected to the light entrance end 32 of the light guide element 30. In this embodiment, the first agent is riboflavin and/or a riboflavin salt, which is an anti-restenosis agent, and the light source device 40 is capable of emitting light beams of a specific wavelength, which penetrate the inner wall of the variant 10 and act on the vessel wall 60, thereby activating the riboflavin, which is capable of promoting the collagen or other proteins on the wall of the tissue to attach, thereby forming the vascular micro-stent in situ at a predetermined location.

As shown in fig. 3, the present application also provides a method of administering an agent intravascularly, comprising:

Step S10: administering a first agent and a second agent to a predetermined location in the blood vessel, the first agent being riboflavin and/or a riboflavin salt, the second agent being an inhibitor that inhibits intimal hyperplasia;

step S20: after administration of the first agent, light is applied to the predetermined location, and the first agent is activated to effect the first agent to the predetermined location to form the vascular in-situ stent.

The method of administering each agent may be: the coating is applied and delivered to a predetermined location by an interventional device. The interventional device may be a drug delivery device or a therapeutic system as described above.

The order of administration of the two agents affects the therapeutic effect, and in one embodiment, the second agent and the first agent are administered sequentially at predetermined locations. This sequence of application also determines the order in which the above-described first 51 and second 52 drug coatings are disposed on the deformed body 10.

To avoid photolysis of the released second reagent, in one embodiment, the wavelength of the applied light is 300-700 nm; preferably 400 to 500nm. The illumination intensity is 5-500 mW/cm ²; preferably 100-500 mW/cm ²; the application time is 0.1-30 min; preferably 1 to 5 minutes.

A number of preparation examples are provided further below, each of which is commercially available.

Preparation example 1

(1) Preparing a solution of a first drug coating:

thoroughly mixing 32mg of polyethylene glycol with 2mL of acetic acid to prepare a carrier solution; 32mg of riboflavin was added to the carrier solution and sonicated to prepare a solution of the first drug coating.

(2) Preparing a solution of a second drug coating:

Dissolving 40mg of DEPC, 5mg of DSPE-mPEG2000 and 5mg of cholesterol in 5mL of n-heptane, ultrasonically dissolving, weighing 50mg of rapamycin in the solution, and performing vortex ultrasonic dispersion to prepare a solution of a second drug coating;

(3) Firstly, spraying a solution of a first drug coating on the surface of a balloon body (in an inflated state) and drying, wherein the spraying amount is 3 mug/mm ² based on riboflavin, and the thickness of the formed first drug coating is 14 mu m;

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 2 mug/mm ² calculated by rapamycin, and the thickness of the formed second drug coating is 10 mu m.

(4) Vacuumizing the saccule body, split folding, and performing heat setting at 50 ℃ for 10min to obtain the medicine carrying saccule.

Preparation example 2

(1) Preparing a solution of a first drug coating:

Thoroughly mixing 32mg of polyethylene glycol with 2mL of acetic acid to prepare a carrier solution; adding 32mg of riboflavin into a carrier solution for ultrasonic oscillation to prepare a solution of a first drug coating;

(2) Preparing a solution of a second drug coating:

250mg of PLGA and 250mg of rapamycin were dissolved in 10mL of methylene chloride and vortexed until the PLGA was completely dissolved. 10g of PVA was dissolved in 1000mL of water to prepare a PVA solution. 40mL of PVA solution was measured and PLGA-rapamycin mixed solution was added thereto during homogenization. After homogenization was completed, it was added to a beaker containing 160mL of PVA solution and stirred for 3h. Centrifugal cleaning with deionized water for 3 times, discarding supernatant, washing and drying to obtain rapamycin microsphere. 50mg of rapamycin microspheres were uniformly dispersed in 5mL of n-heptane to prepare a solution of the second drug coating.

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 2 mug/mm ² calculated by rapamycin and the thickness of the formed second drug coating is 8 mu m.

Preparation example 3

(1) Preparing a solution of a first drug coating:

(2) Preparing a solution of a second drug coating:

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 3 mug/mm ² calculated by rapamycin and the thickness of the formed second drug coating is 15 mu m.

Preparation example 4

(1) Preparing a solution of a first drug coating:

thoroughly mixing 32mg of polyethylene glycol with 2mL of acetic acid to prepare a carrier solution; adding 32mg of riboflavin into carrier solution, and performing ultrasonic oscillation to obtain first medicinal coating solution

(2) Preparing a solution of a second drug coating:

(3) Firstly, spraying a solution of a first drug coating on the surface of a balloon body (in an inflated state) and drying, wherein the spraying amount is 3 mug/mm ² based on riboflavin, and the thickness of the formed first drug coating is 15 mu m;

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 3 mug/mm ² calculated by rapamycin, and the thickness of the formed second drug coating is 16 mu m.

Preparation example 5

(1) Preparing a solution of a first drug coating:

(2) Preparing a solution of a second drug coating:

40mg of DEPC, 5mg of DSPE-mPEG2000 and 5mg of cholesterol are dissolved in 5mL of n-heptane, 50mg of paclitaxel is weighed into the solution after ultrasonic dissolution, vortex ultrasonic dispersion is carried out, and a solution of a second medicament is prepared.

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 2 mug/mm ² in terms of taxol, and the thickness of the formed second drug coating is 8 mu m.

Preparation example 6

(1) Preparing a solution of a first drug coating:

fully mixing 32mg of polyethylene glycol with 2mL of acetic acid to prepare a carrier solution; adding 32mg of riboflavin into a carrier solution for ultrasonic oscillation to prepare a solution of a first drug coating;

(2) Preparing a solution of a second drug coating:

250mg of PLGA and 250mg of paclitaxel were dissolved in 10mL of dichloromethane and vortexed until the PLGA was completely dissolved. 10g of PVA was dissolved in 1000mL of water to prepare a PVA solution. 40mL of PVA solution was measured and PLGA-paclitaxel mixed solution was added thereto during homogenization. After homogenization was completed, it was added to a beaker containing 160mL of PVA solution and stirred for 3h. Centrifugal cleaning with deionized water for 3 times, discarding supernatant, washing, and drying to obtain taxol microsphere. 50mg of paclitaxel microspheres were uniformly dispersed in 5mL of n-heptane to prepare a solution of the second drug coating.

(3) Firstly, spraying a riboflavin solution on the surface of a balloon body (in an inflated state) and drying, wherein the spraying amount is 3 mug/mm ² based on the riboflavin, and the thickness of a formed first medicine coating is 15 mu m;

And spraying a solution of the second drug coating on the formed first drug coating, and drying, wherein the spraying amount is 2 mug/mm ² in terms of taxol, and the thickness of the formed second drug coating is 9 mu m.

Preparation example 7

Referring to preparation example 3, a solution of the first drug coating was prepared, and the first drug coating was provided only on the surface of the balloon body.

Preparation example 8

Referring to preparation example 3, a solution of the second drug coating was prepared, and the second drug coating was provided only on the surface of the balloon body.

Application example 1

The effectiveness of the drug balloon was studied using a porcine overstretched peripheral vascular model. In the pig peripheral blood vessel model, the balloon of preparation example 3 was pushed into the blood vessel, the balloon in a compressed state was inflated by perfusion fluid under a pressure of 6atm, then the light guide element emitted light of 450nm wavelength under the pressure of the balloon, the light curing time was 3 minutes, and the balloon was withdrawn from the blood vessel after illumination. After 28 days, changes in lumen gain and neointimal area control were measured from tissue morphology.

Application example 2

The effectiveness of the drug balloon was studied using a porcine overstretched peripheral vascular model. In the pig peripheral blood vessel model, the balloon of preparation example 4 was pushed into the blood vessel, the balloon in a compressed state was inflated by perfusion fluid under a pressure of 6atm, then the light guide element emitted light of 450nm wavelength under the pressure of the balloon, the light curing time was 3 minutes, and the balloon was withdrawn from the blood vessel after illumination. After 28 days, changes in lumen gain and neointimal area control were measured from tissue morphology.

Comparative example 1

The effectiveness of the drug balloon was studied using a porcine overstretched peripheral vascular model. In the pig peripheral blood vessel model, the balloon of preparation 7 was pushed into the blood vessel, the balloon in a compressed state was inflated by perfusion fluid under a pressure of 6atm, then the light guide element emitted light of 450nm wavelength under the pressure of the balloon, the light curing time was 3 minutes, and the balloon was withdrawn from the blood vessel after illumination. After 28 days, changes in lumen gain and neointimal area control were measured from tissue morphology.

Comparative example 2

The effectiveness of the drug balloon was studied using a porcine overstretched peripheral vascular model. In the pig peripheral blood vessel model, the balloon of preparation 8 was pushed into the blood vessel, the balloon in a compressed state was inflated by perfusion fluid under a pressure of 6atm, then the light guide element emitted light of 450nm wavelength under the pressure of the balloon, the light curing time was 3 minutes, and the balloon was withdrawn from the blood vessel after illumination. After 28 days, changes in vascular lumen gain and neointimal area control were measured from tissue morphology.

TABLE 1 vascular lumen gain Condition

As can be seen from table 1 and fig. 3 to 11, the post-operative lumen gain effects of application example 1 and application example 2 are significantly better than those of comparative example 2. Compared with comparative example 1, the post-operation lumen gain effect of application example 2 can be leveled, and the post-operation lumen gain effect of application example 1 is obviously better.

In summary, the use of the composite drug coated balloon in the pig model resulted in a significant decrease in lumen gain and neointimal area, which resulted in a sustained decrease in neointimal formation and prevention of restenosis.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description. When technical features of different embodiments are embodied in the same drawing, the drawing can be regarded as a combination of the embodiments concerned also being disclosed at the same time.

The above examples merely represent a few embodiments of the present application, which are described in more detail and are not to be construed as limiting the scope of the patent. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the application, which are all within the scope of the application. Accordingly, the scope of the application should be assessed as that of the appended claims.

Claims

1. The drug-carrying device is characterized by comprising a deformation body, wherein a drug coating is arranged on the surface of the deformation body, and the drug coating comprises a first drug coating and a second drug coating;

2. The drug delivery device of claim 1, wherein the second agent is at least one of rapamycin, sirolimus, everolimus, zotarolimus, 42- (dimethylphosphino) rapamycin, dipholimus, bimolimus, aconitum, tacrolimus, paclitaxel, pramoxine, and docetaxel.

3. The drug delivery device of claim 1, wherein the second drug coating is disposed outside of the first drug coating in a radial direction of the shape modification.

4. The drug delivery device of claim 1, wherein the loading method of each drug coating comprises:

Preparing solution of each drug coating in advance by using a solvent, coating each solution on the surface of the deformed body according to a preset sequence, and drying;

The thickness of each drug coating is 0.5-100 mu m; the total thickness of the drug coating is 1-200 mu m.

5. The drug delivery device of claim 1, wherein each agent is used in an amount of 0.5 to 10 μg/mm ² per unit balloon surface area.

6. The drug delivery device of claim 1, wherein each drug coating further comprises a carrier;

The carrier is micelle, liposome, microsphere or nanoparticle formed by raw materials.

7. The drug delivery device of claim 1, wherein the drug delivery device comprises:

8. A therapeutic system, comprising:

9. A method of intravascularly administering a drug comprising:

10. The method of claim 9, wherein the method of administering each agent is: applying a coating and delivering to the predetermined location by an interventional device;

the second agent and the first agent are sequentially administered at a predetermined location.