CN109010931B

CN109010931B - Interventional medical device and application of aphidicolin

Info

Publication number: CN109010931B
Application number: CN201710433315.9A
Authority: CN
Inventors: 王玄; 李俊菲; 陈陆
Original assignee: Shanghai Microport Medical Group Co Ltd
Current assignee: Shanghai Microport Medical Group Co Ltd
Priority date: 2017-06-09
Filing date: 2017-06-09
Publication date: 2022-03-11
Anticipated expiration: 2037-06-09
Also published as: CN109010931A

Abstract

The invention relates to an interventional medical device and application of aphidicolin. The interventional medical device comprises a device body and a medicine loaded on the device body. The active drug in the medicament is selected from at least one of aphidicolin, pharmaceutically acceptable salts of aphidicolin, solvates of aphidicolin and aphidicolin derivatives. The inventor researches and unexpectedly finds that when the aphidicolin is loaded on the surface of an interventional device, the growth of smooth muscle cells can be effectively inhibited, the intima of a blood vessel is not obviously proliferated, and the toxicity to peripheral cells is low, so that a new choice is provided for preventing or treating restenosis after percutaneous transluminal angioplasty.

Description

Interventional medical device and application of aphidicolin

Technical Field

The invention relates to the field of medical instruments, in particular to an interventional medical instrument and application of aphidicolin.

Background

Percutaneous transluminal angioplasty is the most effective means for treating vascular blockage at present, however, after percutaneous transluminal angioplasty is carried out by using a traditional metal bare stent, the stent expansion easily causes transitional hyperplasia of vascular smooth muscle cells, and vascular restenosis can be generated with the probability of 20% -30% after the operation, so that secondary danger is caused. Other interventional medical devices, such as occluders, artificial valves, etc., may also cause cell proliferation at the interventional site if damage is caused to the endothelium of the interventional site tissue during the interventional treatment operation, which affects the interventional treatment effect. Some methods are to load drugs with toxic action on cells on the surface of the device to inhibit the proliferation of the cells, such as arsenic and paclitaxel, and these drug stents can inhibit the proliferation of the cells to a certain extent and reduce the incidence of restenosis. However, these drugs have toxic side effects on other organs in the body or generally require higher concentrations to achieve the purpose of preventing or treating restenosis, and bring certain toxic side effects.

Disclosure of Invention

Based on this, there is a need for an interventional medical device with less toxic and side effects and the use of aphidicolin.

An interventional medical device comprising a device body and a drug carried on the device body, the drug comprising an active drug for preventing or treating restenosis, the active drug being selected from at least one of aphidicolin, a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin and an aphidicolin derivative.

In one embodiment, the pharmaceutically acceptable salt of aphidicolin is aphidicolin glycinate and/or the aphidicolin derivative is 3-deoxy-aphidicolin or 2-oxo-1, 3, 2-dioxathiolane aphidicolin.

In one embodiment, the active agent is applied directly to the surface of the device body.

In one embodiment, the device body is provided with a hole on a surface thereof, and the active agent is disposed in the hole.

In one embodiment, the active agent is distributed over the surface of the device in an amount of 100ng/mm²～100μg/mm²。

In one embodiment, the medicament further comprises an auxiliary medicament, and the active medicament is formulated with the auxiliary medicament.

In one embodiment, the co-drug is rapamycin or paclitaxel.

In one embodiment, the medicament further comprises a medicament carrier, and the mass ratio of the medicament carrier to the active medicament is 0.1-10: 1.

In one embodiment, the device body is a stent, balloon or vascular prosthesis.

Use of aphidicolin, a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin and an aphidicolin derivative as active drug for the manufacture of a medicament or medical device for the prevention or treatment of restenosis.

In one embodiment, the active agent is attached to the surface of the medical device to form a drug layer, and the active agent is distributed on the surface of the medical device in an amount of 100ng/mm per unit area²～100μg/mm²。

In one embodiment, the use is characterized in that the active drug is formulated with an adjuvant drug.

In one embodiment, the adjuvant is rapamycin or paclitaxel.

The interventional medical device comprises a device body and a medicine loaded on the device body. The medicament includes an active drug selected from at least one of aphidicolin, pharmaceutically acceptable salts of aphidicolin, solvates of aphidicolin and aphidicolin derivatives. Aphidicolin (aphiicolin) is commonly used as an anticancer drug or an antiviral drug, and Aphidicolin can also be used as an anticancer auxiliary drug to improve the treatment effect of the anticancer drug, especially the anticancer drug aiming at ovarian cancer, but research reports on the use of Aphidicolin for preventing or treating restenosis are not available. The inventor researches and unexpectedly finds that when the aphidicolin is loaded on the surface of an interventional device, the intima of a blood vessel has no obvious hyperplasia and has low toxicity to surrounding cells, thereby providing a new choice for preventing or treating restenosis after percutaneous transluminal angioplasty.

Drawings

FIG. 1 is a photograph showing staining of cells cultured in a medium containing aphidicolin and cells cultured in a medium without aphidicolin, which are observed under a fluorescent microscope;

FIG. 2 is an angiogram of the vessel 6 months after implantation of an aphidicolin loaded stent;

FIG. 3 is an angiogram of the blood vessel 6 months after implantation of the L605 bare stent;

FIG. 4 is an SEM image of a stent section vessel 6 months after implantation of an aphidicolin loaded stent;

FIG. 5 is an SEM image of a stent section vessel 6 months after implantation of a L605 bare stent;

FIG. 6 is a photograph of a pathological section of a blood vessel 6 months after implantation of an aphidicolin loaded stent;

fig. 7 is a photograph of a pathological section of a blood vessel 6 months after implantation of a L605 bare stent.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.

The "interventional medical device" referred to in the present invention may be a device implanted in the body. The device may be used temporarily for a short period of time, or permanently implanted for a long period of time. In certain embodiments, suitable devices are those typically used to provide medical treatment and/or diagnosis for heart rhythm disorders, heart failure, valvular diseases, vascular diseases, diabetes, neurological diseases and disorders, orthopedic surgery, neurosurgery, oncology, ophthalmology, and ENT procedures. Medical devices to which the present invention relates include, but are not limited to, the following: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, leads, catheters, sensors, surgical instruments, angioplasty balloons, wound drains, shunt tubes (shunts), tubes, infusion sleeves (infusion sleeves), urethral cannulas, pellets, implants, blood oxygenators, pumps, vascular grafts, embedded intervention cartridges (vasular access ports), heart valves, annuloplasty rings, sutures, surgical clips, surgical staples, pacemakers, implantable defibrillators, neurostimulators, orthopedic devices, cerebrospinal fluid shunts, implantable drug pumps, vertebral cages, artificial intervertebral discs, nucleus pulposus replacement devices, ear tubes, intraocular lenses, and any tube used in interventional procedures. Preferably, the interventional medical device to which the present invention relates is, in particular: a stent, balloon, occluder, valve or vascular prosthesis.

The activity contemplated by the present invention may be associated with or carried on the surface of a medical device by a variety of processes such as dipping, spraying, washing, vapor deposition, brushing, rolling and other methods known in the art.

Use of one embodiment of aphidicolin, a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin or an aphidicolin derivative, at least one of which is used as an active drug in the manufacture of a medicament or medical device for the prevention or treatment of restenosis.

Aphidicolin (aphiicolin) is an antibiotic of tetracyclic diterpene tetraols, can be extracted from mold such as Neurospora nigrospora and cephalosporins, and can also be synthesized by chemical method. It has been shown that aphidicolin acts directly on the DNA polymerases α, δ, and e during the S phase of cell division, inhibiting DNA replication, and acting to inhibit the proliferation of eukaryotic cells (particularly other than some yeast-like eukaryotic cells that are not allowed to infiltrate into the cell) and some animal viruses (e.g. SV40, herpes viruses and vaccinia viruses). African doxycycline is often used as an anticancer drug or antiviral drug, and African doxycycline can also be used as an anticancer adjuvant drug to improve the therapeutic effect of the anticancer drug, especially the anticancer drug for ovarian cancer. However, there are few studies on the mechanism of action of aphidicolin on the prevention or treatment of restenosis, and there is no report on the use of aphidicolin in the prevention or treatment of restenosis. The inventor researches and unexpectedly finds that when the aphidicolin is loaded on the surface of an interventional medical device, the intima of a blood vessel has no obvious hyperplasia, and in addition, the aphidicolin has reversible inhibiting effect on DNA synthesis of eukaryotic cells, has no inhibiting effect on RNA synthesis and protein synthesis, does not cause permanent damage to peripheral cells and has low toxicity to the peripheral cells, thereby providing a new choice for preventing or treating restenosis after percutaneous transluminal angioplasty.

In one embodiment, for use, aphidicolin may be applied alone as an active drug to a medicament or medical device for the prevention or treatment of restenosis.

Specifically, aphidicolin has the following structural formula (1):

aphidicolin of formula (1) with molecular formula C₂₀H₃₄O₄. Specifically, aphidicolin, as shown in structural formula (1), can be coated on the surface of the device and inserted into the lumen of the blood vessel, thereby preventing restenosis after percutaneous transluminal angioplasty.

In another embodiment, the aphidicolin may also be configured as a pharmaceutically acceptable salt of aphidicolin or a solvate of aphidicolin for use in a medicament or medical device for the prevention or treatment of restenosis. Aphidicolin is formulated in the form of a salt or solvate to increase the solubility properties of aphidicolin. In particular, a pharmaceutically acceptable salt of aphidicolin is, for example, aphidicolin glycinate. The solvate of aphidicolin is, for example, a solvate of aphidicolin with an organic solvent, such as ethanol, methanol, dimethyl sulfoxide (DMSO), or dichloromethane.

In another embodiment, aphidicolin may also be modified in some groups to form aphidicolin derivatives for use in drugs or medical devices for the prevention or treatment of restenosis. In particular, the aphidicolin derivative is for example 3-deoxy-aphidicolin or 2-oxo-1, 3, 2-dioxathiolane aphidicolin.

Research results show that the aphidicolin, the pharmaceutically acceptable salt of aphidicolin, the solvate of aphidicolin or the aphidicolin derivative are loaded on the surface of the device and intervene in the body, which can effectively inhibit the growth of smooth muscle cells, the intima of the blood vessel has no obvious hyperplasia and can not cause permanent damage to the cells around the blood vessel. After the first 6 months that the incidence of restenosis is higher, the DNA replication function of peripheral cells can be recovered, the endothelial repair is completed, and the late thrombosis is prevented, so that the inhibiting effect of the aphidicolin on the DNA synthesis of eukaryotic cells is reversible, thereby providing a new choice for preventing or treating the restenosis after percutaneous transluminal angioplasty.

In one embodiment, the active agent is applied to the surface of the medical device to form a drug layer, such as by coating or the like. The distribution quantity of the active medicine on the surface unit area of the medical appliance is 100ng/mm²～100μg/mm². For example 100ng/mm²、1μg/mm²、10μg/mm²Or 50. mu.g/mm²And so on. The preferred concentration range is 10. mu.g/mm²～50μg/mm². Too low a concentration does not act to inhibit smooth muscle proliferation, and too high a concentration may over-inhibit cell growth, causing toxicity.

In one embodiment, the active agent is mixed with a pharmaceutical carrier, wherein the mass ratio of the pharmaceutical carrier to the active agent is 0.1-10: 1, such as 1:1, 2:1 or 5: 1. The drug carrier can delay the release of active drugs, thereby achieving the purpose of drug slow release. Preferably, the mass ratio of the drug carrier to the active drug is 0.5-2: 1.

Specifically, the drug carrier is selected from at least one of polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), dextral polylactic acid (PDLA), levorotatory polylactic acid (PLLA), poly D, L-lactide (PDLLA), poly epsilon-caprolactone (PCL), polyethylene glycol (PEG), Polyurethane (PU), poly n-butyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), styrene-isobutylene-styrene triblock copolymer (SISB), polyethylene-vinyl acetate (PEVA), polyvinylpyrrolidone (PVP), Polysulfone (PSU), hydroxyapatite, silicon carbide, sodium hyaluronate, chitosan, heparin, sodium alginate and cellulose. Preferably, the drug carrier is at least one selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), dextrolactic acid (PDLA), levolactic acid (PLLA), poly D, L-lactide (PDLLA) and poly epsilon-caprolactone (PCL), and the polymer has good compatibility with the aphidicolin besides the slow release performance, so that a uniform drug slow release preparation can be formed conveniently.

In one embodiment, the active agent is formulated with an adjuvant. The active medicine and the auxiliary medicine are compounded to form a medicine composition which is jointly used for preventing or treating restenosis. Specifically, the adjuvant drug can act synergistically with the active drug to further inhibit smooth muscle cell proliferation and prevent or treat the occurrence of vascular restenosis.

Specifically, the adjuvant drug is rapamycin, and rapamycin is a macrolide immunosuppressant. Rapamycin can block cytokine receptors to block signal transduction, and block the progression of T lymphocytes and other cells from the G1 phase to the S phase, thereby exerting an immunosuppressive effect. While aphidicolin can directly act on DNA polymerase alpha, delta, epsilon in cell division S phase to inhibit DNA replication. Rapamycin and aphidicolin exert drug synergistic effect to further inhibit smooth muscle cell proliferation.

Specifically, the mass ratio of the active drug to the auxiliary drug is 0.5-5: 1, such as 1: 1.

In addition, the present application provides an interventional medical device of an embodiment, which includes a device body and a drug loaded on the device body, the drug including an active drug for preventing or treating restenosis, the active drug being selected from at least one of aphidicolin, a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin and an aphidicolin derivative.

Specifically, the instrument body is an interventional instrument such as a stent, a balloon or an artificial blood vessel.

In one embodiment, the active agent is attached to the surface of the device body to form a drug layer, for example, the active agent is coated on the surface of a stent, a balloon or an artificial blood vessel to form a drug layer, so as to be introduced into a human body.Specifically, the distribution amount of the active drug on the surface unit area of the device body is 100ng/mm²～100μg/mm²E.g. 100ng/mm²、1μg/mm²、10μg/mm²Or 50. mu.g/mm²And so on. When the active medicine is arranged on the surface of the apparatus body and is inserted into the vascular cavity, the distribution quantity of the active medicine per unit area is low, and the growth of smooth muscle cells can be inhibited, so that the effect of preventing or treating restenosis after percutaneous transluminal angioplasty is achieved. Generally, when the active drug is aphidicolin, the distribution amount is calculated on the mass of aphidicolin. When the active drug is a pharmaceutically acceptable salt of aphidicolin or a solvate of aphidicolin, the amount distributed is calculated on the mass of aphidicolin contained in the pharmaceutically acceptable salt or solvate. When the active drug alfasin derivative is used, the distribution amount is calculated on the mass of the alfasin derivative.

Preferably, the active agent is distributed in an amount of 10 μ g/mm per unit area of the surface of the device body²～50μg/mm². Too high a concentration of the active drug may excessively inhibit the growth of peripheral cells, resulting in toxicity, while too low a concentration may not be effective in inhibiting the growth of smooth muscle cells.

In another embodiment, holes are provided on the surface of the device body and an active drug is placed in the holes of the device body to control the release of the drug.

In one embodiment, the active agent is aphidicolin.

Specifically, aphidicolin has the following structural formula (1):

in another embodiment, the active agent is a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin or an aphidicolin derivative. The aphidicolin is formulated as a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin or modifications of aphidicolin with some groups to form aphidicolin derivatives to increase the solubility properties of aphidicolin.

In particular, a pharmaceutically acceptable salt of aphidicolin is, for example, aphidicolin glycinate. The solvate of aphidicolin is, for example, a solvate of aphidicolin with an organic solvent, such as ethanol, methanol, dimethyl sulfoxide or dichloromethane. An aphidicolin derivative is for example 3-deoxy-aphidicolin or 2-oxo-1, 3, 2-dioxolane aphidicolin.

Specifically, the active drug may be one of aphidicolin, pharmaceutically acceptable salts of aphidicolin, solvates of aphidicolin and aphidicolin derivatives, or a mixed drug formed by two or three of them.

In one embodiment, the medicament further comprises a medicament carrier, and the mass ratio of the medicament carrier to the active medicament is 0.1-10: 1, such as 1:1, 2:1 or 5:1, etc. The drug carrier can delay the release of active drugs, thereby achieving the purpose of drug slow release. Preferably, the mass ratio of the drug carrier to the active drug is 0.5-2: 1.

Specifically, the drug carrier is selected from at least one of polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), poly-D-lactic acid (PDLA), poly-D, L-lactide (PDLLA), poly-e-caprolactone (PCL), polyethylene glycol (PEG), Polyurethane (PU), poly-n-butyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), styrene-isoprene-styrene block polymer (SIS), styrene-butadiene-styrene block polymer (SBS), polyethylene-vinyl acetate (PEVA), polyvinylpyrrolidone (PVP), Polysulfone (PSU), hydroxyapatite, silicon carbide, sodium hyaluronate, chitosan, heparin, sodium alginate, and cellulose.

Preferably, the drug carrier is at least one selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), dextrolactic acid (PDLA), levolactic acid (PLLA), poly D, L-lactide (PDLLA) and poly epsilon-caprolactone (PCL), and the polymer has good compatibility with the aphidicolin besides the slow release performance, so that a uniform drug slow release preparation can be formed conveniently.

The interventional medical device comprises a device body and a medicine loaded on the device body. The medicament includes an active drug selected from at least one of aphidicolin, pharmaceutically acceptable salts of aphidicolin, solvates of aphidicolin and aphidicolin derivatives. Research results show that the aphidicolin, the pharmaceutically acceptable salt of aphidicolin, the solvate of aphidicolin or aphidicolin derivative can effectively inhibit the growth of smooth muscle cells, the intima of blood vessels has no obvious hyperplasia, and the permanent damage to the cells around the blood vessels can not be caused. After the first 6 months when restenosis occurs at a higher rate, the DNA replication function of the surrounding cells can be restored, and endothelial repair is completed. The medical device can be used for preventing or treating restenosis and preventing late thrombosis.

The following are specific examples.

Reagents and instruments used in the examples are all conventional in the art and are not specifically described. The experimental procedures, in which specific conditions are not indicated in the examples, are usually carried out according to conventional conditions, such as those described in the literature, in books, or as recommended by the manufacturer of the kits. The chemical formula of Aphidicolin (aphiicolin) used in the examples is shown in formula (1) above, purchased from Sigma-Aldrich company, under product number 89458.

Example 1

Addisiamycin was dissolved in DMSO to prepare an Addisiamycin solution with a concentration of 100 mg/mL. 100mg of PLGA was dissolved in 10mL of n-propyl acetate to prepare a PLGA solution (drug sustained release carrier solution) having a concentration of 10 mg/mL. 100 μ L of aphidicolin solution was added to 10mL of PLGA solution to prepare a final solution with aphidicolin concentration of 1 mg/mL. Spraying the final solution onto the surface of L605 stent by ultrasonic spraying method, wherein the unit area content of aphidicolin on the surface of the stent is 10 mug/mm²。

Example 2

Aphidicolin was dissolved in DMSO to make up aphidicolin solution with concentration of 1 mg/mL. The aphidicolin solution is sprayed on the surface of the stent by an ultrasonic spraying method. The unit area content of aphidicolin on the surface of the stent is 10 mug/mm²。

Example 3

The aphidicolin and PLA are dissolved in DMSO solution at the same time to prepare final solution with aphidicolin concentration of 10 mug/mL and PLA concentration of 10 mg/mL. The final solution was sprayed onto the stent surface by ultrasonic spraying. The unit area content of aphidicolin on the surface of the stent is 113ng/mm²。

Example 4

Addisiamycin was dissolved in DMSO to prepare an Addisiamycin solution with a concentration of 100 mg/mL. Rapamycin was dissolved in DMSO to make a rapamycin solution with a concentration of 100 mg/mL. PDLA was dissolved in 10mL of n-propyl acetate to prepare a PDLA solution (drug sustained-release carrier solution) having a concentration of 10 mg/mL. 100 μ L of aphidicolin solution and 100 μ L of rapamycin solution were added to 10mL of PDLA solution, respectively, to prepare a final solution with aphidicolin concentration of 1mg/mL and rapamycin concentration of 1 mg/mL. The solution was sprayed onto the stent surface using ultrasonic spraying. The unit area content of aphidicolin on the surface of the stent is 5 mug/mm²The unit area content of rapamycin on the surface of the stent is 5 mu g/mm²。

Example 5

Addisiamycin was dissolved in DMSO to prepare an Addisiamycin solution with a concentration of 10 mg/mL. 100mg of PCL was dissolved in 10mL of methylene chloride solvent to prepare a PCL solution (drug-eluting carrier solution) having a concentration of 10 mg/mL. 100. mu.L of aphidicolin solution was added to 10mL of PCL solution to prepare a final solution with aphidicolin concentration of 1 mg/mL. The solution is sprayed on the inner surface of the artificial vascular membrane by an ultrasonic spraying method. The unit area content of aphidicolin on the surface of the artificial blood vessel is 13 mug/mm²。

Example 6

The aphidicolin glycinate is dissolved in ethanol solution to prepare aphidicolin glycinate solution with the concentration of 50 mg/mL. 100mg of PLGA was dissolved in 10mL of n-propyl acetate to prepare a PLGA solution (drug sustained release carrier solution) having a concentration of 10 mg/mL. 100 μ L of aphidicolin glycinate solution is added into 10mL of PLGA solution to prepare final solution with aphidicolin concentration of 0.5 mg/mL. The final solution was sprayed onto the stent surface by ultrasonic spraying. The unit area content of alfedimycin glycinate on the surface of the stent is 46 mu g/mm²。

Example 7

3-deoxy-aphidicolin is dissolved in methanol solution to prepare 3-deoxy-aphidicolin solution with the concentration of 10 mg/mL. 100mg of PLGA was dissolved in 10mL of n-propyl acetate to prepare a PLGA solution (drug sustained release carrier solution) having a concentration of 10 mg/mL. 100 μ L of 3-deoxy-aphidicolin solution was added to 10mL of PLGA solution to prepare a final solution with a 3-deoxy-aphidicolin concentration of 0.1 mg/mL. The final solution was sprayed onto the stent surface by ultrasonic spraying. The unit area content of the 3-deoxy-aphidicolin on the surface of the stent is 9 mu g/mm²。

Example 8

2-oxo-1, 3, 2-dioxolane alfidimycin and PLA are simultaneously dissolved in a DMSO solution to prepare a final solution with the concentration of alfidimycin of 1mg/mL and the concentration of PLA of 10 mg/mL. The final solution was sprayed onto the stent surface by ultrasonic spraying. Scaffold surface 2-oxo-The unit area content of the 1,3, 2-dioxolane aphidicolin is 17 mug/mm²。

Example 9

Rapamycin was dissolved in DMSO to prepare a rapamycin solution with a concentration of 10 mg/mL. 100mg of PLGA was dissolved in 10mL of n-propyl acetate to prepare a PLGA solution (drug sustained release carrier solution) having a concentration of 10 mg/mL. 100 μ L of rapamycin solution was added to 10mL of PLGA solution to prepare a final solution with rapamycin concentration of 0.1 mg/mL. Spraying the final solution on the surface of an L605 stent by an ultrasonic spraying method, wherein the unit area content of rapamycin on the surface of the stent is 10 mu g/mm²。

Example 10

Dissolving paclitaxel in DMSO solution to obtain 10mg/mL paclitaxel solution. 100mg of PLGA was dissolved in 10mL of n-propyl acetate to prepare a PLGA solution (drug sustained release carrier solution) having a concentration of 10 mg/mL. 100 μ L of paclitaxel solution was added to 10mL of PLGA solution to prepare a final solution with paclitaxel concentration of 0.1 mg/mL. Spraying the final solution onto L605 stent surface with paclitaxel content of 10 μ g/mm per unit area by ultrasonic spraying²。

Example 11

Cell experiments

Inhibition of smooth muscle cell proliferation by aphidicolin

(1) Cell seeding

Human arterial vascular smooth muscle cells were cultured in dmem (gibico) high-glucose medium containing 10% fbs (gibico). When the number of cells reaches 80% of the bottom area of the culture flask, the cells are digested and collected by centrifugation.

0.5mg of aphidicolin was dissolved in 1mL of DMSO to prepare 500. mu.g/mL of aphidicolin stock solution, and 10. mu.L of aphidicolin stock solution was added to 10mL of 10% FBS (Gibico) DMEM (Gibico) high-sugar medium to prepare a medium solution containing 500ng/mL of aphidicolin. In addition, 10mL of a medium containing no aphidicolin stock solution was prepared.

The digested cells were diluted to cell suspensions with a density of 30000 cells/mL using media containing aphidicolin and media without aphidicolin, respectively. The cell suspension was seeded into 12-well plates at 1mL per well. After 72 hours, nuclear staining was performed and cell counting was performed.

(2) Cell staining

The cells were fixed with 4% paraformaldehyde for 10min, stained with 1:10000 DAPI stain (sigma) for 10min, and rinsed 3 times with PBS and purified water. And (4) photographing and observing under a fluorescence microscope. Cell counts were measured using cell counting software.

(3) Results of the experiment

The results of cell nucleus staining observed under a fluorescence microscope are shown in FIG. 1, (a) is a graph showing cells cultured in a medium containing aphidicolin, at a cell seeding density of about 3 ten thousand per well and counting at about 79 cells/mm². (b) The figure shows cells cultured in a medium containing aphidicolin for 72 hours, and counted about 370 cells/mm². (c) The figure shows cells cultured in media without aphidicolin, at a cell seeding density of about 3 million per well and counting of about 79 cells/mm². (d) The figure shows that the cells were cultured for 72 hours in a medium without aphidicolin and counted about 859 cells/mm²。

The results show that the aphidicolin has obvious inhibiting effect on human artery smooth muscle cells, the density of the cells is still kept at a lower level within three days after the aphidicolin is added, and the density of the cells without the aphidicolin is obviously increased. Thus showing that the aphidicolin has obvious inhibiting effect on smooth muscle cells.

Example 12

Function of aphidicolin for inhibiting intimal hyperplasia

Experimental products: aphidicolin loaded scaffold of example 1

Comparison products: same-specification L605 bare stent (cobalt-chromium alloy stent)

Animal model

The atherosclerosis model is beneficial to more accurately researching the problems of intimal hyperplasia or blood vessel restenosis after the stent is implanted. An ideal animal model for the research of porcine atherosclerosis. Farm hybrid domestic pigs with established atherosclerosis models were selected for this experiment. The weight of the animal is in the range of 30 to 40 kg, and ideally an animal weighing approximately 35 kg is selected (the animal is of an age commensurate with body weight).

(1) Stent implantation

The experiment used 3 animals as replicates. Each animal was implanted with 2 stents, one of which was an aphidicolin loaded stent and the other was a L605 bare stent. 2 stents were implanted in two of the major coronary arteries, respectively. The stent is delivered and implanted into the Right Coronary Artery (RCA), left coronary artery (LCX), and/or left anterior descending coronary artery (LAD) and enters the coronary vessel through the left or right femoral artery. The stent size is matched to the vessel size according to a target stent to artery size ratio of 1.10:1.0 to 1.20: 1.0. The target vessel will be evaluated by angiography prior to stent implantation. All target vessels will also be again evaluated angiographically after stent implantation. After 6 months of implantation, visualization was performed. Then dissecting and taking out the blood vessel of the stent section, and carrying out electron microscope observation and pathological section observation on the experimental product and the reference product.

(2) Results of the experiment

1. Pre-anatomical visualization

Before dissection, contrast data shows that the blood vessels implanted with the naked stent are all narrowed to different degrees, while the blood vessels implanted with the aphidicolin loaded stent show better smoothness. Specifically, as shown in fig. 2, the angiogram of the blood vessel after 6 months of implantation of the aphidicolin loaded stent is shown, and the angiogram shows that the blood vessel has good smoothness and no obvious stenosis. Fig. 3 shows the angiogram of the blood vessel after 6 months of implantation of the L605 bare stent, in which some degree of stenosis of the blood vessel is visible.

2. Observation by scanning electron microscope

After the imaging is complete, the animal is sacrificed and the stent segment vessel is removed from the body by dissection. Each stent is transversely cut into two sections, wherein one section is used for Scanning Electron Microscope (SEM) test, and the other section is used for pathological section observation. The stent section for SEM test was cut in half longitudinally, fixed and dehydrated for testing. Fig. 4 is an SEM image of a stent segment vessel 6 months after implantation of an aphidicolin loaded stent. Fig. 5 is an SEM image of a stent segment vessel 6 months after implantation of a L605 bare stent. As can be seen, both stents had uniform intimal coverage on their surface, but the neointima on the alfadipamycin-loaded stent surface was thin, while the neointima on the L605 stent surface was thicker.

3. Pathological section observation

The scaffolds taken out of the body were fixed with 10% formalin, followed by embedding, sectioning, and HE staining. Finally, the pathological section result is recorded by a microscope. Fig. 6 is a photograph of a pathological section of a blood vessel 6 months after implantation of an aphidicolin loaded stent (scale 500 μm in the figure). Fig. 7 is a photograph of a pathological section of a blood vessel 6 months after implantation of a bare L605 stent (the scale in the figure is 500 μm). As can be seen from the figure, the blood vessel of the aphidicolin loaded stent has no obvious intimal hyperplasia, the thickness of the blood vessel intima is about 92 μm, and the toxicity to the surrounding cells is small. While the L605 bare metal stent has obvious intimal hyperplasia, and the thickness of the blood vessel intima is about 453 mu m.

In addition, the stents or artificial vascular membranes of examples 2 to 10 were implanted into animal blood vessels of an atherosclerotic model according to the method of example 12. In the examples 2 to 8, no significant hyperplasia of the intima of the blood vessel exists, and in the example 4, the pathological section of the stent containing the adriamycin and the rapamycin has the most significant inhibition effect on the intima of the blood vessel, and the thickness of the intima of the blood vessel is the smallest. The thickness data of specific vascular intima 6 months after implantation of the stents or artificial blood vessels of examples 1-10 and the bare metal L605 stent are as follows:

the above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. An interventional medical device comprising a device body and a drug carried on the device body, the drug comprising an active drug for preventing or treating restenosis, the active drug being selected from at least one of aphidicolin, a pharmaceutically acceptable salt of aphidicolin, a solvate of aphidicolin and an aphidicolin derivative; the active medicine is distributed on the surface unit area of the device in the amount of

The medicine also comprises a medicine carrier, and the mass ratio of the medicine carrier to the active medicine is 0.1-10: 1; the medicine also comprises an auxiliary medicine, the active medicine and the auxiliary medicine are compounded, the auxiliary medicine is rapamycin, and the mass ratio of the active medicine to the auxiliary medicine is 0.5-5: 1.

2. The interventional medical device of claim 1, wherein the pharmaceutically acceptable salt of aphidicolin is aphidicolin glycinate and/or the aphidicolin derivative is 3-deoxy-aphidicolin or 2-oxo-1, 3, 2-dioxathiolane aphidicolin.

3. The interventional medical device of claim 1, wherein the active agent is coated directly on a surface of the device body.

4. The interventional medical device of claim 1, wherein a surface of the device body is provided with a hole, the active agent being disposed in the hole.

5. The interventional medical device of any one of claims 1-4, wherein the device body is a stent, balloon or artificial blood vessel.

6. The application of the combination of at least one of pharmaceutically acceptable salts of aphidicolin and aphidicolin derivatives and solvates of aphidicolin as an active medicament in preparing medicaments or medical devices for preventing or treating restenosis is characterized in that the active medicament is compounded with an auxiliary medicament, the auxiliary medicament is rapamycin, and the mass ratio of the active medicament to the auxiliary medicament is 0.5-5: 1.

7. Use according to claim 6, wherein the pharmaceutically acceptable salt of aphidicolin is aphidicolin glycinate and/or the aphidicolin derivative is 3-deoxy-aphidicolin or 2-oxo-1, 3, 2-dioxathiolane aphidicolin.

8. The use of claim 6, wherein the active agent is attached to the surface of the medical device to form a drug layer, and the active agent is distributed on the surface of the medical device in an amount per unit area

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