Method for preventing blood coagulation and drug-eluting implant for percutaneous coronary intervention

Abstract

The present disclosure provides a method for preventing blood coagulation, comprising administering an effective amount of ginsenoside compound K (CK) to a subject in need thereof. The present disclosure also provides a use of ginsenoside compound K (CK) in the manufacture of a medicament for preventing blood coagulation. The present disclosure further provides a drug-eluting percutaneous coronary intervention (PCI) device comprising a vascular implant, the surface of which is coated with a first layer comprising ginsenoside compound K (CK) and a first bioabsorbable polymer, the first bioabsorbable polymer comprising poly-L-lactic acid (PLLA) and poly(L-lactide-co-ε-caprolactone) (PLCL) in a mass ratio of 60%-80%:20%-40%.

Description

[Technical Field]

[0001] Coronary stents are medical devices that help treat patients with severe coronary artery disease. They are typically used in conjunction with balloon angioplasty. Briefly, balloon angioplasty is performed to open a narrowed artery, and a stent is placed in the blood vessel for support. [Background technology]

[0002] Until now, the incidence of stent thrombosis and in-stent restenosis within one month after implantation of conventional coronary stents was 1% and 15–20%, respectively. However, with the invention of drug-eluting stents (DES) and drug-eluting balloons (DEBs), which can inhibit endothelial cell growth, the incidence of in-stent restenosis has significantly decreased to less than 1%. Drugs used in DES and DEBs include paclitaxel, sirolimus (also known as rapamycin), and limus family drugs (e.g., everolimus, zotarolimus, and bilimus). These drugs inhibit endothelial cell proliferation and act as immunosuppressants, effectively reducing the risk of in-stent restenosis. While current DES and DEBs can solve the problem of restenosis, they require patients to take anticoagulants for long periods of time and live with the risk of late stent thrombosis. Furthermore, paclitaxel and sirolimus have proven to be highly toxic and have low lipid solubility, respectively. On the other hand, spray temperature is a major issue if the composition solvent has high viscosity below 100°C and clogs the space, but we know that CK has a much higher solubility and can overcome this disadvantage. Therefore, there is a need to discover new drugs for DES and DEB. Previous techniques have not revealed the anticoagulant effect of ginsenoside compound K (CK) and its potential as an alternative drug for DES and DEB. In the present invention, CK is used in DES and DEB to help overcome the disadvantages of stent thrombosis and restenosis caused by current techniques. Ginsenosides are the main active ingredients in ginseng and are known to possess various pharmacological activities, including antitumor, antifatigue, antiallergic, and antioxidant activities. Ginsenosides share a basic structure consisting of a gonanesteroid nucleus with 17 carbon atoms arranged in four rings. Ginsenosides are metallated in the body, and recent studies have shown that ginsenoside metabolites, rather than natural ginsenosides, are more readily absorbed and act as active ingredients. Among these, ginsenoside CK, also known as compound K (CK), is known as one of the metabolites of protopanaxadiol-type ginsenosides in humans via the intestinal bacterial gypenosidic pathway. To date, no prior art references have reported on the anticoagulation effects of ginsenoside CK or its use in preparing coronary artery stents. Summary of the Invention

[0003] In this case, CK is well dispersed on the surface of the stent and the balloon (used in balloon angioplasty) by low-pressure plasma spraying (VPS) technology. CK has unique properties of low toxicity and antithrombosis, making it a potential choice for clinical use in preventing stent thrombosis and restenosis. In one embodiment, the present disclosure provides a method for preventing blood clotting, comprising administering to a subject in need thereof an effective amount of ginsenoside compound K (CK). In another aspect, the present disclosure provides the use of ginsenoside compound K (CK) in the manufacture of a medicament for preventing blood clotting. In a further aspect, the present disclosure provides ginsenoside compound K (CK) for use in a method for preventing blood clotting.

[0004] In yet a further aspect, the present disclosure provides a drug-eluting percutaneous coronary intervention (PCI) comprising a vascular implant, the surface of which is coated with a first layer comprising ginsenoside compound K (CK) and a first bioabsorbable polymer. In one embodiment of the drug-eluting PCI, the first bioabsorbable polymer comprises poly-L-lactic acid (PLLA) and poly(L-lactide-co-ε-caprolactone) (PLCL) in a mass ratio of 60%-80%:20%-40%. In one embodiment of the drug-eluting PCI, the thickness of the first layer is 0.5 to 2 μm, 0.5 to 1.5 μm, or 0.8 to 1 μm. In one embodiment of the drug-eluting PCI, the CK in the first bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.1 to 3 μg / mm 2 , 0.1 to 1 μg / mm 2 , 0.25 to 0.75 μg / mm 2 or 1 to 3 μg / mm 2 is. In one embodiment of drug-eluting PCI, the vascular implant is a stent. In one embodiment of the drug-eluting PCI, a second layer is further included on the first layer, the second layer including a second bioabsorbable polymer, the second bioabsorbable polymer including polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100% based on the total mass of the second bioabsorbable polymer. In one embodiment of the drug-eluting PCI, the thickness of the second layer is 0.5 to 3 μm, 1 to 3 μm, or 0.5 to 1.5 μm. In one embodiment of the drug-eluting PCI, a third layer is further included between the first and second layers, the third layer including CK and a third bioabsorbable polymer, the third bioabsorbable polymer including PLLA and PLCL in a mass ratio of 25%-35%:65%-85%. In one embodiment of the drug-eluting PCI, the third layer has a thickness of 0.5 to 1.5 μm. In one embodiment of the drug-eluting PCI, the CK in the third bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.5 to 2 μg / mm 2 , preferably 0.75 to 1.25 μg / mm 2 is. In one embodiment of the drug-eluting PCI, the mass of CK applied to the vascular implant is greater than 100 μg and less than 1000 μg. In one embodiment of the drug-eluting PCI, a second layer is further included below the first layer, the second layer including a second bioabsorbable polymer, the second bioabsorbable polymer including polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100%. In one embodiment of the drug-eluting PCI, the thickness of the second layer is 0.5 to 3 μm, 1 to 3 μm, or 0.5 to 1.5 μm. In one embodiment of the drug-eluting PCI, the first layer coated on the surface of the vascular implant is coated by low pressure plasma spraying (VPS). [Brief explanation of the drawings]

[0005] [Figure 1] 1 shows an exemplary ginsenoside CK triple layer coating on a stent. [Figure 2] The release kinetics curve of ginsenoside CK during the healing process is shown. Nearly 80% of the drug is released within one month (initial burst). The remaining drug is planned to be released over a three-month period, which is designed to cover the entire period of arterial wound healing in actual patients. 90 days after drug release, the amount of drug remaining in the stent is too small to exceed the detection / quantification limit. [Figure 3] 1 shows an exemplary two-layer coating of ginsenoside CK on a balloon. [Figure 4] The release kinetics curve of ginsenoside CK during the healing process is shown. Nearly 80% of the drug is released within one month (initial burst). The remaining drug is planned to be released over a three-month period, which is designed to cover the entire period of arterial wound healing in actual patients. 90 days after drug release, the amount of drug remaining in the stent is too small to exceed the detection / quantification limit. [Figure 5]

[0023] Figure 1 shows the inhibition curve of astemizole using the hERG FP assay. Data points are the average of triplicate measurements. [Figure 6] Figure 1 shows the inhibition curve of CK using the hERG FP assay. Data points are the average of triplicate measurements. [Figure 7] 1 shows the effect of CK on platelet aggregation. [Figure 8] HUVECs were incubated with CK alone (1 μM, 3 μM and 10 μM) for 24 hours and cell viability was analyzed by CCK-8 assay. [Figure 9] The effect of ginsenoside CK on LPS-induced IL-6 and TNF-α expression in HUVECs is shown. HUVECs were treated with ginsenoside CK (1 μM, 3 μM, and 10 μM) for 1 hour before 24-hour stimulation with LPS (1 μg / ml). (A) IL-6 and (B) TNF-α expression. Values ​​are means ± SEM from three independent experiments. Statistical significance was assessed by one-way ANOVA followed by Scheffe post-hoc test for multiple comparisons (***P<0.01, *P<0.05 vs. LPS). [Figure 10] The effect of ginsenoside CK on LPS-induced ICAM-1 and VCAM-1 mRNA expression in HUVECs is shown. HUVECs were treated with ginsenoside CK (1 μM, 3 μM, and 10 μM) for 1 hour before 24-hour stimulation with LPS (1 μg / ml). (A) ICAM-1 and (B) VCAM-1 mRNA expression. Values ​​are means ± SEM from three independent experiments. Statistical significance was assessed by one-way ANOVA followed by Scheffe post-hoc test for multiple comparisons (***P<0.01, *P<0.05 vs. LPS). DETAILED DESCRIPTION OF THE INVENTION

[0006] These and other aspects of the present disclosure will be described in further detail below with respect to other embodiments described herein. It should be understood that the present invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to limit the invention. When used in the description of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or other variations thereof, are intended to include a non-exclusive inclusion, subject to any limitations expressly indicated. For example, a composition, mixture, process, or method comprising a list of elements is not necessarily limited to only those elements and may include other elements not expressly indicated or inherent to the composition, mixture, process, or method. As used herein, the term "about" indicates that a value includes the inherent variation, for example, of error in a measuring device, the method used to measure the value, or variation between study subjects. The term typically means approximately, or encompasses less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, depending on the context. Use of the term "or" in the claims is used to mean "and / or" unless it is expressly stated that it refers to alternatives only or that the alternatives are mutually exclusive. However, this disclosure supports a definition that refers to alternatives only and "and / or."

[0007] Unless otherwise defined, 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. All publications, patent disclosures, patents, and other references cited herein are incorporated by reference in their entirety for the teachings relevant to the sentence and / or paragraph in which the reference is cited. The following representative examples and embodiments illustrate various features and embodiments of the present disclosure. These are illustrative and not intended to be limiting. Those skilled in the art will readily understand that the specific examples are merely illustrative of the present invention, as fully described in the following claims. It should be understood that all embodiments and features described herein are interchangeable and can be combined with any of the included embodiments.

[0008] 1. Materials and Methods 1.1 Study drug JPEG2026506457000001.jpg581701.2 Laboratory equipment a. 2.7 ml blood collection tube (containing 3.2% sodium citrate) b. Safety blood collection set with 21G Luer adapter c. Alcohol cotton balls d. Tourniquet e. 15 ml centrifuge tubes and 1.5 ml microcentrifuge tubes f. 200 and 1000 μl plastic tips g. 96-well microplate h. Adjustable volume pipette 1.3 Experimental equipment a. Biosensors Technology - Automated Pipette b.Epoch(TM) Microvolume Spectrophotometer System (BioTek) c. AggRAM Analyzer (Helena Laboratories) d. Evolution™ Spectrophotometer (Thermo Scientific™) e. Tecan Infinite® F200 microplate reader with fluorescence polarization module was purchased from Tecan Group (Switzerland). Channel handheld disposable-tip pipettor (8-tip head) was purchased from Axygen (California, USA).

[0009] 2. Experimental procedures and operating procedures CK coating on stents 2.1 Preparation of CK coating on Superflex Cruz A composition of PLLA (80-95%) and PLCL (1-10%) was thoroughly mixed with chloroform under heated water conditions, followed by the addition of DMSO at 25°C and CK (0.5-1.5 μg / ml). The temperature of the spray chamber was controlled below 100°C to avoid polymer decomposition at high temperatures. The detailed process is as follows: The CK-based DES has a conformal coating. As shown in Figure 1, it has a three-layer coating, which includes: The top layer is 0.5-1.5 μm thick. This layer is a drug-free polymer layer containing hydrophilic PVP (polyvinylpyrrolidone). It protects against light, moisture, and premature drug release, and also provides lubrication during stent implantation. Intermediate layer: 0.5-1.5 μm thick. Similar to the base layer, it contains PLLA (poly-L-lactic acid), PLCL (poly(L-lactide-co-ε-caprolactone)), and CK drug (0.5-2 μg / mm 2 ) blend. It is designed to provide sufficient amounts of drug after stent implantation. Base layer: The thickness is 0.5-1.5 μm. This layer is composed of PLLA (poly-L-lactic acid), PLCL (poly(L-lactide-co-ε-caprolactone)), and CK drug (0.1-1 μg / mm 2 ) blend. It is designed to provide sustained release of the drug. 2.2 The healing process as shown in Figure 2 The kinetic curves are indicated by arrows. 2.3 Coating process 2.4 Polymer and Drug Preparation [Table 1] * The total drug concentration in DES using CK is 0.5 to 2.5 μg / mm 2 is. *The total drug dose in DES using CK was 250-350 μg per stent (3.0 mm × 20 mm).

[0010] CK coating on balloon 2.5 Preparation of CK coating on balloon DEB using CK has a wall-side coating. As shown in Figure 3, it has a two-layer coating. Top layer: The thickness is 1-3 μm. This layer is composed of PLLA (poly-L-lactic acid), PLCL (poly(L-lactide-co-ε-caprolactone)), and CK drug (2 μg / mm 2 ) blend. DEB is designed to provide sufficient amounts of the drug after transplant. Base layer: 0.5-2 μm thick. This layer is a drug-free polymer layer mixed with hydrophilic PVP (polyvinylpyrrolidone). It is designed to provide a top layer that contacts the balloon surface and peels off after DEB implantation. 2.6 Healing processes such as Drug release kinetics: It can cover the vascular healing process for 120 days, as shown in Figure 4. The kinetic curve is indicated by the arrow. 2.7 Coating Process Polymer and Drug Preparation [Table 2] * The total drug concentration in DEB using CK was 1–3 μg / mm 2 is. * The total drug dose in DEB using CK is 350-450 μg per balloon (3.0 mm × 20 mm).

[0011] hERG assay 2.8 Preparation of Chemicals and Solutions a. Primary stock solutions of CK and astemizole at 3 mM in 100% DMSO were serially diluted 3-fold using the same solvent to obtain 16 different concentrations ranging from 3 mM to 210 pM. These solutions were further diluted 25-fold with FP (fluorescence polarization) assay buffer before being transferred to the assay plate. b. Each test solution in the assay plate was further diluted 4-fold with FP assay buffer. Predictor™ hERG membrane preparation was thawed at room temperature and sonicated. Predictor™ hERG Tracer Red (250 nM) was diluted to 4 nM with hERG FP assay buffer. All experiments were performed in FP assay buffer containing 5% DMSO. 2.9 Experimental Procedure a. FP assays were performed using the Predictor™ hERG Fluorescence Polarization Assay Kit. Binding assays were performed according to the manufacturer's recommended protocol with some modifications. Aliquots (5 μL) of each concentration of reference test article were pipetted into appropriate wells of a black 384-well microplate. The microplate contained 10 μL of hERG membrane and 5 μL of 4 nM fluorescent tracer, covered with a plate lid to protect the reagents from light exposure. b. Experiments were performed using triplicate wells for each concentration. After 3 hours of incubation at room temperature, the microplate was read on a Tecan Infinite® F200 plate reader using a polarized excitation filter set of 535 nm and an emission filter set of 590 nm (25 and 20 nm bandwidths, respectively). Assay robustness was assessed by measuring 16 replicates of positive control wells (containing 30 μM of E-4031, a known hERG channel blocker, in the FP assay mixture) and negative control wells (no hERG channel blocker in the FP assay mixture).

[0012] 2.10 Determining Assay Z' Values a. To assess the robustness of the hERG assay, the signal-to-noise ratio was quantified by calculating the Z' factor for each assay. Statistically, the Z' factor provides a way to assess the quality of an assay. A Z value greater than 0.5 is generally considered to be excellent assay performance, while a value of 1 indicates a theoretically ideal assay with no variability. Z' factor values ​​were determined using blank-subtracted polarization values ​​obtained from 16 wells of negative and positive controls using the formula from Zhang et al. [1].

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[0013] Anticoagulant testing 2.12 Chemical and Solution Preparation a. Prepare a 20 mM CK stock solution using DMSO and dilute it using 1x PBS to different working concentrations (0, 62.5, 125, 250, 500, 1000 and 2000 μM) before the experiment. 2.13 Experimental Procedure a. Blood sample collection Donors must rest, fast, and not smoke for 12 hours before blood collection. Medications such as antihistamines, antibiotics, aspirin, and anti-inflammatory drugs must not be taken for 10 to 14 days before the test, as these may affect platelet function. To ensure non-clotting, blood samples should be thoroughly mixed with anticoagulant and stored at 24-27°C. It is recommended that platelet aggregation tests be performed within 30-150 minutes of blood sample collection. b. Preparation of platelet-rich plasma (PRP) Gently invert the blood collection tube 3-4 times to resuspend the blood cells. Centrifuge the sample at 170 x g for 7 minutes and transfer the supernatant to a new tube. Use the sample within 5-10 minutes of isolation, or store the sample at 4°C to avoid clumping. c. Preparation of platelet-poor plasma (PPP) Gently invert the blood collection tube 3-4 times to resuspend the blood cells. Centrifuge the sample at 2,400 x g for 10 minutes and transfer the supernatant to a new tube. Test the sample within 5 minutes of separation from the whole blood, or store the sample at 4°C. d. Platelet count The concentration of PRP was 3 x 10 using PPP. 8 Dilute to cells / ml. e. Platelet aggregation test To test the effect of CK on platelet aggregation, different concentrations of CK (0, 2.5, 5, 10, 20, 40, and 80 μM) were added to 0.25 ml of PRP. The mixture samples were incubated at 37°C for 2 minutes and immediately treated with 5 μg / ml collagen (100 μg / ml stock solution). A PRP-DMSO-distilled water mixture was used as a non-aggregation control. Blank control groups were prepared: (1) the original PPP, (2) a PPP-DMSO-distilled water mixture, (3) a PPP-DMSO-collagen mixture, and (4) a PPP-CK-collagen mixture. All mixture samples and control groups were incubated at 37°C for 5 minutes at 200 rpm on an orbital shaker. The samples were then centrifuged at 170 × g for 7 minutes, and 200 μl of the supernatant was transferred to a 96-well microplate. The OD values ​​were measured at 650 nm using a spectrophotometer and converted to percentage aggregation. [Table 4] 2.14 Data Analysis The percentage of platelets clotted is calculated using the following formula: a. Platelet aggregation in group 1 (%)

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[0014] 3. Results and Discussion hERG assay IC of astemizole (reference compound) on hERG 50 The IC value was 0.004 μM from three measurements. Figure 5 shows the log concentration-response curve for the inhibitor astemizole. 50 The values ​​were in good agreement with those reported in the literature using this method. CK demonstrates small inhibition in the fluorescence polarization assay (Figure 6). CK was only slightly effective in inhibiting tracer binding to the hERG membrane protein at 30 μM (from three measurements), and the IC 50 Values ​​were reported as >30 μM. CK was used as a weak ligand (IC 50 >1 μM) (Table 1). [Table 5] * IC of astemizole 50 Values ​​are IC reported in the literature 50 It agrees well with the value.

[0015] Cytochrome P450 inhibition in human liver microsomes using LC-MS / MS analysis Mean IC of inhibitor CK against eight CYP-specific probe substrates: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 in pooled human liver microsomes 50The values ​​were >50, 14.84, >50, >50, >50, >50, 9.76 (midazolam as a CYP3A4 substrate), and 13.86 (testosterone as a CYP3A4 substrate) μM, respectively (Table 2). CK showed IC values ​​of 1.08, 0.98, and 1.06-fold for the CYP2B6, 3A4 (midazolam as a substrate), and 3A4 (testosterone as a substrate) inhibition assays with a 30-minute preincubation, respectively. 50 After 30 min of preincubation in the presence or absence of NADPH, CK did not inhibit CYP1A2, 2C8, 2C9, 2C19, and 2D6 at a concentration of 50 μM (Table 3), thus showing a meaningful IC 50 Shift values ​​could not be calculated for these isoforms. [Table 6] [Table 7]

[0016] Anticoagulant testing This experiment aims to not exclude the effect of CK on platelet aggregation. After treating platelets with CK, the aggregation level is reduced. Furthermore, the platelet aggregation level in group 9 is nearly 7 times lower than that in group 4. These results indicate that CK can act as an anticoagulant for platelets (Figure 7). Effect of ginsenoside CK on LPS-induced IL-6 and TNF-α expression in HUVECs The results revealed that 24-hour treatment with ginsenoside CK alone at various concentrations (1 μM, 3 μM, and 10 μM) did not affect cell viability, demonstrating the non-toxicity of ginsenoside CK (Figure 8). Treatment of HUVECs with LPS (1 μg / ml) increased IL-6 and TNF-α expression. To determine whether LPS-induced IL-6 and TNF-α expression was affected by ginsenoside CK, HUVECs were treated with ginsenoside CK (1 μM, 3 μM, and 10 μM) for 1 hour before stimulation with LPS (1 μg / ml) for 24 hours. Ginsenoside CK significantly reduced LPS-induced IL-6 (Figure 9, A) and TNF-α (Figure 9, B) expression in a concentration-dependent manner. Effect of ginsenoside CK on LPS-induced ICAM-1 and VCAM-1 mRNA expression in HUVECs Treatment of HUVECs with LPS (1 μg / ml) increased ICAM-1 and VCAM-1 mRNA expression. Twenty-four hours after LPS treatment, ICAM-1 and VCAM-1 expression reached a maximum. To determine whether LPS-stimulated ICAM-1 and VCAM-1 mRNA expression was affected by ginsenoside CK, HUVECs were treated with ginsenoside CK (1 μM, 3 μM, and 10 μM) for 1 hour before 24-hour stimulation with LPS (1 μg / ml). Ginsenoside CK significantly inhibited LPS-stimulated ICAM-1 (Figure 10, A) and VCAM-1 (Figure 10, B) mRNA expression in a concentration-dependent manner.

[0017] The present invention will now be described and further illustrated by the following embodiments. Embodiment 1. A drug-eluting percutaneous coronary intervention (PCI) comprising a vascular implant, The surface of the vascular implant is coated with a first layer comprising ginsenoside compound K (CK) and a first bioabsorbable polymer, for use in drug-eluting percutaneous coronary intervention (PCI). Embodiment 2. A drug-eluting PCI according to embodiment 1, wherein the first bioabsorbable polymer comprises poly-L-lactic acid (PLLA) and poly(L-lactide-co-ε-caprolactone) (PLCL) in a mass ratio of 60%-80%:20%-40%. Embodiment 3. The drug-eluting PCI according to embodiments 1 and 2, wherein the thickness of the first layer is 0.5 to 2 μm, 0.5 to 1.5 μm, or 0.8 to 1 μm. Embodiment 4: The CK in the first bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.1 to 3 μg / mm 2 , 0.1 to 1 μg / mm 2 , 0.25 to 0.75 μg / mm 2 or 1 to 3 μg / mm 2 The drug-eluting PCI according to any one of embodiments 1 to 3, wherein Embodiment 5. The drug-eluting PCI of any one of Embodiments 1 to 4, wherein the vascular implant is a stent. Embodiment 6. The drug-eluting PCI of any one of Embodiments 1 to 5, further comprising a second layer on the first layer, Preferably, the second layer comprises a second bioabsorbable polymer, and more preferably, the second bioabsorbable polymer comprises polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100% based on the total mass of the second bioabsorbable polymer. Embodiment 7. The drug-eluting PCI according to any one of embodiments 1 to 6, wherein the thickness of the second layer is 0.5 to 3 μm, 1 to 3 μm, or 0.5 to 1.5 μm. Embodiment 8. The drug-eluting PCI of any one of Embodiments 1 to 7, further comprising a third layer between the first and second layers, Preferably, the third layer comprises CK and a third bioabsorbable polymer, more preferably, the third bioabsorbable polymer comprises PLLA and PLCL in a mass ratio of 25%-35%:65%-85%. Embodiment 9. The drug-eluting PCI according to any one of embodiments 1 to 8, wherein the thickness of the third layer is 0.5 to 1.5 μm. Embodiment 10: The CK in the third bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.5 to 2 μg / mm 2 , preferably 0.75 to 1.25 μg / mm 2 The drug-eluting PCI according to any one of embodiments 1 to 9, wherein

[0018] Embodiment 11. The drug-eluting PCI according to any one of embodiments 1 to 10, wherein the mass of CK applied to the vascular implant is more than 100 μg and less than 1000 μg. Embodiment 12. The drug-eluting PCI of any one of embodiments 1 to 11, wherein the vascular implant is a balloon. Embodiment 13. The drug-eluting PCI of any one of Embodiments 1 to 12, further comprising a second layer below the first layer, Preferably, the second layer includes a second bioabsorbable polymer, and more preferably, the second bioabsorbable polymer includes polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100%. Embodiment 14. A drug-eluting PCI according to embodiment 13, wherein the thickness of the second layer is 0.5 to 3 μm, 1 to 3 μm, or 0.5 to 1.5 μm. Embodiment 15. A drug-eluting PCI according to any one of embodiments 1 to 14, wherein the first layer coated on the surface of the vascular implant is coated by low-pressure plasma spraying (VPS).

[0019] Embodiment 16. A method for preventing blood clotting, comprising administering an effective amount of ginsenoside compound K (CK) to a subject in need thereof. Embodiment 17. Use of ginsenoside compound K (CK) in the manufacture of a medicament for preventing blood clotting. Embodiment 18. Ginsenoside compound K (CK) for use in a method for preventing blood clotting. References TIFF2026506457000014.tif24169

Claims

1. 1. A drug-eluting percutaneous coronary intervention (PCI) comprising a vascular implant, comprising: A drug-eluting percutaneous coronary intervention (PCI) device, wherein the surface of the vascular implant is coated with a first layer comprising ginsenoside compound K (CK) and a first bioabsorbable polymer.

2. The drug-eluting PCI of claim 1, wherein the first bioabsorbable polymer comprises poly-L-lactic acid (PLLA) and poly(L-lactide-co-ε-caprolactone) (PLCL) in a mass ratio of 60% to 80%:20% to 40%.

3. 3. The drug-eluting PCI according to claim 1, wherein the first layer has a thickness of 0.5 to 2 μm, 0.5 to 1.5 μm, or 0.8 to 1 μm.

4. The CK in the first bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.1-3μg / mm 2 , 0.1-1μg / mm 2 , 0.25-0.75μg / mm 2 or 1 to 3 μg / mm 2 The drug-eluting PCI according to any one of claims 1 to 3, wherein

5. The drug-eluting PCI according to any one of claims 1 to 4, wherein the vascular implant is a stent.

6. The drug-eluting PCI of any one of claims 1 to 5, further comprising a second layer on the first layer, Preferably, the second layer comprises a second bioabsorbable polymer, and more preferably, the second bioabsorbable polymer comprises polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100% based on the total mass of the second bioabsorbable polymer.

7. The drug-eluting PCI according to any one of claims 1 to 6, wherein the second layer has a thickness of 0.5 to 3 µm, 1 to 3 µm, or 0.5 to 1.5 µm.

8. The drug-eluting PCI according to any one of claims 1 to 7, further comprising a third layer between the first layer and the second layer, Preferably, the third layer comprises the CK and a third bioabsorbable polymer, and more preferably, the third bioabsorbable polymer comprises PLLA and PLCL in a mass ratio of 25% to 35%:65% to 85%.

9. The drug-eluting PCI according to any one of claims 1 to 8, wherein the third layer has a thickness of 0.5 to 1.5 µm.

10. The CK in the third bioabsorbable polymer is 0.1 to 5 μg / mm 2 , 0.5-2μg / mm 2 , preferably 0.75 to 1.25 μg / mm 2 The drug-eluting PCI according to any one of claims 1 to 9, wherein

11. The drug-eluting PCI according to any one of claims 1 to 10, wherein the mass of the CK applied to the vascular implant is more than 100 μg and less than 1000 μg.

12. The drug-eluting PCI according to any one of claims 1 to 11, wherein the vascular implant is a balloon.

13. The drug-eluting PCI of any one of claims 1 to 12, further comprising a second layer below the first layer, Preferably, the second layer comprises a second bioabsorbable polymer, and more preferably, the second bioabsorbable polymer comprises polyvinylpyrrolidone (PVP) in a mass ratio of 80% to 100%.

14. The drug-eluting PCI of claim 13, wherein the second layer has a thickness of 0.5 to 3 μm, 1 to 3 μm, or 0.5 to 1.5 μm.

15. The drug-eluting PCI according to any one of claims 1 to 14, wherein the first layer coated on the surface of the vascular implant is coated by low-pressure plasma spraying (VPS).

16. A method for preventing blood clotting, comprising administering an effective amount of ginsenoside compound K (CK) to a subject in need thereof.

17. Use of ginsenoside compound K (CK) in the manufacture of a medicament for preventing blood clotting.

18. Ginsenoside compound K (CK) for use in a method for preventing blood clotting.

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