Drug-eluting stent and preparation method thereof

Abstract

A drug stent includes a distal and proximal end and a middle section, wherein the length of the middle section accounts for 50% to 100% of the entire stent; the drug stent contains multiple layers of drugs, and the release rate of each layer of the drug of the multi-layer drug stent gradually decreases from the outer layer to the inner layer. Therefore, the rate of drug release can be controlled layer by layer according to the lesion healing mechanism, and the drug is stable and firm and not easy to fall off; at the same time, in the axial distribution of the stent, the number of drug layers in contact with the main lesion area in the middle of the stent is relatively large, while the drug coating at the distal and proximal ends of the stent is relatively small. This design can not only treat the lesion area in a targeted manner and save costs, but also because the drug coating at the distal and proximal ends is relatively small, its radial support force is slightly greater than that of the middle section, so it can well avoid the migration of the stent in the blood vessel, and at the same time, it can avoid the stent from damaging the lesion area of ​​the blood vessel again.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a drug stent and a preparation method thereof. Background Art

[0002] Cardiovascular diseases are becoming more and more common worldwide. Since the 1970s, it has become more and more common to treat various cardiovascular diseases through interventional medical devices. It has experienced three milestones of rapid development: percutaneous balloon angioplasty (PTCA), bare metal stent (BMS), and drug-eluting stent (DES). In particular, the emergence of drug-coated stents has achieved great success in treating vascular stenosis, demonstrating the potential of DES in treating stenosis.

[0003] The existing drug stent coating technology is to mix and dissolve sirolimus, polylactic acid and acetone in a certain proportion to prepare a drug solution. Under a suitable environment, the sprayer uses appropriate parameters to spray on the stent to form a sirolimus drug eluting stent.

[0004] However, the existing spraying process has the following defects: poor stability, poor coating firmness, unstable drug release after the stent enters the lesion site, and there is still a risk of stent thrombosis and restenosis. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a drug stent that is delivered to the diseased blood vessel via a catheter. Since the drug coating of the stent is a multi-layer structure and the cross-linking degree and drug ratio of the drugs in each layer are inconsistent, the speed of drug release can be controlled layer by layer according to the lesion healing mechanism; at the same time, in the axial distribution of the stent, the number of drug layers in contact with the main lesion area in the middle of the stent is relatively large, while the drug coating at the distal and proximal ends of the stent is relatively small. This design can not only treat the lesion area in a targeted manner and save costs, but also because the drug coating at the distal and proximal ends is relatively small, its radial supporting force is slightly greater than that of the middle section, so that the migration of the stent in the blood vessel can be well avoided, and at the same time, the stent can be prevented from damaging the vascular lesion area again.

[0006] To achieve the above-mentioned purpose, the present invention provides a drug stent, comprising a distal end, a proximal end and a middle section, and comprising multiple layers of drugs; the arrangement of the multiple layers of drugs in the entire stent is as follows: the drug stent is divided into a middle section, a distal end and a proximal end, wherein the length of the middle section accounts for 50% to 100% of the entire stent; the multiple layers of drugs at the distal and proximal ends of the drug stent are 1 to 2 layers, the multiple layers of drugs in the middle section are 2 to 5 layers, and the release rate of each layer of drugs of the multi-layer drug stent, preferably the multiple layers of drugs in the middle section, gradually decreases from the outer layer to the inner layer.

[0007] Furthermore, the multi-layered drug is composed of a sustained-release carrier and a drug, wherein the sustained-release carrier is composed of a biopolymer, and the cross-linking degree of each layer can be the same or different. The sustained-release carrier includes one or more of polyesteramide, polylactic acid, polycaprolactone, polylactic acid-co-glycolic acid, polyglycolide, polyglycolic acid, and polyglycolic acid. The sustained-release carrier and drug ratio of each layer of the multi-layered drug are different.

[0008] Furthermore, the ratio of the sustained-release carrier to the drug in each layer of the multi-layer drug gradually decreases from the inside to the outside.

[0009] Furthermore, the proportion of the sustained-release carrier in the multi-layer drug is 0-80%. Preferably, the ratio of the sustained-release carrier to the drug is 5:1, 4:1, 3:1, 2:1, 1:1, or 1:2.

[0010] Furthermore, the multi-layer drug is composed of drugs, and the cross-linking degree of each layer of drugs gradually decreases from the inner layer to the outer layer. The cross-linking degree of the multi-layer drugs is changed by plasma-induced cross-linking or controlled by other chemical and physical methods.

[0011] Furthermore, the multilayered drug is an anti-smooth muscle cell proliferation drug.

[0012] Furthermore, the smooth muscle cell proliferation drug is composed of one or more active drugs such as sirolimus, acipimox, tacrolimus, eromosine, immunosuppressant ABT-578, dexamethasone, paclitaxel and its derivatives, actinomycin, vincristine and its derivatives, statins, 2-chlorodeoxyadenosine, ribozymes, probucol, estradiol, etc.

[0013] Furthermore, the multi-layered drugs are composed of antibody drugs that specifically capture endothelial progenitor cells.

[0014] Furthermore, the antibody drug capable of specifically capturing endothelial progenitor cells comprises one or more of CD31 antibody, CD133 antibody, CD34 antibody, CD45 antibody, and vascular endothelial growth factor (VEGF).

[0015] Furthermore, the multi-layered drugs are composed of a combination of an anti-smooth muscle cell proliferation drug and an antibody drug that specifically captures endothelial progenitor cells.

[0016] Furthermore, the innermost layer of the multi-layer drug is grafted onto the surface of the stent through chemical bonds, and the stent may be treated so that the drug is embedded in holes or trenches on the surface of the stent.

[0017] Furthermore, the preparation method of the drug stent is as follows: (1) Processing of the stent: the stent can be woven by a weaving machine or cut from a tubular material; (2) Innermost layer drug grafting: for the drug or drug and sustained-release carrier on the innermost layer of the stent, the processed bare stent must first be subjected to plasma glow treatment, preferably oxygen plasma, with a discharge power of 20-300W, a treatment time of 5-30min, and an oxygen flow rate of 100mL / min-800mL / min; the stent treated with oxygen plasma is placed on a stent support, and the drug is treated in a plasma state, and the treated drug plasma state is deposited on the stent, the glow discharge deposition time is 2min-45min, and the discharge power is 30-300W. Furthermore, the inner layer drug can be grafted on the stent by chemical grafting, and the innermost layer is chemically grafted, rather than ordinary physical covering. (3) Spraying of the second layer of drug coating: ① Prepare an organic solution of the drug with a solubility of 1% to 10%; the organic solvent includes one or more of n-butyl acetate, acetonitrile, acetic acid, methanol, ethanol, acetone, butanone, ethyl acetate, isopropanol, n-propyl acetate, and isopropyl acetate. Physically spray the drug solution on the distal, proximal and middle sections with a spraying thickness of 10nm to 100μm; ② After spraying, the stent is placed on a stent support and cross-linked using plasma. The plasma glow discharge time is 2 to 30 minutes and the discharge power is 15-500W; (4) Spraying of other drug layers: Repeat the spraying process of step (3) for the middle section of the drug stent. In the spraying of each layer, the time and power of the plasma glow discharge treatment are gradually reduced from the inside to the outside.

[0018] Compared with the prior art, the drug stent of the present invention is delivered to the diseased blood vessel via a catheter. Since the drug coating of the stent is a multi-layer structure, and the cross-linking degree and drug ratio of the drug in each layer are inconsistent, the speed of drug release can be controlled layer by layer according to the lesion healing mechanism, and the drug is stable and firm and not easy to fall off; at the same time, in the axial distribution of the stent, the number of drug layers in contact with the main lesion area in the middle of the stent is relatively large, while the drug coating at the distal and proximal ends of the stent is relatively small. This design can not only treat the lesion area in a targeted manner and save costs, but also because the distal and proximal ends have less drug coating, their radial supporting force is slightly greater than that of the middle section, so the migration of the stent in the blood vessel can be well avoided, and the stent can be prevented from damaging the vascular lesion area again. DETAILED DESCRIPTION

[0019] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, proceed according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be purchased commercially.

[0020] The drug stent provided by the present invention comprises a distal end, a proximal end and a middle section, wherein the length of the middle section accounts for 50% to 100% of the entire stent; the drug of the entire drug stent is composed of multiple layers of drugs, the multiple layers of drugs at the distal end and the proximal end are 1 to 2 layers, and the multiple layers of drugs in the middle section are 2 to 5 layers; when the drug stent is transported into the diseased blood vessel through a catheter, the middle section contacts the main area of ​​the diseased blood vessel, so the number of drug layers here is relatively large; correspondingly, the number of drug layers at the distal end and the proximal end is relatively small; the innovatively designed stent can not only treat the diseased area in a targeted manner and save costs, but also because the distal end and the proximal end have less drug coating, the radial supporting force thereof is slightly greater than that of the middle section, so the migration of the stent in the blood vessel can be well avoided, and the stent can be prevented from damaging the diseased area of ​​the blood vessel again.

[0021] The multilayer drugs of the drug stent can be the drug itself or a mixture of the drug and the sustained-release carrier. If it is the drug itself, the cross-linking degree of the drug in each layer structure gradually decreases from the inside to the outside; if it is a mixture of the sustained-release carrier and the drug, the ratio of the sustained-release carrier to the drug gradually decreases from the inner layer to the outside. Through this design, the speed of drug release can be well controlled, so as to adapt to the mechanism of lesion healing.

[0022] The preparation method of the present invention is further illustrated by several specific examples below.

[0023] Example 1

[0024] The preparation method of the drug-eluting stent is as follows: (1) Processing of the stent: the stent can be woven by a weaving machine or cut from a tubular material; (2) Grafting of the innermost layer of sirolimus drug: the processed bare stent must first be subjected to oxygen plasma glow treatment, with a discharge power of 80 W, a treatment time of 15 min, and an oxygen flow rate of 400 mL / min; the stent treated with oxygen plasma is placed on a stent support, and the sirolimus drug is dissolved in acetone at a concentration of 5%; a plasma generator is used to perform plasma glow discharge, so that sirolimus is deposited on the stent in an ionic state, with a glow discharge deposition time of 25 min and a discharge power of 120 W; (3) Spraying of the second layer of drug coating: ① Prepare an acetone solution of the drug, the drug solubility is 3%; physically spray the drug solution on the entire stent, the spray thickness is 0.1 μm; ② After spraying, place the stent on a stent support, and continue to use oxygen plasma to cross-link it, the plasma glow discharge time is 15 minutes, and the discharge power is 120W; (4) Spraying of other drug layers: Repeat the spraying process of step (3) on the middle section of the drug stent, wherein in the spraying of each layer, the plasma glow process from inside to outside is as follows: the third layer glow discharge time is 10 minutes, the discharge power is 80W, the fourth layer glow discharge time is 8 minutes, the discharge power is 80W, the fifth layer glow discharge time is 5 minutes, and the discharge power is 50W.

[0025] Example 2

[0026] The preparation method of the drug-eluting stent is as follows: (1) stent processing: the stent can be woven by a weaving machine or cut from a tubular material; (2) grafting of the innermost drug layer: the sustained-release carrier is polylactic acid and the drug is sirolimus, the ratio of the two is 5:1, and acetone is used for dissolution, and the solubility is 3%; the processed bare stent must first be subjected to oxygen plasma glow treatment, with a discharge power of 80W, a treatment time of 15min, and an oxygen flow rate of 400mL / min; The stent treated with oxygen plasma is placed on the stent support, and the prepared solution is used for plasma glow discharge using a plasma generator to deposit polylactic acid and sirolimus on the stent in an ionic state. The glow discharge deposition time is 30 minutes and the discharge power is 100W. (3) Spraying of the second layer of drug coating: ① The ratio of the sustained-release carrier to the drug is 2:1, and acetone is used for dissolution with a solubility of 3%. The drug solution is physically sprayed on the entire stent with a spray thickness of 0.5 μm. ② After spraying, the stent is placed on the stent support. On the other hand, oxygen plasma was continued to be used for cross-linking treatment, and the plasma glow discharge time was 12 minutes and the discharge power was 120W; (4) Spraying of other drug layers: the spraying process of step (3) was repeated for the middle section of the drug stent, wherein in the spraying of each layer, the plasma glow process from the inside to the outside was as follows: the ratio of the third layer sustained-release carrier to the drug was 1:1, the glow discharge time was 10 minutes, and the discharge power was 100W; the ratio of the fourth layer sustained-release carrier to the drug was 1:2, the glow discharge time was 5 minutes, and the discharge power was 50W.

[0027] The drug stent and its preparation method of the present invention can also be suitable for the preparation of other interventional devices (such as drug balloons). Those skilled in the art will understand that the above description is only exemplary. That is, all equivalent changes and modifications made according to the content of the patent application scope of the present invention should be within the technical scope of the present invention.

Claims

1. A drug-eluting stent, comprising a distal end, a proximal end and a middle section, wherein the drug-eluting stent contains multiple layers of drugs, characterized in that: The length of the middle section of the drug stent accounts for 50% to 100% of the entire stent; the multilayer drugs at the distal and proximal ends of the drug stent are 2 layers, and the multilayer drugs in the middle section are 2 to 5 layers; the number of drug layers in the middle section is more than that at the distal and proximal ends; the radial support force at the distal and proximal ends is slightly greater than that of the middle section to prevent the stent from migrating in the blood vessel; the release rate of each layer of the multilayer drugs gradually decreases from the outer layer to the inner layer; the preparation method of the drug stent is as follows: (1) stent processing: the stent is woven by a braiding machine, or is cut from a tubular material; (2) the innermost layer of drug grafting: ① the processed stent is subjected to oxygen plasma glow discharge treatment: the discharge power is 20-300W, the treatment time is 5 to 30min, and the oxygen flow rate is 100mL / min to 800mL / min; ② the stent treated with oxygen plasma is The stent is placed on a stent support, and an organic solvent is used to dissolve the drug and the sustained-release carrier; the drug solution is treated in a plasma state, and the treated drug plasma is deposited on the stent, the glow discharge deposition time is 2min~45min, and the discharge power is 30-300W; (3) Spraying of the second layer of drug coating: ① Prepare an organic solution of the drug; physically spray the drug solution on the distal, proximal and middle sections, and the spraying thickness is 10nm~100μm; ② After spraying, the stent is placed on a stent support and cross-linked by plasma, the plasma glow discharge time is 2~30min, and the discharge power is 15-500W; (4) Spraying of other drug coatings: Repeat the spraying process of step (3) for the middle section of the drug stent, wherein in the spraying of each layer, the time and power of the plasma glow discharge treatment are gradually reduced from the inner layer to the outer layer.

2. The drug stent according to claim 1, characterized in that The ratio of the sustained-release carrier to the drug in each layer of the multi-layer drug gradually decreases from the inner layer to the outer layer.

3. The drug stent according to claim 2, characterized in that The ratio of the sustained-release carrier to the drug in the multi-layer medicine is 5:1, 4:1, 3:1, 2:1, 1:1 or 1:

2.

4. The drug stent according to claim 1, characterized in that The drug cross-linking degree of each drug coating layer gradually decreases from the inner layer to the outer layer.

5. The drug stent according to claim 1, characterized in that The multilayered medicine is a medicine for resisting smooth muscle cell proliferation.

6. The drug stent according to claim 1, characterized in that The multilayered medicine is an antibody medicine capable of specifically capturing endothelial progenitor cells.

7. The drug stent according to claim 1, characterized in that The innermost layer of the multi-layer drug is grafted onto the surface of the stent through chemical bonds.

8. The drug stent according to claim 5, characterized in that The anti-smooth muscle cell proliferation drugs include one or more active drugs such as sirolimus, acipimox, tacrolimus, eromoxil, immunosuppressant ABT-578, dexamethasone, paclitaxel and its derivatives, actinomycin, vincristine and its derivatives, statins, 2-chlorodeoxyadenosine, ribozymes, probucol, estradiol, etc.