COMPOSITE ANTI-RESTENOSIS DRUG FOR CORONARY DRUG-ELUTING STENT AND CONTROLLED RELEASE SYSTEM THEREOF

Abstract

A composite anti-restenosis drug for use with a coronary drug-eluting stent, and a controlled release system for the drug. The composite drug comprises arsenic trioxide and rapamycin, which may be used in combination to prevent in-stent restenosis and reduce the incidence of intravascular thrombosis. The controlled release system for the composite drug may control the release of the composite drug so as to achieve the therapeutic effect of controlling restenosis and preventing the formation of thromboses.

Claims

1. A composite drug for a coronary drug-eluting stent comprising As.sub.2O.sub.3 and Sirolimus.

2. The composite drug according to claim 1, wherein, based on a stent having an opened external diameter of 3.0 mm, the amount of As.sub.2O.sub.3 used is 1 to 8 g/mm and the amount of the Sirolimus used is 1 to 8 g/mm.

3. Use of the composite anti-restenosis drug for coronary drug-eluting stent according to claim 1 in the manufacture of a controlled release system of a composite drug for a coronary drug-eluting stent for controlling restenosis and preventing thrombosis.

4. A composite drug controlled release system for a coronary drug-eluting stent comprising a drug layer formed by coating the composite drug according to claim 1 on the stent.

5. The composite drug controlled release system according to claim 4, further comprising a degradable polymer material as a drug carrier to control the drug release, which degradable polymer material includes one or more of polyactide (PLA), polyglycolide (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolac(PCL), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).

6. The composite drug controlled release system according to claim 5, wherein the weight ratio between the degradable polymer material and the composite drug is between 1:0.3 and 1:10.

7. The composite drug controlled release system according to claim 4, wherein during the preparation of the composite drug controlled release system from the composite drug for coronary drug-eluting stent, As.sub.2O.sub.3 and Sirolimus, or As.sub.2O.sub.3, Sirolimus and the degradable polymer material are mixed in a designed ratio.

8. The composite drug controlled release system according to claim 4, wherein the drug layer is a composite drug monolayer structure, which is a layer of the composite drug or the composite drug and the degradable polymer material proportionally and uniformly mixed.

9. The composite drug controlled release system according to claim 4, wherein the drug layer is a composite drug multilayer structure, which comprises a plurality of layers of the composite drug or the composite drug and the degradable polymer material that are proportionally and uniformly mixed, wherein in the composite drug multilayer structure, each layer independently: comprises only one drug; comprises only the composite drug; comprises only the degradable polymer material; comprises only one drug and the degradable polymer material; and/or comprises only the composite drug and the degradable polymer material.

10. The composite drug controlled release system according to claim 4, further comprising a transitional layer interposed between the stent surface and the composite drug controlled release system having a material selected from a degradable polymer material or other materials with good biocompatibility.

11. A method for controlling restenosis and preventing thrombosis with a coronary drug-eluting stent, comprising: implanting a stent having a drug layer into the coronary artery of an individual in need thereof, wherein the drug layer includes a drug layer formed by coating the composite drug for coronary drug-eluting stent according to claim 1.

12. The method for controlling restenosis and preventing thrombosis with a coronary drug-eluting stent according to claim 11, wherein, based on a stent having an opened external diameter of 3.0 mm, the amount of As.sub.2O.sub.3 used is 1 to 8 g/mm and the amount of the Sirolimus used is 1 to 8 g/mm.

13. The composite drug controlled release system according to claim 4, wherein, based on a stent having an opened external diameter of 3.0 mm, the amount of As.sub.2O.sub.3 used is 1 to 8 g/mm and the amount of the Sirolimus used is 1 to 8 g/mm.

14. The composite drug controlled release system according to claim 8, wherein based on the stent having an opened external diameter of 3.0 mm, the amount of As.sub.2O.sub.3 used is 4 to 8 g/mm and the amount of the Sirolimus used is 1 to 5 g/mm.

15. The composite drug controlled release system according to claim 9, wherein based on the stent having an opened external diameter of 3.0 mm, the amount of As.sub.2O.sub.3 used is 4 to 8 g/mm and the amount of the Sirolimus used is 1 to 5 g/mm.

16. The composite drug controlled release system according to claim 10, wherein the composite drug controlled release system further comprises a surface protecting layer consisting of a degradable polymer material.

Description

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

[0030] FIG. 1 shows the effect of arsenic trioxide on primary porcine coronary vascular smooth muscle cells in an in vitro experiment.

[0031] FIG. 2 shows the effect of arsenic trioxide on primary porcine coronary endothelial cells in an in vitro experiment.

[0032] FIG. 3 shows the profile of the arsenic trioxide release rate of a drug coating in which the mixing ratio of arsenic trioxide to polymer material (degradable PLGA) is 1:1.

[0033] FIG. 4 shows the profile of the arsenic trioxide release rate of a drug coating in which the mixing ratio between arsenic trioxide, polymer material (degradable PLGA) and Sirolimus is 1:1:0.4.

[0034] FIG. 5A shows the OCT results of porcine coronary (LAD) lumen and vascular endothelium repair when a stent with optimized composite drug (Group 4, monolayer structure, Formulation B) is used. In the figure, the bright short-bar image along the inner wall of the vessel is the cross section of the stent.

[0035] FIG. 5B shows the OCT angiography of pure arsenic trioxide-plated stent (3.017 mm, control group 1, monolayer structure) one month after being implanted into the porcine right circumflex coronary artery.

[0036] FIG. 5C shows the OCT angiography of a pure RAPA-plated stent (3.017 mm, control group 2, monolayer structure)one month after being implanted into the porcine left circumflex coronary artery.

[0037] FIG. 5D shows the OCT angiography of a composite drug stent (3.017 mm) with the composite drug monolayer-structured release system (Implementation Method 1, Group 3, monolayer structure, Formulation A) three months after being implanted into the porcine left circumflex coronary artery.

[0038] FIG. 5E shows the OCT angiography of a composite drug stent (3.017 mm) with the composite drug multilayer-structured release system (each layer comprising only a single drug of arsenic trioxide or Sirolimus, Implementation Method 2, Group 5, bilayer structure) composite drug stent (3.017 mm) three months after being implanted into the porcine left anterior descending coronary artery.

[0039] FIG. 6 shows a profile of optimized arsenic trioxide cumulative release.

[0040] FIG. 7 shows a profile of Sirolimus cumulative release in the controlled release system of Group 4.

DETAILED DESCRIPTION OF THE INVENTION

[0041] For better understanding of the technical features, purposes and beneficial effects of the present invention, the technical solutions of the present invention will now be set forth in details in connection with the specific examples and the accompanying drawings. It will be appreciated that these examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

Example 1

1. In Vitro Experiment of the Effect of Arsenic Trioxide on Smooth Muscle Cells and Endothelial Cells of Porcine Coronary Vessels

[0042] FIGS. 1 and 2 show the effects of arsenic trioxide on primary smooth muscle cells and primary endothelial cells of porcine coronary vessels in in vitro experiments. In the figures, the vertical axis represents the total number of cells in the wells of the culture plate, and the horizontal axis represents the concentration of the arsenic trioxide solution. Each curve represents the effect of arsenic trioxide at various concentrations on apoptosis (decrease in total number of cells) at a given time. It can be clearly seen from the figure (FIG. 2) that arsenic trioxide has little effect of on endothelial cells (at a concentration of 12 M or below) and even has an effect of promoting proliferation of endothelial cell to a certain extent (FIG. 2). However, for smooth muscle cells, cells apoptosis began even at low concentrations (3 M) from Day 2 (FIG. 1). It is sufficiently demonstrated that arsenic trioxide has different effects on different types of cells of coronary vessels. Arsenic trioxide may induce apoptosis of smooth muscle cells while having poor inhibitory effect on endothelial cells or even promoting their growth.

2. Impact of Adding Sirolimus in the Drug Delivery System on Arsenic Trioxide Release

[0043] In designing a drug controlled release system for a drug-eluting stent, the drug and degradable polymer material must be mixed together in a certain manner to be sprayed on the stent, and the drug will be released from the polymer materials after the stent is implanted. Sirolimus can be dissolved in a variety of common organic solvents, and controlled release system can be easily designed by using Sirolimus as an anti-restenosis drug. Arsenic trioxide is an inorganic oxide, with only one crystal form thereof out of three slightly soluble in water, while it cannot be dissolved in common solvents such as ethanol. This makes the subsequent mixing with the polymer material difficult. In addition, it has shown in the experiments that even if arsenic trioxide was mixed in a polymer material in a particulate state, the release rate of the drug could not meet the requirement for clinically effective therapeutic effect until the arsenic trioxide reached a very high concentration. However, this high concentration state significantly reduces the total spraying amount (0.3 g/mm.sup.2) of the polymer material and the drug, which not only makes it difficult to control the spraying process but affects the uniformity of the drug in clinical use as well.

[0044] FIG. 3 shows profile of arsenic trioxide release from a drug coating in which the mixing ratio of arsenic trioxide/polymer material is 1:1. The release rate reached a maximum of about 28% in about a week and then increased very slowly.

[0045] After adding Sirolimus to the arsenic trioxide/polymer material mixture at the same ratio (FIG. 4, the mixed ratio of arsenic trioxide, polymer material and Sirolimus is 1:1:0.4), for the stents of all sizes in the experiment, The release rate of arsenic trioxide was almost three times that of the original.

Example 2

[0046] In this example, two implementation methods, which achieve controlled drug release by changing the structure (monolayer or multilayer) of the drug release system (drug coating) and the ratio between drug and polymer material in each layer, are exemplified.

Implementation Method 1: Monolayer-Structured Composite Drug Release System

[0047] In this monolayer-structured release system of mixed drugs, arsenic trioxide, Sirolimus, and a polymer material PLGA are included. By adjusting the ratio between drugs and that between the drug and the polymer material, the drug release profile is changed to achieve the objective of controlled drug release.

[0048] As long as there is no adverse interaction between the mixed drugs, a variety of anti-restenosis drugs such as arsenic trioxide, Sirolimus, paclitaxel or the like can be selected for drug mixing in theory. In consideration of clinical and manufacturing optimization, two drugs, arsenic trioxide and Sirolimus, may be selected for mixing. Upon consideration for further optimization, in the formulation of the composite drug, the amount of As.sub.2O.sub.3 used is 4 to 8 g/mm, and the amount of the Sirolimus used is 1 to 5 g/mm. These amounts are based on a stent having an opened external diameter of 3.0 mm, and the use amount of drugs should be increased in proportion to the actual surface area of the stent for a stent having a larger opened external diameter.

[0049] In such a structure, a layer of polymer material or other materials may be added between the single layer of the mixed drug layer and the stent surface, so as to increase the adhesion of the drug layer to the stent surface. A polymer material or other materials may be spray coated on the outer surface of the monolayer mixed drug layer in order to protect the mixed drug layer, preventing the mixed drug layer from rupture during stent implantation.

[0050] In the process of implementing the monolayer-structured composite drug release system, the ratio between Sirolimus and the degradable polymer material PLGA could be adjusted to allow the release of Sirolimus to reach an optimal profile (FIG. 6), and arsenic trioxide was further added into the system without any substantial impact on the Sirolimus release profile. However, as the mixed ratio between arsenic trioxide and Sirolimus varied, the release rate of arsenic trioxide also changed. The release rate of arsenic trioxide increased as the ratio of arsenic trioxide to Sirolimus became higher. FIG. 4 shows these changes, in which the ratio of arsenic trioxide to Sirolimus is 5:2 in Formulation B and the ratio of arsenic trioxide to Sirolimus is 5:4 in Formulation A, with the release rate of arsenic trioxide of Formulation B significantly higher than that of Formulation A, which is substantially consistent with the optimal profile of arsenic trioxide release (FIG. 7). The stent with Formulation B also performed better in subsequent animal model tests.

[0051] With the mixing of Sirolimus and arsenic trioxide, the release property of arsenic trioxide is greatly improved, and it is thus possible to make the release of both Sirolimus and arsenic trioxide meet the release profile in accordance with clinical requirements by properly adjusting the usage ratio of Sirolimus to arsenic trioxide, thereby producing optimal clinical results. Also, since there is only one mixed drug layer, the drug spraying process for the stent becomes simple and easy.

Implementation Method 2: Multilayer-Structured (Each Layer Comprising a Single Drug) Composite Drug Release System

[0052] In this release system, there are a plurality of drug layers, with each layer comprising only a single drug and an optional polymer material. By adjusting the number of drug layers, the ratio between the drugs and the polymer material in each layer and the relative position of each drug layer, an optimal drug release is achieved.

[0053] With regard to the use amount for the drug, the total amount of As.sub.2O.sub.3 used in the overall system is 4 to 8 g/mm and the total amount of the Sirolimus used in the overall system is 1 to 5 g/mm. These amounts are based on a stent having an opened external diameter of 3.0 mm, and the use amount of drugs should be increased in proportion to the actual surface area of the stent for a stent having a larger opened external diameter.

[0054] In such a structure, a layer of polymer material or other materials with good biocompatibility may be added between the lowest drug layer and the stent surface, for example, a layer of porous metal titanium may be plated on the metallic stent surface, so as to increase the adhesion of the drug layer to the stent surface. A polymer material or other materials may be spray coated on the outer surface of the outermost drug layer in order to protect the drug layers, preventing the drug layers from rupture during stent implantation.

Implementation Method 3: Multilayer-Structured (Each Layer Comprising One Drug or a Mixed Drug of Two or More Drugs) Composite Drug Release System

[0055] In this release system, there are a plurality of drug layers, with each layer comprising one or two or more drugs and an optional polymer material. By adjusting the number of drug layers, the ratio between the drugs and that between the drugs and the polymer material in each layer, as well as the relative position of each drug layer, an optimal drug release is achieved.

[0056] With regard to the drug use amount, the total amount of As.sub.2O.sub.3used in the overall system is 2 to 10 g/mm and the total amount of the Sirolimus used in the overall system is 2 to 12 g/mm. These amounts are based on a stent having an opened external diameter of 3.0 mm, and the use amount of drugs should be increased in proportion to the actual surface area of the stent for a stent having a larger opened external diameter.

[0057] In such a structure, a layer of polymer material or other materials with good biocompatibility may be added between the lowest drug layer and the stent surface, so as to increase the adhesion of the drug layer to the stent surface. A polymer material or other materials may be spray coated on the outer surface of the outermost drug layer in order to protect the drug layers, preventing the drug layers from rupture during stent implantation.

Animal Model Experiment Results with Implementation Methods 1 and 2

[0058] Comparative experiments were conducted on porcine coronary animal models by using drug-eluting stents prepared by the implementation methods 1 and 2, respectively. Grouping is shown below:

TABLE-US-00001 Number of Implementation Structure of stents Group Drug method the coating layer implanted 1 As.sub.2O.sub.3 Control group Monolayer structure 7 As.sub.2O.sub.3: 3 g/mm + PLGA surface protecting layer 2 Sirolimus Control group Monolayer structure 8 RAPA: 8 g/mm PLGA: 18 g/mm 3 As.sub.2O.sub.3 + Method 1 Mixed drug monolayer 10 Sirolimus structure (Formulation A) As.sub.2O.sub.3: 5 g/mm RAPA: 4 g/mm PLGA: 9 g/mm 4 As.sub.2O.sub.3 + Method 1 Mixed drug monolayer 8 Sirolimus structure (Formulation B) As.sub.2O.sub.3: 5 g/mm RAPA: 2 g/mm PLGA: 4.6 g/mm 5 As.sub.2O.sub.3 + Method 2 Bilayered drug 10 Sirolimus structure As.sub.2O.sub.3: 3 g/mm RAPA: 4 g/mm + PLGA surface protecting layer

[0059] Coronary angiography and OCT examination results from some stents after stent implantation are shown in the following table:

TABLE-US-00002 Number of Implementation stents Duration of Examination Group Drug method implanted implantation method Result 1 As.sub.2O.sub.3 Control 7 1 month Angiography 3 stents with mediate group to mild stenosis The rest fine 2 Sirolimus Control 8 1 month Angiography 3 stents with mediate group to mild stenosis The rest fine 3 As.sub.2O.sub.3 + Method 1 10 3 months Angiography, All showed good Sirolimus OCT angiography, with no in-stent restenosis; 2 stents with mild stenosis at the opening 3 were subjected to OCT observation Good endothelialization 4 As.sub.2O.sub.3 + Method 1 8 3 months Angiography, All showed good Sirolimus OCT angiography, with no in-stent restenosis; 3 stents with mild stenosis at the opening 3 were subjected to OCT observation Good endothelialization 5 As.sub.2O.sub.3 + Method 2 10 3 months Angiography, All showed good Sirolimus OCT angiography, with no in-stent restenosis; 4 stents with mild stenosis at the opening 4 were subjected to OCT observation Good endothelialization, with 2 having thicker endothelium

[0060] Groups 1 and 2 were stents with pure arsenic trioxide or Sirolimus respectively that were used as a control group. Groups 3, 4, and 5 were stents with a composite drug (arsenic trioxide and Sirolimus). As compared to those with pure anti-restenosis drugs (arsenic trioxide or Sirolimus as used in this experiment), stents with the composite drug (arsenic trioxide and Sirolimus) showed better in-stent anti-restenosis ability under coronary angiography conditions. The results from OCT observation showed that the coronary vascular endothelium completely covered the stent surface within 3 months when the stent with composite drug was used. Here, FIG. 5A shows the OCT results of porcine coronary (LAD) lumen and vascular endothelium repair when a stent with optimized composite drug (Group 4, monolayer structure, Formulation B) was used; in this figure, the bright short-bar image along the inner wall of the vessel is the cross section of the stent, showing that no in-stent restenosis is observed and the stent is completely covered by the endothelium three months after the stent with the monolayer mixed drug formulation B (Group 4) was implanted. FIG. 5B shows the OCT angiography of pure arsenic trioxide-plated stent (3.017 mm, control group 1, monolayer structure) one month after being implanted into the porcine right circumflex coronary artery; the image shows that the stent surface is completely covered by the endothelium, with a slightly thicker endothelium. FIG. 5C shows the OCT angiography of a pure RAPA-plated stent (3.017 mm, control group 2, monolayer structure) one month after being implanted into the porcine left circumflex coronary artery; the image shows that part of the stent surface is not well covered by the endothelium. FIG. 5D shows the OCT angiography of a composite drug stent (3.017 mm) with the composite drug monolayer-structured release system (Implementation Method 1, Group 3, monolayer structure, Formulation A) three months after being implanted into the porcine left circumflex coronary artery; the image shows that the stent surface is completely covered by the endothelium with an uniform endothelial thickness. FIG. 5E shows the OCT angiography of a composite drug stent (3.017 mm) with the composite drug multilayer-structured release system (each layer comprising only a single drug of arsenic trioxide or Sirolimus, Implementation Method 2, Group 5, bilayer structure) composite drug stent (3.017 mm) three months after being implanted into the porcine left anterior descending coronary artery; the image shows that the stent surface is completely covered by the endothelium with an uniform endothelial thickness.

[0061] Last but not least, it should be noted that the above examples are merely illustrative of the implementation processes and features of the present invention and not limiting the technical solutions of the present invention. Even though the present invention are described in details with reference to these examples, persons skilled in the art would recognize that modification or equivalent substitution can be made to the present invention and any modification or partial substitution made without departing from the spirit and scope of the present invention is intended to be encompassed within the scope of protection of the present invention.