CN117860976A

CN117860976A - Drug stent and preparation method thereof

Info

Publication number: CN117860976A
Application number: CN202410033894.8A
Authority: CN
Inventors: 王兴娅; 候娟
Original assignee: Microport Neurotech Shanghai Co Ltd
Current assignee: Microport Neurotech Shanghai Co Ltd
Priority date: 2024-01-09
Filing date: 2024-01-09
Publication date: 2024-04-12

Abstract

The invention provides a drug stent and a preparation method thereof, wherein a grid framework is treated by using a drug solution under a preset condition, a drug coating with holes is further formed on the grid framework, and the drug coating has target porosity, so that the optimal drug release rate and the optimal blood vessel wall drug concentration are achieved.

Description

Drug stent and preparation method thereof

Technical Field

The invention relates to the technical field of medical equipment, in particular to a drug stent and a preparation method thereof.

Background

Vascular atherosclerosis is an important causative factor in causing vascular stenosis and inducing ischemia in tissue. According to the "pan-vascular" theory, vascular atherosclerotic stenosis can occur in the internal carotid, coronary, iliac, femoral, popliteal, etc. systemic arterial vessels. Vascular intervention is an effective means for treating arteriosclerotic vascular stenosis, and the treatment scheme of the vascular intervention is subjected to the evolution process of simple balloon expansion, metal bare stent expansion, drug eluting stent expansion, drug balloon expansion and degradable drug stent expansion. Currently, drug eluting stents are the mainstay of treatment for atherosclerotic stenoses by virtue of the good inhibition of smooth muscle cells by drugs and the good support of bare metal stents. The drug eluting stent is easy to induce activation and adhesion of substances such as blood platelets, fibrinogen and the like in blood in the early stage of implantation, forms thrombus on the stent and even causes vascular restenosis, so that cerebral blood supply of patients is insufficient, even cerebral infarction and the like. Because the double-antibody medicine is taken for anticoagulation treatment after stent implantation, the risk of bleeding caused by unknown reasons is increased. For the above reasons, the combination of antithrombotic and drug-loaded stents would be a new medical device to address thrombotic and restenosis events.

The traditional drug-loading mode of the drug-eluting stent comprises ultrasonic full-spray drug loading, notch drug loading, micropore drug loading and the like, wherein the notch drug loading is carried out by a mode of single-sided notch drug loading of the stent, so that the effective dosage of vascular lesions is ensured, the problems of abrasion and stripping of a drug coating are avoided, meanwhile, the notch drug-loading stent has a certain thickness due to the drug coating, and in the process of polymer degradation and drug release caused by the stent being attached to the vascular wall, the rate of polymer degradation is influenced due to the attaching degree of the thickness direction of the drug coating and the vascular wall and the structure inside the coating, and the rate of drug release is influenced, so that the occurrence of vascular restenosis is inhibited to the maximum extent in order to optimally match the proliferation period of smooth muscle, and the drug release rate is regulated to be equivalent to the proliferation period of smooth muscle, so that the stent is the most important problem which needs to be urgently solved at present. If the degradation period of the antiproliferative drug is not completely matched with the proliferation period of smooth muscle, the problems of restenosis in blood vessels or incomplete endothelialization of blood vessels can be caused, so that the matching of the degradation period of different drugs with the proliferation period of smooth muscle is the most important. However, the problem cannot be solved well at present, and the medicine is degraded too fast or slow.

Therefore, it is a urgent problem for those skilled in the art how to design a drug stent that optimally matches the proliferation cycle of smooth muscle and maximally inhibits occurrence of restenosis.

It should be noted that the information disclosed in the background section of the present application is only for enhancement of understanding of the general background of the present application and should not be taken as an admission or any form of suggestion that this information forms the prior art already known to a person skilled in the art.

Disclosure of Invention

Therefore, the invention aims to provide a drug stent and a preparation method thereof, which aim to regulate the porosity of a drug coating so that the drug release rate is better matched with smooth muscle proliferation and migration periods.

In order to achieve the above object, the present invention provides a method for preparing a drug stent, comprising:

treating the lattice framework with a drug solution comprising a drug and a degradable polymer under predetermined conditions to form a drug coating with holes on the lattice framework and to provide the drug coating with a target porosity.

Optionally, the predetermined condition is that an inert gas is sprayed to the drug solution by using a nozzle, so that the drug solution generates holes in the process of forming the drug coating on the grid framework under the action of the inert gas.

Optionally, the drug coating achieves the target porosity based on a porosity of the nozzle, the porosity of the nozzle being not less than a porosity of the drug coating.

Optionally, the pressure at which the inert gas is injected is 0.1MPa to 0.3MPa, and/or the porosity of the nozzle is 20% to 40%.

Optionally, the predetermined condition is that a surfactant is added to the drug solution, so that the drug solution generates holes in the process of forming the drug coating on the grid framework under the action of the surfactant.

Optionally, the drug coating achieves the target porosity based on the surfactant content.

Optionally, the content of the surfactant is 0.02% -20%.

Optionally, the target porosity is obtained based on a number of factors including the type of degradable polymer, the molecular weight of the degradable polymer, the drug loading mode, the drug-to-polymer ratio, and the drug coating thickness.

Optionally, the method further comprises:

and arranging the drug coating in the notch of the grid framework, wherein the target porosity of the drug coating in the same notch is increased from inside to outside.

Optionally, two layers of the drug coating are arranged in the same notch, and the target porosity of the outer layer in the two layers of the drug coating is greater than that of the inner layer.

Optionally, the method further comprises:

and a plurality of drug coatings are arranged on the grid framework, the drug coatings are arranged in the same notch of the grid framework, and/or the drug coatings are arranged on the surface of the grid framework.

Optionally, the plurality of the drug coatings include an antiproliferative drug coating, the plurality of the drug coatings further includes at least one of an anticoagulant drug coating and an endothelialization-promoting drug coating, the antiproliferative drug coating is disposed in the grooves of the lattice framework, the anticoagulant drug coating is disposed on the surface of the lattice framework, and the endothelialization-promoting drug coating is disposed on the surface of the lattice framework or in the same groove as the antiproliferative drug coating.

Based on the same inventive concept, the invention also provides a drug stent, which is prepared by the preparation method of any one of the drug stents.

As described above, in preparing the drug stent, the present invention may treat the lattice framework with a drug solution containing a drug and a degradable polymer under predetermined conditions to form a drug coating layer with holes on the lattice framework and to provide the drug coating layer with a target porosity. By the arrangement, the drug release rate can be regulated more conveniently and accurately, the drug release rate can be faster, the regulating difficulty of the drug release rate is reduced, and the drug release rate can be controlled more accurately, so that the drug release rate is better matched with the smooth muscle proliferation and migration period.

Because the preparation methods of the drug stent and the drug stent provided by the application belong to the same invention conception, the drug stent provided by the application has all the advantages of the preparation method of the drug stent provided by the application, and the beneficial effects of the drug stent provided by the application are not repeated here.

Drawings

Those of ordinary skill in the art will appreciate that the figures are provided for a better understanding of the present invention and do not constitute any limitation on the scope of the present invention. Wherein:

fig. 1 to 4 are schematic structural views of a drug coating layer according to an embodiment of the present invention disposed in grooves on a lattice framework;

fig. 5 is a schematic structural diagram of a tooling device according to an embodiment of the present invention;

FIG. 6 is an experimental result of drug release rate provided according to an embodiment of the present invention; wherein, the abscissa is time, and the ordinate is drug release rate (%);

fig. 7 is a schematic diagram of a skeleton surface structure for forming a drug coating by surface coating according to a second embodiment of the present invention;

FIG. 8 is a schematic cross-sectional view of a skeleton with drug coating formed by surface coating drug delivery according to a second embodiment of the present invention;

FIG. 9 is a graph showing the experimental results of drug release rates provided in accordance with the second embodiment of the present invention; wherein, the abscissa is time, and the ordinate is drug release rate (%);

FIG. 10 is a schematic cross-sectional view of a skeleton for forming a drug coating in a slotted drug delivery mode, according to a third embodiment of the present invention;

FIG. 11 is an experimental result of drug release rate provided in accordance with example III of the present invention; wherein, the abscissa is time, and the ordinate is drug release rate (%);

fig. 12 is a schematic cross-sectional view of a skeleton for forming a drug coating in a grooved drug delivery manner according to a fourth embodiment of the present invention, wherein the drug coating in the same groove has different porosities from inside to outside.

Wherein reference numerals are as follows:

1-a nozzle; 2-a spray head; 3-a drug solution; 4-gas channels; 10-a drug coating; 101-an outer layer; 102-an inner layer; 11-holes; 21-grid bars; 22-grooving; 23-corner.

Detailed Description

The invention will be described in further detail with reference to the drawings and the specific embodiments thereof in order to make the objects, advantages and features of the invention more apparent. It should be noted that the drawings are in a very simplified form and are not drawn to scale, merely for convenience and clarity in aiding in the description of embodiments of the invention. Furthermore, the structures shown in the drawings are often part of actual structures. In particular, the drawings are shown with different emphasis instead being placed upon illustrating the various embodiments.

As used in this disclosure, the singular forms "a," "an," and "the" include plural referents, the term "or" is generally used in the sense of comprising "and/or" and the term "several" is generally used in the sense of comprising "at least one," the term "at least two" is generally used in the sense of comprising "two or more," and the term "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying any relative importance or implying any particular order of such items. Thus, a feature defining "first", "second" may explicitly or implicitly include one or at least two such features, the term "proximal" typically being one end near the operator, the term "distal" typically being one end near the patient, "one end" and "another end" and "proximal" and "distal" typically referring to corresponding two parts, including not only the endpoints, the terms "mounted", "connected" should be construed broadly, e.g., may be a fixed connection, may be a removable connection, or may be integral; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communicated with the inside of two elements or the interaction relationship of the two elements. Furthermore, as used in this disclosure, an element disposed on another element generally only refers to a connection, coupling, cooperation or transmission between two elements, and the connection, coupling, cooperation or transmission between two elements may be direct or indirect through intermediate elements, and should not be construed as indicating or implying any spatial positional relationship between the two elements, i.e., an element may be in any orientation, such as inside, outside, above, below, or on one side, of the other element unless the context clearly indicates otherwise. The specific meaning of the above terms in the present invention can be understood by those of ordinary skill in the art according to the specific circumstances.

The core idea of the invention is to provide a drug stent and a preparation method thereof, which aim to regulate the porosity of a drug coating so that the drug release rate is better matched with the smooth muscle proliferation and migration cycle.

Compared with the prior art, the invention can more precisely control the release rate of the medicine, thereby better inhibiting the proliferation of smooth muscle cells in early implantation and promoting vascular endothelialization in time in late implantation so as to improve the treatment effect.

The following description refers to the accompanying drawings.

Referring to fig. 1 to 4, 7 to 8, 10 and 12, an embodiment of the present invention provides a drug stent including a lattice framework and a drug coating 10 formed on the lattice framework. The grid framework is a cutting bracket or a weaving bracket, and most of the grid frameworks are cutting brackets. The drug coating 10 is formed by coating the mesh skeleton with a drug solution. The drug coating 10 comprises a drug and a degradable polymer, and typically the drug coating 10 is composed of only the drug and the degradable polymer. The drug coating 10 may comprise a drug or a combination of drugs, or may comprise a degradable polymer or a combination of degradable polymers.

The drug stent of the invention carries at least an antiproliferative drug, preferably, the drug stent can also carry at least one of an endothelialization promoting drug and an anticoagulant drug. Antiproliferative agents such as sirolimus, paclitaxel, derivatives of sirolimus or other commonly used agents. The degradable polymer is, for example, a common degradable polymer such as polylactic acid (PLA), polycaprolactone (PCL), polylactic acid-polyglycolic acid copolymer (PLGA) and corresponding copolymer formed by combining any monomers in any proportion, or corresponding homopolymer. It should be understood that the drug may be various conventional antiproliferative drugs, and the degradable polymer may be various conventional degradable polymers. Therefore, in addition to the drugs and degradable polymers exemplified in the examples, those skilled in the art can find other alternative materials to achieve the functions/effects described in the present invention based on the description of the present invention, and do not include only the embodiments disclosed in the examples of the present invention.

The drug-carrying mode of the drug stent of the present invention is preferably at least one of notched drug-carrying and surface-coated drug-carrying.

The grooving and drug loading means that the grid rods 21 on the grid framework are provided with grooves 22 (namely grooves), and the grooves 22 are filled with drug solution to form the drug coating 10. It will be appreciated from the example depicted in fig. 4 that the drug coating 10 is disposed within the score groove 22, the score groove 22 being disposed on the mesh rod 21, with particular regard to the score groove 22 being disposed on the mesh rod 21 at a location other than the corner 23.

The surface coating drug-carrying means that the drug solution is directly coated on the surface of the mesh rod 21 of the mesh skeleton to form the drug coating 10. As will be appreciated from the embodiment described in fig. 7 and 8, the drug coating 10 is directly adhered to the surface of the mesh rod 21, at least the outer surface of the mesh rod 21 needs to be covered, and the degree of covering the mesh rod 21 is not limited on the basis of covering the outer surface of the mesh rod 21, and for example, the side surface and/or the inner surface of the mesh rod 21 may be further covered, and the side surface of the mesh rod 21 refers to a portion located between the outer surface and the inner surface of the mesh rod 21.

The treatment of the lattice framework with the drug solution includes, but is not limited to, spraying, for example, dip coating.

The thickness of the drug coating 10 should be set according to the drug release requirements. The drug coating 10 should not be too thick or too thin, which avoids increasing the delivery resistance, ensures the effectiveness of drug delivery, and reduces drug loss during delivery. Alternatively, the thickness of the drug coating 10 is 1 μm to 100 μm, and more preferably 1 μm to 60 μm.

Further, the drug coating 10 contains holes 11, and the shape of the holes 11 is not required. The number and size of the holes 11 can be adjusted and controlled during the coating process, and finally the drug coating 10 formed on the grid framework is ensured to have the target porosity (i.e. the optimal porosity).

After the drug coating 10 with the holes 11 is arranged, the drug release rate can be regulated more conveniently and accurately, the drug release rate can be faster, the regulating difficulty of the drug release rate is reduced, and the drug release rate can be controlled more accurately, so that the drug release rate is better matched with the smooth muscle proliferation and migration period.

Although those skilled in the art know that the mechanism for preventing the occurrence of restenosis of blood vessels after implantation of a drug stent in vivo is mainly to inhibit proliferation and migration of smooth muscle cells, for this purpose, it is required that the drug should achieve "release of most of the drug for about 28 days (approximately 50%), peak the drug concentration in the vessel wall for about 28 days, and the cumulative release rate of the drug for the first 90 days is approximately 100%, and the drug concentration in the vessel wall for the first 90 days is higher than the theoretical drug effective concentration". However, this is a major difficulty in drug stent design because the rate of drug release is affected by many factors, and great difficulty in regulation.

Unlike the prior art, the invention tries to regulate and control the drug release rate from different angles so as to simplify the complex problem and further overcome the technical difficulty in regulating and controlling the drug release rate. In this regard, the control of the drug release rate by controlling the porosity of the drug coating 10 facilitates the selection of the drug coating 10 with the optimal porosity for the drug formulation, thereby achieving the optimal drug release rate and optimal blood vessel wall drug concentration.

The target porosity of the drug coating 10 should be controlled according to the release rate of the drug. The target porosity of the drug coating 10 may be 1% to 90%, more suitably 1% to 60%, such as 15% to 45%, 40% to 60%, etc.

In the present invention, the target porosity is obtained based on a number of factors including the kind of polymer, the molecular weight of the polymer, the mode of drug delivery, the drug-to-polymer ratio (i.e., the ratio of drug to degradable polymer), and the drug coating thickness, and when these factors are fixed, only the optimal porosity needs to be set. Wherein, the optimal porosity is the porosity which enables the degradation period to meet the growth period of the blood vessel, namely, the porosity enables the drug release to meet the requirement of releasing most of the drug (approximately 50%) in about 28 days, enables the concentration of the drug in the blood vessel wall to reach the peak value in about 28 days, and enables the accumulated release rate of the drug to be approximately 100% in the first 90 days. The optimal porosity can be adjusted and designed during the preparation of the drug coating 10 to ultimately optimize drug release rate and vessel wall drug concentration. However, the present invention is not particularly limited to the kind of the degradable polymer, the molecular weight of the degradable polymer, the mode of drug delivery, the drug-to-polymer ratio (mass ratio), and the thickness of the drug coating, and these factors may be set according to clinical treatment requirements.

Alternatively, the degradable polymer has a molecular weight of 6 to 16 Da, for example, the polylactic acid has a molecular weight of 6 to 16 Da, or 10 to 16 Da, or 6 to 12 Da. Optionally, the mass ratio of the drug to the degradable polymer is 50% -400%.

Further, an embodiment of the present invention also provides a method for preparing a drug stent, by which the drug coating 10 rich in the holes 11 can be prepared on the lattice framework. Specifically, when preparing, the mesh skeleton is treated with the drug solution under predetermined conditions, thereby forming the drug coating 10 with the holes 11 on the mesh skeleton and imparting the drug coating 10 with a target porosity.

There are many ways of achieving the predetermined condition, and at least one way may be selected to be performed. The following is an exemplary illustration.

According to one embodiment illustrated in fig. 5, the predetermined condition is to spray inert gas (mainly compressed gas) to the drug solution 3 by means of the nozzle 1, so that the drug solution 3 generates the holes 11 during the formation of the drug coating 10 on the lattice framework by the inert gas. In practice, the drug solution 3 is sprayed from the spray head 2 to form a liquid column, the nozzle 1 directly sprays inert gas to the liquid column sprayed from the spray head 2, so that the mixed inert gas of the liquid column of the drug solution 3 is deposited on the grid framework, and then the drug coating 10 with the holes 11 is solidified on the grid framework. Inert gases include, but are not limited to, nitrogen. The nozzle 1 may be connected to a gas passage 4, the compressed gas is supplied from the gas passage 4 to the nozzle 1, and finally the inert gas is ejected from the nozzle 1 at a certain flow rate and speed.

Further, the drug coating 10 obtains a target porosity based on the porosity of the nozzle 1, and the porosity of the nozzle 1 should be not less than the target porosity of the drug coating 10. In this way, only the porosity of the nozzle 1 needs to be adjusted and designed so that the porosity of the nozzle 1 is set according to different drug formulations. Ideally, the porosity of the nozzle 1 corresponds to the target porosity of the drug coating 10, but because the bubbles generated by the nozzle 1 may collapse, the porosity of the nozzle 1 is preferably slightly higher than the target porosity of the drug coating 10. In this embodiment, the nozzle 1 is a disc with a plurality of through holes, and the porosity is a proportion of the area of the through holes to the total area of the disc, and the size of the through holes on the nozzle 1 may be uniform or nonuniform, the uniform through holes tend to form a drug coating 10 with a relatively uniform pore size in preparation, and the nonuniform through holes tend to form a drug coating 10 with a nonuniform pore size in preparation. In some embodiments, the nozzle 1 may also have a spherical or cubic shape with a plurality of through holes.

Alternatively, the porosity of the nozzle 1 is 20% to 40%. Alternatively, the apertures in the nozzle 1 may have a pore size of 0.1 μm to 5 μm, or other suitable dimensions. The number of nozzles 1 is one or more, and a plurality is, for example, 2 or 3. The plurality of nozzles 1 may be identical or different. It is to be understood that when a plurality of nozzles 1 are employed to simultaneously inject inert gas, the drug coating 10 is based on the porosities of all the nozzles 1 to obtain a target porosity.

With continued reference to fig. 5, according to an embodiment of the present invention, there is also provided a tooling apparatus including a nozzle 1, a spray head 2, and a gas passage 4. The nozzle 1 is used to spray compressed gas which does not react with the drug solution. Furthermore, the porosity (e.g., pore size, shape, and number) of the nozzle 1 can be designed and adjusted to meet the porosity requirements of the drug coating 10, depending on the drug and degradable polymer formulation. The spray head 2 is used to spray a drug solution, which provides a suitable spray orifice diameter depending on the spray pattern and the size of the score groove 22. The size and shape of the spray head 2 is designed and adjusted according to the requirements of the drug solution. Preferably, the spray head 2 adopts a conical spray hole, so that the spray effect and the spray efficiency of the drug solution can be effectively improved, and the aperture of the spray head refers to the aperture of the bottom opening of the conical spray hole. The gas channel 4 can be designed and adjusted for aeration flow and aeration rate according to different drugs and degradable polymer formulations. The number of gas channels 4 matches the number of nozzles 1, each gas channel 4 being provided with one nozzle 1. In practice, the compressed gas may be injected through one or more nozzles 1.

Preferably, the pressure of the inert gas sprayed from the nozzle 1 is 0.1MPa to 0.3MPa. In the air pressure range, the spraying of the drug coating 10 with bubbles can be well completed, and the sprayed drug solution 3 can not be blown off, so that the spraying effectiveness is ensured.

In another embodiment, the predetermined condition is to add a surfactant to the drug solution, so that the drug solution forms the pores 11 during the formation of the drug coating 10 on the lattice framework by the surfactant. The surfactant has a function similar to that of a foaming agent, and is capable of generating bubbles in the drug solution, thereby forming pores (i.e., holes 11) in the drug coating 10. The dispersibility of the surfactant is good, and the content is proper, so that the pores can be generated. Further, the drug coating 10 achieves a target porosity based on the surfactant content. Thus, the porosity of the drug coating 10 can be directly controlled by adjusting the content of the surfactant. Optionally, the mass percentage of the surfactant is 0.02% -20%. The surfactant may be any material known to those skilled in the art.

The drug stent of the present embodiment may carry one or more drug coatings 10. The size of the holes 11 of the same drug coating 10 can be the same or different, and the shape can be the same or different, which is not limited by the invention, and the porosity of the drug coating 10 is required to meet the requirement. As shown in fig. 1, the same drug coating 10 contains holes 11 of different sizes; as shown in fig. 2, the size of the holes 11 in the drug coating 10 is not very different, and the hole sizes are more uniform than those of the holes 11 in fig. 1; alternatively, as shown in fig. 3, the holes 11 in the drug coating 10 are all large holes. Of course, the practice may not be limited thereto.

Further, when preparing the drug stent, the method can further comprise: a plurality of drug coatings 10 are formed on the lattice framework, and the functions of the different drug coatings 10 are different. The various drug coatings 10 should first include an antiproliferative drug coating, and may further include at least one of an endothelialization promoting drug coating and an anticoagulant drug coating. The plurality of medicine coatings 10 are disposed in the same notch 22 of the lattice framework, at this time, the plurality of medicine coatings 10 are stacked from inside to outside, or the plurality of medicine coatings 10 are disposed on the surface of the lattice framework, or some of the medicine coatings 10 are disposed in the same notch 22 of the lattice framework, and other medicine coatings 10 are disposed on the surface of the lattice framework. The drug coating 10 provided on the surface of the lattice framework is mainly at least one of an endothelialization promoting drug coating and an anticoagulation drug coating. Preferably, the antiproliferative drug coating is disposed in the score groove 22 of the lattice skeleton, the anticoagulant drug coating is disposed on the surface of the lattice skeleton, preferably, the anticoagulant drug coating is disposed entirely on the surface of the lattice skeleton, and the endothelialization-promoting drug coating is disposed on the surface of the lattice skeleton or in the same score groove 22 as the antiproliferative drug coating.

For example, in the same notch 22, the outer layer of the multiple drug coating layers 10 is an anti-proliferation drug coating (for inhibiting smooth muscle proliferation), the inner layer of the multiple drug coating layers 10 is an endothelialization promoting drug coating, or the anti-proliferation drug coating layers are arranged in the notch 22, the whole body except the notch 22 of the grid skeleton adopts the endothelialization promoting drug coating, or the combination of the anti-proliferation drug coating layers and the endothelialization promoting drug coating layers is arranged in the same notch 22, and the whole body except the notch 22 of the grid skeleton adopts the anticoagulation drug coating. When the drug stent carries an endothelialization promoting drug coating, the drug stent can provide a function of promoting endothelialization after stent implantation, so that the endothelial layer covers the stent, thereby reducing the probability of restenosis or thrombosis. When the drug stent also carries anticoagulant drugs, the drug stent has an anticoagulant function, not only can solve the restenosis problem, but also can solve the occurrence of thrombus events, so that the complication occurrence rate after the implantation of the vascular stent is greatly reduced.

Further, when preparing the drug stent, the method can further comprise: the target porosity of the drug coating 10 within the same score 22 increases from the inside to the outside, thus allowing the outer drug coating 10 to release faster to meet the rapid release of the early drug while the inner drug coating 10 releases slower to meet the slow release of the late drug. In this embodiment, as shown in fig. 12, two drug coatings 10 are disposed in the same notch 22, the target porosity of the outer layer 101 is greater than that of the inner layer 102, and it is specifically considered that both drug coatings 10 are antiproliferative drug coatings.

The drug coating 10 prepared according to the present invention will be further described by way of specific examples.

Embodiment one:

drug solution: polylactic acid with molecular weight of 10-16 Da and sirolimus are mixed according to a medicine poly ratio of 4:3 in the solvent of n-propyl acetate, ethyl acetate, propyl propionate, etc. or other volatile solvents capable of dissolving both medicine and polymer for 12 hr to obtain homogeneous stable medicine solution.

The preset conditions are that the tooling equipment: the pore diameters of pores on the nozzle 1 are selected to be 0.2 μm and 0.5 μm, wherein the nozzle 1 with the pore diameters of 0.25 μm can be selected, or the nozzle 1 with the pore diameters of 0.5 μm can be selected, or the nozzle 1 with the pore diameters of 0.25 μm and 0.5 μm can be selected, and the porosity of the nozzle 1 is 20% -40%; compressed nitrogen is used, and the gas pressure is 0.1MPa to 0.3MPa; the diameter of the shower head 2 is 30 μm (i.e., the diameter of the bottommost opening of the shower head 2 is 30 μm); the thickness of the drug coating 10 is 15 μm to 40 μm.

The medicine carrying mode is as follows: grooving and carrying medicine.

Preparing a drug coating: the grid framework is treated by using the drug solution of polylactic acid and sirolimus drugs, and in the process, the drug solution is sprayed through a spray head 2, and compressed nitrogen is sprayed through a spray nozzle 1 until the spraying is completed; after the spraying is finished, naturally drying for 24 hours, wherein the target porosity of the finally obtained drug coating 10 is about 40% -60%; the drug stent is obtained after the solvent in the notch 22 is volatilized completely, and the state of the drug coating in the notch 22 is shown in fig. 1.

The in vitro release test results are shown in fig. 6, wherein the control group refers to the drug coating without holes, and the test group refers to the drug coating with holes. As can be seen from fig. 6, the drug release rate (upper orange line) of the drug coating 10 with the hole 11 is significantly faster than that of the control experiment (lower blue line), and thus the drug coating 10 with the hole 11 can achieve the above-mentioned purpose of "releasing most of the drug (approximately 50%) for around 28 days, peaking the drug concentration in the vessel wall around 28 days, and the cumulative drug release rate for the first 90 days being approximately 100%, making the drug concentration in the vessel wall over the first 90 days higher than the theoretical effective concentration".

Therefore, even if other relevant factors affect the release rate of the drug and the blood vessel wall drug concentration, the optimal drug release rate and the optimal blood vessel wall drug concentration can be obtained by only controlling the porosity of the drug coating.

Embodiment two:

drug solution: polylactic acid with molecular weight of 6-12 Da and sirolimus are mixed according to a medicine poly ratio of 5:3 in the solvent of n-propyl acetate, ethyl acetate, propyl propionate, etc. or other volatile solvents capable of dissolving both medicine and polymer for 12 hr to obtain homogeneous stable medicine solution.

The preset conditions are that the tooling equipment: the pore diameter of the pore of the nozzle 1 is 0.1 mu m, and the porosity of the nozzle 1 is 20% -40%; compressed nitrogen is used, and the gas pressure is 0.1MPa to 0.3MPa; the diameter of the spray head 2 is 20-70 mu m; the diameter of the spray head 2 can be selected according to the dosage of the spray head 2 and the thickness of the coating; the thickness of the drug coating is 2-15 μm.

The medicine carrying mode is as follows: the surface is coated with medicine carrying agent.

Preparing a drug coating: the grid framework is treated by using the drug solution of polylactic acid and sirolimus drugs, and in the process, the drug solution is sprayed through a spray head 2, and compressed nitrogen is sprayed through a spray nozzle 1 until the spraying is completed; after the spraying is finished, naturally drying for 24 hours, wherein the target porosity of the finally obtained drug coating 10 is about 15% -45%; and (3) obtaining the drug stent after the solvent on the surface of the grid framework is volatilized completely, wherein the state of the drug coating on the surface of the grid framework is shown in fig. 7 and 8.

The results of the in vitro release experiments are shown in figure 9. As can be seen from fig. 9, the drug release rate (upper orange line) of the drug coating 10 with the holes 11 was significantly faster than the drug release rate (lower blue line) of the control experiment, and the target porosity of the drug coating 10 was in an optimal state under the current drug formulation conditions, and the optimal drug release rate and blood vessel wall concentration were obtained.

Embodiment III:

drug solution: polylactic acid with the molecular weight of 6-16 Da and sirolimus are dissolved in solvents such as n-propyl acetate, ethyl acetate, propyl propionate and the like or other volatile solvents which can dissolve the drugs and polymers in a mode that the drug-to-polymer ratio is 50-400%, and after dissolution is carried out for 12 hours, uniform and stable drug solution is obtained.

The predetermined condition is a surfactant; adding 0.02% -20% of surfactant into the medicine solution, continuously stirring for 12h, and then spraying; the spray nozzle 2 mentioned above can be adopted in spraying, and the diameter of the spray nozzle 2 is 20-70 μm; the thickness of the drug coating is 2-15 μm.

The medicine carrying mode is as follows: grooving and carrying medicine.

Preparing a drug coating: the grid framework is treated by using the drug solution of polylactic acid and sirolimus drugs, in the process, the drug solution is sprayed through a spray head 2, and after the spraying is completed, the drug solution is naturally dried for 24 hours, the target porosity of the finally obtained drug coating 10 is about 15% -45%, the drug stent is obtained after the solvent on the surface of the grid framework is volatilized completely, and the state of the drug on the grid framework is shown in figure 10.

The results of the in vitro release experiments are shown with reference to figure 11. Similarly, in this example, the drug release rate (upper orange line) of the drug coating 10 with the holes 11 was also significantly faster than the drug release rate (lower blue line) of the control experiment, and the optimal drug release rate and the optimal blood vessel wall drug concentration were also obtained. Therefore, the surfactant also has the function of promoting the formation of holes in the drug coating, and has good effect.

Embodiment four:

the implementation manner of this embodiment is basically the same as that of the first and second embodiments, except that, as shown in fig. 12, the same notch 22 is provided with drug coatings 10 with different porosities, the drug coatings 10 are antiproliferative drug coatings, the outer layer 101 of the drug coating 100 is a sparse drug structure, the porosity of the outer layer 101 is 15% -60%, the inner layer 102 of the drug coating 100 is a dense drug structure, and the porosity of the inner layer 101 is below 15%. After the setting, the invention can quickly release the medicine according to the requirement of 28 days before the medicine spraying period, the medicine concentration reaches a higher value, the effects of effectively inhibiting the migration and the proliferation of vascular smooth muscle are achieved, the medicine concentration is required to be lower than the medicine effective concentration after 90 days, the medicine can not influence vascular endothelialization, and the occurrence of restenosis is prevented.

In summary, the invention can adjust the porosity of the drug coating according to the molecular weight and degradation cycle characteristics of the degradable polymer, thereby designing the drug release rate meeting clinical requirements, and the related tooling equipment can adjust the internal shape of the nozzle 1 according to the viscosity of the actual drug formulation and adjust the conditions of air outlet rate, flow and the like according to the speed of the drug release rate, so that the air injection can not influence the spraying effect, but also can generate air outlet holes. Therefore, the invention provides a brand new thought for regulating and controlling the drug release rate, and provides a practical and effective porosity regulating scheme, and finally, the proliferation cycle of smooth muscle can be optimally matched, the occurrence of vascular restenosis is maximally inhibited, and the drug stent can better meet clinical use requirements.

The foregoing description is only illustrative of the preferred embodiments of the present invention, and is not intended to limit the scope of the present invention in any way, and any changes and modifications made by those skilled in the art in light of the foregoing disclosure will be deemed to fall within the scope and spirit of the present invention.

Claims

1. A method of preparing a drug stent comprising:

2. The method of manufacturing a drug stent according to claim 1, wherein the predetermined condition is that an inert gas is injected into the drug solution by a nozzle so that the drug solution generates holes in the course of forming the drug coating on the mesh skeleton by the inert gas.

3. The method of manufacturing a drug stent according to claim 2, wherein the drug coating achieves the target porosity based on the porosity of the nozzle, the porosity of the nozzle being not less than the porosity of the drug coating.

4. The method of preparing a drug stent according to claim 2, wherein the pressure at the time of jetting the inert gas is 0.1MPa to 0.3MPa, and/or the porosity of the nozzle is 20% to 40%.

5. The method of preparing a drug stent according to claim 1, wherein the predetermined condition is that a surfactant is added to the drug solution so that the drug solution forms pores in the course of forming the drug coating on the lattice framework under the action of the surfactant.

6. The method of preparing a drug stent of claim 5, wherein the drug coating achieves the target porosity based on the surfactant content.

7. The method for preparing a drug stent according to claim 6, wherein the content of the surfactant is 0.02% -20%.

8. The method of preparing a drug stent of claim 1, wherein the target porosity is obtained based on a number of factors including the type of degradable polymer, the molecular weight of the degradable polymer, the drug loading mode, the drug-to-polymer ratio, and the drug coating thickness.

9. The method of preparing a drug stent of claim 1, further comprising:

10. The method of claim 9, wherein two layers of the drug coating are disposed in the same notch, and the target porosity of the outer layer of the two layers of the drug coating is greater than the target porosity of the inner layer.

11. The method of preparing a drug stent of claim 1, further comprising:

12. The method of manufacturing a drug stent of claim 11, wherein a plurality of the drug coatings comprise an antiproliferative drug coating, and wherein a plurality of the drug coatings further comprise at least one of an anticoagulant drug coating and an endothelialization-promoting drug coating, the antiproliferative drug coating being disposed in the grooves of the lattice framework, the anticoagulant drug coating being disposed on the surface of the lattice framework, and the endothelialization-promoting drug coating being disposed on the surface of the lattice framework or in the same groove of the lattice framework as the antiproliferative drug coating.

13. A pharmaceutical stent prepared by the method of preparing a pharmaceutical stent according to any one of claims 1 to 12.