阅读说明：本技术 载药植入医疗器械及其制备方法 (Medicine-carrying implantation medical apparatus and preparation method thereof ) 是由 汪晶 周奇 李俊菲 于 2020-02-21 设计创作，主要内容包括：本发明涉及一种载药植入医疗器械及其制备方法,该载药植入医疗器械包括本体和负载在本体上的药物,药物以结晶度呈梯度变化的方式负载在本体上。上述载药植入医疗器械通过在本体上负载药物,并利用药物结晶度不同,释放速率不同,使载药植入医疗器械上药物的结晶度在本体上呈梯度变化,实现载药植入医疗器械上药物的释放速率的控制,适当延长药物释放时间,提高了药物的生物利用度,使得有效解决植入初期药物释放过快,以及降低长期植入人体后支架内腔和两端再狭窄的风险。(The invention relates to a medicine-carrying implantation medical device and a preparation method thereof. Above-mentioned medical instrument is implanted to medicine carrying is through loading the medicine on the body, and utilize the medicine degree of crystallinity different, release rate is different, the degree of crystallinity that makes the medicine carrying implant medical instrument go up the medicine is gradient change on the body, realize the medicine carrying implant medical instrument go up the control of release rate of medicine, suitably prolong the medicine release time, the bioavailability of medicine has been improved, make effectively solve and implant initial stage medicine release too fast, and reduce the risk of long-term implantation human back support inner chamber and both ends restenosis.)

1. The utility model provides a medical equipment is implanted in medicine carrying, its characterized in that includes body and medicine, the medicine is in with the crystallinity is gradient change's mode load on the body.

2. The pre-loaded implantable medical device according to claim 1, wherein in a first direction the crystallinity of the drug gradually increases and then gradually decreases; or

In a first direction, the crystallinity of the drug gradually decreases and then gradually increases.

3. The pre-loaded implantable medical device of claim 2, wherein the body comprises a plurality of base units, and wherein the plurality of base units are arranged in sequence along the first direction, the drug being loaded on each of the base units;

In the first direction, the crystallinity of the drug gradually increases and then gradually decreases from the basic unit at one end to the basic unit at the other end; or

In the first direction, the crystallinity of the drug gradually decreases and then gradually increases from the basic unit at one end to the basic unit at the other end.

4. The pre-loaded implantable medical device according to claim 3, wherein the drug has a minimum crystallinity of 5% to 25% in each basic unit.

5. The pre-loaded implantable medical device according to claim 4, wherein the difference between the crystallinity of the drug in two adjacent basic units is 10-25%.

6. The drug-loaded implantable medical device of any one of claims 1-5, wherein the drug comprises a plurality of drug layers stacked in a second direction;

in the second direction, the crystallinity of the drug gradually increases; or

In the second direction, the crystallinity of the drug gradually decreases.

7. The device of claim 6, wherein the base unit defines a recess and/or a through hole, and the drug is loaded into the recess and/or through hole.

8. The device of claim 7, wherein each base unit has at least 10 grooves and/or through holes, and the opening area of all the grooves and/or through holes on the body accounts for 10-70% of the total area of the body.

9. A preparation method of a medicine-carrying implantation medical device is characterized by comprising the following steps:

providing a body;

loading the drug on the body in a manner that the crystallinity changes in a gradient manner.

10. The method of claim 9, wherein the body comprises a plurality of basic units, and the basic units are sequentially arranged along a first direction; and loading the drug on each basic unit of the body in a mode that the crystallinity changes in a gradient manner.

11. The method for preparing according to claim 10, wherein the step of loading the drug on each basic unit of the body in such a manner that the crystallinity is changed in a gradient manner comprises the steps of:

dissolving the drug in a first solvent to prepare a drug solution;

loading the drug solution onto each base unit of the body and drying to form an amorphous drug layer;

Adding a second solvent to said amorphous drug layer on each of said base units for crystallization to form a first crystal layer; and in the first direction, the mass ratio of the drug and the second solvent added to each of the basic units changes in a gradient manner.

12. The method for preparing according to claim 10, wherein the step of loading the drug on each basic unit of the body in such a manner that the crystallinity is changed in a gradient manner comprises the steps of:

dissolving the drug in a first solvent to prepare a drug solution;

loading the drug solution onto each basic unit of the body and drying to form an amorphous drug layer;

adding a second solvent to said amorphous drug layer on each of said base units for crystallization to form a first crystal layer;

repeating the steps of forming the amorphous drug layer and adding a second solvent for crystallization n times on the same base unit to form n +1 crystal layers, wherein the mass ratio of the added drug to the second solvent changes in a gradient from the step of forming the first crystal layer to the step of forming the n +1 crystal layer, wherein n is an integer greater than or equal to 1.

13. The production method according to claim 12, wherein in the step of forming the n +1 th crystal layer, the mass ratio of the drug and the second solvent added to each of the basic units changes in a gradient in the first direction.

14. The method of any one of claims 11-13, wherein the first solvent is selected from the group consisting of: one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid, and dichloromethane; and/or

The second solvent comprises one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

15. The production method according to claim 14, wherein the second solvent is a mixed solvent of a good solvent and a poor solvent, and the volume ratio of the good solvent to the poor solvent is 1: (5-25);

wherein the good solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid and dichloromethane;

the poor solvent is selected from one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

Technical Field

The invention relates to the technical field of medical instruments, in particular to a medicine-carrying implantation medical instrument and a preparation method thereof.

Background

Stents have become more and more widely used as an important means of treating luminal stenosis in the human body. In the case of a stent, the stent is delivered to a stenotic lesion blood vessel by a catheter during treatment, and then the diameter of the stent is enlarged by balloon expansion or self-expansion to open the stenotic part.

At present, most of the drug stents are provided with grooves on the surface of the stent for filling drug coatings, or are coated with drug coatings on the surface of a stent substrate. In the way of filling the grooves with the drug coating, the drug usually coexists in a crystalline form and an amorphous form, and the control of drug release cannot be realized. And the drug coating comprises a biodegradable polymer and an active drug. Although the polymer in the coating can play a role in controlling the release of the drug, the mode needs to utilize the polymer to carry the drug, and a continuous inflammatory reaction can occur, so that the endothelialization of the blood vessel is delayed and the risk of advanced blood vessel restenosis is caused.

Disclosure of Invention

In view of the above, there is a need for a drug-loaded implantable medical device and a method of making the same. The medical device for drug loading implantation can realize effective control of drug release rate and effectively reduce the risk of reoccurrence of thrombus.

A medical device is implanted in medicine carrying, includes body and medicine, the medicine is in with the crystallinity is gradient change's mode load on the body.

In one embodiment, in the first direction, the crystallinity of the drug gradually increases and then gradually decreases; or

In a first direction, the crystallinity of the drug gradually decreases and then gradually increases.

In one embodiment, the body comprises a plurality of basic units, the basic units are sequentially arranged along the first direction, and the medicine is loaded on each basic unit;

in the first direction, the crystallinity of the drug gradually increases and then gradually decreases from the basic unit at one end to the basic unit at the other end; or

In the first direction, the crystallinity of the drug gradually decreases and then gradually increases from the basic unit at one end to the basic unit at the other end.

In one embodiment, the drug has a minimum crystallinity of 5% to 20% in each of the base units.

In one embodiment, the difference in crystallinity between adjacent base units is 10% to 25%.

In one embodiment, the medicament comprises a plurality of medicament layers, and the medicament layers are stacked in a second direction;

in a second direction, the crystallinity of the drug gradually increases; or

In the second direction, the crystallinity of the drug gradually decreases.

In one embodiment, at least one of the drug layers has a first direction in which the crystallinity of the drug gradually increases and then gradually decreases; or

In a first direction, the crystallinity of the drug gradually decreases and then gradually increases.

In one embodiment, the base unit is provided with a groove and/or a through hole, and the medicine is loaded in the groove and/or the through hole.

In one embodiment, each basic unit is provided with at least 10 grooves and/or through holes, and the opening area of all the grooves and/or through holes on the body accounts for 10% -70% of the total area of the body.

In one embodiment, the grooves have a width of 40-80 μm and a depth of 10-60 μm.

A preparation method of a drug-loaded implantable medical device comprises the following steps:

providing a body;

loading the drug on the body in a manner that the crystallinity changes in a gradient manner.

In one embodiment, the body comprises a plurality of basic units, the basic units are sequentially arranged along a first direction, and the drug is loaded on each basic unit of the body in a manner that the crystallinity changes in a gradient manner.

In one embodiment, the step of loading the drug on each basic unit of the body in a manner that the crystallinity changes in a gradient manner comprises the following steps:

dissolving the drug in a first solvent to prepare a drug solution;

loading the drug solution onto each base unit of the body and drying to form an amorphous drug layer;

Adding a second solvent to the amorphous drug layer on each of the base units for crystallization to form a first crystal layer, wherein the mass ratio of the drug to the second solvent added to each of the base units varies in a gradient manner in the first direction.

In one embodiment, in the step of forming the first crystal layer, the mass of the drug added to each basic unit is the same, and the volume of the second solvent added varies in a gradient manner in the first direction.

In one embodiment, the step of loading the drug on each basic unit of the body in a manner that the crystallinity changes in a gradient manner comprises the following steps:

dissolving the drug in a first solvent to prepare a drug solution;

loading the drug solution onto each basic unit of the body and drying to form an amorphous drug layer;

adding a second solvent to said amorphous drug layer on each of said base units for crystallization to form a first crystal layer;

repeating the steps of forming the amorphous drug layer and adding a second solvent for crystallization n times on the same base unit to form n +1 crystal layers, wherein the mass ratio of the added drug to the second solvent changes in a gradient from the step of forming the first crystal layer to the step of forming the n +1 crystal layer, wherein n is an integer greater than or equal to 1.

In one embodiment, the amount of the drug added to form each crystal layer is the same, and the volume of the second solvent added varies in a gradient from the step of forming the first crystal layer to the step of forming the n +1 th crystal layer.

In one embodiment, in the step of forming the n +1 th crystal layer, the mass ratio of the drug and the second solvent added to each of the basic units varies in a gradient in the first direction.

In one embodiment, in the step of forming the n +1 th crystal layer, the added amount of the drug is the same, and the volume of the second solvent added varies in a gradient manner in the first direction.

In one embodiment, the first solvent is selected from: one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid, and dichloromethane; and/or

The second solvent comprises one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

In one embodiment, the second solvent is a mixed solvent of a good solvent and a poor solvent, and the volume ratio of the good solvent to the poor solvent is 1: (5-25);

Wherein the good solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid and dichloromethane;

the poor solvent is selected from one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

Above-mentioned medical instrument is implanted to medicine carrying is through loading the medicine on the body, and it is different to utilize the medicine degree of crystallinity, the release rate is different, the degree of crystallinity that makes the medicine carrying implant medical instrument go up the medicine is gradient change on the body, realize the medicine carrying implant medical instrument go up the control of the release rate of medicine, and then suitably prolong the medicine release time, the bioavailability of medicine has been improved, effectively solve and implant initial stage medicine release too fast, and reduce the risk of implanting human back support inner chamber and both ends restenosis for a long time, and then reduce the risk of thrombus appearing again effectively.

Drawings

Fig. 1 is a schematic view of an embodiment drug-loaded implantable medical device;

fig. 2 is a schematic view of a recess in the base unit of the drug-loaded implantable medical device of fig. 1;

fig. 3 is a microimaging infrared image of drug loading of a recess in the drug-loaded implantable medical device of example 1.

Detailed Description

In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many 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.

Unless defined otherwise, 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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The drug-loaded implantable medical device can be used in vivo or in vitro, and can be used for a short time or permanently implanted for a long time. In addition, the medical devices described above may provide medical and/or diagnostic devices for heart rhythm disorders, heart failure, valvular diseases, vascular diseases, diabetes, neurological diseases and disorders, orthopedic surgery, neurosurgery, oncology, ophthalmology and ENT procedures. Medical devices to which the present invention relates include, but are not limited to, the following: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, guidewires, catheters, sensors, surgical instruments, angioplasty balloons, wound drains, shunt tubes (shunts), tubes, infusion sleeves (infusion sleeves), urethral cannulas, pellets, implants, blood oxygenators, pumps, vascular grafts, embedded intervention cartridges (vascucessors), heart valves, annuloplasty rings, sutures, surgical clips, surgical staples, pacemakers, implantable defibrillators, neurostimulators, orthopedic instruments, cerebrospinal fluid shunts, implantable drug pumps, vertebral cages, artificial intervertebral discs, nucleus pulposus replacement instruments, ear tubes, intraocular lenses, and any tube used in interventional procedures.

The drug-loaded implantable medical device 10 according to an embodiment of the present invention includes a body 100 and a drug loaded on the body, and the drug is loaded on the body 100 in such a manner that crystallinity is changed in a gradient manner. The gradient change refers to a phenomenon that the crystallinity degree is increased or decreased along the direction of the body in a certain rule, and understandably, the gradient change includes but is not limited to: the body gradually increases along a direction of the body, gradually decreases, gradually increases first and then gradually decreases, and gradually decreases first and then gradually increases. And the gradient change tendency of the crystallinity of the drug on the bulk can be determined according to the shape of the bulk and the kind of the loaded drug. Compared with a medicine-carrying implantation medical device in a common crystallization mode, the gradient crystallization can better control the release concentration of the medicine. In the region with low crystallinity, the drug can be quickly released, and the drug concentration in a short period is provided; the drug is slowly released in the areas with larger crystallinity, and the drug concentration can be maintained for a longer time.

In the present invention, crystallinity refers to the percentage of crystalline drug to total drug content (i.e., total content of crystalline and amorphous drug) in the drug layer. The greater the crystallinity, the slower the drug release rate. Control of the drug release rate can be achieved by controlling the crystallinity in the drug layer.

The body 100 may be made of cobalt-chromium alloy, which may include a plurality of basic units. It is understood that the basic unit refers to a repeating unit loaded with a drug, and in the present invention, the basic unit may adopt a structure conventional in the art of an implantable medical device, and the size and shape of each basic unit may be the same or different. As shown in fig. 1, the body 100 includes a first base unit 101 at one end, a second base unit 102 at the other end, and a third base unit 103 at a middle portion.

In one embodiment, the basic unit comprises a plurality of unit waves 200, each unit wave 200 comprises a circular arc-shaped reinforcing ring 201, a straight rod section 202 and a transition section 203, wherein the transition section 203 is arranged between the reinforcing ring 201 and the straight rod section 202, and smooth transition from the circular arc-shaped reinforcing ring 201 to the straight rod section 202 is realized. Wherein the width of the straight rod section is 85-105 μm, the width of the reinforcing ring is 80-95 μm, and the thickness of the body is 90-110 μm. In one embodiment, the straight pole segments have a width of 96 μm, the stiffening rings have a width of 91 μm, and the body has a thickness of 100 μm.

In addition, a drug-loaded groove 204 may be formed in the outer surface of the straight shaft section 202. The shape and number of the grooves 204 are not particularly limited, and may be square, oval, circular, or other regular or irregular patterns, and the distribution of the grooves on each basic unit is not particularly limited, and may be arranged regularly or randomly. The width and depth of the groove 204 can be adjusted according to the requirement, and preferably, the width of the groove 204 is 40-80 μm, and the depth is 10-60 μm.

In one embodiment, the body has a through hole (not shown) for loading the drug. The shape and number of the through holes are not particularly limited, and may be square, oval, circular or other regular or irregular patterns, and the distribution of the through holes on each basic unit is not particularly limited, and may be arranged regularly or randomly.

In one embodiment, each basic unit is provided with at least 10 grooves and/or through holes, and the opening area of all the grooves and/or through holes accounts for 10% -70%, preferably 30% -70% of the body. In another embodiment, the number of the grooves and/or the through holes formed in each basic unit is the same, so that the coating amount of the medicine on each basic unit can be controlled, and the crystallinity of the medicine in each groove and/or through hole can be controlled.

The number of basic cells is not particularly limited, and may be an odd number or an even number. As shown in figure 1, a plurality of basic units are sequentially arranged along a first direction, and the medicine is loaded on each basic unit, and the first direction is the direction in which each basic unit is arranged and is determined according to the arrangement mode of the basic units. In one embodiment, each of the basic units is annular, and the basic units are sequentially arranged along the central axis direction of the basic units through the connecting portion 300, that is, the first direction is the direction of the central axis of each of the basic units.

The shape and number of the connecting portion 300 are not particularly limited as long as the connection between the basic units can be achieved, and the connecting portion 300 preferably has an arc-shaped bendable structure to facilitate the nesting between the adjacent basic units. In addition, the connection positions of the basic units and the connection parts can be the same or different, the number of the connection parts for connecting two adjacent basic units can be the same or different, and the connection parts on the adjacent basic units are preferably arranged in a staggered mode, so that the adjacent basic units can be nested with each other to form a nested structure.

In one embodiment, each of the basic units is loaded with a drug, and the crystallinity of the drug gradually increases and then gradually decreases in a first direction; or in the first direction, the crystallinity of the drug gradually decreases and then gradually increases. Preferably, the base unit located in the middle is used as a boundary point, and the gradient change is presented to both ends. Specifically, as shown in fig. 1, the crystallinity of the drug gradually increases or gradually decreases along the third base unit 103 in the middle portion toward the first base unit 101 and the second base unit 102 in the both end portions. It can be understood that when the number of the basic units is odd, the basic unit in the middle refers to a basic unit in the middle; when the number of the basic units is even, the middle basic unit refers to two basic units located in the middle.

In one embodiment, the drug has a minimum crystallinity of 5% to 25% in each of the base units. In another embodiment, the drug substance has a minimum crystallinity of 10% to 20% in each of the base units. The risk of restenosis at two ends caused by too fast release of the drug is avoided by controlling the minimum crystallinity of the drug on the basic unit, thereby effectively reducing the risk of thrombus reoccurrence.

In one embodiment, the maximum crystallinity of the drug in each of the base units is from 85% to 98%.

In the present invention, the difference in crystallinity between adjacent unit cells is a gradient, and it is understood that the gradient between the adjacent unit cells may be the same or different, and is not particularly limited. In one embodiment, the gradient of crystallinity of the drug between two adjacent base units is between 10% and 25%. In another embodiment, the gradient of crystallinity of the drug between two adjacent base units is between 15% and 20%. The crystallinity gradient of adjacent basic units can be adjusted according to the specific type of the used medicine, so that the gradient arrangement is matched with the release period of the medicine in vivo, a better slow release effect is achieved, the medicine release time is prolonged while the medicine amount released in unit time is ensured, and the risk of restenosis at two ends is effectively avoided.

In one embodiment, the drug is loaded in the recess and forms at least two drug layers, the drug layering direction being a second direction, the crystallinity of each drug layer varying in a gradient along the second direction. Specifically, the crystallinity is graded up, graded down, graded up first and graded down second or graded down first and graded up second from the first drug layer near the bottom of the groove to the m +1 th drug layer far from the bottom of the groove, wherein m is an integer greater than or equal to 1. In one embodiment, the crystallinity of the drug is gradually increased or gradually decreased in the second direction. When the crystallinity of the first medicament layer close to the bottom of the groove is gradually reduced to the m +1 medicament layer far away from the bottom of the groove, the first quick release with small crystallinity at the initial stage of implantation can be realized, and a certain medicament concentration is provided; the subsequent slow release with large crystallinity maintains a certain drug concentration to reach the effective drug concentration for a longer time. When the crystallinity of the first medicine layer close to the bottom of the groove is gradually increased to the m +1 th medicine layer far away from the bottom of the groove, the slow release of the medicine coating with higher crystallinity can be realized at the initial stage of implantation, the burst release is avoided, and after a certain medicine concentration is reached, the coating with lower crystallinity starts to release, so that the higher blood medicine concentration can be maintained for a longer time.

It will be appreciated that the difference in crystallinity between adjacent drug layers is a gradient, and that the gradient between adjacent drug layers may be the same or different. In one embodiment, the crystallinity gradient is from 10% to 45% for adjacent drug layers, and in another embodiment, from 25% to 40% for adjacent drug layers. The crystallinity gradient of the adjacent medicine layers can be adjusted according to the specific type of the used medicine, so that the gradient arrangement is matched with the release period of the medicine in the body, a better slow release effect is achieved, the medicine release time is prolonged while the medicine release amount in unit time is ensured, and the risk of restenosis at two ends is effectively avoided.

In one embodiment, the crystallinity of at least one of the drug layers in the plurality of drug layers is graded in a first direction, preferably the crystallinity of the top drug layer distal to the base of the recess is graded in the first direction for ease of manufacture and ease of control. In one embodiment, at least one layer has a first direction in which the crystallinity of the drug gradually increases and then gradually decreases; or in the first direction, the crystallinity of the drug gradually decreases and then gradually increases.

In addition, the loaded drug can be one or more of mTOR inhibitor, paclitaxel drug, antiplatelet drug, cilostazol, ticlopidine, triptolide and dexamethasone. Wherein the mTOR inhibitor is selected from one or more of rapamycin (sirolimus), everolimus, ridaforolimus, temsirolimus, and zotarolimus.

It should be noted that, one implanted medical device may be loaded with one or more drugs, and the basic units may be divided into several groups according to the amount of the loaded drugs, and the crystallinity of the drug varies in a gradient manner in the group of basic units as a whole. For example: the implanted medical device comprises six basic units, namely a first basic unit and a second basic unit from a first end to a second end, wherein the first basic unit to the third basic unit are used for loading A medicines, and the fourth basic unit to the sixth basic unit are used for loading B medicines. The crystallinity of the A medicament is changed in a gradient manner from the second basic unit to the first basic unit and the third basic unit, and the crystallinity of the B medicament is changed in a gradient manner from the fifth basic unit to the fourth basic unit and the sixth basic unit.

In addition, several kinds of medicine may be compounded into mixed liquid to form mixed medicine coating, and the medicine crystallinity of the basic units may be coated with single medicine in the same way and this is not repeated.

The preparation method of the drug-loaded implantable medical device provided by the embodiment of the invention comprises the following steps:

S101: a body is provided.

The specific structure of the body is the same as that described above, and is not described herein again.

S102: the medicine is loaded on the body in a mode that the crystallinity is changed in a gradient way.

In one embodiment, step S102 includes the steps of:

s1021 a: dissolving the drug in a first solvent to prepare a drug solution.

It can be understood that the first solvent is a good solvent for the drug, and can sufficiently dissolve the drug to prepare a drug solution. Wherein the first solvent may be selected from: one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid, and dichloromethane.

The concentration of the drug solution can be selected according to the drug and the requirement, and in one embodiment, the mass percentage of the drug solution is 0.5% -15%.

S1022 a: the drug solution is loaded onto each base unit of the body and dried to form an amorphous drug layer.

It will be appreciated that the drug solution may be loaded into the drug pre-loaded areas of each base unit, such as in the grooves, etc., by spraying, printing, etc. The thickness of the amorphous drug layer is not particularly limited, and the dripping may be repeated to form a drug layer of an appropriate thickness.

S1023 a: adding a second solvent to the amorphous drug layer on each base unit to crystallize to form a first crystal layer; and in the first direction, the mass ratio of the added medicine and the second solvent on each basic unit changes in a gradient manner.

It is understood that the method of making the mass ratio of the drug and the second solvent added to each basic unit vary in a gradient manner along the first direction includes, but is not limited to: fixing the mass of the added medicine on each basic unit, and enabling the volume of the second solvent added on each basic unit to change in a gradient manner along the first direction; or fixing the volume of the second solvent, and adjusting the mass of the medicine added on each basic unit to enable the mass of the medicine added on each basic unit to change in a gradient manner along the first direction.

In one embodiment, the volume of the second solvent added varies in a gradient from the middle portion basic unit to the both end portions basic unit of the body. The control of the crystallinity is realized by controlling the volume of the second solvent, and the operation is simpler and more convenient.

Wherein the second solvent is a poor solvent for the drug. In one embodiment, the second solvent comprises at least one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water, and petroleum ether.

In addition, the second solvent may be a mixed solvent of a good solvent and a poor solvent, and the ratio of the good solvent to the poor solvent is adjusted according to the type of the drug and the selected solvent, thereby realizing crystallization of the amorphous drug. In one embodiment, the volume ratio of the good solvent to the poor solvent is 1: (5-25). Wherein the good solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid and dichloromethane; the poor solvent is selected from one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

In one embodiment, the second solvent is a mixed solvent of: ethyl acetate/n-hexane, ethyl acetate/n-heptane, isopropyl acetate/n-hexane, isopropyl acetate/n-heptane, n-propyl acetate/n-hexane, n-propyl acetate/n-heptane, acetone/cyclohexane, acetone/n-hexane, acetone/n-heptane, acetonitrile/water or methanol/diethyl ether.

By the method of this embodiment, a drug-loaded implantable medical device can be formed in which the crystallinity of the drug varies in a gradient along a first direction (direction a as shown in fig. 1).

In another embodiment, step S102 includes the steps of:

S1021 b: dissolving the drug in a first solvent to prepare a drug solution.

It can be understood that the first solvent is a good solvent for the drug, and can sufficiently dissolve the drug to prepare a drug solution. Wherein the first solvent may be selected from: one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid, and dichloromethane.

The concentration of the drug solution can be selected according to the drug and the requirement, and in one embodiment, the mass percentage of the drug solution is 0.5% -15%.

S1022 b: the drug solution is loaded onto each base unit of the body and dried to form an amorphous drug layer.

It will be appreciated that the drug solution may be loaded into the drug pre-loaded areas of each base unit, such as in the grooves, etc., by spraying, printing, etc. The thickness of the amorphous drug layer is not particularly limited, and the dripping may be repeated to form a drug layer of an appropriate thickness.

S1023 b: adding a second solvent to the amorphous drug layer on each base unit to crystallize to form a first crystal layer.

The second solvent is a poor solvent for the drug, and in one embodiment, the second solvent at least comprises one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

In addition, the second solvent may also be a mixed solvent of a good solvent and a poor solvent, and the ratio of the good solvent to the poor solvent is adjusted according to the type of the drug and the selected solvent, so as to realize the crystallization of the amorphous drug, wherein in one embodiment, the volume ratio of the good solvent to the poor solvent is 1: (5-25). Wherein the good solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, acetic acid and dichloromethane; the poor solvent is selected from one or more of n-hexane, n-heptane, cyclohexane, diethyl ether, water and petroleum ether.

S1024 b: repeating the steps of forming an amorphous drug layer and adding a second solvent for crystallization n times on the same basic unit to form n +1 crystal layers, wherein the mass ratio of the added drug to the second solvent changes in a gradient manner from the step of forming the first crystal layer to the step of forming the n +1 crystal layer, wherein n is an integer greater than or equal to 1.

It is understood that the method of changing the mass ratio of the drug and the second solvent added in a gradient includes, but is not limited to: fixing the mass of the added drug in each amorphous drug layer, wherein the volume of the added second solvent is changed in a gradient manner from the step of forming the first crystal layer to the step of forming the n +1 th crystal layer; or, fixing the volume of the second solvent to make the mass of the drug added from the formation of the first crystal layer to the formation of the n +1 th crystal layer change in a gradient manner.

Further, the second solvent used in the step S1023b and the second solvent used in the step S1024b may be the same or different solvents. By repeating the above steps S1022b and S1023b, several drug layers with gradient crystallinity can be formed. As shown in fig. 2, three drug layers 2041, namely a first drug layer 2014a, a second drug layer 2014b and a third drug layer 2041c, are disposed in the groove 240, and the crystallinity of the drug layers varies in a gradient from the first drug layer 2014a to the third drug layer 2041c, so that a drug release gradient is formed in each groove to gradually release the drug, thereby effectively prolonging the release period of the drug.

By the method of this embodiment, a drug-loaded implantable medical device in which the crystallinity of the drug varies in a gradient along the second direction (e.g., the B direction shown in fig. 2) can be formed.

In another embodiment, step S1024 is followed by the following steps:

s1025 b: in the step of forming the n +1 th crystal layer, the mass ratio of the drug to be added to each of the basic units and the second solvent is changed in a gradient manner in the first direction.

Thus, the crystallinity of the n +1 th crystal layer can be changed in a gradient manner in the first direction.

In one embodiment, the volume of the second solvent added varies in a gradient from the middle portion basic unit to the both end portions basic unit of the body.

It is understood that the second solvent used in step S1025b may be the same as or different from that used in step S1023b or step S1024b, and is not particularly limited.

By the method of the embodiment, a drug-loaded implantable medical device with the crystallinity of the drug varying in a gradient manner in both the first direction and the second direction can be formed.

After the preparation is finished, the prepared drug-loaded implant medical instrument can be disinfected, and the specific disinfection process can adopt the existing medical instrument disinfection process, and is not particularly limited.

According to the preparation method, the first solvent is firstly used for preparing the drug solution to form the amorphous drug layer, then the second solvent is used for crystallization, and the mass ratio of the added drug to the second solvent is controlled to realize the adjustment of the crystallinity, so that the crystallinity of the drug is loaded on the body in a gradient change manner, the effective control of the drug release rate can be realized, the release time of the drug is prolonged, and the risk of reoccurrence of thrombus is effectively reduced. In addition, the method only needs to adjust the volume of the solvent, does not need special instruments and equipment and operation skills, does not need to increase the production cost, and is suitable for industrial production and application.

Compared with the prior art, the invention has the following technical effects:

Firstly, the control of the drug release rate can be realized through gradient crystallization, and finally the long-term and slow-release drug is realized;

secondly, the gradient crystallization of the medicine is carried out along the axial direction of the implanted medical apparatus, so that the medicine concentration distribution in the blood flow direction is in gradient numbering at the initial stage of implantation, the medicine is released in a targeted manner at a lesion part, and the condition that the medicine concentration at the initial stage is too high or too low when amorphous or crystalline medicine is completely used is avoided;

thirdly, the gradient crystallization of the medicine is carried out along the vertical direction of the groove and/or the through hole of the implanted medical appliance, and the longer release time or the higher blood concentration can be realized according to the requirement.

The present invention will be described below with reference to specific embodiments.

The drug-loaded implantable medical device in the following examples is a stent as shown in fig. 1, wherein the straight rod section has a width of 96 μm and the reinforcement ring has a width of 91 μm; the thickness of the stent was 100. mu.m. The method is characterized in that a medicine carrying groove is cut by utilizing a laser cutting technology, the groove width is 60 micrometers, the depth is 30 micrometers, the cumulative groove length accounts for 60 percent of the total wave rod length of a main supporting unit ring, and the medicine carrying groove is processed by a process and sprayed for standby use and is made of cobalt-chromium alloy.