CN116966402A - Medical device for slow release of medicine and preparation method thereof - Google Patents
Medical device for slow release of medicine and preparation method thereof Download PDFInfo
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- CN116966402A CN116966402A CN202210425058.5A CN202210425058A CN116966402A CN 116966402 A CN116966402 A CN 116966402A CN 202210425058 A CN202210425058 A CN 202210425058A CN 116966402 A CN116966402 A CN 116966402A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Anesthesiology (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Materials For Medical Uses (AREA)
Abstract
The invention relates to a medicine slow-release medical device and a preparation method thereof, comprising the following steps: the medical device comprises a device body, a medicine coating and a protective coating, wherein the medicine coating is arranged on the surface of the device body, the medicine coating comprises a first degradable polymer and medicine, and the weight average molecular weight of the first degradable polymer is 60-100 ten thousand; the protective coating is arranged on the surface of the drug coating, which is far away from the instrument body, and comprises a second degradable polymer, wherein the weight average molecular weight of the second degradable polymer is 10-50 ten thousand. The medicine slow-release medical device can improve the medicine retention rate, has proper release rate and effectively promotes endothelialization by selecting proper degradable polymers with different molecular weights to form the coating structure which is degraded from outside to inside and is graded from beginning to end, thereby reducing the risk of vascular embolism and inflammatory reaction of vascular wall caused by the medical device.
Description
Technical Field
The invention relates to the technical field of medical instruments, in particular to a medicine slow-release medical instrument and a preparation method thereof.
Background
Peripheral Arterial Disease (PAD) is a chronic ischemic disease of the limb, in which there is a gradual accumulation of fatty substances (atherosclerosis) in the inner layers of the arterial blood vessels, a progressive process, which causes the artery to become blocked, stenosed or fragile, thus causing a blood circulation disorder in the arteries supplying the limbs.
The interventional therapy is widely applied to the treatment of lower limb arterial diseases due to the advantages of small wound, high success rate, low complication occurrence rate, simple operation, repeatability and the like. Percutaneous Transluminal Coronary Angioplasty (PTCA), a catheter assembly having a balloon is percutaneously introduced into the cardiovascular system of a patient via the brachial or femoral artery, the catheter assembly is advanced through to occlusion lesion location, the balloon is expanded to a predetermined size to reconstruct the vessel wall, and the balloon is then depressurized to a smaller size to allow the catheter to be withdrawn from the patient's vasculature. However, the balloon may cause conditions such as tearing of the intima, elastic retraction, inability of the hardened plaque to expand during the expansion process, and the like, resulting in a high vascular remodeling rate one year after the operation. To reduce partial or total occlusion of the artery due to collapse in the artery and to reduce the chance of restenosis, stents may be implanted within the lumen to maintain vessel patency. The stent is capable of compressing plaque and compressing the vessel wall, dilating the vessel by simple mechanical intervention. However, the patency rate of the bare stent after being implanted in the iliac artery for 1 year is about 80% -90%, the patency rate of the bare stent after being implanted in the femoral popliteal artery for 1 year is only 50% -70%, and the restenosis rate in the stent is as high as 30%.
The root cause of restenosis in the blood vessel under investigation is: the balloon or stent expands to cause vascular intimal injury and then induces the transitional proliferation of vascular smooth muscle cells, thereby causing vascular intimal hyperplasia and restenosis after operation. A great deal of experimental investigation was conducted by researchers against the mechanism problem of intravascular restenosis. The current common solutions are: drug Coated Balloons (DCB) and Drug Eluting Stents (DES).
The drug coating balloon combines balloon angioplasty and recent drug coating technology, and the drug is released and dispersed into the vascular wall tissue immediately after the balloon is inflated, so that the high concentration of the local drug and the short-time action within one week can effectively reduce chronic inflammatory reaction and late thrombosis. One technology describes that a water-soluble glue layer, an isolation layer and a drug layer are sequentially coated on the surface of a balloon. The isolation layer and the drug layer are separated from the outer surface of the balloon body and adhered to the vessel wall by the dissolution of the water-soluble adhesive layer under the scouring of blood flow. However, for drugs with poor lipophilicity, the adhesion between the drug coating and the vessel wall is poor, the drug coating cannot effectively adhere to the vessel wall, and drug loss after balloon folding and crimping and balloon over-sheath cannot be avoided during the installation process.
The medicine eluting stent takes the stent as a carrier for carrying medicines, the antithrombotic and antiproliferative medicines are coated on the stent, and after the medicine eluting stent is implanted into the femoral popliteal artery, the medicine is slowly released in an eluting mode, so that the medicine eluting stent not only can provide medicine with sufficient therapeutic concentration for the implantation site of the stent, but also can avoid systemic adverse reaction caused by overhigh blood concentration and reduce restenosis rate. One technique describes coating the surface of a biodegradable stent with a single coating containing an antiproliferative drug-an anti-inflammatory and anti-immune drug-a drug that promotes endothelial cell growth-a contrast agent. Although multiple drugs in the coating can reduce intimal hyperplasia and inflammatory response, the probability of the coating falling off is greatly increased, leading to an increased risk of vascular embolism. Especially in the process of installing and releasing the stent, the drug loss is aggravated under the larger friction effect of the coating and the sheath. In addition, after rapid release of the stent surface coating, endothelialization is delayed and the risk of inflammatory reactions of the vessel wall increases.
Disclosure of Invention
Based on the problems of large drug loss of a drug coating, easy falling of the coating and delayed endothelialization of the device existing in the conventional technology, it is necessary to provide a drug sustained-release medical device capable of improving the retention rate of the drug, having a proper release rate and effectively promoting endothelialization and a preparation method thereof.
The invention is realized by the following technical scheme.
In one aspect of the present invention, there is provided a drug-eluting medical device comprising:
an instrument body;
the drug coating is arranged on the surface of the instrument body and comprises a first degradable polymer and a drug, and the weight average molecular weight of the first degradable polymer is 60-100 ten thousand; a kind of electronic device with high-pressure air-conditioning system
The protective coating is arranged on the surface, far away from the instrument body, of the drug coating, and comprises a second degradable polymer, and the weight average molecular weight of the second degradable polymer is 10-50 ten thousand.
In some of these embodiments, the first degradable polymer has a weight average molecular weight of 70 ten thousand to 100 ten thousand;
and/or the weight average molecular weight of the second degradable polymer is 20 ten thousand-40 ten thousand.
In some of these embodiments, the first and second degradable polymers are each independently selected from at least one of l-polylactic acid, d-polylactic acid, racemic polylactic acid, polylactic acid-glycolic acid copolymer, polyglycolide, poly (DL-lactide-glycolide), and polyethylene glycol.
In some of these embodiments, the drug coating consists of a first degradable polymer and a drug;
The composition of the protective coating is a second degradable polymer.
In some embodiments, the mass ratio of the first degradable polymer to the drug in the drug coating is 4:6 to 8:2.
In some of these embodiments, the drug coating has a thickness of 0.5 to 2 μm;
and/or the thickness of the protective coating is 4-6 mu m.
In some embodiments, the drug is selected from at least one of paclitaxel, a paclitaxel derivative, rapamycin, a rapamycin derivative, fluorouracil, doxorubicin hydrochloride, and lovastatin.
In some embodiments, the device body is made of a degradable polymer material.
In some of these embodiments, the degradable polymer in the device body is the same material as the first and second degradable polymers, and the weight average molecular weight of the degradable polymer in the device body is greater than the weight average molecular weight of the first degradable polymer.
In another aspect of the present invention, a method for preparing a drug-eluting medical device is provided, comprising the steps of:
preparing a first solution, and coating the first solution on the surface of the instrument body to form a drug coating; the first solution comprises a first degradable polymer, a drug and a first solvent which are mixed with each other, wherein the weight average molecular weight of the first degradable polymer is 60 ten thousand to 100 ten thousand; a kind of electronic device with high-pressure air-conditioning system
Preparing a second solution, and coating the second solution on the surface of the drug coating, which is far away from the instrument body, so as to form a protective coating; the second solution comprises a second degradable polymer and a second solvent which are mixed with each other, and the weight average molecular weight of the second degradable polymer is 10 ten thousand to 50 ten thousand.
The drug-release medical device sequentially forms the drug coating and the protective coating which are arranged in a laminated manner on the surface of the device body, the drug coating and the protective coating both contain degradable polymers, the second degradable polymer in the protective coating and the first degradable polymer in the drug coating are controlled to have specific and different molecular weights, and then a coating structure which is degraded from outside to inside and is degraded in a graded manner firstly, quickly and slowly is formed, and the second degradable polymer and the first degradable polymer are degraded sequentially, so that the slow release of the drugs in the drug coating is realized. The first degradable polymer can increase the adhesiveness of the drug coating, thereby enhancing the adhesion of the device body and the drug coating and reducing the falling-off of the drug coating; the protective coating can protect the drug coating, reduce the drug loss of the drug coating in the installation and release process of the drug sustained-release medical device, and thus improve the drug retention rate after installation and release from two aspects. Meanwhile, in the process of slowly degrading and releasing the drug to treat the target lesion blood vessel, the protective coating can adhere to the blood vessel wall, so that the interaction between the drug in the drug release coating and the blood vessel wall can be promoted, on one hand, the adhesiveness between the medical instrument and the blood vessel can be improved, and on the other hand, the drug utilization rate can be improved. In conclusion, the drug-sustained-release medical instrument forms the coating structure which is degraded from outside to inside and is graded from beginning to end by selecting proper degradable polymers with different molecular weights, and finally realizes the complete endothelialization of the instrument body, thereby reducing the risk of vascular embolism and inflammatory reaction of vascular walls caused by the medical instrument.
Drawings
FIG. 1 is a schematic cross-sectional view of a drug-eluting medical device according to an embodiment of the present invention;
FIG. 2 is a graph showing the change of the drug release rate with time of the drug-eluting stent fabricated in comparative examples 1 to 2 and examples 1 to 5 according to the present invention;
FIG. 3 is a graph showing the change of the drug release rate with time of the drug-eluting stent prepared in example 3 and examples 6 to 7 according to the present invention;
FIG. 4 is a graph showing the change of the drug release rate with time of the drug-eluting stent fabricated in example 3 and examples 8 to 9 according to the present invention;
FIG. 5 is a graph showing the change of the drug release rate with time of the drug-eluting stent fabricated in example 3 and examples 10 to 11 according to the present invention.
Reference numerals illustrate:
110. an instrument body; 121. a drug coating; 122. and (3) a protective coating.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. It should be understood that 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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
Referring to fig. 1, an embodiment of the present invention provides a drug-eluting medical device, comprising: the device body 110, the drug coating 121 and the protective coating 122.
The drug coating 121 is provided on the surface of the device body 110. The drug coating 121 includes a first degradable polymer and a drug, the first degradable polymer having a weight average molecular weight of 60 to 100 tens of thousands.
The protective coating 122 is provided on the surface of the drug coating 121 remote from the instrument body 110. The protective coating 122 comprises a second degradable polymer having a weight average molecular weight of 10 to 50 tens of thousands.
The above-mentioned drug-eluting medical device sequentially forms a drug coating 121 and a protective coating 122, which are stacked on the surface of the device body 110, wherein the drug coating 121 and the protective coating 122 each contain a degradable polymer, and the second degradable polymer in the protective coating 122 and the first degradable polymer in the drug coating 121 are controlled to have specific and different molecular weights, so as to form a coating structure which is gradually degraded from outside to inside and from beginning to end, and the second degradable polymer and the first degradable polymer are sequentially degraded, thereby realizing slow release of the drug in the drug coating 121. The first degradable polymer may increase the adhesion of the drug coating 121, thereby enhancing the adhesion of the device body 110 to the drug coating 121 and reducing the release of the drug coating 121; the protective coating 122 can protect the drug coating 121, reduce the drug loss of the drug coating 121 in the installation and release process of the drug sustained-release medical device, and improve the drug retention rate after installation and release in two aspects. Meanwhile, in the process of slowly degrading and releasing the drug to treat the target lesion blood vessel, the protective coating 122 can adhere to the blood vessel wall, so that the interaction between the drug in the drug release coating 121 and the blood vessel wall can be promoted, on one hand, the fit between the medical instrument and the blood vessel can be improved, and on the other hand, the drug utilization rate can be improved. In summary, the drug-eluting medical device forms the coating structure which is degraded from outside to inside and gradually from beginning to end by selecting suitable degradable polymers with different molecular weights, and finally realizes the complete endothelialization of the device body 110, thereby reducing the risk of vascular embolism and inflammatory reaction of the vascular wall caused by the medical device.
It is understood that the weight average molecular weight of the first degradable polymer is 60 ten thousand, 70 ten thousand, 80 ten thousand, 90 ten thousand, 100 ten thousand. In some of these embodiments, the first degradable polymer has a weight average molecular weight of 70 ten thousand to 100 ten thousand.
It is understood that the weight average molecular weight of the second degradable polymer is 10 ten thousand, 20 ten thousand, 30 ten thousand, 40 ten thousand, 50 ten thousand. In some of these embodiments, the second degradable polymer has a weight average molecular weight of 10 to 50 tens of thousands, further 10 to 40 tens of thousands, 20 to 40 tens of thousands.
In some of these embodiments, the first and second degradable polymers are each independently selected from at least one of l-polylactic acid (PLLA), d-polylactic acid (PDLA), DL-polylactic acid (PDLLA), polylactic acid-glycolic acid copolymer (PLGA), polyglycolide (PGA), poly (DL-lactide-glycolide) (PDLGA), and polyethylene glycol (PEG).
In some specific examples, the drug coating 121 is composed of a first degradable polymer and a drug, and the formed coating is uniformly dense throughout and has the functions of adhering to the device body 110 such as a balloon or stent and releasing the drug. Further, in the drug coating 121, the mass ratio of the first degradable polymer to the drug is 4:6 to 8:2, e.g. 4:6, 5:5, 6:4, 7:3, 8:2.
In some specific examples, the composition of the protective coating 122 is a second degradable polymer.
In some embodiments, the drug is selected from at least one of paclitaxel, a paclitaxel derivative, rapamycin, a rapamycin derivative, fluorouracil, doxorubicin hydrochloride, and lovastatin.
In some embodiments, the device body 110 is made of a degradable polymer material. It is understood that the degradable polymer material herein may be selected from the same kinds of ranges as the first degradable polymer and the second degradable polymer, and will not be described herein.
In some of these embodiments, the degradable polymer in the device body 110 is the same material as the first and second degradable polymers (here meaning that the particular types of degradable polymers are the same). It is understood that the degradable polymer in the device body 110 may also be different from the material of the first degradable polymer or the second degradable polymer, without limitation.
Further, the weight average molecular weight of the degradable polymer in the device body 110 is greater than the weight average molecular weight of the first degradable polymer.
Further, the weight average molecular weight of the degradable polymer in the instrument body 110 is 120 to 180 ten thousand, for example 120 ten thousand, 130 ten thousand, 140 ten thousand, 150 ten thousand, 160 ten thousand, 170 ten thousand, 180 ten thousand.
In some of these embodiments, the thickness of the drug coating 121 is 0.5-2 μm, for example 1 μm;
in some of these embodiments, the protective coating 122 has a thickness of 4-6 μm, for example 5 μm.
In some of these embodiments, the instrument body 110 may be a stent. The drug coating 121 and the protective coating 122 are sequentially wrapped around the surface of the device body 110.
The invention also provides a preparation method of the drug sustained-release medical device, which comprises the following steps S10-S20.
Step S10: a first solution is prepared and applied to the surface of the device body 110 to form a drug coating 121.
Wherein, the preparation of the first solution comprises the following steps: the first degradable polymer, the drug and the first solvent are mixed to produce a first solution. Namely: the first solution includes a first degradable polymer, a drug, and a first solvent intermixed.
Further, the first solvent is selected from: at least one of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, toluene, xylene, acetonitrile, butanone and acetone.
Further, the total concentration of the first degradable polymer and the drug in the first solution is 6-15 mg/mL. Preferably, the total concentration of the first degradable polymer and the drug in the first solution is 10mg/mL.
Step S20: a second solution is prepared and applied to the surface of the drug coating 121 remote from the device body 110 to form a protective coating 122.
Wherein, the preparation of the second solution comprises the following steps: the second degradable polymer and the second solvent are mixed to produce a second solution. Namely: the second solution includes a second degradable polymer and a second solvent with respect to each other.
Further, the second solvent is selected from: at least one of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, toluene, xylene, acetonitrile, butanone and acetone.
Further, the total concentration of the second degradable polymer and the drug in the second solution is 6-15 mg/mL. Preferably, the total concentration of the second degradable polymer and the drug in the second solution is 10mg/mL.
Further, the manner of coating of step S10 and step S20 includes, but is not limited to, one of spraying, dipping, brushing, or spraying.
In order to make the objects, technical solutions and advantages of the present invention more concise, the present invention will be described in the following specific examples, but the present invention is by no means limited to these examples. The following examples are only preferred embodiments of the present invention, which can be used to describe the present invention, and should not be construed as limiting the scope of the invention. It should be noted that any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
In order to better illustrate the present invention, the following description of the present invention will be given with reference to examples. The following are specific examples.
Comparative example 1
(1) Preparing a closed-loop degradable stent with a wall thickness of 0.13mm from L-polylactic acid (PLLA) with a molecular weight of 150 ten thousand (weight average molecular weight Mw, hereinafter referred to as Mw unless otherwise specified) by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the ratio of 7:3 (mass ratio, m: m) to obtain mixed solution with total concentration (sum of L-polylactic acid and taxol) of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact drug coating is obtained on the surface of the degradable stent, and the thickness of the coating is 1 mu m.
Comparative example 2
(1) Preparing a closed-loop degradable stent with a wall thickness of 0.13mm from L-polylactic acid (PLLA) with a molecular weight of 150 ten thousand (weight average molecular weight Mw, hereinafter referred to as Mw unless otherwise specified) by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact drug coating is obtained on the surface of the degradable stent, and the thickness of the coating is 1 mu m.
(4) Dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand in acetone to obtain polymer solution with concentration of 10 mg/mL; spraying the polymer solution on the surface of the drug coating obtained in the step (3) by a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact polymer coating (namely a protective coating) with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 1
Example 1 is substantially the same as comparative example 2, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (4) is 10 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with molecular weight of 10 ten thousand in acetone to obtain polymer solution with concentration of 10 mg/mL; spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 2
Example 2 is substantially the same as example 1, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (4) is 20 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with molecular weight of 20 ten thousand in acetone to obtain polymer solution with concentration of 10 mg/mL; spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 3
Example 3 is substantially the same as example 1, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (4) is 30 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 4
Example 4 is substantially the same as example 1, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (4) was 40 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving 40 ten thousand of L-polylactic acid (PLLA) with molecular weight in acetone to obtain polymer solution with concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a compact polymer coating layer with thickness of 5 mu m is obtained on the surface of the drug coating layer.
Example 5
Example 5 is substantially the same as example 1, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (4) was 50 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m; (4) Dissolving L-polylactic acid (PLLA) with molecular weight of 50 ten thousand in acetone to obtain polymer solution with concentration of 10 mg/mL; spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone cleanly, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 6
Example 6 is substantially the same as example 3, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (3) is 60 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 60 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 7
Example 7 is substantially identical to example 3, except that: the molecular weight of the L-polylactic acid (PLLA) in the step (3) is 100 ten thousand. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 100 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 8
Example 8 is substantially the same as example 3, except that: the thickness of the drug coating of the intermediate layer in the step (3) is 0.5 mu m. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating with the thickness of 0.5 mu m is obtained on the surface of the degradable stent;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 9
Example 9 is substantially the same as example 3, except that: the thickness of the drug coating of the intermediate layer in the step (3) is 2 mu m. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 2 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 5 mu m is obtained on the surface of the drug coating.
Example 10
Example 10 is substantially the same as example 3, except that: the thickness of the drug coating layer of the outermost layer in the step (4) is 4 μm. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 4 mu m is obtained on the surface of the drug coating.
Example 11
Example 11 is substantially the same as example 3, except that: the thickness of the drug coating layer at the outermost layer in the step (4) is 6 mu m. The method comprises the following specific steps:
(1) Preparing a closed-loop degradable bracket with the wall thickness of 0.13mm from L-polylactic acid (PLLA) with the molecular weight of 150 ten thousand by melt extrusion, laser engraving and the like;
(2) Ultrasonically cleaning the bracket for 3 minutes to remove surface impurities and simultaneously eliminate static electricity on the surface of the degradable bracket;
(3) Completely dissolving L-polylactic acid (PLLA) with molecular weight of 80 ten thousand and taxol in acetone according to the proportion of 7:3 (m: m) to obtain mixed solution with total concentration of 10 mg/mL; spraying the mixed solution on the surface of the degradable stent obtained in the step (2) in a spraying mode, and drying for 1h at 37 ℃ to volatilize acetone completely, so that a layer of compact drug coating is obtained on the surface of the degradable stent, wherein the thickness of the coating is 1 mu m;
(4) Dissolving L-polylactic acid (PLLA) with the molecular weight of 30 ten thousand in acetone to obtain a polymer solution with the concentration of 10mg/mL, spraying the polymer solution on the surface of the drug coating obtained in the step (3) in a spraying mode, and drying for 1h at 37 ℃ to volatilize the acetone, so that a layer of compact polymer coating with the thickness of 6 mu m is obtained on the surface of the drug coating.
Comparative example 1, in which the outermost layer did not contain a polymer coating, had the same molecular weight of the L-polylactic acid (i.e., the intermediate layer polymer hereinafter) as that of the intermediate layer drug coating in examples 1 to 5, which were 80 ten thousand; the molecular weights of the l-polylactic acid (i.e., the following outermost polymer) in the outermost polymer coatings of examples 1 to 5 were different, and as shown in table 1 below, the effect of the difference in the molecular weights of the outermost polymer on the drug retention rate of the prepared drug-eluting stent was known from examples 1 to 5, and the specific results are shown in table 1 below:
TABLE 1
Wherein, initial drug loading refers to: paclitaxel content of the initial spray stent; the testing method comprises the steps of immersing the bracket in acetone solution completely, carrying out ultrasonic treatment for 5min, collecting the solution, and carrying out high performance liquid chromatography test;
drug loading after installation and release means: paclitaxel content of the stent after being released by the outer tube installation; the testing method comprises the steps of immersing the bracket after being released in acetone solution completely, carrying out ultrasonic treatment for 5min, collecting the solution, and carrying out high performance liquid chromatography test;
drug retention refers to the percentage of drug loading after installation and release as compared to the initial drug loading.
The drug release rate performance test was performed on comparative example 1, comparative example 2, and examples 1 to 5, and the results are shown in fig. 2. The drug release rate refers to: percent drug release of the stent at different time points; the method for testing the performance of the drug release rate comprises the steps of immersing the stent after installation and release in a mixed solvent of acetone and water, carrying out shaking table oscillation, and then sampling the drug content in the test solution at different time points.
As can be seen from fig. 2, the effect of the difference in molecular weight of the outermost polymer on the drug release rate of the prepared drug-eluting stent was that the drug release rate was in the order of example 3, example 4, example 5, example 2, example 1, comparative example 2 and comparative example 1 from low to high at the same release time. Wherein the release rates of example 3, example 4, example 5, example 2, example 1, comparative example 2 and comparative example 1 were 65.3%, 74.3%, 78.5%, 82.3%, 87.1%, 90.6% and 99.0%, respectively, at a release time of 3 days.
The molecular weights of the L-polylactic acid in the outermost polymer coating layers in examples 3 and 6 to 7 are all 30 ten thousand; the molecular weights of the l-polylactic acid (i.e., the intermediate layer polymers hereinafter) in the intermediate layer drug coatings of examples 3 and 6 to 7 were different, and as shown in table 2 below, the influence of the intermediate layer polymer molecular weights on the drug retention rate of the prepared drug-eluting stent was known from examples 3 and 6 to 7, and specific results are shown in table 2 below:
TABLE 2
Drug release rate performance tests were performed on examples 3 and 6 to 7, and the results are shown in fig. 3.
As can be seen from fig. 3, the effects of different molecular weights of the middle layer polymers on the drug release rate of the prepared drug-eluting stent were that the drug release rate was in the order of example 3, example 7 and example 6 from low to high at the same release time. Wherein, at a release time of 3 days, the release rates of example 3, example 7 and example 6 were 65.3%, 72.2% and 83.6%, respectively.
The molecular weight of the L-polylactic acid in the outermost polymer coating in examples 3 and 8 to 9 is 30 ten thousand, and the thickness of the coating is 5 μm; the molecular weight of the L-polylactic acid in the drug coating layers of the intermediate layers of examples 3 and 8 to 9 is the same, the thicknesses of the coating layers are different, and as shown in the following table 3, the influence of the thickness of the intermediate layer on the drug retention rate of the prepared drug sustained-release stent is known from examples 3 and 8 to 9, and the specific results are shown in the following table 3:
TABLE 3 Table 3
| Example 8 | Example 3 | Example 9 | |
| Thickness of intermediate layer (μm) | 0.5 | 1 | 2 |
| Thickness of outermost layer (μm) | 5 | 5 | 5 |
| Initial drug loading (μg/mm) 2 ) | 1.385 | 1.385 | 1.385 |
| Drug loading after installation release (μg/mm) 2 ) | 1.321 | 1.284 | 1.167 |
| Drug retention (%) | 95.37 | 92.71 | 84.26 |
Drug release rate performance tests were performed on examples 3 and 8 to 9, and the results are shown in fig. 4.
As can be seen from fig. 4, the effect of the difference in thickness of the intermediate layer drug coating on the drug release rate of the prepared drug-eluting stent was that the drug release rate was in the order of example 9, example 3 and example 8 from low to high at the same release time. Wherein, at a release time of 3 days, the release rates of example 9, example 3 and example 8 were 42.3%, 65.3% and 77.9%, respectively.
The molecular weight of the L-polylactic acid in the middle layer drug coating layers of examples 3 and 10-11 is the same, and the thickness of the coating layers is 1 μm; the molecular weight of the left-handed polylactic acid in the outermost polymer coating layers in examples 3 and 10 to 11 was 30 ten thousand, and the coating thicknesses were different, and as shown in table 4 below, the effect of the outermost polymer coating layer thickness on the drug retention rate of the prepared drug sustained-release stent was found from examples 3 and 10 to 11, and the specific results are shown in table 4 below:
TABLE 4 Table 4
| Example 10 | Example 3 | Example 11 | |
| Thickness of intermediate layer (μm) | 1 | 1 | 1 |
| Thickness of outermost layer (μm) | 4 | 5 | 6 |
| Initial drug loading (μg/mm) 2 ) | 1.385 | 1.385 | 1.385 |
| Drug loading after installation release (μg/mm) 2 ) | 1.313 | 1.284 | 1.220 |
| Drug retention (%) | 94.78 | 92.71 | 88.12 |
Drug release rate performance tests were performed on examples 3 and 10 to 11, and the results are shown in fig. 5.
As can be seen from fig. 5, the effect of the difference in the thickness of the outermost polymer layer on the drug release rate of the prepared drug-eluting stent was that the drug release rate was in the order of example 11, example 3 and example 10 from low to high at the same release time. Wherein, at a release time of 3 days, the release rates of example 11, example 3 and example 10 were 61.3%, 65.3% and 71.4%, respectively.
As can be seen from tables 1 and 2, compared with comparative example 1, the coating of the degradable polymer coating on the surface of the drug coating in comparative example 2 and each example can obviously reduce the drug loss of the stent in the simulated release process and improve the drug utilization rate. Therefore, the retention rate and the drug release performance of the drug are combined, and the molecular weight of the polymer in the middle layer is required to be moderate and is 10-40 ten thousand; preferably 20 to 40 tens of thousands, more preferably 30 to 40 tens of thousands.
Further, as shown in fig. 2 and 3, when the molecular weight of the middle layer polymer is 80 ten thousand and the molecular weight of the outermost layer polymer is 30 ten thousand, the drug-releasing property of the drug-releasing stent manufactured in example 3 is optimal.
As can be seen from table 3, the thickness of the drug coating of the intermediate layer is increased, the firmness of the coating is poor, the drug loss of the stent after being released by the outer tube installation is increased, and the drug retention rate is reduced; further, as can be seen from fig. 4, the thickness of the drug coating layer of the intermediate layer is increased, that is, the content of the polymer in the intermediate layer and the drug content are increased in a same ratio, the degradation rate of the polymer in the intermediate layer is slowed down, the drug is relatively difficult to release from the drug coating layer, and the drug release rate is reduced. Therefore, the drug retention rate and the drug release performance are combined, and the thickness of the drug coating of the middle layer is preferably moderate, preferably 1 mu m.
As can be seen from table 4, the thickness of the outermost polymer layer increases, the coating firmness becomes poor, the drug loss of the stent after being released by the outer tube installation increases, and the drug retention rate decreases; further, as can be seen from fig. 5, the thickness of the outermost polymer layer increases, i.e., the content of the outermost polymer layer increases, the degradation rate of the outermost polymer slows down, the drug is relatively difficult to release from the drug coating, and the drug release rate decreases. Therefore, the thickness of the outermost polymer layer is preferably moderate, preferably 5 μm, in combination with the drug retention rate and drug release properties.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. The scope of the invention is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted in accordance with the contents of the claims.
Claims (10)
1. A drug-eluting medical device, comprising:
an instrument body;
the drug coating is arranged on the surface of the instrument body and comprises a first degradable polymer and a drug, and the weight average molecular weight of the first degradable polymer is 60-100 ten thousand; a kind of electronic device with high-pressure air-conditioning system
The protective coating is arranged on the surface, far away from the instrument body, of the drug coating, and comprises a second degradable polymer, and the weight average molecular weight of the second degradable polymer is 10-50 ten thousand.
2. The drug-eluting medical device according to claim 1, wherein the first degradable polymer has a weight average molecular weight of 70-100 tens of thousands;
And/or the weight average molecular weight of the second degradable polymer is 20 ten thousand-40 ten thousand.
3. The drug-eluting medical device according to claim 1, wherein the first degradable polymer and the second degradable polymer are each independently selected from at least one of l-polylactic acid, d-polylactic acid, racemic polylactic acid, polylactic acid-glycolic acid copolymer, polyglycolide, poly (DL-lactide-glycolide), and polyethylene glycol.
4. The drug-eluting medical device according to claim 1, wherein the drug coating is comprised of a first degradable polymer and a drug;
the composition of the protective coating is a second degradable polymer.
5. The drug-eluting medical device according to claim 1, wherein the mass ratio of the first degradable polymer to the drug in the drug coating is 4:6 to 8:2.
6. The drug-eluting medical device according to claim 1, wherein the drug coating has a thickness of 0.5-2 μm;
and/or the thickness of the protective coating is 4-6 mu m.
7. The drug-eluting medical device according to claim 1, wherein the drug is selected from at least one of paclitaxel, a paclitaxel derivative, rapamycin, a rapamycin derivative, fluorouracil, doxorubicin hydrochloride, and lovastatin.
8. A drug-eluting medical device according to any of claims 1 to 7, wherein the device body is of a degradable polymer material.
9. The drug-eluting medical device according to claim 8, wherein the degradable polymer in the device body is the same material as the first and second degradable polymers, and wherein the degradable polymer in the device body has a weight average molecular weight that is greater than the weight average molecular weight of the first degradable polymer.
10. The preparation method of the medicine slow-release medical device is characterized by comprising the following steps:
preparing a first solution, and coating the first solution on the surface of the instrument body to form a drug coating; the first solution comprises a first degradable polymer, a drug and a first solvent which are mixed with each other, wherein the weight average molecular weight of the first degradable polymer is 60 ten thousand to 100 ten thousand; a kind of electronic device with high-pressure air-conditioning system
Preparing a second solution, and coating the second solution on the surface of the drug coating, which is far away from the instrument body, so as to form a protective coating; the second solution comprises a second degradable polymer and a second solvent which are mixed with each other, and the weight average molecular weight of the second degradable polymer is 10 ten thousand to 50 ten thousand.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210425058.5A CN116966402A (en) | 2022-04-22 | 2022-04-22 | Medical device for slow release of medicine and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210425058.5A CN116966402A (en) | 2022-04-22 | 2022-04-22 | Medical device for slow release of medicine and preparation method thereof |
Publications (1)
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| CN116966402A true CN116966402A (en) | 2023-10-31 |
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| CN202210425058.5A Pending CN116966402A (en) | 2022-04-22 | 2022-04-22 | Medical device for slow release of medicine and preparation method thereof |
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| Country | Link |
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| CN (1) | CN116966402A (en) |
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2022
- 2022-04-22 CN CN202210425058.5A patent/CN116966402A/en active Pending
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