Drug-loaded implantable medical devices and methods of making the same

Abstract

The present application relates to a drug-loaded implant medical device and a preparation method thereof, the drug-loaded implant medical device comprising a device body, a microporous membrane fixed on the device body, and nanocrystal drugs loaded on the microporous membrane. The drug-loaded implant medical device has long-term sustained-release effect and high safety without causing embolism and toxic side effects.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to drug-loaded implantable medical devices and their preparation methods. Background Technology

[0002] With socio-economic development, people's lifestyles have undergone profound changes. In particular, the accelerated aging of the population and urbanization have led to a significant increase in the prevalence of cardiovascular disease risk factors in China, resulting in a continuous rise in the number of people suffering from cardiovascular diseases. Therefore, the prevention and treatment of cardiovascular diseases has increasingly become a focus of attention for doctors worldwide.

[0003] Since the 1970s, the treatment of various cardiovascular diseases through interventional medical devices has become increasingly common. It has experienced three milestone developments: simple balloon angioplasty (PTCA), bare-metal stents (BMS), and drug-eluting stents (DES). The advent of drug-eluting stents, in particular, has achieved great success in treating vascular stenosis, demonstrating the potential of DES in this area. However, drug-eluting stents still have the following problems: (1) They still have a restenosis rate of about 5%, and this problem is becoming increasingly significant as the number of PCI procedures continues to increase; (2) The polymer coating matrix of drug-eluting stents can induce inflammatory responses, delay wound healing, and the coating drug, while inhibiting smooth muscle cell proliferation, also inhibits endothelial cell regeneration, leading to a delay in the vascular endothelialization process after stent implantation; (3) Drug-eluting stents are difficult to adapt to in-stent restenosis, small vessel lesions, and bifurcation lesions. Furthermore, the need for prolonged dual antiplatelet therapy limits their application in patients prone to bleeding. In this context, the drug-coated balloon (DCB) emerged, offering a new option for managing these conditions and bringing new hope for the long-term prognosis of interventional treatment for coronary artery disease. The DCB has an anti-proliferative drug uniformly coated on its surface, which is then delivered to the lesion site and released within a short expansion time (30-60 seconds) to inhibit the proliferation of vascular smooth muscle cells. Its advantages, such as non-implantable intervention, no risk of thrombosis, and rapid treatment effect, have made it increasingly popular.

[0004] The anti-proliferative drugs on the surface of drug-coated balloons are mainly in amorphous and crystalline forms. It has been found that when the drug in the drug coating of a drug-coated balloon exists in an amorphous form, the coating is more uniform, the particles formed during drug release are smaller, the risk of embolism is lower, and it has higher safety. However, amorphous drugs have poor retention in tissues; the tissue concentration usually drops below the therapeutic concentration in less than a week, making it difficult to effectively inhibit the proliferation of vascular smooth muscle cells. On the other hand, although crystalline drugs have excellent sustained-release effects and long tissue retention time, the surface uniformity of the drug coating becomes very poor, and it is easier to form larger particles, which can easily cause terminal embolism. Furthermore, very large crystalline drugs can lead to very high local drug concentrations, resulting in toxic side effects and posing a significant risk. Summary of the Invention

[0005] Therefore, it is necessary to provide a drug-loaded implantable medical device and its preparation method that have both long-term sustained-release effect and high safety without causing embolism or toxic side effects.

[0006] A drug-loaded implantable medical device includes a device body, a microporous membrane fixed to the device body, and a nanocrystalline drug loaded on the surface of the microporous membrane.

[0007] In one embodiment, both the surface of the microporous membrane and the nanocrystalline drug are charged, and the charge on the surface of the microporous membrane and the charge on the nanocrystalline drug are the same.

[0008] In one embodiment, the microporous membrane is a network-structured microporous membrane formed from at least one of the following materials: nylon, polyvinylidene fluoride, mixed cellulose, polytetrafluoroethylene, polypropylene, polyethersulfone, or glass fiber; and / or

[0009] The porosity of the microporous membrane is 40%-90%; and / or

[0010] The microporous membrane has a pore size of 0.02 μm-0.8 μm; and / or

[0011] The thickness of the microporous membrane is 1μm-200μm.

[0012] In one embodiment, the surface of the nanocrystalline drug is adsorbed with a stabilizer, and the content of the stabilizer is 0.2%-20% of the nanocrystalline drug.

[0013] In one embodiment, the stabilizer is selected from one or more of: poloxamer, polyvinylpyrrolidone (PVP), Tween, hydroxypropyl methylcellulose (HPMC), dextran, sodium lauryl sulfate (SDS), sodium carboxymethyl cellulose, and polyvinyl alcohol (PVA); and / or

[0014] The nanocrystalline drug is an anti-proliferative drug.

[0015] In one embodiment, the nanocrystalline drug has a particle size of 20 nm-300 nm; and / or

[0016] The nanocrystalline drug has a morphology of spheres, rods, worms, or discs; and / or

[0017] In the nanocrystalline drug, the mass percentage of crystalline drug is 70%-100%.

[0018] A method for preparing a drug-loaded implantable medical device includes the following steps:

[0019] Provide microporous membranes;

[0020] Nanocrystalline drugs are loaded onto the microporous membrane;

[0021] The microporous membrane loaded with the nanocrystalline drug is fixed to the device body.

[0022] In one embodiment, the nanocrystalline drug is loaded onto the microporous membrane using mechanical filtration; and / or

[0023] The microporous membrane loaded with the nanocrystalline drug is fixed onto the device body using laser welding.

[0024] In one embodiment, the step of loading the nanocrystalline drug onto the microporous membrane includes the following steps:

[0025] The drug is dissolved in the first solvent to obtain a drug solution;

[0026] The stabilizer is suspended in the second solvent to obtain a stabilizer suspension;

[0027] Under stirring conditions, the drug solution is added to the stabilizer suspension to obtain a mixture;

[0028] The mixture was sonicated, and after sonication, it was dialyzed and concentrated to obtain a nanocrystalline drug suspension.

[0029] The nanocrystalline drug in the nanocrystalline drug suspension is loaded onto the microporous membrane and dried.

[0030] In this process, one solvent is an organic solvent miscible with water, and the other solvent is water.

[0031] A drug delivery balloon includes a balloon body, a microporous membrane fixed on the balloon body, and a nanocrystalline drug loaded on the surface of the microporous membrane.

[0032] The aforementioned drug-loaded implantable medical device innovatively employs a microporous membrane-loaded nanocrystalline drug delivery method. This method securely loads the nanocrystalline drug onto the microporous membrane, preventing it from detaching during transport. Upon reaching the target lesion, the nanocrystalline drug redissolves and disperses due to the device's own expansion and the dissolving effect of blood, thus improving drug utilization. Furthermore, the nanocrystalline drug loaded on this microporous membrane, compared to traditional core-shell nanomedicine structures, significantly increases drug loading capacity, avoids the use of large amounts of excipients and carriers, and improves safety. It also helps to reduce the size of the nanocrystalline drug, avoiding the risk of embolism and toxic side effects. Additionally, it effectively increases the content of crystalline drugs within the nanocrystalline drug, thereby improving the sustained-release effect and prolonging tissue retention time. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of a drug-loaded implantable medical device according to an embodiment of the present invention;

[0034] Figure 2 This shows the morphology of a microporous membrane made of nylon magnified 10,000 times under an electron microscope;

[0035] Figure 3 This shows the morphology of a microporous membrane made of PTFE magnified 5,000 times under an electron microscope;

[0036] Figure 4 This shows the morphology of the microporous membrane made of PVDF under an electron microscope at 10,000x magnification;

[0037] Figure 5 This diagram shows the size distribution of the nanocrystalline drug prepared in Example 1.

[0038] Figure 6 The image shows the XRD pattern of the nanocrystalline drug prepared in Example 1. Detailed Implementation

[0039] To facilitate understanding of the present invention, a more comprehensive description is provided below, along with preferred embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0040] Unless otherwise defined, 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 pertains. The terminology used herein in the specification of this 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.

[0041] like Figure 1As shown, the present invention provides a drug-loaded implantable medical device 10, including a device body 100, a microporous membrane 200 fixed on the device body, and a nanocrystalline drug 300 loaded on the microporous membrane 200.

[0042] Understandably, the aforementioned drug-eluting implantable medical device 10 can be used internally or externally, and can be used for short-term or long-term permanent implantation. Furthermore, the aforementioned medical device can provide medical and / or diagnostic tools for arrhythmias, heart failure, valvular diseases, vascular diseases, diabetes, neurological diseases and disorders, plastic surgery, neurosurgery, oncology, ophthalmology, and ENT surgery. The medical devices involved in this invention include, but are not limited to, the following devices: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, wires, catheters, sensors, surgical instruments, angioplasty balloons, wound drainage tubes, shunts, tubes, infusion sleeves, urethral cannulas, small balls, implants, blood oxygenation generators, pumps, vascular grafts, implantable interventional drug delivery ports, heart valves, annuloplasty rings, sutures, surgical clips, surgical staples, pacemakers, implantable defibrillators, neurostimulators, orthopedic instruments, cerebrospinal fluid shunts, implantable drug delivery pumps, vertebral cages, artificial intervertebral discs, nucleus pulposus replacement devices, ear tubes, intraocular lenses, and any tubes used in interventional procedures. Among these, stents include, but are not limited to, coronary stents, peripheral vascular stents, intracranial vascular stents, urethral stents, and esophageal stents, with coronary stents being preferred. Further, it is preferred that the above-mentioned drug-loaded implantable medical devices be drug-coated balloons, i.e., the device body is a balloon.

[0043] In this invention, the microporous membrane 200 refers to a membrane containing micropores, the pore size of which can be adjusted according to the particle size of the nanocrystalline drug. Thus, by selecting a microporous membrane with a suitable pore size, the size of the nanocrystalline drug loaded on the microporous membrane can be adjusted.

[0044] In one embodiment, the particle size of the nanocrystalline drug 300 is greater than or equal to the pore size of the microporous membrane 200, thus facilitating the loading of the nanocrystalline drug onto the microporous membrane via mechanical filtration. More preferably, the pore size of the microporous membrane 200 is 0.02 μm-0.8 μm, more preferably 0.1 μm-0.5 μm, and even more preferably 0.1 μm-0.3 μm. The thickness of the microporous membrane 200 is preferably 1 μm-200 μm, and more preferably 1 μm-50 μm.

[0045] Furthermore, it is preferable to load the nanocrystalline drug onto the side of the microporous membrane that is away from the device body.

[0046] It should be noted that the microporous membrane 200 is a network structure microporous membrane formed from one or more of the following materials: nylon, polyvinylidene fluoride, mixed cellulose, polytetrafluoroethylene, polypropylene, polyethersulfone or glass fiber, preferably nylon; more preferably a network structure microporous membrane formed from nylon 66 material, so as to improve loading efficiency and facilitate the firm loading of nanocrystalline drug 300 on the microporous membrane 200. Figure 2 This shows the morphology of a microporous membrane made of nylon magnified 10,000 times under an electron microscope; Figure 3 This shows the morphology of a microporous membrane made of PTFE magnified 5,000 times under an electron microscope; Figure 4 This shows the morphology of a microporous membrane made of PVDF magnified 10,000 times under an electron microscope. From... Figures 2-5 As can be seen, the aforementioned microporous membranes have high porosity and uniform pores, making them suitable for loading nanocrystalline drugs. Furthermore, nylon transfer membranes used for the transfer and detection of proteins and nucleic acids are also thin films with high porosity, and should be understood as falling within the scope of protection of this invention.

[0047] Furthermore, it is preferred that both the surface of the microporous membrane 200 and the nanocrystalline drug are charged, and the charge on the surface of the microporous membrane 200 is the same as the charge on the nanocrystalline drug 300. In this way, the release of the nanocrystalline drug is greatly promoted by utilizing the charge repulsion effect, resulting in high drug utilization and low required drug dosage.

[0048] Furthermore, the porosity of the preferred microporous membrane 200 is 40%-90%.

[0049] The nanocrystalline drug 300 in this invention refers to drug crystals with a nanoscale size (less than 1000 nm). It is understood that it may contain some crystalline and non-crystalline drugs. Preferably, the crystalline drug in the nanocrystalline drug 300 has a mass percentage content of 0-100%, and more preferably, the crystalline drug has a mass percentage content of 70%-100%.

[0050] Furthermore, a stabilizer is adsorbed on the surface of the nanocrystalline drug 300, preferably at a content of 0.2%-20% of the nanocrystalline drug. By adsorbing a small amount of stabilizer on the surface of the nanocrystalline drug 300, the stability of the nanocrystalline drug is increased, while preventing phenomena such as nanoparticle aggregation. This facilitates the formation of smaller nanocrystalline drugs 300. Compared with traditional core-shell structured nanomedicines, the aforementioned nanocrystalline drug 300 can significantly increase the drug loading (the drug loading can approach 100%), and the particle size of the nanocrystalline drug is more easily adjusted. The stabilizer is preferably one or more of poloxamer, polyvinylpyrrolidone (PVP), Tween, hydroxypropyl methylcellulose (HPMC), dextran, sodium dodecyl sulfate (SDS), sodium carboxymethyl cellulose, and polyvinyl alcohol (PVA).

[0051] Furthermore, the preferred drug loading of the nanocrystalline drug 300 is 1%-99%, and more preferably 50%-100%.

[0052] Furthermore, the particle size of the nanocrystalline drug 300 is 1nm-1000nm, preferably 3nm-300nm, and more preferably 50nm-250nm.

[0053] Furthermore, the morphology of the nanocrystalline drug is spherical, rod-shaped, worm-like, or disc-shaped; the preferred morphology is spherical.

[0054] In addition, medications can be selected based on actual needs, such as anti-proliferative, anti-inflammatory, anti-inflammatory, anti-proliferative, antibacterial, antitumor, anti-mitotic, cell-inhibiting, cytotoxic, anti-osteoporosis drugs, anti-angiogenic, anti-restenosis, microtubule-inhibiting, anti-metastatic, or antithrombotic drugs. These medications include, but are not limited to, dexamethasone, prednisolone, corticosteroids, budesonide, estrogens, sulfasalazine and aminosalicylic acid, acemetidine, aescin, aminopterin, antifungals, arsenic trioxide, aristolochic acid, aspirin, berberine, ginkgo biloba extract, rapamycin and its derivatives (including zotamoxetine, everolimus, biomus, 7-O-demethylrapamycin, tesiromoxetine, desfolimex, etc.), endothelial statins, and angiotensin II receptor blockers. Statins, angiopeptides, monoclonal antibodies that block smooth muscle cell proliferation, levofloxacin, paclitaxel, docetaxel, hydroxycamptothecin, vinblastine, doxorubicin, 5-fluorouracil, cisplatin, thymidine kinase inhibitors (especially actinomycin-D), hormones, antibody-based cancer drugs, bisphosphonates, selective estrogen receptor modulators, strontium ranitide, cyclosporine A, cyclosporine C, and brevidin A.

[0055] Furthermore, the nanocrystalline drug 300 is an anti-proliferative drug; even further, it is paclitaxel, a paclitaxel derivative, rapamycin, or a rapamycin derivative. Among these, the preferred rapamycin derivatives are everolimus and zotarolimus.

[0056] The aforementioned drug-loaded implantable medical device 10 innovatively employs a microporous membrane 200 to load nanocrystalline drugs 300, firmly securing the nanocrystalline drugs 300 onto the microporous membrane 200. This prevents the drugs from easily detaching during transport. Upon reaching the target lesion, the nanocrystalline drugs 300 redissolve and disperse due to the device's own expansion and the dissolving effect of blood, improving drug utilization. Furthermore, the microporous membrane loads nanocrystalline drugs, which, compared to traditional core-shell nanomedicine structures, significantly increase drug loading capacity, avoid the use of large amounts of excipients and carriers, and improve safety. It also helps to reduce the size of the nanocrystalline drugs 300, avoiding the risk of embolism and toxic side effects. Additionally, it effectively increases the content of crystalline drugs in the nanocrystalline drugs 300, thereby improving the sustained-release effect and prolonging tissue retention time.

[0057] This invention also provides a method for preparing a drug-loaded implantable medical device, comprising the following steps:

[0058] S101: Provides a microporous membrane;

[0059] The selection of the microporous membrane in step S101 is as described above and will not be repeated here.

[0060] S102: Loading nanocrystalline drugs onto a microporous membrane;

[0061] Mechanical filtration is the preferred method for loading nanocrystalline drugs onto microporous membranes. This method is simple and quick, eliminating the need for the expensive and time-consuming ultrasonic spraying process commonly used in the industry. It allows for simple, large-scale preparation and has great industrial potential. Furthermore, this filtration method ensures a tight bond between the nanocrystalline drug and the microporous membrane, preventing it from easily detaching during transport.

[0062] In one embodiment, step S102 includes the following steps:

[0063] S1021: Dissolve the drug in a first solvent to obtain a drug solution, and suspend the stabilizer in a second solvent to obtain a stabilizer suspension; wherein, of the first solvent and the second solvent, one solvent is an organic solvent miscible with water, and the other solvent is water.

[0064] The choice of the first and second solvents can be based on the types of the drug and the stabilizer. In one embodiment, the first solvent is an organic solvent and the second solvent is water. Further, the concentration of the drug solution is 20 mg / mL to 60 mg / mL; the concentration of the stabilizer in the stabilizer suspension is 0.05% to 0.3%.

[0065] S1022: Under stirring conditions, the drug solution is added to the stabilizer suspension to obtain a mixture;

[0066] The drug solution is slowly added to the stabilizer suspension. Utilizing the principle of reverse solvent, the drug gradually precipitates out. Due to the presence of the stabilizer in the suspension, a small amount of stabilizer is adsorbed on the surface of the precipitate, which can effectively prevent the aggregation between nanoparticles and facilitate the formation of small-diameter precipitate particles. It is also conducive to the formation of crystalline drugs.

[0067] Furthermore, by employing the method in S1022, a particle morphology in which pure nanoparticles adsorb a small amount of stabilizer can be formed. This not only has high stability but also a higher drug loading capacity compared to traditional core-shell nanoparticles. It can also avoid the addition of a large amount of carrier excipients, thereby reducing toxic side effects.

[0068] S1023: The mixture is sonicated, and after sonication, it is dialyzed and concentrated to obtain a nanocrystalline drug suspension.

[0069] Ultrasonication of the mixture not only facilitates the formation of small nanocrystalline drugs but also promotes the transformation of amorphous drugs into crystalline drugs, increasing the proportion of crystalline drugs in nanocrystalline drugs and thus improving the sustained-release effect of drug-loaded implantable medical devices.

[0070] In step S1023, ultrasound can be performed using a probe-type ultrasound (also known as an ultrasonic cell disruptor) or a water bath ultrasound (also known as an ultrasonic cleaner). The ultrasound time can be adjusted as needed, preferably 15-30 minutes. After ultrasound, the sample can be placed in a dialysis bag for dialysis, with the water changed periodically. Finally, the prepared nanocrystalline drug suspension is concentrated for later use.

[0071] S1024: Load the nanocrystalline drug in the nanocrystalline drug suspension onto a microporous membrane and dry it;

[0072] Preferably, the drug is loaded on one side of the microporous membrane, so that the unloaded side of the microporous membrane adheres to the device body, which facilitates the fixation of the microporous membrane. In a further step S1024, the microporous membrane can be fixed on the filter mold first, and then an appropriate amount of the above-mentioned nanocrystalline drug suspension can be drawn using a syringe or other equipment and injected onto the microporous membrane, so that the nanocrystalline drug is loaded onto the microporous membrane, and then dried.

[0073] S103: Fix the microporous membrane loaded with nanocrystalline drugs onto the device body.

[0074] In step S103, laser welding can be used for fixation to improve the bonding strength between the microporous membrane and the instrument body and prevent the microporous membrane from slipping off. This method is also relatively simple and suitable for mass production.

[0075] The above-mentioned method for preparing drug-loaded implantable medical devices has the following advantages:

[0076] (1) By innovatively combining nanotechnology and crystallization technology, smaller nanocrystalline drugs can be obtained, reducing embolism and toxic side effects. Moreover, the above-mentioned nanocrystalline drugs are pure drug crystals with only a small amount of stabilizer adsorbed on the surface. The drug loading can be close to 100%, which is different from the traditional core-shell structure nanomedicines with drug-encapsulated carriers. This can significantly increase the content of crystalline drugs, giving them excellent sustained-release effect and long tissue retention time. Furthermore, the nano-sized nanocrystalline drugs can avoid the risk of embolism and toxic side effects, making them safe and effective.

[0077] (2) The innovative use of microporous membranes allows nanocrystalline drugs to be loaded onto the surface of the membrane, which is firm and stable and does not easily fall off during delivery. When the target lesion is reached, the nanocrystalline drugs are redissolved and dispersed due to the action of the device itself and the dissolving effect of the blood. In addition, the microporous membrane and the nanocrystalline drugs can be made to carry the same charge. Based on the charge repulsion between the microporous membrane and the nanocrystalline drugs, the release of nanocrystalline drugs can be further improved, thereby further improving the drug utilization rate and reducing the required drug dosage.

[0078] (3) It has high adjustability. For example, the concentration of the nanocrystalline drug suspension and the pore size of the microporous membrane can be adjusted as needed to adjust the target drug loading. Alternatively, a suitable microporous membrane can be selected as needed to adjust the nanocrystalline drug particle size. Alternatively, a microporous membrane with a suitable charge and nanocrystalline drug can be selected as needed to control the release rate of nanocrystalline drug particles by utilizing the charge effect.

[0079] The present invention will be illustrated below with specific examples.

[0080] Example 1

[0081] Poloxamer 188 was dissolved in pure water to a concentration of 0.15% (w / v). Rapamycin was dissolved in acetone to a concentration of 40 mg / mL. The rapamycin acetone solution was slowly added to the poloxamer aqueous solution with stirring. The mixture was then transferred to an ultrasonic cell disruptor and sonicated for 20 minutes. This yielded a nanocrystalline drug suspension. The suspension was then placed in a dialysis bag and dialyzed for 12 hours, with the water changed every 2 hours. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0082] A nylon microporous membrane with a negative surface charge and a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension was drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane was then vacuum dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug was tightly welded to the surface of a regular balloon using laser welding. The balloon was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0083] Example 2

[0084] Polyvinylpyrrolidone K30 was dissolved in pure water to a concentration of 0.15% (w / v). Rapamycin was dissolved in acetone to a concentration of 40 mg / mL. The above rapamycin acetone solution was slowly added to the above poloxamer aqueous solution under stirring. The mixture was then transferred to an ultrasonic cell disruptor and sonicated for 20 min. After sonication, a nanocrystalline drug suspension was prepared. This suspension was then placed in a dialysis bag and dialyzed for 12 h, with the water changed every 2 h. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0085] A nylon microporous membrane with a negative surface charge and a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension was drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane was then vacuum dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug was tightly welded to the surface of a regular balloon using laser welding. The balloon was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0086] Example 3

[0087] Tween 80 was dissolved in pure water to a concentration of 0.15% (w / v). Rapamycin was dissolved in acetone to a concentration of 40 mg / mL. The above rapamycin acetone solution was slowly added to the above poloxamer aqueous solution with stirring. The mixture was then transferred to an ultrasonic cell disruptor and sonicated for 20 min. After sonication, a nanocrystalline drug suspension was prepared. This suspension was then placed in a dialysis bag and dialyzed for 12 h, with the water changed every 2 h. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0088] A nylon microporous membrane with a negative surface charge and a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension was drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane was then vacuum dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug was tightly welded to the surface of a regular balloon using laser welding. The balloon was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0089] Example 4

[0090] HPMC E5 was dissolved in pure water to a concentration of 0.15% (w / v). Rapamycin was dissolved in acetone to a concentration of 40 mg / mL. The above rapamycin acetone solution was slowly added to the above poloxamer aqueous solution under stirring. The mixture was then transferred to an ultrasonic cell disruptor and sonicated for 20 min. After sonication, a nanocrystalline drug suspension was prepared. This suspension was then placed in a dialysis bag and dialyzed for 12 h, with the water changed every 2 h. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0091] A nylon microporous membrane with a negative surface charge and a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension was drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane was then vacuum dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug was tightly welded to the surface of a regular balloon using laser welding. The balloon was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0092] Example 5

[0093] Poloxamer 188 was dissolved in pure water to a concentration of 0.15% (w / v). Everolimus was dissolved in acetone to a concentration of 50 mg / mL. The everolimus-acetone solution was slowly added to the poloxamer aqueous solution with stirring. The mixture was then transferred to an ultrasonic cell disruptor and sonicated for 20 min. After sonication, a nanocrystalline drug suspension was prepared. This suspension was then placed in a dialysis bag and dialyzed for 12 h, with the water changed every 2 h. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0094] A nylon microporous membrane with a negative surface charge and a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension was drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane was then vacuum dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug was tightly welded to the surface of a regular balloon using laser welding. The balloon was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0095] Example 6

[0096] Hydroxypropyltrimethylammonium chloride chitosan was fully dissolved in pure water to a concentration of 0.15% (w / v). Rapamycin was dissolved in acetone to a concentration of 40 mg / mL. The above rapamycin acetone solution was slowly added to the above poloxamer aqueous solution under stirring. The mixture was then transferred to a water bath sonicator and sonicated for 20 min. After sonication, a nanocrystalline drug suspension was prepared. This suspension was then placed in a dialysis bag and dialyzed for 12 h, with the water changed every 2 h. The prepared nanocrystalline drug suspension was then concentrated for later use. The size and surface charge of the nanocrystalline drug were characterized using a Malvern ZS90 analyzer. The drug loading of the nanocrystalline drug was calculated by high-performance liquid chromatography (HPLC), and the crystal form of the nanocrystalline drug was detected by X-ray powder diffraction (XRPD).

[0097] A nylon microporous membrane with a positive surface charge and a pore size of 0.22 μm is clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension is drawn up using a syringe and loaded onto the nylon microporous membrane. The membrane is then vacuum-dried overnight. Subsequently, the nylon microporous membrane loaded with nanocrystalline drug is tightly welded to the surface of a regular balloon using laser welding. The balloon is then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0098] Example 7

[0099] A neutral nylon microporous membrane with a pore size of 0.22 μm was clamped onto a filter mold. A suitable concentration of nanocrystalline drug suspension prepared in Example 1 was drawn onto the nylon microporous membrane using a syringe and loaded onto the membrane. The membrane was then vacuum-dried overnight. Subsequently, the nylon microporous membrane loaded with the nanocrystalline drug was tightly welded to the surface of a standard balloon using laser welding. The membrane was then sterilized with ethylene oxide to obtain a drug-loaded implantable medical device (i.e., a drug-coated balloon).

[0100] Comparative Example 1

[0101] The nanocrystalline drug suspension prepared in Example 1 was sprayed onto the surface of a regular balloon (without welded nylon microporous membrane) by ultrasonic spraying, dried overnight, and sterilized with ethylene oxide to obtain a drug-coated balloon.

[0102] Performance Characterization

[0103] The nanocrystalline drugs loaded on the microporous membrane in Examples 1-7 and Comparative Example 1 were characterized, and the test results are shown in Table 1.

[0104] Test method:

[0105] Particle size: Photon correlation spectroscopy, instrument: Malvern Zetasizer Nano ZS90; Polydispersity index: Photon correlation spectroscopy, instrument: Malvern Zetasizer Nano ZS90; Surface charge: Photon correlation spectroscopy, instrument: Malvern Zetasizer Nano ZS90.

[0106] Drug loading: High performance liquid chromatography (HPLC), model Agilent 1100;

[0107] Table 1

[0108]

[0109]

[0110] As can be seen from Table 1, the nanocrystalline drugs of Examples 1-6 all have small particle size and relatively uniform distribution, and high drug loading. Furthermore, the nanocrystalline drugs of Examples 1-5 are all negatively charged, so they can work together with the negatively charged microporous membrane. The nanocrystalline drug of Example 6 is positively charged, so it can work together with the positively charged microporous membrane to promote the release of crystalline drugs on the drug-coated balloon.

[0111] in addition, Figure 5 This is a size distribution diagram of the nanocrystalline drug prepared in Example 1. Figure 6 The XRD pattern of the nanocrystalline drug prepared in Example 1 is shown; from Figure 5 and Figure 6 It can be seen that the nanocrystalline drug in Example 1 not only has a small particle size, but also a high content of crystalline drug, which is beneficial to the sustained release effect of the drug-coated balloon.

[0112] Transport loss test

[0113] The drug-eluting balloon prepared in the above embodiments was inserted into an in vitro vascular model. The time to reach the target was controlled to be 60 seconds without expansion. Then it was removed, and the drug residue on the surface of the balloon was measured by high performance liquid chromatography (HPLC). The drug loss rate during the delivery process was calculated. The test results are shown in Table 2.

[0114] Table 2

[0115]

[0116]

[0117] As can be seen from Table 2, the loss rates of Examples 1-7 are all low and significantly lower than those of Comparative Example 1, indicating that the crystalline drug on the drug-loaded implantable medical device of the present invention is more firmly bonded to the microporous membrane.

[0118] Tissue absorption test

[0119] Isolated porcine arterial segments were harvested and kept at a constant temperature of 37°C. Sterile naked balloons were used to dilate the vessels for 1 minute at 6 atm, followed by decompression and removal. Drug-coated balloons prepared according to the different embodiments described above were then placed into the dilated vessels and inflated for 1 minute at 6 atm, followed by decompression and removal. The vessels were immediately rinsed three times with 1 mL of PBS each time. The drug concentration in the tissue was then measured using gas chromatography-mass spectrometry (GC-MS), and the residual drug on the balloon surface was simultaneously tested using HPLC. The test results are shown in Table 3.

[0120] Table 3

[0121] Tissue concentration (ng / mg) % of drug residue on balloon surface Example 1 349.2±97ng / mg 4％ Example 2 417.8±128ng / mg 3％ Example 3 477.1±62ng / mg 6％ Example 4 560.4±96ng / mg 8％ Example 5 305.3±143ng / mg 6％ Example 6 644.3±115ng / mg 4％ Example 7 211.8±152ng / mg 22％ Comparative Example 1 102.3±52ng / mg 17％

[0122] As shown in Table 3, the tissue concentrations in Examples 1-6 were all high, and the amount of drug residue on the balloon surface was low, significantly better than the comparative examples. Meanwhile, Example 7 showed a higher level of drug residue on the balloon surface at the end, indicating that the drug-loaded implantable medical device of the present invention can release drugs more effectively in the presence of charge repulsion in tissues, achieving the target tissue concentration and demonstrating high drug utilization.

[0123] Organizational stay time test

[0124] Isolated porcine arterial segments were harvested and kept at a constant temperature of 37°C. Sterile naked balloons were used to dilate the vessels for 1 minute at 6 atm, followed by decompression and removal. Drug-coated balloons prepared according to the different embodiments described above were then inserted into the dilated vessels and inflated for 1 minute at 6 atm, followed by decompression and removal. The vessels were immediately rinsed three times with 1 mL of PBS each time. The vessels were then incubated in culture medium for 7 and 28 days, with three replicates at each time point. After sampling, the drug concentration in the tissues was measured using gas chromatography-mass spectrometry (GC-MS). The test results are shown in Table 4.

[0125] Table 4

[0126]

[0127] BQL: Below the detection limit

[0128] As shown in Table 4, the coated balloons of Examples 1-7 exhibit excellent sustained-release effects, significantly better than the comparative examples, and Examples 1-6 are superior to Example 7. This indicates that the drug-loaded implantable medical device of the present invention has a superior sustained-release effect, and when the charge of the nanocrystalline drug and the charge of the microporous membrane are the same, the sustained-release effect is even better.

[0129] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0130] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A drug-loaded implantable medical device, characterized in that, The device includes a device body, a microporous membrane fixed on the device body, and a nanocrystalline drug loaded on the surface of the microporous membrane, wherein the nanocrystalline drug is rapamycin. Both the surface of the microporous membrane and the nanocrystalline drug are charged, and the charge on the surface of the microporous membrane and the charge on the nanocrystalline drug are the same. The surface of the nanocrystalline drug is adsorbed with a stabilizer, which is selected from poloxamer or polyvinylpyrrolidone. The particle size of the nanocrystalline drug is 50 nm - 250 nm, and the particle size of the nanocrystalline drug is greater than or equal to the pore size of the microporous membrane.

2. The drug-loaded implantable medical device according to claim 1, characterized in that, The microporous membrane is a network structure microporous membrane formed from at least one of the following materials: nylon, polyvinylidene fluoride, mixed cellulose, polytetrafluoroethylene, polypropylene, polyethersulfone, or glass fiber; and / or The porosity of the microporous membrane is 40%-90%; and / or The microporous membrane has a pore size of 0.02 μm - 0.8 μm; and / or The thickness of the microporous membrane is 1 μm - 200 μm.

3. The drug-loaded implantable medical device according to any one of claims 1-2, characterized in that, The nanocrystalline drug has a morphology of spheres, rods, worms, or discs; and / or In the nanocrystalline drug, the mass percentage of crystalline drug is 70%-100%.

4. A method for preparing a drug-loaded implantable medical device, characterized in that, Includes the following steps: Provide microporous membranes; Nanocrystalline drugs are loaded onto the microporous membrane; The microporous membrane loaded with the nanocrystalline drug is fixed to the device body; The nanocrystalline drug is rapamycin; both the surface of the microporous membrane and the nanocrystalline drug are charged, and the charge on the surface of the microporous membrane and the charge on the nanocrystalline drug are the same; a stabilizer is adsorbed on the surface of the nanocrystalline drug, and the stabilizer is selected from poloxamer or polyvinylpyrrolidone; the particle size of the nanocrystalline drug is 50 nm-250 nm, and the particle size of the nanocrystalline drug is greater than or equal to the pore size of the microporous membrane.

5. The preparation method according to claim 4, characterized in that, The nanocrystalline drug is loaded onto the microporous membrane using mechanical filtration; and / or The microporous membrane loaded with the nanocrystalline drug is fixed onto the device body using laser welding.

6. The preparation method according to claim 4, characterized in that, The step of loading nanocrystalline drugs onto the microporous membrane includes the following steps: The drug is dissolved in the first solvent to obtain a drug solution; The stabilizer is suspended in the second solvent to obtain a stabilizer suspension; Under stirring conditions, the drug solution is added to the stabilizer suspension to obtain a mixture; The mixture was sonicated, and after sonication, it was dialyzed and concentrated to obtain a nanocrystalline drug suspension. The nanocrystalline drug in the nanocrystalline drug suspension is loaded onto the microporous membrane and dried. In this process, one solvent is an organic solvent miscible with water, and the other solvent is water.

7. A drug-eluting balloon, characterized in that, The device includes a balloon body, a microporous membrane fixed to the balloon body, and a nanocrystalline drug loaded on the surface of the microporous membrane; wherein the nanocrystalline drug is rapamycin; both the surface of the microporous membrane and the nanocrystalline drug are charged, and the charge on the surface of the microporous membrane and the charge on the nanocrystalline drug are the same; a stabilizer is adsorbed on the surface of the nanocrystalline drug, and the stabilizer is selected from poloxamer or polyvinylpyrrolidone; the particle size of the nanocrystalline drug is 50 nm-250 nm, and the particle size of the nanocrystalline drug is greater than or equal to the pore size of the microporous membrane.

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