Drug eluting balloon

Abstract

This invention provides a drug-loaded balloon, comprising a balloon body and a drug coating. The drug coating contains rapamycin and does not contain excipients. The drug coating is attached to the surface of the balloon body and consists of a plurality of drug crystals uniformly distributed on the surface of the balloon body in an amorphous cluster manner. The drug crystals are columnar crystals with three or four edges. The drug coating is composed of at least one of the three- and four-edge drug crystals, and the number of drug crystals per unit area is 5.5 × 10⁵ / cm² to 6.5 × 10⁶ / cm². The drug crystals are formed by growing on drug particles with a particle size of less than 1.0 μm. The drug particles are uniformly attached to the surface of the balloon body by physical adsorption, and the crystal growth time is 0.5 min to 30 min. The drug loss rate of the drug-loaded balloon during delivery is less than 30%, and the amount of drug transferred after the balloon expands the narrowed area is greater than 10%. Thus, the drug coating can ensure coating firmness and increase drug action time and drug transfer amount without the use of excipients.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and more specifically, to a drug-loaded balloon. Background Technology

[0002] Intracranial atherosclerotic stenosis (ICAS), also known as intracranial atherosclerotic disease (ICAD), is a common cause of ischemic stroke. Symptomatic intracranial atherosclerotic stenosis (sICAS) refers to narrowing of intracranial arteries caused by atherosclerosis, resulting in ischemic stroke or transient ischemic attack (TIA) in the area supplied by the narrowed artery. sICAS is a significant cause of stroke worldwide, accounting for 8%-10%, and is particularly prominent in Chinese and Asian populations, with 30%–50% of intracranial atherosclerotic stroke cases occurring in Asian populations.

[0003] Treatment options for ICAS include medical, surgical, and endovascular therapies. The main endovascular treatments are percutaneous transluminal balloon angioplasty (PTBA) and stent placement. Compared to stent placement, PTBA is more suitable for lesions in tortuous, bifurcate, long, or angulated cerebral vessels and can be used for in-stent restenosis. PTBA includes simple balloon dilation and drug-eluting balloons. Due to the high incidence of immediate elastic recoil of the diseased vessel after simple balloon dilation, high rate of vascular dissection, and often >50% residual stenosis and a high restenosis rate, drug-eluting balloons have replaced traditional simple PTBA as an emerging technology in recent years. Drug-eluting balloons have advantages such as simple operation, no implantation required, short duration of postoperative dual antiplatelet therapy, and low risk of postoperative bleeding. They can significantly reduce postoperative restenosis and may be more advantageous in treating in-stent restenosis, small vessel lesions, and bifurcation lesions.

[0004] Current drug-coated balloons all use paclitaxel, a highly lipid-soluble drug, as the base drug. However, due to its non-targeted cytotoxicity, paclitaxel has been gradually replaced by safer rapamycin-based drugs in drug-eluting stents. But rapamycin-based drugs are difficult to apply to drug-coated balloons due to their poor lipid solubility, slow tissue absorption, and short half-life. Most current rapamycin drug-coating technologies use polymers or other substances as excipients mixed with the drug. Excipients are needed to improve the adhesion of rapamycin to the balloon surface. However, excipients are foreign bodies and can easily cause inflammatory reactions at the lesion site, thus failing to achieve a good therapeutic effect.

[0005] It should be noted that the information disclosed in the background section of this application is intended only to enhance the understanding of the general background of this application, and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention

[0006] In view of this, the present invention aims to provide a drug-loaded balloon that can firmly attach a drug coating to the balloon surface without the use of excipients, while also increasing the duration of drug action and the amount of drug transferred.

[0007] To achieve the above objectives, the present invention provides a drug-loaded balloon, comprising a balloon body and a drug coating. The drug coating is composed of a plurality of drug crystals, which are uniformly distributed on the surface of the balloon body in an amorphous cluster manner. The drug crystals are columnar crystals with three or four edges. The drug coating is composed of at least one of the three- and four-edged drug crystals, and the number of drug crystals per unit area is 5.5 × 10⁻⁶. 5 / cm 2 ~6.5×10 6 / cm 2 .

[0008] In one embodiment, the effective height of the drug crystal is 3.0 μm to 10 μm, and the effective width of the drug crystal is 1.0 μm to 5.0 μm.

[0009] In one embodiment, each of the drug crystals is in contact with and connected to at least one other drug crystal, and the drug crystals, except for their bottom surface which is in contact with the surface of the balloon body and their top surface which is opposite to the bottom surface, are in contact with and connected to at least one other drug crystal on their sides.

[0010] In one embodiment, the cross-section of the drug crystal having four edges is rhomboid.

[0011] In one embodiment, the drug coating comprises at least one of rapamycin and its derivatives, as well as statins.

[0012] In one embodiment, the drug coating comprises at least one of zotamoxetine, everolimus, tansimoxetine, biomus, tesimolimus, desfomus, atorvastatin, simvastatin, and fluvastatin.

[0013] In one embodiment, the drug crystals are formed by growing drug particles with a particle size of less than 1.0 μm, the drug particles being uniformly attached to the surface of the balloon body by physical adsorption.

[0014] In one embodiment, a plurality of the drug particles constitute a base drug, wherein at least 50% of the drug particles in the base drug have a particle size of less than 0.5 μm.

[0015] In one embodiment, the number of drug particles per unit area on the surface of the balloon body is 1.5 × 10⁻⁶. 7 / cm 2 ~2.5×10 8 / cm 2 .

[0016] In one embodiment, after the drug-loaded balloon dilates the narrowed site, at least a portion of the drug crystals are transferred to the narrowed site, and the transferred drug crystals have a retention rate of more than 3% after 28 days of release from the narrowed site.

[0017] In one embodiment, after the drug-loaded balloon dilates the narrowed site, at least a portion of the drug crystals are transferred to the narrowed site, and the transferred drug crystals have a retention rate of more than 10% after 14 days of release from the narrowed site.

[0018] In one embodiment, the drug-loaded balloon experiences a drug loss rate of less than 30% during delivery.

[0019] In one embodiment, the amount of drug transferred after the drug-loaded balloon dilates the narrowed area is greater than 10%.

[0020] As described above, this invention provides a drug-loaded balloon that, by controlling the morphology and size of drug crystals on the balloon's surface, ensures the adhesion of the pure drug coating to the balloon's surface. This allows the pure drug coating to firmly adhere to the balloon's surface, preventing it from easily detaching and reducing drug loss during delivery. It also avoids side effects caused by excipients. The number of drug crystals per unit area is neither too high nor too low, ensuring an appropriate crystal size. This avoids phagocytosis by macrophages, increasing the drug's residence time at the lesion site and extending the drug release cycle. Furthermore, it allows the drug to exert a stable and sustained effect after being transferred to tissues. On the other hand, it avoids the risk of thrombosis caused by drug particle detachment, improving safety and drug efficacy. Attached Figure Description

[0021] Those skilled in the art will understand that the accompanying drawings are provided to better understand the invention and do not constitute any limitation on the scope of the invention. Wherein:

[0022] Figure 1 Scanning electron microscope image of the microcrystalline drug coating prepared in Example 1;

[0023] Figure 2 Here is a scanning electron microscope image of the drug crystals in the drug coating prepared in Example 1;

[0024] Figure 3 Scanning electron microscope image of the amorphous drug coating prepared in Comparative Example 1;

[0025] Figure 4 Release curves for Example 1 and Comparative Example 1 in simulated blood vessels;

[0026] Figure 5 The remaining drug amount at different vascular sites in Example 2 and Comparative Example 2;

[0027] Figure 6 A scanning electron microscope image of the underlying drug prepared in Example 3;

[0028] Figure 7 Scanning electron microscope image of the underlying drug prepared in Comparative Example 3;

[0029] Figure 8 The amount of drug transferred in different vascular tissues in Example 3 and Comparative Example 3;

[0030] Figure 9 Scanning electron microscope images of the underlying drug layer formed by different grinding processes;

[0031] Figure 10 Scanning electron microscope images of surface drugs formed by different grinding processes. Detailed Implementation

[0032] To make the objectives, advantages, and features of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that the drawings are all in a very simplified form and are not drawn to scale, and are only used to facilitate and clearly illustrate the objectives of the embodiments of the present invention. Furthermore, the structures shown in the drawings are often part of the actual structures. In particular, different figures may have different emphases and sometimes different scales. As used in this specification, the singular forms “a,” “an,” and “the” include plural objects unless otherwise expressly indicated. As used in this specification, the term “or” is generally used to include the meaning of “and / or” unless otherwise expressly indicated.

[0033] It should be noted that in existing technologies, drug coatings are mainly prepared by mixing excipients and drugs, allowing the drug coating to adhere to the balloon surface. Excipients can improve drug adhesion to the balloon surface. Furthermore, the sustained-release effect of the drug needs to be controlled through polymer degradation. Although excipients (including polymers or other substances) have good biocompatibility, they are still foreign bodies to human tissue, increasing local inflammation and reducing drug loading. Therefore, it is best to use the drug coating without mixing excipients, using only the drug.

[0034] Therefore, the present invention provides a drug-loaded balloon that can firmly attach drugs to the balloon surface without the use of excipients, can increase the drug release cycle, and can enable the drug to exert a stable and continuous effect for a long time after being transferred to tissues.

[0035] This invention relates to a drug-loaded balloon, comprising a balloon body and a drug coating uniformly distributed on the surface of the balloon body. In preparing the drug coating, a base layer of drug is first uniformly distributed on the surface of the balloon body, and then drug crystals are uniformly grown on the base layer to form a surface drug layer. The drug coating of this invention is a pure drug and does not contain any other non-drug substances.

[0036] The particle size of the drug particles in the bottom layer is preferably less than 1.0 μm. This ensures that the drug particles in the bottom layer can be uniformly and firmly adsorbed onto the surface of the balloon body, improving the adhesion between the pure drug coating and the balloon surface while ensuring drug loading. Theoretically, the smaller the particle size of the drug particles in the bottom layer, the better, as it facilitates adsorption of drug particles onto the balloon body surface. However, smaller particle sizes increase the manufacturing difficulty. In this invention, the particle size of the drug particles in the bottom layer is all less than 1.0 μm. More preferably, at least 50% of the drug particles in the bottom layer have a particle size less than 0.5 μm. This results in finer drug particles in the bottom layer, which facilitates firm adsorption of drug particles onto the balloon body surface and prevents them from easily detaching. Furthermore, the number of drug particles per unit area in the bottom layer can be limited. Preferably, the number of drug particles per unit area on the surface of the balloon body is 1.5 × 10⁻⁶. 7 / cm 2 ~2.5×10 8 / cm 2 Preferably, the particle size of the drug particles in the bottom layer of the drug is not less than 100 nm.

[0037] The final drug coating consists of several drug crystals, which are uniformly distributed on the surface of the balloon body in an amorphous cluster manner. That is, drug crystals are uniformly grown on the underlying drug layer, rather than forming clusters. In the drug coating of this invention, the drug crystals are tightly connected to each other and do not form clusters. Preferably, the drug crystals are formed by growing on drug particles with a particle size of less than 1.0 μm, and the drug particles are preferably uniformly attached to the surface of the balloon body by physical adsorption. In particular, the drug crystals in the drug coating have a predetermined size and morphology. By controlling the size of the drug crystals in the drug coating, it is possible to avoid drug crystals that are too small and being phagocytosed by macrophages, which is beneficial for drug retention in vascular tissue, increases the sustained-release effect of the drug, and allows the drug to act stably on vascular tissue for a long time. It also prevents drug crystals that are too large from detaching during delivery and expansion, becoming crystal emboli, increasing the risk of vascular embolism, and ultimately improving the safety and effectiveness of the procedure. Furthermore, the number of drug crystals per unit area on the surface of the balloon body is limited to 5.5 × 10⁻⁶. 5 / cm 2 ~6.5×10 6 / cm 2 This ensures that the number of drug crystals per unit area in the drug coating is appropriate, thereby ensuring that the size of the drug crystals in the drug coating is neither too large nor too small, and that the size of the drug crystals in the drug coating is in an optimal state.

[0038] Furthermore, by controlling the morphology of the drug crystals in the drug coating, the adhesion of the pure drug coating to the balloon surface is improved, reducing drug loss during drug delivery. Specifically, the drug crystals in the drug coating are columnar crystals with three or four edges. The crystal morphology contained in the drug coating is a single columnar crystal, and the single columnar crystal includes three or four edges. Its cross-section (the section perpendicular to the height direction) can be triangular or quadrilateral, preferably rhomboid. It should be understood that the drug coating can contain at least one of three-edge and four-edge drug crystals. The above-mentioned three-edge or four-edge drug crystals can effectively improve the adhesion performance of the pure drug coating to the balloon body surface, reduce drug loss during delivery, and prolong the drug release time.

[0039] This overcomes the technical bias of traditional techniques that only allow for the preparation of drug coatings by mixing excipients and drugs. It enables drug coatings to maintain adhesion and increase the drug's residence time in tissues without the use of excipients, resulting in a long-term sustained-release effect and enhanced safety. When drug delivery is needed, a drug-loaded balloon is delivered to the lesion site, then the balloon is inflated to bring it into contact with the blood vessel wall, and pressure is applied to release the drug coating into the diseased blood vessel wall, allowing the drug to exert its therapeutic effect at the lesion site.

[0040] Furthermore, in the drug coating, the drug crystals are tightly connected to each other, with each individual drug crystal in contact with and tightly connected to at least one other drug crystal. Except for the bottom surface in contact with the balloon body and the top surface facing away from the balloon body (top and bottom surfaces opposite each other), all other sides of the drug crystal are in contact with and tightly connected to at least one other drug crystal, ensuring that all drug crystals are uniformly and orderly distributed across the surface of the balloon body. This tight and uniform distribution of drug crystals effectively improves the uniformity of the pure drug coating on the balloon body surface, increases the drug loading capacity on the balloon surface, and ensures drug efficacy.

[0041] The drug coating described above may have at least one of the following characteristics: the columnar crystal is a solid body with a smooth surface and obvious edges; the bottom surface of the columnar crystal is in contact with the surface of the balloon body, and the bottom surface of the columnar crystal may be a plane or multiple planes; the edges of the bottom surface of the columnar crystal are straight lines; the side edges of the columnar crystal are almost straight lines; the bottom and top surfaces of the columnar crystal may be parallel or non-parallel; the columnar crystals in the drug coating are basically the same size, and two adjacent columnar crystals may be connected to each other or staggered; in addition, the side edges of the columnar crystal form an angle of 0° to 90° with the surface of the balloon body; the angle formed by adjacent sides of the columnar crystal is preferably less than 90°.

[0042] Preferably, the effective height (or average height) of the drug crystal is 3.0 μm-10 μm, and the effective width (or average width) is 1.0 μm-5.0 μm. Thus, based on the aforementioned number of crystals, the size of individual drug crystals can be precisely controlled by controlling the growth time, ensuring that the particle size of each individual drug crystal is neither too large nor too small. Optionally, the crystal growth time is 0.5 min-30 min.

[0043] In some embodiments, the drug in the drug coating may be selected from one or more of rapamycin and its derivatives, such as zotarolimus, everolimus, tesirolimus, biolimus, temsirolimus, deforolimus, and ridaforolimus.

[0044] In some embodiments, the drug in the drug coating may be selected from statins, such as one or more of atorvastatin, simvastatin, and fluvastatin.

[0045] Preparing the drug-loaded balloon of the present invention may include the following steps:

[0046] (1) Prepare a balloon body of appropriate size. The balloon body is a bare balloon that can be inflated and deflated. There are no special restrictions on the shape and size of the bare balloon.

[0047] (2) Clean the balloon body; generally, rinse the balloon body after it is inflated to remove impurities from the surface of the balloon body and avoid affecting subsequent processing.

[0048] (3) The balloon body in the inflated state is treated with a dispersion containing drug particles and dispersant and dried to obtain a balloon intermediate with the drug adhering to the surface.

[0049] (4) The balloon body in step (3) is treated with a drug supersaturated solution to grow drug crystals precipitated from the drug supersaturated solution on the bottom drug layer and form a surface drug layer, and then dried to obtain a drug-loaded balloon with a drug coating on the surface.

[0050] In step (3) above, the drug particles are uniformly attached to the surface of the balloon body by physical adsorption. Physical adsorption facilitates drug transfer to the target blood vessel, improving efficacy. In addition, in step (3), the dispersant helps the drug particles to be uniformly dispersed in the dispersion, which in turn makes the drug particles densely and uniformly distributed on the surface of the balloon body. The bottom layer contains only drug particles and no dispersant. Generally, the balloon body is directly immersed in the dispersion, and then ultrasonic oscillation is applied. Under the specified ultrasonic power and processing time, the drug particles in the dispersion are adsorbed onto the surface of the balloon body.

[0051] The underlying drug can be directly and physically adsorbed onto the surface of the balloon body. Even without excipients, the adhesion between the underlying drug and the balloon surface is maintained, preventing the coating from easily peeling off. Furthermore, the underlying drug is used to further grow drug crystals, thereby increasing the drug loading capacity. Preferably, the balloon body can be surface-treated before dispersion to improve its surface cleanliness and roughness, which is beneficial for the adsorption of drug particles on the balloon surface and increases adsorption performance.

[0052] The type of dispersant is not limited, as long as it can uniformly disperse the drug particles. Common dispersants such as purified water, n-heptane, n-hexane, or diethyl ether are typically selected.

[0053] Preferably, the concentration of drug crystal particles in the dispersant is 0.25 mg / ml to 1 mg / ml. This concentration can avoid drug waste and ensure that a sufficient amount of drug particles are dispersed on the surface of the balloon body, which is conducive to the dense and uniform distribution of the underlying drug on the surface of the balloon body, and facilitates subsequent crystal growth.

[0054] In some embodiments, drug particles with a particle size of less than 1.0 micrometer are prepared before preparing the dispersion. The preparation of drug particles is crucial; specifically, the active pharmaceutical ingredient (API) is directly refined into drug particles with a particle size of less than 1.0 micrometer. Preferably, the API is ground into drug particles of the desired size using a top-down technique, such as media milling or high-pressure homogenization. During media milling, the API is dispersed in a milling solvent, and in the liquid environment provided by the milling solvent, the API is refined into small particles by the milling media. When preparing drug particles, it is necessary to strictly control the particle size so that the drug particles can be uniformly and densely dispersed on the surface of the capsule body and have a certain adsorption capacity to ensure the strong adhesion of the coating.

[0055] In step (4) above, the drug in the supersaturated solution is the same as the raw material used to prepare the drug particles.

[0056] After crystal growth is completed, the drug-loaded capsule is dried in the dark to obtain a drug-loaded capsule with a microcrystalline drug coating on its surface.

[0057] The above preparation method is only an exemplary method for preparing the drug-loaded balloon (or drug balloon or balloon catheter) of the present invention. The drug-loaded balloon of the present invention can also be prepared by other methods, as long as the preparation method can obtain drug crystals of the required size, distribution and morphology.

[0058] Preferably, after the drug-loaded balloon of the present invention dilates the narrowed site, at least a portion of the drug crystals are transferred to the narrowed site, and the retention rate of the transferred drug crystals at the narrowed site after 14 days of release is greater than 10%, more preferably greater than 15%, greater than 18%, and greater than 20%. Preferably, after the drug-loaded balloon of the present invention dilates the narrowed site, at least a portion of the drug crystals are transferred to the narrowed site, and the retention rate of the transferred drug crystals at the narrowed site after 28 days of release is greater than 3%, more preferably greater than 5%, greater than 10%, and greater than 15%. The retention rate is the ratio of the residual drug amount at the narrowed site after balloon dilation and metabolism for a period of time to the initial transferred drug amount. Preferably, the drug loss rate of the drug-loaded balloon of the present invention during delivery is less than 30%, more preferably less than 25%, less than 20%, and less than 15%. Preferably, the amount of drug transferred after the drug-loaded balloon of the present invention dilates the narrowed site is greater than 20%, more preferably greater than 25%, 30%, and 35%.

[0059] The embodiments of the present invention will be described in detail below with reference to examples.

[0060] In the following embodiments, the bare balloons used all had a diameter of 5 mm and a length of 30 mm, and the drug used was rapamycin. However, it should be understood that although the following embodiments are described in conjunction with rapamycin, in fact, other types of drugs may be used besides rapamycin, and this application is not limited thereto.

[0061] Example 1

[0062] The process for preparing drug-loaded balloons with a drug coating containing microcrystalline morphology is as follows:

[0063] Step a): Select a bare balloon with a diameter of 5 mm and a length of 30 mm;

[0064] Step b): After inflating the bare balloon, rinse with pure water and dry for later use;

[0065] Step c): The rapamycin drug is subjected to media milling to obtain drug particles with a particle size of 200 nm ± 30 nm;

[0066] Step d): Disperse the rapamycin particles obtained from grinding in step c) in n-heptane solvent to obtain a dispersion, wherein the concentration of rapamycin particles is 1 mg / ml;

[0067] Step e): Immerse the naked balloon in the state of inflation in step b) into the dispersion prepared in step e) and perform ultrasonic oscillation treatment. The ultrasonic power is 300W and the ultrasonic treatment lasts for 10 minutes. After the ultrasonic treatment, a uniform rapamycin coating (i.e. the bottom drug) can be formed on the surface of the naked balloon. Wait for the rapamycin coating to dry.

[0068] Step f): Add 15 mg / ml rapamycin (unground) to 5 ml of methanol solution, dissolve it completely, then add 10 ml of n-heptane, mix well, and immerse the capsule intermediate obtained in step e) in the supersaturated solution to allow the crystals to grow fully. After standing for 10 minutes, remove the capsule and dry it in the dark for later use.

[0069] Comparative Example 1

[0070] The difference between preparing a drug-loaded capsule with an amorphous drug coating and preparing a drug-loaded capsule with a microcrystalline drug coating is that the rapamycin drug is not ground; instead, the unground rapamycin drug is directly dispersed in n-heptane solvent to obtain a dispersion. The other steps are the same as the preparation process described above.

[0071] Experimental results

[0072] 1. Scanning electron microscope image

[0073] Figure 1 and Figure 2 This is a scanning electron microscope image of a drug-loaded capsule with a drug coating containing microcrystalline morphology. Figure 3 This is a scanning electron microscope image of a drug-loaded balloon containing a drug coating with an amorphous morphology.

[0074] from Figure 1 and Figure 2 It can be seen that in drug-loaded capsules with drug coatings containing microcrystalline morphology, the drug crystals in the drug coating are uniform in size, with small differences in grain size, uniform and dense distribution, and the crystal morphology is rhomboid or triangular. However, from Figure 3 It can be seen that in drug-loaded capsules containing amorphous drug coatings, the drug crystals within the coating vary in size, exhibit significant differences in grain size, are unevenly distributed, and have irregular morphologies. Therefore, refining the active pharmaceutical ingredient into microparticles has a significant impact on the subsequent growth of drug crystals.

[0075] 2. Crystal count test

[0076] In drug-loaded balloons with a drug coating containing microcrystalline morphology, the number of crystal grains per unit area is approximately 6.0 × 10⁻⁶. 6 / cm 2 In contrast, drug-loaded balloons containing amorphous drug coatings have approximately 15.0 × 10⁻⁶ crystal grains per unit area. 6 / cm 2 This indicates that the grain size of amorphous drug coatings is difficult to meet the requirements of this invention.

[0077] It is worth noting that in microcrystalline drug coatings, the crystals are uniform in size, resulting in a uniform overall coating thickness. During in vitro use, the amount of drug transferred to the blood vessel site is also uniform, preventing excessive local drug concentration and safety issues. Furthermore, the uniform crystal size results in greater adhesion to the balloon surface, leading to less loss during delivery.

[0078] 3. Release cycle test

[0079] The specific steps are as follows: A drug-loaded balloon is placed in a simulated blood vessel and inflated. The inflated simulated blood vessel is then placed in a certain volume of physiological saline and placed in a 37°C constant-temperature shaker to simulate blood flushing. The remaining rapamycin content in the simulated blood vessel is tested at different time points. The cumulative release curves on days 2, 5, 10, 15, 21, and 28 are shown below. Figure 4 As shown, Figure 4 S2 represents the release curve of the drug coating with microcrystalline morphology, and S1 represents the release curve of the drug coating with amorphous morphology. The horizontal axis represents the number of release days in the narrow site, and the vertical axis represents the cumulative release rate (%) in the narrow site.

[0080] from Figure 4 It can be seen that after expansion and transfer in simulated blood vessels, the drug-loaded balloon with a microcrystalline drug coating retained approximately 20% of its release rate. In contrast, the drug-loaded balloon with an amorphous drug coating, after expansion and transfer in simulated blood vessels, showed 100% release of its drug coating after 28 days, and rapamycin levels were undetectable in the simulated blood vessels. This indicates that after transfer to simulated blood vessels, the drug release rate of the microcrystalline drug-loaded balloon is slower, and the residence time is longer. The microcrystalline drug coating dissolves slowly, while the amorphous drug coating easily detaches from the simulated blood vessels into the sustained-release solution, resulting in a shorter drug duration and an inability to stably and continuously act on vascular tissue for an extended period.

[0081] Example 2

[0082] The process for preparing drug-loaded balloons with a drug coating containing microcrystalline morphology is as follows:

[0083] Step a): Select a bare balloon with a diameter of 1.5 mm and a length of 15 mm;

[0084] Step b): After inflating the bare balloon, rinse with pure water and dry for later use;

[0085] Step c): The rapamycin drug is subjected to media milling to obtain drug particles with a particle size of 300 nm ± 50 nm.

[0086] Step d): Disperse the rapamycin particles obtained from grinding in step c) in n-heptane solvent to obtain a dispersion, wherein the concentration of rapamycin particles is 0.75 mg / ml;

[0087] Step e): Immerse the naked balloon in the state of inflation in step b) into the dispersion prepared in step e) and perform ultrasonic oscillation treatment. The ultrasonic power is 400W and the ultrasonic treatment lasts for 10 minutes. After the ultrasonic treatment, a uniform rapamycin coating (i.e. the bottom drug) can be formed on the surface of the naked balloon. Wait for the rapamycin coating to dry.

[0088] Step f): Rapamycin (unground) at a concentration of 20 mg / ml is added to 5 ml of methanol solution. After it is fully dissolved, 10 ml of n-heptane is added and mixed. The capsule intermediate obtained in step e) is then immersed in the supersaturated solution to allow the crystals to grow fully. After standing for 10 minutes, the capsule is removed and dried in the dark for later use.

[0089] Comparative Example 2

[0090] The difference between preparing a drug-loaded balloon with an amorphous drug coating and preparing a drug-loaded balloon with a microcrystalline drug coating is that the rapamycin drug is not ground; instead, the unground rapamycin drug is directly dispersed in n-heptane solvent to obtain a dispersion. The other steps are the same as the preparation process in Example 2 above.

[0091] Experimental results

[0092] 4. Coating adhesion test

[0093] Specifically, the drug-loaded balloon is delivered to different blood vessels within the animal's body. After reaching the target location, it is immediately withdrawn without dilation. The remaining drug level on the balloon surface is then tested. The coating adhesion is assessed within 1 minute of delivery; a higher remaining drug level indicates better coating adhesion. Theoretically, different delivery locations and delivery times within the blood vessel result in varying drug losses during delivery. Generally, longer delivery times lead to more prolonged blood flow impact and greater losses.

[0094] See test results Figure 5 ,from Figure 5 The provided table shows that drug-loaded balloons with microcrystalline drug coatings have a large amount of residual drug on the surface after delivery, with a drug loss rate of no more than 20%. In contrast, drug-loaded balloons with amorphous drug coatings have a small amount of residual drug after delivery, with a drug loss rate far exceeding 20%. Therefore, microcrystalline drug coatings are less likely to detach during delivery, meaning they have higher durability.

[0095] Example 3

[0096] The process for preparing drug-loaded balloons with a drug coating containing microcrystalline morphology is as follows:

[0097] Step a): Select a bare balloon with a diameter of 5 mm and a length of 30 mm;

[0098] Step b): After inflating the bare balloon, rinse with pure water and dry for later use;

[0099] Step c): The rapamycin drug is subjected to media milling to obtain drug particles with a particle size of 200 nm ± 30 nm;

[0100] Step d): Disperse the rapamycin particles obtained from grinding in step c) in n-heptane solvent to obtain a dispersion, wherein the concentration of rapamycin particles is 1 mg / ml;

[0101] Step e): Immerse the naked balloon in the state of inflation in step b) into the dispersion prepared in step e) and perform ultrasonic oscillation treatment. The ultrasonic power is 300W and the ultrasonic treatment lasts for 10 minutes. After the ultrasonic treatment, a uniform rapamycin coating (i.e. the bottom drug) can be formed on the surface of the naked balloon. Wait for the rapamycin coating to dry.

[0102] Step f): Add 15 mg / ml rapamycin (unground) to 5 ml of methanol solution, dissolve it completely, then add 10 ml of n-heptane, mix well, and immerse the capsule intermediate obtained in step e) in the supersaturated solution to allow the crystals to grow fully. After standing for 10 minutes, remove the capsule and dry it in the dark for later use.

[0103] Comparative Example 3

[0104] The difference between preparing a drug-loaded balloon with an amorphous drug coating and preparing a drug-loaded balloon with a microcrystalline drug coating is that the rapamycin drug is not ground; instead, the unground rapamycin drug is directly dispersed in n-heptane solvent to obtain a dispersion. The other steps are the same as the preparation process in Example 3 above.

[0105] Experimental results

[0106] 5. Scanning electron microscope image

[0107] Figure 6 Electron micrograph of the underlying drug layer with a microcrystalline structure. Figure 7 Electron micrograph of the underlying drug used to prepare the amorphous structure.

[0108] from Figure 6It can be seen that after rapamycin is ground and redispersed on the balloon surface, a bottom layer of drug with basically uniform size and distribution can be formed on the balloon surface. The particle size is basically in the range of 0.15μm~1.0μm, and the number of crystals per unit area on the balloon surface is 1.5×10 7 / cm 2 ~2.5×10 8 / cm 2 This facilitates the growth of rhomboid or triangular drug crystals on the underlying drug layer. However, according to... Figure 7 Electron microscopy images show that when rapamycin is not ground and dispersed on the capsule surface, not only are there few particles adhering to the capsule surface, but they are also uneven in size and sparsely distributed. This further illustrates the importance of refining the active pharmaceutical ingredient into microparticles for preparing a pure drug coating. By controlling the particle size and distribution of the underlying drug, the drug crystals can grow in a regular manner. Furthermore, controlling the crystal growth time can prevent excessive crystal growth, which would result in an overly thick coating that is prone to peeling off.

[0109] 6. Drug transfer test

[0110] Specifically, after vasodilation in the animal, the drug-loaded balloon was withdrawn. One hour later, vascular tissue from the dilated site was harvested, and the amount of drug transferred to the vascular tissue was tested, i.e., the percentage of drug transferred. See details below. Figure 8 . Figure 8 In the text, " / " indicates that no balloon of this size was implanted in the blood vessel area, and the two blood vessels were compared by symmetrically implanting microcrystalline balloons and amorphous balloons.

[0111] from Figure 8 The data in the table shows that the drug coating with microcrystalline morphology has a higher transfer rate after balloon dilation, with the amount of drug transferred being no less than 20%. Combined with Example 2, it can be concluded that the drug coating with microcrystalline morphology has a lower shedding rate during delivery and a higher transfer rate during dilation compared to the drug coating with amorphous morphology.

[0112] Example 4

[0113] In this embodiment, the preparation process of the drug-loaded balloon is as follows:

[0114] Step a): Select a bare balloon with a diameter of 1.5 mm and a length of 10 mm;

[0115] Step b): After inflating the bare balloon, rinse with pure water and dry for later use;

[0116] Step c): Perform media grinding on rapamycin; during the grinding process, provide two sets of comparative data: one set with a grinding time of 60 min, a drug-to-solvent ratio of 2%, and a grinding speed of 3000 rpm / min, labeled as Group A; the other set with a grinding time of 30 min, a drug-to-solvent ratio of 5%, and a grinding speed of 1000 rpm / min, labeled as Group B.

[0117] Step d): Prepare a heptane dispersion with a concentration of 1 mg / ml of ground rapamycin;

[0118] Step e): Immerse the cleaned bare balloon in the dispersion solution, sonicate at 300W for 10 minutes to form a uniform coating on the balloon surface, and wait for the coating to dry.

[0119] Step f): Prepare 5 ml of 12 mg / ml unground rapamycin methanol solution, dissolve it completely, add 10 ml of n-heptane, mix well, and then immerse the balloon obtained in step e) in the supersaturated solution to allow the crystals to grow fully. Let it stand for 10 min, then remove the balloon, and dry it in the dark for later use.

[0120] The morphology of the surface and bottom layers of the drug-loaded balloons prepared by the processes in groups A and B above was characterized, such as... Figure 9 and Figure 10 As shown. Figure 9 Scanning electron microscope (SEM) images of the underlying drug morphology under different grinding processes. Figure 10 Scanning electron microscope images of the surface drug morphology under different grinding processes.

[0121] from Figure 9 It can be seen that the drug layer prepared by process A is densely and uniformly distributed on the surface of the balloon body, with a generally consistent particle size. In contrast, the drug layer prepared by process B is unevenly distributed, with inconsistent particle sizes. Furthermore, from... Figure 10 It can be seen that in the surface drug prepared by process A, the drug crystals do not stack into clusters and are evenly distributed, while in the surface drug prepared by process B, the drug crystals do stack into clusters and are unevenly distributed. Therefore, the size and distribution of drug particles in the bottom layer of the drug layer affect the morphology and distribution of drug crystals. If the particle size and distribution of the bottom layer are not controlled, the drug crystals will stack into clusters and be unevenly distributed. If the drug crystals stack into clusters, their stability decreases, making them prone to detachment during delivery, and also affecting the drug release rate and the amount of drug transferred.

[0122] It should also be noted that the technical difficulty of rapamycin drug-loaded balloons lies in the fact that rapamycin is relatively hydrophilic and difficult to spray onto the balloon surface. Most existing technologies use excipients to increase the adhesion of the drug to the balloon surface, while this invention provides a solution that does not require excipients and only requires controlling the crystal structure of the drug on the balloon surface to achieve the same effect.

[0123] In summary, this invention improves the adhesion of pure drug to the balloon surface without polymers or other excipients by controlling the morphology and size of the crystals on the balloon surface, reducing drug loss during balloon delivery. Simultaneously, the appropriate crystal size avoids phagocytosis by macrophages, increasing the drug's residence time in vascular tissue and preventing thrombosis caused by detached drug particles, thus improving safety and efficacy. Furthermore, by constructing a uniform microcrystalline structure on the balloon surface, the operation is simple, avoiding side effects such as inflammation caused by polymer carriers, increasing coating adhesion, increasing the amount of drug transferred to blood vessels or simulated blood vessels, and increasing its residence time, resulting in a better sustained-release effect.

[0124] The above description is only a description of preferred embodiments of the present invention and is not intended to limit the scope of the present invention in any way. Any changes or modifications made by those skilled in the art based on the above disclosure shall fall within the protection scope of the present invention.

Claims

1. A drug-loaded balloon, characterized in that, The device includes a balloon body and a drug coating. The drug coating contains rapamycin and does not contain excipients. The drug coating is attached to the surface of the balloon body and consists of a plurality of drug crystals uniformly distributed on the surface of the balloon body in an amorphous cluster manner. The drug crystals are columnar crystals with three or four edges. The drug coating consists of at least one of the three- and four-edged drug crystals, and the number of drug crystals per unit area is 5.5 × 10⁻⁶. 5 / cm 2 ~6.5×10 6 / cm 2 ; The drug crystals are formed by growing on drug particles with a particle size of less than 1.0 μm. The drug particles are uniformly attached to the surface of the balloon body by physical adsorption. The crystal growth time is 0.5 min to 30 min. The drug-loaded balloon has a drug loss rate of less than 30% during delivery, and the amount of drug transferred after the drug-loaded balloon expands the narrowed area is greater than 10%.

2. The drug-loaded balloon as described in claim 1, characterized in that, The effective height of the drug crystal is 3.0 μm to 10 μm, and the effective width of the drug crystal is 1.0 μm to 5.0 μm.

3. The drug-loaded balloon as described in claim 1, characterized in that, Each of the drug crystals is in contact with and connected to at least one other drug crystal, and the drug crystals, except for their bottom surface which is in contact with the surface of the balloon body and their top surface which is opposite to the bottom surface, are in contact with and connected to at least one other drug crystal on their sides.

4. The drug-loaded balloon as described in claim 1, characterized in that, The cross-section of the drug crystal, which has four edges, is rhomboid.

5. The drug-loaded balloon as described in claim 1, characterized in that, A plurality of the drug particles constitute a base drug, wherein at least 50% of the drug particles in the base drug have a particle size of less than 0.5 μm.

6. The drug-loaded balloon as described in claim 1, characterized in that, The number of drug particles per unit area on the surface of the balloon body is 1.5 × 10⁻⁶. 7 / cm 2 ~2.5×10 8 / cm 2 .

7. The drug-loaded balloon as described in claim 1, characterized in that, After the drug-loaded balloon dilates the narrowed area, at least a portion of the drug crystals are transferred to the narrowed area, and the retention rate of the transferred drug crystals is greater than 3% after 28 days of release from the narrowed area.

8. The drug-loaded balloon as described in claim 1, characterized in that, After the drug-loaded balloon dilates the narrowed area, at least a portion of the drug crystals are transferred to the narrowed area, and the retention rate of the transferred drug crystals is greater than 10% when released from the narrowed area for 14 days.

Images