WO2024139383A1 - 涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法 - Google Patents
涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法 Download PDFInfo
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- WO2024139383A1 WO2024139383A1 PCT/CN2023/117591 CN2023117591W WO2024139383A1 WO 2024139383 A1 WO2024139383 A1 WO 2024139383A1 CN 2023117591 W CN2023117591 W CN 2023117591W WO 2024139383 A1 WO2024139383 A1 WO 2024139383A1
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- A61L2420/02—Methods for coating medical devices
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Definitions
- drug-eluting balloons are recommended for indications such as coronary in-stent restenosis, primary coronary artery lesions, and bifurcation lesions.
- physician-eluting balloon interventional treatment have been increasing.
- the natural cavity of the human body is generally in a shriveled state, that is, under normal circumstances, the inner wall of the cavity is closed on both sides, so a large amount of physiological saline is needed to flush it during the operation to maintain the filling state of the cavity, and the loss rate of the drug will also increase during the continuous flushing process.
- the drug balloon reaches the lesion site for expansion, the presence of scar tissue will also lead to a decrease in the transfer rate of the drug. Therefore, although the cause of natural cavity stenosis in the human body is similar to vascular atherosclerosis, the requirements for drug balloons are higher, and the drug balloons need to have a good drug transfer rate while having very good coating firmness. This has led to the inability of drug formulations in the field of blood vessels to be used in natural cavities in the human body.
- the purpose of the present invention is to provide a method for preparing a coating solution, a drug balloon for non-vascular intervention and a preparation method, so that the drug on the balloon can reduce the drug loss in the process of reaching the target position, and at the same time transfer more drugs to the tube wall at the target position during the expansion process of the target position.
- the mass ratio of the anti-proliferative drug to the second carrier is 10:1 to 1:1; the first carrier is an ionic contrast agent, and the first carrier is measured according to a ratio of a predetermined capacity of the coating solution to the capacity of the first carrier of 100:1 to 5:1; or, the first carrier is a monosaccharide, and the first carrier is weighed according to a mass ratio of the anti-proliferative drug to the first carrier of 10:1 to 2:1.
- the concentration of the anti-proliferative drug in the coating solution is 5 mg/ml-50 mg/ml.
- the coating solution is atomized by ultrasonic vibration, and then the atomized coating solution is sprayed on the balloon surface by a high-pressure nozzle.
- the present invention also provides a drug balloon for non-vascular intervention, comprising a balloon, the outer surface of which is coated with a drug coating, the drug coating comprising an anti-proliferative drug, a first carrier and a second carrier, the first carrier being a water-soluble compound, the first carrier being an ionic contrast agent or a monosaccharide, and the second carrier being a fat-soluble compound having two or three hydrophilic groups.
- the loading amount of the anti-proliferative drug on the surface of the drug balloon is 1 ⁇ g/mm2-10 ⁇ g/mm2.
- the drug coating is formed by spraying the coating solution prepared by the above preparation method onto the balloon surface after being atomized by ultrasonic vibration.
- the present invention has the following beneficial effects: the preparation method of the coating solution provided by the present invention, the drug balloon for non-vascular intervention and the preparation method, the anti-proliferative drug coated on the balloon surface is added with two carriers, the first carrier is a hydrophilic carrier, and during the water flow process, the first carrier can still fix or attach the anti-proliferative drug to the balloon surface; the second carrier is fat-soluble, and can form liposomes or polymer agglomerates with the drug, and the lipophilic carrier can also obtain drug particles with fine and uniform particle size, and finally ensure the release rate of the drug at the lesion site.
- the first carrier is a hydrophilic carrier, and during the water flow process, the first carrier can still fix or attach the anti-proliferative drug to the balloon surface
- the second carrier is fat-soluble, and can form liposomes or polymer agglomerates with the drug
- the lipophilic carrier can also obtain drug particles with fine and uniform particle size, and finally ensure the release rate of the drug at the lesion site
- the first carrier is a water-soluble carrier and has a certain viscosity in water
- part of the water can be locked on the balloon surface, and the hydrophilic group of the second carrier will be affinity with this part of the water, and the drug is fixed on the balloon surface during the delivery process, and the drug loss is lower.
- the balloon reaches the lesion site, it starts to expand.
- the second carrier will quickly separate from the first carrier and enter the inner wall of the natural cavity of the human body, thereby transferring a large amount of drug to the lesion site. Therefore, the drug balloon provided by the present invention can reduce the loss of the drug in the process of reaching the target location, and transfer more drugs to the wall of the target location during the expansion process of the target location.
- FIG. 1 is a flow chart of the preparation of a drug solution in an embodiment of the present invention.
- the drug balloon for non-vascular intervention includes a balloon, the outer surface of which is coated with a drug coating, the drug coating including an anti-proliferative drug, a first carrier and a second carrier, the first carrier is an ionic contrast agent or a monosaccharide, and the second carrier is a fat-soluble compound having two or three hydrophilic groups.
- the drug coated on the surface of the balloon of the present invention uses two carriers, and the coating solution is preferably sprayed on the surface of the balloon by ultrasonic spraying to form a drug coating, and delivered to the stenosis of the natural cavity of the human body.
- the anti-proliferative drug is selected from paclitaxel or paclitaxel derivatives, such as paclitaxel, docetaxel, etc., or the anti-proliferative drug is selected from rapamycin or rapamycin derivatives, such as sirolimus, eudomos, everolimus, etc.
- Such anti-proliferative drugs can be absorbed by the inner wall of the human body system due to their lipophilicity to inhibit the recurrence of stenosis.
- the first carrier is an ionic contrast agent or a monosaccharide
- the ionic contrast agent mainly includes diatrizoate, iodixanol or urofen, preferably urofen, and urofen is a compound diatrizoate, and the main components are diatrizoate and sodium diatrizoate.
- Monosaccharides mainly include sorbitol, glucose or mannose, preferably mannose.
- the main reason for using an ionic contrast agent is that, compared with a non-ionic contrast agent, an ionic contrast agent is also hydrophilic, but after being dissolved in water, the viscosity does not decrease rapidly, but still maintains a certain viscosity.
- the first carrier can still fix the anti-proliferative drug on the balloon surface.
- the main reason for using monosaccharides is that the monosaccharide molecule contains many hydrophilic groups, is easily soluble in water, and also produces a certain viscosity, and can also attach the anti-proliferative drug to the balloon surface.
- the hydrophilic carrier may cause uneven drug particle size, in order to solve this problem, the present invention introduces a second carrier.
- the second carrier is a fat-soluble compound with two or three hydrophilic groups, such as ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, ethylene glycol salicylate, resveratrol, astaxanthin, etc. Since the second carrier is fat-soluble, it can form liposomes or polymer aggregates with the drug, and the lipophilic carrier can also obtain drug particles with small and uniform particle size, ultimately ensuring the release rate of the drug at the lesion site.
- hydrophilic groups such as ferulic acid, salicylic acid, salicyl alcohol, citrazinic acid, caffeic acid, vanillic acid, ethylene glycol salicylate, resveratrol, astaxanthin, etc. Since the second carrier is fat-soluble, it can form liposomes or polymer aggregates with the drug, and the lipophilic carrier can also obtain drug particles with small and uniform particle size, ultimately ensuring the release rate of the drug at the lesion site.
- the first carrier is a water-soluble carrier and has a certain viscosity in water
- part of the water can be locked on the balloon surface, and the hydrophilic group of the second carrier will be affinity with this part of the water, and the drug will be fixed on the balloon surface during the delivery process, and the drug loss is lower.
- the balloon reaches the lesion site, it begins to expand.
- the affinity with water is less than the affinity with the liposome when it contacts the inner wall. Therefore, the second carrier will quickly separate from the first carrier with the drug and enter the inner wall of the natural cavity of the human body, thereby transferring a large amount of drug to the lesion site.
- the drug loading on the surface of the drug balloon is 1 ⁇ g/mm 2 to 10 ⁇ g/mm 2 .
- the preparation method of the coating solution is as follows:
- S1 Weighing an anti-proliferative drug, a first carrier, and a second carrier according to a predetermined amount, wherein the first carrier is an ionic contrast agent or a monosaccharide, and the second carrier is a fat-soluble compound having two or three hydrophilic groups.
- the anti-proliferative drug and the second carrier are weighed to control the mass ratio of the anti-proliferative drug to the second carrier to be between 10:1 and 1:1;
- the first carrier is an ionic contrast agent
- the first carrier is placed in a reagent bottle according to a ratio of 100:1 to 5:1 between the required coating solution volume and the first carrier volume; if the first carrier is a monosaccharide, the first carrier is weighed according to a mass ratio of 10:1 to 2:1 between the anti-proliferative drug and the first carrier.
- S2 preparing an organic solvent and water in a predetermined ratio to form a solvent; wherein the organic solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran, isopropanol, and ether.
- the coating solution can be sprayed on the balloon surface by ultrasonic spraying to form a drug coating, and the drug is coated on the balloon to obtain a drug balloon.
- the coating solution is atomized by ultrasonic vibration, and then the atomized coating solution is sprayed on the balloon surface evenly and stably by a high-pressure nozzle to form a drug coating.
- the drug balloon provided by the present invention is used for balloon dilatation treatment of non-vascular (natural human cavity) stenosis, and the natural human cavity mainly includes ureter, urethra, digestive tract, bile duct, respiratory tract, etc.
- the anti-proliferative drug used in the coating solution is paclitaxel
- the first carrier is ureaflutol
- the second carrier is resveratrol
- the solvent is prepared from ethanol, acetone, tetrahydrofuran and water.
- the anti-proliferative drugs and solvents are the same as those in the present embodiment, except that: in comparative example 1, no carrier is added; in comparative example 2, only the first carrier Urofen is added; and in comparative example 3, only the second carrier resveratrol is added.
- the drug loss rate and drug transfer rate of the present embodiment and the three comparative examples are compared below.
- the drug balloon provided in this embodiment can significantly reduce the drug loss in the process of reaching the target position, and at the same time transfer more drugs to the tube wall at the target position during the expansion process of the target position.
- the anti-proliferative drugs and solvents are the same as those in the present embodiment, except that: in comparative example 4, no carrier is added; in comparative example 5, only the first carrier mannose is added; and in comparative example 6, only the second carrier ferulic acid is added.
- the drug loss rate and drug transfer rate of the present embodiment and the three comparative examples are compared below.
- Example 1 and Example 2 show longer residual time at the target location and higher drug content, which means that these two formulations can act on the lesion site for a long time, showing the excellent effect of the present invention.
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Abstract
本发明公开了一种涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法，所述球囊的外表面涂覆有药物涂层，所述药物涂层包括抗增生药物、第一载体和第二载体，所述第一载体为水溶性化合物，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物。抗增生药物为紫杉醇、紫杉醇衍生物、雷帕霉素或雷帕霉素衍生物。第一载体为泛影葡胺、碘克沙醇、优路芬、山梨糖、葡萄糖或甘露糖。第二载体为具阿魏酸、水杨酸、水杨醇、柠嗪酸、咖啡酸、香草酸、乙二醇水杨酸酯、白藜芦醇或虾青素。本发明提供的药物球囊使药物在达到目标位置的过程中能够减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁上。
Description
本发明涉及医疗器械技术领域，尤其涉及一种涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法。
药物球囊的概念始于冠状动脉介入术。自从2004年Scheller 率先报告了药物球囊预防猪冠状动脉支架内再狭窄与普通球囊相比的结果，表明紫杉醇涂层球囊可显著降低ISR（in-stent restenosis，支架内再狭窄）发生率，以及在2009年全球第一款药物球囊获得CE认证，并且在欧洲上市以来。药物球囊作为一种新的介入治疗技术在欧洲和中国逐渐广泛应用于冠状动脉及外周介入领域。此外，在《2016药物涂层球囊临床应用中国专家共识》中，药物球囊被推荐应用于冠状动脉支架内再狭窄，冠状动脉原发病变以及分叉病变等适应症。随着近年来“介入无植入”的临床特点和治疗理念，药物球囊介入治疗的重要性和地位日益增强。
但目前已上市的产品主要关注于血管内狭窄的药物球囊治疗，对于人体自然腔道狭窄却很少有相关药物球囊治疗的报道，人体自然腔道主要包括输尿管，尿道，消化道，胆道，呼吸道等。目前针对这些人体自然腔道狭窄常用的腔内治疗方法主要是通过裸球囊扩张并使用支架对人体自然腔道进行治疗。但是研究表明，使用裸球囊扩张后，患者的再狭窄率将高达30%~50%。而支架的使用会对腔道内壁产生损伤，并且由于植入时间较长，可能会引起刺激，从而导致炎症的发生，此外，支架的植入也会使支架与腔道内壁结合，后续取出的过程较为困难。在血管领域，目前在“植入无介入”的理念下，药物球囊成为了一种较为常用的手术方式，同时也有研究表明，药物球囊可以防止再狭窄的发生。
众所周知，药物球囊所需要具备的特性主要包括在递送过程中较低的药物损失量以及在病变部位进行扩张时较为优异的药物转移率。现在已上市的药物球囊的配方大多是由一种抗增生药物与一种载体组成。其中抗增生药物大多为紫杉醇及其衍生物或者雷帕霉素及其衍生物，因为其可以抑制细胞的分裂或增殖的特性，可以防止再狭窄的发生。
对于载体的研究，目前使用最多的载体为碘普罗胺，碘海醇等非离子造影剂。此类载体本身具有一定的粘性，可以药物在球囊表面具有一定的“附着力”。但实验表明，此类载体在递送至病变部位过程中，会有较大的药量损失，主要原因是非离子造影剂具有很强的水溶性（非离子造影剂在苯环上引入了多个含羟基的亲水性侧链，其空间分布对称，包绕在碘原子周围，侧链上的羟基还保证了很强的水溶性）。此外，当其溶于水后，不易聚集，导致粘度下降。而递送药物球囊的过程中，由于有大量的水性溶液在不断地流动，这些载体溶于水性溶液后导致粘度下降，药物的损失率相对较高。
目前还有使用尿素等水溶性粘合剂作为载体的产品，其溶于水后会具有一定的粘性，因此在递送过程中，虽然在水流动过程中会有部分载体被冲刷，但是仍然能保证有大量的药物被递送进入目标位置。但是使用此类载体的药物球囊在药物转移至病变部位时，并未展现出较高的药物转移率。主要原因是此类载体容易造成紫杉醇粒径不均匀，在药物转移至目标位置管壁时效率较低，因此无法将大量的紫杉醇转移到病变位置。
此外，还有使用紫胶铵盐等低亲水性或者硬脂酸镁等亲脂性载体的药物球囊。此类载体与亲脂性药物混合后可形成脂质体，或聚合物团聚，在递送至目标位置时可以展现较高的药物转移率并保持组织中较高浓度。但是亲水性差的载体涂层吸附性差，易脱落，造成远端栓塞，而且也无法获得较高的涂层牢固度，在递送过程中也会有较大的药量损失。
曾有学者使用两种已上市的冠脉药物球囊进行体外穿越实验，得出损失率为26±3%（尿素配方）和36±11%（碘普罗胺配方），虽然在靶血管的药量同样可以抑制细胞增生，但是大家仍然在探究一种可以获得更少销量损失以及更多药量转移的配方。但是目前仍未找到一种载体，可以完美的平衡药物球囊递送能力及药物吸收率。据报道，现已有药物球囊开始使用一种抗增生药物和两种载体组成的药物球囊配方，其载体为两种水溶性的载体。此类载体均具备水亲和部分以及药物亲和部分，通过氢键或者范德华力与药物进行连接，在到达目标位置时，药物可以快速释放。但是这两种水溶性载体没有足够的粘性，而且由于其均为亲水性，紫杉醇粒径不均的问题并未得到解决，因此在到达目标位置前，仍会展现出较大的药量损失。
与血管领域类似，人体自然腔道狭窄的形成主要原因也是细胞的增生导致内膜增厚，从而形成狭窄。人体自然腔道的狭窄形成主要原因是外伤，炎症或者其他病变而导致的。且形成的狭窄多为瘢痕组织，其硬度相对于血管的动脉粥样硬化要高很多，当药物球囊在通过狭窄部位时会与瘢痕组织不断接触，导致一部分的药量损失。此外，由于人体自然腔道一般为干瘪状态，即正常情况下，腔道内壁两侧为闭合状，因此在手术过程中需要通过大量的生理盐水进行冲刷以保持腔道的充盈状态，而在不断冲刷的过程中，药量的损失率也会增加。当药物球囊到达病变部位进行扩张时，由于瘢痕组织的存在也会导致药物的转移率的下降。因此虽然人体自然腔道狭窄的原因与血管动脉粥样硬化类似，但是对于药物球囊的要求更高，需要药物球囊在具有非常好的涂层牢固度的情况下，也具有好的药物转移率。这就导致了血管领域的药物配方无法使用在人体自然腔道中。
因此，对于非血管介入的药物球囊，需要开发一种用于医疗器械的高针对性的药物涂层，使药物在达到目标位置的过程中尽可能减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁。
本发明的目的是提供一种涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法，使球囊上的药物在达到目标位置的过程中减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁上。
为实现上述目的，本发明提供一种涂层溶液的制备方法，包括如下步骤：S1：按照预定量称量抗增生药物、第一载体和第二载体，所述第一载体为水溶性化合物，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物；S2：按预定配比的有机溶剂和水进行配制，形成溶剂；S3：将所述第一载体，所述第二载体和所述抗增生药物倒入所述溶剂中溶解，获得涂层溶液。
优选地，所述步骤S1中，所述抗增生药物与所述第二载体的质量比例为10：1至1：1；所述第一载体为离子型造影剂，根据所述涂层溶液的预定容量与所述第一载体容量比例为100：1至5：1量取所述第一载体，或，所述第一载体为单糖，根据所述抗增生药物与所述第一载体质量比为10：1至2：1称取所述第一载体。
优选地，所述步骤S3中，所述涂层溶液中抗增生药物浓度5mg/ml~50mg/ml。
优选地，所述步骤S2中，所述有机溶剂为甲醇，乙醇，丙酮，四氢呋喃，异丙醇和乙醚中的一种或几种。
为实现上述目的，本发明还提供一种用于非血管介入的药物球囊的制备方法，将上述的涂层溶液喷涂在球囊表面，制备得到所述药物球囊。
优选地，通过超声振动将所述涂层溶液雾化，然后用高压喷嘴将雾化后的涂层溶液喷在所述球囊表面。
为实现上述目的，本发明还提供一种用于非血管介入的药物球囊，包括球囊，所述球囊的外表面涂覆有药物涂层，所述药物涂层包括抗增生药物、第一载体和第二载体，所述第一载体为水溶性化合物，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物。
优选地，所述抗增生药物为紫杉醇、多西他赛、卡巴他赛、雷帕霉素、西罗莫司、优美莫斯、依维莫司或佐他莫司；所述第一载体为泛影葡胺、碘克沙醇、优路芬、山梨糖、葡萄糖或甘露糖；所述第二载体为具阿魏酸、水杨酸、水杨醇、柠嗪酸、咖啡酸、香草酸、乙二醇水杨酸酯、白藜芦醇或虾青素。
优选地，所述药物球囊表面抗增生药物的载药量为1μg/mm2~10μg/mm2。
优选地，所述药物涂层由上述制备方法制取的涂层溶液通过超声振动雾化后喷涂在所述球囊表面形成。
本发明对比现有技术有如下的有益效果：本发明提供的涂层溶液的制备方法、用于非血管介入的药物球囊及制备方法，球囊表面涂敷的抗增生药物添加两种载体，第一载体为亲水性载体，在水流动过程中，第一载体仍然可以将抗增生药物固定或附着在球囊表面；第二载体为脂溶性，可以与药物形成脂质体或聚合物团聚，同时亲脂性载体也可以获得粒径细小均匀的药物颗粒，最终保证药物在病变位置的释放率。同时由于第一载体为水溶性载体，并且在水中也会有一定的粘度，因此可以将部分水锁定在球囊表面，而第二载体的亲水基团就会与这部分的水亲和，在递送过程中把药物固定在球囊表面，药量损失更低。而到了病变部位球囊开始扩张，当药物与人体自然腔道的内管壁接触时，由于第二载体的羟基数量少，与水亲和的能力小于其与内管壁接触时与脂质体的亲和力，因此第二载体会带着药物迅速脱离第一载体进入人体自然腔道的内管壁，从而将大量药物转移到病变位置。因此，本发明提供的药物球囊使药物在达到目标位置的过程中能够减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁上。
图1为本发明实施例中药物溶液的制备流程图。
下面结合附图和实施例对本发明作进一步的描述。
本实施例提供的用于非血管介入的药物球囊，包括球囊，所述球囊的外表面涂覆有药物涂层，所述药物涂层包括抗增生药物、第一载体和第二载体，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物。
本发明球囊表面涂覆的药物使用了两种载体，优选通过超声喷涂的方式将涂层溶液喷涂在球囊表面以形成药物涂层，并递送至人体自然腔道的狭窄部位。其中抗增生药物选择紫杉醇或紫杉醇衍生物，如紫杉醇，多西他赛等，或者抗增生药物选择雷帕霉素或雷帕霉素衍生物，如西罗莫司，优美莫斯，依维莫司等。此类抗增生药物由于其亲脂性可以被人体系统内管壁吸收，以抑制狭窄的再次发生。
本实施例中，第一载体为离子型造影剂或者单糖，离子型造影剂主要包括泛影葡胺，碘克沙醇或优路芬，优选优路芬，优路芬为复合泛影葡胺，主要成分是泛影葡胺和泛影酸钠。单糖主要包括山梨糖、葡萄糖或甘露糖，优选为甘露糖。使用离子型造影剂的主要原因是，相比于非离子型造影剂，离子型造影剂虽然也具有亲水性，但是在溶于水后，粘度并不会迅速降低，而仍会保持一定的粘度，因此在水流动过程中，该第一载体仍然可以将抗增生药物固定在球囊表面。而使用单糖的原因主要是，单糖分子含有许多亲水基团，易溶于水，同时也会产生一定的粘性，也可以将抗增生药物附着在球囊表面。但是由于亲水性载体可能会造成药物粒径不均，为了解决这个问题，本发明引入了第二载体。
第二载体为具有两个或者三个亲水基团的脂溶性化合物，如：阿魏酸、水杨酸、水杨醇、柠嗪酸、咖啡酸、香草酸、乙二醇水杨酸酯、白藜芦醇、虾青素等。由于该第二载体为脂溶性，因此可以与药物形成脂质体或聚合物团聚，同时亲脂性载体也可以获得粒径细小均匀的药物颗粒，最终保证药物在病变位置的释放率。同时由于第一载体为水溶性载体，并且在水中也会有一定的粘度，因此可以将部分水锁定在球囊表面，而第二载体的亲水基团就会与这部分的水亲和，在递送过程中把药物固定在球囊表面，药量损失更低。而到了病变部位球囊开始扩张，当药物与人体自然腔道的内管壁接触时，由于第二载体的羟基数量少，与水亲和的能力小于其与内管壁接触时与脂质体的亲和力，因此第二载体会带着药物迅速脱离第一载体进入人体自然腔道的内管壁，从而将大量药物转移到病变位置。
较佳地，药物球囊表面的载药量为1μg/mm
2~10μg/mm
2。请参见图1，涂层溶液的配制方法如下：
S1：按照预定量称量抗增生药物、第一载体和第二载体，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物。
首先，确定需要配制喷涂前涂层溶液的容量，并按照溶液所需药物浓度计算所需称量的药物质量。一般控制抗增生药物浓度在5mg/ml至50mg/ml之间。
接着，称量抗增生药物和第二载体。控制抗增生药物与第二载体的质量比例在10：1至1：1之间；
然后，若第一载体选择离子型造影剂，则根据所需涂层溶液容量与第一载体容量比例为100：1至5：1将第一载体放入试剂瓶；若第一载体选择单糖，则根据抗增生药物与第一载体质量比为10：1至2：1称量第一载体。
S2：按预定配比的有机溶剂和水进行配制，形成溶剂；其中有机溶剂包括甲醇，乙醇，丙酮，四氢呋喃，异丙醇，乙醚中的一种或几种。
S3：将所述第一载体，所述第二载体和所述抗增生药物倒入所述溶剂中溶解，获得涂层溶液。具体地，逐步将第一载体，第二载体和抗增生药物倒入溶剂中充分振荡获得喷涂前涂层溶液。
涂层溶液配制完成后，可以使用超声喷涂的方法将涂层溶液喷在球囊表面，形成药物涂层，完成药物在球囊上的涂敷，得到药物球囊。具体地，通过超声振动将所述涂层溶液雾化，然后用用高压喷嘴均匀稳定的将雾化后的涂层溶液喷在所述球囊表面，形成药物涂层。
本发明提供的药物球囊用于非血管（人体自然腔道）狭窄的球囊扩张治疗，人体自然腔道主要包括输尿管，尿道，消化道，胆道，呼吸道等。
本实施例中，涂层溶液使用的抗增生药物为紫杉醇，第一载体为优路芬，第二载体为白藜芦醇，溶剂由乙醇、丙酮、四氢呋喃和水配制得到。
三个对比例中，抗增生药物、溶剂均与本实施例相同，不同的是：对比例1中不添加载体；对比例2只添加第一载体优路芬；对比例3中只添加第二载体白藜芦醇，下面分别将本实施例和三个对比例的药量损失率、药物转移率进行比较。
从上表可以看出，本实施例提供的药物球囊，使药物在达到目标位置的过程中能够大幅减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁上。
本实施例中，涂层溶液使用的抗增生药物为紫杉醇，第一载体为甘露糖，第二载体为阿魏酸，溶剂由丙酮、四氢呋喃和水配制得到。
三个对比例中，抗增生药物、溶剂均与本实施例相同，不同的是：对比例4中不添加载体；对比例5只添加第一载体甘露糖；对比例6中只添加第二载体阿魏酸，下面分别将本实施例和三个对比例的药量损失率、药物转移率进行比较。
从上表可以看出，本实施例提供的药物球囊，使药物在达到目标位置的过程中能够大幅减少其药量损失，同时在目标位置扩张过程中将更多的药物转移至目标位置的管壁上。
对重约45kg的雌性猪进行实验评估本发明对于输尿管靶位置点的紫杉醇药代动力学的结果。
术前对猪进行麻醉，并对所有术中需使用的耗材和器械进行灭菌消毒。手术开始时，将猪固定在手术台上，用安尔碘常规消毒液在手术部位（阴部）周围皮肤消毒，干燥后即可贴无菌手术膜或铺无菌手术巾。
术中，医生通过固定手术操作流程，最终将四种不同配方的药物球囊从猪尿道口逆行递送至输尿管中的预定的靶位置，根据实际情况扩张1次，持续充盈5min。通过压力泵将球囊抽吸后进行回撤。
术后防止双J管，并在8天随访时将其取出。分别在术后1h，8d，28d和60d解剖既定的猪，对其扩张位置的药物含量进行分析，结果如下：
从上表可以看出，实施例1和实施例2均展现出在靶位置上残留时间更长，药物含量更多的结果，意味着此两种配方可以长时间的对病变部位进行作用，展现出本发明的优异效果。
虽然本发明已以较佳实施例揭示如上，然其并非用以限定本发明，任何本领域技术人员，在不脱离本发明的精神和范围内，当可作些许的修改和完善，因此本发明的保护范围当以权利要求书所界定的为准。
Claims (10)
- 一种涂层溶液的制备方法，其特征在于，包括如下步骤：S1：按照预定量称量抗增生药物、第一载体和第二载体，所述第一载体为水溶性化合物，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物；S2：按预定配比的有机溶剂和水进行配制，形成溶剂；S3：将所述第一载体，所述第二载体和所述抗增生药物倒入所述溶剂中溶解，获得涂层溶液。
- 根据权利要求1所述的制备方法，其特征在于，所述步骤S1中，所述抗增生药物与所述第二载体的质量比例为10：1至1：1；所述第一载体为离子型造影剂，根据所述涂层溶液的预定容量与所述第一载体容量比例为100：1至5：1量取所述第一载体，或，所述第一载体为单糖，根据所述抗增生药物与所述第一载体质量比为10：1至2：1称取所述第一载体。
- 根据权利要求1所述的制备方法，其特征在于，所述步骤S3中，所述涂层溶液中抗增生药物浓度为5mg/ml~50mg/ml。
- 根据权利要求1所述的制备方法，其特征在于，所述步骤S2中，所述有机溶剂为甲醇，乙醇，丙酮，四氢呋喃，异丙醇和乙醚中的一种或几种。
- 一种用于非血管介入的药物球囊的制备方法，其特征在于，将权利要求1-4任一项所述的涂层溶液喷涂在球囊表面，制备得到所述药物球囊。
- 根据权利要求5所述的制备方法，其特征在于，通过超声振动将所述涂层溶液雾化，然后用高压喷嘴将雾化后的涂层溶液喷在所述球囊表面。
- 一种用于非血管介入的药物球囊，其特征在于，包括球囊，所述球囊的外表面涂覆有药物涂层，所述药物涂层包括抗增生药物、第一载体和第二载体，所述第一载体为水溶性化合物，所述第一载体为离子型造影剂或单糖，所述第二载体为具有两个或者三个亲水基团的脂溶性化合物。
- 根据权利要求7所述的药物球囊，其特征在于，所述抗增生药物为紫杉醇、多西他赛、卡巴他赛、雷帕霉素、西罗莫司、优美莫斯、依维莫司或佐他莫司；所述第一载体为泛影葡胺、碘克沙醇、优路芬、山梨糖、葡萄糖或甘露糖；所述第二载体为具阿魏酸、水杨酸、水杨醇、柠嗪酸、咖啡酸、香草酸、乙二醇水杨酸酯、白藜芦醇或虾青素。
- 根据权利要求7所述的药物球囊，其特征在于，所述药物球囊表面抗增生药物的载药量为1μg/mm 2~10μg/mm 2。
- 根据权利要求7所述的药物球囊，其特征在于，所述药物涂层由权利要求1-5任一项所述制备方法制取的涂层溶液通过超声振动雾化后喷涂在所述球囊表面形成。
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| CN104857573A (zh) * | 2010-03-25 | 2015-08-26 | 路通医疗股份有限公司 | 用于医疗设备的释药涂层 |
| CN107635593A (zh) * | 2015-04-24 | 2018-01-26 | 优敦力公司 | 用于非血管狭窄的药物涂布的球囊导管 |
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| CN104841060A (zh) * | 2014-02-13 | 2015-08-19 | 张海军 | 一种超声控释药物洗脱球囊导管及其制备方法 |
| CN107635593A (zh) * | 2015-04-24 | 2018-01-26 | 优敦力公司 | 用于非血管狭窄的药物涂布的球囊导管 |
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