CN114042044B - Trace polylactic acid/rifampicin drug-loaded microsphere and preparation method thereof - Google Patents

Abstract

Translated fromChinese

本发明公开了一种可示踪的聚乳酸/利福平载药微球的制备方法，将聚乳酸溶于二氯甲烷中，然后加入司盘‑80及利福平，超声乳化，得到乳液；将乳液倒入PVA水溶液中剪切分散，得到水包油乳液；将水包油乳液在搅拌同时滴加碘佛醇造影剂溶液，然后滴加三聚磷酸钠，微球固化成型，得到聚乳酸两层复合载药；将其置于溶有聚乳酸的二氯甲烷溶液中，得到三层复合载药微球，将其加入碘佛醇造影剂溶液中，滴加TPP，得到溶液；将得到的溶液离心，取出底部微球。本发明的载药微球制备工艺简单快速，且产品即具有示踪功能、较高的载药率和包封率，又具备较长的缓释时间，且制备过程中使用生物降解性较好的聚乳酸，具有广阔的应用前景。

The invention discloses a preparation method of traceable polylactic acid/rifampicin drug-loaded microspheres. Polylactic acid is dissolved in methylene chloride, then Span-80 and rifampicin are added, ultrasonically emulsified to obtain an emulsion ; Pour the emulsion into the PVA aqueous solution to shear and disperse to obtain an oil-in-water emulsion; add ioversol contrast agent solution dropwise to the oil-in-water emulsion while stirring, and then add sodium tripolyphosphate dropwise, and the microspheres are solidified and formed to obtain poly Lactic acid two-layer composite drug-loading; it is placed in a dichloromethane solution dissolved in polylactic acid to obtain a three-layer composite drug-loaded microsphere, which is added to the ioversol contrast agent solution, and TPP is added dropwise to obtain a solution; The resulting solution was centrifuged to remove the bottom microspheres. The preparation process of the drug-loaded microspheres of the present invention is simple and fast, and the product not only has a tracer function, a higher drug loading rate and encapsulation efficiency, but also has a longer sustained release time, and has better biodegradability during the preparation process. Polylactic acid has broad application prospects.

Description

Translated fromChinese

一种可示踪的聚乳酸/利福平载药微球及其制备方法A traceable polylactic acid/rifampicin drug-loaded microsphere and its preparation method

技术领域technical field

本发明涉及一种可降解药物载体材料，特别涉及一种可示踪的复合载药微球，属于生物医用技术领域。The invention relates to a degradable drug carrier material, in particular to a traceable composite drug-loaded microsphere, which belongs to the technical field of biomedicine.

背景技术Background technique

骨关节结核常继发于肺结核，是最常见的肺外继发性结核，骨关节结核治疗是综合性能治疗，包括抗结核药物治疗、营养支持以及病灶清除等。目前，抗结核药物治疗方案是利福平、异烟肼、吡嗪酰胺三联或加入链霉素的四联方案强化治疗2个月。但由于抗结核药物的消化道毒副作用，仍有很多病人难以耐受，病人依从性较差。且由于骨关节结核病灶周围存在硬化骨，全身系统用药药物难以到达病灶局部，更难以渗入病灶中的死骨。因此，在骨关节结核的抗结核治疗中，能够更加准确的定位到病灶部位，减少用药频率，并在病灶局部维持较长时间的有效药物浓度非常重要。Bone and joint tuberculosis is often secondary to pulmonary tuberculosis, and is the most common extrapulmonary secondary tuberculosis. The treatment of bone and joint tuberculosis is a comprehensive treatment, including anti-tuberculosis drug treatment, nutritional support, and debridement. Currently, the anti-tuberculosis drug treatment regimen is rifampicin, isoniazid, pyrazinamide triple or a quadruple regimen with streptomycin for intensive treatment for 2 months. However, due to the toxic and side effects of the digestive tract of anti-tuberculosis drugs, many patients still find it difficult to tolerate, and the patient's compliance is poor. And because there is sclerotic bone around the bone and joint tuberculosis lesion, it is difficult for systemic medication to reach the local lesion, and it is even more difficult to penetrate into the sequestrum in the lesion. Therefore, in the anti-tuberculosis treatment of bone and joint tuberculosis, it is very important to locate the lesion more accurately, reduce the frequency of medication, and maintain the effective drug concentration in the lesion for a long time.

聚乳酸(简称PLA)是生物可降解的功能高分子有机化合物，不但具有无毒，可降解，生物相容性好等特点，并且已经被美国食品和药物管理局(FDA)批准用于人体，在制药领域有着巨大的应用前景。目前其在骨缺损修复、蛋白质、抗肿瘤、多肽及疫苗等药物载体方面均具有非常好的发展前景。用为载体材料制备的纳米囊、微球、凝胶等注射剂可以起到保护药物、增加药物溶解度及提高药物生物利用度的作用，达到较长时间的缓释、控释目的，具有广阔的开发前景。Polylactic acid (abbreviated as PLA) is a biodegradable functional polymer organic compound, not only has the characteristics of non-toxic, degradable, and good biocompatibility, but also has been approved by the US Food and Drug Administration (FDA) for use in humans. It has great application prospects in the pharmaceutical field. At present, it has very good development prospects in bone defect repair, protein, anti-tumor, peptide and vaccine and other drug carriers. Injections such as nanocapsules, microspheres, and gels prepared as carrier materials can protect drugs, increase drug solubility and improve drug bioavailability, and achieve the purpose of sustained and controlled release for a long time, and have broad development potential. prospect.

利福平(RFP)为利福霉素类抗生素，在结核分枝杆菌转录水平抑制RNA合成，具有良好的治愈结核类疾病的作用。且价廉易得，无毒无味，与其它抗结核药有协同作用，无交叉耐药性。对于骨关节结核具有良好的治疗作用。Rifampicin (RFP) is a rifamycin antibiotic that inhibits RNA synthesis at the transcriptional level of Mycobacterium tuberculosis, and has a good effect on curing tuberculosis-like diseases. It is cheap and easy to obtain, non-toxic and tasteless, has synergistic effect with other anti-tuberculosis drugs, and has no cross-drug resistance. It has a good therapeutic effect on bone and joint tuberculosis.

近年来，也有一些治疗骨关节结核的方法，比如利用抗结核药物治疗，但是无法准确的应用到病灶部位，而且容易使病人产生耐受性、释药时间短，需要多次用药，不能满足骨修复的需求。因此，通过可示踪的碘佛醇造影剂加入到载药微球中，并采用层层包裹技术在微球表面包覆，可以准确的对病灶部位治疗，是一种较为理想的药物释放系统。In recent years, there are also some methods for the treatment of bone and joint tuberculosis, such as the use of anti-tuberculosis drugs, but they cannot be accurately applied to the lesion, and it is easy for patients to develop tolerance. Repair needs. Therefore, by adding the traceable ioversol contrast agent into the drug-loaded microspheres, and coating the surface of the microspheres with layer-by-layer coating technology, it can accurately treat the lesion, and it is an ideal drug release system. .

发明内容Contents of the invention

本发明所要解决的技术问题是：提供一种可示踪的聚乳酸/利福平载药微球的制备方法。The technical problem to be solved by the present invention is to provide a preparation method of traceable polylactic acid/rifampicin drug-loaded microspheres.

为了解决上述技术问题，本发明提供的技术方案如下：In order to solve the problems of the technologies described above, the technical solutions provided by the invention are as follows:

一种可示踪的聚乳酸/利福平载药微球的制备方法，包括以下步骤：A preparation method of traceable polylactic acid/rifampicin drug-loaded microspheres, comprising the following steps:

步骤1)：将聚乳酸溶于二氯甲烷中，直至澄清透明，然后加入司盘-80及利福平，超声乳化，得到乳液；Step 1): dissolving polylactic acid in dichloromethane until clear and transparent, then adding Span-80 and rifampicin, ultrasonic emulsification, to obtain an emulsion;

步骤2)：将得到的乳液倒入PVA水溶液中，以转速为3000-8000r/min在高速剪切乳化机中剪切分散，得到水包油乳液；Step 2): Pour the obtained emulsion into the PVA aqueous solution, and shear and disperse it in a high-speed shear emulsifier at a speed of 3000-8000r/min to obtain an oil-in-water emulsion;

步骤3)：将得到的水包油乳液在室温下磁力搅拌，同时滴加碘佛醇造影剂溶液，然后滴加三聚磷酸钠，持续搅拌，使有机溶剂完全挥发，微球固化成型，得到聚乳酸两层复合载药；将其置于溶有聚乳酸的二氯甲烷溶液中，25℃下超声振荡后离心分离清洗，得到三层复合载药微球，将其加入碘佛醇造影剂溶液中，磁力搅拌后滴加TPP，得到溶液；Step 3): The obtained oil-in-water emulsion was magnetically stirred at room temperature, and at the same time, ioversol contrast agent solution was added dropwise, and then sodium tripolyphosphate was added dropwise, and the stirring was continued to completely volatilize the organic solvent, and the microspheres were solidified and formed to obtain Two-layer composite drug-loading of polylactic acid; place it in a dichloromethane solution dissolved in polylactic acid, ultrasonically oscillate at 25°C, and then centrifuge and wash to obtain three-layer composite drug-loaded microspheres, which are added to ioversol contrast agent In the solution, add TPP dropwise after magnetic stirring to obtain a solution;

步骤4)：将得到的溶液离心，取出底部微球，用蒸馏水洗涤，冷冻干燥后即得聚乳酸/利福平载药微球。Step 4): Centrifuge the obtained solution, take out the microspheres at the bottom, wash with distilled water, and freeze-dry to obtain polylactic acid/rifampicin drug-loaded microspheres.

优选地，所述步骤1)中聚乳酸的分子量在3～64KDa之间，采用聚左旋乳酸、聚右旋乳酸或两者的混合物。聚乳酸是具有良好的可生物降解性，且易于得到。Preferably, the molecular weight of the polylactic acid in the step 1) is between 3-64KDa, and poly-L-lactic acid, poly-D-lactic acid or a mixture of the two is used. Polylactic acid has good biodegradability and is easy to obtain.

优选地，所述步骤1)中聚乳酸、二氯甲烷、司盘-80、利福平的重量比为10:40～80:1:1～5。利福平投药量越多，利福平颗粒会更多分布于微球表面，载药量也会增加。Preferably, the weight ratio of polylactic acid, methylene chloride, Span-80 and rifampicin in the step 1) is 10:40-80:1:1-5. The more rifampicin dosage, the more rifampicin particles will be distributed on the surface of the microspheres, and the drug loading will also increase.

优选地，所述步骤2)中PVA水溶液乳液的质量浓度为1％；乳液与PVA水溶液的重量比为1：2～10。Preferably, the mass concentration of the PVA aqueous solution emulsion in the step 2) is 1%; the weight ratio of the emulsion to the PVA aqueous solution is 1:2-10.

优选地，所述步骤3)中碘佛醇造影剂溶液的质量浓度为1％；乳液与碘佛醇造影剂溶液、TPP的重量比为400：5～15：1。碘佛醇造影剂是一种可以精确定位病灶部位的物质。Preferably, the mass concentration of the ioversol contrast agent solution in the step 3) is 1%; the weight ratio of the emulsion to the ioversol contrast agent solution and TPP is 400:5˜15:1. Ioversol contrast agent is a substance that can precisely localize the lesion site.

优选地，所述步骤3)中聚乳酸两层复合载药与聚乳酸的比例为1：10～500；三层复合载药微球与碘佛醇造影剂溶液的重量比为2：1～3，与滴加的TPP的重量比为5：1～3。Preferably, in the step 3), the ratio of the two-layer composite drug-loaded polylactic acid to polylactic acid is 1:10-500; the weight ratio of the three-layer composite drug-loaded microspheres to the ioversol contrast agent solution is 2:1-500. 3. The weight ratio of TPP added dropwise is 5:1~3.

优选地，所述步骤4)中蒸馏水洗涤的次数为3-5次。Preferably, the number of times of washing with distilled water in step 4) is 3-5 times.

本发明还提供了一种上述可示踪的聚乳酸/利福平载药微球的制备方法制得的可示踪的聚乳酸/利福平载药微球。The present invention also provides a traceable polylactic acid/rifampicin drug-loaded microsphere prepared by the preparation method of the traceable polylactic acid/rifampicin drug-loaded microsphere.

与现有技术相比，本发明的优势在于：Compared with the prior art, the present invention has the advantages of:

1)本发明制备的载药微球工艺简单快速，具有较好的载药量和包封率；1) The process of the drug-loaded microspheres prepared by the present invention is simple and fast, and has better drug-loading capacity and encapsulation efficiency;

2)本发明制备的载药微球具有示踪性，可以更加准确的应用到病灶部位。2) The drug-loaded microspheres prepared by the present invention have traceability and can be applied to the lesion more accurately.

附图说明Description of drawings

图1为实施例1制备的载药微球的形貌特征；Fig. 1 is the morphology characteristic of the drug-loaded microsphere prepared by embodiment 1;

图2为实施例2制备的载药微球的形貌特征；Fig. 2 is the morphology characteristic of the drug-loaded microsphere prepared in embodiment 2;

图3为实施例3制备的载药微球的形貌特征；Fig. 3 is the morphology characteristic of the drug-loaded microsphere prepared byembodiment 3;

图4为对比例1制备的载药微球的形貌特征；Fig. 4 is the morphology characteristic of the drug-loaded microsphere prepared in comparative example 1;

图5为本发明的载药微球的药物释放曲线。Fig. 5 is the drug release curve of the drug-loaded microspheres of the present invention.

具体实施方式Detailed ways

为使本发明更明显易懂，兹以优选实施例，并配合附图作详细说明如下。In order to make the present invention more comprehensible, preferred embodiments are described in detail below with accompanying drawings.

本发明使用的1％的PVA采用下述方法制备：The 1% PVA that the present invention uses adopts following method to prepare:

称取10.0g PVA溶于1000mL蒸馏水中，室温下搅拌完全溶解后，即得浓度为1％PVA溶液待用。Weigh 10.0 g of PVA and dissolve it in 1000 mL of distilled water, stir at room temperature to dissolve completely, and obtain a 1% PVA solution for use.

本发明其它试剂都是通过泰坦平台商购获得。All other reagents of the present invention are commercially available through Titan Platform.

粒径大小测定采用激光粒度仪进行测定，测定温度为室温。The particle size measurement is carried out by a laser particle size analyzer, and the measurement temperature is room temperature.

微球形貌采用扫描电镜(SEM)进行测定。Microsphere morphology was determined by scanning electron microscopy (SEM).

载药率、包封率采用紫外分光光度计进行测定。The drug loading rate and encapsulation efficiency were measured by ultraviolet spectrophotometer.

实施例1Example 1

取大约5g PLA溶于大约40mL二氯甲烷中，直至澄清透明。再加入0.25g的司盘-80以及10mg的利福平超声乳化30min，得到乳液；将得到的乳液倒入400mL浓度为1％的PVA(聚乙烯醇)水溶液中，以转速为5000r/min在高速剪切乳化机中剪切分散3min，得到水包油(O/W)乳液；将得到的(O/W)乳液在室温下磁力搅拌，同时滴加5g浓度为1％的碘佛醇造影剂溶液，0.5h后滴加1g三聚磷酸钠(TPP)，之后持续搅拌3h，使有机溶剂完全挥发，微球固化成型，得到PLA两层复合载药微球；将其置于40mL溶有5gPLA的二氯甲烷溶液中，25℃下超声振荡30min后离心分离清洗，得到三层复合载药微球，将其加入5g质量浓度为1％碘佛醇造影剂溶液中，磁力搅拌0.5h后滴加1g TPP，得到溶液；将其中得到的溶液以8000r/min的转速离心10min，用蒸馏水洗涤3次，冷冻干燥24h后即得PLA复合载药微球粉末产品。所得产品的平均粒径大小、载药率及包封率见表1。Dissolve about 5g of PLA in about 40mL of dichloromethane until clear and transparent. Then add 0.25g of Span-80 and 10mg of rifampicin for ultrasonic emulsification for 30min to obtain an emulsion; the obtained emulsion is poured into 400mL concentration of 1% PVA (polyvinyl alcohol) aqueous solution, with a rotating speed of 5000r/min Shear and disperse in a high-speed shear emulsifier for 3 minutes to obtain an oil-in-water (O/W) emulsion; magnetically stir the obtained (O/W) emulsion at room temperature, and simultaneously add 5 g of ioversol with a concentration of 1% for imaging After 0.5h, add 1g of sodium tripolyphosphate (TPP) dropwise, and then continue to stir for 3h to completely volatilize the organic solvent, solidify and form the microspheres, and obtain PLA two-layer composite drug-loaded microspheres; place them in 40mL dissolved In a dichloromethane solution of 5g PLA, ultrasonically oscillate for 30min at 25°C, then centrifuge and wash to obtain a three-layer composite drug-loaded microsphere, which is added to 5g of 1% ioversol contrast medium solution, and stirred magnetically for 0.5h 1 g of TPP was added dropwise to obtain a solution; the obtained solution was centrifuged at a speed of 8000 r/min for 10 min, washed 3 times with distilled water, and freeze-dried for 24 h to obtain the PLA composite drug-loaded microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in Table 1.

实施例2Example 2

取大约5g PLA溶于大约40mL二氯甲烷中，直至澄清透明。再加入0.25g的司盘-80以及10mg的利福平超声乳化30min，得到乳液；将得到的乳液倒入400mL体积浓度为1％的PVA(聚乙烯醇)水溶液中，以转速为5000r/min在高速剪切乳化机中剪切分散3min，得到水包油(O/W)乳液；将得到的(O/W)乳液在室温下磁力搅拌，同时滴加5g质量浓度为1％的碘佛醇造影剂溶液，0.5h后滴加1g三聚磷酸钠(TPP)，之后持续搅拌3h，使有机溶剂完全挥发，微球固化成型，得到PLA两层复合载药；将其置于40mL溶有5g PLA的二氯甲烷溶液中，25℃下超声振荡30min后离心分离清洗，得到三层复合载药微球，将其加入10g质量浓度为1％碘佛醇造影剂溶液中，磁力搅拌0.5h后滴加1g TPP，得到溶液；将其中得到的溶液以8000r/min的转速离心10min，用蒸馏水洗涤3次，冷冻干燥24h后即得PLA复合载药微球粉末产品。所得产品的平均粒径大小、载药率及包封率见表1。Dissolve about 5g of PLA in about 40mL of dichloromethane until clear and transparent. Then add 0.25g of Span-80 and 10mg of rifampicin for ultrasonic emulsification for 30min to obtain an emulsion; the obtained emulsion is poured into 400mL of 1% PVA (polyvinyl alcohol) aqueous solution at a speed of 5000r/min Shear and disperse for 3min in a high-speed shear emulsifier to obtain an oil-in-water (O/W) emulsion; the obtained (O/W) emulsion is magnetically stirred at room temperature, and 5g of iodophor with a mass concentration of 1% is added dropwise Alcohol contrast agent solution, add 1g sodium tripolyphosphate (TPP) dropwise after 0.5h, and then continue to stir for 3h to completely volatilize the organic solvent, solidify the microspheres, and obtain PLA two-layer composite drug loading; put it in 40mL dissolved 5g of PLA in dichloromethane solution, ultrasonically oscillated for 30min at 25°C, and then centrifuged and washed to obtain a three-layer composite drug-loaded microsphere, which was added to 10g of 1% ioversol contrast agent solution, and magnetically stirred for 0.5h Afterwards, 1 g of TPP was added dropwise to obtain a solution; the obtained solution was centrifuged at a speed of 8000 r/min for 10 min, washed 3 times with distilled water, and freeze-dried for 24 h to obtain the PLA composite drug-loaded microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in Table 1.

实施例3Example 3

取大约5g PLA溶于大约40mL二氯甲烷中，直至澄清透明。再加入0.25g的司盘-80以及10mg的利福平超声乳化30min，得到乳液；将得到的乳液倒入400mL浓度为1％的PVA(聚乙烯醇)水溶液中，以转速为5000r/min在高速剪切乳化机中剪切分散3min，得到水包油(O/W)乳液；将得到的(O/W)乳液在室温下磁力搅拌，同时滴加5g质量浓度为1％的碘佛醇造影剂溶液，0.5h后滴加1g三聚磷酸钠(TPP)，之后持续搅拌3h，使有机溶剂完全挥发，微球固化成型，得到PLA两层复合载药；将其置于40mL溶有5g PLA的二氯甲烷溶液中，25℃下超声振荡30min后离心分离清洗，得到三层复合载药微球，将其加入15g浓度为1％碘佛醇造影剂溶液中，磁力搅拌0.5h后滴加1g TPP，得到溶液；将中得到的溶液以8000r/min的转速离心10min，用蒸馏水洗涤3次，冷冻干燥24h后即得PLA复合载药微球粉末产品。所得产品的平均粒径大小、载药率及包封率见表1。Dissolve about 5g of PLA in about 40mL of dichloromethane until clear and transparent. Then add 0.25g of Span-80 and 10mg of rifampicin for ultrasonic emulsification for 30min to obtain an emulsion; the obtained emulsion is poured into 400mL concentration of 1% PVA (polyvinyl alcohol) aqueous solution, with a rotating speed of 5000r/min In a high-speed shear emulsifier, shear and disperse for 3 minutes to obtain an oil-in-water (O/W) emulsion; the obtained (O/W) emulsion is magnetically stirred at room temperature, and 5 g of ioversol with a mass concentration of 1% is added dropwise Contrast agent solution, add 1g sodium tripolyphosphate (TPP) dropwise after 0.5h, and then continue to stir for 3h to completely volatilize the organic solvent, solidify the microspheres, and obtain PLA two-layer composite drug loading; put it in 40mL and dissolve 5g In the dichloromethane solution of PLA, oscillate ultrasonically at 25°C for 30 minutes, then centrifuge and wash to obtain three-layer composite drug-loaded microspheres, which are added to 15 g of 1% ioversol contrast agent solution, magnetically stirred for 0.5 hours, and then dropped Add 1g of TPP to obtain a solution; centrifuge the solution obtained in 8000r/min for 10min, wash with distilled water for 3 times, and freeze-dry for 24h to obtain the PLA composite drug-loaded microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in Table 1.

对比例1Comparative example 1

取大约5g PLA溶于大约40mL二氯甲烷中，直至澄清透明。再加入0.25g的司盘-80以及10mg利福平超声乳化30min，得到乳液；将得到的乳液倒入400mL浓度为1％的PVA(聚乙烯醇)水溶液中，以转速为5000r/min在高速剪切乳化机中剪切分散3min，得到水包油(O/W)乳液；将得到的(O/W)乳液在室温下磁力搅拌，将得到的溶液以8000r/min的转速离心10min，用蒸馏水洗涤3次，冷冻干燥24h后即得PLA复合载药微球粉末产品。所得产品的平均粒径大小、载药率及包封率见表1。Dissolve about 5g of PLA in about 40mL of dichloromethane until clear and transparent. Then add 0.25g of Span-80 and 10mg of rifampicin for ultrasonic emulsification for 30min to obtain an emulsion; the obtained emulsion is poured into 400mL of 1% PVA (polyvinyl alcohol) aqueous solution, with a rotating speed of 5000r/min at a high speed In the shear emulsifier, shear and disperse for 3min to obtain an oil-in-water (O/W) emulsion; the obtained (O/W) emulsion is magnetically stirred at room temperature, and the obtained solution is centrifuged at a speed of 8000r/min for 10min, and the After washing with distilled water for 3 times and freeze-drying for 24 hours, the PLA composite drug-loaded microsphere powder product was obtained. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in Table 1.

对比实施例1为未加碘佛醇造影剂的载药微球的结果，以此对比加入不同碘佛醇造影剂的载药微球粒径、载药率和包封率等性能的影响。Comparative Example 1 is the result of drug-loaded microspheres without adding ioversol contrast agent, so as to compare the effects of drug-loaded microspheres with different ioversol contrast agents on particle size, drug loading rate and encapsulation efficiency.

表1载药微球的性能参数Table 1 Performance parameters of drug-loaded microspheres

平均粒径(μm)Average particle size (μm)载药率(％)Drug loading rate (%)包封率(％)Encapsulation rate (%)实施例1Example 18.8808.88018.0118.0137.0637.06实施例2Example 210.5810.5818.9718.9737.9437.94实施例3Example 329.7929.7919.9619.9639.4539.45对比例1Comparative example 15.3545.35417.3817.3835.9535.95

由表1可知，在进行载药聚乳酸微球制备的时候，随着碘佛醇造影剂含量的增加，微球粒径也随之增大，且载药率和包封率也随之增加。It can be seen from Table 1 that when the drug-loaded polylactic acid microspheres were prepared, as the content of ioversol contrast agent increased, the particle size of the microspheres also increased, and the drug loading rate and encapsulation rate also increased. .

同时申请人还发现，在表1中，对比例1与实施例1、2、3相比，未加入碘佛醇造影剂与加入碘佛醇造影剂的微球粒径较小。At the same time, the applicant also found that in Table 1, compared with Examples 1, 2, and 3 in Comparative Example 1, the particle size of microspheres without ioversol contrast agent and those with ioversol contrast agent were smaller.

从图1-3可以看出，实施例1、2、3呈球形、表面出现浅凹不平整有细孔状，随着碘佛醇造影剂的增加，小孔遍布微球表面越多，可以载更多的药量。As can be seen from Figures 1-3, Examples 1, 2, and 3 are spherical, and the surface is shallow and uneven with pores. With the increase of ioversol contrast agent, the more pores spread on the surface of the microspheres, it can be Load more doses.

从图4可以看出，对比实施例1为未加入碘佛醇造影剂微球形貌，呈球形、表面光滑、无小孔。It can be seen from Fig. 4 that Comparative Example 1 shows the appearance of microspheres without adding ioversol contrast agent, which is spherical, with smooth surface and no pores.

从图5可以看出，实施例1、2、3与对比例1相比药物释放量较慢，这足以说明，加入碘佛醇造影剂可以增加药物释放量，随着该物质的增加，药物释放量越多，这是由于它具有可示踪的作用，方便我们更加准确的定位到病灶部位，将药物释放出来，缓解疾病。而相比较于对比例1，碘佛醇造影剂的示踪作用更加显著。As can be seen from Figure 5, compared with Comparative Example 1, the amount of drug released in Examples 1, 2, and 3 is relatively slow, which is enough to illustrate that adding ioversol contrast agent can increase the amount of drug released. The higher the amount of release, this is because it has a traceable effect, so that we can more accurately locate the lesion, release the drug, and relieve the disease. Compared with Comparative Example 1, the tracer effect of ioversol contrast agent is more significant.

Claims (4)

Translated fromChinese

1.一种可示踪的聚乳酸/利福平载药微球的制备方法，其特征在于，包括以下步骤：1. a preparation method of traceable polylactic acid/rifampicin drug-loaded microspheres, is characterized in that, comprises the following steps:步骤1)：将聚乳酸溶于二氯甲烷中，直至澄清透明，然后加入司盘-80及利福平，超声乳化，得到乳液；聚乳酸、二氯甲烷、司盘-80、利福平的重量比为10:40～80:1:1～5；Step 1): Dissolve polylactic acid in dichloromethane until it is clear and transparent, then add Span-80 and rifampicin, and perform ultrasonic emulsification to obtain an emulsion; polylactic acid, dichloromethane, Span-80, rifampicin The weight ratio is 10:40～80:1:1～5;步骤2)：将得到的乳液倒入PVA水溶液中，以转速为3000-8000r/min在高速剪切乳化机中剪切分散，得到水包油乳液；PVA水溶液乳液的质量浓度为1％；乳液与PVA水溶液的重量比为1：2～10；Step 2): Pour the obtained emulsion into the PVA aqueous solution, and shear and disperse it in a high-speed shear emulsifier at a speed of 3000-8000r/min to obtain an oil-in-water emulsion; the mass concentration of the PVA aqueous solution emulsion is 1%; The weight ratio to PVA aqueous solution is 1:2~10;步骤3)：将得到的水包油乳液在室温下磁力搅拌，同时滴加碘佛醇造影剂溶液，然后滴加三聚磷酸钠，持续搅拌，使有机溶剂完全挥发，微球固化成型，得到聚乳酸两层复合载药；将其置于溶有聚乳酸的二氯甲烷溶液中，25℃下超声振荡后离心分离清洗，得到三层复合载药微球，将其加入碘佛醇造影剂溶液中，磁力搅拌后滴加TPP，得到溶液；碘佛醇造影剂溶液的质量浓度为1％；乳液与碘佛醇造影剂溶液、TPP的重量比为400：5～15：1；聚乳酸两层复合载药与聚乳酸的比例为1：10～500；三层复合载药微球与碘佛醇造影剂溶液的重量比为2：1～3，与滴加的TPP的重量比为5：1～3；Step 3): The obtained oil-in-water emulsion was magnetically stirred at room temperature, and at the same time, ioversol contrast agent solution was added dropwise, and then sodium tripolyphosphate was added dropwise, and the stirring was continued to completely volatilize the organic solvent, and the microspheres were solidified and formed to obtain Two-layer composite drug-loading of polylactic acid; place it in a dichloromethane solution dissolved in polylactic acid, ultrasonically oscillate at 25°C, and then centrifuge and wash to obtain three-layer composite drug-loaded microspheres, which are added to ioversol contrast agent In the solution, add TPP dropwise after magnetic stirring to obtain a solution; the mass concentration of the ioversol contrast agent solution is 1%; the weight ratio of the emulsion to the ioversol contrast agent solution and TPP is 400:5-15:1; polylactic acid The ratio of two-layer composite drug-loaded to polylactic acid is 1:10-500; the weight ratio of three-layer composite drug-loaded microspheres to ioversol contrast agent solution is 2:1-3, and the weight ratio to the dripped TPP is 5: 1~3;步骤4)：将得到的溶液离心，取出底部微球，用蒸馏水洗涤，冷冻干燥后即得聚乳酸/利福平载药微球。Step 4): Centrifuge the obtained solution, take out the microspheres at the bottom, wash with distilled water, and freeze-dry to obtain polylactic acid/rifampicin drug-loaded microspheres.2.如权利要求1所述的可示踪的聚乳酸/利福平载药微球的制备方法，其特征在于，所述步骤1)中聚乳酸的分子量在3～64KDa之间，采用聚左旋乳酸、聚右旋乳酸或两者的混合物；碘佛醇造影剂溶液的质量浓度为1％；乳液与碘佛醇造影剂溶液、TPP的重量比为400：5～15：1。2. the preparation method of traceable polylactic acid/rifampin drug-loaded microspheres as claimed in claim 1, is characterized in that, the molecular weight of polylactic acid in described step 1) is between 3～64KDa, adopts polylactic acid L-lactic acid, poly-D-lactic acid or a mixture of the two; the mass concentration of the ioversol contrast agent solution is 1%; the weight ratio of the emulsion to the ioversol contrast agent solution and TPP is 400:5-15:1.3.如权利要求1所述的可示踪的聚乳酸/利福平载药微球的制备方法，其特征在于，所述步骤4)中蒸馏水洗涤的次数为3-5次。3. The preparation method of traceable polylactic acid/rifampicin drug-loaded microspheres as claimed in claim 1, characterized in that, the number of times of washing with distilled water in the step 4) is 3-5 times.4.一种权利要求1-3任意一项所述的可示踪的聚乳酸/利福平载药微球的制备方法制得的可示踪的聚乳酸/利福平载药微球。4. the traceable polylactic acid/rifampicin drug-loaded microsphere that the preparation method of the traceable polylactic acid/rifampicin drug-loaded microsphere described in any one of claim 1-3 makes.

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