CN105241793B - A kind of assay method of carrier micelle form particle diameter - Google Patents
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- 238000003556 assay Methods 0.000 title claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 65
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- 239000002105 nanoparticle Substances 0.000 claims abstract description 23
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- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 238000005119 centrifugation Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 abstract description 3
- 238000000432 density-gradient centrifugation Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 238000003921 particle size analysis Methods 0.000 abstract 1
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 12
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Abstract
Description
技术领域 technical field
本发明属于载药胶束形态测定领域，涉及一种载药胶束形态粒径的测定方法，尤其涉及一种利用CPS圆盘离心式纳米粒度分析仪进行的载药胶束形态粒径的测定方法。 The invention belongs to the field of drug-loaded micelle morphology determination, and relates to a method for measuring the shape and particle size of drug-loaded micelles, in particular to a method for measuring the shape and particle size of drug-loaded micelles using a CPS disc centrifugal nanoparticle size analyzer. method.
背景技术 Background technique
聚合物胶束是纳米范围内的药物载体，与脂质体、纳米微球等药物载体相比，具有如下优势：①大分子胶束具有良好的生物相容性，胶束能够有效隔离药物与外部介质，削弱副作用较大的药物对人体的影响；②由于大分子胶束外部有亲水部分的保护，其不易与蛋白质和吞噬细胞吸附和识别，保证了其在血浆和组织中的停留时间，体内循环时间长，稳定性好；③大分子胶束具有被动靶向性，表面修饰靶向基团后具有主动靶向性；④粒径小，狭窄区能够富集渗透；⑤便于制备，保存方便。 Polymeric micelles are drug carriers in the nanometer range. Compared with liposomes, nanospheres and other drug carriers, they have the following advantages: ①Macromolecular micelles have good biocompatibility, and micelles can effectively isolate drugs and The external medium weakens the impact of drugs with large side effects on the human body; ②Because the macromolecular micelles are protected by the hydrophilic part outside, it is not easy to adsorb and recognize proteins and phagocytes, ensuring its residence time in plasma and tissues , long circulation time in vivo, good stability; ③Macromolecular micelles have passive targeting, and active targeting after surface modification of targeting groups; ④Small particle size, narrow area can be enriched and permeated; ⑤Easy to prepare, Easy to save.
胶束粒子的大小影响着其在体内的循环时间、在器官组织中的分布，进入细胞的机理以及细胞摄取动力学等等。例如，尺寸小于200nm的胶束例子比较难被RES系统清楚，而小于5μm的可以通过毛细血管，粒径在10～100nm之间的聚合物胶束能够获得足够长的循环时间，小于200nm的胶束能够通过脾脏中内皮细胞的过滤。因此，对于载药胶束形态的粒径的测定具有非常重要的意义。 The size of micellar particles affects its circulation time in the body, distribution in organs and tissues, the mechanism of entering cells, and the kinetics of cellular uptake, etc. For example, micelles with a size smaller than 200nm are difficult to be cleared by the RES system, while those smaller than 5 μm can pass through capillaries, polymer micelles with a particle size between 10 and 100 nm can obtain a sufficiently long circulation time, and micelles smaller than 200 nm The bundles are able to pass through the filtration of endothelial cells in the spleen. Therefore, it is of great significance to measure the particle size of drug-loaded micelles.
CPS圆盘离心式纳米粒度分析仪为圆盘离心式纳米粒度分析仪，采用的是差示离心沉降法进行颗粒粒度的测量和分析。CPS圆盘离心式纳米粒度分析仪 在高速旋转的离心转盘中建立起梯度溶液，之后注入待测样品，测定样品的沉降速度，根据斯多克斯定律(Stokes Law)测定样品的粒径。 CPS disc centrifugal nano particle size analyzer is a disc centrifugal nano particle size analyzer, which uses differential centrifugal sedimentation method to measure and analyze particle size. CPS Disc Centrifugal Nanoparticle Size Analyzer Establish a gradient solution in a high-speed rotating centrifugal turntable, then inject the sample to be tested, measure the sedimentation velocity of the sample, and measure the particle size of the sample according to Stokes Law.
但是，利用CPS圆盘离心式纳米粒度分析仪测定粒径时，要求待测样品大于梯度溶液密度，且具有较大的密度差，这样才能保证顺利发生沉降，测定出沉降速度。而对于载药胶束形态，密度一般较小，采用常规的CPS圆盘离心式纳米粒度分析仪无法获得其粒径大小。 However, when using the CPS disc centrifugal nanoparticle size analyzer to measure the particle size, the sample to be tested is required to be larger than the density of the gradient solution and have a large density difference, so as to ensure smooth sedimentation and determine the sedimentation velocity. For the form of drug-loaded micelles, the density is generally small, and the particle size cannot be obtained by using a conventional CPS disc centrifugal nanoparticle size analyzer.
本领域需要开发一种能够快速测定载药胶束形态粒度的方法。 There is a need in this field to develop a method capable of rapidly determining the particle size of drug-loaded micelles.
发明内容 Contents of the invention
针对现有技术的不足，本发明的目的之一在于提供一种载药胶束形态粒径的测定方法，所述方法采用常规的CPS圆盘离心式纳米粒度分析仪，即可读取载药胶束形态粒径。 In view of the deficiencies in the prior art, one of the objectives of the present invention is to provide a method for determining the particle size of the drug-loaded micelles, which can be read by using a conventional CPS disc centrifugal nanoparticle size analyzer. Micellar morphology particle size.
本发明具体通过如下技术方案实现： The present invention is specifically realized through the following technical solutions:
一种载药胶束形态粒径的测定方法包括如下步骤： A method for measuring the particle size of drug-loaded micelles comprises the following steps:
(1)配制氯化铯梯度溶液，所述氯化铯梯度溶液的平均密度为ρp；向CPS圆盘离心式纳米粒度分析仪的低密度扩展盘由高浓度向低浓度依次注入氯化铯梯度溶液，建立梯度； (1) prepare cesium chloride gradient solution, the average density of described cesium chloride gradient solution is ρ p ; To the low-density extension plate of CPS disc centrifugal nano particle size analyzer, inject cesium chloride successively from high concentration to low concentration Gradient solution, build gradient;
(2)待梯度溶液梯度稳定后，将待测载药胶束溶液从低密度扩展盘边缘上样至CPS离心粒度仪，测定待测载药胶束的沉降速率，获得载药胶束的形态粒径； (2) After the gradient of the gradient solution is stable, load the drug-loaded micelle solution to be tested from the edge of the low-density expansion plate to the CPS centrifugal particle size analyzer, measure the sedimentation rate of the drug-loaded micelles to obtain the shape of the drug-loaded micelles Particle size;
其中，所述氯化铯梯度溶液的最低密度大于载药胶束密度。 Wherein, the lowest density of the cesium chloride gradient solution is greater than the density of the drug-loaded micelles.
本发明通过改变载药胶束的上样位置，获得了载药胶束在梯度溶液中的沉降速度，进而得到载药胶束的形态粒径。 In the present invention, by changing the loading position of the drug-loaded micelles, the sedimentation velocity of the drug-loaded micelles in the gradient solution is obtained, and then the shape particle size of the drug-loaded micelles is obtained.
本发明所述氯化铯梯度溶液的平均密度为1.1～1.5g/mL，例如1.2g/mL、1.3g/mL、1.4g/mL等，优选1.25g/mL。平均密度太大，会降低测试粒径的分辨率；若平均密度太小，则测试时间会太长。 The average density of the cesium chloride gradient solution of the present invention is 1.1-1.5 g/mL, such as 1.2 g/mL, 1.3 g/mL, 1.4 g/mL, etc., preferably 1.25 g/mL. If the average density is too large, the resolution of the test particle size will be reduced; if the average density is too small, the test time will be too long.
本发明所述氯化铯梯度溶液的梯度个数为7～11，例如8、9、10，优选9。 The gradient number of the cesium chloride gradient solution in the present invention is 7-11, such as 8, 9, 10, preferably 9.
本发明所述待测载药胶束的密度为ρs，ρp-ρs≥0.1g/mL。0.1g/mL以上的密度差，在高速离心过程中，能够有效实现载药胶束的运动轨迹的测定。 The density of the drug-loaded micelles to be tested in the present invention is ρ s , ρ p -ρ s ≥ 0.1 g/mL. The density difference above 0.1g/mL can effectively realize the determination of the trajectory of drug-loaded micelles during high-speed centrifugation.
本发明所述待测载药胶束溶液的浓度为1.25～100mg/mL，例如1.5mg/mL、8mg/mL、25mg/mL、40mg/mL、530mg/mL、60mg/mL、70mg/mL、85mg/mL、90mg/mL等。 The concentration of the drug-loaded micelle solution to be tested in the present invention is 1.25 to 100 mg/mL, such as 1.5 mg/mL, 8 mg/mL, 25 mg/mL, 40 mg/mL, 530 mg/mL, 60 mg/mL, 70 mg/mL, 85mg/mL, 90mg/mL, etc.
本发明所述CPS圆盘离心式纳米粒度分析仪的转速≥20000转/min，例如25000转/min、28000转/min、30000转/min、33000转/min等。转速太小，对于测试小粒径的胶束来说，会大大增加测试时间。 The rotation speed of the CPS disc centrifugal nanoparticle size analyzer of the present invention is ≥20000 rpm, such as 25000 rpm, 28000 rpm, 30000 rpm, 33000 rpm, etc. If the rotation speed is too small, the test time will be greatly increased for micelles with small particle size.
本发明所述CPS圆盘离心式纳米粒度分析仪的离心时间≥30min，例如35min、42min、50min、65min等。所述离心时间根据待测载药胶束密度和梯度溶液平均密度的差值增大而缩短，此外，加大离心转速，会缩短测试时间。 The centrifugation time of the CPS disc centrifugal nano particle size analyzer of the present invention is more than or equal to 30 minutes, such as 35 minutes, 42 minutes, 50 minutes, 65 minutes and the like. The centrifugation time is shortened according to the increase of the difference between the density of the drug-loaded micelles to be tested and the average density of the gradient solution. In addition, increasing the centrifugation speed will shorten the test time.
本发明步骤(2)所述上样量为90～110μL，例如93μL、96μL、99μL、103μL、108μL等，优选100μL。 The loading amount in step (2) of the present invention is 90-110 μL, such as 93 μL, 96 μL, 99 μL, 103 μL, 108 μL, etc., preferably 100 μL.
作为优选技术方案，本发明所述一种载药胶束形态粒径的测定方法包括如下步骤： As a preferred technical solution, a method for determining the particle size of a drug-loaded micelle according to the present invention comprises the following steps:
(1)配制氯化铯梯度溶液，所述氯化铯梯度溶液的平均密度为ρp为1.25g/mL，所述梯度为9层；向CPS圆盘离心式纳米粒度分析仪的低密度扩张盘由高浓度向低浓度依次注入氯化铯梯度溶液，建立梯度； (1) preparation cesium chloride gradient solution, the average density of described cesium chloride gradient solution is that p is 1.25g/mL, and described gradient is 9 layers; To the low density expansion of CPS disc centrifugal nanoparticle size analyzer The plate is sequentially injected with cesium chloride gradient solution from high concentration to low concentration to establish a gradient;
(2)待梯度溶液梯度稳定后，将待测载药胶束溶液从低密度扩张盘边缘上样至CPS圆盘离心式纳米粒度分析仪，上样量为100μL，测定待测载药胶束的沉降速率，获得载药胶束的形态粒径；所述CPS圆盘离心式纳米粒度分析仪的转速≥20000转/min，所述CPS圆盘离心式纳米粒度分析仪的离心时间≥30min。 (2) After the gradient of the gradient solution is stable, load the drug-loaded micelle solution to be tested from the edge of the low-density expansion disc to the CPS disc centrifugal nanoparticle size analyzer, with a sample volume of 100 μL, and measure the drug-loaded micelles to be tested. The settling rate of the drug-loaded micelles is obtained by obtaining the particle size of the drug-loaded micelles; the rotating speed of the CPS disc centrifugal nano particle size analyzer is ≥ 20000 rpm, and the centrifugation time of the CPS disc centrifugal nano particle size analyzer is ≥ 30min.
与现有技术相比，本发明具有如下有益效果： Compared with the prior art, the present invention has the following beneficial effects:
本发明采用密度梯度离心法测试载药胶束的形态粒径，通过改变转速和梯度液浓度，克服载药胶束密度小的缺点，准确测试出载药胶束的形态粒径，检测下限为5nm，检测上限为70nm，测定偏差在0.6±0.01％。 The present invention adopts the density gradient centrifugation method to test the particle size of drug-loaded micelles, and overcomes the shortcoming of low density of drug-loaded micelles by changing the rotational speed and gradient liquid concentration, and accurately tests the shape particle size of drug-loaded micelles. The lower limit of detection is 5nm, the detection limit is 70nm, and the measurement deviation is 0.6±0.01%.
附图说明 Description of drawings
图1是本发明实施例1提供的DSPE-PEG载药胶束的粒径； Fig. 1 is the particle size of the DSPE-PEG drug-loaded micelles provided by Example 1 of the present invention;
图2是本发明实施例2提供的DSPE-PEG载药胶束的粒径； Fig. 2 is the particle diameter of the DSPE-PEG drug-loaded micelles provided by Example 2 of the present invention;
图3是本发明实施例3提供的DSPE-PEG载药胶束的粒径。 Figure 3 is the particle size of the DSPE-PEG drug-loaded micelles provided in Example 3 of the present invention.
具体实施方式 detailed description
为便于理解本发明，本发明列举实施例如下。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。 In order to facilitate understanding of the present invention, the present invention enumerates the following examples. It should be clear to those skilled in the art that the embodiments are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention.
制备例1 Preparation Example 1
DSPE-PEG载药胶束的制备，包括如下步骤： The preparation of DSPE-PEG drug-loaded micelles comprises the following steps:
先取DSPE-PEG(磷脂酰乙醇胺-聚乙二醇)试剂一定量在水相中并加入少量葡萄糖作为稳定剂，使DSPE-PEG形成胶束，然后加入疏水性药物阿霉素，不断搅拌直至溶液澄清，即形成包覆阿霉素药物的载药胶束。 First take a certain amount of DSPE-PEG (phosphatidylethanolamine-polyethylene glycol) reagent in the water phase and add a small amount of glucose as a stabilizer to make DSPE-PEG form micelles, then add the hydrophobic drug doxorubicin, and keep stirring until the solution Clarification, that is, the formation of drug-loaded micelles coated with doxorubicin drug.
制备例2 Preparation example 2
DSPE-PEG载药胶束的制备，包括如下步骤： The preparation of DSPE-PEG drug-loaded micelles comprises the following steps:
先取DSPE-PEG(磷脂酰乙醇胺-聚乙二醇)试剂一定量在水相中并加入少量葡萄糖作为稳定剂，使DSPE-PEG形成胶束，然后加入药物盐酸伊立替康，不断搅拌直至溶液澄清，即形成包覆盐酸伊立替康药物的载药胶束。 First take a certain amount of DSPE-PEG (phosphatidylethanolamine-polyethylene glycol) reagent in the water phase and add a small amount of glucose as a stabilizer to make DSPE-PEG form micelles, then add the drug irinotecan hydrochloride, and keep stirring until the solution is clear , that is, to form drug-loaded micelles coated with irinotecan hydrochloride.
制备例3 Preparation example 3
DSPE-PEG载药胶束的制备，包括如下步骤： The preparation of DSPE-PEG drug-loaded micelles comprises the following steps:
先取DSPE-PEG(磷脂酰乙醇胺-聚乙二醇)试剂一定量在水相中并加入少量葡萄糖作为稳定剂，使DSPE-PEG形成胶束，然后加入药物氟比洛芬，不断搅拌直至溶液澄清，即形成包覆氟比洛芬药物的载药胶束。 First take a certain amount of DSPE-PEG (phosphatidylethanolamine-polyethylene glycol) reagent in the water phase and add a small amount of glucose as a stabilizer to make DSPE-PEG form micelles, then add the drug flurbiprofen, and keep stirring until the solution is clear , that is, to form drug-loaded micelles coated with flurbiprofen drug.
实施例1 Example 1
制备例1提供的DSPE-PEG载药阿霉素胶束的粒径的测定方法包括如下步骤： The assay method of the particle diameter of the DSPE-PEG drug-loaded doxorubicin micelles that preparation example 1 provides comprises the steps:
(1)配制氯化铯梯度溶液，所述氯化铯梯度溶液的平均密度为ρp为1.25g/mL，所述梯度为9层；向CPS圆盘离心式纳米粒度分析仪的低密度扩张盘由高浓度向低浓度依次注入氯化铯梯度溶液，建立梯度； (1) preparation cesium chloride gradient solution, the average density of described cesium chloride gradient solution is that p is 1.25g/mL, and described gradient is 9 layers; To the low density expansion of CPS disc centrifugal nanoparticle size analyzer The plate is sequentially injected with cesium chloride gradient solution from high concentration to low concentration to establish a gradient;
(2)待梯度溶液梯度稳定后，将制备例1制备的待测包覆阿霉素药物的载药胶束溶液从低密度扩张盘边缘上样至CPS圆盘离心式纳米粒度分析仪，上样量为100μL，测定待测载药胶束的沉降速率，获得载药胶束的形态粒径，测得包覆阿霉素药物的载药胶束平均粒径为15.68nm，重复测试偏差约0.6％。所述CPS圆盘离心式纳米粒度分析仪的转速≥20000转/min，所述CPS圆盘离心式纳米粒度分析仪的离心时间≥30min。 (2) After the gradient of the gradient solution is stable, load the drug-loaded micelle solution prepared in Preparation Example 1 coated with doxorubicin from the edge of the low-density expansion disc to the CPS disc centrifugal nanoparticle size analyzer, and The sample volume was 100 μL, and the sedimentation rate of the drug-loaded micelles to be tested was measured to obtain the particle size of the drug-loaded micelles. 0.6%. The rotational speed of the CPS disc centrifugal nano particle size analyzer is ≥ 20000 rpm, and the centrifugation time of the CPS disc centrifugal nano particle size analyzer is ≥ 30 min.
实施例2 Example 2
制备例2提供的DSPE-PEG载药盐酸伊立替康胶束的粒径的测定方法，与实施例1的区别仅在于将“制备例1制备的待测包覆阿霉素药物的载药胶束”替换为“制备例2制备的待测包覆盐酸伊立替康药物的载药胶束”；经测定，制备例2制备的包覆盐酸伊立替康药物的载药胶束平均粒径为14.32nm，重复测试偏差约0.6％。 The assay method of the particle size of the DSPE-PEG drug-loaded irinotecan hydrochloride micelles provided in Preparation Example 2 is only different from that of Example 1 in that the drug-loaded gel coated with Adriamycin drug to be tested prepared in Preparation Example 1 Bundle" is replaced by "the drug-loaded micelles of the coating irinotecan hydrochloride drug to be tested prepared in preparation example 2"; after determination, the average particle diameter of the drug-loaded micelles of the coating irinotecan hydrochloride drug prepared in preparation example 2 is 14.32nm, the repeated test deviation is about 0.6%.
实施例3 Example 3
制备例3提供的DSPE-PEG载药氟比洛芬胶束的粒径的测定方法，与实施例1的区别仅在于将“制备例1制备的待测包覆阿霉素药物的载药胶束”替换为“制备例3制备的待测包覆氟比洛芬药物的载药胶束”；经测定，制备例3制备的待测包覆氟比洛芬药物的载药胶束平均粒径为12.89nm，重复测试偏差约0.6％。 The assay method of the particle size of the DSPE-PEG drug-loaded flurbiprofen micelles provided in Preparation Example 3 differs from Example 1 only in that the drug-loaded gel coated with Adriamycin drug to be tested prepared in Preparation Example 1 Bundle" is replaced by "the drug-loaded micelles of the test-coated flurbiprofen drug prepared in Preparation Example 3"; The diameter is 12.89nm, and the repeated test deviation is about 0.6%.
申请人声明，本发明通过上述实施例来说明本发明的详细工艺设备和工艺流程，但本发明并不局限于上述详细工艺设备和工艺流程，即不意味着本发明必须依赖上述详细工艺设备和工艺流程才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。 The applicant declares that the present invention illustrates the detailed process equipment and process flow of the present invention through the above-mentioned examples, but the present invention is not limited to the above-mentioned detailed process equipment and process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process equipment and process flow process can be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.
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