CN107281100A - 一种难溶性药物纳米混悬液的制备方法 - Google Patents
一种难溶性药物纳米混悬液的制备方法 Download PDFInfo
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- CN107281100A CN107281100A CN201610192782.2A CN201610192782A CN107281100A CN 107281100 A CN107281100 A CN 107281100A CN 201610192782 A CN201610192782 A CN 201610192782A CN 107281100 A CN107281100 A CN 107281100A
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Abstract
本发明公开了一种难溶性药物纳米混悬液的制备方法,包括以下步骤:(1)将难溶性药物分散在含有稳定剂的水溶液中,得初悬液;所述的难溶性药物与所述的稳定剂的质量比为2.5:1~8:1;(2)将步骤(1)制得的初悬液经过高速剪切,得粗悬液;(3)将步骤(2)制得的粗悬液经微射流高压均质,得到所述的难溶性药物纳米混悬液;所述的难溶性药物纳米混悬液中的药物浓度为150~300mg/mL。本发明所述制备方法中,没有有机溶剂的使用,制备工艺简单,重现性好,安全性好;且制得的难溶性药物纳米混悬液中,药物浓度可达到150~300mg/mL,药物粒径小,分布均一。
Description
技术领域
本发明涉及一种难溶性药物纳米混悬液的制备方法。
背景技术
前药指的是一类在体内活性很小或无活性,但在体内经过酶或者非酶作用,释放出药理活性成分而发挥药效的化合物。例如棕榈酸帕潘立酮,是一种非典型抗精神病药,主要用于治疗精神分裂症和两极狂躁症,是由活性成分帕潘立酮与棕榈酸酯化而成,具有极低的溶解度。因此可将其制备成一种储库型制剂,使其进入体内后缓慢水解产生帕潘立酮而发挥药效,可维持稳定血药浓度而降低毒副作用。
药物纳米混悬液,是仅由药物和少量稳定剂组成的稳定的胶体分散体系,通常粒径在10至1000nm,该剂型解决了难溶性药物体内吸收差的问题。根据Noyes-Whitey和Freundlich-Ostwald方程,降低药物粒径至纳米级,可显著增加药物饱和溶解度和溶出速率,从而提高药物生物利用度。当前已市售药物纳米混悬液有甲地孕酮口服混悬液和棕榈酸帕潘立酮肌肉注射混悬液等,还有目前处于临床研究阶段的药物纳米混悬液有紫杉醇静脉注射混悬液、胰岛素和磷酸钙口服混悬液等等。
当前,制备难溶性药物纳米混悬液的方法主要分为两大类,(1)自上而下法,包括介质研磨法、高压均质法等;(2)自下而上法,包括乳化法、纳米沉淀法等。
目前市售难溶性药物纳米混悬液使用的制备方法主要为介质研磨法,主要是通过研磨杆带动研磨介质产生巨大的机械力,使药物分子与研磨介质相互作用而达到减小粒径的目的。介质研磨法需要调整的参数较多主要包括研磨介质大小和装量、研磨转速和时间、流量和温度等;但随着药物颗粒粒径的减小,颗粒间的范德华力也迅速增大,同时还吸收了大量的机械能,颗粒处于极不稳定状态,极易团聚,尤其是在药物浓度较高的情况下,团聚现象会更加明显。专利CN101932327A公开了一种使用球磨法制备长效用帕潘立酮酯的方法,所需控制的工艺参数较多,包括研磨介质装量,研磨介质粒径,物料搅拌速度,轴转速,循环流量,研磨时间、温度等,制备过程复杂。
专利CN104546728A公开了一种使用乳化蒸发法制备难溶性药物的纳米晶体,制备过程中有机溶剂,如二氯甲烷和三氯甲烷的使用可能会造成产品污染。
高压均质法根据作用原理的不同,又可分为微射流技术和活塞-狭缝均质技术。微射流技术,是在高压条件下,将药物分子高速喷射进入Y型或Z型碰撞腔内,利用颗粒间的碰撞力、摩擦力、空穴效应和剪切力的共同作用,达到粒径减小的目的,从而获得药物纳米混悬液。活塞-狭缝均质技术是药物混悬液由柱塞泵吸入后,在一定压力下通过狭窄的限流缝隙,由于横切面积骤减,导致流过狭缝的液体压力骤增,静压力降低至室温下液体沸腾所需的蒸汽压,产生大量气泡,当气泡离开狭缝后受环境大气压作用而发生破裂,由此使药物颗粒粉碎,采用该法制备混悬液药物浓度一般低于100mg/mL,以避免浓度过高导致狭缝堵塞。
药物纳米混悬液仅由药物和少量稳定剂组成,无需载体,辅料用量少,而高浓度的药物纳米混悬液可减少给药体积,安全性较高,对于经肌肉、皮下或皮内等需小体积注射给药的药物,该剂型具有显著优势。专利CN101932327A公开的经介质研磨法制备得到的棕榈酸帕潘立酮混悬剂中的药物浓度最高达到了156mg/mL,不仅制备工艺复杂,而且如果进一步提高药物浓度,很可能会发生团聚现象,使得纳米混悬液不稳定,影响药效,降低了药物的安全性。现有采用高压均质法制备药物纳米混悬液的报道中,药物浓度基本在100mg/mL以下,不能够满足注射给药(尤其是肌肉注等)减少用药体积的要求。
发明内容
本发明所要解决的技术问题是为了克服现有难溶性药物纳米混悬液中药物浓度不高,且其制备工艺复杂等问题,而提供了一种难溶性药物纳米混悬液的制备方法。本发明所述的难溶性药物纳米混悬液的制备方法中,没有有机溶剂的使用,制备工艺简单,重现性好,安全性好;且制得的难溶性药物纳米混悬液中,药物浓度可达到150~300mg/mL,药物粒径小,分布均一。
本发明提供了一种药物纳米混悬液的制备方法,包括以下步骤:
(1)将难溶性药物分散在含有稳定剂的水溶液中,得初悬液;所述的难溶性药物与所述的稳定剂的质量比为2.5:1~8:1;
(2)将步骤(1)制得的初悬液经过高速剪切,得粗悬液;
(3)将步骤(2)制得的粗悬液经微射流高压均质,得到所述的难溶性药物纳米混悬液;
所述的难溶性药物纳米混悬液中的药物浓度为150~300mg/mL;
所述的稳定剂为表面活性剂,或表面活性剂和高分子助悬剂的质量比为4:1~0.25:1的稳定剂。
本发明所述的难溶性药物是指生物药剂学分类系统(BCS)中的Ⅱ类(低溶解度,高渗透性)和Ⅵ类(低溶解度、低渗透性)药物;所述的难溶性药物可以是药物本身难溶的难溶性药物,或是前药范畴的难溶性药物(所述的前药范畴的难溶性药物一般指药物活性成分经酯化后难溶。本发明所述的难溶性药物可为紫杉烷类抗癌药(如多希紫杉醇)、帕潘立酮棕榈酸酯、伊曲康唑、阿奇霉素、西罗莫司、阿瑞吡坦、螺内酯、地塞米松、两性霉素B、泊那替尼、黄芩苷、齐墩果酸、姜黄素二葵酸酯或长效核黄素等。
本发明所述的微射流高压均质为本领域常规的微射流技术实现高压均质,一般指在高压条件下,将药物分子高速喷射进入Y型或Z型碰撞腔内,利用颗粒间的碰撞力、摩擦力、空穴效应和剪切力的共同作用,达到粒径减小的目的,从而获得药物纳米混悬液。所述的微射流高压均质机优选美国NanoDeBEE微射流高压均质机。
本发明中所述的难溶性药物纳米混悬液中的药物浓度为所述的难溶性药物与所述的水的质量体积比,优选234~250mg/mL。
步骤(1)中,所述的表面活性剂的种类可以参照本领域的常规进行选择,本发明优选卵磷脂、十二烷基磺酸钠、吐温类表面活性剂,司盘类表面活性剂、脂肪酸甘油酯和脱氧胆酸钠中的一种或者多种。所述的吐温类表面活性剂优选吐温-20、吐温-40、吐温-60和吐温-80中的一种或者多种。所述的司盘类表面活性剂优选司盘-20、司盘-40、司盘-60和司盘-80中的一种或者多种。所述的高分子助悬剂的种类可以参照本领域的常规进行选择,本发明优选聚乙二醇类高分子助悬剂、聚乙烯吡咯烷酮和纤维素类高分子助悬剂中的一种或者多种。所述的纤维素类高分子助悬剂的种类可以参照本领域的常规进行选择,例如羧甲基纤维素钠和/或羟丙甲基纤维素;所述的聚乙二醇类高分子助悬剂的种类可以参照本领域的常规进行选择,本发明优选PEG6000和/或PEG4000。所述的聚乙烯吡咯烷酮优选聚乙烯吡咯烷酮-K30。当所述的稳定剂为表面活性剂和高分子助悬剂的质量比为4:1~0.25:1的稳定剂时,所述的稳定剂优选为所述的表面活性剂与所述的高分子助悬剂的质量比为2:1~0.5:1的稳定剂。
步骤(1)中,所述的难溶性药物与所述的稳定剂的质量比优选为6:1~3:1(例如4:1)。
步骤(1)中,所述的水为本领域中常规使用的水,一般为注射用水。所述的注射用水一般指蒸馏水或去离子水经蒸馏所得的水,又称重蒸馏水。
步骤(2)中,在制备药物纳米混悬液领域中,所述的高速剪切本领域技术人员均知晓一般是指采用高剪切分散机对初悬液进行分散,对团聚的颗粒进行初步的解团聚,以满足微射流高压均质机的粒径范围要求,本领域中所述的微射流高压均质的粒径范围一般要求为5~30μm(如20μm);本领域中所述的高速剪切的转速一般为10000~30000rpm,本申请优选22000rpm。本发明中所述的高速剪切的时间优选10~30分钟,更优选15~20分钟。所述的高速剪切的温度可参照本领域的常规进行选择,一般为0~10℃。本发明所述的高速剪切优选在冰水浴中进行。本申请可使用美国Fluko F25高剪切分散机进行所述的高速剪切。
步骤(3)中,所述的微射流高压均质的条件可以根据制备得到的难溶性药物纳米混悬液中的药物粒径进行选择,本申请优选如下:所述的微射流高压均质的压力为22000~35000psi,更优选30000~35000psi;所述的微射流高压均质的循环次数优选15~30次,更优选20~24次;所述的难溶性药物纳米混悬液的药物粒径D50优选400~700纳米(例如500或600纳米)。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明所述的难溶性药物纳米混悬液的制备方法中没有有机溶剂使用,制备工艺简单,重现性好,安全性高;且制得的难溶性药物纳米混悬液中,药物浓度可达到150~300mg/mL(例如234或250mg/mL),药物粒径小(D50可为400~700纳米),分布均一。
附图说明
图1为实施例1中棕榈酸帕潘立酮原料药粉末的粒径分布图。
图2为实施例1中棕榈酸帕潘立酮纳米混悬液的粒径分布图。
图3为实施例2中棕榈酸帕潘立酮纳米混悬液的粒径分布图。
图4为实施例3中姜黄素二葵酸酯纳米混悬液的粒径分布图。
图5为实施例4中姜黄素二葵酸酯纳米混悬液的粒径分布图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例中均使用美国Nano DeBEE微射流高压均质机,进行高压均质;使用美国Fluko F25高剪切分散机进行高速剪切。
下述实施例中的药物浓度为难溶性药物的质量(mg)与注射用水的体积的(mL)比值。
实施例1棕榈酸帕潘立酮纳米混悬液的制备:
(1)将2.4g吐温-20和1.5g PEG4000分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将23.4g棕榈酸帕潘立酮分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为234mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切20分钟,得到棕榈酸帕潘立酮的粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,均质压力30000psi,循环次数20次,得到最终产品棕榈酸帕潘立酮纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定棕榈酸帕潘立酮原料药粉末D50为14.8μm(粒度分布如图1所示)和棕榈酸帕潘立酮纳米混悬液中的药物粒径D50为675nm(粒度分布如图2所示),且放置24小时后药物粒径D50几乎没有改变。
实施例2棕榈酸帕潘立酮纳米混悬液的制备:
(1)将2g卵磷脂和8g聚乙烯吡咯烷酮-K30(PVP-K30)分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将25g棕榈酸帕潘立酮分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为250mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切20分钟,得到棕榈酸帕潘立酮的粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,均质压力22000psi,循环次数30次,得到最终产品棕榈酸帕潘立酮纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定棕榈酸帕潘立酮纳米混悬液中的药物粒径D50为434nm(粒度分布如图3所示),且放置24小时后药物粒径D50几乎没有改变。
实施例3姜黄素二葵酸酯纳米混悬液的制备:
(1)将3g吐温-80和0.75g十二烷基磺酸钠分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将30g姜黄素二葵酸酯分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为300mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切30分钟,得到D50为20μm的姜黄素二葵酸酯粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,均质压力35000psi,循环次数15次,得到最终产品姜黄素二葵酸酯纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定姜黄素二葵酸酯纳米混悬液中的药物粒径D50为518nm(粒度分布如图4所示),且放置24小时后药物粒径D50几乎没有改变。
实施例4姜黄素二葵酸酯纳米混悬液的制备:
(1)将7.5g吐温-20分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将30g姜黄素二葵酸酯分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为300mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切30分钟,得到D50为20μm的姜黄素二葵酸酯粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,均质压力30000psi,循环次数20次,得到最终产品姜黄素二葵酸酯纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定姜黄素二葵酸酯纳米混悬液中的药物粒径D50为650nm(粒度分布图如图5所示),且放置24小时后药物粒径D50几乎没有改变。
对比实施例1
(1)将2.4g吐温-20和1.5g PEG4000分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将23.4g棕榈酸帕潘立酮分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为234mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切20分钟,得到棕榈酸帕潘立酮的粗悬液。
(4)将步骤(3)获得的粗悬液,进行研磨,研磨介质为0.8mm的氧化锆珠,装填量为80%(即研磨介质的体积占研磨腔体的80%),研磨杆转速为4000rpm,研磨20min。
用Malvern Mastersizer 3000激光粒度仪测得的D50为630nm,放置24小时后测得的粒径D50为1521nm,50%功率超声30s后测定D50减小至685nm,说明药物颗粒间发生了团聚现象。因此,采用介质研磨法制备药物纳米混悬液时,若药物浓度太高,随着药物颗粒粒径的减小,颗粒间的范德华力也迅速增大,同时还吸收了大量的机械能,颗粒处于极不稳定状态,极易团聚,使得制备得到的药物纳米混悬液极其不稳定。
对比实施例2
(1)将1.2g吐温-20分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将23.4g棕榈酸帕潘立酮分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为234mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切20分钟,得到棕榈酸帕潘立酮的粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,均质压力40000psi,循环次数分别20次、30次、40次,得到棕榈酸帕潘立酮纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定均质20次、25次、30次的棕榈酸帕潘立酮纳米混悬液中的药物粒径D50分别为1320nm、1310nm、1380nm,且放置24小时后药物粒径D50几乎没有改变。
对比实施例2说明,当稳定剂的用量过少时,即使在更高均质压力下,粒径也无法再出现减小。
对比实施例3
(1)将1.2g吐温-20和10g PEG6000分散在100mL的注射用水中,得到含稳定剂的分散介质。
(2)将23.4g棕榈酸帕潘立酮分散在步骤(1)中的含稳定剂的分散介质中,得到药物浓度为234mg/mL的初悬液。
(3)将步骤(2)中获得的初悬液在冰水浴中以22000rpm高速剪切10分钟,得到棕榈酸帕潘立酮的粗悬液。
(4)将步骤(3)获得的粗悬液,进行微射流高压均质,分别以均质压力20000psi、3000psi和40000psi各均质35次,得到棕榈酸帕潘立酮纳米混悬液。
使用Malvern Mastersizer 3000激光粒度仪分别测定20000psi、30000psi、40000psi压力下均质得到的棕榈酸帕潘立酮纳米混悬液中的药物粒径D50分别为2990nm、1670nm和1040nm,且放置24小时后药物粒径D50几乎没有改变。
Claims (10)
1.一种难溶性药物纳米混悬液的制备方法,其特征在于,包括以下步骤:
(1)将难溶性药物分散在含有稳定剂的水溶液中,得初悬液;所述的难溶性药物与所述的稳定剂的质量比为2.5:1~8:1;
(2)将步骤(1)制得的初悬液经过高速剪切,得粗悬液;
(3)将步骤(2)制得的粗悬液经微射流高压均质,得到所述的难溶性药物纳米混悬液;
所述的难溶性药物纳米混悬液中的药物浓度为150~300mg/mL;
所述的稳定剂为表面活性剂,或表面活性剂和高分子助悬剂的质量比为4:1~0.25:1的稳定剂。
2.如权利要求1所述的制备方法,其特征在于:
所述的难溶性药物为紫杉烷类抗癌药、帕潘立酮棕榈酸酯、伊曲康唑、阿奇霉素、西罗莫司、阿瑞吡坦、螺内酯、地塞米松、两性霉素B、泊那替尼、黄芩苷、齐墩果酸、姜黄素二葵酸酯或长效核黄素;所述的紫杉烷类抗癌药优选多希紫杉醇。
3.如权利要求1所述的制备方法,其特征在于:
所述的难溶性药物纳米混悬液中的药物浓度为234~250mg/mL。
4.如权利要求1所述的制备方法,其特征在于:
所述的表面活性剂为卵磷脂、十二烷基磺酸钠、吐温类表面活性剂,司盘类表面活性剂、脂肪酸甘油酯和脱氧胆酸钠中的一种或者多种;所述的吐温类表面活性剂优选吐温-20、吐温-40、吐温-60和吐温-80中的一种或者多种;所述的司盘类表面活性剂优选司盘-20、司盘-40、司盘-60和司盘-80中的一种或者多种;
和/或,所述的高分子助悬剂为聚乙二醇类高分子助悬剂、聚乙烯吡咯烷酮和纤维素类高分子助悬剂中的一种或者多种;所述的聚乙二醇类高分子助悬剂优选PEG6000和/或PEG4000;所述的纤维素类高分子助悬剂优选羧甲基纤维素钠和/或羟丙甲基纤维素;所述的聚乙烯吡咯烷酮优选聚乙烯吡咯烷酮-K30。
5.如权利要求1或4所述的制备方法,其特征在于:所述的稳定剂为所述的表面活性剂与所述的高分子助悬剂的质量比为2:1~0.5:1的稳定剂。
6.如权利要求1所述的制备方法,其特征在于:所述的难溶性药物与所述的稳定剂的质量比为6:1~3:1。
7.如权利要求6所述的制备方法,其特征在于,所述的难溶性药物与所述的稳定剂的质量比为4:1。
8.如权利要求1所述的制备方法,其特征在于,步骤(2)中:
所述的高速剪切的时间为10~30分钟,优选15~20分钟;
和/或,所述的高速剪切的转速为10000~30000rpm,优选22000rpm;
和/或,所述的高速剪切的温度为0~10℃。
9.如权利要求1所述的制备方法,其特征在于,
所述的微射流高压均质的压力为22000~35000psi,优选30000~35000psi;
和/或,所述的微射流高压均质的循环次数为15~30次,更优选20~24次。
10.如权利要求1所述的制备方法,其特征在于,所述的难溶性药物纳米混悬液的药物粒径D50为400~700纳米,优选500~600纳米。
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CN108175748A (zh) * | 2017-12-07 | 2018-06-19 | 国家纳米科学中心 | 一种难溶性药物的纳米颗粒及其制备方法与应用 |
CN108175748B (zh) * | 2017-12-07 | 2020-07-10 | 国家纳米科学中心 | 一种难溶性药物的纳米颗粒及其制备方法与应用 |
CN108175752A (zh) * | 2018-01-24 | 2018-06-19 | 广州中医药大学(广州中医药研究院) | 灯盏花素纳米颗粒及其制备方法 |
CN108175752B (zh) * | 2018-01-24 | 2021-01-15 | 广州中医药大学(广州中医药研究院) | 灯盏花素纳米颗粒及其制备方法 |
CN108653206A (zh) * | 2018-06-14 | 2018-10-16 | 中国药科大学 | 一种黄芩素纳米混悬剂及其制备方法 |
CN108653206B (zh) * | 2018-06-14 | 2020-04-07 | 中国药科大学 | 一种黄芩素纳米混悬剂及其制备方法 |
CN109846821A (zh) * | 2019-01-03 | 2019-06-07 | 昆药集团股份有限公司 | 一种蒿甲醚纳米制剂及其制备方法 |
CN109846821B (zh) * | 2019-01-03 | 2021-07-06 | 昆药集团股份有限公司 | 一种蒿甲醚纳米制剂及其制备方法 |
CN110044780A (zh) * | 2019-05-05 | 2019-07-23 | 深圳万乐药业有限公司 | 一种利奈唑胺原料药粒径及粒度分布的测试方法 |
CN110279659A (zh) * | 2019-07-08 | 2019-09-27 | 华裕(无锡)制药有限公司 | 棕榈酸帕利哌酮制剂及其制备方法 |
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CN113521001A (zh) * | 2020-04-15 | 2021-10-22 | 江苏长泰药业有限公司 | 一种含地塞米松的混悬剂的制备方法 |
CN111658610A (zh) * | 2020-07-31 | 2020-09-15 | 上海方予健康医药科技有限公司 | 一种供雾化器用的三氮唑类抗真菌药物的混悬液 |
WO2022022657A1 (zh) * | 2020-07-31 | 2022-02-03 | 上海方予健康医药科技有限公司 | 一种供雾化器用的三氮唑类抗真菌药物的混悬液 |
CN111658610B (zh) * | 2020-07-31 | 2022-05-24 | 上海方予健康医药科技有限公司 | 一种供雾化器用的三氮唑类抗真菌药物的混悬液 |
CN113768873A (zh) * | 2021-08-25 | 2021-12-10 | 山东师范大学 | 一种福己素脂质纳米混悬剂及其制备方法 |
CN113768873B (zh) * | 2021-08-25 | 2023-05-05 | 山东师范大学 | 一种福己素脂质纳米混悬剂及其制备方法 |
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CN115887372A (zh) * | 2022-10-25 | 2023-04-04 | 苏州欧康维视生物科技有限公司 | 丙酸氟替卡松混悬液及其制备方法 |
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