CN114099472A - 一种磁性利多卡因微球缓释剂的制备方法 - Google Patents
一种磁性利多卡因微球缓释剂的制备方法 Download PDFInfo
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Abstract
本发明公开了一种磁性利多卡因微球缓释剂的制备方法,以PLGA为微球外壳,利多卡因、Fe3O4明胶溶液为内水相,二氯甲烷为油相溶剂,聚乙烯醇(PVA)为外水相,使用复乳法制备而成;本发明制备的磁性利多卡因微球缓释剂的微球直径在50μm左右,具有良好的通针性,通过局部注射磁性利多卡因微球缓释剂,同时施加外部静磁场,使微球局部聚集,达到药物作用时长及效果精准可控的目的。
Description
技术领域
本发明属于利多卡因应用技术领域,具体涉及一种磁性利多卡因微球缓释剂的制备方法。
背景技术
利多卡因因其起效快,弥散广,穿透性强,无明显扩张血管的特点,成为目前临床上最常用的局麻药之一。
利多卡因的毒性随药物浓度而增加,除了用于麻醉,还可静脉注射或静脉滴注利多卡因治疗室性心律失常。临床上往往选用不同利多卡因浓度来保证作用效果及延长作用时效。口咽及气管表面麻醉可用4%溶液(幼儿则用2%溶液),起效时间为5分钟,时效约可维持15-30分钟;0.5%-1%溶液用于局部浸润麻醉,时效可达60-120分钟,依其是否加用肾上腺素而定;神经阻滞应用1%-1.5%溶液,起效约10-20分钟,时效可达120-240分钟;硬膜外和骶管阻滞则用1%-2%溶液,出现镇痛作用约需5分钟,达到完善的节段扩散约需16分钟,时效为90-120分钟。
但是,上述作用持续时间仍旧偏短,无法超过24小时,往往不能很好地满足临床镇痛需求。目前虽可通过继续增加药物用量、合用肾上腺素、置管连续用药等方式延长作用时间,但是盲目增大药物用量可能增加局麻药中毒风险,而导管置入会带来其他不良反应,如尖端移位、神经损伤、导管相关感染等。所以需要寻找安全、稳定的方法,达到更加精准地靶向用药,从而在尽可能延长局麻药作用时间的同时减少药物用量,降低毒副作用。
药物缓释微球(Microspheres,MS)是指药物包埋于聚合物基质中形成的粒径尺寸分布在1-250μm的球状实体。药物缓释微球通过延缓药物的释放速率,从而达到减少给药频率与剂量、维持体内药物浓度恒定、延长治疗效果的目的,同时可减少局部和全身毒性,并且避免了体内置管以及由于置管带来的导管尖端移位及感染问题。微球的制备材料主要为可生物降解材料,常用的可分为两类:天然高分子聚合物以及合成高分子聚合物,天然高分子聚合物如壳聚糖、明胶、海藻酸钠、白蛋白等,往往杂质较多,微球制备质量不高;合成高分子聚合物如聚乳酸(PLA)、聚乳酸-羟基乙酸聚合物等(PLGA),合成高分子聚合物往往不溶于水,目前FDA已批准PLGA用于食品药物中。但是,单纯的药物缓释微球会随着血液循环全身流动,被巨噬细胞吞噬,无法达到靶向、精准作用的目的。
发明内容
本发明要解决的技术问题是克服现有技术中磁性利多卡因微球无法达到靶向、精准作用的缺陷,提供一种效果精准可控的磁性利多卡因微球缓释剂的制备方法。
为了解决上述技术问题,本发明提供了如下的技术方案:
提供一种磁性利多卡因微球缓释剂的制备方法,包括以下步骤:
S1、按照质量比为1:1:4称取Fe3O4纳米颗粒粉末、利多卡因粉剂、PLGA、PVA、明胶;
S2、配置明胶溶液,加入Fe3O4配置成Fe3O4明胶溶液,超声震荡分散;
S3、配置利多卡因溶液,加入S2所得溶液,作为内水相;
S4、PLGA加入二氯甲烷中,间断涡旋振荡使其完全溶解,作为油相;
S5、将S3配置的内水相与S4配置的油相混合,高速剪切分散剂分散形成稳定的初乳液;
S6、配置PVA水溶液作为外水相;
S7、将S5中得到的初乳液缓慢滴入PVA溶液中,搅拌直至二氯甲烷完全挥发;
S8、将S7中得到的溶液离心、洗涤、收集微球后冻干,即可制备得到磁性利多卡因微球缓释剂。
优选的,S2中,配置的明胶溶液以及Fe3O4明胶溶液质量浓度均为1%。
优选的,S3中,配置利多卡因溶液的浓度为50mg/ml。
优选的,选用的PLGA乳酸和羟基乙酸质量比为50:50;S4中,PLGA浓度为50mg/ml,间断涡旋振荡10-20min,直至PLGA完全溶解。
优选的,S5中,高速剪切分散机转速为7500-8500r/min,时间为3-5分钟,温度为室温。
优选的,S6中,90℃下配置3%PVA水溶液,但需待其完全冷却再加入初乳,速度为30滴/分,搅拌速度为700-900r/min,搅拌时间为6小时。
通过本发明制作得到的微球,其直径在50μm左右,具有良好的通针性。
共有四个因素影响微球的形貌:
第一,乳化时高速剪切分散机及挥发时搅拌的转速;
在高速剪切分散形成初乳时,转速太低无法形成稳定的初乳,转速过高则容易破乳;而搅拌挥发时,转速过低,微球直径增大,经调整后,高速剪切分散机转速为7500-8500r/min,搅拌挥发转速为700-900r/min;
第二,油相中PLGA浓度。
PLGA浓度过低,制作出的微球形状不规则,大小不均;但是浓度过高,制作出的微球极易团聚粘连,析出PLGA絮状物,导致离心后微球不易分散;只有浓度适中(50mg/ml),才能获得均匀的微球。
第三,外水相PVA的浓度。
当PVA浓度低于1%,其粘度无法保证初乳的稳定流动,微球大小不一;当PVA浓度高于4%时,粘度过大,阻碍了初乳的流动性,导致形成更大的微球。只有当PVA浓度适中(2%-3%)时,微球直径均一适中,满足实验要求。
第四,内水相与油相的体积比
当比值过低(1:1-1:2)时,基本不成球;而当比值过高(1:6)时,容易形成较大的微球,且发生团聚;只有比值适中时,才可形成外观圆整。
最后本发明中使用的参数依次分别高速剪切分散机转速8000r/min,挥发转速800r/min,PLGA浓度50mg/ml,PVA质量分数为3%,内水相与油相体积比为1:2。以上条件制作微球大小均匀,分散性好。
本发明所达到的有益效果是:本发明以PLGA为微球外壳,利多卡因、Fe3O4明胶溶液为内水相,二氯甲烷为油相溶剂,聚乙烯醇(PVA)为外水相,使用复乳法制备而成;本发明制备的磁性利多卡因微球缓释剂的微球直径在50μm左右,具有良好的通针性,通过局部注射磁性利多卡因微球缓释剂,同时施加外部静磁场,使微球局部聚集,达到药物作用时长及效果精准可控的目的。
附图说明
附图用来提供对本发明的进一步理解,并且构成说明书的一部分,与本发明的实施例一起用于解释本发明,并不构成对本发明的限制。在附图中:
图1是磁性利多卡因微球缓释剂SEM形貌图和TEM形貌图,(a)为微球扫描电镜图(SEM),(b)为微球透视电镜图(TEM);
图2是磁性利多卡因微球缓释剂磁滞回归线;
图3是磁性利多卡因微球缓释剂体外释放曲线;
图4为不同因素对微球的形貌的影响。
具体实施方式
以下结合附图对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例
1.制备磁性利多卡因微球缓释剂
S1、按照计算称取PLGA、PVA、Fe3O4纳米颗粒粉末、明胶、利多卡因粉剂;
S2、配置1%明胶溶液,加入Fe3O4配置成1%Fe3O4明胶溶液,超声震荡分散10min;
S3、配置50mg/ml的利多卡因溶液2ml,加入2ml步骤2所得溶液,作为内水相;
S4、0.4gPLGA加入8ml二氯甲烷中,间断涡旋振荡15min使其完全溶解,作为油相;
S5、将S3配置的内水相与S4配置的油相混合,高速剪切分散机8000r/min,3min分散形成稳定的初乳液;
S6、配置3%PVA水溶液50ml作为外水相;
S7、将S5中得到的初乳液缓慢滴入PVA溶液中,800r/min搅拌6小时直至二氯甲烷完全挥发;
S8、将S7中得到的溶液离心、洗涤、收集微球后冻干,即可制备得到磁性利多卡因微球缓释剂。
2、磁性利多卡因微球缓释剂性能表征方法
(1)微球形貌观察
①扫描电子显微镜(Scanning Electron Microscope,SEM)
将磁性利多卡因微球缓释剂冻干粉溶于水中,充分摇匀,超声分散,稀释后滴在铜陀上,真空干燥后表面喷金处理。通过扫描电子显微镜观察微球表面形貌,并照相记录(见图1(a),微球为均一圆球,表面具有疏松的孔洞结构。
②透射电子显微镜(Transmission Electron Microscope,TEM)
取适量磁性利多卡因微球缓释剂冻干粉溶于水中,充分摇匀,超声分散,稀释后滴在覆有碳膜的铜网上,室温下真空干燥后在透射电子显微镜下观察其内部结构,并照相记录(见图1(b),微球内部均匀无特殊结构。
(2)磁性利多卡因微球缓释剂磁性能测定
称取磁性利多卡因微球缓释剂冻干粉,在室温下,用振动样品磁强计测定微球的磁性能(见图2),微球具有超顺磁性。
3.磁性利多卡因微球缓释剂体外释放规律的研究
(1)利多卡因溶液标准曲线建立
配置不同浓度的利多卡因溶液,利用紫外可见吸收光谱测定不同浓度下的利多卡因标准溶液在选定的吸收波长(263nm)处的吸光度。以溶液浓度为横坐标,相应吸光度为纵坐标,进行线性拟合,绘制出利多卡因溶液标准曲线。
(2)磁性利多卡因微球缓释剂载药量、包封率测定
精密称取适量磁性利多卡因微球缓释剂,二氯甲烷溶解破坏,以纯水涡旋萃取后离心收集此溶液,测定该溶液在选定吸收波长处(263nm)的吸光度,以标准曲线计算溶液中利多卡因含量。
按照以下公式1,公式2计算微球的载药量和包封率。
(3)磁性利多卡因微球缓释剂体外释放测定
称取30mg磁性利多卡因微球缓释剂冻干粉,放置于10ml EP管中,加入5ml pH 7.4的PBS溶液作为释药介质,同时分为磁场组和非磁场组。将装有药物的EP管置于恒温摇床中,在100rpm,37℃±0.5℃的条件下进行孵育。分别于0.5h、1h、2h、4h、8h、12h、24h、48h取上层液体1.5ml并向体系中补充等体积的PBS溶液直至14d。采用紫外可见吸收光谱测定取出液在选定的吸收波长处(263nm)的吸光度,计算药物含量。通过计算微球的药物累积释放率绘制药物体外释放曲线图。其中将微球0.5h时的累积释药量记为突释量,突释率为27.4%。
图4中,(a)中PLGA浓度为100mg/ml,基本不成球,(b)中PVA浓度适中6%,(c)中内水相与油相的体积为1:2,基本不成球,(d)中内水相与油相的体积比为1:6时容易形成较大的微球,且发生团聚,由此可见只有比值适中时,才可形成外观圆整。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种磁性利多卡因微球缓释剂的制备方法,其特征在于,以PLGA为微球外壳,利多卡因、Fe3O4明胶溶液为内水相,二氯甲烷为油相溶剂,聚乙烯醇为外水相,使用复乳法制备而成。
2.如权利要求1所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,包括以下步骤:
S1、按照质量比为1:1:4称取Fe3O4纳米颗粒粉末、利多卡因粉剂、PLGA、PVA、明胶;
S2、配置明胶溶液,加入Fe3O4配置成Fe3O4明胶溶液,超声震荡分散;
S3、配置利多卡因溶液,加入S2所得溶液,作为内水相;
S4、PLGA加入二氯甲烷中,间断涡旋振荡使其完全溶解,作为油相;
S5、将S3配置的内水相与S4配置的油相混合,高速剪切分散剂分散形成稳定的初乳液;
S6、配置PVA水溶液作为外水相;
S7、将S5中得到的初乳液缓慢滴入PVA溶液中,搅拌直至二氯甲烷完全挥发;
S8、将S7中得到的溶液离心、洗涤、收集微球后冻干,即可制备得到磁性利多卡因微球缓释剂。
3.如权利要求2所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,S2中,配置的明胶溶液以及Fe3O4明胶溶液质量浓度均为1%。
4.如权利要求2所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,S3中,配置利多卡因溶液的浓度为50mg/ml。
5.如权利要求2所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,选用的PLGA乳酸和羟基乙酸质量比为50:50。
6.如权利要求5所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,PLGA浓度为50mg/ml,间断涡旋振荡10-20min,直至PLGA完全溶解。
7.如权利要求2所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,S5中,高速剪切分散机转速为7500-8500r/min,时间为3-5分钟,温度为室温。
8.如权利要求2所述的磁性利多卡因微球缓释剂的制备方法,其特征在于,S6中,90℃下配置3%PVA水溶液,但需待其完全冷却再加入初乳,速度为30滴/分,搅拌速度为700-900r/min,搅拌时间为6小时。
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