CN117018422A - 黄体酮脂质体缓释微针的制备方法 - Google Patents
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Abstract
本发明提供黄体酮脂质体缓释微针的制备方法,涉及经皮药物制剂技术领域。该黄体酮脂质体缓释微针的制备方法,包括以下步骤:向黄体酮磷脂溶液中,加入一定处方量的水,后在冰浴上经探针超声10mi n,依次过0.45μm,0.22μm的滤膜,即得黄体酮脂质体;将Ge l MA溶液与上述黄体酮脂质体溶液混匀,并向每个微针模具加入等量的溶液,置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得基质微针;于一定高度水平,对Ge l MA基质微针进行紫外照射光固化。本发明采用溶剂铸造法制备微针,根据微针的外观成型性、溶胀性能筛选合适的微针的处方。利用封口膜穿刺试验测试微针的机械强度,并利用Franz扩散池进行体外透皮研究。
Description
技术领域
本发明涉及经皮药物制剂技术领域,具体为黄体酮脂质体缓释微针的制备方法。
背景技术
黄体酮作为孕激素类药物,广泛应用于女性早期妊娠相关疾病的治疗中,在临床上黄体酮是黄体支持治疗方法中的首选药物,是调节女性生殖系统的重要组成激素,如女性月经不调、先兆流产、习惯性流产、体外受精-胚胎着床及黄体功能不足等疾病。由于黄体酮在水中难以溶解,体内吸收差,且口服后肝脏对药物有强烈的首过效应,同时肝脏毒性明显,临床上常用的是肌注黄体酮油剂,但按此途径给药,不仅给病人带来疼痛和刺激,还会有感染的危险,所以患者的顺应性差,在临床的应用受到了一定限制。已在国内外上市的黄体酮胶丸,临床中需口服微粉化黄体酮100~300mg才能发挥疗效,尽管采用了微粉化技术降低药物的粒径,从而提高药物生物利用度,但其生物利用度仅为肌注的6~8%,不良反应较多。研究显示,透皮给药技术可以避免首关效应、避免刺激胃肠道;无需针头给药,不产生疼痛,方便给药,使患者顺应性提高;降低药物被酶解的概率,使得药物能保持较高的活性;对于某些半衰期较短的药物疗能延长疗效,并能在较长时间内维持恒定的释药速率,降低药物毒性和副作用,血药浓度维持稳定而持久,给药次数减少,疗效提高。
角质层是保护皮肤的有利屏障,但同时限制了药物在透皮给药制剂中的应用。通过皮肤递送的药物必须符合以下条件:相对分子质量在500以下;药物在油水分配系数适中的同时活性较高。这些条件限制了该给药系统的适用范围,只有亲脂性和低分子量药物能够透皮吸收。由于皮肤的屏障性能,黄体酮的饱和水溶液在25℃的条件下经人体皮肤的扩散系数仅有1.5×10-3ug·cm-2·h-1,在EVA和矿物油基质中通过人体皮肤的速率仅为0.26和0.14ug·cm-2·h-1,而黄体酮要达到有效的血药浓度,每天需经皮渗透2~5mg。因此,开发一种黄体酮经皮给药系统的关键是为了提高孕激素经皮渗透的速率,保证用药的有效性。
作为一种透皮给药技术,微针可以根据治疗需求的不同,制成不同大小或形状满足不同临床需求,由于其特殊的三维结构能够刺穿角质层,从而增加药物的渗透力和吸收力。微针给药作为一种微创无痛递药技术,具有皮下注射和透皮给药贴剂双重释放的特点,能够穿透皮肤表面角质层但不触及神经,在不会产生强烈的疼痛感的同时,在表皮上形成微小的孔道,从而克服常规透皮药物递药方法的局限,通过微孔通道将药物送达体内循环。微针引起的刺激较传统注射小,病人的依从性有所改善。由于制取微针给药制剂的材料多为水溶性,而黄体酮难溶于水,在与制取微针的材料结合制取微针时,将黄体酮制成脂质体的形态,从而制得药物均匀的黄体酮微针。
发明内容
(一)解决的技术问题
针对现有技术的不足,本发明提供了黄体酮脂质体缓释微针的制备方法,解决了黄体酮现有剂型药物在目前临床治疗中首关效应大,患者用药不便、需频繁用药的问题,进而将黄体酮制成黄体酮脂质体,通过脂质体的包裹作用,增强黄体酮的稳定性,然后将脂质体载入溶胀型微针材料中,制备出的黄体酮脂质体微针克服了黄体酮传统制剂在临床上存在的不足,避免了黄体酮的首关效应,提高了生物利用度,提高了患者的顺应性。本发明采用可光固化交联的高分子材料甲基丙烯酰化明胶(Ge l MA)制备可溶胀型微针,使包裹的黄体酮脂质体药物缓释释放。
(二)技术方案
为实现以上目的,本发明通过以下技术方案予以实现:黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
在50℃水浴上,将一定量的黄体酮、大豆磷脂溶解于1,2-丙二醇和PEG-400中,得黄体酮磷脂溶液,最终形成的溶液中大豆磷脂的浓度为1g/mL,黄体酮的浓度为50mg/mL,以1:5-1:25的比例向黄体酮磷脂溶液中加入处方量的水,后在冰浴上经探针超声10min(150w,工作3s,停2s),依次过0.45μm、0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25-1%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15-25%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对Ge l MA基质微针进行紫外照射光固化,时长1-5min。
优选的,步骤一中,所述黄体酮磷脂溶液,包括体积比为3:1-2:1的1,2-丙二醇和PEG-400,以及1g/m l的大豆磷脂。
优选的,步骤二中,黄体酮脂质体溶液与Ge l MA溶液的体积比为1:1-1:10。
(三)有益效果
本发明提供了黄体酮脂质体缓释微针的制备方法。具备以下有益效果:
1、降低了患者的痛苦、应运用简单,患者使用便利。
2、本发明为缓释制剂,释放时间平稳且时间持久。
附图说明
图1为本发明的溶胀趋势示意图;
图2为本发明的微针的机械强度示意图;
图3为本发明的黄体酮脂质体缓释微针体外释放曲线示意图;
图4为本发明的黄体酮脂质体缓释微针体外经皮渗透曲线示意图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例一:
本发明实施例提供黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
按3:1的比例量取一定量的1,2-丙二醇和PEG-400,精密称定大豆磷脂适量,加入上述溶液中,45℃水浴加热溶解,得1g/ml大豆磷脂溶液,随后加入一定量的黄体酮,溶解混匀得黄体酮磷脂溶液,向黄体酮磷脂溶液中,以1:5的比例加入水,后在冰浴上经探针超声10min(150w,工作3s,停2s),依次过0.45μm,0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;其中,由于Ge l MA溶液在低温下会凝固,故置于70℃的水中;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对Ge l MA基质微针进行紫外照射光固化,时长1min。
实施例二:
本发明实施例提供黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
按3:1的比例量取一定量的1,2-丙二醇和PEG-400,精密称定大豆磷脂适量,加入上述溶液中,45℃水浴加热溶解,得1g/ml大豆磷脂溶液,随后加入一定量的黄体酮,溶解混匀得黄体酮磷脂溶液,向黄体酮磷脂溶液中,以1:5的比例加入水,后在冰浴上经探针超声10min(150w,工作3s,停2s),依次过0.45μm,0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;其中,由于Ge l MA溶液在低温下会凝固,故置于70℃的水中;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对Ge l MA基质微针进行紫外照射光固化,时长2min。
实施例三:
本发明实施例提供黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
按3:1的比例量取一定量的1,2-丙二醇和PEG-400,精密称定大豆磷脂适量,加入上述溶液中,45℃水浴加热溶解,得1g/ml大豆磷脂溶液,随后加入一定量的黄体酮,溶解混匀得黄体酮磷脂溶液,向黄体酮磷脂溶液中,以1:5的比例加入水,后在冰浴上经探针超声10min(150w,工作3s,停2s),依次过0.45μm,0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;其中,由于Ge l MA溶液在低温下会凝固,故置于70℃的水中;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对Ge l MA基质微针进行紫外照射光固化,时长3min。
实施例四:
本发明实施例提供黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
按3:1的比例量取一定量的1,2-丙二醇和PEG-400,精密称定大豆磷脂适量,加入上述溶液中,45℃水浴加热溶解,得1g/ml大豆磷脂溶液,随后加入一定量的黄体酮,溶解混匀得黄体酮磷脂溶液,向黄体酮磷脂溶液中,以1:5的比例加入水,后在冰浴上经探针超声10min(150w,工作3s,停2s),依次过0.45μm,0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;其中,由于Ge l MA溶液在低温下会凝固,故置于70℃的水中;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对Ge l MA基质微针进行紫外照射光固化,时长5min。
对比例:
黄体酮脂质体缓释微针的制备方法,包括以下步骤:
步骤一:微针的制备:
精密称取Ge l MA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25%的LAP作为光引发剂,即得Ge l MA溶液,将Ge l MA溶液与黄体酮脂质体溶液混匀,形成15%的Ge l MA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;其中,由于Ge l MA溶液在低温下会凝固,故置于70℃的水中;
步骤二:微针的光交联:
于一定高度水平对Ge l MA基质微针进行紫外照射光固化,时长1min。
黄体酮脂质体缓释微针载药量测定:
取制得的黄体酮脂质体缓释微针,加入一定量的甲醇溶液中,超声30分钟充分提取微针中的黄体酮,从中精密量取100μL用甲醇稀释100倍,后使用高效液相色谱仪测量每片微针中黄体酮含量,平行测定三次。结果见下表:
黄体酮脂质体缓释微针的溶胀性评价:
GELMA材料光固化后具有溶胀性质,通过控制光照时间,控制微针的溶胀能力。将光固化后的微针精密称重,记录原始重量后同时置PBS缓冲液中,于设置的时间点取出微针(5min、10min、15min、20min、25min、30min、35min、40min),用滤纸小心吸干表面的水分后称重,记录并处理数据,平行测定三次。经测定,不同交联程度的Ge l MA微针均表现出200%以上的膨胀率,结果如图1所示。由结果可知,Ge l MA基质制备的微针溶胀率与光固化时长即交联程度有关(3min<2min<1min)。但光固化5min与3min的膨胀率相差甚小,即可推测自制微针可能于光照3min时交联完成,3min后延长光固化时长对其交联程度无影响,故得此结果。
黄体酮脂质体缓释微针机械强度评价:
使Parafi lm膜穿刺试验评价微针机械强度,Parafi lm膜可以模拟皮肤的弹性。将光固化时长分别为0min、1min、2min、3min、5min以及未载药微针1min的微针以一定的力(约70N)按压在六层Parafi lm膜上,之后记录每片微针穿过每层封口膜的微针数量,平行测定三次,按下述公式计算穿透率:穿透率%=(每层封口膜微针穿透数量/每片微针的总针数)×100%,评价自制微针机械性能。由所得结果可知,以15%Ge l MA为基质所制得的微针均可穿透3层Parafi lm封口膜,且按压后的微针针形完整,机械强度良好。未载药微针的机械强度比载药微针的好,且机械强度与其光照时长有关,光照时间越长,机械性能越好。自制微针机械强度评价如图2所示。
黄体酮脂质体缓释微针穿透性评价:
大鼠麻醉后取其背部皮肤,除去鼠毛及皮下脂肪,用生理盐水漂洗干净后,用滤纸吸干水分。将自制微针以一定的力应用于大鼠皮肤上,随后使用可以染色受损细胞膜的台盼蓝溶液对按压过的皮肤部分进行染色,在去除多余的台盼蓝后,观察微针在大鼠皮肤上的穿透效果。穿刺皮肤后移除微针,观察发现微针基本保持完整,针尖有些许部分出现略微弯曲的情况。使用台盼蓝溶液对穿刺过的大鼠皮肤进行染色后的情况,可知微针机械强度良好,可穿刺皮肤。
黄体酮脂质体缓释微针体外释放评价:
使用封口膜包裹黄体酮脂质体缓释微针后将针间穿透封口膜,暴露出针尖,固定于Franz扩散池的供试池与接收池之间,置于药物透皮扩散试验仪上,于温度32±0.5℃,搅拌子转速200r·min-1,接收液为20%的无水乙醇生理盐水的条件下进行试验,在设定的取样点(0.25、0.5、1、2、4、6、8、10、12、24、48、72、96h)取样2mL(同时补充同温的接收液2mL),样品经甲醇稀释定容后,经0.220m微孔滤膜过滤后使用高效液相色谱仪测定体外释放量,平行三次。实验结果表明,黄体酮脂质体-GeLMA微针在20%的乙醇生理盐水溶液中96h时,光照1min的释放量为(595.12±24)μg,光照2min的释放量为(445.26±10)μg,光照3min的释放量为(376.84±12)μg。由此可知,不同交联程度的黄体酮脂质体-GeLMA微针的释放速度及释放量均不同(3min<2min<1min),释放曲线如图3所示。
黄体酮脂质体缓释微针体外透皮释放评价:
将脱毛处理及去除皮下脂肪后的大鼠皮肤,在生理盐水中洗净,用滤纸吸干皮肤表面的水分。将黄体酮脂质体缓释微针以一定的力作用于处理后的大鼠皮肤表面上并固定于接收池上,置于药物透皮扩散试验仪上,设定温度32±0.5℃,转速为200r·min-1,接收液为20%的无水乙醇生理盐水,在设定的取样点(0.5、1、2、4、6、8、10、12、24、48、72、96h)取样2mL(同时补充同温的接收液2mL),样品经甲醇稀释定容后,经0.220m微孔滤膜过滤后使用高效液相色谱仪测定体外渗透量。结果表明,黄体酮脂质体-Ge l MA微针在20%的乙醇生理盐水溶液中96h时,光固化1min微针的累积渗透量(Q)为(167.08±4.75)μg/cm2,光固化2min微针的Q为(159.69±6.04)μg/cm2,光固化3min微针的Q为(135.47±11.34)μg/cm2,黄体酮混悬液的Q为(54.84±1.84)μg/cm2,黄体酮脂质体的Q为(71.03±9.75)μg/cm2。与黄体酮混悬液相比,黄体酮脂质体的经皮渗透有明显的时滞,后期黄体酮脂质体的透皮效果反超黄体酮混悬液。黄体酮脂质体-GeLMA微针体外经皮渗透曲线如图4所示。
通过本发明制成的微针属于溶胀型微针,该微针具有较高的溶胀性能。刺入皮肤后,微针吸收皮肤下的细胞液,从而发生溶胀,形成一条释放药物的通道,使药物通过溶胀形成的孔洞中释放出来;同时,微针在皮肤表面刺出的微孔,由于微针材料的不可溶性,可以稳定存在,药物释放稳定持久,有望突破使用限制,微针载药量较低,释放药物较少。溶胀型微针的确具备显著的促进释药能力,且与水凝胶微针溶胀性能正相关。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (3)
1.黄体酮脂质体缓释微针的制备方法,其特征在于:包括以下步骤:
步骤一:黄体酮脂质体溶液的制备:
在50℃水浴上,将一定量的黄体酮、大豆磷脂溶解于1,2-丙二醇和PEG-400中,得黄体酮磷脂溶液,最终形成的溶液中大豆磷脂的浓度为1g/mL,黄体酮的浓度为50mg/mL,以1:5-1:25的比例向黄体酮磷脂溶液中加入处方量的水,后在冰浴上经探针超声10min,依次过0.45μm、0.22μm的滤膜,即得黄体酮脂质体;
步骤二:黄体酮脂质体微针的制备:
精密称取GelMA,加入一定量的水,遮光于50-60℃的水浴锅中溶解,加入0.25-1%的LAP作为光引发剂,即得GelMA溶液,将GelMA溶液与黄体酮脂质体溶液混匀,形成15-25%的GelMA含药溶液,向每个微针模具加入等量的溶液后,放入置于70℃水中的真空干燥器里,在负压条件下使溶液进入微针模具中,干燥脱模得初步微针;
步骤三:黄体酮脂质体微针的光交联:
于一定高度水平,对GelMA基质微针进行紫外照射光固化,时长1-5min。
2.根据权利要求1所述的黄体酮脂质体缓释微针的制备方法,其特征在于:步骤一中,所述黄体酮磷脂溶液,包括体积比为3:1-2:1的1,2-丙二醇和PEG-400,以及1g/ml的大豆磷脂。
3.根据权利要求1所述的黄体酮脂质体缓释微针的制备方法,其特征在于:步骤二中,黄体酮脂质体溶液与GelMA溶液的体积比为1:1-1:10。
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