CN114225033B - 前置空泡型大麻脂溶性活性物可溶微针及制备方法和应用 - Google Patents
前置空泡型大麻脂溶性活性物可溶微针及制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种前置空泡型大麻脂溶性活性物可溶微针,包括背衬层和背衬层上固定的微针阵列,所述微针的针尖部埋入活泼金属颗粒、碳酸氢盐、碳酸氢盐、二氧化铈颗粒或铈锆复合氧化物颗粒中的一种;针体填入含大麻脂溶性活性物固体分散体的可溶微针基质材料。本发明的前置空泡型大麻活性成分微针利用前置气泡极大降低了包埋药物向肿瘤深层递送的阻力,透皮渗透系数大幅提高;产生的氢气/氧气/二氧化碳等可以显著改善肿瘤免疫抑制微环境,协同所包埋的其他抗肿瘤药物提高治疗效能;所需的给药剂量大幅降低,有助于降低潜在毒性,并对各类浅表性皮肤肿瘤的治疗综合效能有明显提高。
Description
技术领域
本发明涉及一种前置气泡型大麻脂溶性活性物可溶微针递药系统的制备方法,以及其在浅表性肿瘤治疗中药物深层渗透方面的应用。
背景技术
大麻素是桑科植物大麻发挥药理活性的主要成分,目前分离并鉴定出的大麻素类化合物CBD(大麻二酚)。其中CBD是大麻的第二大活性成分,属于脂溶性非精神活性类大麻素范畴,其口服生物利用度约为6%,在肝、心、脑、肺、脂肪组织、肌肉、胎盘、乳汁等组织及体液中广泛分布,能够与大麻素受体1(CB1R)、大麻素受体2(CB2R)、瞬时受体电位香草素1(TRPV1)、G 蛋白偶联受体-55(GPR-55)、和过氧化物酶增殖物激活受体-γ(PPAR-γ)等多靶点相互作用,可用于治疗黑色素瘤等浅表性肿瘤等疾病,具有良好的耐受性和较高的安全性。以CBD为代表的大麻活性物在医疗领域的研究与应用得到了广泛关注,其通过产生活性氧(ROS)和激活caspase诱导癌细胞凋亡,能显著诱导ROS的生成,GSH耗竭和GPox和GRed酶活性的增加,从而诱导氧化应激,激活caspase-9和caspase-8,进而激活caspase-3,从死亡受体和线粒体两条途径来诱导癌细胞的凋亡。同时,CBD可以通过抑制AKT/mTOR通路来诱导癌细胞凋亡。此外,其他活性成分如CBDA能够明显抑制各类肿瘤细胞的迁移、降低新生血管的形成,对于抗乳腺癌、黑色素瘤等有明显的药理活性。THC可以降低金属基质蛋白酶-2(MMP-2)的表达,进而下调下游侵袭转移蛋白的表达和血管生成因子,达到抗肿瘤的目标。CBL、CBN、CBT等则具有明确的抗炎活性,能够通过抑制或干预NF-κB和PI3K/AKT 等途径降低炎癌转化风险,发挥不同的抗肿瘤效应。
浅表性皮肤癌是世界上常见的癌症类型,澳大利亚等欧美国家是世界上皮肤癌发病率最高的区域。流行病学显示:2018年全球估计每10万人中就有300人是皮肤癌患者。当今由于环境污染等不良因素的影响,我国皮肤癌发病率呈逐年上升趋势。皮肤癌主要分为黑色素瘤、基底细胞癌(BCC)和皮肤鳞状细胞癌(SCC)等。黑色素瘤是一种来源于黑素细胞转化的恶性肿瘤,尽管与其他皮肤癌相比并不常见,但其致命性更强,约占皮肤癌相关死亡病例的73%,死亡的主要原因是广泛转移到淋巴系统和其他重要器官。黑色素瘤预后极差,早期易转移,大麻活性物独特的药理活性使其在治疗黑色素瘤方面有着巨大的潜力,但是受限于活性物的理化性质,目前仍然缺乏足够有效的药物递送手段和策略。
可溶微针阵列给药系统是一种微创、无痛、高效的经皮给药系统,通过物理刺入表皮或表皮-真皮交界部位,迅速吸取组织中的水分,以溶胀或溶解的方式爆释出药物;此外还能通过核心参数的调整,可以将搭载的药物地送至皮肤的不同深度,具有有效克服药物透皮障碍的能力,对于浅表性皮肤瘤来说是一种非常适宜的给药方式。但即便如此,许多药物借助物理方式避开了角质层的阻滞,由于自身缺乏向内扩散渗透的能力仍然会被大量地滞留在表皮中,真正进入靶部位的药量十分有限。设计一种具有自主穿透能力的微针递药系统非常必要。
发明内容
本发明的目的在于针对大麻脂溶性活性物(CBs)提供一种前置空泡型可溶微针。
为实现上述技术目的,本发明采用如下技术方案:
一种前置空泡型大麻脂溶性活性物可溶微针,包括背衬层和背衬层上固定的微针阵列,所述微针的针尖部埋入活泼金属颗粒、碳酸氢盐、碳酸氢盐、二氧化铈颗粒或铈锆复合氧化物颗粒中的一种;针体填入含大麻脂溶性活性物固体分散体的可溶微针基质材料。
本发明中,在微针高度20~60μm处埋入所述活泼金属颗粒、碳酸氢盐、碳酸氢盐、二氧化铈颗粒或铈锆复合氧化物颗粒。在微针高度100~900μm处填入含CBs的固体分散基质材料。
作为一种优选的实施方式,微针的针尖材料选用透明质酸、壳聚糖、明胶淀粉、蔗糖、 PVA或PVP。
作为一种优选的实施方式,微针的背衬材料选用透明质酸、PVP、PVA、壳聚糖、CMC、海藻酸钠、HPMC、明胶或糊精;选取的聚合物材料软硬较为适中。
作为一种优选的实施方式,所述大麻脂溶性活性物固体分散体为过80~200目筛的粉末状大麻脂溶性活性物固体分散体。
作为一种优选的实施方式,所述固体分散基质材料为生物相容性材料,可以是聚乙烯吡咯烷酮K30、聚乙二醇6000、泊洛沙姆、Eudragit EPO100、Plasdone S-630、羟丙基甲基纤维素(CMC)等。
本发明的另一目的在于提供上述前置空泡型大麻脂溶性活性物可溶微针的制备方法。其制备方法可以是溶剂法、溶剂-熔融法或熔融法。
本申请提供了基于溶剂法的可溶微针制备方法,包括:
(1)大麻脂溶性活性物部分设计:利用大麻脂溶性活性物和聚合物载体制备大麻脂溶性活性物固体分散体;
(2)针尖部分设计:取活泼金属颗粒分散于有机溶剂中,将混合溶液滴加在微针模具表面,离心干燥;或:取二氧化铈颗粒/铈锆复合氧化物颗粒分散于表面活性剂中,将混合溶液滴加在微针模具表面,离心干燥;或:取碳酸氢盐/碳酸盐透明质酸混合溶液滴加在微针模具表面,离心干燥;
(3)针体部分设计:将所述大麻脂溶性活性物固体分散体和水溶性针尖材料以水溶解后滴加在微针模具表面,离心干燥;
(4)微针背衬部分设计:取微针背衬材料制作背衬,获取所述可溶微针。
作为一种优选的实施方式,所述方法还包括,在将大麻脂溶性活性物固体分散体和水溶性针尖材料以水溶解时,加入药物与之共溶;所述药物为免疫治疗药物、光动力治疗药物或化学动力治疗药物。
作为一种优选的实施方式,所述(2)中,所述活泼金属颗粒在混合溶液中浓度为1wt%~5wt%;所述二氧化铈颗粒/铈锆复合氧化物在混合溶液中浓度为0.2wt%~1wt%;所述碳酸氢盐/碳酸盐在混合溶液中浓度为0.5wt%~20wt%;优选7wt%。
作为一种优选的实施方式,所述大麻脂溶性活性物和聚合物载体的质量比为1:1~1:10。
作为一种优选的实施方式,将背衬材料溶解于去离子水中,滴加在微针模具表面并高出模具2~15mm。
本发明的又一目的在于提供上述前置空泡型大麻脂溶性活性物可溶微针在浅表性皮肤瘤深层递药中的应用。
相较于以粉末形式存在的脂溶性成分,采用本发明方法制备的针尖埋入活泼金属颗粒对酸性环境敏感,产氢气稳定,药物可深层渗透,脂溶性成分在水中的饱和溶解度提高,其存在形式接近或为无定形,溶出度高,分布均匀且稳定性好。所得微针力学性能稳定,能穿透皮肤递送药物,达到治疗浅表性肿瘤的治疗标准。
采用本发明方法制备的针尖埋入二氧化铈颗粒或铈锆复合氧化物颗粒的微针的微针对酸性和高H2O2环境敏感,产氧稳定,药物可深层渗透,脂溶性成分在水中的饱和溶解度提高,其存在形式接近或为无定形,溶出度高,分布均匀且稳定性好。所得微针力学性能稳定,能穿透皮肤递送药物,达到治疗浅表性肿瘤的治疗标准。
采用本发明方法制备的针尖埋入碳酸氢盐/碳酸氢盐的微针对酸性环境敏感,产二氧化碳稳定,药物可深层渗透,脂溶性成分在水中的饱和溶解度提高,其存在形式接近或为无定形,溶出度高,分布均匀且稳定性好。所得微针力学性能稳定,能穿透皮肤递送药物,达到治疗浅表性肿瘤的治疗标准。
采用本发明方法制备的与其他药物共治疗的微针,以O2-Bub/CB&ICG/SD-MNs微针为例,针尖的二氧化铈颗粒与肿瘤的酸性以及过氧化氢环境反应生产氧气,在微针前端制造一个空气泡,通过降低药物渗透阻力的方式自主“泵送”药物,加速药物进入肿瘤的速度和深度,更快速的发挥CBs的抗肿瘤疗效;另一方面通过特定波段光的照射将ICG激发出可杀伤肿瘤的ROS,并依托产生的氧气为光动力疗法提供源动力。大麻活性成分CBD通过产生活性氧、激活caspase和抑制AKT/mTOR通路来诱导癌细胞凋亡,还能通过修复肿瘤畸形血管的方式促进肿瘤免疫激活,与ICG的光动力疗法有望产生协同抗肿瘤作用。CBD和ICG 以固体分散体的形式存在于微针中,解决了脂溶性组分在亲水生物相容性基质材料中溶解度差的问题,同时CBD、ICG或以无定型分散形式存在于微针中,溶出过程将不需要额外的动力去克服晶格能,药物的溶出速度得到了显著提高。
本发明的前置空泡型大麻活性成分微针相比于现有的其他大麻活性传统剂型,拥有以下有益效果:
1.前置气泡极大降低了包埋药物向肿瘤深层递送的阻力,透皮渗透系数大幅提高;
2.产生的氢气/氧气/二氧化碳等可以显著改善肿瘤免疫抑制微环境,协同所包埋的其他抗肿瘤药物提高治疗效能;
3.所需的给药剂量大幅降低,有助于降低潜在毒性;
4.对各类浅表性皮肤肿瘤的治疗综合效能明显提高。
各前置空泡型大麻脂溶性活性物可溶微针的制备及抗肿瘤使用实例在具体实施例中将逐一展示。
附图说明
图1是H2-Bub/CBD@PD1/SD-MNs的光学图像(左)和显微图像(右)。
图2是H2-Bub/CBD@PD1/SD-MNs刺穿封口膜的显微图像(左:正面,右:背面)。
图3是H2-Bub/CBDA@PD-L1/SD-MNs的光学图像(左)和显微图像(右)。
图4是O2-Bub/CBDA@ICG/SD-MNs的光学图像(左)和显微图像(右)。
图5是O2-Bub/CBD@Ce6/SD-MNs的光学图像(左)和显微图像(右)。
图6是CO2-Bub/CBD/SD-MNs的光学图像(左)和显微图像(右)。
图7是CBD可溶微针刺穿封口膜的显微图像(左:正面,右:背面)。
图8是H2-Bub/THC/SD-MNs的光学图像(左)和显微图像(右)。
图9是CBD圆锥可溶微针的显微图像。
具体实施方式
实施例中微针的成型性和力学性能表征方案如下:
将制备好的微针贴片固定在载玻片上面并且倾斜30°左右,然后将固定好的微针贴片垂直的放置在物镜下方,调整放大倍数使得整个微针贴片刚好能完整的出现在镜头中,然后通过调整清晰度来获得微针的整体清晰形貌,可以观察到微针针体是否有缺失,损坏,断裂等情况。
将微针置于测力计底部钢板上方(微针针尖朝上),使得微针位于钢板与探针中间,探针以一定的速度向微针的针尖移动,在探针接触到针尖的时候,钢板开始挤压针体,进而产生压缩力,利用MARK-10测力计记录在各个不同位移点时微针的作用力大小直到探针停止移动,可以绘制微针的作用力-位移曲线,以判断微针是否有足够的穿透力刺入皮肤。
大麻活性成分微针对黑色素瘤病理模型动物的药效学评价方案如下:
以H2-Bub/CBs@PD1/SD-MNs微针为例,取B16 F10黑色素瘤细胞,离心(1500rpm×9min)获得单细胞悬液,取裸鼠,在左侧背部皮下注射瘤细胞悬液(1×105个/只)共接种45只,约2周肿瘤出现。随后,每天用游标卡尺测量正在生长的肿瘤的大小,大小计算公式为(4π/3) ×(宽度/2)2×(长度/2),从而观察裸鼠成瘤情况。瘤体积达到60mm3后,按照分组开始治疗。每3天测量一次裸鼠肿瘤体积,4周后处死动物。记录各组小鼠的体重变化,肿瘤变化和生存曲线,并随后对肿瘤细胞进行分析。
实施例1
H2-Bub/CBD@PD1/SD-MNs的制备和表征
按质量比1:1精密称取大麻二酚(CBD)和聚乙烯吡咯烷酮-K30(PVP-K30),置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过120目筛,既得大麻二酚固体分散体(CBD-SD)。
称取镁颗粒分散于异丙醇溶液中,混合溶液中镁颗粒质量浓度为1wt%,将混合溶液滴加在圆锥型PDMS模具表面,于超高速离心机中以4500rpm的速度离心30min,于真空干燥箱中50℃干燥1h。
按照质量比5:1称取透明质酸与上述CBD-SD一起溶解于去离子水中,滴加在圆锥型 PDMS模具表面,于超高速离心机中以4500rpm的速度离心45min,取出并除去表面多余溶液,通风干燥1h。随后取聚乙烯醇(PVA)溶解于去离子水中配制成15wt%PVA溶液,滴加在PDMS模具表面,高出模具约10mm左右,置于常温通风橱干燥24h,脱模既得 H2-Bub/CBD/SD-MNs贴片。
H2-Bub/CBD@PD1/SD-MNs制法与上述类似,在溶解CBD-SD步骤时,取PD-1抗体溶液与之共溶(1/100~1/1000,w/w),再按相似步骤制得。上述制法使用的镁颗粒还可以用铁颗粒、钙颗粒、镁-钠颗粒等代替;圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代。PD-1免疫药物还可以用PD-L1、CTLA-4等替代。
将制备好的微针贴片固定在载玻片上面并且倾斜30°左右,然后将固定好的微针贴片垂直的放置在物镜下方,调整放大倍数使得整个微针贴片刚好能完整的出现在镜头中,然后通过调整清晰度来获得微针的整体清晰形貌,可以观察到微针针体是否有缺失,损坏,断裂等情况,以确定微针的成型性,结果如图1所示。
剪取固定数目的微针阵列,分别用Parafilm封口膜穿刺实验考察自制微针的机械强度。 Parafilm封口膜穿刺实验:考虑到皮肤有弹性,采用多层Parafilm封口膜叠加来模拟不同厚度的皮肤,将微针垂直按在封口膜上2min之后拔出,用显微镜观察封口膜上留下的孔,统计微针穿过封口膜后留下针孔数目,评价微针机械性能。结果见图2,该法所制微针能够穿刺3层Parafilm封口膜,表明微针可以刺破有一定弹性的模拟皮肤材料,针孔清晰可见。
实施例2
H2-Bub/CBDA@PD-L1/SD-MNs的制备和表征
按质量比1:5精密称取大麻二酚酸(CBDA)和PVP-K30,置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过120目筛,既得CBDA-SD。
称取钙颗粒分散于氯仿中,混合溶液中钙颗粒浓度为5wt%,将混合溶液滴加在圆锥型 PDMS模具表面,于超高速离心机中以3000rpm的速度离心20min,于真空干燥箱中40℃干燥2h。
精密称取透明质酸+PVP-K30混合基质(3/1,w/w)按质量比10:1与上述CBDA-SD一起溶解于含0.5wt%吐温80的水溶液中,滴加在圆锥型PDMS模具表面,3000rpm离心30min,通风干燥1h。随后取CMC-Na溶解于去离子水中配制成30wt%溶液,滴加在PDMS模具表面作背衬,置于常温通风橱干燥24h,脱模既得H2-Bub/CBDA/SD-MNs贴片。
H2-Bub/CBDA@PD-L1/SD-MNs制法与上述类似,在溶解CBDA-SD步骤时,取PD-L1 抗体溶液与之共溶(1/100~1/1000,w/w),再按相似步骤制得。
上述制法使用的钙颗粒还可以用镁颗粒、铁颗粒、镁-钠颗粒等代替;圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代。PD-L1免疫药物还可以用PD-1、CTLA-4 等替代。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图3,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
实施例3
O2-Bub/CBDA@ICG/SD-MNs的制备和表征
按质量比1:10精密称取大麻二酚酸(CBDA)和PVP-K30,置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过120目筛,既得CBDA-SD。
称取二氧化铈颗粒分散于含0.5wt%吐温80的水溶液,混合溶液中二氧化铈颗粒浓度为 1wt%,将混合溶液滴加在圆锥型PDMS模具表面,于超高速离心机中以3000rpm的速度离心20min,于真空干燥箱中40℃干燥2h。
精密称取透明质酸+PVP混合基质(3/1,w/w),按质量比20:1与上述CBDA-SD一起溶解于含0.5wt%吐温80的水溶液中,滴加在圆锥型PDMS模具表面,于超高速离心机中以3000rpm的速度离心30min,通风干燥1h。随后取CMC-Na溶解于去离子水中配制成30wt%溶液,滴加在PDMS模具表面作背衬,置于常温通风橱干燥24h,脱模既得 O2-Bub/CBDA/SD-MNs贴片。
O2-Bub/CBDA@ICG/SD-MNs制法与上述类似,在溶解CBDA-SD步骤时,取ICG与之共溶解(1/10~1/50,w/w),再按相似步骤制得。
上述制法圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代;光动力治疗药物ICG还可以用Ce6、替莫泊芬、海姆泊芬等;二氧化铈颗粒还可以替换成铈锆复合氧化物颗粒。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图4,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
实施例4
O2-Bub/CBD@Ce6/SD-MNs的制备和表征
按质量比1:2精密称取大麻二酚(CBD)和PVP-K30,置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过200目筛,既得CBD-SD。
称取二氧化铈颗粒分散于含0.5wt%吐温80的水溶液中,混合溶液中二氧化铈颗粒浓度为0.2wt%,将混合溶液滴加在圆锥型PDMS模具表面,4000rpm的速度离心30min,真空干燥箱中40℃干燥2h。
精密称取透明质酸+PVP-K30混合基质(3/1,w/w),按质量比10:1与上述CBD-SD一起溶解于含0.5wt%吐温80的水溶液中,滴加在圆锥型PDMS模具表面,再次4000rpm的速度离心30min,通风干燥1h。随后取PVP-K30溶解于去离子水中配制成20wt%溶液,滴加在PDMS模具表面作背衬,置于常温通风橱干燥24h,脱模既得O2-Bub/CBD/SD-MNs贴片。
O2-Bub/CBD@Ce6/SD-MNs制法与上述类似,在溶解CBD-SD步骤时,取Ce6与之共溶解(1/5~1/100,w/w),再按相似步骤制得。
上述制法圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代;光动力治疗药物Ce6还可以用ICG、替莫泊芬、海姆泊芬等;二氧化铈颗粒还可以替换成铈锆复合氧化物颗粒。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图5,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
实施例5
CO2-Bub/CBD/SD-MNs的制备和表征
按质量比1:2精密称取大麻二酚(CBD)和PVP-K30,置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过120目筛,既得CBD-SD。
量取碳酸氢钠溶于15%(v%)透明质酸溶液,混合溶液中碳酸氢钠质量浓度为0.5wt%,将混合溶液滴加在圆锥型PDMS模具表面,4000rpm的速度离心30min,真空干燥箱中40℃干燥2h。
精密称取透明质酸与上述CBD-SD按质量比10:1一起溶解于含0.5wt%吐温80的水溶液中,再次滴加在圆锥型PDMS模具表面,4000rpm的速度离心30min,通风干燥1h。随后取CMC-Na溶解于去离子水中配制成30wt%溶液,滴加在PDMS模具表面作背衬,置于常温通风橱干燥24h,脱模既得CO2-Bub/CBD/SD-MNs贴片。
上述制法圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代;CBD 还可以用CBD、CBDA、CBG、CBC、复合大麻素等替代。碳酸氢钠还可以用碳酸镁、碳酸钠、碳酸钾、碳酸钙等替代。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图6,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
剪取固定数目的微针阵列,分别用Parafilm封口膜穿刺实验考察自制微针的机械强度。 Parafilm封口膜穿刺实验:考虑到皮肤有弹性,采用多层Parafilm封口膜叠加来模拟不同厚度的皮肤,将微针垂直按在封口膜上2min之后拔出,用显微镜观察封口膜上留下的孔,统计微针穿过封口膜后留下针孔数目,评价微针机械性能。结果见图7,该法所制微针能够穿刺3 层Parafilm封口膜,表明微针可以刺破有一定弹性的模拟皮肤材料,针孔清晰可见。
实施例6
H2-Bub/THC@PD-L1/SD-MNs的制备和表征
按质量比1:2精密称取四氢大麻酚(THC)和PVP-K60,置于圆底烧瓶中,加入无水甲醇,搅拌直至体系成澄明液体,减压旋蒸除甲醇,迅速置于-40℃无水乙醇冷肼中固化0.5h后,取出研碎,过200目筛,既得THC-SD。
称取镁颗粒分散于氯仿中,混合溶液中镁颗粒质量浓度为2wt%,将混合溶液滴加在圆锥型PDMS模具表面,于超高速离心机中以3000rpm的速度离心20min,于真空干燥箱中40℃干燥2h。
精密称取透明质酸+PVP-K60混合基质(5/1,w/w)与上述THC-SD按质量比10:1一起溶解于去含0.5wt%吐温80的水溶液中,滴加在圆锥型PDMS模具表面,3000rpm离心30min,通风干燥1h。随后取PVP溶解于去离子水中配制成20wt%溶液,滴加在PDMS模具表面作背衬,置于常温通风橱干燥24h,脱模既得H2-Bub/THC/SD-MNs贴片。
H2-Bub/THC@PD-L1/SD-MNs制法与上述类似,在溶解THC-SD步骤时,取PD-L1抗体溶液与之共溶(1/100~1/1000,w/w),再按相似步骤制得。上述制法使用的镁颗粒还可以用铁颗粒、钙颗粒、镁-钠颗粒等代替;圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代。PD-L1免疫药物还可以用PD-1、CTLA-4等替代。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图8,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
实施例7
CO2-Bub/CBD@PD1/SD-MNs的制备和表征
按质量比1:1精密称取大麻二酚(CBD)和PVP-K30,置于圆底烧瓶中,加入无水乙醇,搅拌直至体系成澄明液体,减压旋蒸除有机溶剂,迅速置于-20℃冰箱中冷冻固化24h后,将干燥物取出,研碎,过120目筛,既得CBD-SD。
量取碳酸氢钠溶于15%(v%)透明质酸溶液,混合溶液中碳酸氢钠质量浓度为20wt%,将混合溶液滴加在圆锥型PDMS模具表面,4000rpm的速度离心30min,真空干燥箱中40℃干燥2h。
精密称取透明质酸与上述CBD-SD按质量比10:1一起溶解于去含0.5wt%吐温80的水溶液中,将其pH值调节至9~11,再次滴加在圆锥型PDMS模具表面,4000rpm的速度离心30min,通风干燥1h。随后取CMC-Na溶解于去离子水中配制成30wt%溶液,滴加在PDMS 模具表面作背衬,置于常温通风橱干燥24h,脱模既得CO2-Bub/CBD/SD-MNs贴片。
CO2-Bub/CBD@PD1/SD-MNs制法与上述类似,在溶解CBD-SD步骤时,取PD-L1抗体溶液与之共溶(1/100~1/1000,w/w),再按相似步骤制得。上述制法圆锥型PDMS模具表面还可以用四棱锥型、三棱锥、八棱锥等模具替代;CBD还可以用CBD、CBDA、CBG、CBC、复合大麻素等替代。碳酸氢钠还可以用碳酸镁、碳酸钠、碳酸钾、碳酸钙等替代;PD-L1免疫药物还可以用PD-1、CTLA-4等替代。
将制得的微针固定至观察角度,通过光学显微镜观察微针阵列形态和排列。结果见图9,该法所制微针阵列排列整齐,针尖未见破损和弯曲。
实施例8
H2-Bub/CBD@PD1/SD-MNs渗透及皮肤滞留
采用Franz透皮扩散试验仪进行CBD MNs的体外经皮渗透性研究。按实施例1所述方法制备H2-Bub/CBD@PD1/SD-MNs贴片。扩散池的有效渗透面积为2.2cm2,接收池的容积为6.5mL。选择乙醇-PEG400-生理盐水(5:3:2)溶液作为接收液,将适合大小的离体猪皮置于供给池与接收池之间,角质层面向供给池,真皮层面向接收池,接收池内加入6.5mL接收液,接收液与皮肤之间紧密接触无气泡,供给池内分别加入1mL CBD溶液和一片 H2-Bub/CBD@PD1/SD-MNs,上方用保鲜膜封闭,扩散池于37℃水浴温度下,400rpm恒温搅拌。分别于2、4、6、8、12、24h取样5mL,同时补充5mL相同温度接收液,样品过0.22 μm滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算药物累积透过量。
表1 H2-Bub/CBD@PD1/SD-MNs累积透过量(μg/cm2)
Time(h) | CBD溶液 | H2-Bub/CBD@PD1/SD-MNs |
2 | 0 | 0.15±0.05 |
4 | 0 | 0.62±0.11 |
6 | 0.27±0.03 | 1.35±0.27 |
8 | 0.66±0.05 | 2.69±0.41 |
12 | 1.58±0.21 | 7.58±0.35 |
24 | 4.09±0.42 | 20.96±1.07 |
2.离体皮肤滞留实验
体外透皮实验结束后,取下猪皮,皮肤表面用蒸馏水清洗3遍,滤纸吸干,然后剪取有效渗透面积内的猪皮,加入5mL乙腈溶液,匀浆5min,0.22μm滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算单位面积皮肤内药物的滞留量。
表2 CBD皮肤滞留量(μg/cm2)
剂型 | 滞留量 |
CBD溶液 | 45.69±2.53 |
H2-Bub/CBD@PD1/SD-MNs | 121.08±5.66 |
实施例9
O2-Bub/CBDA@ICG/SD-MNs渗透及皮肤滞留
采用Franz透皮扩散试验仪进行O2-Bub/CBDA@ICG/SD-MNs的体外经皮渗透性研究。按实施例3所述方法制备O2-Bub/CBDA@ICG/SD-MNs贴片。扩散池的有效渗透面积为2.2cm2,接收池的容积为6.5mL。选择乙醇-PEG400-生理盐水(5:3:2)溶液作为接收液,将适合大小的离体猪皮置于供给池与接收池之间,角质层面向供给池,真皮层面向接收池,接收池内加入6.5mL接收液,接收液与皮肤之间紧密接触无气泡,供给池内分别加入1mLCBDA 溶液和一片O2-Bub/CBDA@ICG/SD-MNs,上方用保鲜膜封闭,扩散池于37℃水浴温度下, 400rpm恒温搅拌。分别于2、4、6、8、12、24h取样5mL,同时补充5mL相同温度接收液,样品过0.22μm滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算药物累积透过量。
表3 O2-Bub/CBDA@ICG/SD-MNs的CBDA累积透过量(μg/cm2)
Time(h) | CBDA溶液 | O2-Bub/CBDA@ICG/SD-MNs |
2 | 0 | 0.45±0.01 |
4 | 0 | 0.82±0.54 |
6 | 0.03±0.01 | 1.66±0.15 |
8 | 0.16±0.01 | 5.66±0.21 |
12 | 0.67±0.03 | 9.45±0.52 |
24 | 1.02±0.32 | 34.26±4.24 |
2.离体皮肤滞留实验
体外透皮实验结束后,取下猪皮,皮肤表面用蒸馏水清洗3遍,滤纸吸干,然后剪取有效渗透面积内的猪皮,加入5mL乙腈溶液,匀浆5min,0.22μm滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算单位面积皮肤内药物的滞留量。
表4 CBDA皮肤滞留量(μg/cm2)
剂型 | 滞留量 |
CBDA溶液 | 64.24±2.42 |
O2-Bub/CBDA@ICG/SD-MNs | 95.25±8.35 |
实施例10
CO2-Bub/CBD/SD-MNs渗透及皮肤滞留
采用Franz透皮扩散试验仪进行CO2-Bub/CBD/SD-MNs的体外经皮渗透性研究。按实施例5所述方法制备CO2-Bub/CBD/SD-MNs贴片。扩散池的有效渗透面积为2.2cm2,接收池的容积为6.5mL。选择乙醇-PEG400-生理盐水(5:3:2)溶液作为接收液,将适合大小的离体猪皮置于供给池与接收池之间,角质层面向供给池,真皮层面向接收池,接收池内加入6.5mL 接收液,接收液与皮肤之间紧密接触无气泡,供给池内分别加入1mL CBD溶液和一片CO2-Bub/CBD/SD-MNs,上方用保鲜膜封闭,扩散池于37℃水浴温度下,400rpm恒温搅拌。分别于2、4、6、8、12、24h取样5mL,同时补充5mL相同温度接收液,样品过0.22μm 滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算药物累积透过量。
表5 CO2-Bub/CBD/SD-MNs的CBD累积透过量(μg/cm2)
Time(h) | CBD溶液 | CO2-Bub/CBD/SD-MNs |
2 | 0 | 0.74±0.02 |
4 | 0.02±0.01 | 1.42±0.24 |
6 | 0.14±0.01 | 1.71±0.45 |
8 | 0.45±0.03 | 7.63±0.52 |
12 | 0.91±0.01 | 10.33±0.35 |
24 | 3.24±0.06 | 54.33±6.35 |
2.离体皮肤滞留实验
体外透皮实验结束后,取下猪皮,皮肤表面用蒸馏水清洗3遍,滤纸吸干,然后剪取有效渗透面积内的猪皮,加入5mL乙腈溶液,匀浆5min,0.22μm滤膜过滤,以高效液相色谱法进行分析,记录峰面积,计算单位面积皮肤内药物的滞留量。
表6 CBD皮肤滞留量(μg/cm2)
剂型 | 滞留量 |
CBD溶液 | 33.28±1.85 |
CO2-Bub/CBD/SD-MNs | 105.36±6.32 |
实施例11
H2-Bub/CBD@PD1/SD-MNs体内经皮渗透
按实施例1方案制备H2-Bub/CBD@PD1/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBD溶液组以及CBD@PD1/SD-MNs;模型对照组将给予同等剂量的生理盐水。所有给药组用C6绿色荧光探针做标记。雌性C57BL/6J小鼠,年龄6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组,包含 C6/H2-Bub/CBD@PD1/SD-MNs组、C6/CBD@PD1/SD-MNs组和C6/CBD溶液组。单次给药后0.5h、1h、2h、4h、8h,皮肤及肿瘤切片观察荧光探针渗透深度。
结果如表7所示,C6/H2-Bub/CBD@PD1/SD-MNs组在皮肤中滞留相对较少,在肿瘤中深度渗透最高;C6/CBD@PD1/SD-MNs组肿瘤内部渗透次之;游离组的渗透较差。
表7给药8h后各组皮肤及肿瘤渗透(μm)
剂型 | 皮肤滞留探针(a.u.) | 肿瘤渗透(μm) |
C6/CBD溶液 | 324.22±1.85 | 15.24±2.24 |
C6/CBD@PD1/SD-MNs | 635.24±52.15 | 184.42±4.73 |
C6/H2-Bub/CBD@PD1/SD-MNs | 895.24±42.44 | 634.24±52.66 |
实施例12
O2-Bub/CBDA@ICG/SD-MNs体内经皮渗透
按实施例3方案制备O2-Bub/CBDA@ICG/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBAD溶液组以及O2-Bub/CBDA@ICG/SD-MNs;模型对照组将给予同等剂量的生理盐水。所有给药组用C6绿色荧光探针做标记。雌性C57BL/6J小鼠,年龄6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组,包含C6/O2-Bub/CBDA@ICG/SD-MNs组、C6/CBDA@ICG/SD-MNs组和C6/CBDA溶液组。单次给药后0.5h、1h、2h、4h、8h,皮肤及肿瘤切片观察荧光探针渗透深度。
结果如表8所示,C6/O2-Bub/CBDA@ICG/SD-MNs组在皮肤中滞留相对较少,在肿瘤中深度渗透最高;C6/CBDA@ICG/SD-MNs组肿瘤内部渗透次之;游离组的渗透较差。
表8给药8h后各组皮肤及肿瘤渗透(μm)
剂型 | 皮肤滞留探针(a.u.) | 肿瘤渗透(μm) |
C6/CBDA溶液 | 299.62±4.45 | 25.34±5.27 |
C6/CBDA@ICG/SD-MNs | 536.83±26.12 | 158.43±21.43 |
C6/O2-Bub/CBDA@ICG/SD-MNs | 845.35±25.82 | 644.52±62.18 |
实施例13
CO2-Bub/CBD/SD-MNs体内经皮渗透
按实施例3方案制备CO2-Bub/CBDA/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBA溶液组以及CO2-Bub/CBDA/SD-MNs;模型对照组将给予同等剂量的生理盐水。所有给药组用C6绿色荧光探针做标记。雌性C57BL/6J小鼠,年龄 6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组,包含 C6/CO2-Bub/CBDA/SD-MNs组、C6/CBDA/SD-MNs组和C6/CBD溶液组。单次给药后0.5h、 1h、2h、4h、8h,皮肤及肿瘤切片观察荧光探针渗透深度。
结果如表9所示,C6/CO2-Bub/CBDA/SD-MNs组在皮肤中滞留相对较少,在肿瘤中深度渗透最高;C6/CBDA/SD-MNs组肿瘤内部渗透次之;游离组的渗透较差。
表9给药8h后各组皮肤及肿瘤渗透(μm)
剂型 | 皮肤滞留探针(a.u.) | 肿瘤渗透(μm) |
C6/CBD溶液 | 159.35±3.55 | 35.37±8.35 |
C6/CBDA/SD-MNs | 696.35±56.46 | 268.21±46.31 |
C6/CO2-Bub/CBDA/SD-MNs | 943.24±73.35 | 942.45±145.45 |
实施例14
H2-Bub/CBD@PD1/SD-MNs体内抗黑色素瘤实例
结果如表10所示,H2-Bub/CBD@PD1/SD-MNs治疗后,小鼠体重未发生明显变化,肿瘤生长受到明显抑制,最大生存期明显高于游离的CBD治疗组。综合抗肿瘤效能高于游离CBD、PD1抗体以及CBD@PD1/SD-MNs各组。
表10治疗结束后抗肿瘤核心指标数据
实施例15
H2-Bub/CBDA@PD-L1/SD-MNs体内抗黑色素瘤实例
按实施例2方案制备H2-Bub/CBDA@PD-L1/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBDA溶液组、PD-L1抗体组以及 CBDA@PD-L1/SD-MNs;模型对照组将给予同等剂量的生理盐水。雌性C57BL/6J小鼠,年龄6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组。每天一次贴片,连续给药5天,治疗完毕后考察抗肿瘤的各项核心指标,包括体重变化、肿瘤体积、生存时间等。
结果如表11所示,H2-Bub/CBDA@PD-L1/SD-MNs治疗后,小鼠体重未发生明显变化,肿瘤生长受到明显抑制,最大生存期明显高于游离的CBDA治疗组。综合抗肿瘤效能高于游离CBDA、PD-L1抗体以及CBDA@PD-L1/SD-MNs各组。
表11治疗结束后抗肿瘤核心指标数据
实施例16
O2-Bub/CBDA@ICG/SD-MNs体内抗黑色素瘤实例
按实施例3方案制备O2-Bub/CBDA@ICG/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBDA溶液组、ICG组以及CBDA@ICG/SD-MNs;模型对照组将给予同等剂量的生理盐水。雌性C57BL/6J小鼠,年龄6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组。每天一次贴片,给药1h后用650nm 近红外光照10min(50mw),连续给药14天,治疗完毕后考察抗肿瘤的各项核心指标,包括体重变化、肿瘤体积、生存时间等。
结果如表12所示,O2-Bub/CBDA@ICG/SD-MNs治疗后,小鼠体重未发生明显变化,肿瘤生长受到明显抑制,最大生存期明显高于游离的CBDA治疗组。综合抗肿瘤效能高于游离CBDA、ICG以及CBDA@ICG/SD-MNs各组。
表12治疗结束后抗肿瘤核心指标数据
实施例17
CO2-Bub/CBD/SD-MNs体内抗黑色素瘤实例
按前述实施例方案制备CO2-Bub/CBD/SD-MNs,单次给药量为阵列20×20贴片,给药剂量为0.2mg/kg;制剂对照组为CBD溶液组以及CBD/SD-MNs;模型对照组将给予同等剂量的生理盐水。雌性C57BL/6J小鼠,年龄6~10周,体重18~22g,由上海斯莱克实验动物中心提供。动物数为:6只/组。每天一次贴片,连续给药14天,治疗完毕后考察抗肿瘤的各项核心指标,包括体重变化、肿瘤体积、生存时间等。
结果如表13所示,CO2-Bub/CBD/SD-MNs治疗后,小鼠体重未发生明显变化,肿瘤生长受到明显抑制,最大生存期明显高于游离的CBD治疗组。综合抗肿瘤效能高于游离CBD溶液以及CBD/SD-MNs两组。
表13治疗结束后抗肿瘤核心指标数据
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Claims (9)
1.一种前置空泡型大麻脂溶性活性物可溶微针,包括背衬层和背衬层上固定的微针阵列,其特征在于,所述微针的针尖部埋入活泼金属颗粒、碳酸氢盐、碳酸盐、二氧化铈颗粒或铈锆复合氧化物颗粒中的一种;针体填入含大麻脂溶性活性物固体分散体的可溶微针基质材料;
其制备方法为:
(1)利用大麻脂溶性活性物和聚合物载体制备大麻脂溶性活性物固体分散体;
(2)取活泼金属颗粒分散于有机溶剂中,将混合溶液滴加在微针模具表面,离心干燥;或:取二氧化铈颗粒/铈锆复合氧化物颗粒分散于表面活性剂溶液中,将混合溶液滴加在微针模具表面,离心干燥;或:取碳酸氢盐/碳酸盐透明质酸混合溶液滴加在微针模具表面,离心干燥;
(3)将所述大麻脂溶性活性物固体分散体和水溶性针体基质材料以水溶解后滴加在微针模具表面,离心干燥;
(4)取微针背衬材料制作背衬,获取所述可溶微针。
2.根据权利要求1所述的可溶微针,其特征在于,微针的针尖材料选用透明质酸、壳聚糖、明胶淀粉、蔗糖、PVA或PVP。
3.根据权利要求1所述的可溶微针,其特征在于,微针的背衬材料选用透明质酸、PVP、PVA、壳聚糖、CMC、海藻酸钠、HPMC、明胶或糊精。
4.根据权利要求1所述的可溶微针,其特征在于,所述大麻脂溶性活性物固体分散体为过80~200目筛的粉末状大麻脂溶性活性物固体分散体。
5.根据权利要求1所述的可溶微针,其特征在于,还包括,在将大麻脂溶性活性物固体分散体和水溶性针尖材料以水溶解时,加入药物与之共溶;所述药物为免疫治疗药物、光动力治疗药物或化学动力治疗药物。
6. 根据权利要求1所述的可溶微针,其特征在于,所述(2)中,所述活泼金属颗粒在混合溶液中浓度为1 wt% ~ 5 wt%;所述二氧化铈颗粒/铈锆复合氧化物在混合溶液中浓度为0.2 wt% ~ 1 wt%;所述碳酸氢盐/碳酸盐在混合溶液中浓度为0.5 wt%~20 wt%。
7. 根据权利要求1所述的可溶微针,其特征在于,所述大麻脂溶性活性物和聚合物载体的质量比为1:1 ~ 1:10。
8. 根据权利要求1所述的可溶微针,其特征在于,将背衬材料溶解于去离子水中,滴加在微针模具表面并高出模具2 ~ 15 mm。
9.权利要求1~8任一项所述前置空泡型大麻脂溶性活性物可溶微针在制备浅表性皮肤瘤治疗药物中的应用。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9533942B2 (en) * | 2009-08-31 | 2017-01-03 | Zynerba Pharmaceuticals, Inc. | Use of cannabidiol prodrugs in topical and transdermal administration with microneedles |
CN110840823A (zh) * | 2018-08-20 | 2020-02-28 | 中国海洋大学 | 一种传递体复合自溶微针及其制备方法 |
CN113018266A (zh) * | 2019-12-25 | 2021-06-25 | 晨光生物科技集团股份有限公司 | 一种大麻二酚固体分散体的制备方法、制备得到的大麻二酚固体分散体及其用途 |
CN113679692A (zh) * | 2020-05-15 | 2021-11-23 | 华中科技大学 | 一种可产生气体快速起效的微针阵列贴片及其制备与应用 |
-
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- 2021-12-23 CN CN202111587021.4A patent/CN114225033B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9533942B2 (en) * | 2009-08-31 | 2017-01-03 | Zynerba Pharmaceuticals, Inc. | Use of cannabidiol prodrugs in topical and transdermal administration with microneedles |
CN110840823A (zh) * | 2018-08-20 | 2020-02-28 | 中国海洋大学 | 一种传递体复合自溶微针及其制备方法 |
CN113018266A (zh) * | 2019-12-25 | 2021-06-25 | 晨光生物科技集团股份有限公司 | 一种大麻二酚固体分散体的制备方法、制备得到的大麻二酚固体分散体及其用途 |
CN113679692A (zh) * | 2020-05-15 | 2021-11-23 | 华中科技大学 | 一种可产生气体快速起效的微针阵列贴片及其制备与应用 |
Non-Patent Citations (1)
Title |
---|
Rosemary Burch等.Effects of cannabidiol (CBD) on the inhibition of melanoma cells in vitro.《J Immunoassay Immunochem》.2021,第42卷(第3期),第285-291页,摘要. * |
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