CN114848578A - 一种含雄激素受体蛋白靶向联合体的生发微针贴片及其制备方法和应用 - Google Patents
一种含雄激素受体蛋白靶向联合体的生发微针贴片及其制备方法和应用 Download PDFInfo
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- CN114848578A CN114848578A CN202210491718.XA CN202210491718A CN114848578A CN 114848578 A CN114848578 A CN 114848578A CN 202210491718 A CN202210491718 A CN 202210491718A CN 114848578 A CN114848578 A CN 114848578A
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Abstract
本发明公开了一种含雄激素受体蛋白靶向联合体的生发微针贴片,其特征在于,所述生发微针贴片包括片状背衬和排列在该片状背衬上的含雄激素受体蛋白靶向联合体的可溶性微针针体;所述可溶性微针针体包括雄激素受体蛋白靶向联合体、其药学上可接受的盐、其立体异构体、其几何立构体、其互变异构体、其酯、其前药、其溶剂化物、其代谢产物、其氮氧化物或者其氘代化合物中的一种或多种。本发明还公开了上述含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法及在制备治疗雄激素源性脱发药物上的应用。本发明提供的生发微针贴片具有作用安全、高效和使用方便的优点。
Description
技术领域
本发明属于生物医用材料技术领域,具体涉及一种含雄激素受体蛋白靶向联合体的生发微针贴片及其制备方法和应用。
背景技术
雄激素性脱发(Androgenetic alopecia,AGA),是临床上最为常见的病理性脱发类型。男女均可罹患,以进行性的毛囊微型化为特征,表现为额部发际后退,或顶部头发逐渐稀疏、脱落,头发密度进行性减少,最终导致脱发,严重影响患者的心理健康。调查显示,在我国男性患病率约为21.3%,女性患病率约为6.0%。近年来,随着社会的高速发展,竞争愈发激烈,人们精神压力增加,AGA的发病率呈逐年上升趋势,且伴有年轻化趋势。脱发直接影响个人外形美观、社交,对患者的心理产生负面影响,严重影响患者的生活质量。但目前仍缺乏理想的治疗手段,现有药物治疗(米诺地尔、非那雄胺)疗程长、不良反应多、停药易复发、患者依从性差,而毛发移植存在创伤大、费用高昂、术后毛发密度不理想等问题。基于上述发病和治疗现状,从AGA发病机理出发,探索更安全有效的治疗手段是现在的研究热点。
雄激素源性脱发是由包括雄激素在内的多因素共同导致的。雄激素(睾酮、二氢睾酮)与雄激素受体结合的复合物会抑制GSK-3β的去磷酸化,导致β-catenin降解和Wnt/β-catenin通路下调;同时上调TGF-β1、TGF-β2、IL-6和DKK-1等旁分泌因子,Wnt/β-catenin和TGF-β通路的改变会导致毛囊静止期延长、毛囊周期的延迟、抑制上皮细胞增殖,造成毛囊微型化,最终导致雄激素性脱发的发生。研究表明,雄激素源性脱发患者脱发区域的毛乳头处雄激素受体(AR)表达增加,且雄激素与AR的亲和力也更高。近年来,局部抗雄激素疗法因其在治疗雄激素性脱发的潜在功效及与全身药物作用相比副作用减少而受到关注,外用非那雄胺、酮康唑洗发水及外用克拉克特龙均已进入临床试验,但不同患者治疗效果不一。雄激素受体蛋白靶向联合体(Androgen Receptor-Proteolysis Targeting ChimericMolecules,AR-PROTAC)通过一个连接子连接雄激素受体靶蛋白的配体及E3泛素连接酶的招募配体,进入细胞后识别雄激素受体并通过E3酶使其泛素标记,从而实现高效的雄激素受体降解。
微针(Microneedles,MNs)是由硅、金属或其他材料通过微电子制造技术或微铸模技术制成的长度为100μm~2000μm不等的细小的针,通常由大量的微针组成阵列结构,称为微针贴片。微针既可以刺穿角质层在皮肤表面形成微孔道帮助药物进入皮肤,其长度又不足以触及皮下痛觉神经,形成的微孔道也可在数小时内恢复,具有微创微痛性、和使用便捷性。常见的微针包括固体微针、空心微针和可溶性微针等,其中固体微针缺乏载药能力,一般需要其对皮肤进行预处理,形成微孔道后,再涂抹药物,操作较为繁琐,且无法精确控制进入皮肤的药量。空心微针在针的轴线上有类似与传统注射功能的小孔,与微注射相似,但其制备工艺复杂,针尖容易被真皮组织堵塞,无法释药。而可溶性微针可以精准剂量载药,制备工艺相对较为简单,其基质多为生物相容性较高的聚合物材料,能够在皮肤内完全溶解或降解,使用便捷。
发明内容
本发明的目的在于提供一种含雄激素受体蛋白靶向联合体的生发微针贴片及其制备方法,通过将雄激素受体蛋白靶向联合体载于微针中,为AGA的治疗提供一种安全、高效、且微创微痛的治疗手段。
为实现上述目的,按照本发明的一个方面,提供了一种含雄激素受体蛋白靶向联合体的生发微针贴片,包括:片状背衬和排列在该片状背衬上的可溶性微针针体;其中,所述可溶性微针针体包括雄激素受体蛋白靶向联合体、其药学上可接受的盐、其立体异构体、其几何立构体、其互变异构体、其酯、其前药、其溶剂化物、其代谢产物、其氮氧化物或者其氘代化合物中的一种或多种。
可溶性微针针体是通过雄激素受体蛋白靶向联合体与可溶性聚合物溶液进行混合后干燥以使得所述可溶性微针内载有雄激素受体蛋白靶向联合体;所述雄激素受体蛋白靶向联合体通过化学合成得到,结构式如下:
其药物可接受的盐,具体地,酸或碱加成盐。在适用情况下,术语“药物可接受的盐”在本说明书中用于描述本文描述的化合物中的一种或多种的盐的形式。药物可接受的盐包括来源于药物可接受的无机或有机碱和酸(在适用情况下)的那些。适合的盐包括来源于碱金属(如钾和钠)、碱土金属(如钙、镁和铵盐)以及药物领域中熟知的多种其它酸和碱的的那些。
用于制备在本发明中有用的上述碱化合物的药物可接受的酸加成盐的酸是形成无毒酸加成盐的那些,所述无毒酸加成盐即含有药理学可接受的阴离子的盐,如盐酸盐、三氟乙酸盐、甲酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡萄糖酸盐、蔗糖酸盐、苯甲酸酯、甲磺酸酯、乙磺酸酯、苯磺酸酯、对甲苯磺酸酯和双羟萘酸盐[即,1,1-亚甲基-二-(2-羟基-3萘甲酸盐)]盐以及众多其它盐。
药物可接受的碱加成盐也可以用于生产根据本发明的化合物或衍生物的药物可接受的盐形式。可以用作试剂来制备在性质上是酸性的本发明化合物的药物可接受的碱盐的化学碱是与这些化合物形成无毒碱盐的那些。这些无毒碱盐包括(但不限于)来源于这药理学可接受的阳离子,如碱金属阳离子(例如,钾和钠)和碱土金属阳离子(例如,钙、锌和镁)、铵或水溶性胺加成盐,如N-甲葡糖胺-(葡甲胺)和低级烷醇铵以及药物可接受的有机胺的其它碱的那些等;
其中,背衬和可溶性微针针体由不同的聚合物材料构成。
优选地,所述贴片中背衬所采用的聚合物为支链淀粉、聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
优选地,所述可溶性微针针体所采用的聚合物为透明质酸、聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
按照本发明的另一方面,提供了一种上文所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,所述方法包括下列步骤:
1)首先以化合物1和化合物2为原料,在溶剂和碱的作用下搅拌反应至原料反应完全得化合物3;
2)将化合物3溶于二氯甲烷,加入有机酸或无机酸,氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,萃取干燥浓缩后,打浆抽滤得化合物4;
3)以化合物4和化合物5为原料,在溶剂、酰胺连接剂和碱的作用下反应得化合物6;
4)将化合物6溶于二氯甲烷,加入有机酸或无机酸,氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,用二氯甲烷萃取干燥浓缩得化合物7;
5)以化合物7和化合物8为原料,在溶剂、乙酸、三乙酰氧基硼氢化钠的作用下反应,干燥浓缩得化合物9;
6)将化合物9溶于二氯甲烷,加入有机酸或无机酸,三氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,用二氯甲烷萃取干燥浓缩得化合物10;
7)以化合物10、化合物11为原料,在溶剂和碱的作用下反应完全,浓缩和纯化后得到雄激素受体蛋白靶向联合体,其形式可为化合物游离状态或化合物的盐形式;
8)配制可溶性针体聚合物溶液:将雄激素受体蛋白靶向联合体与可溶性针体聚合物溶液混合得到混合溶液,将该混合溶液注入微针模具中,通过离心使混合溶液填满整个微针模具,刮去多余的聚合物溶液,干燥;
9)配制背衬聚合物溶液,将该聚合物溶液注入微针模具中,通过离心使背衬聚合物溶液填满模具背衬部分,干燥后剥离该微针模具,得到生发微针贴片。
优选地,在步骤(1)中,所述溶剂选自水、醚(如THF、甘醇二甲醚等)或氯化溶剂(如DCM、1,2-二氯乙烷(DCE)或CHCl3等)、甲苯、苯等、DMF、DMSO、MeCN;所述碱包括(但不限于)碳酸铯、碳酸钾、氢化钠、三乙胺、DIPEA等。
优选地,在步骤(1)中,在约-78℃至约150℃之间的温度进行;进一步优选地,在约0℃至约100℃之间进行反应。
优选地,在步骤(2)中,有机酸为三氟乙酸或甲酸等,无机酸为盐酸二氧六环、硫酸等。优选地,用二氯甲烷萃取干燥浓缩后,加入甲基叔丁基醚打浆抽滤得化合物4。
优选地,在步骤(3)中,溶剂可选择包括(但不限于)水、醚,如THF、甘醇二甲醚等;氯化溶剂,如DCM、1,2-二氯乙烷(DCE)或CHCl3等、甲苯、苯等、DMF、DMSO、MeCN;如果需要,使用这些溶剂的混合物。进一步优选地,溶剂是DMF或DCM。
优选地,在步骤(3)中,适合的酰胺连接剂包括(但不限于)DCC、EDC、HATU、HBTU、PyBOP等。
优选地,在步骤(3)中,碱包括(但不限于)TEA、DIPEA等。
优选地,在步骤(3)中,在约0℃至约100℃之间进行反应。
优选地,在步骤(4)中,有机酸为三氟乙酸或甲酸等,无机酸为盐酸二氧六环、硫酸等。用二氯甲烷萃取干燥浓缩得化合物7。
优选地,在步骤(5)中,溶剂可选择包括(但不限于)水、醚,如THF、甘醇二甲醚等;氯化溶剂,如DCM、1,2-二氯乙烷(DCE)或CHCl3等、甲苯、苯等、DMF、DMSO、MeCN。
优选地,在步骤(6)中,有机酸为三氟乙酸或甲酸等,无机酸为盐酸二氧六环、硫酸等。用二氯甲烷萃取干燥浓缩得化合物7。
优选地,在步骤(7)中,溶剂可选择包括(但不限于)水、醚,如THF、甘醇二甲醚等;氯化溶剂,如DCM、1,2-二氯乙烷(DCE)或CHCl3等、甲苯、苯等、DMF、DMSO、MeCN,将碱加入反应中,适合的碱包括(但不限于)TEA、DIPEA等。可以在约-78℃至约150℃之间的温度进行。进一步优选地,在约0℃至约100℃之间进行反应。
优选地,所述步骤8)中,配制得到的可溶性针体聚合物溶液的质量分数为10~100%,所述的雄激素受体蛋白靶向联合体占混合溶液总体积的10~2000mg/ml加入进行混合得到,离心速度为1000~10000rpm,离心时间为1~30min,干燥时间为12~24h。
优选地,所述步骤9)中,配置得到的背衬聚合物溶液的质量分数为20~80%,离心速度为1000~10000rpm,离心时间为1~30min,干燥时间为24~72h。
本发明还提供了上述含雄激素受体蛋白靶向联合体的生发微针贴片在制备治疗雄激素源性脱发药物上的应用。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,具有以下优点:
(1)本发明中提供的生发微针贴片由两步离心法制备得到,针体含雄激素受体蛋白靶向联合体,贴片背衬不含雄激素受体蛋白靶向联合体,不会引起药物的浪费。使用时,微针针体吸收组织液快速溶解,贴片背衬可被移除,给药过程较短,且不影响美观,病人依从性较高。
(2)本发明提供的生发微针贴片可直接刺过皮肤角质层屏障,随着微针针体的溶解逐渐释放出所含的雄激素受体蛋白靶向联合体,将雄激素受体蛋白靶向联合体直接递送至毛囊毛乳头细胞处,通过降解雄激素受体而发挥治疗效果,作用安全、高效,使用方便,具有实现临床转化的应用前景。
(3)本发明所涉及的制备方法中,雄激素受体蛋白靶向联合体通过结构内的雄激素受体靶蛋白的配体识别雄激素受体,同时结构内的E3泛素连接酶的招募配体通过E3酶使雄激素受体泛素标记,从而实现高效的雄激素受体降解,抑制AGA发展过程中雄激素与雄激素受体的结合,加快毛囊进入生长期,诱导毛发再生。
(4)本发明从AGA的发病机理出发解决问题,将雄激素受体蛋白靶向联合体的生发微针贴片用于治疗AGA,具有实现临床转化的应用前景,为当前AGA治疗中无法根治、经常复发的问题提供了解决方案。
附图说明
图1是本发明实施例1中提供的针体为四棱锥体形的生发微针贴片的SEM图。
图2是使用本发明制备的含雄激素受体蛋白靶向联合体的生发微针贴片的AGA模型小鼠的毛发再生情况。
图3是使用本发明制备的含雄激素受体蛋白靶向联合体的生发微针贴片的AGA模型小鼠的新生毛发覆盖率的结果图。
图4是使用本发明制备的含雄激素受体蛋白靶向联合体的生发微针贴片的小鼠皮肤中雄激素受体含量。
具体实施方式
下面结合具体实施例和说明书附图对本发明作进一步说明。
实施例1
本实施例提供一种可溶性生发微针贴片的制备方法,包括:
1、制备雄激素受体蛋白靶向联合体:
将化合物2(2.0g,1.0eq.)溶于20mL N,N-二甲基甲酰胺,冰浴,加入氢化钠(60%,0.56g,1.5eq.),搅拌0.5h,将化合物1(1.45g,1.0eq.)溶于10mL N,N-二甲基甲酰胺中,滴入上述反应液,室温反应至原料反应完全,反应液浓缩,柱层析纯化(V石油醚/V乙酸乙酯=6/1),得白色固体3.1g,收率95%,UPLC-MS:m/z 351.15[M+H]+;
将化合物3(1.0g,1.0eq.)溶于12mL二氯甲烷,加入三氟乙酸4mL,氩气保护,室温反应至原料反应完全,用饱和碳酸氢钠调节pH至7,二氯甲烷萃取,干燥浓缩后,加入甲基叔丁基醚20mL打浆20min,抽滤得白色固体0.69g,收率96%,UPLC-MS:m/z 251.10[M+H]+;
将化合物5(1.0g,1.0eq.)溶于15mL无水N,N-二甲基甲酰胺,加入N,N-二异丙基乙胺1.2mL(2.0eq.),O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(1.82g,1.2eq.),氮气保护,室温搅拌15min,加入化合物4(0.82g,1.0eq.),室温反应至反应完全,反应液浓缩后柱层析纯化(V石油醚/V乙酸乙酯=6/1)得白色固体2.02g,收率94%,UPLC-MS:m/z539.24[M+H]+;
将化合物6(1.0g,1.0eq.)溶于10mL二氯甲烷,加入三氟乙酸4mL,氩气保护,室温反应至反应完全,反应液浓缩,用饱和碳酸氢钠调pH至7,二氯甲烷萃取,干燥浓缩,柱层析纯化(D/M 30:1-15:1)得白色固体0.77g,收率95%,UPLC-MS:m/z 439.19[M+H]+;
将化合物7(1.0g,1.0eq.)溶于二氯甲烷15mL,加入化合物8(0.6g,1.2eq.),乙酸3滴,室温反应1h,加入三乙酰氧基硼氢化钠(0.97g,2.0eq.),反应至原料反应完全,加水淬灭反应,二氯甲烷萃取,浓缩干燥,柱层析纯化(V石油醚/V乙酸乙酯=4/1)得白色固体1.33g,收率92%,UPLC-MS:m/z 636.33[M+H]+;
将化合物9(1.0g,1.0eq.)溶于8mL二氯甲烷,加入二氯甲烷3.5mL,氩气保护,室温反应至反应完全,反应液浓缩,用饱和碳酸氢钠调pH至中性,二氯甲烷萃取,干燥浓缩,柱层析纯化(V二氯甲烷/V甲醇=20/1),得产物0.8g,收率95%,UPLC-MS:m/z536.28[M+H]+;
将化合物10(100mg,1.0eq.)、化合物11(62mg,1.0eq.)、N,N-二异丙基乙胺65μL(2.0eq.)溶于6mL无水二氯甲烷中,90℃反应过夜至反应完全,反应液浓缩,经制备HPLC纯化,得荧光绿色固体103mg,收率70%。UPLC-MS calculated for C43H46ClN7O6[M+H]+:792.33found:792.36.UPLC-retention time:6.9min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.05(d,J=7.6Hz,1H),7.80(dd,J=23.7,8.7Hz,3H),7.65(d,J=8.5Hz,1H),7.34(dd,J=6.7,2.3Hz,2H),7.24(dd,J=8.7,2.3Hz,1H),7.11(dd,J=8.8,2.4Hz,1H),7.01(d,J=8.7Hz,2H),5.04(dd,J=12.9,5.4Hz,1H),4.50(dp,J=9.0,4.3Hz,1H),4.07(d,J=13.1Hz,2H),3.93(d,J=9.3Hz,2H),3.81–3.72(m,1H),3.60(d,J=8.2Hz,2H),3.19–2.79(m,10H),2.61–2.47(m,1H),2.21–1.76(m,8H),1.58–1.39(m,4H),1.32–1.17(m,2H).
2、制备预混溶液:制备70%的透明质酸溶液,将根据步骤1得到的雄激素受体蛋白靶向联合体,与该透明质酸溶液按照总体积的50%加入进行混合得到。
3、制备微针贴片:将所述步骤2得到的预混溶液注入定制的聚二甲基硅氧烷(PDMS,Sylgard 184)微针阵列模具中。接着,将该PDMS微针阵列模具以3500rpm离心10分钟,使其被完全填满后取出,刮去多余的预混溶液。将该PDMS微针阵列模具置于硅胶干燥器内,室温下干燥2h。取出该PDMS微针阵列模具,注入40%聚乙烯醇溶液。接着,将该PDMS微针阵列模具以3500rpm离心5分钟,形成背衬后取出。将该PDMS微针阵列模具置于硅胶干燥器内,室温下干燥24h,即得到含雄激素受体蛋白靶向联合体的生发微针贴片。
在本实施例中,雄激素受体蛋白靶向联合体可以替换为或再包括该化合物、其药学上可接受的盐、其立体异构体、其几何立构体、其互变异构体、其酯、其前药、其溶剂化物、其代谢产物、其氮氧化物或者其氘代化合物中的一种或多种。
在本实施例中,透明质酸溶液可以替换为或再包括聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
在本实施例中,聚乙烯醇溶液可以替换为或再包括支链淀粉、聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
本实施例中,通过采用雄激素受体蛋白靶向联合体与聚合物溶液进行混合,最后得到固态的可溶性微针贴片。该固态的可溶性微针贴片制备过程温和,无需极端条件,制备简便,且可在干燥环境中进行常温保存,有效实现雄激素受体蛋白靶向联合体的透皮递送。
本实施例中,生发微针贴片由两步离心法制备得到,针体含雄激素受体蛋白靶向联合体,贴片背衬不含雄激素受体蛋白靶向联合体,不会引起活性物质的浪费。使用时,微针针体吸收组织液快速溶解,贴片背衬可被移除,给药过程较短,且不影响美观,病人依从性较高。
实施例2
本实施例提供一种可溶性生发微针贴片的制备方法,包括:
1、制备雄激素受体蛋白靶向联合体:
将化合物2(2.0g,1.0eq.)溶于20mL N,N-二甲基甲酰胺,冰浴,加入氢化钠(60%,0.56g,1.5eq.),搅拌0.5h,将化合物1(1.45g,1.0eq.)溶于10mL N,N-二甲基甲酰胺中,滴入上述反应液,室温反应至原料反应完全,反应液浓缩,柱层析纯化(V石油醚/V乙酸乙酯=6/1),得白色固体3.1g,收率95%。UPLC-MS:m/z 351.15[M+H]+;
将化合物3(1.0g,1.0eq.)溶于12mL二氯甲烷,加入三氟乙酸4mL,氩气保护,室温反应至原料反应完全,用饱和碳酸氢钠调节pH至7,二氯甲烷萃取,干燥浓缩后,加入甲基叔丁基醚20mL打浆20min,抽滤得白色固体0.69g,收率96%。UPLC-MS:m/z 251.10[M+H]+;
将化合物5(1.0g,1.0eq.)溶于15mL无水N,N-二甲基甲酰胺,加入N,N-二异丙基乙胺1.2mL(2.0eq.),O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(1.82g,1.2eq.),氮气保护,室温搅拌15min,加入化合物4(0.82g,1.0eq.),室温反应至反应完全,反应液浓缩后柱层析纯化(V石油醚/V乙酸乙酯=6/1)得白色固体2.02g,收率94%。UPLC-MS:m/z539.24[M+H]+;
将化合物6(1.0g,1.0eq.)溶于10mL二氯甲烷,加入三氟乙酸4mL,氩气保护,室温反应至反应完全,反应液浓缩,用饱和碳酸氢钠调pH至中性,二氯甲烷萃取,干燥浓缩,柱层析纯化(D/M 30:1-15:1)得白色固体0.77g,收率95%。UPLC-MS:m/z439.19[M+H]+;
将化合物7(1.0g,1.0eq.)溶于二氯甲烷15mL,加入化合物8(0.6g,1.2eq.),乙酸3滴,室温反应1h,加入三乙酰氧基硼氢化钠(0.97g,2.0eq.),反应至原料反应完全,加水淬灭反应,二氯甲烷萃取,浓缩干燥,柱层析纯化(V石油醚/V乙酸乙酯=4/1)得白色固体1.33g,收率92%。UPLC-MS:m/z 636.33[M+H]+;
将化合物9(1.0g,1.0eq.)溶于8mL二氯甲烷,加入二氯甲烷3.5mL,氩气保护,室温反应至反应完全,反应液浓缩,用饱和碳酸氢钠调pH至7,二氯甲烷萃取,干燥浓缩,柱层析纯化(V二氯甲烷/V甲醇=20/1),得产物0.8g,收率95%。UPLC-MS:m/z 536.28[M+H]+;
将化合物10(100mg,1.0eq.)、化合物11(62mg,1.0eq.)、N,N-二异丙基乙胺65μL(2.0eq.)溶于6mL无水二氯甲烷中,90℃反应过夜至反应完全,反应液浓缩,经制备HPLC纯化得荧光绿色固体103mg,收率70%。UPLC-MS calculated for C43H46ClN7O6[M+H]+:792.33found:792.36.UPLC-retention time:6.9min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.05(d,J=7.6Hz,1H),7.80(dd,J=23.7,8.7Hz,3H),7.65(d,J=8.5Hz,1H),7.34(dd,J=6.7,2.3Hz,2H),7.24(dd,J=8.7,2.3Hz,1H),7.11(dd,J=8.8,2.4Hz,1H),7.01(d,J=8.7Hz,2H),5.04(dd,J=12.9,5.4Hz,1H),4.50(dp,J=9.0,4.3Hz,1H),4.07(d,J=13.1Hz,2H),3.93(d,J=9.3Hz,2H),3.81–3.72(m,1H),3.60(d,J=8.2Hz,2H),3.19–2.79(m,10H),2.61–2.47(m,1H),2.21–1.76(m,8H),1.58–1.39(m,4H),1.32–1.17(m,2H).
2、制备预混溶液:制备40%的透明质酸溶液,将根据步骤1得到的雄激素受体蛋白靶向联合体,与该透明质酸溶液按照总体积的10%加入进行混合得到。
3、制备微针贴片:将所述步骤2得到的预混溶液注入定制的聚二甲基硅氧烷(PDMS,Sylgard 184)微针阵列模具中。接着,将该PDMS微针阵列模具以3000rpm离心10分钟,使其被完全填满后取出,刮去多余的预混溶液。将该PDMS微针阵列模具置于硅胶干燥器内,室温下干燥1h。取出该PDMS微针阵列模具,注入50%聚乙烯醇溶液。接着,将该PDMS微针阵列模具以3000rpm离心5分钟,形成背衬后取出。将该PDMS微针阵列模具置于硅胶干燥器内,室温下干燥24h,即得到含雄激素受体蛋白靶向联合体的生发微针贴片。
本实施例中,通过采用雄激素受体蛋白靶向联合体与聚合物溶液进行混合,最后得到固态的可溶性微针贴片。该固态的可溶性微针贴片制备过程温和,无需极端条件,制备简便,且可在干燥环境中进行常温保存,有效实现雄激素受体蛋白靶向联合体的透皮递送。
本实施例中,生发微针贴片由两步离心法制备得到,针体含雄激素受体蛋白靶向联合体,贴片背衬不含雄激素受体蛋白靶向联合体,不会引起活性物质的浪费。使用时,微针针体吸收组织液快速溶解,贴片背衬可被移除,给药过程较短,且不影响美观,病人依从性较高。
实施例3
本实施例提供一种可溶性微针贴片的制备方法,本实施例与实施例1的不同之处在于,本实施例中步骤1为合成雄激素受体蛋白靶向联合体的盐。
本实施例中,通过采用雄激素受体蛋白靶向联合体与聚合物溶液进行混合,最后得到固态的可溶性微针贴片。该固态的可溶性微针贴片制备过程温和,无需极端条件,制备简便,且可在干燥环境中进行常温保存,有效实现雄激素受体蛋白靶向联合体的透皮递送。
实施例4
本实施例提供一种可溶性微针贴片的制备方法,本实施例与实施例1的不同之处在于,本实施例中步骤1为合成雄激素受体蛋白靶向联合体的立体异构体。
本实施例中,通过采用雄激素受体蛋白靶向联合体与聚合物溶液进行混合,最后得到固态的可溶性微针贴片。该固态的可溶性微针贴片制备过程温和,无需极端条件,制备简便,且可在干燥环境中进行常温保存,有效实现雄激素受体蛋白靶向联合体的透皮递送。
用于雄激素源性脱发治疗功效评价
选用实施例1制备得到的生发微针贴片(图1),在AGA模型小鼠上以指腹力量按压给微针贴片1片,28天毛发周期结束后,记录小鼠毛发再生情况,并检测新生毛发覆盖率。选用实施例1制备得到的生发微针贴片,在正常小鼠上以指腹力量按压给微针贴片1片,六天后检测皮肤内雄激素受体含量。
如图2所示,含雄激素受体蛋白靶向联合体的生发微针贴片治疗后的AGA模型小鼠发生明显的毛发再生,而未接受任何处理的AGA模型小鼠未发生毛发再生。
如图3所示,含雄激素受体蛋白靶向联合体的生发微针贴片治疗后的AGA模型小鼠的新生毛发覆盖率在60%以上,而未接受任何处理的AGA模型小鼠新生毛发覆盖率接近0。
如图4所示,含雄激素受体蛋白靶向联合体的生发微针贴片应用后小鼠皮肤中的雄激素受体含量比未接受任何处理的小鼠显著降低。
Claims (10)
1.一种含雄激素受体蛋白靶向联合体的生发微针贴片,其特征在于,所述生发微针贴片包括片状背衬和排列在该片状背衬上的含雄激素受体蛋白靶向联合体的可溶性微针针体;所述可溶性微针针体包括雄激素受体蛋白靶向联合体、其药学上可接受的盐、其立体异构体、其几何立构体、其互变异构体、其酯、其前药、其溶剂化物、其代谢产物、其氮氧化物或者其氘代化合物中的一种或多种。
2.根据权利要求1所述的含雄激素受体蛋白靶向联合体的生发微针贴片,其特征在于,所述背衬和可溶性微针针体由不同的聚合物材料构成。
3.根据权利要求1或2所述的含雄激素受体蛋白靶向联合体的生发微针贴片,其特征在于,所述背衬采用的聚合物为支链淀粉、聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
4.根据权利要求1或2所述的含雄激素受体蛋白靶向联合体的生发微针贴片,其特征在于,所述可溶性微针针体采用的聚合物为透明质酸、聚乳酸、聚乙醇酸、聚氧化乙烯、聚丙烯酸、聚丙烯酰胺、聚(甲基乙烯基醚/马来酸)半酯共聚物、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。
5.一种权利要求1-4任一所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,其特征在于,所述制备方法包括以下步骤:
1)首先以化合物1和化合物2为原料,在溶剂和碱的作用下搅拌反应至原料反应完全得化合物3;
2)将化合物3溶于二氯甲烷,加入有机酸或无机酸,氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,萃取干燥浓缩后,打浆抽滤得化合物4;
3)以化合物4和化合物5为原料,在溶剂、酰胺连接剂和碱的作用下反应得化合物6;
4)将化合物6溶于二氯甲烷,加入有机酸或无机酸,氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,用二氯甲烷萃取干燥浓缩得化合物7;
5)以化合物7和化合物8为原料,在溶剂、乙酸、三乙酰氧基硼氢化钠的作用下反应,干燥浓缩得化合物9;
6)将化合物9溶于二氯甲烷,加入有机酸或无机酸,三氩气保护下室温反应完全,用饱和碳酸氢钠调节pH至7-11,用二氯甲烷萃取干燥浓缩得化合物10;
7)以化合物10、化合物11为原料,在溶剂和碱的作用下反应完全,浓缩和纯化后得到雄激素受体蛋白靶向联合体,其形式可为化合物游离状态或化合物的盐形式;
8)配制可溶性针体聚合物溶液:将雄激素受体蛋白靶向联合体与可溶性针体聚合物溶液混合得到混合溶液,将该混合溶液注入微针模具中,通过离心使混合溶液填满整个微针模具,刮去多余的聚合物溶液,干燥;
9)配制背衬聚合物溶液,将该聚合物溶液注入微针模具中,通过离心使背衬聚合物溶液填满模具背衬部分,干燥后剥离该微针模具,得到生发微针贴片。
6.根据权利要求5所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,其特征在于,所述步骤8)的针体聚合物溶液的质量分数为10~100%,所述的雄激素受体蛋白靶向联合体占混合溶液总体积的10~70%。
7.根据权利要求5所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,其特征在于,所述步骤8)的离心速度为1000~10000rpm,离心时间为1~30min;干燥时间为12~24h。
8.根据权利要求5所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,其特征在于,所述步骤9)背衬聚合物溶液的质量分数为20~80%。
9.根据权利要求5所述的含雄激素受体蛋白靶向联合体的生发微针贴片的制备方法,其特征在于,所述步骤9)的离心速度为1000~10000rpm,离心时间为1~30min;干燥时间为24~72h。
10.一种权利要求1~4任一所述的含雄激素受体蛋白靶向联合体的生发微针贴片在制备治疗雄激素源性脱发药物上的应用。
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