CN110841057B - 一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用 - Google Patents
一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用 Download PDFInfo
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Abstract
本发明公开了一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用，所述神经导向因子Sema选自Sema 3a蛋白，Sema 3a蛋白可以选自天然蛋白或重组蛋白。另一方面，本发明公开了一种基于神经导向因子Sema的巴布膏剂及其制备方法，所述巴布膏剂包括背衬层、膏体层和保护膜，所述膏体层包括药物活性成分和载药基质。临床试验证明，本发明制备的巴布膏剂可使早期退行性骨关节炎受试者疼痛得到有效缓解。
Description
技术领域
本发明属于生物医药领域，具体涉及一种神经导向因子Sema大分子蛋白在制备治疗骨关节炎巴布膏剂中的用途。
背景技术
骨关节炎(OA)是指以软骨丢失及伴有关节周围骨反应为特点的一种滑膜关节病，又称骨关节病、退行性骨关节病、肥大性或增生性关节炎等，是全球范围内最常见的风湿性疾病。骨关节炎是由于增龄、肥胖、劳损、创伤、关节先天性异常、关节畸形等诸多因素引起的关节软骨退化损伤、关节边缘和软骨下骨反应性增生。骨关节炎是中老年人群中最常见的关节疾病，调查研究显示，60岁以上的人群中患病率可达50％，75岁以上人群中则达80％，该病致残率高达53％，调查显示，骨关节炎已成为老年人致残头号杀手。
骨关节炎病症大多起病隐袭，进展缓慢，受累关节可间断出现轻中度钝痛，且所述病症可因过度活动、气候变化等原因诱发或加重，严重者症状体征明显且持续不缓解，甚至出现关节畸形、功能障碍。
骨关节炎的治疗目的是减轻症状，延缓关节结构改变，维持关节功能，提高生活质量。2000年ACR制定的OA治疗指南以及欧洲风湿病学会联盟(EULAR)对膝OA治疗的建议基本都是三个方面，即非药物治疗、药物治疗、手术治疗。其中，在药物治疗中非甾体抗炎药(NSAIDs)是一类化学结构不同的具有抗炎、止痛、解热等功能的非类固醇药物，常用于骨关节炎的治疗。值得注意的是，一些试验观察到某些NSAIDs抑制软骨合成，加速软骨退化，此外，口服非甾体抗炎药经常会导致胃肠道问题(尤其是对于老年患者)，长期使用通常伴有肾脏、肝脏和其他功能异常。除了NSAIDs，类固醇类药物由于可迅速改善症状而经常应用于骨关节炎治疗，但频繁使用类固醇药物可能损害关节，所以应慎重考虑类固醇注射治疗。其次，使用透明质酸注射液关节腔内注射，即粘弹性补充疗法在治疗骨关节炎病症中越来越普遍，在中国销售的关节腔内注射制剂含鸡冠花来源的透明质酸钠，平均分子量为800,000道尔顿。其虽然具有缓解疼痛、抗炎特性、改善关节活动度、暂无严重药物不良反应等效应，但却无法抑制骨关节炎进程且仅对早期骨关节炎有效。
Semaphorin蛋白家族是一类以半胱氨酸富集区域为特征的一组分泌型或膜相关的蛋白家族,最初作为影响神经发育的神经轴突导向因子而被发现，Semaphorin是一大类分泌型或跨膜型糖蛋白分子，参与机体多项重要生理过程的调节，包括调控神经系统的轴突发育、血管形成、骨分化、心血管发育等。根据其组成特点将其分为8型，其中有部分家族蛋白分子参与免疫功能的调节从而将其命名为Immune Semaphorin，如Semaphorin 4D(Sema4D，又名CD100)、Semaphorin 3A(Sema3A)、和Semaphorin 7A(Sema7A)等。其中，Sema3A最早被发现，也是最经典的Sema家族成员之一，可调控和引导神经轴突的生长。近年来研究发现Sema3A除发挥神经轴突导向作用外，还与细胞迁移、肿瘤生长、血管生成、骨代谢及免疫调节等多种机体的病理生理现象密切相关。
非专利文献“Semaphorin 3A在类风湿关节炎患者血清及外周血单个核细胞中的表达及意义”中提到Semaphorin3A(Sema3A)在类风湿关节炎(RA)患者外周血及血清中的表达水平，探讨Sema3A在RA发病机制中的作用。结果显示RA患者血清Sema3A水平显著高于健康人，且血清Sema3A水平与血小板计数、ESR、IgM、类风湿因子、HRF-IgG呈正相关。
非专利文献“骨改建中潜在的作用靶点-信号素Sema3A的研究进展”中研究证明Sema3A具有促进成骨细胞生成以及同时抑制破骨细胞生成的功能，且骨折愈合与神经纤维长入骨痂密切相关，神经生长导向因子Sema3A可通过调控感觉神经纤维长入调节骨量代谢。
专利文献“一种采用Sema3A基因促进脂肪干细胞成骨分化、抑制成脂分化的方法”公开了一种采用Sema3A基因促进脂肪干细胞成骨分化、抑制成脂分化的方法。所述发明构建了含有Sema3A基因序列的重组质粒，通过将Sema3A重组质粒和辅助包装质粒转染进入293T细胞获得Sema3A慢病毒载体，慢病毒载体在polybrene的协助下将Sema3A基因导入脂肪干细胞，显著地促进了脂肪干细胞的成骨分化，同时也抑制了脂肪干细胞向成脂方向的分化，导入Sema3A基因可以更好地将脂肪干细胞应用于促进骨缺损愈合和种植体骨结合。
虽然现有技术公开了Sema3A用于治疗骨相关疾病的应用，而且仅是针对骨的治疗，而未涉及软骨，本发明所述的骨关节炎是由于增龄、肥胖、劳损、创伤、关节先天性异常、关节畸形等诸多因素引起的关节软骨退化损伤。因此，本发明所述的药物制剂与现有制剂应用的疾病病种不同，且现有技术未曾公开由Sema大分子蛋白作为有效成分制备的巴布膏剂在治疗骨关节中的应用。
发明内容
为了改善现有技术的缺陷，本发明提供一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用，另外，本发明提供一种基于神经导向因子Sema的巴布膏剂及其制备方法。
第一方面，本发明提供一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用，所述神经导向因子Sema的序列选自下列氨基酸序列中的一种：
1)所述神经导向因子Sema的氨基酸序列为如SEQ ID NO:1所示序列的全部或部分；
2)所述神经导向因子Sema的氨基酸序列为与SEQ ID NO:1具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的同一性程度的序列；
3)所述神经导向因子Sema的氨基酸序列与SEQ ID NO:1所示序列的差异不超过5、4、3、2或1个氨基酸；
4)所述神经导向因子Sema的氨基酸序列为SEQ ID NO:1的变体，其中所述变体与SEQ ID NO:1的差异包括取代、缺失和/或插入一个或多个氨基酸残基的序列或至少一个N-/C-末端延伸。
优选的，所述神经导向因子Sema选自Sema 3a蛋白，所述Sema 3a蛋白的氨基酸序列如SEQ ID NO:1所示。
本发明中SEQ ID NO:1的氨基酸序列如下所示：
第二方面，本发明提供一种基于神经导向因子Sema的巴布膏剂，所述巴布膏剂包括背衬层、膏体层和保护膜，所述膏体层包括药物活性成分和载药基质，所述药物活性成分为Sema 3a蛋白，膏体层中药物活性成分百分比为0.1-1％，所述载药基质包括如下质量份数的制备原料：骨架材料80-100份、交联剂0.1-1份、交联调节剂1-2.5份、保湿剂200-250份、表面活性剂50-60份、增溶剂10-20份、水400-600份。
在本发明中，所述Sema 3a蛋白可以选自天然蛋白或重组蛋白，优选的，所述Sema3a蛋白为人源重组蛋白。
所述骨架材料选自聚丙烯酸钠、聚丙烯酸、甲基纤维素钠、明胶、甲基纤维素、羧甲基纤维素钠中的一种或两种以上的组合。
交联剂选自氢氧化铝、甘羟铝、氯化铝中的一种或两种以上的组合。
交联调节剂选自酒石酸、依地酸及其钠盐、柠檬酸、葡萄糖酸中的一种或两种以上的组合。
保湿剂选自甘油、丙二醇、聚乙二醇、液体石蜡中的一种或两种以上的组合。
表面活性剂选自聚山梨醇酯、聚丙二醇中的一种或两种以上的选择。
增溶剂选自N-甲基-2-吡咯烷酮。
在本发明的优选实施方式中，所述骨架材料选自聚丙烯酸钠、聚丙烯酸、甲基纤维素钠、明胶的组合；交联剂为氢氧化铝；交联调节剂选自酒石酸和EDTA-2Na；保湿剂为甘油；表面活性剂选自聚山梨醇酯20和聚丙二醇-400的组合。
在本发明中，发明人创造性的发现Sema 3a人源重组蛋白与交联调节剂酒石酸和EDTA-2Na的质量比会影响药物的透皮性能，优选的，所述Sema 3a人源重组蛋白、酒石酸、EDTA-2Na质量比为1:(1-2):(1-3)，最优选的，所述Sema 3a人源重组蛋白与交联调节剂质量比为1:1:1.5。
在本发明的最优选实施方式中，每100g载药基质中还包括5-6ml促渗剂，所述促渗剂优选氮酮。
第三方面，本发明提供一种基于神经导向因子Sema的巴布膏剂的制备方法，包括如下步骤：
(1)将甲基纤维素钠溶于部分甘油和水的混合物中，加入聚丙烯酸和聚山梨醇酯20，边搅拌边加热至40-45℃直至溶解，得到I溶液；
(2)将明胶加入水中，≤60℃状态下加热溶解，得到II溶液；
(3)在剩余甘油中加入聚丙烯酸钠、氢氧化铝、EDTA-2Na，搅拌溶解，得到III溶液；
(4)将酒石酸、聚丙二醇-400溶于水中，加入增溶剂N-甲基-2-吡咯烷酮，再加入Sema 3a人源重组蛋白，搅拌溶解，得到IV溶液；
(5)先将I、II、III溶液混合均匀再加入IV，搅拌均匀，涂布、切片、贴保护膜，制得巴布膏剂。
本发明对巴布膏剂的背衬层和保护膜不作具体限定，为本领域技术人员常用的膏剂支撑材料或包装材料。背衬层材料选自棉布、无纺布、防水纸等；保护膜材料选自塑料薄膜、铝箔、聚乙烯复合膜、硬质纱布等。
本发明的有益效果为：现有的治疗技术手段仅能缓解骨关节炎症状，而目前FDA及中国均仍还没有批准用于预防或减缓疾病进展的药物，本发明提供的一种基于神经导向因子Sema的巴布膏剂能预防和减缓骨关节炎进展。另外，巴布膏剂使用方便，经皮吸收直接作用病灶，长效释放药物，且质地柔和，适合用于关节部位，无创，肠胃无负担，患者依从性较好。
附图说明
图1Sema 3a蛋白巴布膏剂临床试验疼痛缓解率散点图
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的部分实施例，而不是全部。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1巴布膏剂的制备
(1)将20g甲基纤维素钠溶于100g甘油和水的混合物中，加入5g聚丙烯酸和10g聚山梨醇酯20，边搅拌边加热至40℃直至溶解，得到I溶液；
(2)将10g明胶加入水中，45℃状态下加热溶解，得到II溶液；
(3)在剩余100g甘油中加入50g聚丙烯酸钠、0.5g氢氧化铝、1.5g EDTA-2Na，搅拌溶解，得到III溶液；
(4)将1g酒石酸、50g聚丙二醇-400溶于水中，加入增溶剂N-甲基-2-吡咯烷酮20g，再加入1g Sema 3a人源重组蛋白，搅拌溶解，得到IV溶液；
(5)先将I、II、III溶液混合均匀再加入IV，搅拌均匀，涂布于无纺布、切片、贴保护膜，制得巴布膏剂。
实施例2巴布膏剂的制备
(1)将25g羧甲基纤维素钠溶于100g丙二醇和水的混合物中，加入5g聚丙烯酸钠和10g聚山梨醇酯80，边搅拌边加热至40℃直至溶解，得到I溶液；
(2)将15g明胶加入水中，45℃状态下加热溶解，得到II溶液；
(3)在100g甘油中加入50g聚丙烯酸、0.5g甘羟铝、2g EDTA-2Na，搅拌溶解，得到III溶液；
(4)将0.5g酒石酸、50g聚丙二醇-400溶于水中，加入增溶剂N-甲基-2-吡咯烷酮15g，再加入1g Sema 3a人源重组蛋白，搅拌溶解，得到IV溶液；
(5)先将I、II、III溶液混合均匀再加入IV，搅拌均匀，涂布于无纺布、切片、贴保护膜，制得巴布膏剂。
实施例3巴布膏剂的制备
制备方法及原料与实施例1相同，区别在于，步骤(3)中EDTA-2Na 1g，步骤(4)中酒石酸2g、Sema 3a人源重组蛋白1g。
实施例4巴布膏剂的制备
制备方法及原料与实施例1相同，区别在于，步骤(3)中EDTA-2Na 3g，步骤(4)中酒石酸1g、Sema 3a人源重组蛋白1g。
效果例1巴布膏剂感官评价
以实施例1-4制备的巴布膏剂为实验组，进行感官评价，评价参数包括膏剂外观性状、涂展性、均匀性、反复揭贴性、膜残留性及渗布程度。
根据上表实验数据可以看出，本发明制备的巴布膏剂膏体颜色均匀、无颗粒无气泡，易于涂布，涂布后膏体均匀不渗布、对人体皮肤粘贴力较好，保护膜无残留，符合巴布膏剂的行业标准。
效果例2体外透皮试验
将实施例1-4制备的巴布膏剂作为实验组，采用巴马小型猪皮进行药物体外透皮试验。
猪皮处理过程如下：将巴马小型猪处死，迅速将背部及两侧毛刮去，用水冲洗皮肤表面，取皮4张，刮除皮下脂肪并使猪皮厚度均一，用pH＝7.4的等渗磷酸盐缓冲液冲洗浸泡。
介质采用pH＝7.4的等渗磷酸盐缓冲液，将实验组4种巴布膏剂去保护膜粘附于猪皮角质层一侧，用夹具将猪皮夹紧，使猪皮覆于释放介质表层，分别在0.5、1、2、4、8、12小时后取样检测介质中的药物浓度，注意每次取样后需要补充同样体积的新鲜介质，计算单位面积累积透过量Q(μg/cm2)，结果如下表所示。
表3体外透皮试验结果
| 蛋白:酒石酸:EDTA | 0.5h | 1h | 2h | 4h | 8h | 12h |
| 实施例1(1:1:1.5) | 1.39 | 1.73 | 2.38 | 2.94 | 3.67 | 4.40 |
| 实施例2(1:0.5:2) | 0.94 | 1.33 | 1.89 | 2.21 | 2.60 | 3.02 |
| 实施例3(1:2:1) | 1.02 | 1.36 | 1.77 | 2.29 | 2.71 | 3.37 |
| 实施例4(1:1:3) | 0.88 | 1.26 | 1.74 | 2.11 | 2.45 | 2.96 |
体外透皮试验能检测药物的透皮性能，尤其是透皮吸收的药物，若具有良好的透皮性能，则保证药物拥有较高的生物利用度。由上表数据可知，本发明制备的巴布膏剂中实施例1的透皮效果最好，实施例1中Sema 3a人源重组蛋白与酒石酸、EDTA-2Na的比例为1:1:1.5，实施例3和实施例4分别是酒石酸和EDTA-2Na的量分别增加1倍，结果证明，酒石酸和EDTA-2Na的量不利于药物的透皮性，分析原因可能是因为酒石酸和EDTA-2Na作为交联调节剂用量增加，导致对高分子骨架材料的交联程度产生影响，从而间接导致药物透皮性能受到影响。
效果例3临床药效试验
本次试验按照《药物临床试验质量管理规范》相关要求拟定临床研究方案，经过四川大学华西医院伦理委员会审查批准，并在四川大学华西医院药物临床试验机构备案。
1、试验目的：评价一种基于Sema 3a蛋白的巴布膏剂治疗原发性退行性膝关节炎患者的临床疗效及安全性。
2、入组标准如下：
①基于美国风湿病学会临床分类标准诊断为膝关节骨关节炎的患者；
②研究侧膝关节分级为Kellgren-Lawrence 1级或2级，研究对侧膝关节的分级不超过研究侧。
③慢性疼痛至少持续1个月；
④第0周时在0–10分数字评定量表中确定的平均骨关节炎指数(WOMAC)疼痛分项评分(5项)符合方案要求；
⑤大于或等于40岁且小于70岁的患者，且在充分知情的情况下自愿签署知情同意书；
⑥不需借助轮椅支持即能行走的门诊患者。
3、排除标准如下：
①诊断为继发性膝关节骨关节炎的患者；
②有其他导致膝关节功能受损的疾病/障碍的患者；
③对侧膝关节有骨关节炎并需要关节腔内药物治疗缓解疼痛的患者；
④不适合采用药物治疗的患者(如有手术指征的患者)；
⑤在首次使用研究药物前2周内接受下面一种或多种治疗的患者：
1)双侧或任意一侧膝关节运动治疗；
2)使用中成药治疗膝关节骨关节炎；
⑥在首次使用研究药物前4周内接受下面一种或多种治疗的患者：
1)双侧或任意一侧膝关节局部注射糖皮质激素或麻醉剂、外用糖皮质激素治疗；
2)使用糖皮质激素的口服、栓剂或静脉制剂治疗；
⑦在首次使用研究药物前的24周内接受膝关节(双侧或任意一侧)玻璃酸注射治疗；
⑧同侧髋关节或踝关节病变；
⑨风湿性疾病或状况；
⑩双侧或任意一侧下肢关节成形术病史；
无法评价其临床表现的患者；
关节部位周围的皮肤病或皮肤感染，有导致注射感染的风险；
严重心脏疾病、肾衰竭、血液学疾病和糖尿病；
对研究用药品(IMP)中任何成分有超敏反应史；
发生妊娠、可疑妊娠、哺乳期女性患者或在研究期间拒绝使用避孕措施患者(男性或女性)；
当前有重度肝损害或有重度肝损害病史；
当前患有恶性肿瘤或筛选前5年内有恶性肿瘤病史；
在首次使用研究药物前24周内接受其他IMP治疗的患者；
研究者或助理研究者判定不适于参与该研究的其他患者。
4、试验过程如下：
①临床招募符合入排标准的原发性退行性膝关节炎病人15人，对入组受试者进行编号，随机分为3组，每组5人；
②组1受试者的膝关节贴实施例1制备的Sema 3a蛋白巴布膏剂，隔天贴一张，一张贴24小时，一共治疗4周；组2为对照组，以市售洛索洛芬钠贴剂为对照药物，按照药品说明书对受试者进行治疗，一共治疗4周；组3为空白对照组，受试者的膝关节贴实施例1制备的不含Sema 3a蛋白的巴布膏剂；
③分别于治疗前和治疗后对病人进行疼痛评分，计算疼痛缓解率(％)＝(治疗前疼痛评分-治疗后疼痛评分)/治疗前疼痛评分×100。
④实验结果如下表所示。
表4基于Sema 3a蛋白的巴布膏剂的临床疗效数据
通过上表所示的临床试验效果数据及图1所示的受试者疼痛缓解率散点图可以看出，与市售洛索洛芬钠贴剂相比，本发明制备的基于Sema 3a蛋白的巴布膏剂在缓解疼痛方面效果更好一些。且为期4周的试验周期内，Sema 3a蛋白巴布膏剂治疗组没有出现任何AE(不良事件)和SAE(严重不良事件)案例，安全性较好。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
序列表
<110> 四川大学华西医院
<120> 一种神经导向因子Sema在制备治疗骨关节炎巴布膏剂中的应用
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<170> SIPOSequenceListing 1.0
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Glu Cys Ala Asn Phe Ile Lys Val Leu Lys Ala Tyr Asn Gln Thr His
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His Phe Glu Asn Gly Arg Gly Lys Ser Pro Tyr Asp Pro Lys Leu Leu
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Asp Phe Met Gly Arg Asp Phe Ala Ile Phe Arg Thr Leu Gly His His
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Lys Phe Ile Ser Ala His Leu Ile Ser Glu Ser Asp Asn Pro Glu Asp
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Asp Lys Val Tyr Phe Phe Phe Arg Glu Asn Ala Ile Asp Gly Glu His
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Ser Gly Lys Ala Thr His Ala Arg Ile Gly Gln Ile Cys Lys Asn Asp
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Phe Gly Gly His Arg Ser Leu Val Asn Lys Trp Thr Thr Phe Leu Lys
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Ala Arg Leu Ile Cys Ser Val Pro Gly Pro Asn Gly Ile Asp Thr His
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Asn Pro Val Val Tyr Gly Val Phe Thr Thr Ser Ser Asn Ile Phe Lys
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Gly Ser Ala Val Cys Met Tyr Ser Met Ser Asp Val Arg Arg Val Phe
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Claims (5)
1.一种神经导向因子Sema作为药物活性成分在制备治疗骨关节炎巴布膏剂中的应用，所述神经导向因子Sema选自Sema 3a蛋白，所述Sema 3a蛋白的氨基酸序列如SEQ ID NO:1所示。
2.一种权利要求1所述的基于神经导向因子Sema的巴布膏剂，所述巴布膏剂包括背衬层、膏体层和保护膜，所述膏体层包括药物活性成分和载药基质，所述药物活性成分为Sema3a蛋白，膏体层中药物活性成分百分比为0.1-1%，所述载药基质包括如下质量份数的制备原料：骨架材料80-100份、交联剂0.1-1份、交联调节剂1-2.5份、保湿剂200-250份、表面活性剂50-60份、增溶剂10-20份、水400-600份；所述骨架材料为聚丙烯酸钠、聚丙烯酸、甲基纤维素钠、明胶的组合；交联剂为氢氧化铝；交联调节剂为酒石酸和EDTA-2Na；保湿剂为甘油；表面活性剂为聚山梨醇酯20和聚丙二醇-400的组合，所述Sema 3a蛋白、酒石酸、EDTA-2Na质量比为1:(1-2):(1-3)。
3.根据权利要求2所述的巴布膏剂，其特征在于，所述Sema 3a蛋白与酒石酸、EDTA-2Na质量比为1:1:1.5。
4.根据权利要求2所述的巴布膏剂，其特征在于，每100 g载药基质中还包括5-6 ml促渗剂氮酮。
5.一种权利要求2-3任一所述的基于神经导向因子Sema的巴布膏剂的制备方法，包括如下步骤：
（1）将甲基纤维素钠溶于部分甘油和水的混合物中，加入聚丙烯酸和聚山梨醇酯20，边搅拌边加热至40-45 ℃直至溶解，得到I溶液；
（2）将明胶加入水中，≤60℃状态下加热溶解，得到II溶液；
（3）在剩余甘油中加入聚丙烯酸钠、氢氧化铝、EDTA-2Na，搅拌溶解，得到III溶液；
（4）将酒石酸、聚丙二醇-400溶于水中，加入增溶剂N-甲基-2-吡咯烷酮，再加入Sema3a蛋白，搅拌溶解，得到IV溶液；
（5）先将I、II、III溶液混合均匀再加入IV，搅拌均匀，涂布、切片、贴保护膜，制得巴布膏剂。
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