CN114225037A - 一种预防或治疗骨质疏松症的组合物及其制剂和用途 - Google Patents
一种预防或治疗骨质疏松症的组合物及其制剂和用途 Download PDFInfo
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Abstract
本发明属于医药领域，具体涉及一种预防或治疗骨质疏松症的组合物及其制剂，以及在预防或治疗骨质疏松症中的应用。具体而言，本发明所述的组合物主要由GPX4激动剂和脂氧合酶15(Alox‑15)抑制剂组成，并辅以维生素E发挥协同作用。在一个实施方式中，GPX4激动剂包括6‑姜酚、8‑姜酚、10‑姜酚、PKUMDL‑LC‑101‑D04中的一种或多种；Alox‑15抑制剂包括槲皮素、阿魏酸、黄芩素、桔皮素、川皮苷、PD146176、橙黄酮和ML351中的一种或多种。在另一个实施方式中，所述组合物包含姜提取物、沙棘提取物和小麦胚芽提取物。药理实验结果表明，本发明组合物能够有效预防、改善和治疗骨质疏松以及临床相关症状。
Description
技术领域
本发明属于医药领域，具体涉及一种预防或治疗骨质疏松症的组合物及其制备和用途。
背景技术
骨质疏松症(osteoporosis,OP)是一种全身性的骨骼代谢疾病，其主要病理特征是骨密度值(bone mineral density,BMD)降低、骨骼微结构/矿化受损及骨折风险增加。现代社会是一个老龄化社会，随着人口老龄化和寿命的延长，骨质疏松和骨质疏松性骨折发生率不断攀升。骨质疏松已成为全球性的健康问题，据不完全统计，全球范围内有超过2亿人患有骨质疏松。此外，国家卫生健康委2018年的流行病学调查数据显示，我国65岁以上人群的骨质疏松患病率高达32％。骨质疏松引起的脊柱、髋部、腕部等部位的脆性骨折严重影响患者的生活质量，为社会带来巨大的经济及医疗负担。因此，骨质疏松症的药物治疗一直是药物研究者关注的重要领域。
目前，在治疗骨质疏松药物研究方面，主要基于两种策略，一种以增加成骨细胞分化，促进骨形成为目的药物开发，旨在通过增加成骨细胞和骨细胞以补充缺失的骨组织，增加骨量；另一种则通过促进破骨细胞凋亡、抑制破骨细胞的活化为目的的药物开发，旨在通过降低骨吸收，缓解骨量持续丢失，改善骨质疏松及相关症状。目前，临床上骨质疏松的治疗药物正是通过以上两种机制实现，市售药物主要为钙制剂、双磷酸盐类、雌激素类、雄激素类、维生素D3类等。但是，这些药物长期使用副作用较多，如长期使用双磷酸盐类药物对肾脏、肝脏和胃肠道等组织器官产生毒副作用；长期使用甲状旁腺激素类药物会增加骨肉瘤的发生风险。因此，研发安全性高、副作用低的、适合长期服用的用于预防、改善和治疗的骨质疏松的食品、保健食品和医药用品及组合物是非常必要且迫切的。
近年来，氧化应激作为骨质疏松症的重要危险因子越来越受到学者和药物研发者的关注。氧化应激产生大量的活性氧自由基(reactive oxygen species,ROS)一方面增加破骨细胞的增殖和吸收活性，促进骨吸收；另一方面ROS促进成骨细胞的凋亡和抑制成骨细胞的分化功能，减少骨形成，最终导致或加剧骨质疏松。因此，寻找改善机体氧化应激状态，抑制ROS产生或清除ROS的药物也逐渐成为骨质疏松症药物研发和开发的新热点、新趋势和新潮流。
GPX4和Alox15在氧化应激，尤其是磷脂过氧化中扮演重要角色，且维生素E能有效的降低细胞和机体磷脂过氧化水平，改善机体氧化应激状态。联合使用GPX4激动剂、Alox15抑制剂和维生素E能更有效的清除ROS，特别是清除脂质ROS，改善机体氧化应激状态，矫正破骨细胞和成骨细胞的功能。此外，Alox15与骨质疏松症密切相关，Alox15基因低表达能有效增加小鼠的骨密度值，且Alox15抑制剂能有效改善去卵巢小鼠的骨质疏松程度。
发明内容
为了解决上述技术问题，本发明提供了一种预防或治疗骨质疏松症的方法，更具体地，一种预防或治疗骨质疏松症的组合物及其制剂和用途。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种预防或治疗骨质疏松症的组合物，所述组合物包含GPX4激动剂和Alox-15抑制剂和以及维生素E，其中，所述GPX4激动剂增强内源性抗氧化酶GPX4的活性，增强机体脂质过氧化物的清除，所述Alox-15抑制剂抑制内源性脂氧合酶15的活性，降低脂质过氧化物的产生，同时辅以小分子还原剂维生素E直接清除脂质过氧化的累积，三者协同发挥作用。
作为可选的方式，在上述组合物中，所述GPX4激动剂、所述Alox-15抑制剂、所述维生素E的重量比为0.5-5：1-5：0.5-5。
优选地，所述GPX4激动剂、所述Alox-15抑制剂、所述维生素E的重量比为1：4：1。
作为可选的方式，在上述组合物中，所述GPX4激动剂选自6-姜酚、8-姜酚、10-姜酚、PKUMDL-LC-101-D04中的一种或多种；所述Alox-15抑制剂选自槲皮素、阿魏酸、黄芩素、桔皮素、川皮苷、PD146176、橙黄酮、ML351中的一种或多种。
优选地，所述GPX4激动剂选自6-姜酚、8-姜酚或10-姜酚；所述Alox-15抑制剂选自槲皮素、阿魏酸、黄芩素、桔皮素或川皮苷。
更优选地，所述GPX4激动剂选自8-姜酚；所述Alox-15抑制剂选自槲皮素。
作为可选的方式，在上述组合物中，所述组合物包含姜提取物(GPX4激动剂)、沙棘提取物(Alox-15抑制剂)和小麦胚芽提取物(维生素E来源)，所述姜提取物、所述沙棘提取物、所述小麦胚芽提取物的重量比为2：5：3。
作为可选的方式，在上述组合物中，所述姜提取物包括从生姜和干姜中通过水提或有机溶剂提取，所述有机溶剂包括低级醇乙醇和乙酸乙酯；所述沙棘提取物包括从沙棘果、沙棘叶中提取获得；所述小麦胚芽提取物从小麦胚芽中通过无水乙醇提取获得。
所述组合物的提取，包括采用热水，或水与甲醇、乙醇等低级醇类、丙酮等极性溶剂中的一种或二种以上任意混合的溶剂进行提取。鉴于组合物是以药剂或食品作为最终产品开发，故从安全性角度考虑提取溶剂尽量选择水和乙醇为宜。
在第二个方面中，本发明提供了一种预防或治疗骨质疏松症的制剂，所述制剂包含上述第一个方面所述的组合物，以及适宜的载体或辅料。
作为可选的方式，在上述制剂中，所述制剂为口服剂型。
优选地，所述口服剂型选自片剂、胶囊剂、口服液、肠溶片、颗粒剂、糖浆剂、滴丸、水蜜丸、散剂、合剂、煎膏剂、酒剂、露剂、酊剂或舌下含片。
或者，所述剂型也可以是外用剂型。外用常用的方式包括但不限于软膏、栓剂、硬质软膏、搽剂、滴眼液、油剂、乳膏、气雾剂、喷雾剂。
本发明提供的组合物，也可以粉末添加到食品及保健食品制品中用于口服。组合物也可与其他原料结合制成一定的饮料制品，如果汁饮料、运动饮料等。
在第三个方面中，本发明提供了上述第一个方面所述的组合物或者上述第二个方面所述的制剂在制备预防或治疗骨质疏松症的产品中的用途。
作为可选的方式，在上述用途中，所述产品是药物、保健品或功能性食品。
作为可选的方式，在上述用途中，所述骨质疏松症包括骨质疏松相关并发症、相关疾病以及相关临床症状。
本发明提供上述组合物在骨质疏松症中的应用，当然对其他成骨细胞分化活性抑制或破骨细胞活性增加相关骨质减少症、脆性骨折和创伤性骨折等骨骼相关疾病也有很好的改善效果用。
本发明相对于现有技术，具有以下有益效果：
本发明提供的预防或治疗骨质疏松症的组合物配方是经过筛选的，其在发挥抑制破骨细胞增殖及促进成骨细胞分化活性的作用时并不是某一个或某几个成分所起的作用，而是各组分相互协同共同作用的结果，尤其在特定重量比的条件下协同作用最佳，从而在应用中明显改善骨质疏松。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
实施例1：组合物对破骨细胞活性的影响
破骨细胞过度增殖和活化会引起骨吸收增多，减少骨骼骨量、降低骨密度、增加骨骼脆性和骨折风险。因此，抑制骨髓单核巨噬细胞分化为破骨细胞有助于预防和治疗骨质疏松症。
从1月龄小鼠(购自广东省医学实验动物中心)的股骨和胫骨分离骨髓单核细胞，均匀铺到24孔板中，每孔1×105个细胞，待细胞贴壁后，用含有25ng/ml M-CSF、25ng/mlRANKL的细胞因子和10％胎牛血清的α-MEM培养基进行培养，同时除正常对照组外，其余组别加入不同的药物组合物，每3天更换一次培养基。6天后利用TRAP染色，计算每组中破骨细胞数据。破骨细胞阳性个数定义为：TRAP阳性，且细胞核数目在3个以上的细胞。协同指数采用金正均q值法进行判定，q值由以下公式求得q＝EA+B+C/(EA+EB+EC-EA×EB×EC)。式中EA、EB、EC分别是A药组、B药组、C药组和三药联用组抑制率。q<1说明三药合用后产生拮抗作用；q>1说明三药联用后产生协同作用，q＝1说明三药联用后产生相加作用。
实验结果如表1所示，组合物在体外可显著抑制破骨细胞的形成，其抑制率可高达86.67％，而相同剂量下的8-姜酚、槲皮素和维生素E的抑制效果均低于组合物，且当组合物的比例为1:4:1时，其对破骨细胞抑制效果最佳。以上结果从侧面说明了本发明提供的组合物在发挥抑制破骨细胞活化的作用是并不是某一个或某几个成分发挥作用的，而是各组分相互协同、共同作用的结果。
表1：破骨细胞的数目及分化抑制率
注：数据以平均值±SD表示，数据统计使用SPSS25.0的one-way ANOVA分析，与正常组比较，*P<0.05，**P<0.01，***P<0.001。
实施例2：组合物对去卵巢小鼠骨密度和骨小梁的影响
本实施例中的使用的动物雌性C57BL/6小鼠，购自广东省医学实验动物中心。小鼠饲养在温度23±2℃，湿度55±5％，换气频率为12-15次/小时，照明时间12小时/天(7:00-19:00光照)，5只/饲养笼(235×325×170H mm)，饲育条件：固体饲料(广东省医学实验动物中心)，自由饮食。待小鼠为3月龄时，将小鼠随机分为假手术组、模型组及给药组。小鼠手术前12小时，禁食不禁水。使用异氟烷麻醉小鼠，然后用75％乙醇清洗皮肤并消毒。各组小鼠均采用腹侧切口进行手术，除假手术组小鼠不摘除卵巢外，其余各组小鼠均进行双侧卵巢切除，所有手术小鼠均腹腔注射青霉素溶液。手术完成后，将手术动物放置恒温箱中待动物清醒后转移到干净的饲养笼中恢复1周，期间隔天腹腔注射青霉素溶液以免小鼠伤口感染。
除假手术组和模型组小鼠外，各给药组小鼠均灌胃相应剂量的药物，每天一次，连续2个月，末次给药12小时后，麻醉小鼠，取小鼠右后肢扫描骨密度值(BMD)与骨小梁数目。
实验结果如表2所示，与假手术组小鼠相比，模型组小鼠的骨密度和骨小梁数目显著降低。单独给予8-姜酚、槲皮素或维生素E后，去卵巢小鼠的骨密度值和骨小梁数目有所改善，而给予组合物之后，去卵巢小鼠的骨密度值和骨小梁数目的改善效果更显著，且8-姜酚、槲皮素和维生素E联合使用的效果优于6-姜酚、槲皮素和维生素E联合使用。
表2：去卵巢小鼠的BMD和骨小梁数目
注：数据以平均值±SD表示，数据统计使用SPSS25.0的one-way ANOVA分析，与假手术组比较，***P<0.001；与模型组比较，#P<0.05，##P<0.01,###P<0.001。
实施例3：组合物对去卵巢小鼠骨组织抗氧化能力的影响
小鼠骨组织的抗氧化能力通过氧化自由基吸收能力(Oxygen RadicalAbsorbance Capacity,ORAC)实验测定。
骨组织样品预处理：在实施例2中，取小鼠左后肢，剥离肌肉和结缔组织后，在液氮中研磨后收集至离心管，加入高氯酸溶液(3％)制备2％的骨组织匀浆液，4℃条件下以10000r/min离心15min，取上清液作为测定ORAC的样品溶液。
ORAC实验过程：在96孔板中加入不同组别小鼠的20μL骨组织匀浆上清液和20μL磷酸盐缓冲液，再加入20μL荧光素钠，最后添加140μL AAPH后迅速将96孔板置于控温37℃的荧光酶标仪中开始测定。每2min测定一个点，共测定2h。ORAC值以1μmol/L的Trolox在荧光衰减曲线上对应的保护积分面积作为标准对照计算。
结果如表3所示，与模型组相比，8-姜酚、槲皮素和维生素E均能明显升高去卵巢小鼠骨组织的ORAC值，降低MDA水平，增强其抗氧化能力。此外，联用组1和联用组2能更显著的增加去卵巢小鼠的抗氧化能力，且8-姜酚、槲皮素和维生素E联用的抗氧化效果更优。
表3：去卵巢小鼠骨组织的抗氧化能力
注：数据以平均值±SD表示，数据统计使用SPSS25.0的one-way ANOVA分析，与假手术组比较，***P<0.001；与模型组比较，##P<0.01,###P<0.001。
实施例4：组合物对去卵巢小鼠骨密度的影响
本实施例中的使用的动物雌性C57BL/6小鼠，购自广东省医学实验动物中心。小鼠饲养在温度23±2℃，湿度55±5％，换气频率为12-15次/小时，照明时间12小时/天(7:00～19:00光照)，5只/饲养笼(235×325×170H mm)，饲育条件：固体饲料(广东省医学实验动物中心)，自由饮食。待小鼠为3月龄时，将小鼠随机分为假手术组、模型组及给药组。小鼠手术前12小时，禁食不禁水。使用异氟烷麻醉小鼠，然后用75％乙醇清洗皮肤并消毒。各组小鼠均采用腹侧切口进行手术，除假手术组小鼠不摘除卵巢外，其余各组小鼠均进行双侧卵巢切除，所有手术小鼠均腹腔注射青霉素溶液。手术完成后，将手术动物放置恒温箱中待动物清醒后转移到干净的饲养笼中恢复1周，期间隔天腹腔注射青霉素溶液以免小鼠伤口感染。
除假手术组和模型组小鼠外，各给药组小鼠均灌胃相应剂量的药物，每天一次，连续2个月，末次给药12小时后，麻醉小鼠，取小鼠右后肢扫描骨密度值(BMD)与骨小梁数目。
实验结果如表4所示，生姜提取物、沙棘提取物和小麦胚芽提取物能有效增加去卵巢小鼠的BMD值，而生姜提取物、沙棘提取物和小麦胚芽提取物联合使用时，对卵巢小鼠的BMD改善效果更加显著，且生姜提取物、沙棘提取物和小麦胚芽提取物的重量比为2:5:3时效果更佳。
表4：本发明组合物对去卵巢小鼠BMD的影响
注：数据以平均值±SD表示，数据统计使用SPSS25.0的one-way ANOVA分析，与假手术组比较，***P<0.001；与模型组比较，#P<0.05,##P<0.01。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (10)
1.一种预防或治疗骨质疏松症的组合物，其特征在于：所述组合物包含GPX4激动剂和Alox-15抑制剂和以及维生素E，其中，所述GPX4激动剂增强内源性抗氧化酶GPX4的活性，增强机体脂质过氧化物的清除，所述Alox-15抑制剂抑制内源性脂氧合酶15的活性，降低脂质过氧化物的产生，同时辅以小分子还原剂维生素E直接清除脂质过氧化的累积，三者协同发挥作用。
2.根据权利要求1所述的组合物，其特征在于：所述GPX4激动剂、所述Alox-15抑制剂、所述维生素E的重量比为0.5-5：1-5：0.5-5。
3.根据权利要求1或权利要求2所述的组合物，其特征在于：所述GPX4激动剂选自6-姜酚、8-姜酚、10-姜酚、PKUMDL-LC-101-D04中的一种或多种；所述Alox-15抑制剂选自槲皮素、阿魏酸、黄芩素、桔皮素、川皮苷、PD146176、橙黄酮、ML351中的一种或多种。
4.根据权利要求1或权利要求2所述的组合物，其特征在于：所述组合物包含姜提取物、沙棘提取物和小麦胚芽提取物，所述姜提取物、所述沙棘提取物、所述小麦胚芽提取物的重量比为2：5：3。
5.根据权利要求4所述的组合物，其特征在于：所述姜提取物包括从生姜和干姜中通过水提或有机溶剂提取，所述有机溶剂包括低级醇乙醇和乙酸乙酯；所述沙棘提取物包括从沙棘果、沙棘叶中提取获得；所述小麦胚芽提取物从小麦胚芽中通过无水乙醇提取获得。
6.一种预防或治疗骨质疏松症的制剂，其特征在于：所述制剂包含权利要求1至5中任一项所述的组合物，以及适宜的载体或辅料。
7.根据权利要求6所述的制剂，其特征在于：所述制剂为口服剂型或外用剂型，优选地，所述口服剂型选自片剂、胶囊剂、口服液、肠溶片、颗粒剂、糖浆剂、滴丸、水蜜丸、散剂、合剂、煎膏剂、酒剂、露剂、酊剂或舌下含片；所述外用剂型选自软膏、栓剂、硬质软膏、搽剂、滴眼液、油剂、乳膏、气雾剂或喷雾剂。
8.权利要求1至5中任一项所述的组合物或者权利要求6或权利要求7所述的制剂在制备预防或治疗骨质疏松症的产品中的用途。
9.根据权利要求8所述的用途，其特征在于：所述产品是药物、保健品或功能性食品。
10.根据权利要求8或权利要求9所述的用途，其特征在于：所述骨质疏松症包括骨质疏松相关并发症、相关疾病以及相关临床症状。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114344289A (zh) * | 2022-01-29 | 2022-04-15 | 暨南大学 | 一种具有抗衰老活性的组合物及其制剂和用途 |
| CN115671195A (zh) * | 2022-11-22 | 2023-02-03 | 暨南大学 | 一种山药皮提取物及其制备方法与应用 |
| WO2023143221A1 (zh) * | 2022-01-29 | 2023-08-03 | 暨南大学 | 一种预防或治疗骨质疏松症的组合物及其制剂和用途 |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020165169A1 (en) * | 2000-08-14 | 2002-11-07 | Chung-Sook Kim | Therapeutic agent of osteoporosis comprising an active ingredient of quercetin derivatives |
| JP2003095971A (ja) * | 2001-09-27 | 2003-04-03 | National Institute Of Health & Nutrition | 骨粗鬆症治療剤または組成物 |
| US20090304827A1 (en) * | 2008-05-08 | 2009-12-10 | Kim Darrick S H L | Combinations of Ingredients Having Synergistic Anti-Inflammatory Effects |
| WO2010008150A2 (ko) * | 2008-07-18 | 2010-01-21 | 한국화학연구원 | 삼백초와 황금의 혼합 추출물을 유효성분으로 함유하는 골다공증 예방 또는 치료용 조성물 |
| JP2012158579A (ja) * | 2011-02-02 | 2012-08-23 | Shonan Institute For Medical & Preventive Science | 骨粗鬆症の予防及び改善する食品、医薬品動物用飼料 |
| WO2014184484A1 (fr) * | 2013-05-13 | 2014-11-20 | Institut National De La Recherche Agronomique - Inra | Utilisation d'une association de deux composés pour le traitement et/ou la prévention de troubles osseux |
| CN104721678A (zh) * | 2014-07-12 | 2015-06-24 | 广东医学院 | 高良姜提取物在制备抗骨质疏松保健食品及药品方面的应用 |
| WO2017005159A1 (zh) * | 2015-07-06 | 2017-01-12 | 陕西天奎生物医药科技有限公司 | 一种治疗骨质疏松性骨折和/或骨关节炎的天然药物组合物及其用途 |
| US20190015384A1 (en) * | 2017-07-13 | 2019-01-17 | Summit Innovation Labs LLC | Treatment and Prevention of Joint Disorders |
| US20190015448A1 (en) * | 2017-07-13 | 2019-01-17 | Summit Innovation Labs LLC | Treatment and Prevention of Bone and Joint Disorders |
| JP2021177705A (ja) * | 2020-05-11 | 2021-11-18 | 辻製油株式会社 | 骨代謝改善組成物およびその製造方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2379043C2 (ru) * | 2007-08-02 | 2010-01-20 | Закрытое акционерное общество "Биологические исследования и системы" | Фармацевтическая композиция для профилактики и лечения остеопороза у женщин в период менопаузы |
| CN102240388B (zh) * | 2010-05-11 | 2014-05-07 | 廖晖 | 一种姜提取物、其制备方法及其用途 |
| CN110934883A (zh) * | 2019-12-14 | 2020-03-31 | 湛江广医医药科技开发有限公司 | 一组改善男性骨质疏松预防骨折的柚皮苷制剂 |
| CN114344289B (zh) * | 2022-01-29 | 2023-06-20 | 暨南大学 | 一种具有抗衰老活性的组合物及其制剂和用途 |
| CN114225037B (zh) * | 2022-01-29 | 2023-02-07 | 暨南大学 | 一种预防或治疗骨质疏松症的组合物及其制剂和用途 |
-
2022
- 2022-01-29 CN CN202210112526.3A patent/CN114225037B/zh active Active
-
2023
- 2023-01-17 WO PCT/CN2023/072505 patent/WO2023143221A1/zh unknown
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020165169A1 (en) * | 2000-08-14 | 2002-11-07 | Chung-Sook Kim | Therapeutic agent of osteoporosis comprising an active ingredient of quercetin derivatives |
| JP2003095971A (ja) * | 2001-09-27 | 2003-04-03 | National Institute Of Health & Nutrition | 骨粗鬆症治療剤または組成物 |
| US20090304827A1 (en) * | 2008-05-08 | 2009-12-10 | Kim Darrick S H L | Combinations of Ingredients Having Synergistic Anti-Inflammatory Effects |
| WO2010008150A2 (ko) * | 2008-07-18 | 2010-01-21 | 한국화학연구원 | 삼백초와 황금의 혼합 추출물을 유효성분으로 함유하는 골다공증 예방 또는 치료용 조성물 |
| JP2012158579A (ja) * | 2011-02-02 | 2012-08-23 | Shonan Institute For Medical & Preventive Science | 骨粗鬆症の予防及び改善する食品、医薬品動物用飼料 |
| WO2014184484A1 (fr) * | 2013-05-13 | 2014-11-20 | Institut National De La Recherche Agronomique - Inra | Utilisation d'une association de deux composés pour le traitement et/ou la prévention de troubles osseux |
| CN104721678A (zh) * | 2014-07-12 | 2015-06-24 | 广东医学院 | 高良姜提取物在制备抗骨质疏松保健食品及药品方面的应用 |
| WO2017005159A1 (zh) * | 2015-07-06 | 2017-01-12 | 陕西天奎生物医药科技有限公司 | 一种治疗骨质疏松性骨折和/或骨关节炎的天然药物组合物及其用途 |
| US20190015384A1 (en) * | 2017-07-13 | 2019-01-17 | Summit Innovation Labs LLC | Treatment and Prevention of Joint Disorders |
| US20190015448A1 (en) * | 2017-07-13 | 2019-01-17 | Summit Innovation Labs LLC | Treatment and Prevention of Bone and Joint Disorders |
| JP2021177705A (ja) * | 2020-05-11 | 2021-11-18 | 辻製油株式会社 | 骨代謝改善組成物およびその製造方法 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114344289A (zh) * | 2022-01-29 | 2022-04-15 | 暨南大学 | 一种具有抗衰老活性的组合物及其制剂和用途 |
| WO2023143221A1 (zh) * | 2022-01-29 | 2023-08-03 | 暨南大学 | 一种预防或治疗骨质疏松症的组合物及其制剂和用途 |
| CN115671195A (zh) * | 2022-11-22 | 2023-02-03 | 暨南大学 | 一种山药皮提取物及其制备方法与应用 |
| CN115671195B (zh) * | 2022-11-22 | 2023-07-25 | 暨南大学 | 一种山药皮提取物及其制备方法与应用 |
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