CN106943421A - 二丁酰环磷腺苷盐在制备外用消脂减肥药物中的应用 - Google Patents
二丁酰环磷腺苷盐在制备外用消脂减肥药物中的应用 Download PDFInfo
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Abstract
本发明公开了二丁酰环磷腺苷盐在制备外用消脂减肥药物中的应用。二丁酰环磷腺苷盐能够直接进入脂肪细胞中激活PKA蛋白进而活化激素敏感性酯酶（HSL）催化脂肪分解成游离脂肪酸和甘油。同时，能对抗机体内磷酸二酯酶的破坏作用，作用时间和速度均比cAMP持久和迅速。
Description
技术领域
本发明涉及医药领域，具体是二丁酰环磷腺苷盐在制备外用消脂减肥药物中的用途。
背景技术
根据全身脂肪组织分布部位的不同，肥胖可分为全身性肥胖和局部肥胖（上身肥胖和下身肥胖、腹型肥胖）两大类。全身性肥胖目前已经成为全球性的、严重的社会公共卫生问题，世界卫生组织发布的统计结果表明，全球目前至少有10亿成年人超重，3亿人肥胖，人口过度肥胖已严重威胁全球发展。而局部肥胖虽然一般不会造成严重的健康问题，但却是一个更为普通的社会问题，它指的是身体某一部分脂肪蓄积过多而发生的肥胖，以腹部（将军肚/啤酒肚）、手臂（蝴蝶臂）、大腿（大象腿）和臀部等部位最为常见。当前，随着人们生活水平的不断提高，饮食丰富，营养过剩，几乎所有人都或多或少的存在局部肥胖的问题，严重影响个人整体形象与美观，对许多人造成极大的困扰！
目前的局部消脂美容方法主要包括抽脂、注射溶脂针等。但是，抽脂可能会导致皮肤凹陷、松弛，甚至出现皮下淤血和和出血等严重副作用。而溶脂针的溶脂成分复杂且不明确，容易出现肿胀、疼痛，甚至感染坏死的严重问题，已被世界多国包括中国明令禁止使用。而市面上琳琅满目的消脂、瘦身和塑身美容产品绝大多数属于无效产品。
综上，目前市面上尚无安全有效的局部减肥产品和技术，开发安全、便捷和高效的局部消脂美容产品无疑具有巨大的市场潜力！
二丁酰环磷腺苷盐的分子式为C18H23N5XO8P，其结构式由以下式（1）表示：
式（1）
二丁酰环磷腺苷盐可用于心绞痛、急性心肌梗死的辅助治疗，亦可用于心肌炎、心源性休克，手术后网膜下出血和银屑病，并可辅助其他抗癌药治疗白血病。但是，对于二丁酰环磷腺苷盐的消脂减肥作用未见报道。
发明内容
为解决上述问题，本发明提供了以下技术方案：
二丁酰环磷腺苷盐在制备外用消脂减肥药物中的应用。
一种外用消脂减肥药物组合物，其特征在于包含上述二丁酰环磷腺苷盐。
一种外用消脂减肥药物组合物，其特征在于包含上述二丁酰环磷腺苷盐，以及毛喉素（或毛喉鞘蕊花提取物）、左旋肉碱、茶碱中的一种或几种。
上述二丁酰环磷腺苷盐为二丁酰环磷腺苷钠、二丁酰环磷腺苷钙或其他形式的盐。
二丁酰环磷腺苷盐能够直接进入脂肪细胞中激活PKA蛋白进而活化激素敏感性酯酶（HSL）催化脂肪分解成游离脂肪酸和甘油。同时，能对抗机体内磷酸二酯酶的破坏作用，作用时间和速度均比cAMP持久和迅速。
附图说明
图1为二丁酰环磷腺苷盐对脂肪积累的影响。
图2为毛喉素对脂肪积累的影响。
图3为茶碱对脂肪积累的影响。
图4为药物组合对脂肪积累的影响。
图5为药物组合对肥胖小鼠体重和腹部皮下脂肪的影响（A：体重，*P<0.05，**P<0.01；B：皮下脂肪，*P<0.05）。
图6为药物组合物对肥胖小鼠心、肝、肾、脾、肺和睾丸的影响。
具体实施方式
实施例：二丁酰环磷腺苷盐的制备
在干燥反应瓶中，加入环磷酸腺苷三乙胺盐3.2g(0.0lmol)、三氯甲烷100ml、吡啶4g(0.05ml)和正丁酸酐15.82g(0.10mol)于60℃搅拌48h。反应毕，回收溶剂后，加入水100ml，用异己酮提取数次弃去。水层减压浓缩至15ml，用三氯甲烷30ml×3提取，合并有机层，回收溶剂后，向剩余物中加入水30ml，搅拌溶解后，经过Amberlite IR-120树脂纯化，浓缩冷却，析出固体，干燥，制得二丁酰环磷腺苷盐 4.32g(88%)，mp240℃(dec)。
实验准备：3T3-L1前脂肪细胞诱导分化成脂肪细胞。将大鼠的纤维原细胞系3T3-L1以5×104/毫升的密度接种细胞于12孔的培养板中，并在含有10%胎牛血清（FBS，GIBCO，Life technology）的高糖DMEM培养基（GIBCO，Life technology）中培养。待细胞长至70%融合度时将培养基换成含1微克/毫升胰岛素、0.25微摩尔/升地塞米松（dexamethasone）和0.5毫摩尔/升3-异丁基-1-甲基黄嘌呤（IBMX）的新DMEM培养基中（含10%FBS）诱导分化；2天后将培养基换成1微克/毫升胰岛素的新DMEM培养基（含10%FBS）中；2天后将培养基换成正常DMEM培养基（含10%FBS）并观察，直至形成脂肪细胞。
实验方法1：通过油红O染色法以及酶标仪检测脂肪的累积情况。使用从sigma购买的油红O，用异丙醇配置成10毫克/毫升的溶液，过滤后避光保存。3T3-L1脂肪细胞用磷酸盐缓冲液（PBS）润洗2遍，10%甲醛固定30分钟以上；以油红：去离子水=3:2稀释，滤纸过滤，室温放置10min；细胞染色10min左右，然后用75%酒精/60%异丙醇漂洗，除去多余的染料；显微镜观察及拍照。拍照后采用100%异丙醇溶解，收获溶解液，经酶标仪在510nm波长处检测吸光值。处理组为各组分单独或联合使用的组，对照组为无添加任何组分的组。
实验方法2：肥胖动物模型的建立与分组给药：动物模型制备及分组：4周龄C57/BJ6L雄性小鼠在试验环境下喂普通饲料7d，称体重，选择体重基本一致的小鼠用高脂饲料喂养8周，以体重超过用普通饲料饲养小鼠体重20%的小鼠为肥胖小鼠，将其纳入实验组:肥胖对照组、药物组合治疗组。小鼠分笼喂养，自由进食饮水；自然昼夜采光，室温18℃-25℃；药物组合治疗组每日定时以涂抹的方式将药物用于小鼠的腹部，涂抹前去毛。每2-3日换食，隔日换水；相对湿度50％左右；实验为期30天。各组动物均以高脂饲料喂养。治疗完成后测量体重，然后，将小鼠处死取其腹部皮肤、心、肝、肾、脾、肺和睾丸。腹部皮肤经固定包埋后进行H&E染色并拍照计算皮下脂肪的厚度。其他组织经固定包埋后进行H&E染色并拍照观察组织形态。注：普通饲料为：水分：8.4%，粗蛋白25.8%，粗脂肪6.53%，粗灰分6.2%，粗纤维4.12%，无氮浸出物46.8%，钙1.26%，磷0.89%，赖氨酸1.36%。高脂饲料为：水分：8.6%，粗蛋白18.8%，粗脂肪：18.83%，粗灰分5.2%，粗纤维3.98%，无氮浸出物45.2%，钙1.24%，磷0.83%，赖氨酸1.38%。
实验例1：二丁酰环磷腺苷盐促发脂肪分解的功效。为了测定二丁酰环磷腺苷盐促进脂肪细胞中的脂肪分解的效果，使用在实验准备中分化的3T3-L1脂肪细胞。将细胞培养基换成10毫克/毫升二丁酰环磷腺苷盐的新DMEM培养基（含10%FBS），然后，按实验方法1检测脂肪细胞中脂肪的累积情况。结果如图1所示。
图1结果显示，与对照组相比，二丁酰环磷腺苷盐处理后的脂肪细胞脂肪量明显降低，并且分解脂肪的效果优于已知具有分解脂肪作用的阳性比较对照咖啡因。
实验例2：毛喉素促发脂肪分解的功效。为了测定毛喉素促进脂肪细胞中的脂肪分解的效果，使用在实验准备中分化的3T3-L1脂肪细胞。将细胞培养基换成8.2微克/升毛喉素的新DMEM培养基（含10%FBS），然后，按实验方法1检测脂肪细胞中脂肪的累积情况。结果如图2所示。
图2结果显示，与对照组相比，毛喉素处理后的脂肪细胞中中性脂肪量有一定程度的降低。
实验例3：茶碱促发脂肪分解的功效。为了测定茶碱促进脂肪细胞中的脂肪分解的效果，使用在实验准备中分化的3T3-L1脂肪细胞。将细胞培养基换成20毫克/升茶碱的新DMEM培养基（含10%FBS），然后，按实验方法1检测脂肪细胞中脂肪的累积情况。结果如图3所示。
图3结果显示，与对照组相比，茶碱处理后的脂肪细胞中脂肪量有一定程度的降低。
实验例4：二丁酰环磷腺苷盐、毛喉素、左旋肉碱和茶碱的协同作用。为了证实二丁酰环磷腺苷盐、毛喉素、左旋肉碱和茶碱在分解脂肪时是否具有协同作用，用上述的各组分组合物对通过实验准备诱导的3T3-L1脂肪细胞进行处理。每种组分的浓度与单独处理时相同。结果如图4所示。
图4结果显示，与对照组相比，组合物处理后的脂肪细胞中脂肪量显著降低，并且分解脂肪的效果明显优于已知具有分解脂肪作用的阳性比较对照咖啡因。
实验例5：采用实施例4所述药物组合物对肥胖小鼠进行脂肪分解的功效。为了检验药物组合物促进肥胖小鼠腹部脂肪分解的效果，使用在实验方法2中养成的肥胖小鼠，按实验方法2的方法计算小鼠体重及腹部皮下脂肪的厚度，观察肥胖小鼠心、肝、肾、脾、肺和睾丸的组织形态。结果如图5和图6所示。
图5结果显示，该药物组合物能够显著降低小鼠的体重和腹部皮下脂肪的厚度。
图6结果显示，该药物组合物对肥胖小鼠心、肝、肾、脾、肺和睾丸的组织形态并无明显影响。
Claims (4)
1.二丁酰环磷腺苷盐在制备外用消脂减肥药物中的应用。
2.一种外用消脂减肥药物组合物，其特征在于包含权利要求1所述的二丁酰环磷腺苷盐。
3.一种外用消脂减肥药物组合物，其特征在于包含权利要求1所述的二丁酰环磷腺苷盐，以及毛喉素、左旋肉碱、茶碱中的一种或几种。
4.权利要求1—3所述二丁酰环磷腺苷盐为二丁酰环磷腺苷钠、二丁酰环磷腺苷钙。
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| CN108997430A (zh) * | 2018-07-16 | 2018-12-14 | 南京工业大学 | 一种二丁酰环磷腺苷钙盐的晶体 |
| CN109528748A (zh) * | 2018-12-28 | 2019-03-29 | 广州奕昕生物科技有限公司 | 环磷酸腺苷盐在制备外用消脂减肥产品中的应用 |
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| CN109528748A (zh) * | 2018-12-28 | 2019-03-29 | 广州奕昕生物科技有限公司 | 环磷酸腺苷盐在制备外用消脂减肥产品中的应用 |
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Address after: 510032 cliff Eagle Road No. 8 A306, Guangzhou high tech Industrial Development Zone, Guangdong Province Applicant after: Guangzhou Yixin Biological Technology Co., Ltd. Address before: 510520 Guangdong Guangzhou City, Tianhe District Longdong North Road 321 Guangdong province food and Drug Institute Library Science and Technology Building 10 building 1068 unit Applicant before: Guangzhou Yixin Biological Technology Co., Ltd. |
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Application publication date: 20170714 |
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