CN116549512B - 一种治疗痤疮的复方精油和含有其的药物组合物 - Google Patents
一种治疗痤疮的复方精油和含有其的药物组合物 Download PDFInfo
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Abstract
本发明提供了一种治疗痤疮的复方精油和含有其的药物组合物,该复方精油包含下述成分:马鞭草酮迷迭香精油、依兰精油、茶树精油和广藿香精油。各单方精油通过下述方法制得:分别以马鞭草酮迷迭香、依兰、互叶白千层、广藿香为原料,通过水蒸气蒸馏取得挥发油。优选地,该复方精油还包含青蒿精油。青蒿精油是通过以下方法制得:以黄花蒿为原料,通过水蒸气蒸馏取得挥发油。本发明的复方精油具有抑制皮脂腺细胞SZ95脂质合成和抑制细菌生长繁殖的效果。
Description
技术领域
本发明涉及医药领域,具体涉及一种治疗痤疮的复方精油和含有其的药物组合物。
背景技术
痤疮是一种毛囊皮脂腺慢性炎症性疾病,好发于皮脂分泌旺盛部位,比如额头、面部、背部、胸部等,症状轻微表现为粉刺,严重则表现为脓包、囊肿、瘢痕和色素沉着,甚至造成毁容,给患者身心带来极大压力。痤疮的发生是多因素综合作用的结果,主要与雄性激素诱导的皮脂腺过度分泌脂质、毛囊皮脂腺导管角化异常及毛囊内痤疮丙酸杆菌等相关细菌的大量增殖有关。
皮脂腺内含有参与雄激素代谢及转化的酶,是雄激素的重要靶组织,也是雄激素在皮肤中代谢的主要场所,具有维持皮肤中雄激素稳态的作用。雄激素是最重要的促皮脂腺活性激素。在雄激素的作用下,皮脂腺活性增强导致脂质大量分泌是痤疮发生的关键因素。作用于皮脂腺的活性雄激素(睾酮,T;双氢睾酮,DHT)一部分由睾丸和肾上腺产生经血循环进入;另一部分由雄激素前体(脱氢表雄酮,DHEA;硫酸脱氢表雄酮,DHEAs;雄烯二酮,AD)在皮肤类固醇生成酶的作用下生成具有活性的雄性激素T,后者在雄性激素代谢酶5α-还原酶 (5α-reductase,5α-R) 作用下不可逆地转化为活性更强的DHT。雄激素主要通过雄激素受体(androgen receptor, AR)对皮肤产生作用,二者相结合,激发相关基因的转录,引起皮脂腺活性增加,导致脂质分泌过多,堵塞皮脂排泄通道,从而引起痤疮。
皮脂腺是雄激素的靶组织,除了雄激素能通过雄激素受体结合对皮脂腺细胞的分化起促进作用外,另一个重要的调节因子是转录因子过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors, PPARs)。皮脂腺细胞分化成熟后,脂质分泌增加,PPARs与视黄醇X受体形成异源二聚体发挥作用,并充当多种基因的转录调节器,主要负责调节在脂肪组织、肝脏和皮肤中参与脂质代谢的基因表达,参与体内多种生理病理过程,如脂肪细胞的分化、肥胖、动脉粥样硬化等,在脂质合成的细胞发育中起到重要作用。PPARs可分为α、β(或δ)和γ三种类型,皮脂腺细胞中以PPARγ表达为主,PPARγ的激活有促进皮脂腺细胞脂质合成作用。脂质是皮脂腺细胞分化的终末产物,是寻常痤疮发生的重要致病因素。
皮肤微生物组学发现痤疮发病与痤疮丙酸杆菌(P.acnes)和金黄色葡萄球菌(S.aureus)为代表的痤疮相关致病菌的增殖有密切关系。P.acnes属于革兰氏阳性杆菌,是一种厌氧或兼性厌氧菌,其在人体中繁殖环境多与皮脂腺分泌旺盛、皮肤毛囊内皮脂堆积营造的厌氧环境有关。P.acnes通过诱导炎症反应,促进毛囊皮脂腺上皮角质化以及促进皮脂分泌而发挥作用。P.acnes产生的酶能分解皮脂,产主的游离脂肪酸是刺激毛囊引起炎症反应的重要原因。P.acnes还产生一些低分子多肽,对中性粒细胞具有趋化作用,后者产主的水解酶使毛囊壁发生渗漏甚至破裂,毛囊内容物进入周围真皮组织,造成了从炎性丘疹到囊肿性损害的一系列临床表现。S.aureus属于革兰氏阳性菌,存在于人体皮肤的各个方面,属于条件致病菌。S.aureus作为痤疮重要的致病菌,在毛囊内产生游离脂肪酸,致使毛囊壁破裂,形成炎症性皮损。大量细菌的繁殖可导致炎症在毛囊内发生,产生大量炎症因子,是痤疮加重的重要因素。
目前市场上用于治疗痤疮的药物通常有刺激性较大、容易导致皮肤干燥和依赖性等副作用。精油具有较好的抑菌抗炎活性,是一种可行的替代药物治疗痤疮的物质。精油是从植物的叶子、花朵、种子、果实、根部、树皮、树脂、木心等部位以水蒸气蒸馏法、冷压榨法、脂吸法、二氧化碳超临界萃取等方法提炼出来的。由于其天然来源,被广泛认为是比合成药物更接近自然,是一种更健康、更可持续的选择。精油是多种化学成分组成的复杂混合物,各单体成分具有抗菌、抗炎、抗氧化、镇痛等功效,并通过共同作用产生整体效果。精油分子通常是脂溶性的,能够更好地与皮肤的脂质层相容,更容易渗透到皮肤的深层发挥作用。同时大部分精油分子量小于300道尔顿(Dalton),可以更容易地穿透皮肤表面并渗透到皮肤的不同层次,从而实现更好的吸收和效果。近年来越来越多高品质精油被作为皮肤疾病及皮肤养护的外用药物成分选择。
单方精油所含药效物质基础有限,难以完全治愈或控制累及多种器官的器质性病变的发展。配方精油是由各种疗效确定或药效物质基础明确的精油成分经一定比例混合而成的复方精油,源于疗效确切的单方精油之间的归类组合,经过实验室安全性及药理毒理研究和临床疗效验证,归属于组分中药。组分中药是创新中药研究的一个途径,是以中医理论为指导,遵循方剂配伍理论与原则,结合现代药物研制方法和技术,由有效组分配伍而成。配方精油的药效物质和作用机制相对清楚,可在治疗临床疾病或改善症状时,从不同的角度、多个方面发挥协同药理作用,提高疗效并减少不良反应,在皮肤外治和皮肤保健中具有广泛的用途。
发明内容
本发明的目的在于提供一种治疗痤疮的复方精油,该复方精油具有抑制皮脂腺细胞SZ95脂质合成和抑制痤疮相关细菌生长繁殖的功效。
该复方精油包含马鞭草酮迷迭香精油、依兰精油、茶树精油和广藿香精油(下文中用复方精油4F表示)。
上述单方精油通过以下方法制得:
分别以马鞭草酮迷迭香(Rosmarinus officinalis)、依兰(Cananga odorata (Lamk.) Hook. f. et Thoms.)、互叶白千层(Melaleuca alternifolia Cheel)、广藿香(Pogostemon cablin (Blanco) Benth.)为原料,通过水蒸气蒸馏取得挥发油。
优选地,本发明复方精油4F中,马鞭草酮迷迭香精油、依兰精油、茶树精油和广藿香精油的体积比为4.2:2.7:2.1:1。
优选地,本发明的复方精油还包含青蒿精油(下文中用复方精油4T表示)。青蒿精油是以黄花蒿(Artemisia annua L.)为原料,通过水蒸气蒸馏取得的挥发油。
优选地,本发明的复方精油4T中马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油和青蒿精油的体积比为4.2:2.7:2.1:1:2.5。
本发明还提供了一种修复皮肤的药物组合物,包含上述复方精油和生理上或药学上可接受的辅料。
优选地,本发明药物组合物中复方精油的含量为:10 μg/mL~500 μg/mL。
优选地,本发明药物组合物中复方精油的含量为:50 μg/mL~100 μg/mL。
优选地,本发明药物组合物为软膏剂、乳剂或者乳膏剂。
辅料可选自凡士林、固体石蜡、液体石蜡、地蜡、微晶蜡、饱和脂肪酸酯、不饱和脂肪酸酯、抗氧剂、二甲基硅油、羊毛脂、胆固醇、羊毛甾醇及其它类固醇、乙酰类固醇或是多元的酯类(如司盘)、甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基甲基纤维素、耆胶西黄、果胶、海藻酸、黄原胶、瓜尔胶、琼脂、茶多酚(TP)、生育酚等等。
本发明还提供了一种化妆品组合物,该化妆品组合物包含上述的复方精油和化妆品基质。
本发明的复方精油4F的组方依据:
本发明的复方精油4F以马鞭草酮迷迭香精油为主,马鞭草酮迷迭香精油的主要成分包括马鞭草酮、α-蒎烯、桉叶油醇、樟烯、乙酸龙脑酯等,这些成分有抗菌消炎、促进血液循环、帮助减少皮肤的油脂分泌和收敛作用,可以收缩毛孔,减少皮肤的油脂堆积,并帮助调节皮肤的油水平衡;依兰精油主要成分为大根香叶烯、杜松烯、芳樟醇、乙酸苄酯、香茅酮等,具有抗炎、抗氧化功效,有助于平衡头皮油脂分泌,清洁皮肤;茶树精油主要成分包括松油烯、γ-蒎烯、1,8-桉叶油醇、α-蒎烯等,具有抗病原微生物、抗炎、抗氧化、清凉镇静的功效,可减轻皮肤炎症和红肿,促进痤疮愈合;广藿香精油主要成分包括广藿香醇、广藿香烯、丁香酚、杜松烯、甲基香茅醇酮等,具有抗菌抗炎、减少皮肤油脂分泌、收敛毛孔、促进皮肤组织修复等功效,能减轻痤疮的炎症、红肿问题。这些精油组成配方后,主要成分产生1+1>2的效果,协同加强起到抗菌消炎、控油收敛、消肿祛痘、促进愈合的功效。依兰精油、广藿香精油还具有镇静和放松神经系统的作用,可舒缓敏感辅助痤疮修复。
进一步地,在本发明复方精油4F的基础上,再添加中药青蒿精油,形成本发明的另一复方精油4T。青蒿精油主要成分为α-蒎烯、1,8-桉树脑、β-石竹烯、β-蒎烯等,具有抗病原微生物、抗菌抗炎、抗过敏等作用。《神农本草经》中记载青蒿具有清虚热,除骨蒸,解暑热,截疟,退黄之功效,常用于温邪伤阴,夜热早凉,阴虚发热,骨蒸劳热,暑邪发热,疟疾寒热,湿热黄疸等病症的治疗。痤疮的临床表现为丘疹、脓疱、结节和脓肿,多是因为湿邪常裹挟热毒壅滞局部,变生为湿热蕴结、脉络淤阻、气血凝滞所致。青蒿味苦、辛,性寒,在本发明的复方精油4T中,青蒿可辅助君药解毒的同时又托毒外出,增强复方精油清热解毒、祛湿化浊、调节腠理、治疗痤疮的功效。
研究表明,本发明的复方精油4F在以下方面表现出明显的优势:在50μg/m和100μg/ml的浓度下,本发明复方精油4F对SZ95细胞中的脂质合成的抑制率分别达到23.98%、30.16%,具有优良的控油效果;对痤疮发病主要相关细菌如痤疮丙酸杆菌和金黄色葡萄球菌均具有强效抑菌作用:复方精油4F在256倍稀释浓度内(>3.9mg/ml)具有对痤疮丙酸杆菌的强效抑菌作用(>90%抑菌率),在1024倍稀释浓度内(>0.98mg/ml)有对痤疮丙酸杆菌的抑菌作用(>50%抑菌率),复方精油4F在512倍稀释浓度内(>1.95mg/ml)具有对金黄色葡萄球菌的强效抑菌作用(>90%抑菌率),在4096倍稀释浓度内(>0.24 mg/ml)有对金黄色葡萄球菌的抑菌作用(>50%抑菌率)。
本发明的复方精油4T在50μg/ml、100μg/ml的浓度下,相较于同浓度的复方精油4F具有更加突出的抑制SZ95细胞中脂质合成的效果,其抑制率分别高达33.67%(50μg/ml)和37.55%(100μg/ml);且本发明复方精油4T具有显著降低SZ95细胞的脂质合成相关基因AR、PPARγ的mRNA的表达(P<0.05)的作用。本发明复方精油4T对痤疮发病主要相关细菌如痤疮丙酸杆菌和金黄色葡萄球菌也均具有强效抑菌作用。此外,本发明复方精油4T中各单精油使用剂量比4F中的单精油使用剂量小,在量产投入使用复方精油时,本发明的复方精油4T具有成本低,效果突出的优势。
附图说明
图1:精油处理后的SZ95细胞基因AR的mRNA的表达变化;
图2:精油处理后的SZ95细胞基因PPARγ的mRNA的表达变化;
图3:精油4A、4B、4C、4D和复方精油4F对痤疮丙酸杆菌的抑菌功效曲线;
图4:精油4X和复方精油4F、4T对痤疮丙酸杆菌的抑菌功效曲线;
图5:精油4X和复方精油4F、4T对金黄色葡萄球菌的抑菌功效曲线;
图6:马鞭草酮迷迭香精油的气质联用检测结果;
图7:依兰精油的气质联用检测结果;
图8:茶树精油的气质联用检测结果;
图9:广藿香精油的气质联用检测结果;
图10:青蒿精油的气质联用检测结果。
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。
下述实施例2-实施例5中所使用的马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油、青蒿精油均为商购所得,或者由实施例1的方法提取而得。
马鞭草酮迷迭香精油:从牧九野 (上海) 科技有限公司采购,批号为:JY005706,企业标准为: 相对密度(20℃):0.881~0.975;折光指数(20℃):1.461~1.481。马鞭草酮迷迭香精油化妆品原料安全信息报送码为 004689-02571-9895;
依兰精油:从牧九野 (上海) 科技有限公司采购,批号为:BEO079110315,企业标准为: 相对密度(20℃):0.916-0.946;折光指数(20℃):1.482~1.502。依兰精油化妆品原料安全信息报送码为 007670-02571-3025;
茶树精油:从牧九野 (上海) 科技有限公司采购,批号为:BEO010410110,企业标准为: 相对密度(20℃):0.876-0.906;折光指数(20℃):1.469-1.489。茶树精油化妆品原料安全信息报送码为 002978-02571-6344;
广藿香精油:从牧九野 (上海) 科技有限公司采购,批号为:BEO025610111,企业标准为: 相对密度(20℃): 0.949-0.983;折光指数(20℃):1.505-1.512。广藿香精油化妆品原料安全信息报送码为 002634-02571-5566;
青蒿精油:从牧九野(上海)科技有限公司采购,批号为:XYJY0069,企业标准为:相对密度(20℃): 0.876~0.906;折光指数(20℃):1.462~1.482。青蒿原料安全信息报送码为005316-02571-5582。
【实施例1】 提取单方精油
水蒸气蒸馏所使用仪器:水封口式蒸馏釜,其设备构成:
蒸馏釜:整体外观为圆柱形,球冠式釜底,上部开口为加料口;
鹅颈管:带有蒸馏釜上口的圆锥形盖子,连接冷凝器;
冷凝器:为铝质列管冷凝器,使蒸汽冷凝和冷却式馏出液;
油水分离器:用铝材做成,既是接受馏出液的容器,又是精油与水的分离器。
提取精油工艺流程:投料→加水→蒸馏→冷却→油水分离→精油→包装。
1.1提取马鞭草酮迷迭香精油
在6月到9月马鞭草开花期之间,选择采摘新鲜、干燥、没有受到污染的马鞭草全株,并将其洗净。将蒸馏器拆开,清洗干净所有零部件,确保无油污和杂质。在蒸馏锅中加入蒸馏锅的2/3到3/4的蒸馏水,并将其放置在加热板上,将加热板加热至水开始沸腾。当蒸馏锅中的水开始煮沸时,将马鞭草全株放入蒸馏锅中,确保全部浸没在水中。等待水开始沸腾后,用冷却管连接蒸馏器,并将另一端的管子放入收集瓶中。蒸汽会通过冷却管冷凝,并流入收集瓶中。等待24小时,精油会浮在水的上层,用滴管或分离漏斗将其从水中分离出来。收集好精油后,使用滤纸或滤布过滤以去除悬浮在精油中的颗粒或其他杂质,得马鞭草精油。
1.2提取依兰精油
在6月到9月依兰开花期之间选择采摘新鲜、干燥、没有受到污染的依兰花朵,并将其洗净。将蒸馏器拆开,清洗干净所有零部件,确保无油污和杂质。在蒸馏锅中加入蒸馏锅的2/3到3/4的蒸馏水,并将其放置在加热板上,将加热板加热至水开始沸腾。当蒸馏锅中的水开始煮沸时,将依兰全株放入蒸馏锅中,确保全部浸没在水中。等待水开始沸腾后,用冷却管连接蒸馏器,并将另一端的管子放入收集瓶中。蒸汽会通过冷却管冷凝,并流入收集瓶中。等待24小时,精油会浮在水的上层,用滴管或分离漏斗将其从水中分离出来。收集好精油后,使用滤纸或滤布过滤以去除悬浮在精油中的颗粒或其或其他杂质,得依兰精油。
1.3提取茶树精油
在6月到9月互叶白千层开花期之间选择采摘新鲜、干燥、没有受到污染的互叶白千层枝叶,并将其洗净。将蒸馏器拆开,清洗干净所有零部件,确保无油污和杂质。在蒸馏锅中加入蒸馏锅的2/3到3/4的蒸馏水,并将其放置在加热板上,将加热板加热至水开始沸腾。当蒸馏锅中的水开始煮沸时,将互叶白千层全株放入蒸馏锅中,确保全部浸没在水中。等待水开始沸腾后,用冷却管连接蒸馏器,并将另一端的管子放入收集瓶中。蒸汽会通过冷却管冷凝,并流入收集瓶中。等待24小时,精油会浮在水的上层,用滴管或分离漏斗将其从水中分离出来。收集好精油后,使用滤纸或滤布过滤以去除悬浮在精油中的颗粒或其或其他杂质,得互叶白千层精油。
1.4提取广藿香精油
在7月到9月广藿香开花期之间,选择采摘新鲜、干燥、没有受到污染的广藿香全株,并将其洗净。将蒸馏器拆开,清洗干净所有零部件,确保无油污和杂质。在蒸馏锅中加入蒸馏锅的2/3到3/4的蒸馏水,并将其放置在加热板上,将加热板加热至水开始沸腾。当蒸馏锅中的水开始煮沸时,将广藿香全株放入蒸馏锅中,确保全部浸没在水中。等待水开始沸腾后,用冷却管连接蒸馏器,并将另一端的管子放入收集瓶中。蒸汽会通过冷却管冷凝,并流入收集瓶中。等待24小时,精油会浮在水的上层,用滴管或分离漏斗将其从水中分离出来。收集好精油后,使用滤纸或滤布过滤以去除悬浮在精油中的颗粒或其他杂质,得广藿香精油。
1.5提取青蒿精油
以河南地区10月果期黄花蒿植株为材料。
采集菊科植物黄花蒿(Artemisia annua L .)全草,以新鲜嫩苗为最佳,除去残茎及无用部位,将选好的叶子和花蕾洗净,滤干水分,置于电热恒温干燥箱中进行干燥,温度控制在60度以下,干燥时间为3h。用切割机将干燥黄花蒿切成4-6mm碎段,便于精油分子的挥发。实验证明,叶子受蒸汽加热易发生粘合,有阻碍蒸汽透入现象,本次选用水中蒸馏,使黄花蒿与水接触,通过水渗出作用,从植物体渗透,提高精油出油率。
将粉粹的黄花蒿置于蒸馏内槽中,加入等量的蒸馏水,注于外蒸馏槽中,并将蒸馏槽置放于水槽之上,密封外蒸馏槽,浸泡1.5h后进行蒸馏。萃取温度90℃,冷凝管温度15~25℃,蒸馏时间1.5h,得精油纯露混合液,用分离器分离,得青蒿精油。
【实施例2】制备复方精油
本文中马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油和青蒿精油分别用代号4A、4B、4C、4D和4X表示。将实施例1.1~1.4获得的或者上述从牧九野 (上海) 科技有限公司商购的4A、4B、4C和4D均匀混合一起,即得本发明的复方精油4F。在4F的基础上再加上由实施例1.5获得的或者从牧九野(上海)科技有限公司商购的4X均匀混合在一起,即得本发明的复方精油4T。
复方精油4F:4A+4B+4C+4D,体积比为4.2:2.7:2.1:1。即复方精油4F中马鞭草酮迷迭香精油含量为42%,依兰精油含量为27%,茶树精油含量为21%,广藿香精油含量为10%。
复方精油4T:4A+4B+4C+4D+4X,体积比为4.2:2.7:2.1:1:2.5。即复方精油4T中马鞭草酮迷迭香精油含量为33.6%,依兰精油含量为21.6%,茶树精油含量为16.8%,广藿香精油含量为8%,青蒿精油含量为20%。
【实施例3】精油对SZ95细胞脂质合成的影响
一、实验材料
3.1.1 实验细胞
SZ95人永生化皮脂腺细胞,购买自青旗(上海)生物技术发展有限公司。
3.1.2 试药与试剂
试药:马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油、青蒿精油、复方精油4F和复方精油4T。
试剂:DMEM高糖培养基、胎牛血清、PBS、胰酶、尼罗红、总RNA提取试剂(Trizol)、三氯甲烷、异丙醇、乙醇、DEPC水、PrimeScriptTMRT Master Mix (Takara)、TB Green PremixEx TaqTMⅡ(Takara)。
3.1.3 仪器与设备
T 25培养瓶、不透光96孔板、6孔板、多功能酶标仪、LightCycler480实时荧光定量PCR仪,普通PCR仪。
二、实验方法
3.2.1 SZ95细胞培养
SZ95细胞用含10% FBS的DMEM培养基于 37℃细胞培养箱中培养,每24 h更换一次培养基,细胞生长至 60%~70% 传代,保持细胞呈对数生长。待细胞传至3代,状态稳定后,用于实验。
3.2.2 精油配制
3.2.2.1单精油的配制:分别取1ml实施例1获得的单精油与1ml DMSO涡旋2~3min混合均匀,取上述精油溶液200 mg加入DMEM培养基至体积为10 mL,涡旋混匀为各精油储备溶液(20 mg/mL)。
3.2.2.2复方精油的配制:分别取1ml实施例2获得的复方精油与1ml DMSO涡旋2~3min混合均匀,取上述精油溶液200 mg加入DMEM培养基至体积为10 mL,涡旋混匀为各精油储备溶液(20 mg/mL)。1ml复方精油4F的组成是0.42ml马鞭草酮迷迭香精油,0.27ml依兰精油,0.21ml茶树精油,0.1ml广藿香精油;1ml复方精油4T的组成是0.336ml马鞭草酮迷迭香精油,0.216ml依兰精油,0.168ml茶树精油,0.08ml广藿香精油和0.2ml青蒿精油。
细胞实验中含精油的培养基均由上述精油储备溶液(20 mg/mL)按比例稀释配制。
3.2.3精油对 SZ95 细胞中脂质合成的影响
将细胞接种到不透光96孔板(每孔105个),培养24小时后分组处理。实验设空白对照组和各精油干预组,单精油和复方精油均分别稀释至浓度为50μg/ml、100μg/ml。共同培养24 h 后弃上清,PBS 清洗2次后进行尼罗红染色(尼罗红工作浓度10μg/ml),37℃避光孵育10min,用多功能酶标仪以激发波长485nm/发射波长523nm检测尼罗红荧光强度,以干预组较空白对照组荧光强度下降程度来反映抑制脂质合成的作用。按照下式计算精油对脂质合成的抑制率:。
3.2.4精油对脂质合成相关基因的影响
将SZ95细胞按每孔2×105个接种于6孔板,培养24小时后分组处理。实验设空白对照组和各精油干预组,单精油和复方精油分别稀释至浓度为100μg/ml,空白对照组加入同体积培养基,继续培养48h。按照试剂盒说明书提取SZ95细胞总RNA并进行逆转录反应。根据脂质合成相关基因AR、PPARγ的基因及内参GAPDH序列,设计合成引物。按照试剂盒说明书条件进行实时定量PCR反应。每个指标每组设 3个重复,取平均 Ct值(Cycle threshold,阈值循环数),以 GAPDH 为内参基因,用2-△△Ct相对定量分析法对目的基因进行计算。△△Ct=(Ct目的基因- Ct内参基因)干预组-(Ct目的基因- Ct内参基因)空白组,2-△△Ct表示干预组的目的基因表达相对于空白组的倍数,即目的基因的相对表达量。
三、实验结果
3.3.1精油对 SZ95 细胞中脂质合成的影响
利用尼罗红染色法检测空白组未经精油处理的和实验组经精油处理后的SZ95细胞中的脂质合成情况,结果见表1。
表1 尼罗红染色后SZ95细胞的荧光值(抑制率%)(Mean,n=3)
人永生化皮脂腺细胞(SZ95)是研究皮脂腺病理生理及痤疮等发病机制、筛选治疗药物的重要手段。皮脂腺活性及其脂质分泌功能的异常与痤疮、皮肤屏障功能损害及皮肤老化等许多皮肤疾病有关。使用尼罗红染色法检测SZ95细胞的荧光强度,如果SZ95细胞的荧光强度高,则说明SZ95细胞的脂质含量高,提示皮脂腺油脂分泌旺盛;如果SZ95细胞的荧光强度低,则说明SZ95细胞的脂质含量低,提示皮脂腺油脂分泌低下。
由表1可知,与空白组相比,本发明的复方精油4F和4T在50μg/ml及100μg/ml浓度下均能显著降低尼罗红染色荧光强度,表明本发明的复方精油4F和4T均可显著抑制SZ95细胞中的脂质合成,其中,100μg/ml的复方精油4F、50μg/ml及100μg/ml的复方精油4T的抑制率达到30%以上,具有突出的抑制SZ95细胞中脂质合成的优异效果。并且复方精油4T的效果相较于复方精油4F更优。
3.3.2精油对 SZ95细胞的脂质合成相关基因AR、PPARγ的mRNA表达的影响
脂质是皮脂腺细胞分化的终末产物,是痤疮发生的重要致病因素。与脂质合成相关的基因有AR、PPARγ。脂质合成相关基因AR、PPARγ的表达能促进人皮脂腺细胞中脂质合成,其高表达说明SZ95细胞合成脂质能力强,其低表达则说明SZ95细胞合成脂质能力弱。
利用qRT-PCR(Quantitative Real-time PCR)法检测经精油处理24小时后SZ95细胞脂质合成相关基因的表达情况。AR基因的表达结果见图1,PPARγ的mRNA表达的结果见图2。
由图1可知,相较于空白组,复方精油4F显著提高了AR的mRNA水平表达(P<0.001),而复方精油4T则显著降低AR的mRNA表达水平(P<0.05)。由图2可知,相较于空白组,复方精油4F对PPARγ的mRNA的表达无明显的影响(P>0.05),而复方精油4T显著降低PPARγ的mRNA水平表达(P<0.05)。由此可知,本发明的复方精油4T具有显著降低AR、PPARγ的mRNA表达的功效,可抑制SZ95细胞合成脂质。
四、小结
综上,本发明的复方精油4F和复方精油4T在浓度为50μg/ml和100μg/ml时均可显著抑制SZ95细胞中合成脂质,表现出优良的控油效果。其中,相比空白组,经复方精油4T处理后的SZ95细胞在尼罗红染色检测时的荧光强度下降的程度比经复方精油4F处理的更为明显,说明本发明复方精油4T抑制SZ95细胞中脂质合成的能力比复方精油4F更强。且本发明更进一步地研究发现,本发明的复方精油4F未明显降低SZ95细胞的脂质合成相关基因AR、PPARγ的mRNA的表达,本发明的复方精油4T则显著降低SZ95细胞的脂质合成相关基因AR、PPARγ的mRNA的表达。因此,本发明的复方精油4T在抑制脂质合成方面相较于复方精油4F更加突出。此外,复方精油4T中各单方精油的使用剂量比复方精油4F中的各单方精油使用剂量小,在量产投入使用复方精油时,4T具有成本低的优势。
【实施例4】精油对痤疮丙酸杆菌、金黄色葡萄球菌的影响
一、实验材料
4.1.1 实验菌株
痤疮丙酸杆菌菌株(SC5314)购买自北纳生物;金黄色葡萄球菌菌株(ATCC 6538)购买自北京三药科技开发公司
4.1.2 试药与试剂
试药:马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油、青蒿精油、复方精油4F和复方精油4T。
试剂:厌氧指示剂、胰酪大豆胨琼脂 (Tryptic Soy Agar, TSA) 琼脂平板、营养肉汤(Nutrient Broth, NB)培养基、脑心浸出液肉汤(Brain Heart Infusion Broth,BHI)培养基、BHI琼脂平板。
4.1.3 仪器与设备
10cm培养皿、灭菌接种环、96孔板、多功能酶标仪、厌氧发生袋、摇床。
二、实验方法
4.2.1菌株的制备:
4.2.1.1在实验期间,菌株痤疮丙酸杆菌和金黄色葡萄球菌在脱脂牛奶菌种保存管中长期保藏于-80℃。
4.2.1.2金黄色葡萄球菌的培养:培养前,取出冻存的菌株,复苏后用接种环借助划线法将细菌接种至TSA琼脂平板上,37℃培养24-48 h至有明显菌落,将其作为工作板。工作板每20天更换一次以保证菌落活性,4℃保存。为获得对数生长期后的金黄色葡萄球菌菌液,每次挑取工作板上的小块圆形菌落,置于1ml NB液体培养基中,在转速250rpm、温度37℃的条件下摇菌过夜,第二天收获菌株用于实验。
4.2.1.3痤疮丙酸杆菌的培养:痤疮丙酸杆菌为厌氧菌,需置于厌氧环境中培养,于厌氧培养袋中放置打开的厌氧发生袋以营造厌氧环境,并利用厌氧指示剂观察培养袋中含氧情况。培养前,取出冻存的菌株,复苏后用接种环借助划线法将细菌接种至BHI琼脂平板上,并放入厌氧环境中37℃培养48-72h至有明显菌落作为工作板,工作板每20天更换一次以保证菌落活性,4℃保存。为获得对数生长期后的痤疮丙酸杆菌菌液,每次挑取工作板上的小块圆形菌落,置于1ml BHI液体培养基中,于厌氧环境、转速250 rpm、温度37℃的条件下摇菌过夜,第二天收获菌株用于实验。
4.2.2对金黄色葡萄球菌、痤疮丙酸杆菌抑菌率的测定:微量二倍稀释法用于测试精油4A、4B、4C、4D、4X、4F、4T对金黄色葡萄球菌和痤疮丙酸杆菌的抑菌率。
4.2.2.1在96孔板每个孔加入100µl培养基(NB-金黄色葡萄球菌;BHI-痤疮丙酸杆菌)。
4.2.2.2在第1排中加入精油100µl,然后对药物进行二倍稀释。即,第一孔加入精油后用移液枪充分吹打混匀,然后吸取100µl加入第二孔再充分吹打混匀,照此重复至最后一孔,最后一孔吸出100µl扔掉,每个药物浓度重复3次。此时每测试孔应含100µL溶液。
4.2.2.3每孔中加入稀释好的金黄色葡萄球菌或痤疮丙酸杆菌菌液100µl(稀释好的菌液浓度均为2×106 CFU/ml),加入每孔后菌液最终浓度为1×106 CFU/ml,第一孔的精油最终稀释倍数为4倍,精油浓度为250mg/ml;依次稀释倍数为8倍、16倍、32倍、64倍、128倍、256倍、512倍、1024倍、2048倍、4096倍、8192倍。
4.2.2.4在同一块板上设置阴性对照(含不同稀释倍数的精油及培养基,去除药物背景OD630)和阳性对照(100µl培养基+100µl菌液,菌液终浓度为1×106 CFU/mL)。
4.2.2.5金黄色葡萄球菌以50rpm在培养条件下孵育24小时,痤疮丙酸杆菌则以50rpm在培养条件下孵育48小时,随后用酶标仪测定每个孔的OD630,计算细菌活力。抑菌率(%) = 100%-[OD630(测试)-OD630(阴性)]/[OD630(阳性)-OD630(阴性)]。
4.2.3抑菌功效评估及抑菌功效曲线,每组精油每个稀释浓度3个重复实验,数据以抑菌率(%)±标准差(%)表示,抑菌率≥50%,则认为精油在该稀释倍数下存在抑菌作用;抑菌率≥90%,精油在该稀释倍数下有较强抑菌作用。以稀释倍数为X轴,抑菌率为Y轴,绘制精油抑菌功效曲线。
三、实验结果
4.3.1精油对痤疮丙酸杆菌的抑菌作用
结果如图3和图4所示(由于线条多,分成图3和图4,以更加清楚地展示各精油的抑菌效果)。
复方精油4F在256倍稀释浓度内(>3.9mg/ml)具有对痤疮丙酸杆菌的强效抑菌作用(>90%抑菌率),在1024倍稀释浓度内(>0.98mg/ml)有抑菌作用(>50%抑菌率)。
青蒿精油4X在128倍稀释浓度内(>7.8mg/ml)具有对痤疮丙酸杆菌的强效抑菌作用(>90%抑菌率),在512倍稀释浓度时(>1.95mg/ml)仍有抑菌作用(>50%抑菌率)。
复方精油4T在256倍稀释浓度内(>3.9mg/ml)具有对痤疮丙酸杆菌的强效抑菌作用(>90%抑菌率),在512倍稀释浓度时(>1.95mg/ml)仍有抑菌作用(>50%抑菌率)。
综合来看,本发明复方精油4F和4T对痤疮丙酸杆菌在256倍稀释浓度内均具有对痤疮丙酸杆菌的强效抑菌作用。
4.3.2精油对金黄色葡萄球菌的抑菌作用
结果如图5所示。
复方精油4F在512倍稀释浓度内(>1.95mg/ml)具有对金黄色葡萄球菌的强效抑菌作用(>90%抑菌率),在4096倍稀释浓度内(>0.24 mg/ml)有抑菌作用(>50%抑菌率)。
青蒿精油4X在256倍稀释浓度内(>3.9mg/ml)具有对金黄色葡萄球菌的强效抑菌作用(>90%抑菌率),在1024倍稀释浓度内(>0.976mg/ml)有抑菌作用(>50%抑菌率)。
复方精油4T在512倍稀释浓度内(>1.95mg/ml)具有对金黄色葡萄球菌的强效抑菌作用(>90%抑菌率),在2048倍稀释浓度内(>0.45 mg/ml)有抑菌作用(>50%抑菌率)。
综合来看,本发明复方精油4F和4T在512稀释倍数内均能强效抑制金黄色葡萄球菌的生长。
四、小结
综上,本发明的复方精油4F和复方精油4T对痤疮发病主要相关细菌如痤疮丙酸杆菌和金黄色葡萄球菌均具有强效抑菌作用。在功效相当的前提下,复方精油4T中各单方精油使用剂量比复方精油4F中小,在量产投入生产复方精油时,复方精油4T具有成本低的优势。
【实施例5】利用气质联用分别检测本发明的5种单方精油
本实施例采用气质联用的方法对本发明的各单方精油进行质量检测,以对本发明复方精油的原料进行质量控制。
5.1供试品的制备
将待测精油移取 0.5 mL 置于 1.5 mL 离心管中,离心 1 min;取上清液 50 μL,称重,加入乙酸乙酯,配成浓度为 100 mg/mL 的精油溶液;按 1 : 10 的质量比,加入无水硫酸钠粉末,混匀,静置,离心;取上清液 10 μL,以乙酸乙酯稀释 100 倍,得浓度为 1 mg/mL的待测溶液;将待测溶液离心 1 min,取上清液,气质联用检测。
待测精油分别是本发明的单方精油:马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油和青蒿精油。
5.2检测方法
色谱柱:安捷伦 HP-5 MS UI(30 m×0.25 mm×0.25 μm)
载气:高纯氦
流速 :1.0 mL/min
进样口温度: 250℃
分流比: 10 : 1
进样量: 1 μL
升温程序: 50 ℃—180℃(3℃/min)—300 ℃( 20 ℃/min, 保持 5 min)
离子源: EI+
离子源温度:230℃
扫描模式: 全离子扫描
扫描范围:m/z 40 -600
溶剂延迟: 4 min。
5.3检测结果
检测结果如图6~图10所示。气质联用检测的原始数据经 Agilent MassHunterQualitative Analysis(V B.07.00)软件分析,得各组分峰的信息(保留时间,积分峰面积,峰面积总和百分比,以及峰高)。
Claims (7)
1.一种用于治疗痤疮的复方精油,其特征在于,所述复方精油包含下述成分:马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油和青蒿精油;其中各精油通过下述方法制得:
分别以马鞭草酮迷迭香、依兰、互叶白千层、广藿香和黄花蒿为原料,通过水蒸气蒸馏取得挥发油;所述复方精油中马鞭草酮迷迭香精油、依兰精油、茶树精油、广藿香精油和青蒿精油的体积比为4.2:2.7:2.1:1:2.5。
2.根据权利要求1所述的复方精油,其特征在于,所述复方精油具有抑制皮脂腺细胞SZ95的脂质合成和抑制细菌生长繁殖的效果。
3.一种用于治疗痤疮的药物组合物,其特征在于,所述药物组合物包含如权利要求1~2中任意一项所述的复方精油和生理上或药学上可接受的辅料。
4.根据权利要求3所述的药物组合物,其特征在于,所述药物组合物中复方精油的含量为:10 μg/mL~500 μg/mL。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物中复方精油的含量为:50 μg/mL~100 μg/mL。
6.根据权利要求3所述的药物组合物,其特征在于,所述药物组合物为软膏剂、乳剂或者乳膏剂。
7.一种化妆品组合物,其特征在于,所述化妆品组合物包含如权利要求1~2中任意一项所述的复方精油和化妆品基质。
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