CN106913515B - 一种重建皮肤屏障稳态的牛磺酸螯合钙外用制剂及其应用 - Google Patents
一种重建皮肤屏障稳态的牛磺酸螯合钙外用制剂及其应用 Download PDFInfo
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- CN106913515B CN106913515B CN201510987963.XA CN201510987963A CN106913515B CN 106913515 B CN106913515 B CN 106913515B CN 201510987963 A CN201510987963 A CN 201510987963A CN 106913515 B CN106913515 B CN 106913515B
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- taurine
- calcium
- chelated calcium
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- chelated
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Abstract
本发明公开了一种含牛磺酸螯合钙的外用制剂及其应用,所述的外用制剂中主要包括以下组分:牛磺酸螯合钙、水、促透剂和防腐剂。该含牛磺酸螯合钙的外用制剂主要具有修复人体表皮屏障系统的作用,以此达到保护皮肤、保湿、紧致、抗敏等效果,可应用于化妆品外用制剂、药物外用制剂、保健品外用制剂、医疗卫生外用制剂等。
Description
技术领域
本发明涉及一种含牛磺酸螯合钙并治疗皮肤病症或全身系统补钙的外用制剂,其能够用于向人体皮肤系统直接补充钙,解决皮肤缺钙和钙紊乱的问题,具有修复皮肤屏障、保湿、抗炎等作用,并研究了适用于牛磺酸螯合钙制剂的促透体系,增强了其透皮吸收效果。可用于化妆品、药品、保健品、医疗卫生等领域。同时还提供了牛磺酸螯合钙外用制剂的制备方法。
背景技术
钙对人体皮肤是非常重要的,美国皮肤医学界首先发现了钙离子对皮肤的重要性并形成了理论基础,认为钙离子在皮肤屏障功能的稳态和修复过程中起着非常重要的作用,目前国内医学界也开发了一些医院制剂用于对破损皮肤的修复治疗。
在正常人体皮肤表皮中存在着钙离子浓度梯度,钙离子浓度呈现基底层浓度低、越接近角质层浓度越高的‘T’形分布,且细胞内、外的钙离子浓度也由低到高。钙离子在表皮中的这种特殊浓度梯度分布,调控表皮细胞的增生、正常分裂、分化、细胞间皮脂的合成、细胞间连接,进而影响皮肤屏障的形成、自律以及受损后的再生。美国皮肤医学界有研究证明,表皮损伤后,如立刻恢复和维持表皮层钙离子浓度梯度,皮肤屏障功能的恢复将明显加速(24小时达80%),而没有及时恢复钙离子浓度的创面,皮肤屏障功能,仅恢复50%。沐浴于富含钙的死海水中,可改善皮肤屏障受损相关的皮肤疾病,如过敏性皮炎、牛皮癣、湿疹等,增加皮肤含水量,都是利用高浓度钙离子,加速正常皮肤屏障再生的证明。
愈来愈多的研究发现,调节皮肤表皮层的钙离子正常浓度梯度,对于美容肌肤的修复、皮肤屏障的再生自律;皮肤屏障受损相关的皮肤疾病的治疗,都具有相当大的重要性。
人体皮肤系统缺钙现象是普遍存在的,也是比较严重的,人体皮肤缺钙会引发多种皮肤病、皮肤屏障作用差、易感染起炎症、易损且破损后愈合周期长、皮肤干燥、敏感、水油平衡失调、加速皮肤老化、环境耐受性弱等各种皮肤问题,特别是面部肌肤处于裸露状态,受强紫外线、污染、辐射等不良环境的影响,更容易引起各种不良的皮肤状态。人体皮肤系统长期处于缺钙状态主要有以下两个方面的原因:
1、人体中离子型钙缺乏
人体中的钙长期处于动态流失状态,目前人体补钙的途径有两种,一种是通过口服的方式补钙,主要有各种补钙制剂为口服钙片类和口服液类;一种是通过静脉注射的方式补钙,但通过静脉注射的方式危险性大,必须是专业医师方可进行,所以目前通用的摄入钙方式只有口服补钙一种。
人体处于缺钙的状态时,经口服补充的钙剂优先用于骨骼、牙齿等所需的结合钙的补充,这时所补充的钙已经失去了生理活性,并不能补充或者只能极少量补充离子钙,但这对于调节机体的生理活性是不足的,所以在人体缺钙的情况下通过血液循环向表皮层输送钙离子来保持表皮层钙离子的平衡稳态是非常困难的。
口服钙剂难吸收、吸收率低、受影响因素多而复杂,这主要是胃肠道的复杂环境所引起的。口服补充的钙剂是通过胃肠道来消化吸收的,胃部环境属于强酸性环境,PH值在0.8~3.6之间变化,小肠环境属于弱碱性,pH值在7.2~8.0之间变化,这种酸碱环境的变化对于钙离子的吸收是不利的,如钙离子易在碱性的肠道环境中形成胶稠状氢氧化钙沉淀,使钙离子难以被人体吸收,同时,这种胶稠状物可粘附在肠壁上,进一步影响其他营养元素的吸收。特别是口服钙易受胃肠道中的阴离子污染而生成不溶性的钙,导致钙离子的吸收率大幅降低,例如摄取的食物中含有的植酸、草酸、碱性磷酸盐、脂肪、膳食纤维中的糖醛酸残基、核苷酸、尿酸等都可与钙离子反应生成不溶或难溶的草酸钙、植酸钙、碱性磷酸钙、尿酸钙盐等,不但干扰钙离子的吸收,还会引起钙在组织中沉淀成为钙化灶,在器官内不断沉积形成结石,影响身体健康。
2、人体表皮系统不存在血液循环系统,具有生理活性的钙离子输送难
人体主要通过血液循环系统向人体各系统各部位输送所吸收的营养物质,但是在表皮系统中不存在血液系统,其营养物质的输送主要通过组织液传输,但其传输量和传输效率非常低,同时由于前述的口服钙离子优先用于结合钙的需求,所以通过口服给表皮系统补充其所需的离子钙是很困难的,具有生理活性的离子钙对维持人体表皮系统的稳态健康是非常重要的,人体表皮系统是机体抵御脱水、损伤、感染、抗病菌的第一道防线,正常的离子钙浓度是维持人体表皮屏障系统稳定、破损后修复的最主要因素,当钙离子缺乏或紊乱时会导致表皮屏障遭受破坏,进而引发各种皮肤问题甚至病变,所以维持表皮系统正常的钙离子浓度对于表皮屏障保持稳定或破损后的修复是非常重要的。所以直接补充易于经皮吸收的具有生理活性的离子钙特别是维持表皮系统钙平衡是具有非常重要的意义的。
3、目前市场上缺乏可外用的靶向补钙剂
目前市场上的各种补钙剂均为口服制剂,包括各种钙片和口服液,这主要是针对胃肠道特殊的消化系统开发的,胃肠道的pH值在1.5~3.2之间,属于强酸环境,同时还存在各种菌类、有机酸、阴离子对钙离子存在污染变成难溶物不被人体吸收,而人体表皮正常的PH值范围在5.2~6.5之间,属于弱酸性环境,所以一般用于经胃肠道消化吸收的口服钙剂难于经皮吸收。同时,一般口服钙剂多选用无机钙、离子型有机酸钙如氯化钙、碳酸钙、乳酸钙、丙酸钙、柠檬酸钙、葡萄糖酸钙等,这些钙剂均为离子态,同时有的钙盐还存在溶解性差的问题,在经皮吸收领域,难溶性的化合物和离子型的化合物是非常难吸收的。
同时目前尚无学者研究钙的经皮吸收问题,所以研究有利于经皮吸收的补钙剂是非常有必要的,也是非常具有创新性的研究课题,经皮吸收补钙的方式可以实现直接向机体补充具有生理活性的离子型钙,特别是可以实现优先向不存在血液循环系统表皮系统靶向补钙,且吸收效率高,而且不受胃肠道特殊而复杂的环境的影响,能够解决钙离子易受阴离子污染而导致吸收利用率低的问题。
并且在化妆品领域,所有的膏霜、水剂均无法保证其在面部的作用时间,特别是水剂,很容易从皮肤表层蒸发散失,因而如果化妆品中的钙离子不能在尽可能短的时间内被皮肤吸收利用,那么很可能因流失而不能起到相应的作用。所以,提高钙离子前2h~3h的吸收量是非常重要的。
所以开发能够直接经皮吸收的补钙制剂和研究其促透体系增强钙的透皮吸收效果对于重新建立表皮钙离子稳态梯度进而加速表皮屏障功能的修复是有必要的,表皮屏障的修复能够全方位的改善。
发明内容
鉴于钙对皮肤的重要性以及钙的经皮吸收存在的上述问题,本发明在于提供一种含牛磺酸螯合钙的外用制剂,其主要以牛磺酸螯合钙为主,配合促透体系一起组成含牛磺酸螯合钙的外用制剂,其解决了现有钙剂不易经皮吸收的问题,且大大提高了前2h~3h的吸收量。本发明的水剂用于化妆品中具有很好的保湿、抗炎、恢复皮肤屏障等作用。以上所述的牛磺酸螯合钙外用制剂中还可以添加具有其他功效的药物成分,如祛斑美白、杀菌抑菌、消炎止疼、营养补充等。
本发明比较了牛磺酸螯合钙与市售各种钙剂的经皮吸收性能,通过比较牛磺酸螯合钙、氯化钙、葡萄糖酸钙水溶液的经皮吸收效果,说明了牛磺酸螯合钙较其他的钙制剂具有良好的经皮吸收性能,特别是在初始阶段牛磺酸螯合钙的经皮吸收量远大于氯化钙和葡萄糖酸钙,而在6h内的吸收总量也远高于氯化钙和葡萄糖酸钙。
本发明还研究了不同量的牛磺酸螯合钙对经皮吸收性能的影响,当牛磺酸螯合钙的浓度增大时,其经皮吸收性能增大,特别是能够增加其在起始阶段的经皮吸收效果,在起始1h内,浓度为2%的牛磺酸螯合钙的经皮吸收量约为浓度为0.5%时的9倍,约为浓度为1%时的4倍,这对于其在化妆品中的应用是非常重要的。同时,浓度为2%时在6h内的吸收率达到75%,远高于浓度为0.5%时的37%,浓度为2%时6h内的总吸收量为0.5%时的10倍以上。
本发明的牛磺酸螯合钙外用制剂,其中牛磺酸螯合钙的质量百分含量在小于60.00%,优选为小于40%,更优选为小于20%,更进一步优选为小于8%。
在药物经皮吸收过程中,促透体系有着非常重要的作用,其可以有效提升药物的经皮吸收速率,而由于液体喷剂剂型的特殊性,对于其中的功效成分能够快速吸收是非常重要的。
一般的药物成分的促透剂包括以下几类:萜烯类、精油及内酯(如簿荷脑、龙脑、桉油及川穹、小豆蔻提取物等)、吡咯烷酮类、磷脂及磷酸盐类、有机酸及酯类和酰胺类、表面活性剂类、油酸、月桂氮卓酮、薄荷类、多元醇类,还有新近发现一些氨基酸类物质和多糖类物质也具有促透效果。但是在这些类型的促透剂中只有多元醇类、氨基酸类、多糖类的促透机理对表皮屏障即角质层没有破坏,其他类型的促透剂均为以削薄角质层的厚度和降低角质细胞之间的粘连性等破坏角质层的方式增加药物的经皮吸收效果,而在化妆品中特别是牛磺酸螯合钙喷剂的重点功效在于调节并修复表皮屏障功能,故本发明对于促透体系的选择重点在于多元醇体系、氨基酸、多糖类物质的研究上,选择其中的一种或多种,其中的多元醇类、多糖类、氨基酸类的促透剂还具有保湿剂、营养剂的作用;
本发明的牛磺酸螯合钙外用制剂,其中促透剂的质量百分含量小于80.00%,优选为小于50%,更优选为小于30%。
本发明的促透体系对于多元醇体系的选择:通过对多元醇的种类及其配比关系对牛磺酸螯合钙经皮吸收性能影响的研究,发现多种多元醇配合使用时其对牛磺酸螯合钙的促透效果要优于其单独使用,并且各类多元醇之间的配比关系对牛磺酸螯合钙的经皮吸收性能的影响不同,多元醇类促透剂包括丙三醇、戊二醇、丁二醇、丙二醇中的一种或多种。其中丙三醇的质量百分含量小于30%,优选小于15%,更优选小于6%;丙二醇的质量百分含量小于50%,优选小于30%,更优选小于10%;丁二醇的质量百分含量小于50%,优选小于30%,更优选小于10%;戊二醇的质量百分含量小于50%,优选小于30%,更优选小于10%。
本发明考察了多元醇促透体系添加量对牛磺酸螯合钙经皮吸收性能的影响,发现多元醇促透体系对牛磺酸螯合钙具有很大的影响,且促透效果随着添加量的增大而增大,特别是在初始1h内,具有明显的影响,当添加量达到6%与8%时牛磺酸螯合钙的经皮吸收量相差不大,说明在多元醇体系的添加量达到6%时,促透效果逐渐达到峰值,说明多元醇促透体系在1h内对牛磺酸螯合钙的经皮吸收效果时非常有利的。
本发明还考察了氨基酸类物质对牛磺酸螯合钙经皮吸收性能的影响,发现氨基酸类物质对于牛磺酸螯合钙的经皮吸收具有促透效果,这可能是由于氨基酸类物质中同时具有的类脂性结构氨基和亲水性结构羧基所致,这种具有双亲性的结构可能能够促进药物的透皮吸收效果。在牛磺酸螯合钙制剂中氨基酸类物质的质量百分含量小于50%,优选小于20.00%,进一步优选小于6%。
本发明还考察了多糖类物质对牛磺酸螯合钙经皮吸收效果的影响,发现多糖类物质对于牛磺酸螯合钙的经皮吸收具有促透效果,这可能是由于多糖类物质具有吸收水分并保持皮肤中的水分含量,皮肤中水分含量的增加能够软化角质层,降低角质层的屏障作用,增加药物成分的透皮吸收效果。这些多糖类物质包括海藻糖、银耳多糖、水解壳多糖、透明质酸钠、酵母多糖、可溶性蛋白多糖多种多糖类物质,本发明中特别选取了多糖类的海藻糖和透明质酸进行了牛磺酸螯合钙的透皮效果影响实验,并对二者的添加量对牛磺酸螯合钙的影响进行了研究,结果表明海藻糖和透明质酸钠对牛磺酸螯合钙的经皮吸收具有促透效果,但透明质酸钠对牛磺酸螯合钙的促透作用具有一定的量效性,即在一定浓度范围内对牛磺酸螯合钙具有促透效果,而高于一定浓度时,反而对牛磺酸螯合钙的经皮吸收起抑制作用,这可能是由于透明质酸属于大分子量的物质会对药物成分形成吸附或包裹从而降低药物的释放速率,进一步导致了药物成分的透皮效果降低。同时这些多糖类物质还具有补水保湿效果,增加皮肤含水量,进一步帮助改善皮肤。
本发明含牛磺酸螯合钙的外用制剂中,多糖类物质的质量百分含量小于50%,优选小于20.00%,进一步优选小于6%。
本发明的牛磺酸螯合钙外用制剂,其中水的质量百分含量在0.01%~99.99%之间,优选5%~99%之间,更优选为10%~99%之间,进一步优选为20%~99%之间。
本发明的牛磺酸螯合钙外用制剂,还含有防腐剂,其含量小于5%,优选为小于1%。
本发明中的牛磺酸螯合钙外用制剂,还可以含有其他具有祛斑美白、杀菌抑菌、消炎、控油、祛除疤痕、营养补充等功效的药物营养成分。
本发明中的牛磺酸螯合钙外用制剂,其可作为化妆品、药物外用剂、保健品外用剂、医疗卫生外用制剂使用。
当以一体法制备本发明的牛磺酸螯合钙外用制剂时,合成牛磺酸螯合钙所需的中心离子来源可以为无机钙盐如氯化钙、碳酸钙、磷酸钙、磷酸氢钙、硅酸钙等,也可以是非螯合型有机钙盐如乳酸钙、丙酸钙、柠檬酸钙、葡萄糖酸钙等,还可以为氧化钙、氢氧化钙,可以来源于矿物质中的钙,也可以为生物来源如动物体的骨骼等;优选为氯化钙、碳酸钙、乳酸钙、丙酸钙、柠檬酸钙、氧化钙、氢氧化钙。
本发明的目的是制备一种含牛磺酸螯合钙的外用制剂,并且其可以快速被皮肤吸收,以达到皮肤对钙的充分吸收利用,其包括两种制备方法:分步法和一体法,这主要是通过牛磺酸螯合钙的制备过程来说。其中分步法指先制备出牛磺酸螯合钙晶体,在与其它的成分如促透剂、营养剂、药物功效成分和水在一定的温度、pH值、搅拌速率的条件下制备成含有牛磺酸螯合钙的外用制剂;一体法是指在制备牛磺酸螯合钙的时候选择安全且对皮肤无刺激的钙源制备成含牛磺酸螯合钙的原溶液,不用进行牛磺酸螯合钙结晶纯化,直接以牛磺酸螯合钙的原溶液与其它的成分如促透剂、营养剂、药物功效成分和水在一定的温度、pH值、搅拌速率的条件下制备成含有牛磺酸螯合钙的外用制剂。
具体实施方式
实施例1
1、牛磺酸螯合钙的制备:实验中以牛磺酸为配位体,任意选择氯化钙、碳酸钙、磷酸钙、磷酸氢钙、硅酸钙、乳酸钙、丙酸钙、柠檬酸钙、葡萄糖酸钙中的一种作为提供中心离子钙的钙源制备氨基酸螯合钙,以做进一步实验研究,具体如下:
1)称取45 g的牛磺酸,用150 ml去离子水溶解在三口烧瓶中,水浴加热至80℃恒温,至谷氨酸完全溶解;
2)称取20g乳酸钙,完全溶解于足量的水中,调节pH至7.8;
3)将2)中配制好的乳酸钙溶液逐滴慢慢加入到1)中的牛磺酸溶液中,边加入乳酸钙溶液边轻轻搅拌,搅拌过程中保持恒温状态;
4)加完乳酸钙溶液后,反应约60min,反应完毕;
5)过滤去杂质,滤液可直接备用或将滤液蒸发至牛磺酸螯合钙析出,并干燥后粉碎备用;
2、牛磺酸螯合钙定性检测
由于牛磺酸螯合钙的水溶液中钙并不是以离子形态存在,所以可以通过检测反应后所得到的物质中是否存在游离的钙离子和游离的氨基酸根可以确定是否有氨基酸螯合钙生成,对氨基酸螯合钙的生成进行定性检测。本实验主要是通过二硫腙试剂与游离金属钙离子的显色反应或者茚三酮试剂与牛磺酸根的显色反应来比较反应前后的变化确定是否生成牛磺酸螯合钙,具体实验如下:
实验定性检测用试剂:二硫腙试剂、茚三酮试剂、硫化钠。
牛磺酸螯合钙的纯化:此实验主要是排除上述制得的牛磺酸螯合钙产品中的未反应的钙离子与牛磺酸的影响。
游离钙离子去除:称取少量前述制备的牛磺酸螯合钙的样品,加入适量的无水乙醇,进行充分搅拌,后静置一段时间进行沉淀,过滤,取少量滤液中加入几滴二硫腙试剂,观察滤液是否变色,若变色则按照上述办法对牛磺酸螯合钙继续进行洗涤纯化,直到加入二硫腙试剂后滤液不变色为止,以确定金属钙离子被完全除净;
游离牛磺酸去除:取已除去游离钙离子的牛磺酸螯合钙少许溶于水中,加入几滴茚三酮试剂,加热至溶液沸腾,若颜色溶液颜色变为蓝紫色,则样品中还存在游离的牛磺酸,继续以无水乙醇为纯化剂进行纯化,直到受加热的溶液颜色不变为蓝紫色为止,以确定游离的牛磺酸被完全除净。
实施例2
牛磺酸螯合钙的含量对经皮吸收效果的影响:本发明中不同浓度牛磺酸螯合钙经皮吸收量比较,分别配制浓度为0.5%、1%、1.5%、2%的牛磺酸螯合钙溶液,以小鼠皮为模型,选取0.9%氯化钠水溶液为接受液,在Franz智能透皮扩散池中考察了在没有添加促透剂的条件下,比较上述牛磺酸螯合钙水溶液在6h内的透皮性能,得到结果如下表所示:
表1、不同浓度牛磺酸螯合钙经皮吸收量
从上述实验结果可以看出,牛磺酸螯合钙的浓度越高经皮吸收效果越好。
实施例 3
牛磺酸螯合钙与其它钙剂的经皮吸收效果的影响:本发明中牛磺酸螯合钙与其他不同钙剂之间透皮效果的比较,分别配制浓度同为2%的牛磺酸螯合钙溶液、氯化钙溶液和葡萄糖酸钙溶液,以小鼠皮为模型,选取0.9%氯化钠水溶液为接受液,在Franz智能透皮扩散池中考察没有添加促透剂的条件下,上述溶液在6h内的透皮性能,结果如下表:
表2 、牛磺酸螯合钙-氯化钙-葡萄糖酸钙的经皮吸收效果比较
时间/h | 牛磺酸螯合钙 | 氯化钙 | 葡萄糖酸钙 |
0.25 | 4.8193 | 0.1837 | 0.6608 |
0.5 | 5.9813 | 0.3479 | 1.1971 |
0.75 | 7.1741 | 0.5663 | 1.7874 |
1 | 8.5438 | 0.7517 | 2.3913 |
1.5 | 11.1079 | 1.1083 | 3.3703 |
2 | 13.1157 | 1.4172 | 4.5388 |
3 | 16.0673 | 1.7461 | 5.6717 |
4 | 18.2714 | 2.0783 | 6.5419 |
6 | 21.1469 | 2.3893 | 7.3272 |
从以上实验结果可以看出,牛磺酸螯合钙的经皮吸收效果远远优于其他离子型的钙制剂。
实施例4
多元醇促透体系对牛磺酸螯合钙经皮吸收性能的影响:本发明中不同多元醇体系对牛磺酸螯合钙的经皮吸收性能的影响的测定,配制不同配比的丁二醇、丙二醇、1,2-戊二醇混合液作为促透液,另外配制一定浓度的牛磺酸螯合钙溶液,以小鼠皮为模型,选取0.9%氯化钠水溶液为接受液,在Franz智能透皮扩散池中考察添加上述促透液的条件下比较牛磺酸螯合钙水溶液在6h内的透皮性能,结果如下表所示:
表3、不同多元醇体系对牛磺酸螯合钙经皮吸收量影响
从以上实验结果可以看出,不同的多元醇促透体系对牛磺酸螯合钙的经皮吸收效果影响不同,所以研究不同的多元醇促透体系对牛磺酸螯合钙的经皮吸收时非常有用的。
实施例5
本发明中不同多元醇促透体系添加量对牛磺酸螯合钙经皮吸收性能的影响测定,按照,丁二醇:丙二醇:1,2-戊二醇=1:2:2配制促透液,并配制浓度为2%的牛磺酸螯合钙溶液,以小鼠皮为模型,选取0.9%氯化钠水溶液为接受液,在Franz智能透皮扩散池中考察上述促透液添加量分别为0,2%,6%,8%时牛磺酸螯合钙水溶液在6h内的透皮性能,结果如下表所示:
表4、不同多元醇促透体系添加量对牛磺酸螯合钙经皮吸收量影响
从以上实验结果可以看出,多元醇的添加量对牛磺酸螯合钙的经皮吸收效果具有一定的影响。
实施例6
本发明中多糖类物质对牛磺酸螯合钙经皮吸收性能的影响的测定,本发明中主要考察了海藻糖和透明质酸钠对牛磺酸螯合钙的经皮吸收性能影响,并对二者的添加量对牛磺酸螯合钙的影响进行了研究,具体方法如下:
配制浓度为2%的牛磺酸螯合钙溶液,以小鼠皮为模型,选取0.9%氯化钠水溶液为接受液,在Franz智能透皮扩散池中考察促透剂分别为海藻糖添加量为0%、1%、2%时和透明质酸添加量为0%、0.05%、0.15%、0.2%时的牛磺酸多元螯合钙的经皮吸收效果,结果如下表所示:
表5、不同海藻糖的添加量对牛磺酸螯合钙的经皮吸收量的影响
表6、不同透明质酸钠添加量对牛磺酸螯合钙的经皮吸收量的影响
从以上实验结果可以看出,多糖类物质对牛磺酸螯合钙的经皮吸收效果具有不同的影响,且对于一些多糖类物质对牛磺酸螯合钙的促透效果具有一定的量效性。
实施例7
本发明中牛磺酸螯合钙水剂的制备方法一:分步法
1)制备牛磺酸螯合钙晶体,将浓度为30%的牛磺酸溶液与乳酸钙放入反应容器中,用乳酸调节pH值至7.5,加热至80℃,反应140min后,将溶液烘干得到牛磺酸螯合钙样品。取牛磺酸螯合钙样品,加入无水乙醇,充分搅拌过后,静置一段时间,过滤,在滤液中加入几滴二硫踪试剂。若滤液变为红色,说明样品中可能还存在游离的金属钙离子,那么继续用乙醇进行洗涤直到二硫踪试剂进行检测不变色为止。从已去除游离金属钙离子的样品中取出少量样品,溶于水中,加入几滴茚三酮试剂,在电炉上加热至沸腾。若颜色变成蓝紫色,说明样品中可能还存在游离的牛磺酸,继续用无水乙醇洗涤直至茚三酮颜色反应呈现无色。将已经过分离纯化的样品放在冷冻干燥机内干燥,可以得到纯度很好的牛磺酸螯合钙样品;
2)按下列重量百分比称取各成分:
牛磺酸螯合钙2%,海藻糖2%,透明质酸钠0.15%,丙二醇1%,甘油1%,丁二醇2%,1,2-戊二醇2%,牛磺酸0.2%,北美金缕梅水2%,防腐抗菌剂0.05%,去离子水87.6%;
3)配制促透体系溶液,用部分去离子水溶解海藻糖和牛磺酸,再向其中加入透明质酸钠,充分溶胀溶解后再继续加入丙二醇、甘油、丁二醇和1,2-戊二醇,充分搅拌溶解,即得到促透体系溶液;
4)用剩余去离子水溶解牛磺酸螯合钙,完全溶解后加入促透体系溶液、北美金缕梅水和防腐抗菌剂,搅拌混匀;
5)出料,装瓶包装即可。
实施例 8
本发明中牛磺酸螯合钙水剂的制备方法二:一体法
1)根据牛磺酸螯合钙的合成条件,确定反应条件为,反应时间140min,反应pH值7.5,反应温度80℃,牛磺酸浓度30%;
2)按照下列重量百分比称取各成分:
牛磺酸4%,乳酸钙2%,海藻糖2%,透明质酸钠0.15%,丙二醇1%,甘油1%,丁二醇2%,1,2-戊二醇2%,北美金缕梅水2%,防腐抗菌剂0.05%,去离子水83.9%;
3)配制促透体系溶液,用部分去离子水溶解海藻糖,再向其中加入透明质酸钠,充分溶胀溶解后再继续加入丙二醇、甘油、丁二醇和1,2-戊二醇,充分搅拌溶解,即得到促透体系溶液;
4)配制浓度为30%的牛磺酸溶液,向溶液中加入乳酸钙,搅拌加热至80℃,用乳酸调节pH至7.5,再向溶液中加入促透体系溶液、北美金缕梅水,反应140min后再向溶液中加入防腐抗菌剂和剩余的去离子水,搅匀得到含牛磺酸螯合钙的水剂。
5)出料,包装即可。
实施例9
牛磺酸螯合钙水溶液稳定性考察:本实验以实施例7中制备的牛磺酸螯合钙制剂,考察其稳定性,实验结果如下所示:
表、牛磺酸螯合钙在不同条件下的水溶液的稳定性
从以上试验结果可以看出:牛磺酸螯合钙的制剂在不同温度下的均稳定,对于外用液体制剂来说,这种稳定性是十分必要的,说明其更适用于制备外用含水制剂,如喷剂、凝胶剂、涂抹剂、搽剂等。
实施例10
本实验考察了月桂氮卓酮(Azone)对牛磺酸螯合钙的经皮吸收时的促透效果,试验中以实施例1中制备的牛磺酸螯合钙为试验样品,并设置Azone的对照组进行实验,透皮测试方法与前述各实施例中的方法相同,试验时间为6h,实验结果如下表所示:
表、Azone对牛磺酸螯合钙的透皮性能的影响
从以上试验结果可以看出,Azone对牛磺酸螯合钙的透皮效果具有较好的促进作用。
实施例11
牛磺酸螯合钙对离体角质细胞的增殖效果影响:本实验以实施例1中制备的牛磺酸螯合钙为试验样品,通过考察牛磺酸螯合钙对离体角质细胞增殖效果的影响来说明牛磺酸螯合钙对皮肤屏障作用恢复的影响。试验中以小鼠外移皮肤进行表皮屏障修复实验,使用一定浓度的牛磺酸螯合钙溶液处理,另设一组空白对照组,进行平行比较试验,并通过免疫荧光的方法追踪表皮角质细胞,考察24小时后在重建表皮中处于增殖过程中的角质细胞的变化情况。实验中观察并比较了一定浓度的牛磺酸螯合钙、氯化钙、葡萄糖酸钙对在重建表皮的过程中处于增殖过程中的角质细胞的变化情况,说明谷氨酸螯合钙在表皮屏障修复过程中对角质细胞的增殖作用,具体结果见下表:
表、不同钙剂在24h内对表皮屏障修复过程中对角质细胞的增殖作用
空白组 | 牛磺酸螯合钙 | 氯化钙 | 葡萄糖酸钙 | |
角质细胞增长率/% | 1.5 | 27.6 | 9.3 | 13.7 |
从以上试验结果可以看出,牛磺酸螯合钙对角质细胞增殖作用的影响最大,这可以说明牛磺酸螯合钙对皮肤表皮屏障功能的恢复性能要优于不加牛磺酸螯合钙和其他非氨基酸螯合钙组。
实施例12
本实验以实施例1中制备的牛磺酸螯合钙为试验样品,通过设计空白组、比较对照组实验,考察了牛磺酸螯合钙对表皮角质层屏障恢复效果的影响,直观地了解了牛磺酸螯合钙对表皮屏障恢复的影响,试验中通过小鼠外移皮肤进行表皮屏障修复实验,使用牛磺酸螯合钙喷剂对表皮进行3次/天的处理,实验过程中对表皮层进行Trichrom-Masson染色,观察其表皮厚度的变化情况,实验结果见下表:
表、不同钙剂在6d内对表皮角质层的修复作用
空白组 | 牛磺酸螯合钙 | 氯化钙 | 葡萄糖酸钙 | |
角质层厚度变化/% | 0.9 | 24.7 | 7.5 | 9.3 |
通过以上实验结果可以看出,使用牛磺酸螯合钙6天后,其表皮层的厚度明显增加,要优于不加牛磺酸螯合钙的空白组和其它钙剂的对照组,说明牛磺酸螯合钙在表皮屏障修复过程中有着明显的作用。
实施例13
以实施例1中制备的牛磺酸螯合钙为原料,添加前述实施例中的促透剂,制备成喷剂,进行了志愿者测试,试验中设置空白组、对照组、试验组,考察牛磺酸螯合钙对皮肤的改善调节效果,并与其它无机钙、有机酸钙进行比较。测试部位为面部,测试时间为两周,受试志愿者共有40名,其中20名为干性敏感肌肤,20名为油性肌肤,受试期间未进行其他治疗方式,禁用其它护肤品。采用VISIA测试仪和SOFT5.5测试受试者面部肌肤的变化情况,包括皮肤的含水量变化、弹性值、皮脂量、面部pH值变化、面部细菌生长变化、皮肤光泽度、紧致效果、毛孔改变、抗敏效果、不同类型肌肤适应性等,综合评价牛磺酸螯合钙对面部肌肤的修复调节作用。VISIA皮肤图像分析测试仪和SOFT5.5 皮肤性质测试对治疗前后皮肤性质进行定量评价,各项指标如下:
1)水分:皮肤水分值高低可用于衡量皮肤的干燥程度,同时也是反映皮肤屏障功能的重要指标之一;水分测试值越高,表明补水效果非常好;
2)皮脂:表示皮肤油脂分泌能力,测试结果值越高,表明油分含量过高;
3)弹性:测试结果值越高,表明皮肤弹性越好;
4)酸碱值:一般情况下油性肌肤的PH值较低,这是由于分泌的油脂中含有游离的脂肪酸的缘故;
5)皱纹:反应脸部的干纹、细纹、静态纹等状况,皱纹一般与皮肤的弹性降低有密切关系;
6)纹理:反映皮肤的平滑度以及饱满感,健康的角质层的“峰”和“谷”差异越小,皮肤饱满感越好,角质层的锁水、保湿能力越强;
7)紫质:油性皮肤所关注的检测项之一,对于控制皮肤炎症、控油效果具有重要意义,主要检测毛囊口的各种细菌如痤疮丙酸杆菌、马拉色菌等的代谢产物,其检测结果越低,说明毛囊口处的以上细菌越少,产品的抑菌效果明显;
8)毛孔:反映皮脂腺开孔的扩张情况和平整度,因为张开的毛孔会有阴影,它的颜色会比正常的肤色深,VISIA就是利用这一原理识别毛孔。干性肌肤应用试验效果:将干性肌肤类型的20名志愿者随机分为4组,每组5人,分别为空白组、牛磺酸螯合钙组、氯化钙组、葡萄糖酸钙组,实验中观察不同组中各项目中的指标变化区间中的有效的志愿者例数,进行效果对比,本实验结果如下表所示:
表、不同钙剂对干性肌肤的修复效果
油性肌肤应用试验效果:将油性肌肤类型的20名志愿者随机分为4组,每组5人,分别为空白组、牛磺酸螯合钙组、氯化钙组、葡萄糖酸钙组,进行效果对比试验,本实验结果如下表所示:
表、不同钙剂对油性肌肤的修复效果
由以上试验结果可以看出,与空白组相比较,含钙组对皮肤修复效果要优于空白组,在三种不同钙剂的试验组中,含牛磺酸螯合钙组要明显优于氯化钙组和葡萄糖酸钙组,其对于油性肌肤和干性肌肤都是适应的,这说明了牛磺酸螯合钙对皮肤表皮屏障修复具有很好的作用,皮肤屏障的修复体现在肌肤整体状况的改善,这和单纯的补水保湿是不同的。
实施例14
本发明的一种含牛磺酸螯合钙的水剂可用于制备化妆品液体喷雾,以及其他具有保湿、抗炎、恢复皮肤屏障等作用的保健品、药品的喷雾和涂抹剂。
实施例15
一种含牛磺酸螯合钙的外用喷雾剂,其组成以质量百分含量计包括:牛磺酸螯合钙0.5%,丙二醇2.5%,丙三醇0.5%,戊二醇4%,海藻糖0.3%,透明质酸钠0.05%,金缕梅3%,谷氨酸0.3%,山梨酸钾0.2,积雪草0.5%,去离子水88.15%。
实施例16
一种含牛磺酸螯合钙的外用膏霜剂,其组成以质量百分含量计包括:牛磺酸螯合钙1%,丙二醇3%,丙三醇1.3%,丁二醇3%,角鲨烷3.5%,银耳多糖0.7%,VE1%,VC1.5%,脯氨酸0.3%,缬氨酸0.1%,山梨酸钾0.1%,乳化剂1.5%,去离子水83%。
实施例17
一种含牛磺酸螯合钙的外用制剂,其组成以质量百分含量计包括:牛磺酸螯合钙2%,丙二醇2%,戊二醇5%,角鲨烷2%,银耳多糖0.6%,脯氨酸0.2%,亮氨酸0.2%,美白剂如熊果苷、谷胱甘肽、鞣花酸等1%,氮酮1.5%,乳化剂1.5%,防腐剂0.2%,去离子水83.8%。
以上所述是体现本发明研究过程及结果的实施例,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以进行若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (16)
1.含牛磺酸螯合钙的外用制剂,含有牛磺酸螯合钙、水、促透剂和防腐剂,其中牛磺酸螯合钙的质量百分含量小于60.00%,水的质量百分含量大于20.00%,促透剂的质量百分含量小于80.00%,防腐剂的质量百分含量小于5%,所述的牛磺酸螯合钙的外用制剂不含有维生素D;所述的牛磺酸螯合钙中钙离子为螯合体中心离子,牛磺酸为螯合体,上述牛磺酸螯合钙中牛磺酸与钙离子的螯合比为1:1~4:1之间。
2.根据权利要求1所述的含牛磺酸螯合钙的外用制剂,其特征在于所述牛磺酸螯合钙的分子量范围在100~1500之间。
3.根据权利要求2所述的含牛磺酸螯合钙的外用制剂,其特征在于所述牛磺酸螯合钙的分子量范围在100~650之间。
4.根据权利要求1所述的含牛磺酸螯合钙的外用制剂,牛磺酸与钙离子的螯合比为1:1与2:1。
5.根据权利要求1所述的含牛磺酸螯合钙的外用制剂,其中牛磺酸螯合钙的质量百分含量小于20%。
6.根据权利要求5所述的牛磺酸螯合钙的外用制剂,其中的牛磺酸螯合钙的质量百分含量小于8%。
7.根据权利要求1所述的牛磺酸螯合钙外用制剂,其中的促透剂为多元醇类、多糖类、氮酮、氨基酸类中的一种或多种。
8.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中多元醇类促透剂为丙三醇,其质量百分含量小于15%。
9.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中多元醇类促透剂为丙二醇,其质量百分含量小于10%。
10.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中多元醇类促透剂为丁二醇,其质量百分含量小于10%。
11.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中多元醇类促透剂为戊二醇,其质量百分含量小于10%。
12.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中多糖类物质为海藻糖、银耳多糖、水解壳多糖、透明质酸钠、酵母多糖、可溶性蛋白多糖中的一种或多种,其质量百分含量小于20.00%。
13.根据权利要求7所述的牛磺酸螯合钙外用制剂,其中氨基酸类物质为蛋白质氨基酸和非蛋白质氨基酸中的一种或多种,其质量百分含量小于20.00%。
14.根据权利要求1~13任意一项所述的牛磺酸螯合钙外用制剂在制备外用吸收制剂中的应用,所述制剂为药物外用制剂、医疗器械外用制剂、保健品外用制剂、化妆品。
15.根据权利要求14所述的应用,所述的牛磺酸螯合钙外用制剂用于治疗或预防皮肤缺钙所引起的疾病。
16.根据权利要求15所述的应用,其特征在于,所述的皮肤缺钙所引起的疾病为皮肤屏障损伤、痤疮、色素障碍性皮肤病、营养与代谢障碍性皮肤病、变态反应性皮肤病、皮肤脉管性疾病、皮肤血管炎类疾病、红斑性皮肤病。
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