CN114099646B - 一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法 - Google Patents
一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法 Download PDFInfo
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- CN114099646B CN114099646B CN202111455383.8A CN202111455383A CN114099646B CN 114099646 B CN114099646 B CN 114099646B CN 202111455383 A CN202111455383 A CN 202111455383A CN 114099646 B CN114099646 B CN 114099646B
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- collagen
- liposome
- nanofiber
- phospholipid
- slow
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 28
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Abstract
本发明公开了一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法,所述混悬液包含粒度为70‑1100nm和/或3000‑5500nm的脂质体颗粒;所述混悬液由有机相和水相形成,所述有机相中含柔性碳链连接剂连接的磷脂纳米纤维的浓度为0.14~0.17g/mL,所述水相中胶原蛋白的浓度为1.5~3.5mg/mL。本发明提供的制备方法中,包封胶原蛋白的脂质体通过手臂链连接到纳米纤维上,定向附着于粘胶纤维无纺布上,使脂质体具有良好的空间灵活性,提高表面可及性和贴敷性能;由于手臂链的存在,使脂质体浮于无纺布表面,提高胶原蛋白的作用效果;同时,包封率高,可实现重复使用,提高胶原蛋白持续缓释的效果。
Description
技术领域
本发明涉及药物制剂、护肤品及化妆品领域,具体涉及一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法。
背景技术
脂质体是一种人工膜,在水中磷脂分子亲水头部插入水中,脂质体疏水尾部伸向空气,搅动后形成双层脂分子的球形脂质体,直径25-1000nm不等。脂质体的结构为一层或多层同心脂质双分子层。脂质体技术于20世纪60年代中期即应用于化妆品领域,但直到20世纪70年代才将脂质体应用于药物载体,并引起广泛关注。脂质体材料与生物体细胞膜成分相似,具有良好的生物相容性和可降解性,故而对机体的刺激性较低。此外,脂质体还具有靶向和缓释的作用,因而有高效低毒的特点。
理想的脂质体应具备以下特点:包封率高、粒径分布范围窄、稳定性好。这也正是目前脂质体制备技术所面临的最大困难,也是目前需要迫切解决的问题。目前脂质体的制备方法较多,常规的方法有薄膜分散法、逆向蒸发法、表面活性剂除去法、乙醇/乙醚注入法、乳化法以及pH梯度法、硫酸铵梯度法等。上述方法原理虽有不同,但其共同点在于均需将脂材首先分布于有机溶剂中,再分散于水相中。脂质体作为一种新型的药物传递系统,具有很多的优点,有着更为广阔的应用前景。
胶原蛋白是生物高分子,动物体内含量最丰富的蛋白质,占人体蛋白质总量的25-30%,起到维持皮肤与肌肉弹性、增强钙质与骨细胞结合、联结骨骼与肌肉、保持眼角膜透明等作用。它属于不溶性纤维型蛋白质,也是细胞外基质中的一类。皮肤之所以富有弹性,主要因为皮肤真皮层内胶原纤维的胶原质形成皮肤的支架。从结构上看,胶原的分子结构独特,在电子显微镜看到三个分子呈现螺旋结构,并有多型性,胶原肽链的氨基酸组成独特,甘氨酸含量三分之一,脯氨酸及羟脯氨酸各占10%,其中羟脯氨酸在动物组织中,仅见于胶原,皮肤中的胶原转换率一般比较慢,儿童的皮肤以III型胶原为主,到了成年皮肤以I型胶原为主,随着年龄的增长,工作的繁忙和劳累,外部环境因素的影响,使娇嫩的肌肤开始变松弛、干燥,就出现了皱纹和光泽减退等问题。同时,胶原的交联键的日益增多,胶原纤维亦越紧密与皮肤老化变僵硬相关,所以,皮肤表现松弛。
现有脂质体技术制备的脂质体主要为游离脂质体,应用过程中基本是一次性使用。但是,脂质体作为载体包封有效成分,因其释放有效成分需要一定的时间周期,而一次性使用脂质体难于做到全部释放有效成分,造成有效成分的损失。此外,脂质体附着于固体表面,受到空间位阻的影响,脂质体表面可及性受到限制,无法做到全表面接触。因此,本发明提供一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供一种具有缓释胶原蛋白的脂质体混悬液。
本发明还要解决的技术问题是提供上述具有缓释胶原蛋白的脂质体混悬液的制备方法。
本发明还要解决的技术问题是提供一种制备具有缓释胶原蛋白的脂质体颗粒的方法。
本发明还要解决的技术问题是提供一种制备美容和/或护肤产品的方法。
本发明还要解决的技术问题是提供上述美容和/或护肤产品的使用方法。
为了解决上述第一个技术问题,本发明公开了一种具有缓释胶原蛋白的脂质体混悬液,包含粒度为70-1100nm,和/或,3000-5500nm的双层脂质体颗粒,所述混悬液由有机相和水相形成,所述有机相中含柔性碳链连接剂连接的磷脂纳米纤维的浓度为0.14~0.17g/mL,优选为0.15~0.16g/mL,进一步优选为0.155g/ml,所述水相中胶原蛋白的浓度为1.5~3.5mg/mL,优选为2.0~3.0mg/mL,进一步优选为2.5mg/mL。
为了解决上述第二个技术问题,本发明公开了一种制备具有缓释胶原蛋白的脂质体混悬液的方法,包括:
a.制备含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相;
b.制备含有抗氧化剂、胶原蛋白的水相;
c.将有机相分散于水相中反应,即得具有缓释胶原蛋白的脂质体混悬液。
为了解决上述第三个技术问题,本发明公开了一种制备具有缓释胶原蛋白的脂质体颗粒的方法,包括:
a.制备含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相;
b.制备含有抗氧化剂、胶原蛋白的水相;
c.将有机相分散于水相中反应,即得具有缓释胶原蛋白的脂质体混悬液;
d.将糖类化合物与具有缓释胶原蛋白的脂质体混悬液混合,干燥,即得具有缓释胶原蛋白的脂质体颗粒;
或,将糖类化合物与上述具有缓释胶原蛋白的脂质体混悬液混合,干燥,即得具有缓释胶原蛋白的脂质体颗粒。
在上述第一~第三个技术问题中,
其中,所述柔性碳链连接剂为甘油醚,优选为碳原子数为3以上的甘油醚,进一步优选为1,4-丁二醇二缩水甘油醚。
其中,所述纳米纤维为纤维素纳米纤维和/或几丁质纳米纤维。
其中,所述抗氧化剂包括但不限于抗坏血酸钠。
其中,所述糖类化合物包括但不限于蔗糖。
步骤a中,所述柔性碳链连接剂连接的磷脂纳米纤维的制备方法为将纳米纤维、磷脂与柔性碳链连接剂溶于水中,分散均匀反应,所得反应物浸泡于水中得到混悬液,所得混悬液干燥去除溶剂,所得固体即为柔性碳链连接剂连接的磷脂纳米纤维。
其中,所述纳米纤维、磷脂与柔性碳链连接剂的质量比为1:(0.5~2.5):(0.05~0.025),优选为1:1:0.1。
其中,所述纳米纤维的浓度为0.01~0.03g/mL,优选为0.02g/mL。
其中,所述反应的温度为25~40℃,优选为28℃。
其中,所述干燥包括但不限于冷冻干燥。
步骤a中,所述含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的质量比为(1~6):(2~6):(0.28~0.68):0.48,优选为(2~5):4:0.48:0.48,进一步优选为3.6:4:0.48:0.48。
步骤a中,所述有机相中含柔性碳链连接剂连接的磷脂纳米纤维的浓度为0.14~0.17g/mL,优选为0.15~0.16g/mL,进一步优选为0.155g/ml。
步骤a中,制备含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相为将柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温溶于有机溶剂中,固液分离,所得液体即为含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相。
其中,所述有机相包括但不限于冰乙醇。
其中,所述固液分离包括但不限于离心。
步骤b中,所述抗氧化剂和胶原蛋白的质量比为(20~28):1,优选为24:1。
步骤b中,所述水相中胶原蛋白的浓度为1.5~3.5mg/mL,优选为2.0~3.0mg/mL,进一步优选为2.5mg/mL。
步骤b中,所述水相的溶剂为缓冲液,包括但不限于柠檬酸缓冲液。
步骤c中,所述反应的温度为30~50℃,优选为40℃。
步骤c中,所述反应的时间为0.5~3.5h,优选为2h。
步骤d中,所述蔗糖与胶原蛋白的质量比为(80~94):1,优选为87:1。
为了解决上述第四个技术问题,本发明公开了一种制备美容和/或护肤产品的方法,将上述方法制备的具有缓释胶原蛋白的脂质体混悬液,上述方法制备的具有缓释胶原蛋白的脂质体颗粒,和上述方法制备的具有缓释胶原蛋白的脂质体中的任意一种或几种组合,与合适的基体合并,以形成采用霜剂、洗剂、凝胶剂、浆液、补剂、乳液、糊剂、喷雾、或面膜形式的产品。
其中,所述产品包括但不限于美容和/或护肤的药物制剂、护肤品、化妆品。
其中,当所述产品为美容和/或护肤的面膜时,其制备方法还包括如下步骤:
e.将酸性的具有缓释胶原蛋白的脂质体颗粒溶液与粘胶纤维无纺布装入袋,密封,灭菌,即得具有缓释胶原蛋白的脂质体。
步骤e中,所述酸性的具有缓释胶原蛋白的脂质体颗粒溶液的pH为2.5~6.5,优选为3.5~5.5,进一步优选为4.5。
步骤e中,所述灭菌为在121℃下灭菌15分钟。
为了解决上述第五个技术问题,本发明公开了上述美容和/或护肤产品的使用方法,先清洁面部皮肤,取一片面膜,均匀地敷于面部,15分钟后取下面膜,洗净面部即可;用后的面膜,装入袋中,密封,置于冰箱中冷藏;再次使用时,重复上述步骤。
综上,本发明提供具有缓释胶原蛋白的脂质体的制备方法中,包封胶原蛋白的脂质体通过手臂链连接到纳米纤维上,定向附着于粘胶纤维无纺布上,使脂质体具有良好的空间灵活性,适应凹凸不同表面,可与皮肤无死角接触,提高表面可及性和贴敷性能;由于手臂链的存在,使脂质体减少与粘胶纤维无纺布的接触,浮于无纺布表面,形成一种“拟游离”状态,进而减少释放后的胶原蛋白被无纺布再吸附,提高胶原蛋白的作用效果;同时,包封率高,可实现重复使用,提高胶原蛋白持续缓释的效果;且多次重复使用过程中脂质体损失少,胶原蛋白释放率高,且舒适、方便,制备工艺简单。
有益效果:与现有技术相比,本发明具有如下优势:
(1)本发明中脂质体通过手臂链连接到纳米纤维上,该脂质体对无纺布贴敷面料具有较佳的亲和性,定向附着于粘胶纤维无纺布上,实现多次重复使用,使用过程中脂质体损失少;同时,由于有手臂链的存在,使脂质体具有极佳的空间灵活性,可与皮肤无死角接触,具有较佳的表面可及性和贴敷性能。
(2)由于手臂链的存在,使脂质体浮于无纺布表面,形成一种“拟游离”状态,进而减少释放后的胶原蛋白被无纺布再吸附,提高胶原蛋白的作用效果。
(3)本发明中定向附着的脂质体包封胶原蛋白,在多次使用中持续缓释,实现脂质体包封胶原蛋白的高效全利用。
(4)本发明中脂质体的纳米纤维来源纯天然,具有极好的生物安全性和生物可降解性,对皮肤具有极好的亲和性,具备极好的生物相容性。
(5)本发明中脂质体具有不同尺寸,包封分子量大小不一的胶原蛋白,胶原蛋白受到脂质体的保护,保持较佳的生物活性。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为实施例1所制备的具有缓释胶原蛋白的脂质体体外胶原蛋白释放曲线图。
图2为实施例1所制备的具有缓释胶原蛋白的脂质体颗粒的粒度分布图。
具体实施方式
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
下述实施例中,所述体外胶原蛋白释放实验过程为:取具有缓释胶原蛋白的脂质体颗粒10g,加入磷酸盐缓冲液(pH=7.4)溶解脂质体颗粒,定容为30mL。将溶液置于气浴摇床中,在37℃、100rpm条件下恒温振荡7天,每天取样检测胶原蛋白的含量。取样用10000道尔顿的超滤离心管在4000r/min下离心5min,获得的清液作为体外释放的检测样品。采用BCA方法对检测样品进行胶原蛋白的含量检测。
实施例1
1.具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)1.5g几丁质纳米纤维、1.5g磷脂酰甘油、0.15g 1,4-丁二醇缩水甘油醚溶于75mL水中,搅拌混合至分散均匀,在28℃条件下反应至完全,所得反应物按照1:10的体积比浸泡于纯化水中,用30000道尔顿的超滤膜浓缩至原体积(此过程浸泡三次以去除未反应完全的1,4-丁二醇缩水甘油醚),得到混悬液;
(2)将(1)中混悬液冷冻干燥去除溶剂,得固体;
(3)称取(2)中的固体3.1g、1.6g磷脂酰甘油、0.2g胆固醇和0.2g吐温80,溶于20mL冰乙醇中,备用;
(4)称取抗坏血酸钠1g和胶原蛋白(胶原蛋白分子量为43kDa)0.05g,溶于20mLpH3.6的柠檬酸缓冲液中,充分搅拌均匀,备用;
(5)将步骤(3)所制备的液体滴加到步骤(4)所制备的液体,在40℃条件下温育2个小时;
(6)向步骤(5)所得产物中加入蔗糖3.6g,冷冻干燥去除溶剂,得到具有缓释胶原蛋白的脂质体颗粒。胶原蛋白包封率达到65.8%。
所制备的具有缓释胶原蛋白的脂质体颗粒的粒度分布如图2所示,粒度在70-1100nm,3000-5500nm两个范围内,脂质体粒度大,说明脂质体尺寸大,可以包裹较大分子量的分子;不同尺寸的脂质体,可以包裹不同分子量大小的分子。
将所制备的可重复使用的具有缓释胶原蛋白的脂质体颗粒进行体外胶原蛋白释放实验,结果图1所示,所制备的脂质体颗粒缓释周期为7天,胶原蛋白累积释放量达到~94%,平均每日胶原蛋白释放量约为13.4%。
2.可重复使用的具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)称取步骤1中的具有缓释胶原蛋白的脂质体颗粒16.3g,加入83.7g纯化水,搅拌溶解,备用;
(2)调节pH值为4.5;
(3)灌装:将步骤(2)所得液体和粘胶纤维无纺布装入袋,密封,备用;
(4)灭菌:在121℃下灭菌15分钟,即得。
3.重复使用
(1)先清洁皮肤,取一片步骤2中制备的可重复使用的具有缓释胶原蛋白的脂质体,均匀地敷于皮肤上,15分钟后取下,洗净皮肤即可;
(2)用后的步骤2中制备的可重复使用的具有缓释胶原蛋白的脂质体,装入袋中,密封,置于冰箱中冷藏;
(3)每天使用1次,重复(1)的步骤,连续7天使用。
同时,平行试验,在连续使用7天后,从袋中取1mL液体,用10000道尔顿的超滤离心管在4000r/min下离心5min,获得的清液,采用BCA方法检测胶原蛋白的含量,胶原蛋白累积释放量达到~71%。
实施例2
1.具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)1.5g纤维素纳米纤维、1.5g磷脂酰肌醇、0.15g 1,4-丁二醇缩水甘油醚溶于75mL水中,搅拌混合至分散均匀,在25℃条件下反应至完全,所述反应物按照1:10的体积比浸泡于纯化水中,用30000道尔顿的超滤膜浓缩至原体积,此过程浸泡三次,得到混悬液;
(2)将步骤(1)所得混悬液冷冻干燥去除溶剂,得固体;
(3)称取步骤(2)所得固体3.1g、1.6g磷脂酰肌醇、0.2g胆固醇和0.2g吐温80,溶于20mL冰乙醇中,备用;
(4)称取抗坏血酸钠1g和胶原蛋白0.05g(胶原蛋白分子量为55kDa),溶于20mLpH3.6的柠檬酸缓冲液中,充分搅拌均匀,备用;
(5)将步骤(3)所制备的液体滴加到步骤(4)所制备的液体,在40℃条件下温育2个小时;
(6)向步骤(5)所得产物中加入蔗糖3.6g,冷冻干燥去除溶剂,得到具有缓释胶原蛋白的脂质体颗粒。胶原蛋白包封率达到60.3%。
2.可重复使用的具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)称取步骤1中的具有缓释胶原蛋白的脂质体颗粒16.3g,加入83.7g纯化水,搅拌溶解,备用;
(2)调节pH值为4.5;
(3)灌装:将步骤(2)所得液体和粘胶纤维无纺布装入袋,密封,备用;
(4)灭菌:在121℃下灭菌15分钟,即得。
实施例3
1.具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)1.5g几丁质纳米纤维、1.5g磷脂酰乙醇胺、0.15g 1,4-丁二醇缩水甘油醚溶于75mL水中,搅拌混合至分散均匀,在40℃条件下反应至完全,所得反应物按照1:10的体积比浸泡于纯化水中,用30000道尔顿的超滤膜浓缩至原体积,此过程浸泡三次,得到混悬液;
(2)将步骤(1)所得混悬液冷冻干燥去除溶剂,得固体;
(3)称取步骤(2)所得固体3.1g、1.6g磷脂酰乙醇胺、0.2g胆固醇和0.2g吐温80,溶于20mL冰乙醇中,备用;
(4)称取抗坏血酸钠1g和胶原蛋白0.05g(胶原蛋白分子量为31kDa),溶于20mLpH3.6的柠檬酸缓冲液中,充分搅拌均匀,备用;
(5)将步骤(3)所制备的液体滴加到步骤(4)所制备的液体,在40℃条件下温育2个小时;
(6)向步骤(5)所得产物中加入蔗糖3.6g,冷冻干燥去除溶剂,得到具有缓释胶原蛋白的脂质体颗粒。胶原蛋白包封率达到57.4%。
2.可重复使用的具有缓释胶原蛋白的脂质体制备方法,包括如下步骤:
(1)称取步骤1中的具有缓释胶原蛋白的脂质体颗粒16.3g,加入83.7g纯化水,搅拌溶解,备用;
(2)调节pH值为4.5;
(3)灌装:将步骤(2)所得液体和粘胶纤维无纺布装入袋,密封,备用;
(4)灭菌:在121℃下灭菌15分钟,即得。
本发明提供了一种可重复使用的具有缓释胶原蛋白的脂质体混悬液及其制备方法的思路及方法,具体实现该技术方案的方法和途径很多,以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (5)
1.一种具有缓释胶原蛋白的脂质体颗粒,其特征在于,由如下方法制备得到,所述方法包括:
a.制备含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相;所述柔性碳链连接剂为碳原子数为3以上的甘油醚;
b.制备含有抗氧化剂、胶原蛋白的水相;
c.将有机相分散于水相中反应,即得具有缓释胶原蛋白的脂质体混悬液;
d.将糖类化合物与具有缓释胶原蛋白的脂质体混悬液混合,干燥,即得具有缓释胶原蛋白的脂质体颗粒;
步骤a中,所述柔性碳链连接剂连接的磷脂纳米纤维的制备方法为将纳米纤维、磷脂与柔性碳链连接剂反应、浸泡、干燥,所得固体即为柔性碳链连接剂连接的磷脂纳米纤维;所述纳米纤维、磷脂与柔性碳链连接剂的质量比为1:(0.5~2.5) :(0.05~0.025);
步骤a中,所述含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的质量比为(1~6):(2~6):(0.28~0.68):0.48;
步骤b中,所述抗氧化剂和胶原蛋白的质量比为(20~28):1;
步骤c中,所述反应的温度为30~50℃。
2.一种制备具有缓释胶原蛋白的脂质体颗粒的方法,其特征在于,包括:
a.制备含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的有机相;所述柔性碳链连接剂为碳原子数为3以上的甘油醚;
b.制备含有抗氧化剂、胶原蛋白的水相;
c.将有机相分散于水相中反应,即得具有缓释胶原蛋白的脂质体混悬液;
d.将糖类化合物与具有缓释胶原蛋白的脂质体混悬液混合,干燥,即得具有缓释胶原蛋白的脂质体颗粒;
步骤a中,所述柔性碳链连接剂连接的磷脂纳米纤维的制备方法为将纳米纤维、磷脂与柔性碳链连接剂反应、浸泡、干燥,所得固体即为柔性碳链连接剂连接的磷脂纳米纤维;所述纳米纤维、磷脂与柔性碳链连接剂的质量比为1:(0.5~2.5) :(0.05~0.025);
步骤a中,所述含有柔性碳链连接剂连接的磷脂纳米纤维、甘油磷脂、胆固醇、吐温的质量比为(1~6):(2~6):(0.28~0.68):0.48;
步骤b中,所述抗氧化剂和胶原蛋白的质量比为(20~28):1;
步骤c中,所述反应的温度为30~50℃。
3.根据权利要求1所述脂质体颗粒或权利要求2所述的方法,其特征在于,所述磷脂纳米纤维制备方法中反应的温度为25~40℃。
4.根据权利要求1所述脂质体颗粒或权利要求2所述的方法,其特征在于,所述具有缓释胶原蛋白的脂质体颗粒为粒度为70-1100nm和3000-5500nm的脂质体颗粒。
5.一种制备护肤产品的方法,其特征在于,将权利要求1所述的具有缓释胶原蛋白的脂质体颗粒或权利要求2所述方法制备的具有缓释胶原蛋白的脂质体颗粒,与合适的基体合并,以形成采用霜剂、洗剂、凝胶剂、浆液、补剂、乳液、糊剂、喷雾、或面膜形式的产品。
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