CN113350288A - 一种全反式维甲酸/倍他米松共载柔性纳米脂质体及其凝胶的制备方法 - Google Patents
一种全反式维甲酸/倍他米松共载柔性纳米脂质体及其凝胶的制备方法 Download PDFInfo
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Abstract
本发明涉及皮肤病治疗领域，具体涉及一种全反式维甲酸/倍他米松共载柔性纳米脂质体及其凝胶的制备方法，由卵磷脂、吐温‑80所制得的柔性脂质体为基础的药物输送系统具有良好的皮肤渗透和药物保护，与传统的刚性膜相比，柔性脂质体可以增强皮肤渗透性；同时提供了全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶的制备方法，外用凝胶使用方便，也能延长药物在皮肤上的滞留能力，有利于治疗银屑病。
Description
技术领域
本发明涉及皮肤病治疗领域，具体涉及一种全反式维甲酸/倍他米松共载柔性纳米脂质体及其凝胶的制备方法。
背景技术
银屑病被认为是最常见的慢性免疫介导的炎症性皮肤病。这种疾病通常表现为皮肤上长期存在红色和尖锐的鳞片状斑块，严重降低患者的生活质量。先前的研究已经报道银屑病常导致共病的风险增加，如炎症性关节炎、肥胖、高血压和炎症性肠病。不幸的是，银屑病的发病率正在逐年上升，全世界约有2-4％的人口患有这种疾病。目前银屑病的治疗方法主要有外用疗法、光疗疗法、免疫疗法和全身疗法。其中，局部治疗是治疗银屑病最常用的手段，由于其方便和减少副作用。然而，传统剂型的局部给药仍然不令人满意，这与药物渗透受限和患者依从性降低有关。因此，对于银屑病患者来说，探索一种新的局部治疗方法以提高治疗效果是非常必要的。
全反式维甲酸是维甲酸家族的一员，常用于治疗皮肤疾病，如痤疮、皮肤癌、伤口愈合和牛皮癣。全反式维甲酸在银屑病治疗中的潜力部分是由于全反式维甲酸可以通过与维甲酸受体结合来调节皮肤细胞生长和分化、皮脂合成和胶原生成。先前的研究表明，全反式维甲酸可以通过大量降低促炎细胞因子(如IL-6、ICAM-1和HLA-DR)的表达水平来抑制炎症反应，这对银屑病的治疗也是有益的。尽管全反式维甲酸是FDA批准的治疗各种皮肤疾病的药物，但由于其对氧和光的稳定性差、水不溶性和皮肤刺激性，它在临床上的广泛应用仍然受到很大限制。因此，迫切需要设计克服上述困难的新方法。
倍他米松作为一种糖皮质激素，在缓解银屑病症状方面也很有效。倍他米松具有多种功能，包括抗炎、血管收缩、凋亡、抗核分裂和免疫调节能力。众所周知，这些功能与倍他米松治疗银屑病的能力密切相关。然而，与局部应用倍他米松有关的一个主要问题是，长期使用倍他米松会引起不良的皮肤反应，如局部萎缩和色素沉着。
联合治疗被认为是克服补偿性机制，以及减少剂量相关的副作用的最有希望的方法之一。联合使用两种或两种以上具有不同治疗机制的药物，有利于通过多靶点治疗方法获得增强的治疗效果。糖皮质激素具有很强的抗炎和抗增殖作用，可以抑制表皮细胞中的前列腺素或细胞因子，从而降低全反式维甲酸的皮肤反应，从而减少全反式维甲酸的刺激。全反式维甲酸可防止糖皮质激素引起的结缔组织基质改变，维持胶原、糖胺聚糖和纤维连接蛋白的正常水平，从而逆转糖皮质激素治疗引起的皮肤萎缩。但是他们均具有相对较差的皮肤渗透性。
发明内容
为了解决以上问题，本发明提供了一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法。
本发明具体采用的技术方案是：
一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，包括以下步骤：
S1：取反应量的卵磷脂、全反式维甲酸、倍他米松和边缘活化剂，溶解于无水乙醇中；
本步骤中所述的反应量为，卵磷脂、全反式维甲酸、倍他米松和边缘活化剂的质量比为30-50:1:1:15-20。
所选用的边缘活化剂为吐温-80。
S2：在40-45℃黑暗条件下通过蒸发去除乙醇，得到混合物膜；
S3：将混合物膜置入磷酸缓冲盐溶液中，在超声波水浴中进行水合，得到混合物；
本步骤中所采用的磷酸缓冲盐溶液的pH值为6.8。
S4：将水合好的溶液放置冰水浴中，使用100w超声波探头进行超声，超声至溶液均一，得到柔性纳米脂质体悬浊液。
本步骤中的超声时间为4-6min。
本发明还提供了一种全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶的制备方法，将S4所得纳米脂质体悬浊液与空白凝胶以质量比75-80:20-25混合，得到脂质体凝胶。
本方法所述的空白凝胶的制备方法为，包括以下步骤：
a.将1wt％的卡波姆940、10wt％的甘油、0.1wt％的EDTA和0.1wt％的尼泊金乙酯溶解于蒸馏水中；
b.使用三乙醇胺将pH值调节到6.5，得到空白凝胶。
有益效果：
1)由卵磷脂、吐温-80所制得的柔性脂质体为基础的药物输送系统具有良好的皮肤渗透和药物保护，与传统的刚性膜相比，柔性脂质体可以增强皮肤渗透性。
2)制备全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶，外用凝胶使用方便，也能延长药物在皮肤上的滞留能力，有利于治疗银屑病。
附图说明
图1是体外释放实验中全反式维甲酸/倍他米松共载柔性纳米脂质体释放维甲酸、倍他米松与游离全反式维甲酸、倍他米松的药物释放率折线图。
图2是体外皮肤渗透实验中全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶、全反式维甲酸/倍他米松共载柔性纳米脂质体和全反式维甲酸/倍他米松混合液的渗透药物量的折线图。
图3是体外皮肤渗透实验中全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶、全反式维甲酸/倍他米松共载柔性纳米脂质体和全反式维甲酸/倍他米松混合液渗透药物量的折线图。
图中，1、全反式维甲酸/倍他米松纳米脂质体释放维甲酸，2、全反式维甲酸/倍他米松纳米脂质体释放倍他米松，3、游离的全反式维甲酸，4、游离的倍他米松，5、全反式维甲酸/倍他米松脂质体凝胶释放维甲酸，6、全反式维甲酸/倍他米松脂质体释放维甲酸，7、全反式维甲酸/倍他米松混合液释放维甲酸，8、全反式维甲酸/倍他米松脂质体凝胶释放倍他米松，9、全反式维甲酸/倍他米松脂质体释放倍他米松，10、全反式维甲酸/倍他米松混合液释放倍他米松。
具体实施方式
下面是结合附图和实施例对本发明进一步说明。
实施例1
将400mg卵磷脂、160mg吐温-80、10mg全反式维甲酸和10mg倍他米松溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的全反式维甲酸/倍他米松共载柔性脂质体悬浮液。
实施例2
将500mg卵磷脂、180mg吐温-80、20mg全反式维甲酸和20mg倍他米松溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的全反式维甲酸/倍他米松共载柔性脂质体悬浮液。
实施例3
将300mg卵磷脂、120mg吐温-80、5mg全反式维甲酸和5mg倍他米松溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的全反式维甲酸/倍他米松共载柔性脂质体悬浮液。
对比例1
将400mg卵磷脂、160mg吐温-80、10mg全反式维甲酸溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的全反式维甲酸柔性脂质体悬浮液。
对比例2
将400mg卵磷脂、160mg吐温-80、10mg倍他米松溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的倍他米松柔性脂质体悬浮液。
空白对比例
将400mg卵磷脂、160mg吐温-80溶解于10mL无水乙醇中。然后在40℃黑暗条件下通过蒸发去除乙醇。然后在超声波水浴中用5ml PBS(pH＝6.8)将形成的膜水合适当时间。最后，将所得混合物用超声波探头超声4min，得到分散性良好的空白脂质体悬浮液。
柔性纳米脂质体参数表征：
采用动态光散射(DLS)仪(litesizer500，antonpaar，Austria)对柔性脂质体进行适当稀释后测定其平均粒径和粒径分布。
采用超滤离心法测定柔性脂质体的载药量和包封率，即对一定量的柔性脂质体悬浮液进行超速离心(MWCO:3.5kd)以5000r/min的转速静置10min，分离未包封的药物。采用高效液相色谱法(HPLC)测定滤液中胶囊药物的含量及制剂中总药物的含量。然后分别根据以下等式1和等式2计算包封率和载药率。
包封率
载药率
结果如下表所示：
| 样品名称 | 粒径nm | 包封率％ | 载药率％ |
| 空白对比例 | 67.1±0.5 | - | - |
| 实施例1 | 76.1±0.5 | 98.74±0.78 | 2.00±0.04 |
| 实施例2 | 81.3±02 | 96.16±0.65 | 1.88±0.05 |
| 实施例3 | 75.7±0.6 | 94.71±0.73 | 1.61±0.12 |
| 对比例1 | 65.4±3.1 | 99.02±0.54 | 2.04±0.15 |
| 对比例2 | 70.2±5.4 | 99.14±0.20 | 1.95±0.05 |
实施例1-3制备的载有维甲酸和倍他米松的纳米脂质体粒径分别为76.1nm，81.3nm和75.7nm，比空白对比例粒径稍大。实施例1-3测试的包封率较高均在90％以上，载药率在2％左右。
体外释放研究：
采用透析法研究了柔性纳米脂质体的体外释药行为。简而言之，将适量的游离药物或实施例1制备的载药柔性纳米脂质体置于透析袋中(MWCO:3.5kd).然后将透析袋浸入含有乙醇和PBS混合物(30:70，v/v，pH6.8)的释放介质中。在100rpm(37℃)下持续搅拌，每隔一定时间，从乙醇/PBS混合液中取出200ul进行检测，同时补充进去200ul新鲜的乙醇/PBS混合液。采用高效液相色谱法测定释放介质中全反式维甲酸/倍他米松的浓度。
结果如图1所示。
3、4均为游离药物，所以很快达到最大释放率。而实施例1制备的载有维甲酸和倍他米松的纳米脂质体均有较为缓慢的释放速率，在12或24h达到维甲酸和倍他米松的最大释放，实现了药物的持续释放，有助于促进伤口愈合。
以下对本发明所述的全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶进行实验说明。
实施例4
在蒸馏水中溶解1wt％的卡波姆940、10wt％的甘油、0.1wt％的EDTA和0.1wt％的尼泊金乙酯，然后用三乙醇胺将pH值调节到6.5。然后将空白凝胶与实施例1所得全反式维甲酸/倍他米松共载柔性脂质体悬浮液以75:25(w/w)的比例混合以形成脂质体凝胶。脂质体凝胶中全反式维甲酸/倍他米松的相对含量为0.05wt％。
对比例3
将10mg全反式维甲酸和10mg倍他米松溶解于10mL乙醇和PBS混合物(30:70，v/v，pH6.8)，得到全反式维甲酸/倍他米松混合液。
将实施例1、实施例4与对比例3进行体外皮肤渗透实验。
体外皮肤渗透实验：
首次从SD大鼠腹侧取全层皮肤。去除多余皮下脂肪后，使用前将大鼠皮肤储存在-80℃。采用Franz扩散池对不同剂型进行体外透皮和滞留实验。简言之，在Franz扩散池上固定适当面积的皮肤样本，使角质层和真皮层分别面对供体和受体室。取1g脂质体凝胶样品置于皮肤表面，以脂质体和游离药物溶液为对照。将7mL释放介质(乙醇/PBS 30:70，pH6.8)填充到受体室中，然后以100rpm(37℃)持续搅拌。在规定的时间间隔内，提取1ml释放培养基，并立即补充1ml新鲜培养基。采用酶联免疫吸附法测定释放介质中全反式维甲酸/倍他米松的含量高效液相色谱法治疗后24小时，用冷PBS冲洗皮肤三次，去除残留的配方。用组织匀浆机切碎适量的皮肤。用甲醇提取皮肤组织中的全反式维甲酸/倍他米松，用HPLC法测定其含量。
结果如图2、图3所示。
图2和图3分别为检测样品中渗透出的维甲酸和倍他米松的动力学。相比于纳米脂质体，凝胶形式会阻碍两种药物的释放效果。但是凝胶渗透的维甲酸和倍他米松比单纯的药物混合液多一些。说明制备成外用凝胶剂型，也可以缓慢释放药物并渗透皮肤，达到治疗效果。
Claims (8)
1.一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，其特征在于，包括以下步骤：
S1：取反应量的卵磷脂、全反式维甲酸、倍他米松和边缘活化剂，溶解于无水乙醇中；
S2：在40-45℃黑暗条件下通过蒸发去除乙醇，得到混合物膜；
S3：将混合物膜置入磷酸缓冲盐溶液中，在超声波水浴中进行水合，得到混合物；
S4：将水合好的溶液放置冰水浴中，使用100w超声波探头进行超声，超声至溶液均一，得到柔性纳米脂质体悬浊液。
2.根据权利要求1所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，其特征在于，S1中卵磷脂、全反式维甲酸、倍他米松和边缘活化剂的质量比为30-50:1:1:15-20。
3.根据权利要求1或2所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，其特征在于，所述边缘活化剂为吐温-80。
4.根据权利要求1所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，其特征在于，S3中所述磷酸缓冲盐溶液的pH值为6.8。
5.根据权利要求1所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体的制备方法，其特征在于，S4中超声时间为4-6min。
6.一种使用权利要求1所述的全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶，其特征在于，将S4所得纳米脂质体悬浊液与空白凝胶以质量比75-80:20-25混合，得到脂质体凝胶。
7.根据权利要求6所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体的凝胶的制备方法，其特征在于，所述脂质体凝胶中，全反式维甲酸/倍他米松的含量为0.05wt％。
8.根据权利要求6或7所述一种全反式维甲酸/倍他米松共载柔性纳米脂质体凝胶的制备方法，其特征在于，所述空白凝胶的制备方法包括以下步骤：
a.将1wt％的卡波姆940、10wt％的甘油、0.1wt％的EDTA和0.1wt％的尼泊金乙酯溶解于蒸馏水中；
b.使用三乙醇胺将pH值调节到6.5，得到空白凝胶。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115737678A (zh) * | 2022-11-30 | 2023-03-07 | 浙江大学金华研究院 | 载三苯基膦修饰的氧化铈和全反式维甲酸的脂质体凝胶 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0717994A1 (en) * | 1994-07-07 | 1996-06-26 | Ignacio Anton Lujambio Galdeano | New formulation for the topical treatment of psoriasis |
| CN1660059A (zh) * | 2004-02-25 | 2005-08-31 | 重庆华邦制药股份有限公司 | 维甲酸复合脂质体及其制备方法与应用 |
| CN106361703A (zh) * | 2016-10-31 | 2017-02-01 | 长沙晶易医药科技有限公司 | 非那雄胺纳米脂质体、凝胶及其制备方法 |
| CN106924176A (zh) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | 一种他莫昔芬柔性纳米脂质体凝胶剂及其制备方法 |
-
2021
- 2021-06-09 CN CN202110642587.6A patent/CN113350288A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0717994A1 (en) * | 1994-07-07 | 1996-06-26 | Ignacio Anton Lujambio Galdeano | New formulation for the topical treatment of psoriasis |
| CN1660059A (zh) * | 2004-02-25 | 2005-08-31 | 重庆华邦制药股份有限公司 | 维甲酸复合脂质体及其制备方法与应用 |
| CN106361703A (zh) * | 2016-10-31 | 2017-02-01 | 长沙晶易医药科技有限公司 | 非那雄胺纳米脂质体、凝胶及其制备方法 |
| CN106924176A (zh) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | 一种他莫昔芬柔性纳米脂质体凝胶剂及其制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| WEI WANG等: ""Flexible liposomal gel dual loaded with all trans retinoic acid and betamethasone for enhanced therapeutic efficiency of psoriasis"", 《JOURNAL OF NANOBIOTECHNOLOGY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115737678A (zh) * | 2022-11-30 | 2023-03-07 | 浙江大学金华研究院 | 载三苯基膦修饰的氧化铈和全反式维甲酸的脂质体凝胶 |
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