CN108815175A - 一种眼外施用的喷雾剂 - Google Patents
一种眼外施用的喷雾剂 Download PDFInfo
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- CN108815175A CN108815175A CN201810390024.0A CN201810390024A CN108815175A CN 108815175 A CN108815175 A CN 108815175A CN 201810390024 A CN201810390024 A CN 201810390024A CN 108815175 A CN108815175 A CN 108815175A
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Abstract
本发明提供一种含有磷脂和甜菜碱的眼外施用喷雾剂，其中磷脂含量为1‑100mg/ml，甜菜碱含量为1‑100mg/ml；优选的，磷脂含量为1‑20mg/ml，甜菜碱含量为1‑50mg/ml；进一步优选，磷脂含量为5‑15mg/ml，甜菜碱含量为10‑30mg/ml。本发明提供的眼外施用喷雾剂，不仅能够透过眼部皮肤屏障，安全有效治疗干眼症，并且能够延长起效的时间，提高患者的舒适度。并且，本发明的眼外施用喷雾剂作为具有药理或美容活性物质的载体，能够提高活性物质的透膜吸收量，提高生物利用度，同时对眼部不产生刺激性。
Description
技术领域
本发明涉及药物技术领域，具体涉及一种眼外施用的喷雾剂。
背景技术
干眼症是一种常见的眼科疾病，是由多种原因引起泪液分泌减少或蒸发过强、泪膜稳定性降低，进而导致眼表损害为特征的一组疾病的总称。干眼症的常见症状是眼局部刺激、畏光、疼痛、视力模糊、易疲劳等。如果干眼症得不到有效治疗，可能会形成角膜、结膜的角质化、溃疡，从而导致视力严重下降。随着视频显示终端如电脑、电视和手机等在人们生活中的广泛渗透以及角膜接触镜的广泛使用，由于长时间瞬目频率降低、眼表组织暴露增加等导致干眼症人群越来越多。目前对于干眼症的治疗主要是人工泪液以及各种类型的眼药水。无论人工泪液还是眼药水在使用时都需要直接滴入眼内，患者的顺应性较差。
专利CN1456167A提供了一种含有磷脂的人工泪液，专利CN1634123A提供了一种含有磷脂和玻璃酸钠的眼科给药系统，专利CN1651090A提供了一种含有海藻糖和玻璃酸的眼部用药传递系统。上述现有技术中提到的眼科用药均是直接滴入眼内使用，对于患者来说依从性较差。目前国内针对干眼症仅有滴入眼内使用的制剂。
为了提高患者的依从性，英国Reckitt Benckiser公司上市了一种眼用喷雾，商品名为Optrex，主要成分包含大豆磷脂、维生素A、维生素E，该喷雾能够通过眼外施用的方式缓解干眼症。但是由于肌肤的屏障作用，其针对干眼症的缓解持续时间较短，患者的使用感受不佳。
喷雾剂属于目前皮肤或黏膜给药的安全性较高的剂型，使用也较为便捷。但是，喷雾剂也存在一些缺点，主要有：1)由于皮肤的屏障作用，喷雾剂仅适用于剂量小、药理作用强的药物；2)对皮肤产生刺激性与过敏性；3)皮肤的代谢与储库作用。皮肤和黏膜层是人体对药物吸收的一种屏障，两亲性差或分子量大的药物很难透过皮肤和黏膜组织进入到深层组织和血液循环发挥治疗作用。目前促进药物穿透皮肤、黏膜的方法主要依靠化学吸收促进剂来增加药物的吸收。虽然这些化学促进剂能提高药物穿透率，但是大部分的化学促进剂会对皮肤、黏膜造成损害或刺激。
为了克服现有技术的缺陷，需要提供一种眼外施用的喷雾剂，不仅能够透过眼部皮肤屏障，安全有效治疗干眼症，并且能够延长起效的时间，提高患者的舒适度。出人意料的是，本发明的眼外施用喷雾剂作为具有药理或美容活性物质的载体，能够提高活性物质的透膜吸收量，提高生物利用度，同时对眼部不产生刺激性。
发明内容
本发明提供一种眼外施用的喷雾剂，可以透过皮肤屏障治疗干眼症，能够明显延长起效时间，大大提高了使用者的舒适程度，并且能够作为具有药理或美容活性物质的载体，促进活性物质的吸收，提高其生物利用度。
为了实现上述目的，本发明的技术方案如下：
本发明提供一种眼外施用喷雾剂，包含磷脂和甜菜碱。
上述眼外施用喷雾剂中，还包含常规眼用制剂辅料和纯化水。
上述眼外施用喷雾剂中，磷脂含量为1-100mg/ml，甜菜碱含量为1-100mg/ml。
上述眼外施用喷雾剂中，磷脂含量为1-20mg/ml，甜菜碱含量为1-50mg/ml。
上述眼外施用喷雾剂中，磷脂含量为5-15mg/ml，甜菜碱含量为10-30mg/ml。
上述眼外施用喷雾剂中，还包含挥发性溶剂，选自乙醇、挥发性硅油。
上述眼外施用喷雾剂中，还包含防腐剂，选自苯扎溴铵、苯扎氯安、苯氧乙醇、羟苯甲酯、羟苯乙酯、羟苯丁酯、羟苯丙酯、苯氧乙醇、丁羟甲苯、苯甲酸钠、山梨酸钾、苯甲酸、氯苯甘醚、EDTA。
上述眼外施用喷雾剂中，还包含保湿剂，选自丝氨酸、透明质酸钠、丙二醇、丁二醇、甘油、双丙甘醇、乙酰化透明质酸钠、杨桃叶提取物、1,2-戊二醇、泛醇、海藻糖。
上述眼外施用喷雾剂中，还包含抗氧剂，选自维生素E腺苷、视黄醇、生育酚乙酸酯、生育酚烟酸酯、棕榈酰五肽-4、谷胱甘肽、天冬氨酸。
上述眼外施用喷雾剂中，还包含pH调节剂，选自磷酸缓冲对、硼酸缓冲对、碳酸缓冲对、盐酸、氢氧化钠、柠檬酸钠、氢氧化钾、氨丁三醇。
上述眼外施用喷雾剂中，还包含等渗调节剂，选自氯化钠、甘露醇、葡萄糖等。
上述眼外施用喷雾剂中，还包含天然产物提取物，选自银杏提取物、大花紫薇提取物、人参根提取物、视黄醇乙酸酯、迷迭香提取物、红花提取物、蒲桃叶提取物、咖啡黄葵果提取物、樱花叶提取物、刺梨果提取物、鱼腥草提取物、野大豆籽提取物、大麦提取物、小麦胚芽提取物、酵母提取物、黄芩根提取物、鸡桑根提取物、乳酸杆菌发酵产物、藻提取物、茯苓菌核提取物、、紫松果菊提取物、白花春黄菊花油、、植物鞘氨醇、白桦树皮/叶提取物、大蕉果提取物、燕麦提取物、合欢树皮提取物、柠檬百里香花/叶提取物。
本发明提供一种上述眼外施用喷雾剂的制备方法，包含以下步骤：
(1)将甜菜碱加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
上述眼外施用喷雾剂可以作为载体加入药理活性或者美容活性成分。
本发明所指的甜菜碱是指任何来源的甜菜碱，包括动植物组织提取分离而得、微生物发酵或者基因工程制备得到的等。
本发明所指的磷脂是指任何来源的磷脂，包括蛋黄或大豆中提取的磷脂，以及以合成或者半合成方法得到的磷脂，或者其组合。
具体实施方式
对比例1
制备方法：
(1)将透明质酸钠、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
对比例2
制备方法：
(1)将氯霉素、透明质酸钠、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
对比例3
Optrex眼用喷雾，每1ml包含大豆磷脂10mg，维生素A棕榈酸盐0.25mg，维生素E0.02mg，苯氧乙醇5mg，乙醇8mg，氯化钠8mg，其余为纯化水。
实施例1
制备方法：
(1)将甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例2
制备方法：
(1)将甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例3
制备方法：
(1)将甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例4
制备方法：
(1)将甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例5
制备方法：
(1)将甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例6
制备方法：
(1)将氯霉素、甜菜碱、氯化钠加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入蛋黄卵磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
实施例7
制备方法：
(1)甜菜碱、氯化钠、乙醇、苯氧乙醇加入纯化水中，高速剪切；
(2)在步骤(1)高速剪切的同时加入大豆磷脂；
(3)将步骤(2)所得混合物高压均质匀化；
(4)过滤，灌装。
测试例1家兔干眼症模型测试试验
实验动物和材料健康家兔56只，体重2.5-3.0kg，年龄4-5个月。手术摘除兔右眼泪腺、Harder腺和瞬膜后，用50％三氯醋酸涂抹距角膜缘3mm以外球结膜，制成兔干眼模型，术后第3周开始观察。将56只家兔随机分为7组，每组8只。
给药：一组为对照组，给予只含氯化钠、乙醇和纯化水的空白喷雾剂，其余六组试验组分别给予对比例1、实施例1-5的眼外施用喷雾剂。每只兔右眼每日给予3次，每次两喷，连用10天，每两天检查1次右眼角结膜SchirmerⅠ试验湿长及虎红染色情况，根据治疗10天后的数据评价疗效。
结果如下表1和表2所示：
表1不同时期SchirmerⅠ试验湿长比较
表2不同时期角结膜平均虎红着点数比较
根据上述实验结果可以发现，本发明实施例1(磷脂+甜菜碱)与对比例1(磷脂+海藻糖)的对比可以发现，本发明的眼外施用喷雾对于干眼症的治疗效果更好。根据实施例1-5的数据可以发现，本发明所制备的眼外施用喷雾对干眼症疗效很好，并且实施例2和3的效果更优。
测试例2透膜能力测试试验
使用鸡素囊膜测定实施例6以及对比例2所制得的含氯霉素的眼外施用喷雾剂透过生物膜的能力。
鸡素囊膜的处理：取新鲜鸡素囊，洗净，剥离脂肪层，浸泡于生理盐水中备用。
透过生物膜实验：采用透皮扩散池，取鸡素囊膜剪成适宜的大小，固定在供给室与接收室之间，在接收室中注入生理盐水使取样管液面略高于膜，记录加入的液量。开启磁力搅拌器和恒温油浴，保持恒速搅拌，37℃恒温，喷200μL喷雾剂溶液于供给室的鸡素囊膜面上，于5min、10min，30min从取样口吸取接收室溶液1ml进行测定，并在接收室中补充新鲜生理盐水1ml，将三次测定所取得样品采用高效液相法测定药物透过率。高效液相色谱柱：用十八烷基硅烷键合硅胶为填充剂；流动相A为0.01mol/L庚烷磺酸钠缓冲溶液(取磷酸二氢钾6.8g，用0.01mol/L庚烷磺酸铵溶液溶解并稀释至1000ml，再加三乙胺5ml，混匀，用磷酸调节pH值至2.5)，流动相B为甲醇；检测波长为277nm，按下表进行线性梯度洗脱。进样体积：10μl。
试验结果如下表3所示：
表3透膜能力测试结果
| 10min透膜率/％ | |
| 对比例1 | 37.5 |
| 实施例6 | 77.2 |
根据上述结果可以发现，本发明实施例6所制备的氯霉素眼外喷雾剂透过生物膜能力显著较强，在10min内透过率大于75％，有助于药物迅速进入眼部发挥疗效。
测试例3生物利用度研究
使用对比例2和实施例6的含氯霉素的眼外喷雾剂，每次两喷。参照聂绩等发表的文献《HPLC法测定氯霉素滴眼液在兔眼房水中的质量浓度》中的检测方法，考察其在家兔眼房水中的生物利用度，结果见下表4。
表4家兔眼房水中的药代动力学参数
| 组别 | Cmax(μg/ml) | AUC(min·μg/ml) |
| 对比例2 | 0.13 | 10.42 |
| 实施例6 | 0.35 | 26.11 |
根据上述结果可以发现，本发明制备的含氯霉素的眼外喷雾剂，具有更高的生物利用度。
测试例4起效延续时间研究
实验动物和材料健康家兔18只，体重2.5-3.0kg，年龄4-5个月。手术摘除兔右眼泪腺、Harder腺和瞬膜后，用50％三氯醋酸涂抹距角膜缘3mm以外球结膜，制成兔干眼模型，术后第3周开始观察。将18只家兔随机分为3组，每组6只。
给药：一组为对照组，给予只含氯化钠和纯化水的空白喷雾剂，其余两组试验组分别给予对比例3、实施例7的喷雾剂。每只兔右眼给予两喷后，在0.5h、1h、2h、3h、4h检查右眼角膜SchirmerⅠ试验湿长(每只兔在给药前测定的数据为0h数据)，记录试验结果。
根据上市试验结果可以发现，本发明实施例7的眼用喷雾对于干眼症的缓解可持续至4h，而对比例3的眼用喷雾对于干眼症的缓解仅能持续2h。
实施例8
实施例9
采用实施例8-9所制备的眼外施用喷雾剂，能够有效治疗干眼症，并在加入药理或美容活性物质时能够提高渗透率和生物利用度。
上述内容详细描述了本发明的优选实施方式。但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何方式进行组合。为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要不违背本发明的思想，其同样应当视为本发明所公开的内容。
Claims (10)
1.一种眼外施用喷雾剂，其特征在于，包含磷脂和甜菜碱。
2.根据权利要求1所述的眼外施用喷雾剂，其特征在于，还包含常规眼用制剂辅料和纯化水。
3.根据权利要求1所述的眼外施用喷雾剂，其特征在于，所述的磷脂含量为1-100mg/ml，甜菜碱含量为1-100mg/ml。
4.根据权利要求3所述的眼外施用喷雾剂，其特征在于，所述的磷脂含量为1-20mg/ml，甜菜碱含量为1-50mg/ml。
5.根据权利要求4所述的眼外施用喷雾剂，其特征在于，所述的磷脂含量为5-15mg/ml，甜菜碱含量为10-30mg/ml。
6.根据权利要求1所述的眼外施用喷雾剂，其特征在于，还包含防腐剂，选自苯扎溴铵、苯扎氯安、苯氧乙醇、羟苯甲酯、羟苯乙酯、羟苯丁酯、羟苯丙酯、苯氧乙醇、丁羟甲苯、苯甲酸钠、山梨酸钾、苯甲酸、氯苯甘醚、EDTA。
7.根据权利要求1所述的眼外施用喷雾剂，其特征在于，还包含抗氧剂，选自维生素E腺苷、视黄醇、生育酚乙酸酯、生育酚烟酸酯、棕榈酰五肽-4、谷胱甘肽、天冬氨酸。
8.根据权利要求1所述的眼外施用喷雾剂，其特征在于，还包含pH调节剂，选自磷酸缓冲对、硼酸缓冲对、碳酸缓冲对、盐酸、氢氧化钠、柠檬酸钠、氢氧化钾、氨丁三醇。
9.根据权利要求1-8任一所述的眼外施用喷雾剂的制备方法，包含以下步骤：
（1）将甜菜碱加入纯化水中，高速剪切；
（2）在步骤（1）高速剪切的同时加入磷脂；
（3）将步骤（2）所得混合物高压均质匀化；
（4）过滤，灌装。
10.根据权利要求1-9所述的眼外施用喷雾剂，其特征在于，所述的眼外施用喷雾剂可以作为载体加入药理活性或者美容活性成分。
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