CN113081953B - 一种局部用抗菌肽凝胶剂及其制备方法 - Google Patents
一种局部用抗菌肽凝胶剂及其制备方法 Download PDFInfo
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- A61P31/10—Antimycotics
Abstract
本发明公开了一种抗菌肽凝胶剂及其制备方法，其中抗菌肽氨基酸序列为KWKSFLKTFKSAAKTVLHTALKAISS。抗菌肽凝胶剂含抗菌肽(0.1％～1％)，羟丙甲纤维素E50(4％～9％)，二丁基羟基甲苯(0.005％～0.02％)，依地酸二钠(0.05％～0.5％)，丙二醇(5％～20％)，醋酸调节pH值至4.5～5.5。本发明提供的抗菌肽凝胶剂为局部外用抗感染药物，适用于致病菌尤其是耐药菌引起的各种皮肤及创面感染，该制剂制备工艺简单，给药方便，生物利用率高，应用前景广泛。
Description
技术领域
本发明涉及生物技术领域，具体而言，涉及一种局部用抗菌肽凝胶剂及其制备方法。
背景技术
水凝胶是以水为分散介质的凝胶。凡是水溶性或亲水性的高分子，通过一定的化学交联或物理交联，都可以形成水凝胶。水凝胶可以达到药物控释的作用，药物可以通过载体凝胶的孔隙渗透或者通过载体凝胶的逐渐分散扩散到指定的病灶处，这种渗透或扩散作用进行得较为缓慢，可使装载的药物以一定浓度持续的释放，从而延长药物作用时间而充分发挥药效并且可避免较高的给药频率。
CN 105534878 A公开了一种pH和氧化双响应性可注射超分子智能水凝胶的制备方法，其对pH和氧化还原环境敏感，能够作为亲水和疏水性药物的共同控释载体，可轻松完成注射。此外，CN 104274391 A公开了一种治疗腹泻的凝胶剂和口服乳，有利于药物口服、吸收，达到较高的生物利用度。CN108066278B公开了一种含有壳寡糖的妇科用凝胶及其制备方法，克服了药物对患处刺激性较大的技术不足。
抗菌肽是一类广泛存在于自然界生物体中的小肽类物质，是机体先天性免疫系统的重要组成部分。抗菌肽对细菌、真菌、寄生虫、病毒、肿瘤细胞等有着广泛的抑制作用，并且随着越来越多的抗生素耐药微生物的出现，使得抗菌肽在生物医药领域日益成为研究热点。抗菌肽用于抗菌研究的报道日益增加。CN100333789C(CN1583165A)公开了一种林蛙抗菌肽凝胶剂及其制备方法，针对抗菌镇痛药物及其制备领域，具有抑菌活性高，毒副作用小，给药方便，释药快，与皮肤粘附效果极佳。但林蛙抗菌肽凝胶剂中林蛙的比例占到了10％～40％。本发明的抗菌肽凝胶中抗菌肽的占比仅为0.1％～1％。
发明内容
本发明的目的是提供一种抗菌肽凝胶剂及其制备方法。以期望提供一种制备工艺简单、给药方便的局部用抗菌凝胶剂，解决细菌、真菌等日益严重的抗药性问题及顽固感染给广大患者带来的痛苦。
凝胶剂型涂展性好，易于清洗，透皮吸收速度快，同时又有一定的黏附性，性质温和，有利于药物的释放吸收。本发明结合抗菌肽的理化特性及凝胶剂的剂型特点，提供了一种局部用抗菌肽凝胶剂。
本发明所提供的抗菌肽凝胶剂，包括下述组分：抗菌肽、水溶性凝胶基质。
其中，所述抗菌肽为如下通式的多肽：
区段甲-Ⅰ-A-II-区段乙；
Ⅰ选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
II选自下述任意氨基酸残基：选自下述任意氨基酸残基：L-亮氨酸、D-亮氨酸、L-缬氨酸、D-缬氨酸、L-丙氨酸、D-丙氨酸、甘氨酸、L-丝氨酸、D-丝氨酸、L-赖氨酸及D-赖氨酸(L-和D-光学异构形式的L、A、S、V和K，以及G)；
区段甲如SEQ ID No：1所示，其序列为：KWKSFLKTFK；
区段乙如SEQ ID No：2所示，其序列为：KTVLHTALKAISS；
A代表丙氨酸残基；
所述通式中，方向为自N端至C端。
优选的，所述抗菌肽为NAL以及D-NAL。
所述NAL具有SEQ ID No：3的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS；
所述D-NAL具有SEQ ID No：4的序列，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS(除了第13位的A为L构型外，所有氨基酸都是D-构型)。
所述水溶性凝胶基质选自甲基纤维素、羟丙甲基纤维素衍生物(如羟丙甲纤维素E50)、泊洛沙姆(如泊洛沙姆188)、明胶中的一种或几种，优选羟丙甲纤维素E50。
进一步的，所述抗菌肽凝胶剂，按质量百分含量计，包括下述组分：抗菌肽0.1％～1％、水溶性凝胶基质4％～9％。
进一步的，所述抗菌肽凝胶剂还可包括下述至少一种组分：抗氧剂、促渗透剂和保湿剂。
进一步的，所述抗菌肽凝胶剂，按质量百分含量计，包括下述组分：抗菌肽0.1％～1％、水溶性凝胶基质4％～9％、抗氧剂0.005％～0.02％、促渗透剂0.05％～0.5％、保湿剂5％～20％。
进一步的，所述抗菌肽凝胶剂还可包括pH调节剂，调节所述抗菌肽凝胶剂的pH值至4.5～5.5。
本发明中所述抗氧剂可选自亚硫酸钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基羟基甲苯等中的一种或几种，优选二丁基羟基甲苯；
本发明中所述促渗透剂可选自依地酸二钠、吐温-80、月桂氮酮等中的一种或几种，优选依地酸二钠；
本发明中所述保湿剂可选自甘油、丙二醇等中的一种或几种，优选丙二醇；
本发明中所述pH调节剂可选自选自枸橼酸、醋酸、磷酸中的一种或几种，优选醋酸。
具体的，所述抗菌肽凝胶剂，按质量百分含量计，包括下述组分：抗菌肽0.5～1％、羟丙甲纤维素E50 5％～9％、二丁基羟基甲苯0.01％～0.02％、丙二醇5～10％、依地酸二钠0.2％～0.3％；调节所述抗菌肽凝胶剂的pH值至4.5～5.5。
本发明还提供了上述抗菌肽凝胶剂的制备方法。
本发明所提供的抗菌肽凝胶剂的制备方法，包括下述步骤：
首先将水溶性凝胶基质加水混合充分溶胀；取适量水加入促渗透剂，抗氧剂溶解，再加入抗菌肽充分溶解；加入保湿剂，搅拌溶解；将上述各溶液混合，用pH调节剂调节pH值至4.5～5.5。
本发明提供的抗菌肽凝胶剂为局部外用抗感染药物，适用于致病菌尤其是耐药菌引起的各种皮肤及创面感染，该制剂制备工艺简单，给药方便，生物利用率高，应用前景广泛。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
下述实施例中使用的抗菌肽的序列(具有SEQ ID No：3的序列)能够通过人工合成。
下述实施例中的“％”均为质量百分含量。
实施例1抗菌肽凝胶剂基质筛选
常用的水溶性凝胶基质包括甲基纤维素、羟丙甲基纤维素衍生物、泊洛沙姆、明胶等，选择7％的羟丙甲纤维素E50和5％泊洛沙姆188作为凝胶基质，分别制备凝胶基质与水混合形成的凝胶，考察凝胶的成型性、均匀性以及黏度(采用MR101流变仪测定)等，结果见表1。
表1抗菌肽凝胶空白基质筛选
| 基质 | 成型情况 | 均匀性 | 黏度 |
| 7％羟丙甲纤维素 | 形成凝胶 | 均匀 | 适中 |
| 5％泊洛沙姆188 | 形成凝胶 | 略不均匀 | 偏高 |
由表1可见，选择7％羟丙甲纤维素E50作为凝胶基质能够形成质量较好的凝胶。
实施例2、抗菌肽凝胶剂抗氧剂筛选
选择二丁基羟基甲苯(0.02％)，硫代硫酸钠(0.1％)等作为抗氧剂，分别制备抗菌肽凝胶(抗菌肽浓度为0.5％，7％羟丙甲纤维素E50作为凝胶基质)，考察抗菌肽凝胶的稳定性，检测指标包括有关物质(总杂)和含量。
1)有关物质：照高效液相色谱法(中国药典2020版二部附录V D)试验，用十八烷基硅烷键合硅胶为填充剂，取溶液20μL注入液相色谱仪，记录色谱图。有关物质及限度：面积归一化法总杂质不得超过3.0％。
2)含量：照高效液相色谱法(中国药典2020版四部通则0512)测定，精密量取本品适量，加水溶解并定量稀释制成每1ml中含0.25mg的溶液，作为供试品溶液，精密量取10μl注入液相色谱仪，记录色谱图；另取适量抗菌肽原料药作为对照品，同法测定。
表2抗菌肽凝胶稳定性考察结果
由表2可知，选择二丁基羟基甲苯(0.02％)，硫代硫酸钠(0.1％)作为抗氧剂，可以保证抗菌肽凝胶在25℃条件下放置3个月，抗菌肽含量的仍在96％以上。优选二丁基羟基甲苯(0.02％)作为抗氧剂。
实施例3、抗菌肽凝胶剂pH值考察
分别选择醋酸(0.01M)作为pH调节剂，考察不同pH值抗菌肽凝胶剂的稳定性，下表各抗菌肽组合物缓冲体系中抗菌肽的质量浓度均为0.5％，7％羟丙甲纤维素E50作为凝胶基质。
表3不同pH值抗菌肽凝胶剂的稳定性考察结果
由表3可知，抗菌肽凝胶剂体系pH值在3.5～6.5之间，均可以保证抗菌肽组合物能够在3个月(25℃条件)抗菌肽的含量仍具有97％以上。考虑到局部用药，优选pH值在4.5～5.5。
实施例4、抗菌肽凝胶剂保湿剂筛选
选择甘油(10％)，丙二醇(10％)等作为保湿剂，分别制备抗菌肽凝胶(抗菌肽浓度为0.5％，7％羟丙甲纤维素E50作为凝胶基质)，考察抗菌肽凝胶的稳定性，检测指标包括有关物质(总杂)和含量。
表4不同保湿剂抗菌肽凝胶剂的稳定性考察结果
由表4可知，选择甘油(10％)，丙二醇(10％)等作为保湿剂，可以保证抗菌肽凝胶在25℃条件下放置3个月，抗菌肽含量的仍在97％以上。优选丙二醇作为保湿剂。
实施例5
一种抗菌肽凝胶剂，非无菌制剂，其成分组成及质量含量占比如下：
首先将羟丙甲纤维素E50加水混合充分溶胀；取适量水加入依地酸二钠，二丁基羟基甲苯溶解，再加入抗菌肽充分溶解，加入丙二醇，搅拌溶解；将上述各溶液混合，醋酸调节pH值至4.5～5.5，纯化水补足至100％。
实施例6
一种抗菌肽凝胶剂，无菌制剂，其成分组成及含量占比如下：
首先将羟丙甲纤维素E50加水混合充分溶胀；取适量水加入依地酸二钠，二丁基羟基甲苯溶解，再加入抗菌肽充分溶解，加入丙二醇，搅拌溶解；将上述各溶液混合，枸橼酸调节pH值至4.5～5.5，纯化水补足至100％。
实施例7
一种抗菌肽凝胶剂，无菌制剂，其成分组成及含量占比如下：
首先将羟丙甲纤维素E15加水混合充分溶胀；取适量水加入依地酸二钠，二丁基羟基甲苯溶解，再加入抗菌肽充分溶解；加入丙二醇，搅拌溶解；将上述各溶液混合，醋酸调节pH值至4.5～5.5，纯化水补足至100％。
抗菌肽凝胶剂质量评价方法：
1)有关物质：照高效液相色谱法(中国药典2010年版二部附录V D)试验，用十八烷基硅烷键合硅胶为填充剂，取溶液20μL注入液相色谱仪，记录色谱图。有关物质及限度：面积归一化法总杂质不得超过3.0％。
2)含量：照高效液相色谱法(中国药典2015年版四部通则0512)测定，精密量取本品适量，加水溶解并定量稀释制成每1ml中含0.25mg的溶液，作为供试品溶液，精密量取10μl注入液相色谱仪，记录色谱图；另取抗菌肽(原料药作为对照品)适量，同法测定。
以实施例5制剂及实施例7制剂进行了稳定性考察，结果见表5。
表5抗菌肽凝胶剂(4℃条件下)稳定性考察结果
由表5可见，实施例5和实施例7处方在4℃条件下，在12个月内抗菌肽的含量均能够维持在98％以上。
实施例8：抗菌肽凝胶抗皮肤感染试验
ICR小鼠，20±2g，雄性。按体重随机分组。每组10只，共5组，分为模型组，实施例5凝胶基质对照组，左氧氟沙星凝胶阳性对照组，抗菌肽凝胶(实施例5)组。普通级动物房饲养，喂以普通饲料，自由摄水，光照12小时明暗交替。
试验菌株：金黄色葡萄球菌CMCC(B)26003。
制剂：抗菌肽凝胶(实施例5)，凝胶基质(实施例5对应的凝胶基质)，左氧氟沙星凝胶(0.5％制剂，山东方明药业集团股份有限公司)。
方案：(1)取保存于液氮的金黄色葡萄球菌菌株接种于血液平板，37℃过夜培养。
(2)次日将生长于血平板的单个菌落接种于MH液体培养基中，于控温摇床中37℃震荡培养1h。
(3)将被测定菌液与0.5麦氏比浊标准液比色，稀释至5×106CFU/ml备用。
(4)皮肤造模：将小鼠背部剪毛，脱毛膏脱毛，待毛全部褪去后，用600目砂纸打磨至渗血。渗血皮肤皮下注射浓度为5×106CFU/ml的菌液，0.05ml。
(5)给药：左氧氟沙星凝胶(0.5％制剂，山东方明药业集团股份有限公司)给药0.1ml，抗菌肽凝胶及实施例5的凝胶基质给药剂量均为50mg，每天早晚各外用1次，连续3天一疗程。
(6)3天后，无菌取感染部位皮肤，按体积1:10稀释并研磨匀浆，取20μl涂皿，检测活菌并计数统计。
结果：感染皮肤检测结果见表6。
表6抗菌肽凝胶对金葡菌皮肤感染影响
| 组别 | 药物 | 抑菌率(％) |
| 模型组 | -- | -- |
| 基质对照 | 实施例5空白凝胶基质 | -- |
| 阳性对照 | 0.5％左氧氟沙星凝胶 | 99.58 |
| 抗菌肽凝胶(实施例5) | 5‰抗菌肽凝胶 | 89.67 |
由表6可知，抗菌肽凝胶与基质对照组以及模型组相比较效果明显，对抗金黄色葡萄球菌皮肤感染效果较好。
序列表
<110> 江苏普莱医药生物技术有限公司
<120> 一种局部用抗菌肽凝胶剂及其制备方法
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Claims (1)
1.一种局部用抗菌肽凝胶剂，其特征在于，所述抗菌肽凝胶剂按质量百分含量计，包括下述组分：抗菌肽0.5％、羟丙甲纤维素E50 7％、二丁基羟基甲苯0.02％、丙二醇10％、依地酸二钠0.3％；醋酸调节所述抗菌肽凝胶剂的pH值至4.5～5.5；
所述抗菌肽为NAL；所述NAL如SEQIDNo：3所示，其氨基酸序列为：KWKSFLKTFKSAAKTVLHTALKAISS；
所述的局部用抗菌肽凝胶剂的制备方法，包括下述步骤：
首先将羟丙甲纤维素E50加水混合充分溶胀；取适量水加入依地酸二钠，二丁基羟基甲苯溶解，再加入抗菌肽充分溶解，加入丙二醇，搅拌溶解；将上述各溶液混合，醋酸调节pH值至4.5~5.5，纯化水补足至100%。
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