CN112755175B - 一种抗菌肽液体组合物及其制剂 - Google Patents
一种抗菌肽液体组合物及其制剂 Download PDFInfo
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- CN112755175B CN112755175B CN202110068276.3A CN202110068276A CN112755175B CN 112755175 B CN112755175 B CN 112755175B CN 202110068276 A CN202110068276 A CN 202110068276A CN 112755175 B CN112755175 B CN 112755175B
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Abstract
本发明提供了一种抗菌肽组合物,其中抗菌肽氨基酸序列为KWKSFLKTFaAbKTVLHTALKAISS,其中,a和b取代位点选自下述任意氨基酸;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,至少一种稳定剂和抗菌肽稳定的缓冲体系(优选磷酸氢二钠与枸橼酸),所述组合物的pH值为3.5~5.5。抗菌肽组合物为局部外用广谱抗感染药物,适用于致病菌尤其是耐药菌引起的各种原发性皮肤感染,以及湿疹合并感染、溃疡合并感染等继发性皮肤感染,包括糖尿病足、烧伤创面感染、褥疮感染等顽固感染性疾病,具有广泛的应用前景。
Description
技术领域
本发明涉及生物技术领域,具体而言,涉及一种抗菌肽液体组合物及其制剂。
背景技术
抗菌药物主要包括抗生素类以及合成抗细菌药物。上世纪二三十年代以来,抗生素的发现和应用拯救了无数人的生命。抗生素是由细菌或其他微生物在生活过程中所产生的物质,具有抑制或杀灭细菌、螺旋体、支原体、衣原体等致病微生物的作用。已上市的抗生素主要包括β-内酰胺类,大环内酯类,多糖类(万古霉素,替考拉宁),氨基糖苷类,四环素类,氯霉素类,肽内酯类(达托霉素)等。
如果早前人类因其受益,那么,如今全世界则不得不致力解决抗生素滥用所导致的后果——耐药细菌的出现及传播。超级细菌产生的对抗生素不敏感现象,“超级细菌”之外还有“超超级细菌”,随着一个个“超级细菌”被发现,耐药细菌的阵容愈发强大。
抗生素替代品的研发已成为生物医药领域的热点话题。其中,抗菌肽因其对细菌具有广谱高效杀菌活性,且又不易产生耐药性而成为抗生素替代品的“希望之星”。已报道细胞膜是抗菌肽的主要靶点,抗菌肽分子在细胞膜上的聚集会导致细胞膜的通透性增加,使细胞膜丧失其屏障功能。微生物产生对抗菌肽的抗药性需要对微生物细胞膜脂成分产生实质性改变。
抗菌肽是生物体内经诱导产生的一种具有生物活性的小分子多肽,分子量在2000~7000左右,由20~60个氨基酸残基组成。按照来源,抗菌肽可分为:植物抗菌肽,动物抗菌肽,细菌抗菌肽(又称细菌素,包括阳离子肽和中性肽,革兰氏阳性菌和革兰氏阴性菌均可分泌)以及人源性抗菌肽等。
2013年11月,中科院昆明动物研究所研究员张云课题组发现,天然抗菌肽具有选择性免疫激活和调节功能,对败血症有良好的预防和治疗作用。
另有文献报道,人源性抗菌肽具有广谱抗菌作用,可调节创伤炎症,促进创伤部位血管生成及其上皮组织再生。在人体创伤愈合过程中,抗菌肽是内生型免疫系统的关键信号分子之一,与各类细胞及各种生长因子相互作用,协调达到平衡状态,实现创伤修复。
CN101111256A公开了抗菌肽NAL以及D-NAL的氨基酸序列Ac-Lys-Trp-Lys-Ser-Phe-Leu-Lys-Thr-Phe-Lys-Ser-Ala-Ala-Lys-Thr-Val-Leu-His-Thr-Ala-Leu-Lys-Ala-Ile-Ser-Ser-NH2。该抗菌肽具有抗微生物活性、期望的溶血活性水平及针对革兰氏阳性细菌和革兰氏阴性细菌以及其它带有脂双层膜的细胞成分或结构组分的微生物的广谱治疗系数。
蛋白质类药物制剂的主要问题是药物稳定性差。改善蛋白类药物的稳定性,很容易可以想到通过将蛋白类药物制备成无菌冻干粉末,从而增强蛋白类药物的稳定性。针对液体组合物,可通过加入辅料(稳定剂)如多元醇(如山梨醇、甘露醇、甘油以及丙二醇等)、糖类(如乳糖、胶质、糊精、葡萄糖和海藻糖等)、氨基酸(如甘氨酸、丝氨酸、谷氨酸和赖氨酸等)、盐类(如枸橼酸盐,醋酸盐和磷酸盐等)、表面活性剂等,从而增加其稳定性。但是冻干制剂存在处方、工艺复杂的缺陷,因此如果能提供稳定的蛋白类液体制剂将具有重要的意义。
发明内容
本发明旨在提供一种抗菌肽液体组合物,以期望解决细菌等日益严重的抗药性问题及顽固感染对广大患者造成的痛苦。
本发明所提供的抗菌肽液体组合物,包括抗菌肽、至少一种稳定剂以及缓冲体系;所述组合物中所述抗菌肽的质量浓度为0.1‰~10‰;所述稳定剂的质量浓度为0.5%~5%,所述缓冲体系为磷酸盐缓冲体系或醋酸盐缓冲体系。
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)。
在抗菌肽名称中,大写母D-(非下标)表示除特指位点外,该抗菌肽全部由D-型氨基酸所组成(例如:D-NAL代表该抗菌肽除了含有非极性表面中心的L-丙氨酸取代之外全部由D-型氨酸所组成,非极性表面用大写字母N代表)。
优选的,抗菌肽的浓度为0.5‰~6‰,更优选1‰~4‰,进一步优选为1‰~2‰,具体可为0.2‰、0.5‰、1‰、2‰。
优选的,所述缓冲体系为磷酸氢二钠-枸橼酸的缓冲体系,其中,所述组合物中缓冲体系的离子浓度为0.01M~0.1M,优选离子浓度为0.01M~0.02M,更优选离子浓度为0.015M。
优选的,所述组合物的pH值为3.5~5.5,具体如3.5、4.5或5.5。
本发明中所述稳定剂可选自下述至少一种:多元醇(如山梨醇、甘露醇、甘油以及丙二醇等)、糖类(如乳糖、胶质、糊精、葡萄糖和海藻糖等)、氨基酸(如甘氨酸、丝氨酸、谷氨酸和赖氨酸等)、盐类(如枸橼酸盐,醋酸盐和磷酸盐等)、表面活性剂等,不仅使抗菌肽稳定,且能够维持抗菌肽的抑菌能力。
优选的,所述稳定剂为甘露醇,其中,所述抗菌肽液体组合物中甘露醇的浓度为0.5%~5%,优选甘露醇的浓度为1%~2%,更优选甘露醇的浓度为1%,具体如0.5%、1%、1.25%、1.5%或5%。
稳定性试验表明,本发明提供的抗菌肽组合物至少在24个月内稳定(4℃条件);
本发明提供的抗菌肽组合物主要适用于治疗皮肤感染性疾病。喷雾剂用药相比凝胶剂和乳膏剂等可有效避免与皮肤创面直接接触,直接作用于病变部位,减少了全身的毒性反应,且稳定性好,易吸收,提高了临床用药的安全性和顺应性,更适于临床需要。
因此,本发明提供的组合物制剂形式为液体制剂,其剂型可为喷雾剂、溶液剂、凝胶剂、乳剂、溶胶剂、滴剂、糖浆剂、混悬剂、口服液、洗剂或擦剂等,优选为喷雾剂。
本发明还提供了上述抗菌肽液体组合物的制备方法。
进一步的,本发明外用组合物制备方法简单,选择各组合物所需的原辅料,按照现有技术中公开的各剂型的常规制备方法制备即可。
本发明所提供的抗菌肽液体组合物的制备方法包括下述步骤:
1)量取70~90%用量的注射用水,分别加入形成所述缓冲体系的物质,搅拌至溶解;再将稳定剂加入上述溶液中,搅拌至全部溶解;
2)称取抗菌肽加入步骤1)的溶液中,搅拌溶解,注射用水补至全量,即得。
所述方法还包括用0.22微米的微孔滤膜过滤上述抗菌肽液体组合物的步骤。
根据本发明的一个实施例,公开了一种喷雾制剂的具体制备方式,采用上述方法制备得到抗菌肽液体组合物后,以5ml/瓶灌装于喷雾瓶中,旋紧喷雾泵,得到抗菌肽喷雾剂。
本发明中采用的抗菌肽是以破坏细菌细胞膜,从而达到杀灭细菌效用的全新广谱抗感染药物,具有独特的药理作用和强效的杀菌效果,使其不同于传统的抗生素,不易产生耐药性,同时和传统的抗生素基本没有交叉耐药现象,是解决病菌耐药性问题非常有效的途径和方法。
蛋白质类药物制剂的主要问题是药物稳定性差。改善蛋白类药物的稳定性,很容易可以想到通过将蛋白类药物制备成无菌冻干粉末,从而增强蛋白类药物的稳定性。针对液体组合物,可通过加入辅料(稳定剂)如多元醇(如山梨醇、甘露醇、甘油以及丙二醇等)、糖类(如乳糖、胶质、糊精、葡萄糖和海藻糖等)、氨基酸(如甘氨酸、丝氨酸、谷氨酸和赖氨酸等)、盐类(如枸橼酸盐,醋酸盐和磷酸盐等)、表面活性剂等,从而增加其稳定性。无疑蛋白类液体组合物的稳定性相比冻干粉末的稳定性更难以保证。本发明着重解决抗菌肽液体组合物的稳定性。
本发明的研究团队发现,与其它稳定剂(如甘油、乳糖、甘氨酸)相比,甘露醇能显著增加抗菌肽的稳定性。
本发明的研究团队发现,酸性pH缓冲体系能使抗菌肽更加稳定,缓冲体系可考虑磷酸盐缓冲体系(如磷酸氢二钠+枸橼酸,或者磷酸氢二钠+磷酸二氢钠,等),醋酸盐缓冲体系(如醋酸钠+磷酸,或者醋酸钠+醋酸,等),枸橼酸缓冲体系(如枸橼酸钠+醋酸,或者枸橼酸钠+枸橼酸,等),结合抗菌肽的稳定性及抑菌试验,优选磷酸盐缓冲体系和醋酸盐缓冲体系(包含磷酸氢二钠、枸橼酸、醋酸钠、冰醋酸),更优选磷酸氢二钠与枸橼酸组成的缓冲体系。
本发明的组合物中,缓冲体系的离子浓度对抗菌肽的稳定性也存在一定的影响,发明人研究发现缓冲体系的离子浓度为0.01M~0.1M,优选离子浓度为0.01M~0.02M,更优选离子浓度为0.015M。
本发明涉及的抗菌肽喷雾剂,表现出良好的生物利用度及使用安全性;能够减弱对皮肤和/或创面的刺激性;具有高稳定性,在长期覆盖创面中可改善创面的微环境抑制细菌的生长;使创伤快速修复;能促进愈合,缩短伤口愈合时间,在临床创伤护理应用领域前景广泛。
本发明的抗菌肽组合物可用于制备局部外用广谱抗感染药物制剂,适用于致病菌包括耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林敏感金黄色葡萄球菌(MSSA)、化脓性链球菌红霉素耐药和敏感株、铜绿假单胞菌IPM-R和IPM-S株,尤其是耐药菌引起的各种原发性皮肤感染,以及湿疹合并感染、溃疡合并感染等继发性皮肤感染,包括糖尿病足、烧伤创面感染、褥疮感染等顽固感染性疾病,具有广泛的应用前景。
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。
实施例1、抗菌肽组合物稳定剂筛选
选择甘露醇,甘油,乳糖和甘氨酸等作为抗菌肽的稳定剂,分别制备抗菌肽组合物水溶液(抗菌肽浓度为2‰),考察抗菌肽组合物的稳定性,检测指标包括性状、有关物质(最大单杂及总杂)、含量等。
有关物质检测方法:
照高效液相色谱法(中国药典2015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:已知杂质A、B、C、D及未知单杂,每个杂质都不得超过1.0%,最大单杂以所有单个杂质的最大值进行汇总统计;总杂包括杂质A,B,C和D以及其他未知单杂的总和,总杂质不得超过3.0%。
下表中:抗菌肽(2‰)+甘露醇(1%)组合物;
抗菌肽(2‰)+甘油(1%)组合物;
抗菌肽(2‰)+乳糖(1%)组合物;
抗菌肽(2‰)+甘氨酸(1%)组合物。
表1抗菌肽组合物(25℃条件下)考察结果
表2抗菌肽组合物(4℃条件下)试验考察结果
由表1和表2抗菌肽组合物稳定性考察结果可知,甘露醇(1%)作为抗菌肽的稳定剂,可以保证抗菌肽组合物溶液能够在36个月(4℃条件)抗菌肽的含量仍具有97%以上。
考虑到不同抗菌肽浓度在不同甘露醇体系的稳定性,进一步考察了不同抗菌肽浓度(2‰和0.2‰)在不同甘露醇(0.5%~5%)体系的稳定性,结果见表3。
表3不同甘露醇体系抗菌肽组合物的稳定性考察结果
由表3可知,当抗菌肽浓度为2‰时,组合物体系中甘露醇浓度为0.5%时,抗菌肽组合物溶液在6个月(25℃条件)抗菌肽的含量为97.55%;当组合物体系中甘露醇浓度达到1%以上时,抗菌肽组合物溶液在6个月(25℃条件)抗菌肽的含量可保持在98%以上。故而优选甘露醇浓度为1%。
实施例2抗菌肽组合物缓冲体系及缓冲体系的摩尔浓度考察
抗菌肽组合物缓冲体系按照下表组合考察,下表各抗菌肽组合物缓冲体系中抗菌肽的质量浓度均为4‰。
表4抗菌肽组合物缓冲体系
表5抗菌肽组合物缓冲体系试验考察结果
由表5可知,选择磷酸氢二钠与枸橼酸缓冲体系,可以保证抗菌肽组合物溶液能够在3个月(25℃条件)抗菌肽的含量仍具有98%以上。因此,磷酸氢二钠与枸橼酸缓冲体系为优选的缓冲体系。
针对优选的磷酸氢二钠与枸橼酸缓冲体系,考察缓冲体系离子浓度(0.01M~0.1M)对抗菌肽稳定性的影响,考察结果见表6。
表6缓冲体系离子浓度对抗菌肽稳定性的影响
由表6可知,缓冲体系离子浓度对抗菌肽组合物溶液稳定性的考察结果可见,离子浓度约为0.015M,可以保证抗菌肽组合物溶液能够在3个月(25℃条件)抗菌肽的含量仍具有98%。
实施例3、抗菌肽组合物pH值考察
选择甘露醇(1%)作为稳定性,磷酸氢二钠与枸橼酸作为缓冲体系(0.015M)配制不同pH值(3.0,3.5,4.5,5.5,6.5)抗菌肽(2‰)组合物溶液,考察抗菌肽组合物在不同pH值条件下的稳定性,结果见表7。
同时选择盐酸作为pH调节剂,调节抗菌肽水溶液的pH值至4.5,考察抗菌肽的稳定性,并与磷酸氢二钠与枸橼酸作为缓冲体系的抗菌肽组合物溶液进行对比,结果见表8。
表7组合物pH值对抗菌肽稳定性的影响
表8不同pH调节剂对抗菌肽稳定性的影响(pH4.5)
由表7和表8可知,抗菌肽组合物在pH值3.5~5.5条件下,可以保证抗菌肽组合物溶液能够在3个月(25℃条件)抗菌肽的含量仍具有98%以上。当以盐酸调节抗菌肽水溶液pH值为4.5时,在3个月(25℃条件)抗菌肽水溶液中抗菌肽的含量已下降至95%以下。
实施例4抗菌肽喷雾组合物
(1)处方
处方1、处方组成
处方2、处方组成
处方3、处方组成
处方4、处方组成
处方5、处方组成
处方6、处方组成
(2)制备工艺
①量取70~90%处方量的注射用水,分别加入处方量磷酸氢二钠和枸橼酸,搅拌15分钟,搅拌至溶解;再将处方量甘露醇加入上述溶液中,搅拌10分钟,至全部溶解。
②称取处方量的抗菌肽加入上述溶液中,搅拌溶解,注射用水补至全量。
③用0.22微米的微孔滤膜过滤,取样测定中间体性状、含量、pH值等。
以5ml/瓶灌装于喷雾瓶中,旋紧喷雾泵,得到抗菌肽喷雾剂。
灌装后将抽取适量的成品按照质量标准项下各检测方法进行检验。
(3)质量要求
1)有关物质:照高效液相色谱法(中国药典2015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:已知杂质A、B、C、D及未知单杂,每个杂质都不得超过1.0%;总杂包括杂质A,B,C、D以及其他未知单杂的总和,总杂质不得超过3.0%。
2)pH:应符合规定pH 3.5~5.5。
3)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;另取抗菌肽对照品适量,同法测定。
以处方1及处方6进行了稳定性考察,结果见表9。
表9抗菌肽组合物(25℃条件下)考察结果
由表9可见,处方1和处方6在25℃条件下,在6个月内抗菌肽的含量均能够维持在98%以上。
(4)体外抑菌和杀菌试验
测试抗菌肽组合物(处方2与处方4)对耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林敏感金黄色葡萄球菌(MSSA)、耐甲氧西林凝固酶阴性葡萄球菌(MRSCNS)和甲氧西林敏感凝固酶阴性葡萄球菌(MSSCNS)临床分离菌株的体外抑菌作用和杀菌效力。对照药为万古霉素。结果见表10和表11。
试验菌株:
标准株:金黄色葡萄球菌ATCC29213(来源于江苏省人民医院临床检验中心,南京皮肤研究所保存);
临床株:MRSA、MSSA、MRSCNS、以及MSSCNS株均来源于江苏省人民医院临床检验中心,南京皮肤研究所保存。
表10抗菌肽和万古霉素对金黄色葡萄球菌、凝固酶阴性葡萄球菌的体外抑菌作用
表11抗菌肽和万古霉素对金黄色葡萄球菌、凝固酶阴性葡萄球菌的体外杀菌作用
(5)体内药效试验
选择临床上局部皮肤细菌感染中最常见的金黄色葡萄球菌和化脓性链球菌以及临床顽固性感染中常见的铜绿假单胞菌作为感染菌,分别通过小鼠皮肤局部感染或轻度破损感染,建立包括MRSA(耐甲氧西林金黄色葡萄球菌)、MSSA(甲氧西林敏感金黄色葡萄球菌)、化脓性链球菌红霉素耐药和敏感株、铜绿假单胞菌IPM-R和IPM-S株临床株的局部皮肤感染模型[1~3],并以0.5%氧氟沙星凝胶作对照药,溶媒组(1%的甘露醇,0.015M的磷酸氢二钠与枸橼酸的缓冲体系,pH4.5)作为阴性对照组,定量评价抗菌肽喷雾剂对上述菌株局部皮肤感染的药效。结果见表12~14。
试验菌株均来源于江苏省人民医院临床检验中心,南京皮肤研究所保存,菌株代码由南京皮研所编制。
1‰(处方1),0.5‰(处方4)和0.2‰抗菌肽喷雾剂(处方6)对金黄色葡萄球菌(MRSA和MSSA)、化脓性链球菌(红霉素敏感和耐药株)引起的小鼠局部皮肤感染有明显的抑制作用。1‰抗菌肽喷雾剂对铜绿假单胞菌(IPM-R和IPM-S)引起的小鼠局部皮肤感染亦有抑制作用(抗菌肽组抑制率的计算=[1-(给药组匀浆中的菌液浓度/溶媒组匀浆中的菌液浓度)]×100%;氧氟沙星凝胶组抑制率的计算=[1-(给药组匀浆中的菌液浓度/模型组匀浆中的菌液浓度)]×100%)。通过对治疗后的抑菌率统计汇总,表明达到相同的治疗效应情况下,抗菌肽的给药量远远低于氧氟沙星。
表12-1抗菌肽喷雾剂治疗小鼠浅表皮肤局部感染MRSA后皮损匀浆培养计算抑制率结果
表12-2抗菌肽喷雾剂治疗小鼠浅表皮肤局部感染MSSA后皮损匀浆培养计算抑制率结果
表13抗菌肽喷雾剂治疗小鼠局部皮肤感染化脓性链球菌后皮损匀浆培养计算抑制率结果
表14-1抗菌肽喷雾剂治疗小鼠局部皮肤感染IPM-R后皮损匀浆培养计算抑制率结果
表14-2抗菌肽喷雾剂治疗小鼠局部皮肤感染IPM-S后皮损匀浆培养计算抑制率结果
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参考文献:
1、单纯性和复杂性皮肤感染抗菌药物临床研究指导原则,1998年7月美国FDA发布,2009年药审中心组织翻译
2、徐叔云等。药理实验方法学。人民卫生出版社,2006,11,第三版
3、新药(西药)临床前研究指导原则汇编,中华人民共和国卫生部药政局,1993.7
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<400> 3
Lys Trp Lys Ser Phe Leu Lys Thr Phe Lys Ser Ala Ala Lys Thr Val
1 5 10 15
Leu His Thr Ala Leu Lys Ala Ile Ser Ser
20 25
<210> 4
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Lys Trp Lys Ser Phe Leu Lys Thr Phe Lys Ser Ala Ala Lys Thr Val
1 5 10 15
Leu His Thr Ala Leu Lys Ala Ile Ser Ser
20 25
Claims (2)
1.一种抗菌肽喷雾组合物,其特征在于,所述组合物的组成为:抗菌肽5.00g、甘露醇50.00g、磷酸二氢钠5.47g、枸橼酸6.46g,注射用水加至5000ml;所述抗菌肽为NAL,所述NAL如SEQIDNo:3所示,其氨基酸序列为:KWKSFLKTFKSAAKTVLHTALKAISS;所述组合物的pH值为3.5~5.5。
2.如权利要求1所述的组合物在制备局部外用广谱抗感染产品中的应用;所述产品为药品;所述感染由下述至少一种致病菌引起:耐甲氧西林金黄色葡萄球菌、甲氧西林敏感金黄色葡萄球菌、化脓性链球菌红霉素耐药株、化脓性链球菌红霉素敏感株、铜绿假单胞菌IPM-R和IPM-S株。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101111256A (zh) * | 2004-12-15 | 2008-01-23 | 科罗拉多大学 | 抗菌肽及其使用方法 |
CN101570569A (zh) * | 2008-04-29 | 2009-11-04 | 昆山博青生物科技有限公司 | 合成抗菌肽、其制备方法及应用 |
CN102219831A (zh) * | 2011-04-18 | 2011-10-19 | 江阴普莱医药生物技术有限公司 | 一种抗菌肽及其制备方法和应用 |
KR20130104718A (ko) * | 2012-03-15 | 2013-09-25 | 조선대학교산학협력단 | 미더덕 유래 항균 펩타이드의 신규한 유사체 및 이의 용도 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101111256A (zh) * | 2004-12-15 | 2008-01-23 | 科罗拉多大学 | 抗菌肽及其使用方法 |
CN101570569A (zh) * | 2008-04-29 | 2009-11-04 | 昆山博青生物科技有限公司 | 合成抗菌肽、其制备方法及应用 |
CN102219831A (zh) * | 2011-04-18 | 2011-10-19 | 江阴普莱医药生物技术有限公司 | 一种抗菌肽及其制备方法和应用 |
KR20130104718A (ko) * | 2012-03-15 | 2013-09-25 | 조선대학교산학협력단 | 미더덕 유래 항균 펩타이드의 신규한 유사체 및 이의 용도 |
Non-Patent Citations (1)
Title |
---|
Functional synergy of α-helical antimicrobial peptides and traditional antibiotics against Gram-negative and Gram-positive bacteria in vitro and in vivo;Q. Feng 等;《Eur J Clin Microbiol Infect Dis》;第34卷;摘要、表1 * |
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