CN114887037B - 治疗糖尿病足溃疡的双相喷雾剂 - Google Patents
治疗糖尿病足溃疡的双相喷雾剂 Download PDFInfo
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Abstract
本发明提供了治疗糖尿病足溃疡的双相喷雾剂，是由携载酸性成纤维细胞生长因子(aFGF)的水凝胶和携载氧气的全氟化碳溶液组成，全氟化碳溶液是以乳剂形式均匀分散于水凝胶中。本发明的治疗糖尿病足溃疡的双相喷雾剂使用方便，经定位喷雾后立即呈凝胶状态，形成物理保护层，有利于协同发挥aFGF和氧气对于糖尿病足溃疡的治疗效果。
Description
技术领域
本发明涉及一种治疗糖尿病足溃疡的制剂，具体涉及治疗糖尿病足溃疡的双相喷雾剂。
背景技术
糖尿病是由于胰岛素分泌不足导致血糖过高代谢障碍。约15％的糖尿病患者会在一生中发生糖尿病足病，糖尿病足病目前已成为慢性皮肤创面的主要原因。糖尿病足病危害极大，严重者会导致截趾、截肢，甚至死亡。糖尿病足病的治疗措施主要包括：及时的血运重建、止痛、综合性治疗、高压氧治疗、干细胞治疗等。其中，高压氧治疗可改善组织缺氧，增强灌注，改善水肿，减轻炎症，促进成纤维细胞增殖、胶原生成和血管生成，有助于慢性伤口的愈合。
国际足病工作组推荐使用高压氧疗法作为糖尿病足溃疡的有效辅助治疗，有助于促进足溃疡的愈合，可降低大截肢的发生风险，部分改善患者生活质量。但高压氧疗法也存在不良反应，包括：中耳气压性创伤、鼻窦/副鼻窦气压伤、牙齿挤压伤、肺气压性创伤、幽闭恐怖症、氧中毒、高氧近视、既往的白内障加快进展、低血糖、急性肺水肿等。
但是高压氧疗法对于糖尿病足溃疡的治疗也存在瓶颈，即使是2～3倍的高压氧气，也无法有效提升氧气渗透进入溃疡组织内的效率，此外高压作用容易引发血管阻塞和血栓，引起不良副作用。
氧气是气体形态，无法制成直接贴敷应用的皮肤制剂。已报道的文献中仅有含氧气微泡型制剂的报道，氧气微泡粒径在微米级，无法穿透皮肤屏障进入组织内部，制剂必须结合超声波的空化效应才能有效进入组织内部，从而增加了治疗操作的复杂性。
此外文献报道，酸性成纤维细胞生长因子(aFGF)作为重要的调控因子，可以通过控制血糖、损伤神经修复、损伤血管再生等作用有效促进糖尿病足溃疡的创面愈合。但是aFGF起效时间较慢，并且aFGF容易降解导致无法持续起效。
因此，如果能通过缓控释的递释系统将氧气和aFGF联合应用，在保证两者稳定性的同时发挥两者优势，形成“快速修复+长期修复”的协同治疗效果，实现糖尿病足溃疡的有效治疗。
经过检索，除了联合超声应用的含氧气微泡型制剂外，目前尚未见到任何aFGF和氧气共同包载于同一递释系统用于治疗糖尿病足溃疡的报道，因此无法发挥aFGF和氧气对于糖尿病足的协同增效治疗效果。
发明内容
为了克服糖尿病足溃疡高压氧气治疗的限制性瓶颈，克服现有技术的缺点(即：缺乏aFGF和氧气共同包载于同一递释系统的技术)，本发明的目的在于提供一种将aFGF和氧气共同包载于同一递释系统应用于糖尿病足治疗的双相喷雾剂，保证了aFGF和氧气稳定性的同时发挥两者“快速修复+长期修复”的协同治疗效果，同时满足临床治疗的安全、有效、便捷、经济的要求。
通过大量实验发现，本发明人获得治疗糖尿病足溃疡的双相喷雾剂，上述的双相喷雾剂是由携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液组成，携载氧气的全氟化碳溶液是以乳剂形式均匀分散于携载酸性成纤维细胞生长因子的水凝胶中；上述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为1～4:1，携载酸性成纤维细胞生长因子的水凝胶是由酸性成纤维细胞生长因子、聚赖氨酸和肝素-泊洛沙姆和水组成，水的质量是聚赖氨酸和肝素-泊洛沙姆的总质量的7倍，聚赖氨酸和肝素-泊洛沙姆的质量比为1～8:100，酸性成纤维细胞生长因子与肝素-泊洛沙姆5％的质量相等；上述的携载氧气的全氟化碳溶液是将氧气溶解于全氟化碳中形成的饱和溶液。
上述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为2～3:1。
上述的携载酸性成纤维细胞生长因子的水凝胶中聚赖氨酸和肝素-泊洛沙姆的质量比为3～5:100。
上述的携载酸性成纤维细胞生长因子的水凝胶中加入：电解质盐、氨基酸、pH值缓冲剂、抗氧化剂中的一种或几种。
上述的携载氧气的全氟化碳溶液是摩尔比1～3:1的全氟正戊烷与全氟己烷的混合溶液溶解氧气后形成的饱和溶液。
上述的携载氧气的全氟化碳溶液是摩尔比为2:1的全氟正戊烷与全氟己烷的混合溶液溶解氧气后形成的饱和溶液。
一种上述的治疗糖尿病足溃疡的双相喷雾剂的制备方法，包括以下步骤：
a：将聚赖氨酸和肝素-泊洛沙姆分散在15℃注射用水中，缓慢溶解，加入酸性成纤维细胞生长因子，混匀，形成携载酸性成纤维细胞生长因子的水凝胶；
b：取全氟化碳溶液置于容器中，15℃环境下充入氧气至饱和，混匀，形成携载氧气的全氟化碳溶液；
c：在15℃条件下将上述步骤b制备的携载氧气的全氟化碳溶液加入步骤a制备的携载酸性成纤维细胞生长因子的水凝胶中，分散混匀，制得治疗糖尿病足溃疡的双相喷雾剂溶液，15℃条件下灌注于喷雾瓶中，加盖阀门，即得治疗糖尿病足溃疡的双相喷雾剂，10～15℃环境中保存，用前摇匀。
上述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为2～3:1；所述的携载酸性成纤维细胞生长因子的水凝胶中聚赖氨酸和肝素-泊洛沙姆的质量比为3～5:100；所述的全氟化碳溶液是摩尔比为2:1的全氟正戊烷与全氟己烷的混合溶液。
上述的水凝胶溶液中加入：电解质盐、氨基酸、pH值缓冲剂、抗氧化剂中的一种或几种。
上述的双相喷雾剂经定位喷雾后立即呈凝胶状态，形成物理保护层，发挥aFGF和氧气协同增效作用，用于糖尿病足溃疡的治疗。
本发明的治疗糖尿病足溃疡的双相喷雾剂具有以下优点：①起效快且作用时间长，保证了aFGF和氧气稳定性的同时发挥两者“快速修复+长期修复”的协同治疗效果；②保证糖尿病足溃疡创面无菌同时为创面提供营养，水凝胶基质中的聚赖氨酸是一种营养型抑菌剂，具有营养和抑菌的双重作用；③糖尿病足创面的生物黏附作用强，聚赖氨酸结合肝素-泊洛沙姆作为水凝胶基质，对糖尿病足溃疡创面具有很好的生物黏附作用，且对糖尿病足溃疡创面具有良好的亲和性和生物相容性；④双相喷雾剂使用方便，经定位喷雾后立即呈凝胶状态，形成物理保护层，同时有利于各组分协同增效作用；⑤双相喷雾剂不使用任何氧气供体化合物和超声介导的氧气微泡，不会因为氧气供体化合物或超声空化作用对机体组织产生任何不良反应；⑥双相喷雾剂的储存和运输便捷。
具体实施方式
下文将详细描述本发明具体实施例。应当注意的是，下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的，它们可以被相互组合从而达到更好的技术效果。
实施例1治疗糖尿病足溃疡的双相喷雾剂的制备
按照表1设计，制备实验组的双相喷雾剂，具体包括以下步骤：
a：将聚赖氨酸和肝素-泊洛沙姆分散在15℃注射用水中，注射用水的质量是聚赖氨酸和肝素-泊洛沙姆的总质量的7倍，缓慢溶解，加入酸性成纤维细胞生长因子，混匀，形成携载酸性成纤维细胞生长因子的水凝胶；
b：取全氟化碳溶液置于容器中，15℃环境下充入氧气至饱和，混匀，形成携载氧气的全氟化碳溶液；
c：在15℃条件下将上述步骤b制备的携载氧气的全氟化碳溶液加入步骤a制备的携载酸性成纤维细胞生长因子的水凝胶中，分散混匀，制得治疗糖尿病足溃疡的双相喷雾剂溶液，15℃条件下灌注于喷雾瓶中，加盖阀门，即得治疗糖尿病足溃疡的双相喷雾剂，10～15℃环境中保存，用前摇匀。
表1实验组和对照组的设计
注：√：该项符合表头对应的参数设置；/：该项不存在；*：该项组分或参数被改变；aFGF：酸性成纤维细胞生长因子；A：全氟正戊烷；B：全氟己烷；TGF-α：转化生长因子-α；NO：一氧化氮；O2：氧气；N2：氮气。
参照实验组的设计和制备方法，根据表1的参数制备对照组制剂。各个实验组是根据本申请权利要求项保护范围内的组分和比例配置的，而各个对照组是某项组分缺失或组分质量百分含量超出本申请权利要求项保护的范围。
实施例2治疗糖尿病足溃疡的双相喷雾剂的应用效果
(1)糖尿病足溃疡模型动物
依据文献，建立糖尿病足溃疡模型动物，方法简述为：选择Wistar大鼠，经链脲佐菌素诱导产生糖尿病。造模第2周开始予大鼠每天游泳15min，并将大鼠置冰块上30min。1周之后大鼠后肢皮肤冰冷，颜色紫黯，在第2周末用液氮棉签法冷冻大鼠双后肢各3次，2Os/次，待皮肤复温后再行下次冷冻。液氮棉签法冷冻后出现后肢的冷冻局部充血水肿，冷冻后第2天后肢充血水肿范围扩大，冷冻后第3天水肿范围局限化，皮色变暗红色，冷冻后第5天基本形成血痂，至第3周末大鼠患肢血痂先后脱落，形成大小深浅不一的溃疡模型。
(2)实验动物治疗效果评价
按照表1设计将糖尿病足溃疡模型动物随机分组，每组5只，在糖尿病足溃疡面喷涂双相喷雾剂，按80mg/cm2均匀喷药，2天给药1次，3次给药后结束治疗，于第7天进行糖尿病足溃疡修复情况的观察，然后处死动物，通过取样进行病理学分析，采用双盲法请同一专业医师评价微血管闭塞程度、炎性渗出、硬结形成、创面愈合速度及愈合后疤痕情况，给出综合效果评分，评分以百分制表示，数值越高表示双相喷雾剂对于糖尿病足溃疡的治疗效果越好。
实验结果：以上各组制剂对于糖尿病足溃疡模型动物的治疗效果见表2。
表2各组制剂对于糖尿病足溃疡的治疗效果评价
由表2实验结果可见，实验组的双相喷雾剂对于糖尿病足的治疗效果好，特别是实验组3～5，微血管闭塞、炎性渗出、硬结等情况消除，创面愈合快，愈合后几乎无疤痕，治疗作用很好。相比实验组，对照组对于糖尿病足的治疗效果明显较差，特别是对照组8和13的治疗效果最差，微血管闭塞、炎性渗出、硬结等情况没有得到遏制，创面不能愈合。
表2的实验结果证明，本发明技术保护方案中的任一组分和条件都是相互协同、缺一不可的，缺乏本发明技术保护方案中的任一组分和条件，都会对糖尿病足的治疗效果产生明显的影响。本发明的双相喷雾剂能治疗糖尿病足，具有良好的应用前景。
上述详细说明是针对发明的可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明的等效实施或变更，均应当包含于本发明的专利范围内。另外，本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然，这些依据本发明精神所做的各种修改、添加和替换等变化，都应包含在本发明所要求保护的范围之内。
Claims (6)
1.治疗糖尿病足溃疡的双相喷雾剂，其特征在于：包括携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液，所述的携载氧气的全氟化碳溶液是以乳剂形式均匀分散于携载酸性成纤维细胞生长因子的水凝胶中；所述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为1～4:1；所述的携载酸性成纤维细胞生长因子的水凝胶是由酸性成纤维细胞生长因子、聚赖氨酸、肝素-泊洛沙姆和水组成，水的质量是聚赖氨酸和肝素-泊洛沙姆的总质量的7倍，聚赖氨酸和肝素-泊洛沙姆的质量比为1～8:100，酸性成纤维细胞生长因子与肝素-泊洛沙姆5％的质量相等；所述的携载氧气的全氟化碳溶液是摩尔比1～3:1的全氟正戊烷与全氟己烷的混合溶液溶解氧气后形成的饱和溶液。
2.根据权利要求1所述的治疗糖尿病足溃疡的双相喷雾剂，其特征是：所述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为2～3:1。
3.根据权利要求1所述的治疗糖尿病足溃疡的双相喷雾剂，其特征是：所述的携载酸性成纤维细胞生长因子的水凝胶中聚赖氨酸和肝素-泊洛沙姆的质量比为3～5:100。
4.根据权利要求1所述的治疗糖尿病足溃疡的双相喷雾剂，其特征是：所述的携载氧气的全氟化碳溶液是摩尔比为2:1的全氟正戊烷与全氟己烷的混合溶液溶解氧气后形成的饱和溶液。
5.一种权利要求1～4任一项所述的治疗糖尿病足溃疡的双相喷雾剂的制备方法，其特征是：所述的治疗糖尿病足溃疡的双相喷雾剂的制备方法包括以下步骤：
a：将聚赖氨酸和肝素-泊洛沙姆分散在15℃注射用水中，缓慢溶解，加入酸性成纤维细胞生长因子，混匀，形成携载酸性成纤维细胞生长因子的水凝胶；
b：取全氟化碳溶液置于容器中，15℃环境下充入氧气至饱和，混匀，形成携载氧气的全氟化碳溶液；
c：在15℃条件下将上述步骤b制备的携载氧气的全氟化碳溶液加入步骤a制备的携载酸性成纤维细胞生长因子的水凝胶中，分散混匀，制得治疗糖尿病足溃疡的双相喷雾剂溶液，15℃条件下灌注于喷雾瓶中，加盖阀门，即得治疗糖尿病足溃疡的双相喷雾剂，10～15℃环境中保存，用前摇匀。
6.根据权利要求5所述的治疗糖尿病足溃疡的双相喷雾剂的制备方法，其特征是：所述的双相喷雾剂中携载酸性成纤维细胞生长因子的水凝胶和携载氧气的全氟化碳溶液的质量比为2～3:1；所述的携载酸性成纤维细胞生长因子的水凝胶中聚赖氨酸和肝素-泊洛沙姆的质量比为3～5:100；所述的全氟化碳溶液是摩尔比为2:1的全氟正戊烷与全氟己烷的混合溶液。
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| AU2017351950A1 (en) * | 2016-10-26 | 2019-05-02 | Oxy Solutions As | Formulations |
| US20210001001A1 (en) * | 2018-03-22 | 2021-01-07 | The University Of Toledo | Micropatterned silicone oxygenating dressing for chronic wounds |
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