CN116390778A - 由含磷脂的纳米分散体生产伤口敷料的方法 - Google Patents
由含磷脂的纳米分散体生产伤口敷料的方法 Download PDFInfo
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- CN116390778A CN116390778A CN202180072145.0A CN202180072145A CN116390778A CN 116390778 A CN116390778 A CN 116390778A CN 202180072145 A CN202180072145 A CN 202180072145A CN 116390778 A CN116390778 A CN 116390778A
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Abstract
本发明涉及由含磷脂的纳米分散体生产伤口敷料的方法。
Description
本发明涉及由含磷脂的纳米分散体生产伤口敷料的方法。
已知用伤口敷料覆盖人或动物皮肤中的伤口。这些旨在吸收血液和伤口渗出液并防止异物渗入。根据设计,伤口敷料可以确保伤口环境湿润或通过所含物质减轻疼痛、促进伤口愈合或具有抗菌作用。简单且广泛使用的伤口敷料由棉织物和胶带组成并且被称为创可贴。较新的伤口敷料包含例如藻酸盐、水凝胶或水胶体。这种伤口敷料通常必须固定到未受伤的皮肤上,例如通过本身涂有丙烯酸酯胶粘剂的膜。
尽管伤口敷料领域取得了所有进展,但仍然需要具有改进性能的伤口敷料。
WO 2019/243988 A1描述了使用静电纺丝制成纤维形式的磷脂纳米分散体,其可用于生产伤口敷料。本发明描述了用于由WO 2019/243988A1中原则上所示的纳米分散体生产伤口敷料的替代性生产方法。
进一步的现有技术由以下文件形成:
·Choudhury等人,Recent Update on Nanoemulgel as Topical Drug DeliverySystem,Journal ofPharmaceutical Sciences,第06卷,7,2017年7月,第1736-1751页描述了基于纳米乳胶剂的透皮给药系统。
·WO2016/198238A1描述了包含水凝胶和孔隙率可调的纳米颗粒的材料,其用于形成细胞培养物。
·Hajialyani等人,Natural product-based nanomedicines for woundhealing purposes,Internat.Journal of Nanomedicine 2018,13,第5023-5043页描述了用于伤口愈合的各种基于水凝胶的纳米颗粒体系。
本发明涉及根据权利要求1的由含磷脂的纳米分散体生产伤口敷料的方法,其具有下列方法步骤:
a)将至少一种磷脂与至少一种药学上可接受的油和水混合,
b)通过转子-定子乳化或超声乳化或通过混合物的高压均化进行乳化,以获得分散体,其中至少90%的颗粒液滴的直径小于10μm(优选<1μm),
c)将来自步骤b)的分散体与药学上可接受的聚合物的水溶液混合,
d)将包含分散颗粒的所得聚合物溶液以层形式施加到载体上,
e)在高温、减压下干燥和/或冷冻干燥
f)任选地机械分割该层和/或从载体上分离。
本发明的其它有利实施方式是从属权利要求的主题。
根据方法步骤a),首先将至少一种磷脂与至少一种药学上可接受的油和水混合。原则上,所有已知的磷脂都可以用作磷脂。优选的磷脂是磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸或其混合物。特别优选的磷脂是氢化磷脂,其例如可以名称 或“Phospholipon 80H”获得。其主要是氢化磷脂酰胆碱。也可以成功地使用用于药用目的的由磷脂,特别是由氢化磷脂制成的其它市售产品。
原则上,药学上可接受的油可以选自大量已知的植物油。蓖麻油、玉米油、椰子油、亚麻籽油、橄榄油、花生油或其混合物已证明特别有用。
来自方法步骤a)的混合物通常包含:
约1-15%的磷脂,优选2.5-9%
约1-10%的药学上可接受的油,优选1-5%
加至100%的水。
任选地,该水性混合物还可以含有0.05至5重量%的桦木提取物。为此,特别优选包含下列组分的桦木提取物(数据以重量百分比(重量%)计):
和任选其它桦木提取物组分,特别是齐墩果酸、桦木酸、桦木酸甲酯2-13重量%。
含桦木提取物的纳米分散体的一个优点是,桦树皮提取物的药物活性成分分布在最细的颗粒或液滴中,这提高生物利用度。这种纳米分散体可以直接施加在伤口或受感染皮肤上,例如通过喷涂到身体的相关位置。与油凝胶相比,根据本发明的纳米分散体在处理性能方面更优越。其是液体,其甚至可以喷涂或分布在受感染的皮肤区域上。
使用合适的混合器-均化器混合最初描述的磷脂和药学上可接受的油和任选的桦木提取物的水性混合物,并且以这种方式产生预分散体。然后进一步处理该预分散体,以将各个液滴颗粒的所需粒度从<10μm的平均液滴粒度任选减小至约<1μm和优选低于400nm的亚微米尺寸。这可以通过使用转子-定子均化器或超声乳化的强力剪切来完成,这在减小液滴尺寸方面非常有效。
替代地,可以使用高压均化,例如活塞间隙式的高压均化器,以生产具有低至几纳米的极小粒度的纳米乳液。超声应用和微流化是用于生产纳米乳液的其它已知和充分描述的方法。
众所周知,这种分散体受粒度分布的影响。根据生产方法的情况,颗粒的尺寸分布(特别是中值和跨度)可能有所不同。对于本方法已发现,粒度的中值应在纳米范围内,即小于1000nm,优选小于800nm,特别优选小于800nm。然而,在个别情况下,粒度分布的中值为5000nm(5μm)的分散体可能足够稳定,以达到所需结果。在各个情况下,至少90%的颗粒应具有小于10000nm(10μm)的尺寸,优选90%的颗粒应具有小于5000nm(5μm)的尺寸,特别优选90%的颗粒应具有小于1000nm(1μm)的尺寸。以上定义的所有分散体在本文中被称为纳米分散体。上述用于生产具有特别是用于实现所需粒度分布的上述性能的分散体的方法原则上是已知的,因此在这一点上不需要详细解释。例如,参考著作Emulgiertechnik,B.Behr's Verlag,2012年第3版,ISBN 978-3-89947-869-3,特别是第VII.5章。
在该方法的步骤b)中,将预乳液转化成纳米分散体。该纳米分散体中包含的颗粒液滴的尺寸分布在较低的微米范围内。至少90%的颗粒液滴的直径必须小于10微米。
现有技术中的各种方法可用于将步骤a)中产生的预乳液转化成纳米分散体,例如使用具有高剪切的转子-定子均化器(例如齿环分散器或胶体磨)、通过超声应用、通过高压均化或通过微流化。所有这些方法在现有技术中都有充分的描述,其中在这一点上不需要详细解释。
根据本发明,然后将形成的纳米分散体与聚合物水溶液混合。以这种方式,纳米分散体的极小液滴分散在载体聚合物中。桦树皮提取物的分散颗粒精细分布在聚合物基质中,因此超均化步骤也可能有帮助。
可用于优选实施方案的聚合物必须是药学上可接受的。这种聚合物可选自聚环氧乙烷、聚乙烯醇、聚乙酸乙烯酯、聚乙烯吡咯烷酮、透明质酸、海藻酸盐、角叉菜胶、黄原胶、纤维素衍生物如羧甲基纤维素、甲基纤维素钠、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸乙酸纤维素、淀粉衍生物如羟乙基淀粉、羟基乙酸淀粉钠、壳聚糖及其衍生物、白蛋白、明胶、胶原蛋白、聚丙烯酸酯及其衍生物。特别优选地使用在伤口上容易溶解且没有不希望的性能的这种聚合物。特别优选地使用聚乙烯醇或聚(丙交酯-共-乙交酯)。非常特别优选地使用亲水聚合物聚乙烯醇(PVA),其已经被FDA批准用于人类。PVA聚合物具有诸如良好的耐化学性、热稳定性、生物降解性、生物相容性和无毒性之类的独特性能,这使其适用于伤口敷料。
通常,制备聚合物的水溶液。该溶液含有约5-20重量%的聚合物,优选约10%。聚合物水溶液与来自方法步骤b)的纳米分散体以25:75至75:25的重量比混合。优选的混合比是60-70%的聚合物溶液对40-30%的纳米分散体。
在该方法的步骤d)中,将以这种方式制备的溶解有聚合物的纳米分散体以层形式施加到载体上。合适的载体例如是铝膜、塑料膜、玻璃、棉织物或无纺布、或聚合物织物或无纺布。任选地,将该层机械抹平并且同时去除过量的分散体,例如通过使用刮刀。
也可以这样将纳米分散体施加到载体上:首先通过引入气体(例如在施加压力的情况下引入丙烷/丁烷;N2O或二甲醚)使纳米分散体发泡并然后将该泡沫均匀施加到载体上。
在该方法的步骤e)中,干燥纳米分散体层。这种干燥可以在高温和/或减压下进行。在此温度不应超过60摄氏度。常见的干燥压力范围为10至100毫巴,其中更低的压力是完全可行的。
替代地,也可以通过冷冻干燥来进行干燥。
干燥的纳米分散体的层厚度应为0.05至5mm。
干燥后,所产生的层通常被机械切割或冲压成块。各块的尺寸和形状可能有所不同。常见尺寸为1至100平方厘米大小并且形状各异(例如圆形、椭圆形或矩形)。然而,根据要求,也可以生产更大块。这些可以任选地适配伤口的几何形状。
在此,切割成块可以在有或没有载体的情况下进行。例如,该层可以从载体上分离,然后切割。替代地,可以切割具有载体膜的该层,然后可以在使用前不久将作为载体的膜分离。
在所述方法中,当然也可以进行灭菌,例如通过加热、无菌过滤和/或照射步骤1中制备的水性混合物。替代地或附加地,在该方法结束时产生的伤口敷料也可以通过热方式或通过照射进行灭菌。
根据该方法制备的干燥的纳米分散体适合作为伤口敷料。由于该层本身仅具有低胶粘性能,通常将其通过具有粘附性能的另一膜(胶粘层)或合适的胶粘剂固定到伤口或伤口边缘上。
实施例
下面的实施例显示了根据本发明的方法的进一步细节,但不旨在具有限制作用。本领域技术人员可以基于此处示出的信息进行进一步的开发,而不必具有创造性。
实施例1
用于生产纳米分散体的基础混合物
实施例2
根据实施例1制备的混合物首先如下转化成纳米分散体:
将来自方法步骤a)的磷脂和药学上可接受的油和任选的桦木提取物的混合物在混合器-均化器中混合,并且以此方式产生预分散体。然后通过高压均化(Emulsiflex C-3,Avestin,Mannheim,德国)进一步处理该预乳液(在100MPa,70℃下至少3,优选8个循环),以将各个液滴颗粒的粒度从>10μm的平均液滴粒度减小到约<1μm,优选低于400nm的亚微米尺寸。
然后将纳米分散体与聚合物溶液(10%PVA溶液)强力混合(例如Bekomix或Frymacoruma型号的混合器-均化器)并如下进一步加工:
变体1)
将溶解有聚合物的纳米分散体施加(优选喷涂)到载体层,例如纺织织物或无纺布上,然后在高温,例如60℃下干燥,其中施加或不施加真空。
由此例如产生配备有活性层的伤口绷带。
变体2)
将溶解有聚合物的纳米分散体施加(浇注或喷涂)到合适的基材,例如载体膜上,然后在高温度,例如60℃下干燥,其中施加或不施加真空。
将在此形成的膜(膜厚度为约0.1-0.2mm)从基材上分离,任选切割成合适的尺寸,现在可以本身单独分开地用作伤口敷料、或与用于伤口敷料的其它材料和/或与粘附层组合拼合成复合伤口敷料。
变体3)
通过经由喷嘴引入空气或另一合适气体或通过机械引入空气或另一合适气体,将溶解有聚合物的纳米分散体转化成泡沫。将该泡沫施加(涂抹、浇注或喷涂)到合适的基底,例如载体膜上,然后在高温,例如60℃下干燥,其中施加或不施加真空。
将在此形成的多孔膜从基底上分离,任选切割成合适的尺寸,现在可以本身单独分开地用作伤口敷料、或与用于伤口敷料的其它材料和/或与粘附层组合拼合成复合伤口敷料。
变体4)
将溶解有聚合物的纳米分散体以合适的层厚度在常规冷冻干燥过程中在<-20℃的温度下冷冻,然后冷冻干燥。
将在此形成的多孔海绵状层从基材,例如载体膜上分离,任选切割成合适的尺寸,然后可以本身单独分开地用作伤口敷料、或与用于伤口敷料的其它材料和/或与粘附层组合拼合成复合伤口敷料。
实施例2a
作为实施例2的替代方案,纳米分散体可以如下制备:
将磷脂酰胆碱和桦树皮提取物分散在70℃的水中,并在真空下搅拌30分钟。随后进行10分钟的均化(转子-定子>10m/s)。在进一步搅拌和真空下加入葵花籽油并再均化30分钟(转子-定子>10m/s)。将该相冷却至40℃。加入聚合物溶液(10%PVA溶液)并强力混合(例如Bekomix或Frymacoruma型号的混合器-均化器)。可如实施例2(变体1-4)中所述进一步加工溶解有聚合物的纳米分散体。
实施例3
为了验证根据本发明的伤口敷料的活性,可以对猪进行离体伤口愈合试验。在此,来自屠宰场(供人食用)的猪耳在屠宰后立即送到实验室、清洗和消毒。然后从耳垂取6毫米穿孔活检,去除脂肪和皮下组织。结果,通过去除7.1mm2的中心区域的表皮和上层真皮而产生伤口。然后将由此形成的离体伤口愈合模型在培养皿中以真皮朝下置于纱布上,并与添加有氢化可的松、2%胎牛血清、青霉素和链霉素的Dulbecco改良Eagle培养基在气液界面处培养。在致伤后立即施加4cm2的伤口敷料并将模型在37℃和5%CO2下培养48小时。
进一步的步骤包括急速冷冻,伤口愈合模型中心部分的低温恒温切片在显微镜中用尺子识别,并且——通过在评估期间检查伤口的总长度——用苏木精和曙红染色。通过用显微镜测量伤口边缘和再生表皮顶部之间的距离来评估伤口愈合过程(再上皮化)。
在实施例中,作为对照的伤口根本没有进行处理。油凝胶用作与现有技术的对比。可以观察到轻微的改进。此外,使用不含桦树皮提取物的聚乙烯醇垫(PVA垫)。表明了,愈合性能比对照的情况更好,甚至比用油凝胶的情况更好。
图1显示了所进行的实验的结果:
第1列(最左侧)显示了未处理的对照。
第2列显示了用油凝胶进行处理(对应于批准的成品药物Episalvan)
第3列显示了用根据WO 2019/243988 A1的含有桦木提取物的静电纺丝伤口敷料进行处理。
第4列显示了用静电纺丝安慰剂伤口敷料进行处理。
第5列显示了用图1的含TE的膜进行处理。
Claims (16)
1.由含磷脂的纳米分散体生产伤口敷料的方法,其具有下列方法步骤:
a)将至少一种磷脂与至少一种药学上可接受的油和水混合,
b)通过转子-定子乳化或超声乳化或通过混合物的高压均化进行乳化,以获得分散体,其中至少90%的颗粒液滴的直径小于10μm,
c)将分散体与药学上可接受的聚合物的水溶液混合,
d)将包含分散的纳米颗粒的所得聚合物溶液以层形式施加到载体上,
e)在高温、减压下干燥和/或冷冻干燥
f)任选地机械分割该层和/或从载体上分离。
2.根据权利要求1所述的方法,其特征在于,所述磷脂选自磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸、氢化磷脂(尤其是氢化磷脂酰胆碱)或其混合物。
3.根据权利要求1或2所述的方法,其特征在于,至少一种药学上可接受的油选自葵花籽油、蓖麻油、玉米油、椰子油、亚麻籽油、橄榄油、花生油或其混合物。
4.根据权利要求1、2或3所述的方法,其特征在于,所述磷脂与油和水的混合物含有0.05至5重量%的桦木提取物。
5.根据权利要求4所述的方法,其特征在于,所述桦木提取物包含下列组分,按重量百分比计算:
桦木醇74-85重量%,
羽扇豆醇1.0-4.0重量%,
桦木酸3.0-5.0重量%,
高根二醇0.3-2.8重量%
和任选其它桦木提取物组分,特别是齐墩果酸、桦木酸、桦木酸甲酯2-13重量%。
6.根据权利要求1至5中至少一项所述的方法,其特征在于,所述纳米分散体通过使用
具有高剪切的混合装置
通过超声应用,
通过高压均化或
通过微流化
来生产。
7.根据权利要求1至6中至少一项所述的方法,其特征在于,所述药学上可接受的聚合物选自聚环氧乙烷、聚乙烯醇、聚乙酸乙烯酯、聚乙烯吡咯烷酮、透明质酸、海藻酸盐、角叉菜胶、黄原胶、纤维素衍生物、甲基纤维素钠、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸乙酸纤维素、淀粉衍生物、羟基乙酸淀粉钠、壳聚糖及其衍生物、白蛋白、明胶、胶原蛋白、聚丙烯酸酯及其衍生物、聚乙烯醇或聚(丙交酯-共-乙交酯)。
8.根据权利要求1至7中至少一项所述的方法,其特征在于,将分散在聚合物中的纳米分散体施加到载体上,其中所述载体选自铝膜、塑料膜、玻璃、棉织物或无纺布、或聚合物织物或无纺布。
9.根据权利要求1至7中至少一项所述的方法,其特征在于,将分散在聚合物中的纳米分散体在发泡的情况下施加到载体上,其中所述载体选自铝膜、塑料膜、玻璃、棉织物或无纺布、或聚合物织物或无纺布。
10.根据权利要求1至9中至少一项所述的方法,其特征在于,分散在聚合物中的纳米分散体的干燥在高温和/或减压下进行。
11.根据权利要求1至9中至少一项所述的方法,其特征在于,分散在聚合物中的纳米分散体的干燥通过冷冻干燥进行。
12.根据权利要求1至11中至少一项所述的方法,其特征在于,分散在聚合物中的纳米分散体的干燥层具有0.1至5mm的层厚度。
13.根据权利要求1至12中至少一项所述的方法,其特征在于,在干燥之后,将干燥层机械分割成1-100cm2尺寸的部分。
14.根据权利要求1至13中至少一项所述的方法,其特征在于,在干燥后进行所述载体的分离。
15.根据权利要求1至14中至少一项所述的方法生产的伤口敷料。
16.根据权利要求1至14中至少一项所述的方法生产的干燥的分散在聚合物中的纳米分散体作为伤口敷料的用途。
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