CN111437270A - 一种卡拉胶鼻用即型凝胶喷雾剂及其制备方法 - Google Patents
一种卡拉胶鼻用即型凝胶喷雾剂及其制备方法 Download PDFInfo
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- CN111437270A CN111437270A CN202010335197.XA CN202010335197A CN111437270A CN 111437270 A CN111437270 A CN 111437270A CN 202010335197 A CN202010335197 A CN 202010335197A CN 111437270 A CN111437270 A CN 111437270A
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- carrageenan
- nasal
- gel
- gel spray
- spray
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Abstract
本发明涉及一种卡拉胶鼻用即型凝胶喷雾剂及其制备方法,属于医药技术领域。该凝胶喷雾剂按重量百分比计,包括如下组分:κ型卡拉胶5‑7%,ι型卡拉胶3‑5%,λ型卡拉胶0.001‑0.005%,皮肤外用制剂中可以接受的辅料5‑16%,余量为水。首先通过调节κ型卡拉胶和ι型卡拉胶的用量比,改变混合物中硫酸酯含量的比例,当将该凝胶喷雾剂喷入鼻中,可利用鼻腔分泌物中钾离子、钙离子来提高凝胶的弹性,同时还能防止凝胶脱水收缩。再利用适量的λ型卡拉胶激活炎症反应,激活人体局部免疫能力物质在鼻腔表面形成一层“薄膜”,阻断病毒传染的途径,预防呼吸疾病的传染。该凝胶喷雾剂制备方法简单,易操作,对设备要求低,适合扩大化生产。
Description
技术领域
本发明属于医药技术领域,具体涉及一种卡拉胶鼻用即型凝胶喷雾剂及其制备方法。
背景技术
2003年4月24日国家食品药品监督管理局批准/重组人干扰素A2b喷雾剂用于高危人群临床观察,预防非典型肺炎,初步试验证明,干扰素通过鼻腔给药,直接作用于呼吸道粘膜,通过激活位于鼻腔粘膜和周围淋巴组织上的受体而直接作用于免疫系统,使呼吸道粘膜表面细胞迅速进入抗病毒状态,从而有效阻断呼吸道病毒感染。除此之外,干扰素也能通过鼻腔吸入体内,调节机体免疫功能,对阻断呼吸道感染途径具有一定的作用。
如今新型冠状病毒SARS-CoV-2(之前称为2019-nCoV)正在全球肆虐,有必要在干扰素鼻喷雾的基础上寻找合适的材料和激活人体局部免疫能力物质,在鼻腔表面形成一层“薄膜”,以此阻断病毒传染的途径,从而达到预防呼吸疾病传染的目的。
卡拉胶(Carrageenan),又称为麒麟菜胶、石花菜胶、鹿角菜胶、角叉菜胶,是从麒麟菜、石花菜、鹿角菜等红藻类海草中提炼出来的亲水性胶体。其是由1,3-苷键连接β-D-半乳糖吡喃基和1,4-苷键连接α-D-半乳糖吡喃基为基本单位的线型聚糖。根据卡拉胶中硫酸酯结合形态的不同,可分为κ、ι和λ型等8种类型。
卡拉胶的凝胶形成过程分为4个阶段:第一阶段,卡拉胶溶解在热水中,其分子形成不规则的卷曲状;第二阶段,其分子向螺旋化转化,形成单螺旋体;第三阶段,分子间形成双螺旋体,为立体网状结构,这时开始有凝固现象;第四阶段,双螺旋体聚集形成凝胶。
近年来,即型凝胶作为鼻腔给药系统的研究已有相关报道。其中,温度敏感即型凝胶需要冷藏保存,其作为鼻腔给药使用不方便;pH敏感即型凝胶酸性较强对鼻黏膜会有刺激作用。因此,急需一种给药方便,无刺激且疗效好的鼻用即型凝胶。
发明内容
有鉴于此,本发明的目的之一在于提供一种卡拉胶鼻用即型凝胶喷雾剂;目的之二在于提供一种卡拉胶鼻用即型凝胶喷雾剂的制备方法。
为达到上述目的,本发明提供如下技术方案:
1、一种卡拉胶鼻用即型凝胶喷雾剂,按重量百分比计,所述凝胶喷雾剂包括如下组分:κ型卡拉胶5-7%,ι型卡拉胶3-5%,λ型卡拉胶0.001-0.005%,皮肤外用制剂中可以接受的辅料5-16%,余量为水。
优选的,所述凝胶喷雾剂还包括处方量的抗病毒药物或抗生素中的至少一种。
优选的,所述抗病毒药物为干扰素、盐酸金刚烷胺、盐酸金刚乙胺、替洛隆、扎那米韦、奥司他韦、阿替洛韦、利巴韦林、替诺福韦或恩曲他滨中的至少一种。
优选的,所述抗生素为氟氯西林、克林霉素、阿奇霉素、罗红霉素或左氧氟沙星中的至少一种。
优选的,所述κ型卡拉胶分子量为20-40k;所述ι型卡拉胶分子量为20-40k;所述λ型卡拉胶分子量为10-20k。
优选的,所述辅料包括助悬剂、润湿剂、防腐剂或pH调节剂中的至少一种。
优选的,所述助悬剂占所述凝胶喷雾剂总重量的0.3-5%;所述润湿剂占所述凝胶喷雾剂总重量的5-10%;所述防腐剂占所述凝胶喷雾剂总重量的0.01-1%;所述pH调节剂调节所述凝胶喷雾剂的pH至5.5-6.5。
优选的,所述助悬剂为丙烯酸聚合物、卡波普、羧甲基纤维素钠、羟丙基甲基纤维素、黄原胶或去乙酰结冷胶中的至少一种;所述润湿剂为乙醇、甘油、丙二醇、透明质酸钠、聚谷氨酸或吐温60中的至少一种;所述防腐剂为尼泊金类、三氯叔丁醇、氯甲酚、山梨酸钾、苯甲酸或苯甲酸钠中的至少一种;所述pH调节剂为氢氧化钠、氢氧化钾、乙醇胺、乙二胺、碳酸氢钠、盐酸、柠檬酸、山梨酸或磷酸二氢钠中的至少一种。
2、所述的一种卡拉胶鼻用即型凝胶喷雾剂的制备方法,所述方法如下:将κ型卡拉胶、ι型卡拉胶、λ型卡拉胶、抗病毒药物或抗生素中的至少一种、皮肤外用制剂中可以接受的辅料加入水中,混匀即可。
本发明的有益效果在于:本发明提供了一种卡拉胶鼻用即型凝胶喷雾剂及其制备方法,该凝胶喷雾剂中将κ型卡拉胶、ι型卡拉胶、λ型卡拉胶三种卡拉胶配合使用,首先通过调节κ型卡拉胶和ι型卡拉胶的用量比,改变混合物中硫酸酯含量的比例,当将该凝胶喷雾剂喷入鼻中,可利用鼻腔分泌物中钾离子、钙离子来提高凝胶的弹性,同时还能防止凝胶脱水收缩。再利用适量的λ型卡拉胶激活炎症反应,引发THP-1单核/巨细胞免疫响应,有效提高巨噬细胞分泌TNF-α,特别是能够增强脂多糖对巨噬细胞的刺激作用,可激活人体局部免疫能力物质在鼻腔表面形成一层“薄膜”,阻断病毒传染的途径,预防呼吸疾病的传染。另外,在该凝胶喷雾剂中还可加入抗病毒药物或抗生素等活性成分,可以抑制病毒吸附细胞、抑制冠状病毒、流感病毒等RNA病毒的复制,进一步增强该凝胶喷雾剂的预防呼吸传染病能力。该凝胶喷雾剂制备方法简单,易操作,对设备要求低,适合扩大化生产。
本发明的其他优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书来实现和获得。
附图说明
为了使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作优选的详细描述,其中:
图1为实施例1中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液按体积比1:1混合后发生胶凝形成的凝胶的体外累积溶蚀度曲线图。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
实施例1
一种卡拉胶鼻用即型凝胶喷雾剂,按重量百分比计,该凝胶喷雾剂包括如下组分:分子量为30k的κ型卡拉胶6%,分子量为30k的ι型卡拉胶4%,分子量为20k的λ型卡拉胶0.001%,抗病毒药物(干扰素)1%,皮肤外用制剂中可以接受的辅料(助悬剂[黄原胶]0.3%、润湿剂[甘油]10%、防腐剂[三氯叔丁醇]0.3%、pH调节剂[氢氧化钠、盐酸])10.6%,余量为去离子水。该凝胶喷雾剂按如下方法制备:
将分子量为30k的κ型卡拉胶、分子量为30k的ι型卡拉胶、分子量为20k的λ型卡拉胶、抗病毒药物(干扰素)、皮肤外用制剂中可以接受的辅料(助悬剂[黄原胶]、润湿剂[甘油]、防腐剂[三氯叔丁醇])加入去离子水中,混匀加入pH调节剂[氢氧化钠、盐酸]调pH至6即可。
实施例2
一种卡拉胶鼻用即型凝胶喷雾剂,按重量百分比计,该凝胶喷雾剂包括如下组分:分子量为20k的κ型卡拉胶7%,分子量为40k的ι型卡拉胶3%,分子量为10k的λ型卡拉胶0.005%,抗病毒药物(盐酸金刚烷胺)1%,皮肤外用制剂中可以接受的辅料(助悬剂[羧甲基纤维素钠]5%、润湿剂[吐温60]8%、防腐剂[尼泊金乙酯]0.3%、pH调节剂[乙醇胺、柠檬酸])13.3%,余量为去离子水。该凝胶喷雾剂按如下方法制备:
将分子量为20k的κ型卡拉胶、分子量为40k的ι型卡拉胶、分子量为10k的λ型卡拉胶、抗病毒药物(盐酸金刚烷胺)、皮肤外用制剂中可以接受的辅料(助悬剂[羧甲基纤维素钠]、润湿剂[吐温60]、防腐剂[尼泊金乙酯])加入去离子水中,混匀加入pH调节剂[乙醇胺、柠檬酸]调pH至5.5即可。
实施例3
一种卡拉胶鼻用即型凝胶喷雾剂,按重量百分比计,该凝胶喷雾剂包括如下组分:分子量为40k的κ型卡拉胶5%,分子量为20k的ι型卡拉胶5%,分子量为10k的λ型卡拉胶0.001%,抗病毒药物(阿替洛韦)1.5%,皮肤外用制剂中可以接受的辅料(助悬剂[卡波普]5%、润湿剂[乙醇]5%、防腐剂[山梨酸钾]1%、pH调节剂[乙二胺、山梨酸])11%,余量为去离子水。该凝胶喷雾剂按如下方法制备:
将分子量为40k的κ型卡拉胶、分子量为20k的ι型卡拉胶、分子量为10k的λ型卡拉胶、抗病毒药物(阿替洛韦)、皮肤外用制剂中可以接受的辅料(助悬剂[卡波普]、润湿剂[乙醇]、防腐剂[山梨酸钾])加入去离子水中,混匀加入pH调节剂[乙二胺、山梨酸]调pH至6.5即可。
对比实施例1
与实施例1的区别在于,不含有ι型卡拉胶。
对比实施例2
与实施例1的区别在于,不含有λ型卡拉胶。
实施例4
本发明中卡拉胶鼻用即型凝胶喷雾剂粘度测试
参照2005版《中华人民共和国药典》二部附录VIG项下粘度测定第二法,使用旋转粘度计在室温条件下测定实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂在不同剪切速率下的粘度变化,测试结果见表1。
表1实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂粘度测试结果
由表1可知,实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂的粘度随剪切速率增大呈下降趋势,表现出剪切变稀现象。
实施例5
本发明中卡拉胶鼻用即型凝胶喷雾剂在人工鼻液中的成凝性测试
人工鼻液的制备:根据鼻液的电解质组成配制人工鼻液,其组成成分为150±32mMNa+、41±18mM K+、4±2mM Ca+。
将实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂分别按体积比1:1与上述人工鼻液混合,观测各凝胶喷雾剂与人工鼻液接触后形成凝胶的速度与粘度变化,结果见表2。
表2实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂在人工鼻液中的成凝性测试结果
由表2可知,实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂与等体积的人工鼻液接触后均立即形成凝胶,且形成凝胶后的粘度均高于原体系溶液的粘度。本发明中卡拉胶鼻用即型凝胶喷雾剂反应前粘度变化范围为200-350mPa·s,反应后粘度变化范围为1500-2500mPa·s,这能确保本发明中凝胶喷雾剂以混悬液状态存在时,既能使药物分散均匀不沉淀,又适合喷雾给药,保证喷出均匀的雾滴。
实施例6
本发明中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液混合后发生胶凝形成的凝胶析水率测试
分别精确称取5mL实施例1至实施例3及对比实施例1中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液按体积比1:1混合后发生胶凝形成的凝胶,用滤纸轻轻地吸干凝胶表面水珠后再次进行精确称重。按如下公式计算析水率:
式中:K为凝胶析水率;
m1为初始凝胶质量;
m2为除去表面水分后凝胶质量。
测试结果见表3。
表3实施例1至实施例3及对比实施例1中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液混合后发生胶凝形成的凝胶析水率测试结果
由表3可知,对比实施例1中凝胶喷雾剂与人工鼻液发生胶凝形成的凝胶具有较大的析水率,而实施例1至实施例3中凝胶喷雾剂与人工鼻液发生胶凝形成的凝胶不具有析水率,说明本发明中凝胶喷雾剂与人工鼻液发生胶凝形成的凝胶不会因脱水而体积缩小,凝胶具有较好的稳定性。
实施例7
本发明中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液混合后发生胶凝形成的凝胶质构性质分析
采用CT-3质构仪测试实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液按体积比1:1混合后发生胶凝形成的凝胶在37℃下的凝胶强度和胶着性。选择圆柱形P/0.5探头,设定测试为下压模式,以1mm/s的速度降低探头,触发力为5g。当探头接触各样品(已由水浴加热至37℃)表面后,探头以2mm/s下压至10mm,然后以10mm/s的速度回升,记录应力—时间曲线,处理图形,得到凝胶强度为正峰的最大值和胶着性为负峰的面积。结果见表4。
表4实施例1至实施例3中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液混合后发生胶凝形成的凝胶质构性质分析结果
由表4可知,本发明中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液发生胶凝形成的凝胶质地较软,凝胶强度和胶着力较高。
实施例8
溶蚀实验
将实施例1中卡拉胶鼻用即型凝胶喷雾剂与人工鼻液按体积比1:1混合后发生胶凝形成的凝胶装入西林瓶中,密封,称重,37℃凝固,精密加入预热至37℃的释放介质PBS1mL,密封,摇床中振荡20min,小心吸出上层液体,再次称重,得失重。重复操作,直至凝胶溶蚀完全,然后以累积溶蚀重量为纵坐标,时间为横坐标制图,得体外累积溶蚀度曲线,如图1所示,由图1可知,凝胶溶蚀重量与时间成正比,表明凝胶溶蚀是控制药物释放的主要因素。
实施例9
检测本发明中卡拉胶鼻用即型凝胶喷雾剂TNF-α的表达量
THP-1细胞用含10%胎牛血清、青霉素(100U/mL)、链霉素(100μg/mL)的RPMI-1640培养基,置于37℃、5%CO2培养箱中常规培养。将细胞接种于不同规格的培养板中,立即加入PMA(终质量浓度100ng/mL),诱导48h,使其完全分化为巨噬细胞。在分化完全的THP-1巨噬细胞中分别加入实施例1至实施例3中和对比实施例2中的卡拉胶鼻用即型凝胶喷雾剂,24h后收集上清液,4℃,1000r/min离心10min,检测上清液中TNF-α的表达量,检测结果见表5。
表5实施例1至实施例3及对比实施例2中卡拉胶鼻用即型凝胶喷雾剂TNF-α的表达量测试结果
由表5可知,本发明中卡拉胶鼻用即型凝胶喷雾剂能够诱导巨噬细胞免疫响应机制,有效提高巨噬细胞分泌TNF-α,可激活人体局部免疫能力,阻断病毒传染的途径,预防呼吸疾病的传染。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (9)
1.一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,按重量百分比计,所述凝胶喷雾剂包括如下组分:κ型卡拉胶5-7%,ι型卡拉胶3-5%,λ型卡拉胶0.001-0.005%,皮肤外用制剂中可以接受的辅料5-16%,余量为水。
2.如权利要求1所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述凝胶喷雾剂还包括处方量的抗病毒药物或抗生素中的至少一种。
3.如权利要求2所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述抗病毒药物为干扰素、盐酸金刚烷胺、盐酸金刚乙胺、替洛隆、扎那米韦、奥司他韦、阿替洛韦、利巴韦林、替诺福韦或恩曲他滨中的至少一种。
4.如权利要求2所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述抗生素为氟氯西林、克林霉素、阿奇霉素、罗红霉素或左氧氟沙星中的至少一种。
5.如权利要求1-4任一项所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述κ型卡拉胶分子量为20-40k;所述ι型卡拉胶分子量为20-40k;所述λ型卡拉胶分子量为10-20k。
6.如权利要求1-4任一项所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述辅料包括助悬剂、润湿剂、防腐剂或pH调节剂中的至少一种。
7.如权利要求6所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述助悬剂占所述凝胶喷雾剂总重量的0.3-5%;所述润湿剂占所述凝胶喷雾剂总重量的5-10%;所述防腐剂占所述凝胶喷雾剂总重量的0.01-1%;所述pH调节剂调节所述凝胶喷雾剂的pH至5.5-6.5。
8.如权利要求7所述的一种卡拉胶鼻用即型凝胶喷雾剂,其特征在于,所述助悬剂为丙烯酸聚合物、卡波普、羧甲基纤维素钠、羟丙基甲基纤维素、黄原胶或去乙酰结冷胶中的至少一种;所述润湿剂为乙醇、甘油、丙二醇、透明质酸钠、聚谷氨酸或吐温60中的至少一种;所述防腐剂为尼泊金类、三氯叔丁醇、氯甲酚、山梨酸钾、苯甲酸或苯甲酸钠中的至少一种;所述pH调节剂为氢氧化钠、氢氧化钾、乙醇胺、乙二胺、碳酸氢钠、盐酸、柠檬酸、山梨酸或磷酸二氢钠中的至少一种。
9.权利要求1-8任一项所述的一种卡拉胶鼻用即型凝胶喷雾剂的制备方法,其特征在于,所述方法如下:将κ型卡拉胶、ι型卡拉胶、λ型卡拉胶、抗病毒药物或抗生素中的至少一种、皮肤外用制剂中可以接受的辅料加入水中,混匀即可。
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