CN113209006A - 一种复方改性几丁质凝胶制剂及其制备方法 - Google Patents
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Abstract
本发明提供一种复方改性几丁质凝胶制剂及其制备方法,属于药物制剂领域。具体的,复方改性几丁质凝胶制剂,包含局麻药、壳聚糖两种活性成分及药学上可接受的辅料。所述辅料包括:凝胶基质、酸和碱组合成的pH调节剂、增溶剂、保湿剂、和溶剂。本发明凝胶不仅可以止血,还可以止痛,患者使用方便,无异物感,能够大大提高患者的依从性。本发明凝胶可以杀菌消毒,促进细胞的活化作用,可大量产生胶原纤维,使伤口不留下疤痕,促进创面愈合。本发明凝胶具有良好的生物相容性、生物降解性,具有较强的抑菌和促进伤口愈合作用。
Description
技术领域
本发明属于药物制剂领域,具体涉及种复方改性几丁质凝胶制剂及其制备方法。
背景技术
几丁质又名甲壳素,是虾蟹等甲壳动物的骨骼和菌类等的细胞膜的重要成分,外观呈白色或微黄色透明体,不溶于水、乙醇和乙醚,是2-乙酰氨基葡萄糖多聚体,其化学结构与天然纤维素相似,分子中除存在羟基外,还含有乙酰氨基和氨基功能基团,属于天然高分子多糖。
几丁质去掉乙酰胺基后生成壳聚糖能溶于烯酸。几丁质脱乙酰化程度越高,生物活性越强,当其脱到分子量低于10万时,能溶于水,称之改性几丁质。
改性几丁质作为一种具有高生物相容性,无毒性和非致敏性的材料,其特有的聚阳离子结构使其与血液接触时可以凝结全血。研究发现血浆中纤维蛋白原和其他血浆蛋白可以与壳聚糖结合,但不与乙酰化壳聚糖结合,证明壳聚糖在结合血浆蛋白质方面明显优于甲壳素,在止血材料研究领域发展迅速。最近的研究表明,壳聚糖具有优异的止血特性,它能够形成阳离子团簇,能够与红细胞上的阴离子相互作用,从而诱导血小板聚集并最终实现止血。这种机制并不取决十患者本身的凝血机制,因此即使在凝血功能障碍患者中也是有效的。
对常见于阻生牙拨除的口腔创伤性出血,常用的止血方法是用可吸收性明胶海绵或药用棉球压迫止血,此法止血时间长,创伤恢复过程中时有继发感染发生。口腔颌面外科手术也因口腔颌面部血供丰富,侧支循环以及静脉丛、网、窦较多,术中、术后出血是医生力图解决的问题。对于口腔创伤、颌面手术等术区出血和疼痛是常见的术后并发症。随着社会的发展,人们的生活水平有了明显提高,不仅仅对拔牙后、颌面手术后止血、止疼有了更高的需求,对于口内舒适感也有了较高的要求。现在临床需要能够止血、止疼并且易于使用、异物感降低的药物制剂,以解决患者顺应性问题。
发明内容
为了解决临床应用中口腔创伤、颌面手术等止血产品效果提升以及患者使用舒适性问题,本发明提供了一种复方改性几丁质凝胶制剂,它能够迅速止血,同时抗菌抗炎有利于创口愈合,同时患者使用不容易有异物感。
本发明第一个目的,提供一种复方改性几丁质凝胶制剂包含局麻药、壳聚糖两种活性成分及药学上可接受的辅料。
所述的局麻药可以是利多卡因或者阿替卡因中的一种或者多种。
所述的壳聚糖脱乙酰度大于70%,优选壳聚糖脱乙酰度大于75%。
所述辅料包括:凝胶基质、酸和碱组合成的pH调节剂、增溶剂、保湿剂、和溶剂。
进一步的所述局麻药含量为1.5-3%,所述壳聚糖含量为0.1-0.5%,所述凝胶基质含量为0.8-1.2%,所述增溶剂含量为0.8-1.2%,所述保湿剂7-8%,所述pH调节剂控制pH6-8。
所述凝胶基质为卡波姆,进一步的凝胶基质为卡波姆940。
所述增溶剂为吐温80。
所述保湿剂为甘油。
所述pH调节剂为醋酸和氢氧化钠组合。
所述溶剂为注射用水或者蒸馏水或者纯化水。
本发明的另一个目的,提供复方改性几丁质凝胶制剂制备方法,步骤如下:
1、将酸、壳聚糖溶于溶剂中;
2、取适量溶剂,搅拌下加入凝胶基质,溶胀得胶液;
3、将局麻药溶于蒸馏水中;
4、第一步溶液中加入保湿剂和增溶剂,再加入第三步局麻药溶液,搅拌均匀得药物溶液;
5、将第4步得到的药物溶液加入到第2步的胶液,搅匀,加溶剂至100g,调节pH至6-8,即得复方改性几丁质凝胶。
有益效果
相比于现有技术,本发明的优点在于:
(1)本发明凝胶不仅可以止血,还可以止痛,患者使用方便,无异物感,能够大大提高患者的依从性。
(2)本发明凝胶可以杀菌消毒,促进细胞的活化作用,可大量产生胶原纤维,使伤口不留下疤痕,促进创面愈合。
(3)本发明凝胶具有良好的生物相容性、生物降解性,具有较强的抑菌和促进伤口愈合作用。
附图说明
图1为本发明的体外凝血试验结果照片。
具体实施方式
下面结合说明书附图和具体的实施例,对本发明作详细描述。
实施例1
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
实施例2
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.0,即得改性几丁质利多卡因凝胶。
实施例3
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至7.2,即得改性几丁质利多卡因凝胶。
实施例4
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至7.8,即得改性几丁质利多卡因凝胶。
实施例5
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至8.0,即得改性几丁质利多卡因凝胶。
实施例6
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
实施例7
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
实施例8
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
实施例9
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
对比例1
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至9.0,即得改性几丁质利多卡因凝胶。
对比例2
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油、吐温80,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,即得改性几丁质利多卡因凝胶,测得pH为5.2。
对比例3
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
对比例4
处方组成如下:
1、将醋酸、壳聚糖溶于蒸馏水中;
2、取适量蒸馏水,搅拌下加入卡波姆,溶胀得卡波姆胶液;
3、将利多卡因盐酸盐溶于蒸馏水中;
4、第一步中醋酸壳聚糖溶液中加入甘油,再加入第三步中利多卡因溶液,搅拌均匀得药物溶液;
5、将药物溶液加入卡波姆胶液,搅匀,加蒸馏水至100g,加入氢氧化钠调剂pH至6.8,即得改性几丁质利多卡因凝胶。
一、稳定性试验:
样品来源:实施例1-8、对比例1-4所制备的改性几丁质利多卡因凝胶
检验方法:分别将实施例1-8、对比例1-4制备得到的样品包装后置于恒温恒湿箱内,按照中国药典2020版中稳定性试验的指导原则的要求,保持温度30℃±2;湿度65%±5,定期取样检测,结果如表1所示。
表1.改性几丁质利多卡因凝胶的加速稳定性试验结果
从以上试验得出,对比实施例1pH 9.0的情况下凝胶稳定性较差,6个月加速试验出现半透明状,并且利多卡因的含量下降,而实施例1-8中pH范围在6-8之间,偏中性,能够保持凝胶的稳定。而对比例2中pH未用碱性调节,使得凝胶中偏酸性,对于伤口而言刺激性较强,对于患者的顺应性较差。
对比例3、4中未使用吐温80和甘油,增容效果变弱,凝胶容易出现分离变质的情况,测得的利多卡因的含量也降低。
二、体外凝血试验
取兔耳动脉血液,置于含有枸橼酸钠(109mmol/L)的抗凝管中,备用。分别取2mL血液于4个塑料离心管中,37℃水浴加热。每管加入0.2mL氯化钙溶液(25mmol/L),同时分别加入0.1g血盾、0.5g改性复方几丁质凝胶(自制实施例1)、最后一组为空白对照。凝血时间为加入样品至血液完全凝固的时间。
不同剂量的纳米凝胶及血盾的体外凝血结果见图1。0.5g改性复方几丁质凝胶30s即可以使2mL血液基本完全凝固(图1,B试管),0.1g血盾却不能使血液完全凝固(图1,A试管),空白对照组5min依然无法使血液凝固(图1,C试管)。
三、动物试验
家兔10只,在全麻下切开牙龈,形成出血创面,分成两组,并分别用纯改性几丁质利多卡因凝胶和生理盐水棉签压迫止血,治疗后24、48、72小时和7天进行观察,并经颈动脉放血致死动物后取检、制片以观察组织学变化。
实验结果表明改性几丁质利多卡因凝胶对牙龈创口出血的止血较生理盐水对照组有极为显著的止血效果,试验结果如下:
表2牙龈不同方法止血时间
生理盐水压迫止血的牙龈创口涂药后24~48小时,创口逐渐形成溃疡伴白色假膜,局部轻度充血,组织切片示重度炎症;48~72小时溃疡面缩小,局部充血基本消失,镜下仍为重度到中度的炎症改变,7天时创口临床愈合,但镜下仍有中度到轻度的炎症改变。改性几丁质利多卡因凝胶止血的牙龈创口涂药后18~24小时,创口逐渐形成溃疡伴白色假膜,局部轻度充血,组织切片示中度炎症;24~60小时溃疡面缩小,局部充血基本消失,镜下显示中度到轻度炎症改变,5天时创口临床愈合。实验结果表明,因改性几丁质自身的抗菌效果,,减轻炎症的发生,可以加速伤口愈合。
同时在观察两组兔子麻药退去后体态反应,明显使用改性几丁质利多卡因凝胶止血的兔子较为安静,表明改性几丁质利多卡因凝胶在阵痛方面也是由于生理盐水止血压迫的。
Claims (10)
1.一种复方改性几丁质凝胶制剂,其特征在于,包含局麻药、壳聚糖两种活性成分及药学上可接受的辅料。
2.权利要求1所述的复方改性几丁质凝胶制剂,其特征在于,所述局麻药是利多卡因或者阿替卡因中的一种或者2种。
3.权利要求1所述的复方改性几丁质凝胶制剂,其特征在于,所述的壳聚糖脱乙酰度大于70%。
4.权利要求3所述的复方改性几丁质凝胶制剂,其特征在于,所述壳聚糖脱乙酰度大于75%。
5.权利要求1所述的复方改性几丁质凝胶制剂,其特征在于,所述辅料包括:凝胶基质、酸和碱组合成的pH调节剂、增溶剂、保湿剂、和溶剂。
6.权利要求5所述的复方改性几丁质凝胶制剂,其特征在于,的所述局麻药含量为1.5-3%,所述壳聚糖含量为0.1-0.5%,所述凝胶基质含量为0.8-1.2%,所述增溶剂含量为0.8-1.2%,所述保湿剂7-8%。
7.权利要求5或6所述的复方改性几丁质凝胶制剂,其特征在于,所述凝胶基质为卡波姆,所述增溶剂为吐温80,所述保湿剂为甘油,所述pH调节剂为醋酸和氢氧化钠组合。
8.权利要求5或6所述的复方改性几丁质凝胶制剂,其特征在于,所述溶剂为注射用水或者蒸馏水或者纯化水。
9.权利要求1所述的复方改性几丁质凝胶制剂,其特征在于,所述凝胶pH6-8。
10.一种复方改性几丁质凝胶制剂制备方法,其特征在于,步骤如下:
1)将酸、壳聚糖溶于溶剂中;
2)取适量溶剂,搅拌下加入凝胶基质,溶胀得胶液;
3)将局麻药溶于蒸馏水中;
4)第一步溶液中加入保湿剂和增溶剂,再加入第三步局麻药溶液,搅拌均匀得药物溶液;
5)将第四步得到的药物溶液加入到第二步的胶液,搅匀,加溶剂,调节pH至6-8,即得复方改性几丁质凝胶。
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