CN113350266B - 一种具有抗菌作用的口腔黏膜修复原位温敏凝胶 - Google Patents
一种具有抗菌作用的口腔黏膜修复原位温敏凝胶 Download PDFInfo
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Abstract
本发明涉及一种具有抗菌作用的口腔黏膜修复原位温敏凝胶及其制备方法。本发明的口腔黏膜修复原位温敏凝胶是由以下原料及其质量份数组成:液态油脂25~55份,植烷三醇1‑8份,大豆磷脂25~45份,多酚5~20份,Tween 0.1~5份,有机溶剂2~15份,薄荷油0.1~5份。本发明的口腔黏膜修复原位温敏凝胶的制备方法包括:i)将大豆磷脂放置入封闭容器内,加入有机溶剂室温振摇溶解,备用;ii)将液态油脂、Tween、薄荷油及多酚依次溶解在上述i)制备的大豆磷脂溶液中,制备得到黄色、澄清的原位温敏凝胶。该原位凝胶不含高分子温敏材料,滴入或喷雾于口腔溃疡黏膜表面,快速形成一层封闭的立方液晶相脂质膜,既具备耐稀释性能和黏膜粘附性,又能缓慢释放多酚抗菌剂,促进溃疡黏膜愈合。本发明的口腔黏膜修复原位温敏凝胶制备简单、重现性好,容易实现大规模生产。
Description
技术领域
本发明属于医疗器械领域,具体涉及一种具有抗菌作用的口腔黏膜修复原位温敏凝胶。
背景技术
口腔粘膜炎是指口腔的炎性和溃疡性反应,为肿瘤患者放化疗常见的几种并发症(如呕吐、食欲降低、过敏反应等)之一,临床常表现为口腔异常疼痛,尤其在说话、进食等刺激后更明显,极大影响了患者的语言交流、正常进食和睡眠,造成生活质量明显下降,甚者阻碍其进一步治疗。目前对于此类并发症的治疗多以含漱液体制剂、散剂,膜剂,软膏剂及凝胶等为主。含漱剂存在滞留时间短,创面闭合效果差等问题。散剂的黏膜粘合性不好,易被唾液稀释、冲散并带离溃疡面,达不到应有的药效;膜剂的制备较为复杂,使用不甚方便,而口腔溃疡软膏主要以凡士林、羊毛脂为辅料,由于它们都是油性基质,不易粘附在口腔粘膜表面,效果不佳。壳聚糖、透明质酸、海藻酸钠及卡波姆等高分子材料制备的凝胶剂铺展性差,难以对不规则创面的塑形封闭。
原位凝胶即在位凝胶,是一类以溶液状态给药,与体液接触或达到体温后在用药部位发生相转变,由液态转化为半固体的凝胶制剂,可以对不规则创面产生较好的塑形封闭效果。王宏等以泊洛沙姆188和泊洛沙姆407为温敏材料,研制了口腔溃疡原位凝胶(中国药师,2020年第23卷第8期)。但该凝胶存在与组织黏附性差和不耐唾液稀释的缺陷,导致其在口腔创面滞留时间短,封闭效果不理想。注射型原位凝胶是将药物和聚合物溶于适宜的溶剂中,局部给药后,在给药部位生理条件刺激下,凝固而形成的半固体凝胶。其中,有机凝胶由水不溶性脂质两性分子和有机溶剂组成的原位凝胶,与水后能膨胀并形成各种形状(片状、六角型、反六角型等)的液晶分离相,广泛用作药物的缓释、控释或脉冲释放等新型给药系统,可以应用于皮肤、鼻腔、口腔、阴道、直肠等多种途径的给药。目前,所研究的两性脂质主要为脂肪酸甘油酯,包括单油酸甘油酯、单棕榈硬脂酸甘油酯和单亚油酸甘油酯。单油酸甘油酯在室温下为蜡质,注入水溶液后形成内有水通道的类似凝胶的三维双层脂质液晶结构,这种液晶结构黏度极大,但加入磷脂、脂肪酸、硫酸叔丁喘宁及烷基甜菜碱后,即可形成黏度小的片状液晶膜,而该片状液晶膜具有温敏性质,室温下黏度小,温度达到37℃时,立即转变成类似凝胶的三维液晶脂质膜结构。但单油酸甘油酯可在组织酯酶的作用下降解,存在引起溶血的风险。中国专利(CN103705442A)公开了一种由磷脂、有机溶剂和水组成原位脂质凝胶。该原位脂质凝胶剂不含脂肪酸甘油脂和高分子温敏材料,接触体液不能自发组装成具有液晶界相的脂质膜。中国专利(CN103705439A)发明了脂质凝胶药物制剂及其制备方法和用途。该脂质凝胶药物制剂由PEG化磷脂、非PEG化磷脂和水性介质组成,不具有原位胶凝特性,用于不规则的口腔创面铺展性差。
多酚类化合物(茶多酚,EGCG,咖啡酸等)具有较强的抗氧化作用,而且安全性好,具有天然的抗龋齿效果。其中,茶多酚作为一种从茶叶中提取的天然多酚类成分,具有抗氧化、抗菌、抗糖尿病、消炎、抗癌等作用。表没食子儿茶素没食子酸酯(epigallocatechin-3-gallate,EGCG)是茶多酚中的有效活性成分,对早期龋齿具有预防和治疗作用。中国专利(CN110876725A)公开了一种含有EGCG防龋齿口腔原位凝胶喷雾剂及其制备方法。该原位凝胶喷雾剂由EGCG、磷脂、表面活性剂、温敏性牙齿粘附剂以及水组成。由于温敏性牙齿粘附剂为泊洛沙姆、羟丙甲基纤维素、甲基纤维素,该原位凝胶剂存在体内口腔应用存在不耐口腔唾液稀释,成膜能力差,粘附能力弱、口腔滞留时间短的缺陷。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足,而提供一种具有抗菌作用的口腔黏膜修复原位温敏凝胶。原位温敏凝胶不含防腐剂和高分子材料,滴入或喷雾于口腔溃疡黏膜表面,快速形成一层封闭的液晶相脂质膜,既具备耐稀释性能和黏膜粘附性,较长时间封闭创面和缓解疼痛。
经过大量实验,本发明制备得到一种具有抗菌作用的口腔黏膜修复原位温敏凝胶,该口腔黏膜修复原位温敏凝胶是由以下原料及其质量份数组成:液态油脂25~55份,植烷三醇1-8份,大豆磷脂25~45份,多酚5~20份,Tween 0.1~5份,有机溶剂2~15份,薄荷油0.1~5份。
上述的液态油酯为35~55份,选自山茶油、肉桂醛油、芝麻油、蓖麻油、二油酸甘油酯、棕榈酸异丙酯中的一种或几种组合。
上述的植烷三醇1-5份。
上述的大豆磷脂为28~40份。
上述的多酚为5~10份,选自茶多酚、EGCG、咖啡酸中的一种或几种。
上述的Tween为0.5~3份,选自Tween-80、Tween-60、Tween-40中的一种或几种。
上述的有机溶剂为2~10份,选自无水乙醇、丙二醇、甘油中的一种或几种组合。
上述的薄荷油为0.5~3份,作为矫味剂。
上述的原位温敏凝胶不含水、防腐剂和温敏性聚合物。
一种上述的口腔黏膜修复原位温敏凝胶的制备方法,其特征在于:制备方法包括以下步骤:
(1)在室温下,称取大豆磷脂至容器内,加入有机溶剂,密闭容器,缓慢振摇溶解形成大豆磷脂溶液;
(2)将液态油脂、植烷三醇、Tween、薄荷油以及多酚依次溶解在上述大豆磷脂溶液中,制备黄色、澄清的溶液,即为口腔黏膜修复原位温敏凝胶。
上述的温敏凝胶临床使用时,可直接滴入或喷雾或涂布至口腔溃疡黏膜区域。
本发明的口腔黏膜修复原位温敏凝胶有益效果如下:原位温敏凝胶中的液态油脂和大豆磷脂作为成膜材料,可包裹多酚于脂质双分子层内,持久粘附于溃疡创面,并使其缓释释放,产生抗菌的作用,有利于口腔溃疡创面的疼痛缓解和创面愈合;该原位凝胶不含高分子温敏材料,滴入或喷雾于口腔溃疡黏膜表面,在唾液和体温诱导下,快速形成一层液晶相脂质膜。该温敏凝胶制备方法简单、重现性好,容易实现大规模生产。
本发明的口腔黏膜修复原位温敏凝胶相比同类温敏凝胶的产品存在如下优势:1)能快速形成脂质膜特性,原位温敏凝胶与唾液接触后,在体温诱导下,能快速形成液晶态的脂质膜,粘附于溃疡面;2)形成的液晶态脂质膜具有耐唾液稀释特性,能较长时间保持凝胶状态,不溶解流失;3)具有不规则创面的塑形封闭特性,原位温敏凝胶为溶液,可以在不规则创面快速扩散铺展,胶凝封闭创面;4)含有天然的多酚组分,具有天然抗菌作用,能加速创面愈合。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,根据这些附图获得其他的附图仍属于本发明的范畴。
图1为实施例一组2制备的原位温敏凝胶图片(左图)和加等体积生理盐水胶化后的图片(右图)。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作进一步地详细描述。
实施例1 原位温敏凝胶的制备
按照表1投料,先称取大豆磷脂置密闭容器内,加入配方量的有机溶剂,在室温下缓慢振摇溶解,制备大豆磷脂溶液;另将液态油脂、植烷三醇、Tween、薄荷油以及多酚依次溶解在上述大豆磷脂溶液中,制备出黄色、澄清的溶液,即为原位温敏凝胶。
实施例2 泊洛沙姆407温敏凝胶的制备
采用溶液-凝胶转变法制备泊洛沙姆407温敏水凝胶作为对照,称取泊洛沙姆407材料粉末适量,分散在冷蒸馏水中,放置4℃冰箱过夜,制备得到聚合物溶液;另将称取茶多酚、Tween-80、薄荷油溶于无水乙醇,制备有机相;在迅速搅拌下,将有机相缓慢滴入冷的泊洛沙姆407溶液中,即可制备得到口腔应用的原位温敏凝胶,用于对比研究。所制备的温敏凝胶含有:17份泊洛沙姆407,10份茶多酚,1份Tween-80,1份薄荷油,71份蒸馏水。
实施例3 原位温敏凝胶成膜性能评价
取原位温敏凝胶溶液1mL轻轻滴入37℃恒温的生理盐水表面,观察滴入后成膜性能并记录成膜时间。用回形针钩取脂质薄膜边缘、提取,对成膜强度进行评分。提取过程中,脂质膜完整未破裂,强度评分为:+++;脂质膜断裂,部分提取,强度评分为:++;脂质膜破裂,完全不被提取,强度评分为:+
各实施例和对照例所制备的原位温敏凝胶成膜性能如表1,凝胶的成膜性能由液态油脂,植烷三醇及大豆磷脂用量决定。当配方中大豆磷脂含量高于40份时,大豆磷脂不能完全溶解在有机溶剂中,形成半固态的脂质凝胶,不具有成膜能力;当配方中大豆磷脂用量低于25份,能制备出澄清的温敏凝胶溶液,但滴入37℃恒温的生理盐水表面仍然不能形成脂质膜。当配方中大豆磷脂用量介于28份~40份、液态油脂用量介于35份~55份、植烷三醇用量介于1份~8份时,能制备出澄清的有机溶剂溶液,与水接触后,在体温的协助下,自发组装成具有液晶态的脂质膜。其中,配方中植烷三醇用量在脂质膜形成以及维持脂质膜强度中起着重要的作用,当配方中植烷三醇用量介于1份~5份时,能自发组装成较好强度的脂质膜。而且,成膜时间呈现随配方中大豆磷脂用量增大而延长的趋势,形成的脂质膜强度呈现随配方随液态油脂组分用量增大而增强。
实施例4 原位温敏凝胶耐溶蚀评价
量取2mL温敏凝胶溶液于玻璃瓶中,加入等体积生理盐水,37℃恒温水浴5min,待其完全胶凝,在水凝胶表面加入8mL的pH7.4 PBS(10mM)。将小瓶置于37℃恒温摇床中,速度设定为8rpm,振摇12h后,对剩余的水凝胶进行拍照并检测其体积。水凝胶溶蚀百分数按如下公式定量计算。溶蚀百分数(%)=[1-(Vt/V0)]×100,其中Vt为t时刻水凝胶体积,V0为水凝胶初始体积。对照例9,直接放置入37℃恒温水浴5min,待其完全胶凝,进行上述方法测试。
各实施例和对照例所制备的凝胶溶蚀百分数结果如表2,本发明实施例中制备的原位温敏凝胶,相比实施例2制备的Poloxamer 407温敏凝胶具有更强的耐溶蚀特性。而且胶化后的脂质凝胶溶蚀百分数与处方中Tween的用量有关,随着Tween用量增大,溶蚀百分数增大。
实施例5 抑菌实验
取大肠杆菌K88、链球菌菌株接种到LB培养基上,37℃培养24h,用接种环挑单菌到3ml LB液体培养基中,37℃、200r/min震荡培养制备菌悬液。取100μL菌悬液均匀涂布于LB/SS平板,放置约30min后,直径为7mm试纸预先覆盖胶凝的脂质膜(实施例及对照例试样),放在平板上,同时抗菌药物浸泡后的药敏试纸放在平板上作为阳性对照,蒸馏水浸泡后的试纸放为阴性对照,37℃培养24h,用游标卡尺量出各抑菌圈的直径,每种样品重复3次取其平均值,观察抑菌圈的大小。本实验中使用0.2g/L林可霉素和0.5g/L的哌拉西林作为阳性对照。
各实施例和对照例所制备的凝胶抑菌结果如表2,抑菌率与处方中多酚用量有关。当多酚用量达到5-15份可达到明显的抑菌效果,而且形成的脂质凝胶抑菌率随多酚用量增加而增强。当配方中多酚用量达到15份时,达到阳性抗菌药物(林可霉素或哌拉西林)相当抑菌效果。
实施例6 口腔黏膜刺激性评价
金色仓鼠用戊巴比妥钠(30mg/kg)腹腔注射将其麻醉,麻醉后用0.2份新洁尔灭消毒仓鼠的口腔内外,取直径约5mm的棉球蘸取0.2mL温敏凝胶溶液(给药组)或氯化钠注射液对照组,分别放入仓鼠口腔两侧颊粘膜最低处,左侧放置温敏凝胶棉球,右侧放置氯化注射液棉球,保持1h。给药用24h,麻醉处死动物,小心取出两侧颊粘膜组织,肉眼观察有无充血、肿胀、糜烂及溃疡反应,反应程度分为无、轻、中及重度。
各实施例1所制备的凝胶抑菌结果见表2,所制备的原位温敏凝胶刺激性与处方中多酚及Tween用量有关。当配方中多酚低于3份时,所制备原位温敏凝胶未见明显的口腔黏膜刺激性;当Tween用量高于5份时,所制原位温敏凝胶未见明显的黏膜刺激性。
实施例7 药效学评价
采用90%苯酚溶液化学烧灼法建立口腔溃疡动物模型。大鼠在10%水合氯醛(0.3mL/100g)麻醉下,将内径为5mm的玻璃管(内有棉球,与端口齐平)放在90%苯酚溶液中,使药液浸透棉球,将玻璃管外侧面苯酚溶液擦拭干净,后将玻璃管的棉球端置于大鼠舌腹中1/3处烧灼60s,1d后形成溃疡,用游标卡尺测量溃疡直径并计算其面积(A0)。溃疡模型形成后,分别局部涂抹实施例和对照例溶液,1次/d,给药后30min禁食禁水,空白对照组用生理盐水冲洗溃疡面。治疗后7d,记录溃疡变化情况,用游标卡尺测量溃疡直径并计算其面积(A7)。根据测量面积,计算治疗后口腔创面闭合率=[1-A7/A0]×100%。
各实施例和对照例所制备的温敏凝胶对口腔溃疡创面闭合效果如表2,所制备实施例制备的原位温敏凝胶对口腔溃疡黏膜闭合效果均超过80%,而对照例制备的原位温敏凝胶对溃疡口腔黏膜的闭合率小于70%,表明本发明所制备的原位温敏凝胶具有更好的创面修复作用。
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。
表1口腔黏膜修复原位温敏凝胶的实验设计和分组
注:茶:山茶油;桂:肉桂醛油;芝:芝麻油;蓖:蓖麻油;DOG:二油酸甘油酯;IPP:棕榈酸异丙酯;EGCG:表没食子儿茶素没食子酸酯;T-80:Tween-80;T-60:Tween-60;T-40:Tween-40;E:乙醇;B:丙二醇;G:甘油;脂质膜完整未破裂,强度评分为:+++;脂质膜断裂,提取部分,强度评分为:++;脂质膜破裂,完全不被提取,强度评分为:+;-:缺少组分;*:未测试;Y:能成膜;N:不能成膜;
表2各组口腔黏膜修复原位温敏凝胶的应用效果评价
Claims (8)
1.一种具有抗菌作用的口腔黏膜修复原位温敏凝胶,其特征在于:所述的口腔黏膜修复原位温敏凝胶是由以下原料及其质量份数组成:液态油脂25~55份,植烷三醇1~8份,大豆磷脂25~45份,多酚5~20份,Tween 0.1~5份,有机溶剂2~15份,薄荷油0.1~5份,所述的液态油脂选自山茶油、肉桂醛油、芝麻油、蓖麻油、二油酸甘油酯、棕榈酸异丙酯中的一种或几种组合,所述的多酚选自茶多酚、EGCG、咖啡酸中的一种或几种,所述的口腔黏膜修复原位温敏凝胶,滴入口腔溃疡黏膜区域,接触口腔黏液,能快速发生相分离,在体温作用下,形成抗菌作用的脂质保护膜覆盖于溃疡面,促进溃疡黏膜愈合;
所述的原位温敏凝胶不含水、防腐剂和温敏性聚合物。
2.根据权利要求1所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述液态油脂为35~55份,所述植烷三醇为1~5份。
3.根据权利要求1和2任一项所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述的大豆磷脂为28~40份。
4.根据权利要求1所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述的多酚为5~10份。
5.根据权利要求1所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述的Tween为0.5~3份,选自Tween-80、Tween-60、Tween-40中的一种或几种。
6.根据权利要求1所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述的有机溶剂为2~10份,选自无水乙醇、丙二醇、甘油中的一种或几种组合。
7.根据权利要求1所述的口腔黏膜修复原位温敏凝胶,其特征在于:所述的薄荷油为0.5~3份,作为矫味剂。
8.一种权利要求1~3任一项所述的口腔黏膜修复原位温敏凝胶的制备方法,其特征在于:所述的制备方法包括以下步骤:
(1)在室温下,称取大豆磷脂至容器内,加入有机溶剂,密闭容器,缓慢振摇溶解形成大豆磷脂溶液;
(2)将液态油脂、植烷三醇、Tween、薄荷油以及多酚依次溶解在上述大豆磷脂溶液中,制备黄色、澄清的溶液,即为口腔黏膜修复原位温敏凝胶。
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