CN117084968A - 一种治疗放射性直肠炎的温敏凝胶及其制备工艺 - Google Patents
一种治疗放射性直肠炎的温敏凝胶及其制备工艺 Download PDFInfo
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Abstract
本发明公开了一种治疗放射性直肠炎的温敏凝胶,属于临床医学尤其是放射肿瘤学领域,所述的温敏凝胶包括生理缓冲体系、温敏凝胶体系、自由基清除体系、冷感通道调节体系、保湿润滑剂、粘膜修复剂、微量元素及抑菌剂,本发明在模拟直肠粘膜的微环境的基础上,利用温敏凝胶技术实现原位保护、快速长效隔离受损的粘膜免受病原微生物及生理金属离子刺激,进而通过冷感通道蛋白TPRM8激动剂的作用,调节冷通道的冷感阈值缓解疼痛;利用自由基清除剂的V‑C‑M循环清除作用,清除放疗过程中因放射线的间接作用在直肠粘膜组织中形成的过量的自由基,进而从源头消除切断放射线直肠炎的发生发展进程,促进直肠粘膜组织的快速修复。
Description
技术领域
本发明属于临床医学尤其是放射肿瘤学领域,涉及一种新型治疗放射性直肠炎的温敏凝胶及其制备工艺。
背景技术
随着医疗技术水平的不断提升,放射治疗在肿瘤的综合治疗中的作用日益突出,约70%的癌症患者在治疗癌症的过程中需要用放射治疗,放射治疗已成为治疗恶性肿瘤的主要手段之一。随着新辅助放化疗带来明显的生存获益的同时,结直肠癌幸存者也越来越多,尽管放疗显著延长了患者的生存时间,但其对正常组织所产生的物理性损伤作用,会导致盆腹腔脏器的损伤,其中以直肠损伤最为常见且顽固。
放射性直肠炎(radiation proctitis,RP)是指因盆腔恶性肿瘤如***、子宫内膜癌、卵巢癌、***癌、直肠癌、膀胱癌等患者接受放疗后引起的直肠放射性损伤。放射性直肠炎是结直肠癌新辅助放疗后常见的肠道并发症,尽管随着放疗技术的不断提升,正常组织的受照射剂量已经得到了很好的控制,但正常的组织辐射毒性仍然是癌症治疗的最大障碍。根据起病时间及病程变化情况,可分为急性放射性直肠炎(acute radiationproctitis,ARP)和慢性放射性直肠炎(chronic radiation proctitis,CRP),通常以3个月为急慢性分界。超过75%的接受盆腔放疗的患者会发生ARP,5%-20%的患者会发展为CRP。实际上.CRP的发病率极有可能被低估,因为不是每位出现症状的患者都会及时就诊。Gami等报道,81%的盆腔放疗患者可出现消化道症状,但仅有55%的患者向专业医生求诊。CRP患者症状迁延反复,易出现晚期严重并发症,如消化道大出血、穿孔、梗阻、肠痿等,临床诊治难度大,患者生活质量受到严重影响。约90%的CRP患者可有永久性的排粪习惯改变,50%的患者表示其生活质量受到各种消化道症状的影响。此外,CRP的患者尚可同时出现放射性小肠炎、放射性膀胱炎、放射性***或原发肿瘤复发转移等情况,这给患者诊治方案的制定带来更大的困难与挑战。
目前对于放射性直肠炎,国内外尚缺乏理想的药物和治疗方法。在实际的临床过程中,医护人员对于放射性直肠炎的处理,主要采用激素、对症支持治疗等方式,来缓解症状,但疗效并不理想。激素治疗存在依赖性强、疗程长、副作用多等问题。对症治疗如抗生素、止血药物、成膜剂等无法从本质上修复受损黏膜。近年来研发的药物和治疗设备,包括氨基酸肽、抗炎药物灌肠、植入式靶向释药***等,疗效各异,部分存在安全性问题,尚未在临床广泛应用,更有甚者严重影响放疗计划的执行,降低患者的生存质量。
CN102302690A公开了一种治疗放射性直肠炎的中药,该发明遵循中医的处方原则,将上述中药筛选,浸泡30分钟后水煎服用,每日1剂、共煎出200ml,每次100ml,早、晚分服。虽然在目前的研究过程,大量的中草药方剂用于放射性直肠炎的治疗,但就其临床效果而言良莠不齐,主要原因是中草药配方中的各组分的配比因人而异,无法形成固定的方剂。
为此,提出一种治疗放射性直肠炎的温敏凝胶及其制备工艺。
发明内容
本发明提供了一种治疗放射性直肠炎温敏凝胶,主要由生理缓冲体系、温敏凝胶体系、自由基清除体系、冷感通道调节体系、保湿润滑剂、微量元素及长效抑菌剂组成,由于直肠粘膜中腺体分泌的直肠液,为中性且缓冲能力极差。
为了实现本发明的目的,本发明所述的生理缓冲体系,主要由磷酸盐缓冲液、柠檬酸盐缓冲液、碳酸盐缓冲液、丙酮酸缓冲液、硼酸盐缓冲液中的一种或多种组合,其中优选磷酸盐、柠檬酸盐、硼酸盐缓冲液。其中缓冲液浓度为浓度为5-50mM,其中优选5-15mM,pH值为6.0-8.0,其中优选为6.5-7.0;所述的缓冲溶液在本产品中占比为523份-832份。
所述的温敏凝胶体系,可以选择壳聚糖-甘油磷酸钠型、泊洛沙姆型、聚-N异丙基丙烯酰胺型中的一种或多种组合,其中优选泊洛沙姆型温敏凝胶。为了进一步满足本发明的需要,泊洛沙姆选择407和188两种型号,为了进一步满足本发明的目的,其中泊洛沙姆407的用量为150份-300份,其中优选为160份-200份,泊洛沙姆188用量为5-30份,其中优选为10-20份。
为了实现本发明清除自由基的目的,放射性直肠炎温敏凝胶中自由基清除体系采用非酶自由基清除剂如:VC、VE、胡萝卜素等;酶类自由基淬灭清除剂如超氧化物歧化酶、还原性谷胱甘肽、过氧化氢酶,以及SOD类似物如依达拉奉氨磷汀等;自由基淬灭剂如肌肽、甘露醇等,为了满足本发明的目的,自由基清除体系可以为上述中的一种或多种组合,其中优选超氧化物歧化酶、过氧化氢酶组合或者VC、肌肽、甘露醇组合。其中由于超氧化物歧化酶及过氧化氢酶的半衰期较短,无法适应实际的产品的剂型及生产需求,故选择VC、肌肽及甘露醇组合形成V-C-M循环式自由基淬灭剂。为了进一步明确本发明中自由基清除体系的用量及生产工艺,其中VC含量为0.1份-1.5份,更进一步优选为0.5-1.0份;肌肽含量1份-10份,更一步的优选为3-6份;甘露醇含量为1-20份,更进一步优选为5-15份。
为了实现本发明快速缓解疼痛的目的,放射性直肠炎温敏凝胶的冷感通道调节体系,由薄荷醇,薄荷脑,薄荷油,水溶性薄荷提取物,冰片、桉油精、薄荷类似物WS-12,WS-23中的一种或多种组合,其中优选水溶性的薄荷提取物以及水溶性的WS-12、WS-23,更进一步优选WS-23。为了进一步明确冷感通道调节体系的用量及满足本发明的功能,其中WS-23的含量为0.01份-0.2份,更进一步地优选为0.05份-0.1份。
为了实现本发明的目的,放射性直肠炎的温敏凝胶中的保湿润滑成分,保湿润滑剂可以由甘油、丙二醇、透明质酸钠、普鲁兰多糖、海藻糖等中的一种或和多种组合。其中优选普鲁兰多糖与甘油的组合,为了进一步明确普兰多糖与甘油的用量以满足本发明的目的,其中普鲁兰多糖用量为1-10份,其中优选为3-6份;甘油用量为5-100份,其中优选为10-50份。
为了实现本发明的目的,微量元素主要由锰离子,钴离子,铜离子,钙离子,镁离子,锌离子等中的一种或多种组合,其中优选为钴离子和锌离子组合。
更进一步地,钴离子优选为甲钴胺、钴氨素、VB12中的一种或多种组合,其中优选为VB12;为了实现本发明的目的,其中VB12的用量为0.01-0.2份,其中优选为0.02-0.1份。
更进一步地,锌离子采用柠檬酸锌、醋酸锌、葡萄糖酸锌、肌肽锌、氨基酸螯合锌的一种或多种组合,其中优选为柠檬酸锌或氨基酸螯合锌。为了实现本发明的目的,当锌离子采用柠檬酸锌时,用量为0.01份-0.5份,其中优选0.01份-0.3份;当锌离子采用氨基酸螯合锌时,用量为0.01份-0.5份,其中优选为0.01-0.3份。
为了实现本发明的目的,在粘膜修复剂方面,可以由肝素钠、硫酸软骨素、尿囊素、交联透明质酸等中的任意一种或多种组合,其中优选为尿囊素,为了实现本发明的目的,其中尿囊素优选为1-10份,其中优选为3-8份。
为了满足本发明的需求,在长效抑菌剂方面,由山梨酸钾、苯甲酸钠、尼泊金、PHMB、PH份B、奥替尼啶等中的一种或多种组合,其中优选为山梨酸钾、PHMB、奥替尼啶中任意一种。当使用山梨酸钾时浓度为0.02-3份,其中优选为0.1-2份,当使用PHMB作为抑菌剂时用量为0.05份-0.5份,其中优选为0.1-0.2份,当使用奥替尼啶作为抑菌剂时用量为0.01份-0.1份,其中优选为0.05-0.1份。
为了进一步描述本发明的放射性直肠炎温敏凝胶的制备工艺,本发明的制备工艺如下:
步骤一、按份数配制生理缓冲体系;
步骤二、在生理缓冲体系中按份数依次加入自由基清除体系、冷感通道调节体系、保湿润滑剂、微量元素、粘膜修复剂及抑菌剂;
步骤三、上述溶液搅拌均匀后,通过0.22μm微滤膜过滤除菌;
步骤四、在过滤液中按份数加入温敏凝胶体系,于4-12℃,搅拌过夜,一直彻底溶解;
步骤五、根据使用需求,无菌分装至一次性预灌封针筒中。
与现有技术相比,本发明的温敏凝胶具有以下有益的技术效果:
1、能形成在体温下快速凝固的保护层,隔绝病原微生物和刺激,减轻黏膜炎症;
2、自由基清除体系可清除放射线产生的活性自由基,减轻放射损伤;
3、冷感通道调节体系可激活冷感受体TRPM8,调节黏膜痛觉阈值,缓解疼痛;
4、保湿剂可保持黏膜水合,促进损伤修复;
5、微量元素和抑菌剂可提高黏膜修复能力,预防感染。
6、本发明制备简便,能显著减轻放射性直肠炎的症状,改善患者生活质量。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式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,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明治疗放射性直肠炎的温敏凝胶的制备流程图。
具体实施方式
为了进一步说明本发明中放射性直肠炎温敏凝胶的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例,进一步阐述本发明。
实施例1到实施例4(温敏凝胶A-D,共计1000份):
步骤1、按照表1内容预先预先配制缓冲溶液1000份;
磷酸盐缓冲液:20mM,pH值为7.0磷酸氢二钠-磷酸二氢钠缓冲溶液;
柠檬酸盐缓冲液:25mM,pH值为7.0柠檬酸-氢氧化钠缓冲溶液;
硼酸盐缓冲液:25mM,pH值为7.0硼酸-氢氧化钠缓冲溶液。
步骤2、根据表1的内容加入取不同量的溶剂,并加入表格对应的溶质一中的产品组分,充分搅拌溶解;
步骤3、将上述配制的溶液利用0.22μm微滤膜过滤除菌;
步骤4、将表1中对应溶质二组分加入过滤后的溶液中,4-12℃,搅拌过夜,彻底溶解。
步骤5、在无菌条件下,进行定量分装至一次性预灌封针筒中,阻菌薄膜袋或铝箔袋、铝箔泡罩等方式进行内包,采用钴60进行灭菌,即可得本发明的放射性直肠炎温敏凝胶。
表1温敏凝胶的配置表
实施例5、温敏凝胶的相变温度及相变时间
在25℃条件下,取上述实施例1-4中产品各1ml样品铺于10mL锥形瓶底部瓶口用封口膜密封将其放人水浴槽中,插人数显温度计(温度计下端完全浸没在待测液体中)。保持水浴持续缓慢升温(速率:0.2℃/min),手动微微倾斜锥形瓶以凝胶不流动时的温度定义为相变温度。
直肠温度得正常值为36.5-37.7℃,为了进一步确认本产品在直肠环境中的相变时间,取环境温度为37℃。将上述实施例1-4中产品各1ml样品转入薄壁试管中,加塞。将其放入37℃恒温水浴槽中。缓慢旋转试管,观察样品形态,记录开始旋转试管至凝胶不流动所需时间。结果如表2所示℃
表2温敏凝胶相变温度及相变时间
产品 | 实施例一 | 实施例二 | 实施例三 | 实施例四 |
相变温度 | 35℃ | 36.5℃ | 37℃ | 35.5℃ |
相变时间 | 45S | 60S | 70S | 50S |
通过实施例的相变温度计相变时间可以发现,本发明的实施例中的温敏凝胶可以在体温环境内完成由也到凝胶状态的转变,同时相变的速度为45-90S内,满足临床使用的要求。
实施例6、温敏凝胶超氧阴离子自由基自由基清除效率的确认
取上述实施例中的温敏凝胶1ml作为试验样品,并且以1000U/ml的超氧化物歧化酶作为参照,按照以下的实验方案进行。
取0.05molLTris-HC1缓冲液(pH8.2)3.5ml,置于25℃水浴中预热20min,分别加入1ml不同的样品和参照品,25℃水浴中预热20min,再加入25℃水浴中预热20min的3mmol/L邻苯三酚溶液1ml,混后于25C水浴中准确反应5min,加入10mol/L HCl 0.5ml终止反应,于325nm处测定吸光度,空白对照组以相同体积的蒸馏水代替样品。每个试样作三个平行样,取其平均值。实验结果以清除率E表示:E=(A空白-A样品)/A空白x100%。
结果如下表3
表3温敏凝胶超氧阴离子自由基的清除效率
放疗过程中放射线在杀伤肿瘤细胞的同时,高能的放射线可以引起组织内水分的电离,产生超氧阴离子自由基进一步对正常组织造成损伤。超氧化物歧化酶SOD作为超氧阴离子自由基专一的清除剂,在放疗引起的放射线损伤收到了广泛的关注。先前的研究及市场上用于放射性损伤的产品,产品的酶活性为1000U/ml。本发明以1000U/ml的超氧化物歧化酶溶液作为参照品,通过本实验可以发现,参照品的超氧阴离子自由基清除率为85%,实施例中的温敏凝胶的清除率与之相差不大,且凝胶C的清除率明显优于参照品。
实施例7、温敏凝胶的羟基自由基自由基清除效率的确认
以实施例1-实施例4中的温敏凝胶作为本实施例的样品,在试管中分别加入2ml的温敏凝胶,9mmol/L水杨酸-乙醇2ml,9mmol/L FeSO4,2ml,最后加入2ml,8.8mmol/L H2O2启动反应,37℃,振荡反应15min。以蒸馏水为空白对照,在510nm下测量各待测液的吸光度。结果如下表4所示。
羟基自由基清除率=A0-Ax/A0*100%
其中:A0为空白对照的吸光值,AX为加入样品的吸光值。
表4温敏凝胶羟基自由基清除效率
样品名称 | 凝胶A | 凝胶B | 凝胶C | 凝胶D |
清除率 | 75% | 60% | 86% | 80% |
从实验结果来看,实施例1-实施例4中的温敏凝胶,对羟基自由基均有一定的清除作用,尤其是实施例3中的温敏凝胶C的清除作用最强。在放疗过程中放射线的电离作用产生超氧阴离子自由基,超氧阴离子作为活性氧的一个部分,可直接转化为更具毒性的羟基自由基,因此彻底解决放射线的对正常组织细胞产生的副反应,需要同时解决超氧阴离子自由基和羟基自由基对细胞造成的损伤。
实施例8、温敏凝胶的生物相容性
为了进一步,确认本发明所述的产品在临床使用过程的安全性,为此我们按照实施例三中的配方和工艺,制备出温敏凝胶C。
取温敏凝胶C,按照0.2g/ml的比例用1640细胞培养液或者胎牛血清细胞培养基,浸提24小时,取样液按照ISO10993-5:2009中规定的MTT法进行试验,平行三组实验。
实验结果,细胞相对增殖度,最小值大于85%,平均值为90%,达到ISO10993-5:2009规定标准(≥70%),表明本发明的所述的温敏凝胶生物相容性好,无毒、安全。
实施例9、温敏凝胶的临床作用(动物实验)
为了验证本发明的临床作用,我们按照实施例三中的配方和工艺,制备出温敏凝胶C,作为样品,以国产医用射线防护喷剂、康复新液作为对照品,以临床常用的复方普鲁卡因灌肠液(0.25%普鲁卡因200ml加庆大霉素8万单位,强的松10mg加1%肾上腺素1~2ml)作为安慰剂。
选用大鼠为试验动物,利用直线加速器单次大剂量盆腔局部照射,建立放射性直肠炎动物模型。模型大鼠出现腹泻、粘液脓血便、消瘦等表现。直肠镜下观察直肠隐窝结构破坏、大量炎细胞浸润,粘膜下血管充血、多灶溃疡。根据ROTG分级标准鉴定为III级。
分别用温敏凝胶C、医用射线防护喷剂、康复新液、普鲁卡因灌肠液对模型大鼠进行分组治疗,每组20只大鼠。正常饲养一周,察动物一般状况、体重、排便情况,光镜及电镜观察直肠粘膜损伤程度,并根据ROTG分类标准进行评判。以治疗前评分与治疗后评分的差值为1,视为有效;以差值为2视为显效,以差值为3时,作为治愈。
表5动物模型治疗效果
通过动物实验结果表明,本发明的温敏凝胶的对于模型动物的放射线直肠炎均有一定的治疗效果。本发明温敏凝胶能有效地改善照射后动物一般状况,控制腹泻及便血,改善放射性直肠炎大鼠之长粘膜损伤,保护肠粘膜,促进溃疡愈合。本发明所述温敏凝胶总有效率100%,其中治愈率25%,显效率80%。本发明所述的温敏凝胶相比较医用射线防护喷剂组、康复新液组,由着优异的治疗效果。
尽管本发明的实施方案已公开如上,但其并不仅限于说明书和实施方式中所列举的运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改。如本发明所公布的温敏凝胶只需要改变温敏凝胶中的缓冲液组成及缓冲液pH值,即可用于放射性***炎、放射性皮肤损伤。
需要说明的是,在本发明中,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下,由语句“包括一个……”限定的要素,并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
以上所述仅是本发明的具体实施方式,使本领域技术人员能够理解或实现本发明。对这些实施例的多种修改对本领域的技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所述发明的原理和新颖特点相一致的最宽的范围。
Claims (10)
1.一种治疗放射性直肠炎的温敏凝胶,其特征在于:包括生理缓冲体系、温敏凝胶体系、自由基清除体系、冷感通道调节体系、保湿润滑剂、微量元素、粘膜修复剂及抑菌剂。
2.根据权利要求1所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述生理缓冲体系的组分为523-832份,所述温敏凝胶体系的组分为160-320份,所述自由基清除体系的组分为2.1-31.5份,所述冷感通道调节体系的组分为0.01-0.2份,所述保湿润滑剂的组分为6-110份,所述微量元素的组分为0.02-0.7份,所述粘膜修复剂的组分为1-10份,所述抑菌剂的组分为0.01份-3份。
3.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的生理缓冲体系由磷酸盐缓冲液、柠檬酸盐缓冲液、硼酸盐缓冲液中的一种或多种组合。
4.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的温敏凝胶体系由壳聚糖-甘油磷酸钠型、泊洛沙姆型、聚-N异丙基丙烯酰胺型中的一种或多种组合。
5.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述自由基清除体系由VC、肌肽及甘露醇组合形成V-C-M循环式自由基淬灭剂,所述的冷感通道调节体系由由薄荷醇、薄荷脑、薄荷油、水溶性薄荷提取物、冰片、桉油精、薄荷类似物WS-12、薄荷类似物WS-23中的一种或多种组合。
6.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的保湿润滑剂由甘油、丙二醇、透明质酸钠、普鲁兰多糖、海藻糖等中的一种或多种组合。
7.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的微量元素由锰离子,钴离子,铜离子,钙离子,镁离子,锌离子等中的一种或多种组合。
8.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的粘膜修复剂,采用肝素、肝素钠、硫酸软骨素、尿囊素、交联透明质酸等中的任意一种或多种组合。
9.根据权利要求2所述的治疗放射性直肠炎的温敏凝胶,其特征在于:所述的抑菌剂由由山梨酸钾、苯甲酸钠、尼泊金、PHMB、PH份B、奥替尼啶等中的一种或多种组合。
10.根据权利要求1-9任意一项所述的治疗放射性直肠炎的温敏凝胶制备工艺,其特征在于,包括如下步骤:
S1:按份数配制生理缓冲体系;
S2:在生理缓冲体系中按份数依次加入自由基清除体系、冷感通道调节体系、保湿润滑剂、微量元素及抑菌剂;
S3:上述溶液搅拌均匀后,通过0.22μm微滤膜过滤除菌;
S4:在过滤液中按份数加入温敏凝胶体系,于4-12℃,搅拌过夜,一直彻底溶解;
S5:根据使用需求,无菌分装至一次性预灌封针筒中。
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