CN117137938B - 用于阴道损伤修复的药物组合物 - Google Patents
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Abstract
本发明提供了一种用于阴道损伤修复的药物组合物。所述药物组合物的剂型优选为凝胶剂，用乙酰化透明质酸和羟乙基脱乙酰壳多糖等作为凝胶基质，在其中引入β‑葡聚糖和地骨皮甲素/乙素。所述凝胶剂制备简单，pH值适当，应用方便，效果突出，具有广泛的市场前景。
Description
技术领域
本发明涉及医药领域，具体而言，本发明涉及一种用于阴道损伤修复的药物组合物。
背景技术
β-葡聚糖是一类由β-糖苷键连接D-葡萄糖单体所构成的非淀粉可溶性葡萄糖复合物，广泛存在与细菌、真菌、植物细胞的细胞壁中。已经发现β-葡聚糖具有降血糖、降血脂、抗感染、抗肿瘤及免疫调节等作用(刘灿,姜燕飞,李勇.β-葡聚糖对创面愈合过程中细胞作用的研究进展[J/OL].中国预防医学杂志,2016,17(01):64-68；BASHIR K M I,CHOI JS.Clinical and Physiological Perspectives ofβ-Glucans:The Past,Present,andFuture[J/OL].International Journal of Molecular Sciences,2017,18(9):E1906)。β-葡聚糖通过活化动物体内的特异性与非特异性免疫达到上述作用，其可以使巨噬细胞、淋巴细胞、成纤维细胞活化，分泌多种细胞因子从而发挥抗肿瘤、促进创面修复等作用(STAPPENBECK T S,MIYOSHI H.The Role of Stromal Stem Cells inTissueRegeneration and Wound Repair[J/OL].Science,2009,324(5935):1666-1669；周瑞瑞,刘爱军,刘建国,等.beta葡聚糖的药理作用研究进展[J].药学实践杂志,2009,27(06):401-403+425)。在皮肤创面修复方面，已发现酵母和灵芝中提取的β-葡聚糖可以保护白化大鼠皮肤的氧化损伤(CEYHAN AM,AKKAYAV B,C,等.Protectiveeffects ofβ-glucan against oxidative injury induced by 2.45-GHzelectromagnetic radiation in the skin tissue of rats[J/OL].Archives ofDermatological Research,2012,304(7):521-527；PILLAI T G,UMA DEVIP.Mushroombeta glucan:potential candidate for post irradiationprotection[J/OL].MutationResearch,2013,751(2):109-115)。其中对于促进创面修复的具体机制方面，有研究发现β-葡聚糖可以促进巨噬细胞及成纤维细胞迁移并刺激肉芽组织酶原和相关金属蛋白酶的分泌和释放一些细胞因子从而修复创面(FRANK L,LEBRETON-DECOSTER C,GODEAU G,等.Dextran derivatives modulate collagen matrix organization in dermalequivalent[J/OL].Journal of Biomaterials Science.Polymer Edition,2006,17(5):499-517；BOREL J P,MAQUART F X.[Molecular mechanisms of wound scarring][J].Annales De Biologie Clinique,1998,56(1):11-19；/>N P,GUASCH M,GUILLEN P,等.Barleyβ-glucan accelerates wound healing by favoring migrationversusproliferation of human dermal fibroblasts[J/OL].Carbohydrate Polymers,2019,210:389-398)。在肠道损伤创面修复方面，有研究发现，β-葡聚糖可以促进兔子、大鼠、牛等肠道损伤的修复，其可以减轻有细菌如大肠杆菌及沙门氏菌对肠道的损伤，并抑制细胞炎症因子的分泌、增强动物的免疫能力和维持肠道菌群稳定(ABO GHANIMA M M,ABD EL-AZIZA H,NORELDIN A E,等.β-glucan administration improves growth performance andgut health in New Zealand White and APRI rabbits with different breedresponses[J/OL].PloS One,2020,15(6):e0234076；VOLMAN J J,MENSINK R P,RAMAKERSJ D,等.Dietary(1-->3),(1-->4)-beta-D-glucans from oat activate nuclearfactor-kappaB in intestinal leukocytes and enterocytes from mice[J/OL].Nutrition Research (New York,N.Y.),2010,30(1):40-48；ZHOU Y,LUO Y,YU B,等.Effect ofβ-Glucan Supplementation on Growth Performance and IntestinalEpithelium Functions in Weaned Pigs Challenged by Enterotoxigenic Escherichiacoli[J/OL].Antibiotics(Basel,Switzerland),2022,11(4):519)。在人溃疡性结肠炎的多种动物实验模型中也观察到相似的结果(KAMIYAT,TANG C,KADOKI M,等.β-Glucans infood modify colonic microflora by inducing antimicrobial protein,calprotectin,in a Dectin-1-induced-IL-17F-dependent manner[J/OL].MucosalImmunology,2018,11(3):763-773；/>-FILHO I,/> AC M,PINHEIRO L AM,等.Prevention of bacterial translocation using beta-(1-3)-D-glucan in smallbowel ischemia and reperfusion in rats[J/OL].Acta Cirurgica Brasileira,2006,21Suppl 4:18-22；SUN Y,SHI X,ZHENG X,等.Inhibition of dextran sodium sulfate-induced colitis in miceby baker’s yeast polysaccharides[J/OL].CarbohydratePolymers,2019,207:371-381；KOPIASZ/>DZIENDZIKOWSKA K,GAJEWSKA M,等.Effects ofDietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs andDectin-1 Signaling Pathways-Crohn’s Disease Model Study[J/OL].Nutrients,2021,13(2):321)。有研究表明，人的成纤维细胞表面有一种葡聚糖受体,它与相应的葡聚糖配体结合后,能够刺激成纤维细胞转录因子活化蛋白AP 21和特异性蛋白1SP1的活化,从而促进成纤维细胞的增殖与迁移，β-葡聚糖还能够刺激神经营养因子NTF-3、血小板衍生的生长因子PDGF-2A、PDGF-2B，血管内皮生长因子VEGF和成纤维细胞生长因子FGF的分泌，这些因子对于促进创面修复具有重要作用(WEID,WILLIAMSD,BROWDER W.Activation of AP-1andSP1 correlates with wound growth factor gene expression in glucan-treatedhuman fibroblasts[J/OL].International Immunopharmacology,2002,2(8):1163-1172；KOUGIAS P,WEID,RICE P J,等.Normal human fibroblasts express patternrecognition receptors for fungal(1-->3)-beta-D-glucans[J/OL].Infection andImmunity,2001,69(6):3933-3938)。
人阴道粘膜上皮主要由腺上皮细胞和鳞状上皮细胞组成(BEKHTEREVA I A,DOROSEVICH A E.[Histophysiology of epithelial and connective tissuecomponents of the vaginal portion of the uterine cervix][J].Morfologiia(SaintPetersburg,Russia),2009,136(5):90-96；CUNHA G R,ROBBOY S J,KURITA T,等.Development of the human femalereproductive tract[J/OL].Differentiation；Research in Biological Diversity,2018,103:46-65)，腺上皮是阴道粘膜修复的主要上皮，与肠腺上皮类似，阴道粘膜腺上皮细胞也具有分泌、吸收、获能等功能，而阴道鳞状上皮细胞则与皮肤鳞状上皮细胞类似。在各种妇产科及阴道私密整形操作中，往往会损伤阴道，对于中老年妇女，阴道一旦损伤，由于体内雌激素水平的下降，恢复常较困难。各种手术修复阴道治愈率各不相同，在阴道前壁损伤修复中，主要应用非移植方法修复阴道，但是这种修复方法复发很常见。使用各种合成网状物或生物移植物来为弱化的筋膜和肌肉组织提供支撑也是修复阴道的一种有效方法，与非移植方法相比，虽然网状物和移植物减少了阴道损伤的客观复发率(JIA X,GLAZENER C,MOWATT G,等.Efficacy and safety of usingmesh or grafts in surgery for anterior and/or posterior vaginalwall prolapse:systematic review and meta-analysis[J/OL].BJOG:an international journalofobstetrics and gynaecology,2008,115(11):1350-1361；BAKO A,DHAR R.Reviewofsynthetic mesh-related complications in pelvic floor reconstructive surgery[J/OL].International Urogynecology Journal and Pelvic Floor Dysfunction,2009,20(1):103-111)。然而，并发症很常见，尤其是阴道纤维化、炎症和上皮糜烂，并且这些装置的长期耐久性和安全性尚不清楚(HUFFAKER R K,MUIR T W,RAO A,等.Histologicresponse of porcinecollagen-coated and uncoated polypropylene grafts in arabbit vagina model[J/OL].American Journal of Obstetrics and Gynecology,2008,198(5):582.e1-7)。对于损伤较轻的阴道损伤，可以选择雌激素保守治疗，但往往其副作用难以避免，例如可能会使子宫内膜癌与乳腺癌的发病风险升高(彭红发,闫晓楠,徐春琳.绝经激素治疗与骨质疏松症[J/OL].中国实用妇科与产科杂志,2020,36(03):230-233；楼春华,兰义兵,马麟娟,等.局部雌激素在绝经后阴道萎缩中的应用及研究进展[J].中国妇幼健康研究,2020,31(11):1562-1567)。
因此，迫切需要提供有效的能够用于修复阴道损伤的药物。
发明内容
针对上述现有技术存在的问题，本发明提供了一种用于阴道损伤修复的药物组合物。所述药物组合物中，β-葡聚糖能够修复阴道损伤，地骨皮甲素和乙素起到增效修复作用的效果。
本发明的一个方面，在于提供了一种用于阴道损伤修复的药物组合物，所述药物组合物包含β-葡聚糖0.5-5份、地骨皮甲素和/或乙素0.1-3份、凝胶基质5-30份、溶剂1-10份、水50-90份、pH调节剂0.01-2份。
进一步的，所述药物组合物为凝胶剂。
进一步的，β-葡聚糖的量为1-5份，优选为3-4份。
进一步的，地骨皮甲素/乙素的量为0.5-1.5份，优选为1-1.25份。
进一步的，β-葡聚糖和地骨皮甲素/乙素的用量比为1-7：1，优选为3-5：1，更优选为3：1或4：1。
进一步的，所述凝胶基质选自透明质酸、壳多糖、胶原蛋白、海藻酸钠、卡波姆、黄原胶，或者其改性物中的一种或多种。优选的，凝胶基质的量为10-30份，优选为16-24份。
进一步的，所述透明质酸包括乙酰化透明质酸，所述壳多糖包括羟乙基脱乙酰壳多糖。
优选的，所述凝胶基质由乙酰化透明质酸和羟乙基脱乙酰壳多糖组成；所述乙酰化透明质酸和羟乙基脱乙酰壳多糖的比例可以为1-3：3-1，优选为1：1。
进一步的，所述溶剂选自甘油、乙二醇、丙二醇、液体石蜡的至少一种，优选为甘油。
进一步的，所述pH调节剂选自三乙醇胺、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、醋酸、乳酸、盐酸、柠檬酸中的至少一种，优选为三乙醇胺。优选的，pH调节剂的量为0.5-1份。
优选的，所述药物组合物的pH值为3.0-4.5。
进一步的，所述药物组合物还包含增稠剂、表面活性剂、杀菌剂、防腐剂中的至少一种。
进一步的，所述增稠剂选自羧甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素中的至少一种。增稠剂的量为0.5-3份。
进一步的，所述表面活性剂选自吐温40、吐温60、吐温80、斯潘40、斯潘60、斯潘80中的至少一种。表面活性剂的量为0.5-3份。
优选的，所述杀菌剂选自酮康唑、甲硝唑、替硝唑中的至少一种。杀菌剂的量为0.1-1份。
优选的，所述防腐剂选自对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、山梨酸、山梨酸钾、苯甲酸、苯甲酸钠中的至少一种。防腐剂的量为0.1-1份。
本发明的另一个方面，在于提供所述药物组合物的制备方法，包括：
将凝胶基质加入到水中，煮沸后冷却至60-80℃，加入β-葡聚糖、地骨皮甲素/乙素溶于溶剂中的溶液，均质，将温度降至40℃以下，加入pH调节剂搅拌均匀即得。
本发明的又一方面，在于提供所述药物组合物在制备药物中的应用，所述药物用于修复阴道损伤、修复阴道粘膜、预防或治疗阴道炎。
有益效果
本发明提供了一种用于阴道损伤修复的药物组合物。所述药物组合物为凝胶剂，用例如乙酰化透明质酸和羟乙基脱乙酰壳多糖组成的凝胶基质，在其中引入β-葡聚糖和地骨皮甲素/乙素，β-葡聚糖有一定的阴道损伤修复作用，而地骨皮甲素和乙素增强了该作用，与β-葡聚糖产生了协同增效作用。所述凝胶剂制备简单，pH值适当，应用方便，效果突出，具有广泛的市场前景。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
应当理解的是，在说明书和权利要求书中使用的术语或词语不应当理解为具有在字典中限定的含义，而应理解为在以下原则的基础上具有与其在本发明上下文中的含义一致的含义：术语的概念可以适当地由发明人为了对本发明的最佳说明而限定。
实施例1-3及对比例1-3的修复凝胶配方如下表所示：
表1：凝胶配方
制备方法如下：将乙酰化透明质酸、羟乙基脱乙酰壳多糖加入到纯水中，煮沸后冷却至75℃，加入β-葡聚糖和/或地骨皮甲素/乙素溶于甘油中的溶液，均质，将温度降至35℃，加入三乙醇胺搅拌均匀制得修复凝胶，凝胶的pH为3.5-4.5。
试验例
1、实验设计
阴道炎模型建造：苯酚胶浆连续给药3d。给药第4d后定义为第1d，在第1d进行试验，于28d进行各指标观察及检测。
2、实验分组
成年雌性大鼠48只，采用随机数字表法分为空白组、模型组、6个给药组，每组6只。
3、实验试剂的浓度、剂量
阴道炎模型建造：苯酚胶浆(配置时取苯酚5ml、西黄蓍胶1g、甘油4ml加蒸馏水至20ml配成含25％(250mg/g)苯酚胶浆)及表1凝胶配方
4、实验试剂注射部位及方法
模型组和给药组大鼠术前12小时禁食，4小时禁水；大鼠称重后，采用10％水合氯醛溶液(0.03ml/kg)进行腹腔注射麻醉，麻醉妥当后对大鼠会阴部皮肤进行备皮，向其阴道内注入25％苯酚胶浆0.1mL，连续给药3d建模。将给药第4d后定义为第1d，于第1d在阴道3点和9点黏膜下注入凝胶，形成水垫，用量为活性成分(β-葡聚糖、地骨皮甲素、地骨皮乙素)20mg/kg。注射后大鼠分笼喂养。于28d处死小鼠进行各指标观察及检测。
表2：大鼠分组及处理情况
5、阴道组织取材
采用脊髓脱臼法处死对应组的大鼠，切除阴道，并将其分成约2-3mm的横切面，横切面编号从1到6(根据阴道的总长度)。HE染色：将生理盐水清洗过后的阴道组织标本浸泡于4％多聚甲醛中固定24小时，流水冲洗后，常规固定脱水处理。石蜡切片脱蜡后移入苏木素中，浸泡15min，移入水中洗去苏木素，1％盐酸酒精作用30s，流水缓慢冲洗30min将组织切片反蓝，移入伊红液中浸染5min后，梯度乙醇脱水，二甲苯透明，中性树脂封片。对取出组织进行编号，在光学显微镜下观察组织样本。常规石蜡包埋制作病理组织切片，可考虑用于后续免疫组织化学染色研究。标本完成观察后置于-80℃冰箱内冷冻保存。Masson三色染色：Masson染色染色按照试剂盒说明书中的方法进行操作。切片常规脱蜡至水，核染液染色1min，冲洗液冲洗30s；质染液染色10s，冲洗液冲洗30s；分化液分色8min；弃去分色液后直接用复染液染色3min，100％乙醇洗净浮色，二甲苯透明，中性树胶封固，普通光学显微镜观察由上皮、固有层和肌层组成的红色染色区域除以胶原纤维和蓝色染色的细胞外基质所占区域的比率变化。
6、检测指标及观察
①一般情况
大鼠经常规饲养，观察大鼠日常行为习惯和进食水等有无异常，注射后动态观察上述行为是否发生改变，观察阴道粘膜注射区域隆起情况，阴道粘膜有无破溃、水肿、红斑等不良反应发生。
②肉眼及显微镜下观察
大鼠处死并取出阴道组织标本后，肉眼观察染色后的植入材料的形态及分布情况。将标本玻片放置于光学显微镜(40X)下进行观察，并采集图片。仔细观察标本周围新生血管细胞生成情况、周围组织炎性细胞浸润情况、masson染色红色区域变化情况、注射材料随时间延长后的均匀度及形态变化情况。根据镜下观察到结果做好记录并采集关键图片，采集中注意不同分组的横向对比与不同时期的纵向对比
③各种实验指标测定：用ELISA法测定血清的炎性因子TNF-α、IL-1β、IL-6、CRP，通过氯化硝基四氮唑蓝(NBT)光化还原法测定阴道组织内超氧化物歧化酶(SOD)、并通过5,5-二硫对硝基苯甲酸(DTNB)法测定谷胱甘肽过氧化物酶(GSH-Px)的活性，通过硫代巴比妥酸(TBA)法测定MDN含量。
7、统计学分析采用SPSS26.0软件行统计学分析，数据用均值±标准差表示，同一列数值上不同字母表示存在显著性差异(P<0.05)。结果示于以下表3和表4中：
表3：炎症因子比较
表4：氧化应激指标比较
在本实验中，观察到本发明组合物处理的大鼠损伤阴道组织标本，HE染色及masson染色镜下新生血管更多、成纤维细胞数量及胶原密度增高，并且损伤阴道粘膜上皮附近的巨噬细胞和成纤维细胞数量与活动度明显高于对照组。在实验组与对照组测定的TNF-α、IL-1、IL-6、CRP等炎症指标中，发现实验组血清炎症因子均显著低于对照组，而丙二醛(MDA)含量显著低于对照组，超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性均显著升高。同时，实验组在降低炎症因子和MDA含量，提升SOD和GSH-Px活性上的效果显著高于同等用量下的β-葡聚糖对照和地骨皮甲素/乙素对照。这表明β-葡聚糖具有抗炎、减轻阴道粘膜损伤并促进损伤阴道粘膜修复的作用，而地骨皮甲素/乙素的使用增加了β-葡聚糖的该作用，起到了协同增效的作用。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
1.一种用于预防或治疗阴道炎的药物组合物，由β-葡聚糖3-4份、地骨皮甲素和/或乙素0.5-1.5份、凝胶基质5-30份、溶剂1-10份、水50-90份、pH调节剂0.01-2份组成；
其中，β-葡聚糖和地骨皮甲素/乙素的用量比为3-4：1；所述凝胶基质由乙酰化透明质酸和羟乙基脱乙酰壳多糖组成，所述乙酰化透明质酸和羟乙基脱乙酰壳多糖的比例为1：1；所述溶剂选自甘油、乙二醇、丙二醇、液体石蜡的至少一种。
2.根据权利要求1所述的药物组合物，其特征在于，β-葡聚糖和地骨皮甲素/乙素的用量比为3：1或4：1。
3.根据权利要求1所述的药物组合物，其特征在于，所述pH调节剂选自三乙醇胺、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、醋酸、乳酸、盐酸、柠檬酸中的至少一种；pH调节剂的量为0.5-1份。
4.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包含增稠剂、表面活性剂、防腐剂中的至少一种。
5.根据权利要求1-4任一项所述的药物组合物的制备方法，包括：
将凝胶基质加入到水中，煮沸后冷却至60-80℃，加入β-葡聚糖、地骨皮甲素/乙素溶于溶剂中的溶液，均质，将温度降至40℃以下，加入pH调节剂搅拌均匀即得。
6.根据权利要求1-4任一项所述的药物组合物在制备药物中的应用，所述药物用于预防或治疗阴道炎。
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