CN114832020A - 一种用于防治儿童发育障碍的药物组合物及其制备方法 - Google Patents
一种用于防治儿童发育障碍的药物组合物及其制备方法 Download PDFInfo
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- CN114832020A CN114832020A CN202210624862.6A CN202210624862A CN114832020A CN 114832020 A CN114832020 A CN 114832020A CN 202210624862 A CN202210624862 A CN 202210624862A CN 114832020 A CN114832020 A CN 114832020A
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- bacillus coagulans
- calcium carbonate
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Abstract
本发明涉及一种用于防治儿童发育障碍的药物组合物,所述组合物由药物活性成分和药学上可接受的载体组成,其中,所述药物活性成分由碳酸钙、维生素D3、维生素K2、葡萄糖酸锌、凝结芽孢杆菌和氨基酸组成,以钙元素计,所述药物活性成分中钙元素:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:氨基酸的重量比为500:0.005:0.04‑0.10:50‑100:30‑100:50‑120。本发明的药物组合物协同利用凝结芽孢杆菌和氨基酸促进机体对钙、锌、维生素D3、维生素K2的吸收和利用,增进骨质形成并促进生长发育,提高了药物组合物的安全有效性。
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于防治儿童发育障碍的药物组合物及其制备方法和其应用。
背景技术
儿童发育障碍是一种原发于婴幼儿时期的神经功能障碍性综合性疾病,多数患者因各种原因导致的中枢神经系统发育异常,表现为中枢神经功能丧失及异常导致的系列性脑部功能、脏腑功能、运动功能、发育异常、认知功能障碍、视觉及听觉障碍、运动功能及学习功能异常、行为功能障碍等,典型病症包括小儿脑性瘫痪、儿童发育障碍、自闭症谱系障碍等。
钙和锌是影响骨骼、牙齿和生长发育的必需矿物质。长期钙锌摄入不足可能会引发儿童生长发育障碍。钙是维持人体神经系统、骨骼肌肉系统、细胞膜和毛细血管通透性正常功能的必需元素。维生素D3可促进人体肠道对钙和磷的吸收并促进骨质形成,促进人体骨骼钙化和骨骼的生长发育,保护牙齿并利于孕妇胎盘及胎儿的生长发育,有效预防流产、早产、胎儿发育缓慢等,促进人体血清中的酸碱平衡,减少电解质紊乱,提高免疫力和抵抗力,预防肾脏氨基酸流失,降低癌症的发生率等,临床用于防治骨质疏松、佝偻病、骨软化症及婴儿手足搐搦症,佝偻病兼有龋齿者等。锌参与多种含锌金属酶的构成,并影响核酸和蛋白质(如胶原蛋白、角蛋白、唾液蛋白等)的生物合成、细胞的生长、分裂和分化等,在生长发育、认知行为、创伤愈合、免疫调节、味觉、食欲等方面发挥重要作用,用于维持并保护上皮组织和黏膜组织、防御细菌和病毒侵入、促进伤口愈合、减少痤疮等,以及促进淋巴细胞的增殖和维持其活动能力,增进脑组织和智力发育。但现有的钙锌制剂存在生物利用度较低以及引发便秘、结石等缺陷。为此,需要开发具有改善生物利用度并降低不良反应的新型药物组合物,以满足临床需求。
发明内容
本发明的目的在于提供一种用于防治儿童发育障碍的药物组合物,所述组合物由药物活性成分和药学上可接受的载体组成,其中,所述药物活性成分由碳酸钙、维生素D3、维生素K2、葡萄糖酸锌、凝结芽孢杆菌和氨基酸组成,以钙元素计,所述药物活性成分中钙元素:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:氨基酸的重量比为500:0.005:0.04-0.10:50-100:30-100:50-120,所述氨基酸选自谷氨酸、谷氨酰胺、盐酸赖氨酸、精氨酸的任一种或其组合,所述碳酸钙的粒径≤20um。
本发明的优选技术方案中,组合物中碳酸钙的粒径≤15um,优选≤10um。
本发明的优选技术方案中,所述凝结芽孢杆菌的活菌数≥5×107CFU/g,优选≥1×108CFU/g。
本发明优选的技术方案中,所述药学上可接受的载体选自甘露醇、山梨醇、木糖醇、微晶纤维素、淀粉、糊精、聚维酮、聚乙烯吡咯烷酮、淀粉浆、羟甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙甲基纤维素、香精、甜味剂、色素中的任一种或其组合。
本发明的优选技术方案中,所述香精选自柠檬香精、苹果香精、草莓香精、薄荷香精、橘子香精的任一种或其组合。
本发明的优选技术方案中,所述甜味剂选自阿斯巴甜、葡萄糖、蔗糖、甜蜜素、乳糖、果糖、安赛蜜、甜菊糖、麦芽糖的任一种或其组合。
本发明的优选技术方案中,所述色素选自柠檬黄、胭脂红、赤藓红、甜菜红、苋菜红、靛蓝、姜黄素、胡萝卜素、日落黄、复合黑、荧光果绿中的任一种或其组合。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:谷氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量为12500:0.05:0.5:550:350:1050:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:谷氨酰胺:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.4:540:400:1000:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:盐酸赖氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.8:520:500:900:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:精氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.8:530:800:1000:1650:1650:120:100:18。
本发明优选的技术方案中,所述药物组合物为口服制剂,优选为片剂、咀嚼片、颗粒剂、胶囊中的任一种。
本发明的药物组合物按照本领域常规的制备方法制备得到。
本发明的另一目的在于提供一种用于防治儿童发育障碍的药物组合物的制备方法,所述组合物由药物活性成分和药学上可接受的载体组成,其中,所述药物活性成分由碳酸钙、维生素D3、维生素K2、葡萄糖酸锌、氨基酸和凝结芽孢杆菌组成,以钙元素计,所述药物活性成分中钙元素:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:氨基酸的重量比为500:0.005:0.04-0.10:50-100:30-100:50-120,所述氨基酸选自谷氨酸、谷氨酰胺、盐酸赖氨酸、精氨酸的任一种或其组合,所述碳酸钙的粒径≤20um,包括如下步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌,将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合,搅拌,将其制成5-8%的水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、谷氨酸、甘露醇、木糖醇和阿斯巴甜,搅拌,将其混合均匀,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌,制软材,过筛,干燥,制粒;
(5)称取所需量的香精,搅拌,将所需量的香精与步骤(4)所得制粒均匀混合,即得。
本发明的优选技术方案中,所述搅拌条件为100rpm-1000rpm,优选为200rpm-800rpm,更优选为300rpm-600rpm。
本发明的优选技术方案中,所述干燥为减压干燥。
本发明的优选技术方案中,所述干燥温度≤60℃,优选干燥温度≤50℃,更优选干燥温度≤45℃。
本发明的优选技术方案中,组合物中碳酸钙的粒径≤15um,优选≤10um。
本发明的优选技术方案中,所述凝结芽孢杆菌的活菌数≥5×107CFU/g,优选≥1×108CFU/g。
本发明优选的技术方案中,所述药学上可接受的载体选自甘露醇、山梨醇、木糖醇、微晶纤维素、淀粉、糊精、聚维酮、聚乙烯吡咯烷酮、淀粉浆、羟甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙甲基纤维素、香精、甜味剂、色素中的任一种或其组合。
本发明的优选技术方案中,所述香精选自柠檬香精、苹果香精、草莓香精、薄荷香精、橘子香精的任一种或其组合。
本发明的优选技术方案中,所述甜味剂选自阿斯巴甜、葡萄糖、蔗糖、甜蜜素、乳糖、果糖、安赛蜜、甜菊糖、麦芽糖的任一种或其组合。
本发明的优选技术方案中,所述色素选自柠檬黄、胭脂红、赤藓红、甜菜红、苋菜红、靛蓝、姜黄素、胡萝卜素、日落黄、复合黑、荧光果绿中的任一种或其组合。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:谷氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量为12500:0.05:0.5:550:350:1050:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:谷氨酰胺:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.4:540:400:1000:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:盐酸赖氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.8:520:500:900:1800:1800:120:100:18。
本发明的优选技术方案中,药物组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:精氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.8:530:800:1000:1650:1650:120:100:18。
本发明优选的技术方案中,所述药物组合物为口服制剂,优选为片剂、咀嚼片、颗粒剂、胶囊中的任一种。
本发明的另一目的在于提供本发明的药物组合物用于制备防治儿童发育障碍、骨质疏松、佝偻病的任一种或其并发症的药物中的应用。
本发明的另一目的在于提供本发明药物组合物用于制备钙锌补充制品中的应用。
本发明优选的技术方案中,所述药物组合物用于老人、儿童、孕妇和其他需要补充钙锌的人群补充所需钙锌。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
与现有技术相比,本发明具有下述有益效果:
1、本发明科学筛选了药物组合物中的组分及配比,包括组合物中碳酸钙(粒径≤20μm)、维生素D3、维生素K2、葡萄糖酸锌、氨基酸、凝结芽孢杆菌的种类或用量,并将维生素D3、维生素K2喷雾至碳酸钙,显著提高了制剂的稳定性和质量均一性,且协同利用凝结芽孢杆菌和氨基酸促进机体对钙、锌、维生素D3、维生素K2的吸收和利用,改善患者肠道菌群并抑制肠道幽门螺杆菌,有效且持久地增加骨密度,缓解骨疼痛,改善骨微结构、保护骨骼健康,增进骨质形成并促进生长发育,保护牙齿并预防蛀牙,利于口腔健康,显著提高其用于防治儿童发育障碍、骨质疏松、佝偻病等病症的治疗效果,且显著改善口感及胃肠功能、胀气、便秘、结石等副反应,显著提高了药物组合物的安全有效性。
2、本发明的制备方法具有操作简便、成本更优、适用于工业化生产等优点。
附图说明
图1实施例1-4的药物组合物的溶出度考察试验。
图2试验例2中试验各组对试验大鼠体重的影响,“*”表示与空白对照组比较,P<0.05,“△”表示与阳性对照组比较,P<0.05。
图3试验例2中试验各组对试验大鼠骨密度的影响,“*”表示与空白对照组比较,P<0.05,“△”表示与阳性对照组比较,P<0.05。
图4试验例2中试验各组对试验大鼠骨钙的影响,“*”表示与空白对照组比较,P<0.05,“△”表示与阳性对照组比较,P<0.05。
图5试验例2中试验各组对试验大鼠骨重的影响,“*”表示与空白对照组比较,P<0.05,“△”表示与阳性对照组比较,P<0.05。
具体实施方式
以下将结合实施例具体说明本发明。本发明的实施例仅用于说明本发明的技术方案,并非限定本发明的实质。
具体实施方式中所用的凝结芽孢杆菌为商购,活菌数不低于1000亿cfu/g。
实施例1本发明药物组合物的制备
本发明药物组合物的组成及配比:
本发明药物组合物的制备包括下述步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌(300rpm),将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚维酮K30,搅拌(200rpm),将其制成5%的聚维酮K30水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、谷氨酸、甘露醇、木糖醇和阿斯巴甜,搅拌(600rpm),将其混合均匀后,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌(600rpm),将其混合均匀后,制软材,过筛,减压干燥(55℃),制粒;
(5)称取所需量的草莓香精,搅拌(600rpm),将其与步骤(4)所得的制粒均匀混合,即得。
实施例2本发明药物组合物的制备
本发明药物组合物的组成及配比:
本发明药物组合物的制备包括下述步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌(300rpm),将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚乙烯吡咯烷酮,搅拌(300rpm),将其制成6%的聚乙烯吡咯烷酮水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、谷氨酰胺、甘露醇、木糖醇和阿斯巴甜,搅拌(600rpm),将其混合均匀后,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌(600rpm),将其混合均匀后,制软材,过筛,减压干燥(50℃),制粒;
(5)称取所需量的柠檬香精,搅拌(600rpm),将其与步骤(4)所得的制粒均匀混合,即得。
实施例3本发明药物组合物的制备
本发明药物组合物的组成及配比:
本发明药物组合物的制备包括下述步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌(300rpm),将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚乙烯吡咯烷酮,搅拌(300rpm),将其制成6%的聚乙烯吡咯烷酮水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、盐酸赖氨酸、甘露醇、木糖醇和阿斯巴甜,搅拌(600rpm),将其混合均匀后,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌(600rpm),将其混合均匀后,制软材,过筛,减压干燥(50℃),制粒;
(5)称取所需量的苹果香精,搅拌(600rpm),将其均匀混合后,再将制得的混合物与步骤(4)所得的制粒均匀混合,即得。
实施例4本发明药物组合物的制备
本发明药物组合物的组成及配比:
本发明药物组合物的制备包括下述步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌(300rpm),将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚维酮K30,搅拌(300rpm),将其制成7%的聚维酮K30水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、精氨酸、甘露醇、木糖醇和阿斯巴甜,搅拌(600rpm),将其混合均匀后,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌(600rpm),将其混合均匀后,制软材,过筛,减压干燥(55℃),制粒;
(5)称取所需量的薄荷香精,搅拌(600rpm),将其与步骤(4)所得的制粒均匀混合,即得。
试验例1本发明药物组合物的溶出度考察试验
参照中国药典2020年版四部通则0931第二法检测实施例1-4的药物组合物的溶出度。分别称取实施例1-4的药物组合物各3g,以0.1mol/L的盐酸溶液1000ml为溶出介质,溶出温度37℃,桨法50rpm。取样时间5min、10min、15min、20min、30min、45min。每次取样10ml。结果见图1。本发明的药物组合物溶出优良。
试验例2本发明药物组合物对试验大鼠骨密度及骨重的影响
选取SPF级雌性离乳SD大鼠50只。试验期间,试验动物自由摄食和饮用去离子水,室温20℃~24℃,相对湿度55%~68%。试验大鼠适应性饲喂一周后,将其随机分为五组,空白对照组(灌胃纯水)、阳性对照组(灌胃北京振东朗迪制药有限公司生产的碳酸钙D3颗粒,以钙计,剂量为240mg/kg.bw)、低剂量组(灌胃实施例3的药物组合物,以钙计,剂量为40mg/kg.bw)、中剂量组(灌胃实施例3的药物组合物,以钙计,剂量为80mg/kg.bw)、高剂量组(灌胃实施例3的药物组合物,以钙计,剂量为240mg/kg.bw),每组10只。试验动物每天灌胃10mL/kg.bw,每天灌胃一次。每周称体重。连续灌胃饲养12周后,麻醉处死动物,取出试验动物双侧股骨,将其置于105℃烘箱中干燥至恒重,称量右股骨骨重。采用原子吸收分光光度计法检测右股骨骨钙含量。采用全自动高分辨率X光机检测左股骨骨密度。结果见图2-图5。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (10)
1.一种用于防治儿童发育障碍的药物组合物,所述组合物由药物活性成分和药学上可接受的载体组成,其中,所述药物活性成分由碳酸钙、维生素D3、维生素K2、葡萄糖酸锌、凝结芽孢杆菌和氨基酸组成,以钙元素计,所述药物活性成分中钙元素:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:氨基酸的重量比为500:0.005:0.04-0.10:50-100:30-100:50-120,所述氨基酸选自谷氨酸、谷氨酰胺、盐酸赖氨酸、精氨酸的任一种或其组合,所述碳酸钙的粒径≤20um。
2.如权利要求1所述的药物组合物,其特征在于,组合物中碳酸钙的粒径≤15um,优选≤10um。
3.如权利要求1-2任一项所述的药物组合物,其特征在于,所述凝结芽孢杆菌的活菌数≥5×107CFU/g,优选≥1×108CFU/g。
4.如权利要求1-3任一项所述的药物组合物,其特征在于,所述药学上可接受的载体选自甘露醇、山梨醇、木糖醇、微晶纤维素、淀粉、糊精、聚维酮、聚乙烯吡咯烷酮、淀粉浆、羟甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙甲基纤维素、香精、甜味剂、色素中的任一种或其组合。
5.如权利要求1-4任一项所述的药物组合物,其特征在于,组合物中的碳酸钙:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:盐酸赖氨酸:甘露醇:木糖醇:聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合:香精:阿斯巴甜之间的质量比为12500:0.05:0.8:520:500:900:1800:1800:120:100:18。
6.如权利要求1-5任一项所述的药物组合物,其特征在于,所述药物组合物为口服制剂,优选为片剂、咀嚼片、颗粒剂、胶囊中的任一种。
7.如权利要求1-6任一项所述的药物组合物的制备方法,所述组合物由药物活性成分和药学上可接受的载体组成,其中,所述药物活性成分由碳酸钙、维生素D3、维生素K2、葡萄糖酸锌、氨基酸和凝结芽孢杆菌组成,以钙元素计,所述药物活性成分中钙元素:维生素D3:维生素K2:葡萄糖酸锌:凝结芽孢杆菌:氨基酸的重量比为500:0.005:0.04-0.10:50-100:30-100:50-120,所述氨基酸选自谷氨酸、谷氨酰胺、盐酸赖氨酸、精氨酸的任一种或其组合,所述碳酸钙的粒径≤20um,包括如下步骤:
(1)称取所需量的维生素D3、维生素K2,搅拌,将其溶解于浓度为95%的乙醇溶液,得备用液一;
(2)称取所需量的聚维酮K30或聚乙烯吡咯烷酮的任一种或其组合,搅拌,将其制成5-8%的水溶液,得备用液二;
(3)称取所需量的碳酸钙、葡萄糖酸锌、凝结芽孢杆菌、谷氨酸、甘露醇、木糖醇和阿斯巴甜,搅拌,将其混合均匀,得混合物;
(4)将备用液一、备用液二依次喷雾至步骤(3)制得的混合物上,搅拌,制软材,过筛,干燥,制粒;
(5)称取所需量的香精,搅拌,将所需量的香精与步骤(4)所得制粒均匀混合,即得。
8.如权利要求7所述的制备方法,其特征在于,所述搅拌条件为100rpm-1000rpm,优选为200rpm-800rpm,更优选为300rpm-600rpm。
9.如权利要求7-8任一项所述的制备方法,其特征在于,所述干燥温度≤60℃,优选干燥温度≤50℃,更优选干燥温度≤45℃。
10.如权利要求1-6任一项所述的药物组合物或者如权利要求7-9任一项所述的方法制得的药物组合物用于制备防治儿童发育障碍、骨质疏松、佝偻病的任一种或其并发症的药物中的应用。
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