CN112569209A - 一种吸入用阿比多尔溶液及其制备方法 - Google Patents
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Abstract
本发明涉及一种吸入用阿比多尔溶液及其制备方法,该吸入溶液包含活性成分阿比多尔、助溶剂、等渗调节剂以及pH值调节剂和溶剂;本发明通过制剂手段解决阿比多尔水溶液中溶解性差的问题,从而拓展该药物的使用途径,提高了其生物利用率。
Description
技术领域
本发明属于医药领域,具体涉及一种吸入用阿比多尔溶液及其制备方法。
背景技术
急性上呼吸道感染是各种病毒和/或细菌引起的主要侵犯鼻、咽或喉部急性炎症的总称,以病毒多见,占70%-80%。流感传播迅速,每年可引起季节性流行,在学校、托幼机构和养老院等人群聚集的场所可发生暴发疫情。每年流感季节性流行在全球可导致300万-500万重症病例,29万-65万死亡。流感流行在人群中导致较重的健康和经济负担,不同人群的流感疾病负担差异较大,孕妇、婴幼儿、老年人和慢性基础疾病患者等高危人群,患流感后出现严重疾病和死亡的风险较高。
目前全球抗感染药物市场销售额约占药品总销售额的15%左右,位居全球药品市场销售额的第二位。据米内网样本数据显示,2018年我国全身抗感染药物市场规模达到1275.8亿元,其中抗病毒药市场规模超过150亿元,较2017年同比上涨6.44%。
《流行性感冒抗病毒药物治疗与预防应用中国专家共识》指出,抗流感病毒药物是治疗和预防流感的有效手段,流感患者早期使用更能显著缓解流感症状、降低并发症的发生率,从而降低病死率。
阿比多尔是前苏联药物化学研究中心研制的非核苷类抗病毒药物,于1993年在俄罗斯首次上市,在俄罗斯用于治疗流行性感冒(流感)已有多年。目前,阿比多尔的疗效已经得到国际专家的认可和青睐,俄罗斯联邦健康保健会及发展部已将此药列为医生无偿医疗救助的处方药和急救机关必备的药物品种。
阿比多尔为国家医保(2019版)收载乙类药物,作为抗病毒药物,限重症流感高危人群及重症患者的抗流感病毒治疗。近日,病毒学国家重点实验室出具的体外及动物体内实验报告结论认为,阿比多尔胶囊在细胞内有明显的抑制甲型H1N1流感病毒生长作用,对甲型流感病毒入侵细胞的阻断作用与达菲相同,对甲型流感病毒入侵细胞的阻断作用强于对病毒生物合成的抑制作用,可改善甲型H1N1流感病毒感染引起的肺炎症状。
目前国内外市场上所售阿比多尔剂型均为口服固体剂,固体制剂制备工艺复杂,技术要求高,用于改善甲型H1N1流感病毒感染引起的肺炎症状起效慢,不能直达病变部位。而本发明所提供的吸入溶液直接将药物传递到呼吸道,吸收快,作用迅速,提高了呼吸道药物浓度,减少给药剂量,降低药物在其他组织中的分布,降低药物副作用。可以避免口服给药的首过效应和胃肠道降解,对于不方便口服给药和血管给药的老人、病重患者及儿童患者,是重要、理想的给药途径。
发明内容
目前阿比多尔存在水溶性低,临床使用不方便,生物利用率低,不能充分发挥它的药效的缺点。针对现有技术不足,本发明通过制剂手段解决阿比多尔水溶液中溶解性差的问题,从而拓展该药物的使用途径,提高其生物利用率。
本发明的目的在于提供一种不含抛射剂,借助雾化泵或压缩空气压力将药物释出的吸入溶液剂,其可有效预防和改善流感病毒感染引起的肺炎。
在上述吸入溶液中,其特征在于,所述吸入溶液为吸入用阿比多尔溶液。
在上述吸入溶液中,其特征在于,所述吸入溶液包括药物活性成分阿比多尔、助溶剂、等渗调节剂、pH值调节剂和溶剂。
在上述吸入溶液中,其特征在于,所述活性成分阿比多尔的浓度为0.01~0.05g/ml,优选为0.02g/ml。
在上述吸入溶液中,其特征在于,所述助溶剂含量为0.02~0.08%w/v,优选为0.04~0.06%w/v;所述助溶剂选自吐温80、氨丁三醇、甘油、丙二醇、聚乙二醇的一种或多种混合;更优选为吐温80。
在上述吸入溶液中,其特征在于,所述等渗调节剂选自氯化钠、氯化钾、氯化镁、氯化钙中的一种或多种,优选为氯化钠。
在上述吸入溶液中,其特征在于,所述pH调节剂选自柠檬酸、柠檬酸钠、稀盐酸、氢氧化钠、碳酸氢钠、乳酸、酒石酸、苹果酸中的一种或多种,优选为柠檬酸和柠檬酸钠的组合;更优选的溶液pH值为5.0~7.0,最优选为6.0。
在上述吸入溶液中,其特征在于,所述溶剂为纯化水、注射用水或无菌注射用水。
本发明的另一目的在于提供一种阿比多尔吸入溶液的制备方法。所述制备流程简单,重现性好,产品稳定性好,易于大规模工业化生产。
具体包括以下步骤:
步骤一:向处方量70%~80%的溶剂中加入助溶剂溶解;
步骤二:用pH调节剂调节pH至5.0~7.0;
步骤三:加入处方量的阿比多尔至步骤二的溶液中,搅拌使溶解;
步骤四:加入处方量渗透压调节剂,搅拌使溶解;
步骤五:用0.45μm滤膜进行初滤,0.22μm滤膜进行精滤,均为无菌过滤,灌封于安瓿中。
在上述制备方法中,所述溶剂为纯化水、注射用水或无菌注射用水。
申请人发现适当提高配液温度,可增加阿比多尔在水溶液中的溶解量和溶解速度。因此,在上述制备过程中温度控制在40~70℃。
此外,在无不利影响的情况下,还可以按常规方法向吸入用阿比多尔溶液中添加一种或多种添加剂,例如表面活性剂。作为表面活性剂,可以是甘油脂肪酸酯、脱水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯或聚乙二醇脂肪酸酯等。
与现有技术相比,本发明技术方案具有如下有益效果:
1、本发明可有效解决阿比多尔吸入溶液中阿比多尔溶解性差的问题,同时可提供质量稳定的阿比多尔吸入溶液。
2、本发明所述的吸入用阿比多尔溶液采用单剂量药物包装,单剂量是指单次吸入所使用的药用活性成分的剂量。在本说明书中,单剂量表示2mL,本发明提供的单剂量,使用过程便捷,无需稀释、配制,可大大降低使用过程中的微生物污染和浪费,采用单次用药的剂量避免了多剂量大包装溶液所导致的反复量取、反复稀释配制易滋生微生物的弊端。
3、本发明的吸入溶液制备工艺简单,重现性好,产品稳定性好,易于大规模工业化生产。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中的实验方法,如无特殊说明,均为常规方法;所用的原料、试剂材料等,如无特殊说明,均为市售购买产品。
实施例1
处方组成
制备方法:
取注射用水800ml,控制水温45~55℃,加入吐温80搅拌溶解后,用柠檬酸-柠檬酸钠调节pH至6.0左右,加入阿比多尔,搅拌溶解后。继续加入处方量的氯化钠,搅拌使溶解,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
实施例2
处方组成
名称 | 组成 |
阿比多尔 | 50g |
吐温80 | 0.18g |
柠檬酸 | 0.35g |
柠檬酸钠 | 0.03g |
氯化钠 | 9g |
加注射用水至 | 1000ml |
制备方法:
取注射用水800ml,控制水温60~70℃,加入吐温80搅拌溶解后,用柠檬酸-柠檬酸钠调节pH至6.0左右,加入阿比多尔,搅拌溶解后。继续加入处方量的氯化钠,搅拌使溶解,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
实施例3
处方组成
名称 | 组成 |
阿比多尔 | 10g |
吐温80 | 0.12g |
柠檬酸 | 0.30g |
柠檬酸钠 | 0.03g |
氯化钠 | 9g |
加注射用水至 | 1000ml |
制备方法:
取注射用水800ml,控制水温40~50℃,加入吐温80搅拌溶解后,用柠檬酸-柠檬酸钠调节pH至6.0左右,加入阿比多尔,搅拌溶解后。继续加入处方量的氯化钠,搅拌使溶解,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
实施例4
处方组成
名称 | 组成 |
阿比多尔 | 20g |
氨丁三醇 | 0.05g |
柠檬酸 | 0.35g |
柠檬酸钠 | 0.03g |
氯化钠 | 9g |
加注射用水至 | 1000ml |
制备方法:
取注射用水700ml,控制水温40~50℃,加入处方量氨丁三醇搅拌溶解后,用柠檬酸-柠檬酸钠调节pH至5.5左右,加入阿比多尔,搅拌溶解后。继续加入处方量的氯化钠,搅拌使溶解,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
实施例5
处方组成
名称 | 组成 |
阿比多尔 | 20g |
聚乙二醇 | 0.08g |
氯化钠 | 9g |
稀盐酸 | 适量 |
加注射用水至 | 1000ml |
制备方法:
取注射用水800ml,控制水温50~60℃,加入处方量聚乙二醇、阿比多尔、氯化钠搅拌溶解后,用稀盐酸调节pH至5.0左右,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
实施例6
处方组成
制备方法:
取注射用水700ml,控制水温50~60℃,加入处方量氨丁三醇、阿比多尔、氯化钠搅拌溶解后,用酒石酸调节pH至6.5左右,定容至1000ml,将所得溶液通过无菌过滤器过滤,然后将过滤后药液灌装于2ml安瓿瓶中,即得吸入用阿比多尔溶液。
试验例1:阿比多尔吸入溶液的稳定性
取实施例1中的阿比多尔吸入溶液,于温度为40±2℃,湿度RH 25%±5%的恒温恒湿箱中放置,于0个月、1个月、2个月、3个月、6个月末分别取样,检测其性状、pH、含量及有关物质。检测结果如下表所示:
阿比多尔吸入溶液加速试验数据
结果显示:实施例1中的阿比多尔吸入溶液在温度为40±2℃,湿度RH 25%±5%的恒温恒湿箱中放置6个月,性状、pH值、含量、有关物质测定均未见明显变化,说明其性质稳定。
本发明所述实施例均可达到与实施例1相似的稳定性试验结果,即根据本发明所述技术方案制备得到的阿比多尔吸入溶液质量稳定。
上述虽然对本发明的具体实施方式进行了描述,但并非对本发明保护范围的限制,在本发明的技术方案的基础上,本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (10)
1.一种吸入用阿比多尔溶液制剂,其特征在于:包含药物活性成分阿比多尔、助溶剂、等渗调节剂、pH值调节剂和溶剂。
2.根据权利要求1所述的制剂,其特征在于:所述阿比多尔含量为0.01~0.05g/ml,优选为0.02g/ml。
3.根据权利要求1所述的制剂,其特征在于:所述助溶剂含量为0.02~0.08%w/v,优选为0.04~0.06%w/v;所述助溶剂选自吐温80、氨丁三醇、甘油、丙二醇、聚乙二醇的一种或多种混合;更优选为吐温80。
4.根据权利要求1所述的制剂,其特征在于:所述等渗调节剂选自氯化钠、氯化钾、氯化镁、氯化钙中的一种或多种,优选为氯化钠。
5.根据权利要求1所述的制剂,其特征在于:所述溶液pH值为5.0~7.0,优选为6.0。
6.根据权利要求1所述的制剂,其特征在于:所述pH调节剂选自柠檬酸、柠檬酸钠、稀盐酸、氢氧化钠、碳酸氢钠、乳酸、酒石酸、苹果酸中的一种或多种,优选为柠檬酸和柠檬酸钠的组合。
7.根据权利要求1所述的制剂,其特征在于:所述溶剂选自纯化水、注射用水或无菌注射用水。
8.根据权利要求1-7任一所述制剂的制备方法:其特征在于,包括如下步骤:
步骤一:向处方量70%~80%的溶剂中加入助溶剂溶解;
步骤二:用pH调节剂调节pH至5.0~7.0;
步骤三:加入处方量的阿比多尔至步骤二的溶液中,搅拌使溶解;
步骤四:加入处方量渗透压调节剂,搅拌使溶解;
步骤五:用0.45μm滤膜进行初滤,0.22μm滤膜进行精滤,均为无菌过滤,灌封于安瓿中。
9.根据权利要求8所述制备方法:其特征在于,所述步骤一中溶液配制温度为40~70℃。
10.根据权利要求8所述制备方法:其特征在于,所述溶液制备过程中需避光操作。
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