CN111481620A - 一种非布司他口服液及其制备工艺 - Google Patents
一种非布司他口服液及其制备工艺 Download PDFInfo
- Publication number
- CN111481620A CN111481620A CN202010321167.3A CN202010321167A CN111481620A CN 111481620 A CN111481620 A CN 111481620A CN 202010321167 A CN202010321167 A CN 202010321167A CN 111481620 A CN111481620 A CN 111481620A
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- CN
- China
- Prior art keywords
- parts
- oral liquid
- febuxostat
- sodium
- mucilage
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Classifications
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8967—Lilium, e.g. tiger lily or Easter lily
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- A—HUMAN NECESSITIES
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Abstract
本发明提供了一种非布司他口服液，涉及医药技术领域。所述口服液的原料组成及重量份数为：非布司他0.1‑0.8份，百合10‑30份，金钱草5‑15份，金银花5‑20份，蒲公英5‑15份，牡丹皮5‑10份，甜味剂1‑5份，芳香剂1‑5份、胶浆剂2‑8份和增强剂1‑3份。本发明在实施过程中将中药和西药混合使用，并控制西药成分与中药成分的质量比，能够更大程度的提高中西药成分的功效，使中药和西药更好的相互作用，发挥互补和提升的效果；控制胶浆剂和增强剂的具体组分以及质量比，能够明显提高口服液的稳定性以及防腐效果长期放置无药物成分析出，延长口服液的存放时间。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种非布司他口服液及其制备工艺。
背景技术
非布司他，其化学名为2-[(3-氰基-4-异丁氧基)苯基]-4-甲基-5-噻唑羧酸，为黄嘌呤氧化酶(XO)抑制剂，适用于具有痛风症状的高尿酸血症的长期治疗。
其结构式如下：
随着人们生活水平的不断提高，饮食习惯和生活方式的改变，人们对痛风的认识和诊断水平不断提高，无论在欧美国家还是在亚洲各国，痛风的患病率逐年增加，我国高尿酸血症和痛风的患病率更是呈直线上升趋势，目前对通风的治疗通常采用的手段是促进尿酸排泄和抑制尿酸生成，并采用相关的措施改善相关症状。体内尿酸的生成与嘌呤代谢有关，在嘌呤代谢过程的最后，次黄嘌呤在黄嘌呤氧化还原酶的作用下生成黄嘌呤，再进一步生成尿酸，抑制该酶的活性可以有效减少尿酸的生成。
非布司他是近年来一个新型黄嘌呤氧化酶抑制剂，是第一个非嘌呤类型的黄嘌呤氧化酶抑制剂，对黄嘌呤氧化酶的抑制作用具有高度的选择性，能同时对氧化性和还原性的黄嘌呤氧化酶产生显著的抑制作用。非布司他与目前痛风黄金治疗药物别嘌呤醇相比，具有更强的药理活性，更高的作用选择性，在临床中表现出更好的疗效和良好的安全性。因此，非布司他是一种能更安全有效治疗高尿酸血症的新型药物，具有十分必要的临床意义。
由于非布司他本身的溶解度较小，含有非布司他的药物制剂存在溶出度低，生物利用度不高的问题。为了提高非布司他的生物利用度，通常会在药物制备过程中添加各种药物辅料提高药物的溶出度，辅料添加会在一定程度上影响到药效，使效果提高并不明显。
例如中国专利申请200910058222.8中公开了一种非布司他分散片药物及其制备方法，该药物以非布司他为有效药物成分与在分散片制剂中可以接受的辅助成分共同组成，其特征是所说辅助成分中含有包括聚氧乙烯硬脂酸脂类成分、聚氧乙烯醚蓖麻油类成分、氢化蓖麻油聚羟氧脂类成份中的至少一种作为增溶剂成分，用量为非布司他重量的0.1-5倍，该药物可以提高难溶性有效药物成分非布司他的溶出度，具有药物分散性大，溶出度高，吸收起效快，生物利用度高的优点，但是经过检测其最高溶出度仅为92.2％。
因此在实施过程中考虑将其制备成一种口服液，可以在减少药物辅料添加的基础上提高药物有效成分的利用率，经过检索发现现有报道中含非布司他的口服液少之又少，并且制备痛风的口服液大多都是中药成分的口服液，例如中国专利申请201711162128.8中公开了一种防治痛风的口服液，它包括以下成分：薏米3～15份，百合3～15份，金银花2～5份，荷叶2～10份，其制备工艺包括：按配方选取药材、煎煮、浓缩、灭菌装罐，该发明提供的一种防治痛风的口服液，其中薏仁含有大量的游离和结合酚，其主要成分为绿原酸、阿魏酸等，这种酚类物质在人体和动物体内是有效的黄嘌呤氧化酶抑制剂和自由基清除剂，能预防和治疗高尿酸血症；百合含有秋水仙碱等多种生物碱，具有清热、安神的功效；荷叶有消肿利湿、散瘀止痛的功效，该发明通过以上中药组合，下调血清尿酸、炎性因子水平，减少炎症发作，减轻关节损害及脏器受损，进而逆转慢性病程，使患者长期受益，该发明中所公开使用的组分均为中药组分，中药治疗疗程长，见效慢，针对性不强。
因此，本发明为了解决现有技术中非布司他药物组合物溶出效率低的问题，开发了一种稳定性好、溶出度高、吸收快、生物利用度高的非布司他口服液。
发明内容
基于现有技术中存在的问题，本发明旨在提供一种稳定性好、溶出度高、吸收快、生物利用度高的非布司他口服液及其制备方法。
为实现上述目的，本发明的技术方案实施如下：
一种非布司他口服液，制成所述口服液有效成分的原料组成及重量份数为：
非布司他0.1-0.8份，百合10-30份，金钱草5-15份，金银花5-20份，蒲公英5-15份，牡丹皮5-10份，甜味剂1-5份，芳香剂1-5份、胶浆剂2-8份和增强剂1-3份。
优选地，所述的口服液有效成分的原料组成及重量份数为：
非布司他0.3-0.6份，百合15-25份，金钱草7-12份，金银花7-15份，蒲公英7-12份，牡丹皮6-8份，甜味剂2-4份，芳香剂2-4份、胶浆剂3-7份和增强剂2-3份。
再优选地，所述的口服液有效成分的原料组成及重量份数为：
非布司他0.5份，百合20份，金钱草10份，金银花12份，蒲公英10份，牡丹皮8份，甜味剂4份，芳香剂4份、胶浆剂5份和增强剂3份。
其中，所述的甜味剂包括蔗糖、单糖浆、糖精钠、阿斯巴甜、蛋白糖、木糖醇、甜蜜素和甜菊糖中的一种或几种；
优选地，所述的甜味剂包括蔗糖、阿斯巴甜、蛋白糖、木糖醇、甜蜜素和甜菊糖中的一种或几种；
再优选地，所述的甜味剂包括蔗糖、木糖醇和甜菊糖中的一种或几种；
所述的芳香剂包括柠檬、薄荷脑和香精中的一种或几种。
所述的胶浆剂包括海藻酸钠、阿拉伯胶、明胶、甲基纤维素和羧甲基纤维素钠中的一种或几种；
优选地，所述的胶浆剂包括海藻酸钠、甲基纤维素和羧甲基纤维素钠中的一种或几种；
再优选地，所述的胶浆剂为质量比2-4：1的海藻酸钠和羧甲基纤维素钠；优选地，所述的胶浆剂为质量比3：1的海藻酸钠和羧甲基纤维素钠。
所述的增强剂包括苯甲酸、苯甲酸钠、山梨酸和山梨酸钾中的一种或几种。
在实施过程中控制苯甲酸钠和山梨酸钠的质量比为5-10：1，能够有效的提高口服液的稳定性，长期放置不变质。
优选地，所述的苯甲酸钠和山梨酸钠的质量比为6-9：1；再优选地。苯甲酸钠和山梨酸钠的质量比为7-8：1。
在一些优选实施方案中所述的非布司他与中药组分的重量比为0.1-0.8：
30-90；优选为0.3-0.6：42-62；再优选为0.5：60。
在实施过程中通过合理控制中药与西药的重量比，可以有效发挥中西药结合的优点，通过中西药之间的相互作用达到更好的治疗效果。
本发明还提供了所述的口服液的制备方法，包括以下西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的甜味剂、芳香剂、胶浆剂和增强剂加乙醇溶解，过滤，得到西药溶液，备用。
所述的口服液的制备方法，还包括以下中药成分的制备工艺，包括以下步骤：
(1)将牡丹皮洗净后，加2-3倍量的乙醇溶液浸泡2-3小时，加热回流提取2-3小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加6-8倍量的水，加热煮沸2-3小时，过滤，浓缩至含水量为2-3倍量，得中药提取液，备用。
所述的非布司他口服液得制备方法，将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
本发明所用的药物药形如下：
非布司他：主要成份为非布佐司他，其化学名为2-[(3-氰基-4-异丁氧基)苯基]-4-甲基-5-噻唑羧酸。为黄嘌呤氧化酶(XO)抑制剂，适用于具有痛风症状的高尿酸血症的长期治疗。
百合：性味甘，微苦，含有特殊营养成分秋水仙碱等多种生物碱，主治功能：养阴润肺；清心安神。主阴虚久嗽；痰中带血；热病后期；余热未清，或情志不遂所致的虚烦惊悸、失眠多梦、精神恍惚；痈肿；湿疮。
金钱草：味苦，酸，微寒。归肝，胆，肾，膀胱经。功能清热解毒，利尿排石，活血散淤。
金银花：性寒，味甘，入肺、心、胃经，具有清热解毒、抗炎、补虚疗风的功效，主治胀满下疾、温病发热，热毒痈疡和肿瘤等。
蒲公英：性味甘，微苦，寒。归肝、胃经。有利尿、缓泻、退黄疸、利胆等功效。
牡丹皮：性味苦、辛，微寒，归心、肝、肾经，具有清热凉血、活血化淤、退虚热等功效。
本发明与现有技术相比，具有以下有益效果：
(1)本发明在实施过程中将中药和西药混合使用，并控制西药成分与中药成分的质量比，能够更大程度的提高中西药成分的功效，使中药和西药更好的相互作用，发挥互补和提升的效果；
(2)本发明在实施过程中在口服液中加入了胶浆剂，并控制胶浆剂为质量比2-4：1的海藻酸钠和羧甲基纤维素钠，能够明显提高口服液的稳定性长期放置无药物成分析出；
(3)本发明在口服液中加入质量比为5-10：1的苯甲酸钠和山梨酸钠作为增强剂可以明显提高口服液的防腐效果，延长口服液的存放时间。
(4)本发明提供的口服液容易吸收，生物利用度高，服用安全可靠，成本廉价。
具体实施方式
下面结合具体实施例对本发明做进一步阐述
实施例1一种非布司他口服液
有效成分的原料组成及重量份数为：
非布司他0.1份，百合10份，金钱草5份，金银花5份，蒲公英5份，牡丹皮5份，蔗糖1份、薄荷脑1份、海藻酸钠2份、羧甲基纤维素钠1份、苯甲酸钠1份、山梨酸钠0.2份。
制备方法：
西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的蔗糖、薄荷脑、海藻酸钠、羧甲基纤维素钠、苯甲酸钠和山梨酸钠加乙醇溶解，过滤，得到西药溶液，备用。
中药成分的制备工艺：
(1)将牡丹皮洗净后，加2倍量的乙醇溶液浸泡3小时，加热回流提取3小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加6倍量的水，加热煮沸3小时，过滤，浓缩至含水量为2倍量，得中药提取液，备用。
将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
实施例2一种非布司他口服液
有效成分的原料组成及重量份数为：
非布司他0.8份，百合30份，金钱草15份，金银花20份，蒲公英15份，牡丹皮10份，木糖醇5份、香精5份、海藻酸钠6.4份、羧甲基纤维素钠1.6份、苯甲酸钠2.7份、山梨酸钠0.3份。
制备方法：
西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的木糖醇、香精、海藻酸钠、羧甲基纤维素钠、苯甲酸钠和山梨酸钠加乙醇溶解，过滤，得到西药溶液，备用。
中药成分的制备工艺：
(1)将牡丹皮洗净后，加3倍量的乙醇溶液浸泡2小时，加热回流提取2小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加8倍量的水，加热煮沸2小时，过滤，浓缩至含水量为3倍量，得中药提取液，备用。
将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
实施例3一种非布司他口服液
有效成分的原料组成及重量份数为：
非布司他0.6份，百合25份，金钱草12份，金银花15份，蒲公英12份，牡丹皮8份，甜菊糖4份、薄荷油4份、海藻酸钠5.25份、羧甲基纤维素钠1.75份、苯甲酸钠2.5份、山梨酸钠0.5份。
制备方法：
西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的甜菊糖、薄荷油、海藻酸钠、羧甲基纤维素钠、苯甲酸钠和山梨酸钠加乙醇溶解，过滤，得到西药溶液，备用。
中药成分的制备工艺：
(1)将牡丹皮洗净后，加2.5倍量的乙醇溶液浸泡2.5小时，加热回流提取2.5小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加7倍量的水，加热煮沸2.5小时，过滤，浓缩至含水量为2.5倍量，得中药提取液，备用。
将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
实施例4一种非布司他口服液
有效成分的原料组成及重量份数为：
非布司他0.5份，百合20份，金钱草10份，金银花12份，蒲公英10份，牡丹皮8份，甜菊糖4份、薄荷油4份、海藻酸钠3.75份、羧甲基纤维素钠1.25份、苯甲酸钠2.625份、山梨酸钠0.375份。
制备方法：
西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的甜菊糖、薄荷油、海藻酸钠、羧甲基纤维素钠、苯甲酸钠和山梨酸钠加乙醇溶解，过滤，得到西药溶液，备用。
中药成分的制备工艺：
(1)将牡丹皮洗净后，加2.5倍量的乙醇溶液浸泡2.5小时，加热回流提取2.5小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加7倍量的水，加热煮沸2.5小时，过滤，浓缩至含水量为2.5倍量，得中药提取液，备用。
将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
对比例1
与实施例4的区别在于：非布司他0.05份，百合20份，金钱草10份，金银花12份，蒲公英10份，牡丹皮8份，甜菊糖4份、薄荷油4份、海藻酸钠3.75份、羧甲基纤维素钠1.25份、苯甲酸钠2.625份、山梨酸钠0.375份，即非布司他与中药组分的重量比为0.05：60；其他操作和步骤与实施例4相同。
对比例2
与实施例4的区别在于：非布司他2份，百合20份，金钱草10份，金银花12份，蒲公英10份，牡丹皮8份，甜菊糖4份、薄荷油4份、海藻酸钠3.75份、羧甲基纤维素钠1.25份、苯甲酸钠2.625份、山梨酸钠0.375份，即非布司他与中药组分的重量比为2：60；其他操作和步骤与实施例4相同。
对比例3
与实施例4的区别在于：胶浆剂为质量比0.6：1的海藻酸钠和羧甲基纤维素钠，即海藻酸钠1.875份、羧甲基纤维素钠3.125份；其他操作和步骤与实施例4相同。
对比例4
与实施例4的区别在于，胶浆剂为单一组分海藻酸钠；其他操作和步骤与实施例4相同。
对比例5
与实施例4的区别在于：增强剂为质量比1：1的苯甲酸钠和山梨酸钠，即苯甲酸钠1.5份、山梨酸钠1.5份；其他操作和步骤与实施例4相同。
对比例6
与实施例4的区别在于：增强剂为单一组分的苯甲酸钠；其他操作和步骤与实施例4相同。
试验例1加速稳定性实验
分别根据实施例1-4以及对比例1-6的配方以及制备方法每个实施例制作20瓶(每瓶10mL)非布司他口服液分别测试口服液的稳定性，然后各个检测项目取平均值，具体数据见下表1-2。
表1实施例1-4制备的口服液的稳定性加速检测
表2对比例1-6制备的药物组合物的稳定性加速检测
根据上表1-2的检测数据可以看出本发明制备的非布司他口服液具有较好的稳定性，长期放置后单杂和总杂的含量增加并不明显，溶解性较好，无固体析出，活性成分依然能保持在100％左右，对比例1-6中，改变某种组分的质量比不在本发明公开的保护范围内时，口服液的稳定性出现明显降低，长期放置口服液中单杂和总杂出现了较明显的增加，溶解性降低，固体析出，表明本发明实施例1-4制备的口服液具有较好的稳定性。
试验例2长期稳定性实验
分别根据实施例1-4以及对比例1-6的配方以及制备方法每个实施例制作20瓶(每瓶10mL)非布司他口服液，分别测试口服液的稳定性，然后各个检测项目取平均值，具体数据见下表3-4。
表3实施例1-4制备的口服液的稳定性长期检测
表4对比例1-6制备的药物组合物的稳定性长期检测
根据上表3-4的检测数据可以看出本发明制备的非布司他口服液具有较好的稳定性，长期放置后单杂和总杂的含量增加并不明显，溶解性较好，无固体析出，活性成分依然能保持在100％左右，对比例1-6中，改变某种组分的质量比不在本发明公开的保护范围内时，口服液的稳定性出现明显降低，长期放置口服液中单杂和总杂出现了较明显的增加，溶解性降低，固体析出，与加速稳定性试验的结果相同，进一步表明本发明实施例1-4制备的口服液具有较好的稳定性。
试验例3抑菌效果检测
分别根据实施例1-4以及对比例5-6的配方以及制备方法每个实施例制作30瓶(每瓶10mL)非布司他口服液，分别测试口服液的抑菌效果，具体数据见下表5。
表5微生物限度检测
根据上表5的检测数据可以看出，本发明制备的口服液具有很好地抑菌效果，长期放置后需氧菌总数和霉菌和酵母菌数变化不大，满足口服液对微生物限度的要求，而对比例5-6制备的口服液中需氧菌总数和霉菌和酵母菌数较实施例均出现了明显增加，虽然满足口服液对微生物限度的要求，但是会明显影响口服液的稳定性。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种非布司他口服液，其特征在于：所述口服液的原料组成及重量份数为：
非布司他0.1-0.8份，百合10-30份，金钱草5-15份，金银花5-20份，蒲公英5-15份，牡丹皮5-10份，甜味剂1-5份，芳香剂1-5份、胶浆剂2-8份和增强剂1-3份。
2.根据权利要求1所述的非布司他口服液，其特征在于：所述口服液的原料组成及重量份数为：
非布司他0.3-0.6份，百合15-25份，金钱草7-12份，金银花7-15份，蒲公英7-12份，牡丹皮6-8份，甜味剂2-4份，芳香剂2-4份、胶浆剂3-7份和增强剂2-3份。
3.根据权利要求1所述的非布司他口服液，其特征在于：所述口服液的原料组成及重量份数为：
非布司他0.5份，百合20份，金钱草10份，金银花12份，蒲公英10份，牡丹皮8份，甜味剂4份，芳香剂4份、胶浆剂5份和增强剂3份。
4.根据权利要求1所述的非布司他口服液，其特征在于：所述的甜味剂包括蔗糖、单糖浆、糖精钠、阿斯巴甜、蛋白糖、木糖醇、甜蜜素和甜菊糖中的一种或几种。
5.根据权利要求1所述的非布司他口服液，其特征在于：所述的胶浆剂包括海藻酸钠、阿拉伯胶、明胶、甲基纤维素和羧甲基纤维素钠中的一种或几种。
6.根据权利要求5所述的非布司他口服液，其特征在于：所述的胶浆剂为质量比2-4：1的海藻酸钠和羧甲基纤维素钠。
7.根据权利要求1所述的非布司他口服液，其特征在于：所述的增强剂包括苯甲酸、苯甲酸钠、山梨酸和山梨酸钾中的一种或几种。
8.根据权利要求7所述的非布司他口服液，其特征在于：所述的增强剂为质量比为5-10：1的苯甲酸钠和山梨酸钠。
9.根据权利要求1所述的非布司他口服液，其特征在于：所述的非布司他与中药组分的重量比为0.1-0.8：30-90。
10.一种如权利要求1所述的口服液的制备方法，其特征在于：包括以下步骤：
(一)西药成分的制备工艺：
将药物有效成分非布司他，加入药罐中，然后加入配方用量的甜味剂、芳香剂、胶浆剂和增强剂加乙醇溶解，过滤，得到西药溶液，备用；
(二)中药成分的制备工艺：
(1)将牡丹皮洗净后，加2-3倍量的乙醇溶液浸泡2-3小时，加热回流提取2-3小时，过滤，回收乙醇，得滤液备用；
(2)将百合、金钱草、金银花和蒲公英洗净，研磨后加6-8倍量的水，加热煮沸2-3小时，过滤，浓缩至含水量为2-3倍量，得中药提取液，备用；
(三)所述的非布司他口服液得制备方法，将所述的西药溶液和中药提取液混合，搅拌均匀，即得到口服液。
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: No. 188, Longbao Road, Shuangdong street, Luoding City, Yunfu City, Guangdong Province Applicant after: Yili Pharmaceutical (Luoding) Co.,Ltd. Address before: No. 188, Longbao Road, Shuangdong street, Luoding City, Yunfu City, Guangdong Province Applicant before: GUANGDONG YILI LUODING PHARMACEUTICAL Co.,Ltd. |
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| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200804 |