CN113057946A - 一种双氢青蒿素哌喹片及其制备方法 - Google Patents
一种双氢青蒿素哌喹片及其制备方法 Download PDFInfo
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- CN113057946A CN113057946A CN202110341760.9A CN202110341760A CN113057946A CN 113057946 A CN113057946 A CN 113057946A CN 202110341760 A CN202110341760 A CN 202110341760A CN 113057946 A CN113057946 A CN 113057946A
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- dihydroartemisinin
- piperaquine
- tablet
- solid dispersion
- surfactant
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Abstract
本发明属于药物制剂领域,具体涉及一种将固体分散法和表面活性剂添加法结合,通过将双氢青蒿素和磷酸哌喹混合制备成固体分散体,并开发为片剂,通过这种方法制备的固体分散体片剂在水或胃液中,依靠崩解剂的联合作用,使得片剂崩解快速,且亲水性基质溶解,药物分子溶解,并在水性介质中会形成一种过饱和状态而不会沉淀,并在胃排空时间内使得两种药物快速的溶出,以提高其药物的生物利用度。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种双氢青蒿素哌喹片及其制备方法。
背景技术
疟疾是当前危害严重的世界性流行疾病,据世界卫生组织报导:全球有102个国家20亿人口生活在疟疾流行区,2.7亿人得疟疾,每年约百余万人死于疟病。特别是目前面临的一个严峻问题是耐药性,恶性疟原虫已经对所有抗疟药产生了耐药性,而抗疟药的耐药性导致感染者人数剧增并代来更严重、更复杂的疟疾,如死亡率很高的脑型疟疾。为此迫切需要创造新化学结构的抗疟新药。长期以来,抗疟药主要以喹宁类药物为主。自60年代氯喹产生抗性以来,很多国家都在研究抗疟新药,美国筛选了30余万种化合物,以甲氟喹为好,作为重点开发。但此药易产生抗性,不好单独使用,曾与周效磺胺、乙胺嘧啶配合使用,制成口服长效片剂“FANSIMEF”但近年来发现甲氟喹有神经毒。
青蒿素是天然青蒿属植物的提取物,它很早就在中国传统中药中被用作抗疟疾、抗肿瘤和驱虫等药物。卫生部中医研究院中药研究所(简称“中研院中药所”,现为中国中医科学院中药研究所)屠呦呦及其研究组在对中药进行大量研究基础上,受中医典籍《肘后备急方》的启迪创建了青蒿提取方法,1971年10月获得青蒿抗疟活性化学部位,1972年11月从中发现青蒿素。青蒿素是一个仅由碳、氢、氧3种元素组成、具有过氧基团特殊结构的新型倍半萜内酯,是与已知抗疟药在化学结构、作用机制完全不同的新化合物。青蒿素主要是干扰疟原虫的表膜一线粒体功能。青蒿素通过影响疟原虫红内期的超微结构,使其膜系结构发生变化。由于对食物泡膜的作用,阻断了疟原虫的营养摄取,当疟原虫损失大量胞浆和营养物质,而又得不到补充,因而很快死亡。其作用方式是通过其内过氧化物(双氧)桥,经血红蛋白分解后产生的游离铁所介导,产生不稳定的有机自由基及/或其他亲电子的中介物,然后与疟原虫的蛋白质形成共价加合物,而使疟原虫死亡。临床疗效几乎可达100%,具有速效、高效和低毒等特点。目前,青蒿素及其衍生物是世界上治疗疟疾最有效的药物,青蒿素联合疗法已被用于几乎所有国家和地区的疟区,每年治疗病例一亿以上,降低了全球疟疾的发生率和死亡率,已挽救了数百万人的生命。
瑞士NORVATIS制药公司从中国购买的一项技术复方蒿甲醚片(含苯芴醇0.12g,蒿甲醚0.02g),其在治疗疟疾方面可能优于目前现有的抗疟剂药物,但其疗程需要3天,且成本较高。英国Glaxo welcome公司正在研制Malarone,其主要成分为奈醌和环氯胍组成,其配方中缺乏速效药,3天一个疗程,每天服药2次。目前临床应用的有青蒿素栓剂、蒿甲醚油肌注剂、青蒿琥酯钠水静注剂等一系列青蒿素衍生物制剂。但这些药物都程度不同的存在着复燃率高、使用不方便及成本较高等不足。
双氢青蒿素(Dihydroartemisinin)为青蒿素的衍生物,是青蒿素的体内活性物质,对疟原虫无性体有较强的杀灭作用,能迅速杀灭疟原虫,从而控制症状。耐药性培育实验表明,疟原虫对双氢青蒿素不易产生耐药性。中国中医科学院1985年开始以还原青蒿素为基础,将其完善成双氢青蒿素,于1992年7月获得新药证书。双氢青蒿素抗疟疗效高于青蒿素10倍,可口服途径给药,而且复燃率明显降低。双氢青蒿素化学名为3R,5aS,6R,8aS,9R,12S,12aR)-八氢-3,6,9三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-苯并二塞平-10(3H)醇,分子式C15H24N3O5,分子量284.348,其结构式为:
磷酸哌喹为4-氨基喹啉类抗疟药,抗疟作用与氯喹类似,影响疟原虫红内期裂殖体的超微结构,主要能使滋养体食物泡膜和线粒体肿胀,导致其生理功能的破坏,从而杀死疟原虫。磷酸哌喹与氯喹没有交叉抗药性。磷酸哌喹化学名为1,3-双(4-(7-氯喹醇IN-4-基)哌嗪-1-基)丙烷;1,3-双[4-(7-氯-喹啉-4-基)哌嗪-1-基]丙烷四磷酸盐四水合物,分子式C29H32NCl2N6,分子量535.511,其结构式为:
根据体外药效学研究提示,二者合用具有增效作用,可延缓疟原虫抗药性的产生,且无毒副作用的增加。目前国内已有上市的复方制剂用于疟疾疾病的治疗药物,贝克诺顿(浙江)制药有限公司、嘉兴市南湖制药有限责任公司等上市的双氢青蒿素哌喹片。但是,双氢青蒿素对高温极为敏感,另外,双氢青蒿素不溶于水,药物的溶出度不好,从而导致药物的人体吸收效果不好,生物利用度低。对于口服药物制剂,大多数药物只有在胃液或肠液中形成分子状态才能通过胃肠粘膜壁并被吸收至血液循环发生治疗作用,在很多情况下,如果口服药物的特性溶解度小于1mg/ml就可能出现吸收问题。鉴于双氢青蒿素在水中几乎不溶,磷酸哌喹在水中略溶,因此制备该复方制剂最大的困难是如何使药物快速溶出。
CN101954090B公开了一种双氢青蒿素β-环糊精包合物及其制备方法和含有该包合物的抗疟疾药物。该技术将双氢青蒿素用环糊精包合后再与磷酸哌喹制备成制剂,尽管提高了双氢青蒿素稳定性,但需要进行低温干燥处理,制备工艺复杂。同时由于磷酸哌喹在水中微溶,因此复方制剂中磷酸哌喹的溶解度令人担忧。
CN102485226A公开了一种复方青蒿素类哌喹微丸及其制备方法,其中复方青蒿素类哌喹微丸包括20-100重量份青蒿素类化合物、100-500重量份磷酸哌喹、50-300重量份乳糖、50-300重量份微晶纤维素、10-100重量份交联聚乙烯吡咯烷酮、0-50重量份羧甲基淀粉钠、1-20重量份共聚维酮和0.05-5重量份增溶剂。该技术制备的复方青蒿素类哌喹微丸外形规则,成型及圆整度较好,流动性好,溶出度不受影响,掩盖了苦味,然而其制备小丸的工艺繁琐,同时小丸溶出速度慢,15min双氢青蒿素、磷酸哌喹仅溶出40%左右,难以迅速起效。
因此,发明人想到,在进行片剂处方开发中,将将固体分散法和表面活性剂添加法以改善双氢青蒿素和磷酸哌喹两种药物的生物利用度。通过将双氢青蒿素和磷酸哌喹混合制备成固体分散体,并开发为片剂,通过这种方法制备的固体分散体片剂在水或胃液中,依靠崩解剂的联合作用,使得片剂崩解快速,且亲水性基质溶解,药物分子溶解,并在水性介质中会形成一种过饱和状态而不会沉淀,并在胃排空时间内使得两种药物快速的溶出,以提高其药物的生物利用度,且药物制剂的稳定性得到改善。
发明内容
本发明的目的是针对上述技术问题,提供一种可以将固体分散法和表面活性剂添加进行联合,通过与亲水性基质,表面活性剂和助溶剂混合制备固体分散体,然后与其他辅料进行混合,然后压片,制备含有固体分散体的口服固体制剂,提高双氢青蒿素的稳定性,使得双氢青蒿素和磷酸哌喹达到完全溶出,并形成一种过饱和状态而不会沉淀,以提高微溶性药物的生物利用度。
为解决上述技术问题,本发明采用的技术方案为:
一种双氢青蒿素哌喹片及其制备方法,包括如下步骤:
一种双氢青蒿素哌喹片,包括双氢青蒿素、磷酸哌喹、亲水性基质、表面活性剂和助溶剂。
发明人在研究中发现,具有适中玻璃转化温度水溶性基质的选择对于双氢青蒿素哌喹固体分散体的制备至关重要。本发明制备的新型固体分散体,以及将其开发为固体药物制剂包含以下成分:
(a)本发明所述双氢青蒿素哌喹片剂中,包含双氢青蒿素和磷酸哌喹片活性剂,单位剂量形式包含双氢青蒿素活性成分为40mg,磷酸哌喹片活性成分为0.32g;
(b)本发明所述双氢青蒿素哌喹片中,包含一种或多种药剂学上可接受的具有适中玻璃转化温度水溶性基质:
优选地,所述双氢青蒿素哌喹片中,可接受的具有适中玻璃转化温度水溶性基质为聚乙烯吡咯烷酮(PVP)、乙烯吡咯烷酮-醋酸乙烯酯共聚物(PVP-VA)、羟丙甲纤维素(HPMC)、醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、邻苯二甲酸羟丙基纤维素(HPMCP)、聚甲基丙烯酸酯、聚乙二醇-醋酸乙烯酯-乙烯己内酰胺接枝共聚物(Soluplus)、甲基丙烯酸和甲基丙烯酸甲酯的约1:1比例的共聚物、聚乙二醇4000(PEG4000)、聚乙二醇6000(PEG6000)中的一种或多种,但不限于这些。
进一步优选地,所述双氢青蒿素哌喹片中,具有适中玻璃转化温度水溶性基质选自聚乙二醇-醋酸乙烯酯-乙烯己内酰胺接枝共聚物(Soluplus)、聚乙二醇4000(PEG4000)、聚乙二醇6000(PEG6000)中的一种或多种。
再进一步优选地,所述双氢青蒿素哌喹片中,聚乙二醇4000在固体分散体中的占比为10至20%。
(c)本发明所述双氢青蒿素哌喹片剂中,包含药剂学上可接受的表面活性剂:
本发明中所用的术语“表面活性剂”是指对难溶性药物具有很好的润湿作用。表面活性剂分子结构中的两亲分子吸附于固体表面,形成定向排列的吸附层,降低界面自由能,从而有效改变固体表面的润湿性质,也能提高液体的润湿能力,增大药物的溶出速度。适宜的表面活性剂包括脂肪酸盐、硫酸脂盐如月桂醇硫酸钠、磺酸盐如二辛基琥珀酰磺酸钠和十二烷基磺酸钠等阴离子表面活性剂;聚乙二醇型(包括聚氧乙烯脂肪醇醚和聚氧乙烯烷基酚醚、聚氧乙烯脂肪酸脂如卖泽类、聚氧乙烯蓖麻油衍生物)及多元醇型如司盘,吐温类,泊洛沙姆(泊洛沙姆407,泊洛沙姆188,泊洛沙姆105,泊洛沙姆108,泊洛沙姆122,泊洛沙姆401)、甘油和单硬脂肪酸甘油脂等非离子型表面活性剂等中的一种或多种。
进一步优选地,所述双氢青蒿素哌喹片中,表面活性剂优选泊洛沙姆类,其特征在于其是一种亲水性、非离子合成的聚氧乙烯-聚氧丙烯嵌段共聚物。一方面由于泊洛沙姆类使肠道蠕动变慢,药物在胃肠道中滞留时间增长,吸收增加,从而能提高口服制剂的生物利用度。另一方面,泊洛沙姆类与皮肤相容性佳,增加皮肤通透性,可促进外用药剂的吸收。
再进一步优选地,所述双氢青蒿素哌喹片中,表面活性剂优选泊洛沙姆188。
再进一步优选地,所述表面活性剂的添加量占固体分散体的1至10%。
(d)本发明所述双氢青蒿素哌喹片中,包含药剂学上可接受的助溶剂:
优选地,所述双氢青蒿素哌喹片中,适宜的药学上可接受的助溶剂包含甘油,异丙醇,PEG-60氢化蓖麻油,PEG-10氢化蓖麻油,PEG-60氢化蓖麻油和甘油的混合物以PEG-10氢化蓖麻油和甘油的混合物。
进一步优选地,所述双氢青蒿素哌喹片中,助溶剂优选PEG-60氢化蓖麻油和甘油的混合物,其中,PEG-60氢化蓖麻油的添加量占固体分散体的的10至20%;甘油的添加量占固体分散体的5至20%。
(e)本发明所述双氢青蒿素哌喹片中,包含药剂学上可接受的填充剂:
优选地,所述双氢青蒿素哌喹片中,适宜的药学上可接受的填充剂包含玉米淀粉、明胶、乳糖、硅化微晶纤维素、微晶纤维素、纤维素乳糖、山梨醇、海藻糖、D-甘露醇、预胶化淀粉中的一种或多种。
进一步优选地,所述双氢青蒿素哌喹片中,填充剂优选乳糖、微晶纤维素、纤维素乳糖、玉米淀粉中的一种或多种。
再进一步优选地,所述双氢青蒿素哌喹片中,填充剂优选纤维素乳糖。
再进一步优选地,所述填充剂的添加量占双氢青蒿素哌喹片重的1至10%。
(f)本发明所述双氢青蒿素哌喹片中,包含一种或多种药剂学上可接受的崩解剂:
优选地,所述头双氢青蒿素哌喹片中,适宜的药学上可接受的崩解剂包含羧甲基纤维素、交联羧甲基纤维素钠、交联羧甲基淀粉钠、低取代羟丙纤维素、交联聚维酮、羧甲基淀粉钠等中的一种或多种。
进一步优选地,所述双氢青蒿素哌喹片中,崩解剂优选羧甲基淀粉钠,其占双氢青蒿素哌喹片片重的1至10%。
(g)本发明所述双氢青蒿素哌喹片中,适宜的药学上可接受的助流剂优选胶态二氧化硅、硅酸铝、滑石、粉状纤维素、三硅酸镁、高岭土、硬脂酸镁、二氧化钛和淀粉。
进一步优选地,所述双氢青蒿素哌喹片中,药用助流剂优选胶态二氧化硅、滑石以及硬脂酸镁中的一种或多种。
再进一步优选地,所述双氢青蒿素哌喹片中,药用助流剂优选胶态二氧化硅。
再进一步优选地,所述的胶态二氧化硅的堆堆密度约为0.03至0.05g/ml。
(h)本发明所述双氢青蒿素哌喹片剂中,包含药剂学上可接受的润滑剂:
本发明中所用的术语“润滑剂”包括降低摩擦力、热以及磨损的润滑剂。适宜的润滑剂包含硬脂酸镁、硬脂富马酸钠、棕榈酸、硬脂酸钙、滑石、巴西棕榈蜡、硬脂酸铝、硬脂酸锌、硬脂酸钠、硬脂酸钙以及硬脂酸。
进一步优选地,所述双氢青蒿素哌喹片中,药用润滑剂优选硬脂酸镁、硬脂富马酸钠以及滑石粉中的一种或多种。
再进一步优选地,所述双氢青蒿素哌喹片中,药用润滑剂优选硬脂酸镁。
本发明制备工艺过程主要包括,例如,固体分散体:将亲水性基质、表面活性剂以及助溶剂形成溶液,加入双氢青蒿和素哌喹混合形成溶液,将得到的热混合物冷却,干燥以获得的固体分散体。然后与药学上可接受的载体混合制备双氢青蒿素哌喹片剂。
有益效果:本发明提供一种可以将固体分散法和表面活性剂添加进行联合,通过与亲水性基质,表面活性剂和助溶剂混合制备固体分散体,然后与其他辅料进行混合,然后压片,制备含有固体分散体的口服固体制剂,提高双氢青蒿素的稳定性,使得双氢青蒿素和磷酸哌喹达到完全溶出,并形成一种过饱和状态而不会沉淀,以提高微溶性药物的生物利用度。
具体实施方式
下面通过实施例来进一步描述本发明的有益效果,应该正确理解的是:本发明的实施例仅仅是用于说明本发明而给出,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实施例1
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素和磷酸哌喹,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表1。
表1双氢青蒿素哌喹片处方组成
实施例2
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素和磷酸哌喹,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表2。
表2双氢青蒿素哌喹片处方组成
实施例3
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素和磷酸哌喹,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表3。
表3双氢青蒿素哌喹片处方组成
实施例4
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素和磷酸哌喹,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表4。
表4双氢青蒿素哌喹片处方组成
对比施例1
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体、磷酸哌喹与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表5。
表5双氢青蒿素哌喹片处方组成
对比实施例2
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体、磷酸哌喹与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表6。
表6双氢青蒿素哌喹片处方组成
对比实施例3
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体、磷酸哌喹与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表7。
表7双氢青蒿素哌喹片处方组成
对比实施例4
本实施例中的一种双氢青蒿素哌喹片剂的制备方法,包括如下步骤:
1)固体分散体
在60℃下将溶剂亲水性基质、表面活性剂以及助溶剂形成溶液,在40℃下保温,依次加入处方量的氢青蒿素,搅拌至溶解,将得到的热混合物冷却,在35至40℃的温度下干燥以获得的固体分散体。
2)双氢青蒿素哌喹片的制备
将处方量的固体分散体、磷酸哌喹与胶态二氧化硅投入低剪切V型混合器中进行混合10min,然后将处方量的纤维素乳糖、羧甲基淀粉钠投入低剪切V型混合器中进行混合,混合30min,加入处方量的硬脂酸镁,然后在低剪切V型混合器中进行混合,混合5min,将得到的混粉分别倒入浅凹痕的模具中压片。处方组成见表8。
表8双氢青蒿素哌喹片处方组成
验证实施例
1、溶出度取本品,照溶出度与释放度测定法(通则0931第二法),以盐酸溶液(9→1000)500ml为溶出介质,转速为每分钟75转,依法操作,经45分钟时,取溶液滤过,取续滤液备用。
(1)、双氢青蒿素溶出度测定:取上述续滤液作为供试品溶液。另取双氢青蒿素对照品适量,精密称定,加乙醇溶解并定量稀释制成每1ml中约含0.4mg的溶液,摇匀,精密量取2ml,置10ml量瓶中,用溶出介质稀释至刻度,于37℃保温45分钟,放冷,作为对照品溶液。照高效液相色谱法(通则0512)试验。用十八烷基硅烷键合硅胶为填充剂;以0.02mol/L磷酸氢二钠溶液(用磷酸调节pH值至2.4)-乙腈(65:35)为流动相;检测波长为237nm。理论板数按双氢青蒿素峰计算不低于3000,双氢青蒿素两峰的分离度应大于2.0。分别精密量取供试品溶液与对照品溶液各5ml,置25ml量瓶中,用3.6%氢氧化钠溶液稀释至刻度,摇匀,置60℃水浴中反应30分钟,取出,放冷,精密加磷酸0.7ml,摇匀,用0.45μm滤膜滤过,在2小时内精密量取20μ1,注入液相色谱仪,记录色谱图,按外标法以峰面积计算每片的溶出量。限度为标示量的70%,应符合规定。
(2)、磷酸哌喹溶出度测定:精密量取上述续滤液1ml,置50ml量瓶中,用溶出介质稀释至刻度,摇匀,照紫外-可见分光光度法(通则0401),在345nm的波长处测定吸光度。另取磷酸哌喹对照品适量,精密称定,加溶出介质溶解并定量稀释制成每1ml中约含12.8μg的溶液,同法测定,计算每片的溶出量。限度为标示量的80%,应符合规定。其他应符合片剂项下有关的各项规定(通则0101)。测定结果如表9所示。
表9双氢青蒿素哌喹片的溶出度测定结果
从表9的实验结果可以看出:本发明实施例1-4制备的双氢青蒿素哌喹片,在15min时,双氢青蒿素和磷酸哌喹基本完全完全溶出,但发现采用分子量大的泊洛沙姆P407和聚乙二醇6000,溶出略偏慢;但比较对比实施例1-4制备的双氢青蒿素哌喹片,在15min时,双氢青蒿素已基本完全溶出,但是磷酸哌喹的溶出度未完全溶出,溶出度约为60%,在45min时,溶出度小于90%。说明采用将两种药物载入固体分散体中可以提高两者的溶出度。
Claims (9)
1.一种双氢青蒿素哌喹片,其特征在于,包括双氢青蒿素、磷酸哌喹、亲水性基质、表面活性剂和助溶剂。
2.根据权利要求1所述的一种双氢青蒿素哌喹片,其特征在于,制备方法为:将亲水性基质、表面活性剂以及助溶剂形成溶液,加入双氢青蒿素和磷酸哌喹混合形成溶液,将得到的热混合物冷却,干燥以获得的固体分散体,添加填充剂、崩解剂、助流剂、润滑剂混合,制备双氢青蒿素哌喹片。
3.根据权利要求2所述的一种双氢青蒿素哌喹片,其特征在于,单位剂量形式包含双氢青蒿素活性成分为40mg,磷酸哌喹活性成分为0.32g。
4.根据权利要求2所述的一种双氢青蒿素哌喹片,其特征在于,亲水性基质为可接受的具有适中玻璃转化温度水溶性基质,选自聚乙二醇-醋酸乙烯酯-乙烯己内酰胺接枝共聚物(Soluplus)、聚乙二醇4000(PEG4000)、聚乙二醇6000(PEG6000)中的一种或多种。
5.根据权利要求2或4所述的一种双氢青蒿素哌喹片,其特征在于,亲水性基质为可接受的具有适中玻璃转化温度水溶性基质,选自聚乙二醇4000(PEG4000),其在固体分散体中的占比为10至20%。
6.根据权利要求2所述的一种双氢青蒿素哌喹片,其特征在于,表面活性剂为泊洛沙姆类188,所述表面活性剂的添加量占固体分散体的1至10%。
7.根据权利要求2或6所述的一种双氢青蒿素哌喹片,其特征在于,助溶剂为PEG-60氢化蓖麻油和甘油的混合物,PEG-60氢化蓖麻油的添加量占固体分散体的的10至20%;甘油的添加量占固体分散体的5至20%。
8.根据权利要求2所述的一种双氢青蒿素哌喹片,其特征在于,填充剂为乳糖、微晶纤维素、纤维素乳糖、玉米淀粉中的一种或多种;崩解剂为羧甲基淀粉钠;助流剂为胶态二氧化硅;润滑剂优选硬脂酸镁、硬脂富马酸钠以及滑石粉中的一种或多种。
9.根据权利要求8所述一种双氢青蒿素哌喹片,其特征在于,填充剂为纤维素乳糖,所述填充剂的添加量占双氢青蒿素哌喹片重的1至10%;崩解剂为羧甲基淀粉钠,其占双氢青蒿素哌喹片片重的1至10%;助流剂为胶态二氧化硅,堆密度约为0.03至0.05g/ml,润滑剂为硬脂酸镁。
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