CN104910077B - 阿苯达唑的制备方法及应用 - Google Patents
阿苯达唑的制备方法及应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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Abstract
本发明涉及阿苯达唑的合成、精制和应用。本发明首先提供了一种阿苯达唑的合成方法，并采用混合溶剂(水和乙醇)‑混酸(甲酸和乙酸)的精制体系，精制后阿苯达唑具有较高的纯度和溶解性。本发明进一步提供了一种结肠靶向微囊的制备方法，首先采用胺基化聚乳酸‑羟基乙酸共聚物(PLGA‑NH2)包覆阿苯达唑，制得载药纳米粒，然后采用pH敏感型肠溶材料同时包覆载药纳米粒和崩解剂，制得阿苯达唑结肠靶向微囊，该结肠靶向微囊同时具备结肠靶向、快速崩解、缓慢释药的三重功效，延长了口服阿苯达唑在体内的循环时间，提高了阿苯达唑的吸收效率。
Description
技术领域
本发明涉及阿苯达唑的合成和应用方法，尤其涉及一种具有高溶解性的阿苯达唑的合成和精制方法，以及一种具有高溶出度的阿苯达唑结肠靶微囊的制备方法。
背景技术
阿苯达唑(Albendazole，ABZ)又名丙硫咪哇，化学名称为5-丙硫基-2-苯并咪哇氨基甲酸甲醋。ABZ主要用于治疗肠道寄生虫病，同时对包虫病有一定疗效。ABZ不溶于水，微溶于有机溶剂。由于ABZ的低溶解性，其在肠道中吸收差，生物利用度低。药物的吸收效率受药物本身性质的影响显著，其中最重要的三个因素为药物的渗透性、溶解度和溶出度。药物吸收分数由药物通过肠壁的渗透性决定；溶解度是影响药物吸收的分子理化性质之一；溶出度则反映了制剂因素对药物在溶液中溶解的速度和程度的影响。控制好阿苯达唑原料药的晶型，增加其比表面积，提高其溶解度，是提高阿苯达唑溶出度的有效方法之一。
另外，通常药物的粒度越小，其溶解性、渗透性以及溶出度越好。因此，现有技术中为了克服疏水性药物吸收率低的问题，可将疏水性药物制备成可生物降解的载药纳米粒(例如，专利文献：CN101361976A；期刊文献：环糊精对阿苯达唑的包合作用及其包合物的制备，刘梦等，中国新药杂志2014年第23卷第23期；期刊文献：阿苯达唑-壳聚糖纳米粒的制备及体内外评价，王晓青等，中国新药杂志2013年第22卷第7期)，载药纳米粒提高了疏水性药物的溶解性和渗透性，增加肠道上皮细胞对载药纳米粒的转运和吸收，从而提高疏水性药物的吸收率。然而，由于普通载药纳米粒易受胃肠道pH和酶的影响，直接口服后易被胃酸破坏。为了解决上述问题，专利文献(CN103417515A)报道了采用可生物降解的高分子材料(PLGA、PLGA-PEG、PLGA-PEG-WGA)包载药物分子制成纳米粒，再对纳米粒进行肠溶材料包衣，制成口服结肠靶向微囊。结合纳米粒和肠溶包衣微囊制剂的双重优势，微囊可顺利经过胃肠道，最终在结肠部位靶向释放出纳米粒，然后利用纳米粒容易被肠道上皮细胞转运的特点增强药物吸收；同时随着纳米粒载体材料降解，药物逐渐缓慢释放出来，提高药物的吸收效率，延长药物的体循环时间，并达到结肠靶向的缓控释效果。然而，上述口服结肠靶向微囊在模拟肠液(pH＝7.4的释放介质)中需经过1-6小时才能达到较高的释药量，因此该口服结肠靶向微囊的释药速率有待进一步提高。
发明内容
为了克服现有技术的不足，本发明提供了一种具有高溶解性的阿苯达唑的合成和精制方法，并提供了一种具有高溶出度的阿苯达唑结肠靶向微囊的制备方法。
为了达到上述目的，本发明采用如下的技术方案：首先制备阿苯达唑粗品，然后采用混合溶剂(水和乙醇)-混酸(甲酸和乙酸)的精制体系，得到具有高溶解性的阿苯达唑纯品。本发明进一步采用可生物降解的聚合物——胺基化聚乳酸-羟基乙酸共聚物(PLGA-NH2)对上述高溶解性阿苯达唑纯品进行包覆，制成肠道增强吸收型载药纳米粒ABZ/PLGA-NH2；利用油包油溶剂挥发法，使用pH敏感型肠溶材料对载药纳米粒进行包覆，制成结肠靶向微囊。在使用肠溶材料对纳米粒进行包覆的过程中添加崩解剂——羧甲基淀粉钠或羟丙纤维素，利用PLGA-NH2上的胺基与羧甲基淀粉钠或羟丙纤维素中的活性基团之间的静电作用使纳米粒与崩解剂结合，进而将纳米粒和崩解剂一起包埋于微囊中。所述阿苯达唑结肠靶向微囊经口服给药后，由于受到微囊外层肠溶材料的保护，其在酸性胃液中不溶解，在进入肠道后，肠溶材料在碱性肠液中溶解，微囊内部的崩解剂吸水膨胀，加速微囊崩解，从而快速释放ABZ/PLGA-NH2纳米粒。纳米粒被肠道上皮细胞转运、吸收。随着纳米粒中PLGA的降解，高溶解性的阿苯达唑逐渐缓慢释放出来，从而延长了阿苯达唑在体内的循环时间，提高了生物体对阿苯达唑的吸收效率。
一种高溶解性阿苯达唑的合成方法，其特征在于包括如下步骤：1)合成阿苯达唑：以邻硝基苯胺为原料，与二丙基二硫醚通过氯气催化反应生成4-丙硫基-2-硝基苯胺；将上述生成物4-丙硫基-2-硝基苯胺溶解于乙醇水溶液中，接着加入硫氢化钠，60℃搅拌还原3-5小时，生成4-丙硫基-1,2-邻苯二胺，用甲苯萃取；向上述萃取物中加入氰氨基甲酸甲酯，升温到80℃，搅拌反应并滴加盐酸和冰醋酸的混合酸溶液，保持反应体系的pH值为4左右，于80℃下保温1～3小时，生成白色固体，离心水洗得阿苯达唑粗品；2)精制阿苯达唑：向步骤1)制得的阿苯达唑粗品中依次加入无水乙醇、去离子水、甲酸和乙酸，加热搅拌至全溶，然后加入氨水进行中和结晶，过滤，干燥，即得具有高溶解性的阿苯达唑。
在上述合成方法中，所述步骤1)中邻硝基苯胺与二丙基二硫醚的摩尔比为1:1-1:1.5，邻硝基苯胺与硫氢化钠的摩尔比为1:1.5-1:2，邻硝基苯胺与氰氨基甲酸甲酯的摩尔比为1:1-1:2。
在上述合成方法中，所述步骤2)中无水乙醇与去离子水的体积比为1:3-3:1，甲酸和乙酸的体积比为1:2-3:2，甲酸与去离子水的体积比为1:2-1:6。
在上述合成方法中，所述步骤2)中所述加热搅拌的温度为60-90℃。
上述合成方法制得的阿苯达唑的纯度大于99％，溶解率高于90％。
一种阿苯达唑结肠靶向微囊的制备方法，包括如下步骤：
1)将5～20mg上述高溶解性阿苯达唑和50～100mg胺基化聚乳酸-羟基乙酸共聚物(PLGA-NH2)溶解于5～10mL三氯甲烷中形成有机相，以10～30mL含3wt％聚乙烯醇(PVA)的水溶液为水相，将有机相滴加至水相中形成O/W的乳液，进一步超声后分散至含0.3wt％聚乙烯醇的水溶液中固化，搅拌挥发去除有机溶剂，水洗、离心、冷冻干燥，即得胺基化聚乳酸-羟基乙酸共聚物包覆阿苯达唑纳米粒(ABZ/PLGA-NH2)；
2)取50～100mg的pH敏感型肠溶材料，溶解至3～10ml100％无水乙醇中；
3)取步骤1)中的纳米粒10-20mg，分散至上述溶有肠溶材料的无水乙醇中，再加入1-10mg羧甲基淀粉钠或羟丙纤维素，搅拌分散；
4)配制30～60ml含1～3wt％span80的植物油；
5)将步骤3)中的乙醇分散液缓慢滴加至步骤4)中的植物油中，持续搅拌，固化，挥发去除无水乙醇，离心，沉淀用正己烷洗涤，即得阿苯达唑结肠靶向微囊。
在上述制备方法中，所述的pH敏感型肠溶材料为尤特奇L-100、MAE-100P、丙烯酸树脂II号和丙烯酸树脂III号中的一种。
在上述制备方法中，所述的植物油为花生油、橄榄油、芝麻油、菜籽油中的一种或几种混合。
在上述制备方法中，步骤1)中的搅拌速度为500～800rpm，搅拌时间为3～8h；离心速度为7000～10000rpm，离心时间为10～15min。
在上述制备方法中，步骤5)中的搅拌速度为700～1500rpm，搅拌时间为8～20h；离心速度为1000～3000rpm，离心时间为5～10min。
上述制备方法得到的所述微囊为球状，所述微囊的平均粒径为50-150μm，所述ABZ/PLGA-NH2纳米粒的平均粒为300-400nm。
与现有技术相比，本发明具有如下有益效果：
1.本发明对阿苯达唑的合成工艺进行改进，合成过程中不产生丙硫醚，环保、安全，废气和废水中无异味，节能降耗。
2.本发明对阿苯达唑的精制工艺进行改进，采用混合溶剂(水和乙醇)-混酸(甲酸和乙酸)的精制体系，精制后的阿苯达唑纯度高(99％以上)、溶解性好(大于90％)，达到人用标准的EP，USP，BP质量要求。
3.本发明所制备的结肠靶向微囊具有pH响应性能，即在酸性(pH＝1.2或4.5)条件下微囊中的载药纳米粒几乎不释放，而在模拟肠液(pH＝7.4)中微囊分解并快速释放出载药纳米粒。本发明制备的口服肠溶性微囊同时具备结肠靶向、快速崩解、缓慢释药的三重功效。1)结肠靶向：本发明所述微囊的外层为pH敏感型肠溶材料，其在pH值较低的胃液中不分解，而在pH较高的肠液中分解并释放微囊内的载药纳米粒，从而实现结肠靶向给药的目。2)快速崩解：在微囊内引入崩解剂，当微囊的外层肠溶材料在肠液中开始分解，崩解剂吸水膨胀，从而加快肠溶材料的分解以及载药纳米粒的释放。3)缓慢释药：释放出的载药纳米粒在肠道中经肠道上皮细胞转运、吸收，进入体内循环；并且，载药纳米粒中PLGA逐渐被降解，药物逐渐缓慢释放出来，从而延长了口服阿苯达唑的体内循环时间，提高了阿苯达唑的吸收效率。
具体实施方式
本发明用以下实验实例说明，但本发明并不限于以下实验实例，在不脱离前后所述宗旨的范围下，变化实施都包含在本发明的技术范围内。
实施例1
将13.8g邻硝基苯胺，15g二丙基二硫醚溶于100mL甲醇中，搅拌均匀，向反应体系中通入氯气，反应1小时，生成固体产物，过滤，洗涤，干燥，得到4-丙硫基-2-硝基苯胺；将上述4-丙硫基-2-硝基苯胺溶解于乙醇水溶液中(乙醇/水＝2:1(v/v))，接着加入12g硫氢化钠，60℃搅拌还原4小时，生成4-丙硫基-1,2-邻苯二胺，用120mL甲苯进行萃取；向上述萃取物中加入12g氰氨基甲酸甲酯，升温到80℃，搅拌反应并滴加混酸(盐酸和冰醋酸的混合酸溶液，盐酸和冰醋酸的摩尔比为2:1)，保持反应体系的pH值为4左右，80℃保温1小时，生成白色固体，离心水洗得阿苯达唑粗品。向阿苯达唑粗品中依次加入60mL无水乙醇、60mL去离子水、10mL甲酸和20mL乙酸，加热至60℃，搅拌至全溶，然后加入氨水进行中和结晶，过滤，干燥，即得具有高溶解性的阿苯达唑。阿苯达唑的纯度为99.6％，溶解率为96％。
实施例2
将13.8g邻硝基苯胺，15g二丙基二硫醚溶于100mL甲醇中，搅拌均匀，向反应体系中通入氯气，反应2小时，生成固体产物，过滤，洗涤，干燥，得到4-丙硫基-2-硝基苯胺；将上述4-丙硫基-2-硝基苯胺溶解于乙醇水溶液中(乙醇/水＝2:1(v/v))，接着加入12g硫氢化钠，70℃搅拌还原3小时，生成4-丙硫基-1,2-邻苯二胺，用120mL甲苯进行萃取；向上述萃取物中加入12g氰氨基甲酸甲酯，升温到70℃，搅拌反应并滴加混酸(盐酸和冰醋酸的混合酸溶液，盐酸和冰醋酸的摩尔比为2:1)，保持反应体系的pH值为4左右，80℃保温2小时，生成白色固体，离心水洗得阿苯达唑粗品。向阿苯达唑粗品中依次加入60mL无水乙醇、60mL去离子水、20mL甲酸和20mL乙酸，加热至70℃，搅拌至全溶，然后加入氨水进行中和结晶，过滤，干燥，即得具有高溶解性的阿苯达唑。阿苯达唑的纯度为99.8％，溶解率为93％。
实施例3
将13.8g邻硝基苯胺，15g二丙基二硫醚溶于100mL甲醇中，搅拌均匀，向反应体系中通入氯气，反应3小时，生成固体产物，过滤，洗涤，干燥，得到4-丙硫基-2-硝基苯胺；将上述4-丙硫基-2-硝基苯胺溶解于乙醇水溶液中(乙醇/水＝2:1(v/v))，接着加入12g硫氢化钠，60℃搅拌还原5小时，生成4-丙硫基-1,2-邻苯二胺，用120mL甲苯进行萃取；向上述萃取物中加入12g氰氨基甲酸甲酯，升温到80℃，搅拌反应并滴加混酸(盐酸和冰醋酸的混合酸溶液，盐酸和冰醋酸的摩尔比为2:1)，保持反应体系的pH值为4左右，80℃保温3小时，生成白色固体，离心水洗得阿苯达唑粗品。向阿苯达唑粗品中依次加入60mL无水乙醇、60mL去离子水、30mL甲酸和20mL乙酸，加热至80℃，搅拌至全溶，然后加入氨水进行中和结晶，过滤，干燥，即得具有高溶解性的阿苯达唑。阿苯达唑的纯度为99.9％，溶解率为95％。
实施例4
称取20mg实施例1中的阿苯达唑和100mg PLGA-NH2溶于5ml三氯甲烷中。配制30ml浓度为3wt％的PVA溶液，将三氯甲烷溶液滴加至PVA溶液中，形成O/W乳液，超声，将超声后的纳米粒分散至40ml浓度为0.3wt％的PVA溶液中，搅拌5h挥发去除有机溶剂，然后在10000rpm下离心10min，收集纳米粒，冷冻干燥后得ABZ/PLGA-NH2纳米粒冻干粉。分别称取该纳米粒冻干粉10mg，羧甲基淀粉钠5mg，一起分散于5ml溶有100mgMAE-100P的100％无水乙醇液中，然后将该乙醇液滴加至60ml含有1wt％span80的花生油中，搅拌12h挥发去除乙醇，于3000rpm下离心5min，收集微囊，最后用正己烷洗涤微囊去除花生油，即得结肠靶向微囊。
采用粒度分析仪测定ABZ/PLGA-NH2纳米粒的平均粒径为310.2nm，所得微囊的平均粒径为98.6μm。对微囊进行6h的pH梯度释放度考察，即考察在pH＝1.2(0、0.5、1、1.5、2h)、pH＝4.5(2.2、3、3.5、4h)、pH＝7.4(4.5、5、5.5、6h)的释放介质中微囊的粒度变化，结果表明微囊具有pH响应特性：在pH＝1.2，pH＝4.5的释放介质中平均粒径分别为96.3、92.5μm；在pH＝7.4的释放介质中平均粒径为325.8nm，说明微囊分解，释放载药纳米粒。
实施例5
称取5mg实施例2中的阿苯达唑和50mg PLGA-NH2溶于5ml三氯甲烷中。配制10ml浓度为3wt％的PVA溶液，将三氯甲烷溶液滴加至PVA溶液中，形成O/W乳液，超声，将超声后的纳米粒分散至40ml浓度为0.3wt％的PVA溶液中，搅拌5h挥发去除有机溶剂，然后在10000rpm下离心10min，收集纳米粒，冷冻干燥后得ABZ/PLGA-NH2纳米粒冻干粉。分别称取该纳米粒冻干粉20mg，羧甲基淀粉钠10mg，一起分散于5ml溶有100mg尤特奇L-100的100％无水乙醇液中，然后将该乙醇液滴加至30ml含有1wt％span80的橄榄油中，搅拌12h挥发去除乙醇，于3000rpm下离心5min，收集微囊，最后用正己烷洗涤微囊去除橄榄油，即得结肠靶向微囊。
采用粒度分析仪测定ABZ/PLGA-NH2纳米粒的平均粒径为358.6nm，所得微囊的平均粒径为107.4μm。对微囊进行6h的pH梯度释放度考察，即考察在pH＝1.2(0、0.5、1、1.5、2h)、pH＝4.5(2.2、3、3.5、4h)、pH＝7.4(4.5、5、5.5、6h)的释放介质中微囊的粒度变化，结果表明微囊具有pH响应特性：在pH＝1.2，pH＝4.5的释放介质中平均粒径分别为106.1、105.8μm；在pH＝7.4的释放介质中平均粒径为367.9nm，说明微囊分解，释放载药纳米粒。
实施例6
称取10mg实施例3中的阿苯达唑和80mg PLGA-NH2溶于10ml三氯甲烷中。配制20ml浓度为3wt％的PVA溶液，将三氯甲烷溶液滴加至PVA溶液中，形成O/W乳液，超声，将超声后的纳米粒分散至40ml浓度为0.3wt％的PVA溶液中，搅拌5h挥发去除有机溶剂，然后在10000rpm下离心10min，收集纳米粒，冷冻干燥后得ABZ/PLGA-NH2纳米粒冻干粉。分别称取该纳米粒冻干粉15mg，羧甲基淀粉钠10mg，一起分散于5ml溶有80mg丙烯酸树脂II号的100％无水乙醇液中，然后将该乙醇液滴加至50ml含有1wt％span80的花生油中，搅拌12h挥发去除乙醇，于3000rpm下离心5min，收集微囊，最后用正己烷洗涤微囊去除花生油，即得结肠靶向微囊。
采用粒度分析仪测定ABZ/PLGA-NH2纳米粒的平均粒径为385.4nm，所得微囊的平均粒径为145.8μm。对微囊进行6h的pH梯度释放度考察，即考察在pH＝1.2(0、0.5、1、1.5、2h)、pH＝4.5(2.2、3、3.5、4h)、pH＝7.4(4.5、5、5.5、6h)的释放介质中微囊的粒度变化，结果表明微囊具有pH响应特性：在pH＝1.2，pH＝4.5的释放介质中平均粒径分别为146.5、143.7μm；在pH＝7.4的释放介质中平均粒径为392.8nm，说明微囊分解，释放载药纳米粒。
Claims (4)
1.一种高溶解性阿苯达唑的合成方法，其特征在于包括如下步骤：1)合成阿苯达唑：以邻硝基苯胺为原料，与二丙基二硫醚通过氯气催化反应生成4-丙硫基-2-硝基苯胺；将上述生成物4-丙硫基-2-硝基苯胺溶解于乙醇水溶液中，接着加入硫氢化钠，60℃搅拌还原3-5小时，生成4-丙硫基-1,2-邻苯二胺，用甲苯萃取；向上述萃取物中加入氰氨基甲酸甲酯，升温到80℃，搅拌反应并滴加盐酸和冰醋酸的混合酸溶液，保持反应体系的pH值为4左右，于80℃下保温1～3小时，生成白色固体，离心水洗得阿苯达唑粗品；2)精制阿苯达唑：向步骤1)制得的阿苯达唑粗品中依次加入无水乙醇、去离子水、甲酸和乙酸，加热搅拌至全溶，然后加入氨水进行中和结晶，过滤，干燥，即得具有高溶解性的阿苯达唑。
2.根据权利要求1所述的制备方法，其特征在于，所述步骤1)中邻硝基苯胺与二丙基二硫醚的摩尔比为1:1-1:1.5，邻硝基苯胺与硫氢化钠的摩尔比为1:1.5-1:2，邻硝基苯胺与氰氨基甲酸甲酯的摩尔比为1:1-1:2。
3.根据权利要求1所述的制备方法，其特征在于，所述步骤2)中无水乙醇与去离子水的体积比为1:3-3:1，甲酸和乙酸的体积比为1:2-3:2，甲酸与去离子水的体积比为1:2-1:6。
4.根据权利要求1所述的制备方法，其特征在于，所述步骤2)中所述加热搅拌的温度为60-90℃。
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