CN103705453A - 含盐酸多西环素/泊洛沙姆载药微粒的油质注射剂 - Google Patents
含盐酸多西环素/泊洛沙姆载药微粒的油质注射剂 Download PDFInfo
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Abstract
将盐酸多西环素与泊洛沙姆407组合，制备成载药微粒；进一步将载药微粒分散于油性介质中，经研磨，制备成含盐酸多西环素/泊洛沙姆407载药微粒的油质长效注射剂。在载药微粒中还可加入羟丙基甲基纤维素或高取代羟丙基纤维素，它们的加入会明显的增强制剂的缓释作用。该注射剂制备工艺简单、释药均匀、生物相容性好、对注射部位的组织无不可逆损伤、所用的缓释载体可降解和排泄。
Description
技术领域
本发明属于兽药制剂制备技术，具体涉及将盐酸多西环素和泊洛沙姆407制备成载药微粒，将载药微粒悬浮于油性介质中，制备含盐酸多西环素载药微粒的兽用长效注射剂。
背景技术
目前已商品化的兽用多西环素注射剂和专利公开的技术，其剂型多为溶液型，制剂需充氮贮存，并且组成制剂的水、有机溶剂、助溶剂、络合剂、抗氧化剂等助剂的用量和制剂的pH值都要求的很严格，稍有偏差，制剂的稳定性便会出现问题，该剂型不易制备出稳定的高浓度制剂，缓释效果也不明显，该剂型对注射部位组织有损伤。专利CN101862293B公开了以植物油和表面活性剂为载体制备的含盐酸多西环素的混悬液，该制剂稳定性好、具有缓释作用，一次用药，药效维持时间长达2天。专利CN102440998A描述的是一种以植物油为载体制备的含盐酸多西环素和磷酸替米可星的复方制剂。专利CN102895245A描述的是一种含盐酸多西环素和甲氧苄啶的水包油型纳米乳制剂。
泊洛沙姆为聚氧乙烯-聚氧丙烯醚类共聚物，此类聚合物有多种规格，其中泊洛沙姆407(以下简称P407)的水溶液具有“随温度升高由溶胶向凝胶转化的特性”，一定浓度的P407水溶液一般在30℃以上即发生胶凝，据此特性，P407被用于缓释注射剂的制备，该制剂被称之为原位胶凝制剂。含P407的原位胶凝注射剂注入体内后，在体温的作用下，一般在1分钟左右，即由溶胶转变为凝胶(半固体)，药物被包裹在凝胶中，从而减缓了释药速率，使药效维持时间延长。文献和专利公开的含P407的原位胶凝注射剂，是以水为主要溶剂，制剂中P407的浓度要达到20％以上才会有较好的缓释作用；在制剂中加入一定量的甲基纤维素、羧甲基纤维素钠、高取代羟丙基纤维素(H-HPC)或羟丙基甲基纤维素(HPMC)等阻滞剂，可增强缓释作用，但会导致制剂粘度升高，使注射更加困难。
P407也是一种水溶性很好的非离子表面活性剂，更多的是被用于制备乳剂、乳膏剂、水性栓剂、滴丸剂等；P407也被作为难溶药物(水溶性很差的药物)的分散载体，用于制备固溶体，已公开的用P407制备的固溶体，多是用于内服制剂的制备。
本发明制剂不同于已公开的含盐酸多西环素的注射剂和含P407的原位胶凝注射剂，本发明是将盐酸多西环素与P407(或与P407和纤维素醚类)组成固溶体或其它形式的载药微粒(如附聚体)，并用油性介质(十四烷酸异丙酯，以下简称IPM；注射用植物油)替代水来制备含P407的注射剂。本制剂稳定性好，经过将盐酸多西环素与P407组合成载药微粒并分散于油性介质中，从而克服了盐酸多西环素易氧化、易降解，很不稳定的缺陷。本制剂注入动物皮下或肌内，载药微粒在“突破”油相接触体液(水)后，借助于P407“吸水(体液)”或吸水溶胀(HPMC或H-HPC存在时)，“粘聚”在一起，在注射部位形成高浓度与高粘度的、并具有“生物粘附性”(在制剂中含有H-HPC或HPMC时)的半固体团块，药物被包裹在团块中，从而有效的延长了释药时间，因此，本制剂还有很好的缓释作用。
发明内容
将盐酸多西环素与P407、或将盐酸多西环素与P407和HPMC(或H-HPC)制备成载药微粒，并将载药微粒悬浮于油性介质中，经研磨制备成含盐酸多西环素的油质长效注射剂，这是本制剂的突出特征。
本制剂组成和制备方法如下：
本制剂包括盐酸多西环素、P407和油性介质。每升制剂中含盐酸多西环素80-200g、P40720-150g、油性介质加至1升。
所述的油性介质为IPM或注射用大豆油、玉米油、茶籽油中的一种。
所述的每升注射剂中还可加入20-60g HPMC或H-HPC，HPMC或H-HPC需与P407组合成固溶体或与P407和盐酸多西环素一起组成载药微粒，才能用于本制剂的制备。H-HPC在甲醇中有很好的溶解性，盐酸多西环素在甲醇中同样有很好的溶解性，这是H-HPC、P407、盐酸多西环素能够组成一体，制备成载药微粒的重要基础。
H-HPC和HPMC无毒、无药理作用，在生理活性上表现出极端惰性。HPMC、H-HPC或P407在IPM等油性介质中不溶，因此，将H-HPC或HPMC与P407组成微粒，即使以较高的浓度分散于油性介质中，也不会使制剂粘度明显升高，但含高浓度H-HPC或HPMC的载药微粒在注射部位能吸水溶胀，形成高粘度的团块，高粘度的团块具有更强的阻滞(减缓)药物释放的作用，因此，根据要求，在载药微粒中添加适量的H-HPC和HPMC可达到预期的缓释效果，尤其对于制备含水溶性药物(如盐酸多西环素)的缓释注射剂，加入H-HPC或HPMC是十分必要的。
含盐酸多西环素的载药微粒在制剂中的含量为10-35％，适宜的含量为15-25％，重量/体积百分比。
在每升制剂中还可加入0.2-2g抗氧剂，抗氧剂包括叔丁基-4-羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)或没食子酸丙酯(PG)中的一种或一种以上任何比例的混合物。
在每升制剂中还可加入1-1.5g EDTA-2钠。
制备方法：归纳起来主要有以下三种。
(1)在加热(55-70℃)或常温条件下，将盐酸多西环素与P407、或盐酸多西环素与P407和HPMC、或盐酸多西环素与P407和H-HPC一起用甲醇溶解(甲醇的适宜加入量为盐酸多西环素的2-5倍，重量/体积比)，然后减压蒸馏除去溶剂，得盐酸多西环素/P407固溶体或盐酸多西环素/P407/HPMC固溶体或盐酸多西环素/P407/H-HPC固溶体；将制备的固溶体粉碎过40目筛，得载药微粒；将载药微粒分散于部分油性介质中，用胶体磨研磨至粒径小于100μm，再用砂磨机研磨至粒径小于20μm，加入剩余成份至终体积，用高剪切均质机在5000-10000rpm进一步均质化即得本制剂。
(2)将药物和P407或药物和固溶体(P407/HPMC或P407/H-HPC)分散于部分油性介质中，用胶体磨和砂磨机研磨至粒径小于20μm，加入剩余成份，用高剪切均质机均质化即得本制剂。
(3)将药物微粉化，然后与已融化和溶解的P407和H-HPC混合均匀，冷却使之固化，粉碎、过筛，得载药微粒，将载药微粒分散于油性介质中，经研磨得本制剂。
P407/H-HPC或P407/HPMC固溶体微粒制备：在加热条件下，将HPMC或H-HPC和P407溶于甲醇或溶于80％乙醇溶液中，混匀，在搅拌下减压除去溶剂，粉碎、过筛即得。
本制剂制备过程需在无菌条件下进行，研磨时物料温度不可超过40℃，制剂中固体微粒的粒径应小于20μm，以小于10μm较合适。
本制剂特点归纳如下：
本药剂释药过程不同于以水为介质的原位胶凝制剂，也不同于传统的油剂，主要不同之处是：存在载药微粒“突破”油相与体液接触并吸水形成高粘度团块过程。
将适量的H-HPC或HPMC与P407组成固溶体颗粒，分散于油相中进一步研磨，解决了单纯用H-HPC(或HPMC)包裹药物很难研磨(粉碎)成细微颗粒(小于20μm)的技术难题，同时保留了H-HPC和HPMC具有吸水溶胀，形成高粘度团块的特性。含药“团块”粘附于注射部位组织中，有利于药物更好的吸收，并且保证了一定程度的缓释效果，这是本剂具有生物利用度高，又有长效作用的基础。
用油性介质替代水制备含P407的缓释注射剂，可减少P407的用量，P407用量在5-10％时，制剂就有很好的缓释作用。以水为溶剂制备含P407的原位胶凝注射剂，P407的用量要达到20～45％，制剂才能显示出很好的缓释作用。目前国产P407价格较贵(医用级在160～200元/kg)，因此，P407在制剂中用量越多，制备成本越高，不利于在兽医领域推广应用。
具体实施方式
实施例1、制备15％盐酸多西环素注射剂
制剂组成：盐酸多西环素150g、P407100g、BHT0.2g、BHA0.1g、IPM加至1升。
制备方法：(1)在65-75℃将P407融化，然后加入盐酸多西环素和相当于多西环素2-3倍量的甲醇，充分搅拌，减压蒸馏，除去甲醇，制得固溶体，将固溶体粉碎，过40目筛，得盐酸多西环素/P407载药微粒。(2)将载药微粒分散于适量的IPM中，用胶体磨研磨至粒径约100μm，用砂磨机进一步研磨至粒径小于10μm，然后加入剩余成份，用高剪切均质机在5000rpm条件下经多次均质化后，制得15％盐酸多西环素注射剂。
实施例2、制备10％盐酸多西环素注射剂
制剂组成：每升含盐酸多西环素100g、P40750g、HPMC30g、BHT0.2g、BHA0.1g、PG0.1g，注射用大豆油加至终体积。
制备方法：(1)在65-75℃将P407融化，然后加入盐酸多西环素和HPMC，充分混匀后加入相当于多西环素2倍量的甲醇，充分搅拌，减压蒸馏，除去甲醇，制得固溶体，将固溶体粉碎，过40目筛，得含盐酸多西环素的载药微粒。(2)将载药微粒分散于适量的大豆油中，用胶体磨研磨至粒径约100μm，用砂磨机进一步研磨至粒径小于8μm，然后加入剩余成份，用高剪切均质机在5000rpm条件下经多次均质化后，制得10％盐酸多西环素注射剂。
实施例3、制备8％盐酸多西环素注射剂
制剂组成：盐酸多西环素80g、P40780g、BHT0.2g、BHA0.1g、PG0.1g，注射用玉米油加至1升。
制备方法：(1)在65-75℃将P407融化，然后加入盐酸多西环素和相当于多西环素2倍量的甲醇，充分搅拌，冷却并减压，除去甲醇，制得固溶体，将固溶体粉碎，过40目筛，得盐酸多西环素/P407载药微粒。(2)将载药微粒分散于适量的玉米油中，用胶体磨研磨至粒径约100μm，用砂磨机进一步研磨至粒径小于8μm，然后加入剩余成份，用高剪切均质机在5000rpm条件下经多次均质化后，制得8％盐酸多西环素注射剂。
实施例4、制备20％盐酸多西环素注射剂
制剂组成：盐酸多西环素20g、P40760g、IPM加至1升。
制备方法：将盐酸多西环素分散于已融化的P407中，冷却固化后粉碎，将粉碎物分散于约2倍量的IPM中，用胶体磨研磨至粒径小于100μm，再用砂磨机研磨至粒径小于5μm，加入剩余介质，用均质机均质化，得20％盐酸多西环素注射剂。
实施例5、制备12％盐酸多西环素注射剂
制剂组成：盐酸多西环素120g、P407/HPMC(1∶0.6)固溶体70g，茶籽油加至1升。
制备方法：(1)将P407和HPMC混合均匀，加入相当于HPMC3-4倍量的甲醇，70-80℃回流，待HPMC完全溶解后，减压蒸馏，除去甲醇，冷却，得P407/HPMC固溶体，经粉碎、过筛，得固溶体颗粒。(2)将盐酸多西环素和固溶体颗粒分散于部分茶籽油中，用胶体磨和砂磨机研磨至粒径小于20μm，加入剩余IPM，用高剪切均质机均质化即得本制剂。
实施例6、制备20％盐酸多西环素注射剂
制剂组成：盐酸多西环素20g、P40760g、IPM加至1升。
制备方法：向相当于盐酸多西环素2倍量的IPM中，加入盐酸多西环素和P407，混合，用胶体磨研磨至粒径小于100μm，再用砂磨机研磨至粒径小于5μm，加入剩余介质，用均质机均质化，得20％盐酸多西环素注射剂。
实施例7、制备15％盐酸多西环素注射剂
制剂组成：每100ml含盐酸多西环素15g、P4078g、H-HPC5g、BHT0.02g、BHA0.01g、PG0.005g、EDTA-2钠0.12g，IPM加至终体积。
制备方法：(1)在65-75℃将P407融化，然后加入盐酸多西环素和H-HPC，充分混匀后加入相当于盐酸多西环素约2倍量的甲醇，充分混匀，降温至50℃左右，减压蒸馏，除去甲醇，制得固溶体，将固溶体粉碎，过40目筛，得含盐酸多西环素的载药微粒。(2)将载药微粒分散于适量(相当于载药微粒量的1.5-2.5倍)的IPM中，用胶体磨研磨至粒径约100μm，用砂磨机进一步研磨至粒径小于8μm，然后加入抗氧剂和其它剩余成份，用高剪切均质机在5000rpm条件下经多次均质化后，制得15％盐酸多西环素注射剂。
实施例8、绵羊注射实施例7制剂和对比制剂后血药浓度检测
对比制剂a：每100ml制剂含盐酸多西环素15g、P4078g、H-HPC3.5g，无菌水加至终体积。现用现配。
对比制剂b：每100ml制剂含盐酸多西环素超微粉15g、BHT0.01g、BHA0.01g、PG0.005g、EDTA-2钠0.12g，IPM加至终体积。
试验方法：选健康绵羊9只，分3组，每组3只；分别皮下注射实施例7制剂和对比制剂，给药剂量为15mg/kg b.w.，按时采血，离心分离血浆，将同一试验组同一时间的血浆样品等量混合后提取，在经离心分离、过滤等过程，制得检测样品，采用高压液相色谱法(C18柱)测定血浆中盐酸多西环素浓度，实验结果如下表所示。
表中数值为每组3只羊检测的平均值。
实施例9、实施例7制剂稳定性试验
将实施例7制剂于30-35℃放置12个月，用HPLC检测盐酸多西环素含量，结果显示12个月期间实施例7制剂多西环素减少量占初始量的1.6-2.2％，表明本制剂很稳定，优于以水为介质制备的制剂。
Claims (7)
1.一种包括盐酸多西环素/泊洛沙姆407载药微粒的兽用油质注射剂。
2.按权利要求1所述的注射剂，其特征在于每升注射剂中包括以下成份：
盐酸多西环素 80-200g
泊洛沙姆407 20-150g
油性介质 加至1升
所述的油性介质为十四烷酸异丙酯、注射用大豆油、玉米油、茶籽油中的一种。
3.按权利要求2所述的注射剂，其特征在于在所述的每升注射剂中还可加入抗氧剂0.2-2g，抗氧剂包括叔丁基-4-羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯或抗坏血酸棕榈酸酯中的一种或一种以上任何比例的混合物。
4.按权利要求2-3任意一项所述的注射剂，其特征在于在每升制剂中还可加入乙二胺四乙酸二钠盐1-1.5g。
5.按权利要求2所述的注射剂，其特征在于将盐酸多西环素与泊洛沙姆407制备成载药微粒，然后将载药微粒悬浮于油性介质中，经研磨制得含盐酸多西环素/泊洛沙姆407载药微粒的油质注射剂，载药微粒在制剂中的重量/体积百分比含量为10-35％。
6.按权利要求2所述的注射剂，其特征在于在所述的每升注射剂中还可加入20-60g高取代羟丙基纤维素；高取代羟丙基纤维素与泊洛沙姆407组合，以固溶体微粒状态存在于制剂中，或与盐酸多西环素和泊洛沙姆407组合，以载药微粒状态存在于制剂中。
7.按权利要求2所述的注射剂，其特征在于在所述的每升注射剂中还可加入20-60g羟丙基甲基纤维素，羟丙基甲基纤维素与泊洛沙姆407组合，以固溶体微粒状态存在于制剂中，或与盐酸多西环素和泊洛沙姆407组合，以载药微粒状态存在于制剂中。
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| CN101862293A (zh) * | 2010-06-22 | 2010-10-20 | 华南农业大学 | 盐酸多西环素的油混悬液及其制备方法和应用 |
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| WO2016138339A1 (en) * | 2015-02-26 | 2016-09-01 | Merial, Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| AU2016222532B2 (en) * | 2015-02-26 | 2018-07-12 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| AU2018205137B2 (en) * | 2015-02-26 | 2019-08-08 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| US10561641B2 (en) | 2015-02-26 | 2020-02-18 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| EA035993B1 (ru) * | 2015-02-26 | 2020-09-10 | Мериал, Инк. | Инъецируемые препараты длительного действия, содержащие изоксазолиновое действующее вещество, способы и применение |
| US11484528B2 (en) | 2015-02-26 | 2022-11-01 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
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Denomination of invention: Oily injection containing doxycycline hydrochloride/poloxamer drug-loading particles Effective date of registration: 20191128 Granted publication date: 20170322 Pledgee: Huaxia Bank Beijing branch Wanliu Limited by Share Ltd Pledgor: Beijing Zhongnonghuawei pharmaceutical Limited by Share Ltd Registration number: Y2019990000606 |
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Address after: 102209 C2034 2, 16 building, No. 37 Chao Yuan Road, Changping District science and Technology Park, Beijing. Patentee after: Zhongnonghuawei Pharmaceutical Co., Ltd Address before: 102209 C2034 2, 16 building, No. 37 Chao Yuan Road, Changping District science and Technology Park, Beijing. Patentee before: Beijing Zhongnong Huawei Pharmaceutical Co.,Ltd. |
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Date of cancellation: 20210531 Granted publication date: 20170322 Pledgee: Huaxia Bank Beijing branch Wanliu Limited by Share Ltd. Pledgor: Beijing Zhongnong Huawei Pharmaceutical Co.,Ltd. Registration number: Y2019990000606 |
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