CN103619335B - 速溶阿扎哌隆颗粒制剂 - Google Patents
速溶阿扎哌隆颗粒制剂 Download PDFInfo
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- CN103619335B CN103619335B CN201280031242.6A CN201280031242A CN103619335B CN 103619335 B CN103619335 B CN 103619335B CN 201280031242 A CN201280031242 A CN 201280031242A CN 103619335 B CN103619335 B CN 103619335B
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- azaperone
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Abstract
本发明涉及一种包含兽用药物阿扎哌隆的速溶颗粒制剂和一种制备所述颗粒制剂的方法。
Description
本申请要求于2011年6月24日申请的系列号为11171263.4的欧洲专利申请的优先权，其全部公开内容都被引入本文作为参考。
本发明涉及一种包含兽用药物阿扎哌隆的速溶颗粒制剂和制备所述颗粒制剂的方法。
阿扎哌隆是一种在二十世纪六十年代初期由杨森制药公司实验室(Janssen Pharmaceutica laboratories)发现的丙基苯基酮类安定药，目前可以以被称为StresnilTM的4%的无菌注射液的形式获得。其化学名为4′-氟-4-(4-(2-吡啶基)-1-哌嗪基-丙基苯基酮并且具有如下结构:
阿扎哌隆
StresnilTM(阿扎哌隆)注射液适用于通过诱导不同程度的镇静来预防攻击性和紧张状态。在给予单剂量的StresnilTM后，可将猪混到一起，好斗性被消除或大大降低。
WO-2010/031805公开了一种通过与食物或饮用水一起以低剂量口服给药阿扎哌隆在不引起镇静的情况下改善动物生长的方法。生长的改善包括在一定时期内生长速率的增加。
WO-2010/031809公开了一种通过与食物或饮用水一起以低剂量口服给药阿扎哌隆来降低动物的抗生素用量的方法。
WO-2010/031805和WO-2010/031809都公开了用于与饮用水一起或通过供水系统来施用阿扎哌隆的可稀释的浓缩水溶液:
WO2010/031805和WO2010/031809中公开的用于与食物或饮用水一起以低剂量连续提供阿扎哌隆的口服施用的优选施用途径是通过一种配水系统如用于提供饮用水的系统来施用阿扎哌隆。许多畜牧场已经配备了通过饮用水来施用药物所需的装置，因此，不需要进行特殊的改造以通过配水系统与饮用水一起施用阿扎哌隆。可以根据家畜的水消耗量来调整阿扎哌隆的药量。
与浓缩液体制剂相比，颗粒制剂更容易运输、常常具有更好的贮存期且活性成分的化学稳定性更高。兽用药品委员会(Committee for MedicinalProducts for Veterinary Use)(CVMP)(欧洲药品管理局(EuropeanMedicines Agency)的一部分)已于2005年4月15日就“有关通过饮用水施用兽用药物的质量(Quality aspects of pharmaceutical veterinary medicinesfor administration via drinking water)”发布了一份陈列了一些质量数据要求的指南EMEA/CVMP/540/03Rev.1(参见www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500004462.pdf)，并且该意见包括用于使用中的稳定性试验的指导。一项主要的要求是要求兽医用产品在5至20℃的温度下在硬水和软水中在10分钟内完全溶解。
现已开发出了一种当按照2005年4月15日的指南EMEA/CVMP/540/03Rev.1提出的要求进行试验时，可在不到10分钟的时间内溶解于硬水和软水中的速溶颗粒制剂。所述速溶制剂包括
-阿扎哌隆，
-一种选自酒石酸或枸橼酸的酸，
-一种选自乳糖、乳糖一水合物或甘露醇的填充剂，
-一种选自麦芽糖糊精、HPMC或聚维酮的粘合剂，和
-任选的着色剂，
-其中阿扎哌隆与酸的比例范围为1:2至1:4(w/w)。
用于本发明的速溶颗粒制剂中的“酒石酸”包括酒石酸所有已知的形式如L-酒石酸、D-酒石酸、内消旋酒石酸以及左旋和右旋形式的1:1混合物DL-酒石酸。因为其是酒石酸最便宜的形式，因此，在实际操作中使用酒石酸天然存在的形式——L-酒石酸，其也被称为右旋酒石酸。
用于本发明制剂中的“枸橼酸”包括无水枸橼酸和枸橼酸一水合物。因为当用无水枸橼酸代替枸橼酸一水合物时，本发明的速溶颗粒趋向于粘性降低，因此，在实际操作中使用无水枸橼酸。
用于本发明的速溶阿扎哌隆颗粒中的适宜填充剂选自乳糖、乳糖一水合物或甘露醇。在实际操作中，优选用乳糖一水合物作为填充剂。
用于本发明的速溶阿扎哌隆颗粒中的适宜粘合剂选自麦芽糖糊精、HPMC(羟丙基甲基纤维素)或聚维酮。在实际操作中，优选用HPMC作为粘合剂。HPMC可以以不同的等级例如HPMC 2910 15 mPa.s商业获得。聚维酮可以以不同的等级例如聚维酮K30商业获得。
本发明的速溶阿扎哌隆颗粒用于通过一种配水系统如用于提供饮用水的配水系统将阿扎哌隆施用给活的存栏动物(stock animal)。术语“活的存栏动物”是指任何非人的恒温动物，特别是其生产目的是用于消费的那些动物如家禽(鸡、火鸡、鸭、鸵鸟、鸸鹋、鹌鹑等)和反刍动物(山羊、绵羊和牛)、猪和兔子。首先，将阿扎哌隆颗粒溶解于水中，从而得到一种具有600至1200mg/L的稀释前目标剂量的浓储备液。然后，将这种浓储备液与配水系统的给药泵相连，从而在饮用水中获得范围为6至12mg/L的最终目标剂量。为了在浓储备液和最终在饮用水中的稀释液之间获得可视的差异，向阿扎哌隆颗粒中加入一种着色剂。阿扎哌隆颗粒中着色剂的剂量和着色剂的类型应能使得储备液具有可视的颜色但在饮用水系统中的最终稀释液是澄清的。适宜的着色剂有例如专利蓝V(E131)、靛蓝(E132，也被称为FD&CBlue No.2)或亮蓝FCF(E133，也被称为FD&C Blue No.1)。
以按照2005年4月15日的指南EMEA/CVMP/540/03Rev.1所述的方式进行测试时可以获得所要求的在10分钟内溶解的方式选择阿扎哌隆、酸、填充剂、粘合剂和任选的着色剂的量。此外，阿扎哌隆与酸的比例范围为1:2至1:4(w/w)以便在确定的预浓缩溶液中获得快速溶解。
适宜的速溶阿扎哌隆颗粒制剂包含:
-含量为5至15%(w/w)的阿扎哌隆,
-含量为10至60%(w/w)的选自酒石酸或枸橼酸的酸，其中阿扎哌隆与酸的比例范围为1:2至1:4(w/w),
-含量为0.5至5%的选自麦芽糖糊精、HPMC或聚维酮的粘合剂，和
-任选的含量为0.01%至0.10%(w/w)的着色剂;和
-补足至100%(w/w)量的选自乳糖、乳糖一水合物或甘露醇的填充剂。
在本发明的速溶颗粒制剂中，阿扎哌隆的含量范围为5至15%(w/w)。一种实际采用的含量为10%(w/w)。
在所述速溶颗粒制剂中所用的酸的含量为使得阿扎哌隆与酸的比例为1:2至1:4(w/w)的量。根据阿扎哌隆的量，这意味着酸的含量范围为10至60%(w/w)。
在一个实施方案中，速溶颗粒制剂中阿扎哌隆和枸橼酸的比例为1:3。在另一个实施方案中，阿扎哌隆和酒石酸的比例为1:2。
该速溶阿扎哌隆颗粒制剂是通过将粘合剂与水混合至得到一种均匀的溶液，然后加入任选的着色剂，在适宜的流化床制粒机中将这种溶液喷洒到阿扎哌隆、酸和填充剂的粉末混合物上来进行制备的。在喷洒后，在流化时对该湿颗粒进行干燥，在适宜的混合器中对干燥了的颗粒进行筛分和收集，并将其混合至均匀。然后，将颗粒填充到适宜的容器中。
该速溶阿扎哌隆颗粒制剂还可以采用高速剪切湿法制粒技术来制备:将阿扎哌隆、酸和填充剂的混合物在高速剪切制粒机中通过干法混合来进行混合，然后向其中滴加包含粘合剂和任选的着色剂的水溶液，将其在高速剪切制粒机中进一步混合至得到所需的颗粒。然后，将这些颗粒干燥并对其进行筛分。
实施例
1)制剂
制剂1的组成:
-阿扎哌隆 5%(w/w)
-枸橼酸一水合物 15%(w/w)
-乳糖一水合物 79.4%(w/w)
-麦芽糖糊精 0.6%(w/w)
制剂2的组成:
-阿扎哌隆 10%(w/w)
-枸橼酸一水合物 30%(w/w)
-乳糖一水合物 59.4%(w/w)
-聚维酮K30 0.6%(w/w)
制剂3的组成:
-阿扎哌隆 5%(w/w)
-枸橼酸一水合物 15%(w/w)
-甘露醇 79.5%(w/w)
-麦芽糖糊精 0.5%(w/w)
制剂4的组成:
-阿扎哌隆 10%(w/w)
-无水枸橼酸 20%(w/w)
-乳糖一水合物 69.5%(w/w)
-麦芽糖糊精 0.5%(w/w)
制剂5的组成:
制剂6的组成:
1)软/硬水的制备
在溶解性研究中使用下面两种质量的水:
-软水/低pH，具有5.0至7.0的pH范围和60mg/L或更低的碳酸钙
-硬水/高pH，具有8.0至9.0的pH范围和180至350mg/L的碳酸钙。
软水和硬水的制备都是根据2005年4月15日由CVMP发布的EMEA/CVMP/540/03Rev.1中的指南完成的。
4)溶解性试验
溶解性试验的进行如下:将3g阿扎哌隆颗粒转移到一个1L的空烧杯中。加入一定量(即500mL)的软水或硬水达到600mg/L的阿扎哌隆浓度(其是稀释前的浓度)。以大约60rpm的速度用玻璃棒对该烧杯的内容物手动搅拌直至目测观察到颗粒完全溶解。
观察到部分1中所述的所有制剂在软水或硬水中都在5分钟之内溶解。在完全溶解后，溶出介质的pH为3.1至3.6。
Claims (6)
1.一种速溶颗粒制剂，其包含
-阿扎哌隆，
-一种选自酒石酸或枸橼酸的酸，
-一种选自乳糖、乳糖一水合物或甘露醇的填充剂，
-一种选自麦芽糖糊精、HPMC或聚维酮的粘合剂，和
-任选的着色剂,
其中阿扎哌隆:酸的比例为1:2至1:4(w/w)。
2.权利要求1的制剂，其中所述的酸是酒石酸。
3.权利要求1或权利要求2的制剂，其中所述的填充剂是乳糖一水合物。
4.权利要求1至3任意一项的制剂，其中所述的粘合剂是HPMC。
5.权利要求1的制剂，其包含
-含量为5至15％(w/w)的阿扎哌隆，
-含量为10至60％(w/w)的选自酒石酸或枸橼酸的酸，其中阿扎哌隆:酸的比例为1:2至1:4(w/w)，
-含量为0.5至5％的选自麦芽糖糊精、HPMC或聚维酮的粘合剂，和
-任选的含量为0.01％至0.10％(w/w)的着色剂；和
-补足至100％(w/w)量的选自乳糖、乳糖一水合物或甘露醇的填充剂。
6.权利要求5的制剂，其包含:
-10％(w/w)的阿扎哌隆，
-20％(w/w)的酒石酸，
-68.95％(w/w)的乳糖一水合物，
-1％(w/w)的HPMC 291015mPa.s和
-0.05％(w/w)的亮蓝(133)。
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| EP11171263A EP2537518A1 (en) | 2011-06-24 | 2011-06-24 | Fast dissolving azaperone granulate formulation |
| EP11171263.4 | 2011-06-24 | ||
| PCT/US2012/043499 WO2012177842A1 (en) | 2011-06-24 | 2012-06-21 | Fast dissolving azaperone granulate formulation |
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| WO2010031805A1 (en) * | 2008-09-18 | 2010-03-25 | Janssen Pharmaceutica Nv | Use of azaperone for improving growth performance |
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| JP2001015070A (ja) | 1999-06-29 | 2001-01-19 | Ushio Inc | 放電ランプ |
| GB0205253D0 (en) * | 2002-03-06 | 2002-04-17 | Univ Gent | Immediate release pharmaceutical granule compositions and a continuous process for making them |
| US20040156894A1 (en) * | 2003-02-07 | 2004-08-12 | Grother Leon Paul | Use of edible acids in fast-dispersing pharmaceutical solid dosage forms |
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| WO2010031809A1 (en) * | 2008-09-18 | 2010-03-25 | Janssen Pharmaceutica Nv | Use of azaperone for reducing antibiotic usage |
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|---|
| Effects of Amperozide and Azaperone on Aggression and Productivity of Growing-Finishing Pigs;H.W.Gonyou等;《Journal of Animal Science》;19881231;第2856-2864页 * |
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| CO6862149A2 (es) | 2014-02-10 |
| EA024030B1 (ru) | 2016-08-31 |
| US20140128407A1 (en) | 2014-05-08 |
| AR087155A1 (es) | 2014-02-26 |
| AU2012272935B2 (en) | 2015-07-16 |
| JP2014517071A (ja) | 2014-07-17 |
| CA2836497A1 (en) | 2012-12-27 |
| CL2013003663A1 (es) | 2014-09-05 |
| ZA201309511B (en) | 2015-09-30 |
| TW201302245A (zh) | 2013-01-16 |
| CN103619335A (zh) | 2014-03-05 |
| MX2013014796A (es) | 2014-01-24 |
| US9339464B2 (en) | 2016-05-17 |
| EP2537518A1 (en) | 2012-12-26 |
| KR20140014290A (ko) | 2014-02-05 |
| EP2723341A1 (en) | 2014-04-30 |
| CA2836497C (en) | 2016-02-16 |
| BR112013032608A2 (pt) | 2017-01-24 |
| AU2012272935A1 (en) | 2013-11-28 |
| WO2012177842A1 (en) | 2012-12-27 |
| KR101497866B1 (ko) | 2015-03-02 |
| JP5984923B2 (ja) | 2016-09-06 |
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