CN107412189A - 一种掩味恩诺沙星可溶性粉及其制备方法 - Google Patents
一种掩味恩诺沙星可溶性粉及其制备方法 Download PDFInfo
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- CN107412189A CN107412189A CN201710830831.5A CN201710830831A CN107412189A CN 107412189 A CN107412189 A CN 107412189A CN 201710830831 A CN201710830831 A CN 201710830831A CN 107412189 A CN107412189 A CN 107412189A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开一种掩味恩诺沙星可溶性粉及其制备方法,该掩味恩诺沙星可溶性粉包括如下质量组份:恩诺沙星10‑15份,包合剂75.5‑84.5份,助溶剂3‑5份,矫味剂0.5‑1.5份,成膜缓释剂2‑3份。本发明公开的恩诺沙星可溶性粉通过分子包合和喷涂缓释双重掩味技术,达到了对恩诺沙星苦味良好的掩蔽效果,同时可在水中搅拌溶解,可完全按照国标要求检测含量。解决了养殖终端拌料饲喂动物适口性差的问题的同时,解决了家禽饮水的问题,提高了药物生物利用度,社会经济效益显著。
Description
技术领域:
本发明涉及兽药制剂技术领域,特别涉及一种掩味恩诺沙星可溶性粉及其制备方法。
背景技术:
恩诺沙星为化学合成的第三代喹诺酮类抗菌药物,也是第一个畜禽专用的氟喹诺酮类药物,上世纪80年代由德国拜耳公司最先研制成功。恩诺沙星通过特异的抑制细菌DNA解旋酶和拓扑异构酶Ⅳ的功能,阻断细菌遗传物质的复制与转录过程而达到杀菌目的。恩诺沙星具有广谱抗菌活性和很强的渗透性,对革兰氏阴性菌有很强的杀灭作用,对革兰氏阳性菌也有良好的抗菌作用。但普通恩诺沙星制剂味苦,溶解度低,严重影响猪只采食量和吸收效果,使用极其受限,造成广大饲料企业和养殖户经济效益受损。
恩诺沙星可溶性粉最大的技术难题是掩蔽苦味,而一般情况下掩味的主要手段是颗粒包衣技术和添加矫味剂,用氢化脂肪、硬脂酸及其衍生酯类为主要辅料再添加甜味剂等进行包被或均质分散。虽然该技术有一定的掩味效果,但制剂产品在国标项下检测往往含量严重偏低,不能过检。另外制剂产品在水中崩解度差、不水溶,只能拌料饲喂,无法在禽类动物上饮水使用,造成使用不便和药物浪费,威胁环境安全。
公开号为CN105902499A公开的一种恩诺沙星可溶性粉及其制备方法,其配方为恩诺沙星5%~10%,有机酸助溶剂为甲磺酸、牛磺酸、烟酸等,质量占比5%~20%,磷酸二氢钠1.5%~5%、其余载体为葡萄糖、麦芽糊精、可溶性淀粉、乳糖等。其生产工艺为简单混合工艺,虽然配方中有机酸可以有效助溶恩诺沙星,达到产品水溶的目的,但无法从根本上解决掩蔽药物苦味的问题,入口即苦,适口性差,难以令家畜口服。又如公开号为CN105267981A公开一种恩诺沙星固体分散体的制备方法,其工艺为先用环糊精混合研磨包合恩诺沙星,再用糖类载体混合研磨制备为固体分散体。虽然溶液包合法对药物苦味具有一定掩蔽作用,但恩诺沙星苦味极强,经家畜试验证明仅仅包合掩味无法达到理想的适口性效果。而且资料显示,猪对恩诺沙星苦味阈值是人的几百分之一,及其敏感。
所以恩诺沙星可溶性粉作为防治大肠杆菌、沙门氏菌等各类细菌引起的畜禽感染保健制剂,改善临床使用适口性和提高生物利用度,提高在兽药中的使用率,克服上述使用限制,具有非常重要的意义。
发明内容:
本发明旨在至少解决现有技术中存在的技术问题之一。
为此,本发明其解决技术问题所采用的技术方案是:一种掩味恩诺沙星可溶性粉,每100质量份数的掩味恩诺沙星可溶性粉中含有恩诺沙星10~15份,包合剂75.5~84.5份,助溶剂3~5份,矫味剂0.5~1.5份,成膜缓释剂2~3份。
作为优选,包合剂为倍他环糊精和羟丙基倍他环糊精中的一种或两种组合。
作为优选,助溶剂为碳酸钠和碳酸氢钠中的任意一种或两种组合。
作为优选,矫味剂为甜菊糖苷。
作为优选,成膜缓释剂为羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠中的一种或数种组合及辛烯基琥珀酸淀粉钠的混合物,羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠中的一种或数种组合为组合1,辛烯基琥珀酸淀粉钠为组合2,组合1和组合2的质量比为1:3。
本发明还提供了一种掩味恩诺沙星可溶性粉的制备方法,其特征在于包括以下几个步骤:
a、按质量份数分别称取恩诺沙星、包合剂、助溶剂、矫味剂、成膜缓释剂备用;
b、恩诺沙星和包合剂混合均匀,投入80~83℃热水中不断搅拌,水料比2:1,为分子包合液;
c、待步骤b中分子包合液温度稳定在80~83℃范围时投入助溶剂和矫味剂使分子包合液澄清,保温1h后离心喷雾干燥,得到恩诺沙星粉末制剂,恩诺沙星粉末制剂的粒径控制在120~160μm;
d、将成膜缓释剂配制成5%的水溶液,温度保持在50~55℃,剪切并通过高压均质机制备成均质胶体;
e、将步骤c中得到的恩诺沙星粉末制剂通过带有喷涂装置的振动流化床,边喷涂步骤d中的均质胶体边干燥,直至干燥完全,然后过80目筛,即得掩味恩诺沙星可溶性粉。
作为优选,步骤c中离心喷雾干燥参数为进风温度175~180℃,出风温度80±2℃,雾化盘转速3000~3200r/min。
作为优选,步骤e中喷涂装置为螺杆泵双气流喷嘴,压缩空气进量为0.82~0.85m3/min,喷雾压力为0.5~0.55Pa。
本发明的有益效果在于:
(1)本发明制备的掩味恩诺沙星可溶性粉,通过分子包合和喷涂缓释双重掩味技术,掩味效果好,解决了恩诺沙星味苦临床使用受限的问题,特别是本发明首次在恩诺沙星粉剂制剂工艺中采用了流化床微粒喷涂工艺,通过精选水溶性成膜变性淀粉辛烯基琥珀酸淀粉钠,并结合羧甲基纤维素钠等纤维素衍生物缓释剂高度均质雾化喷涂,既解决了水溶性问题,又达到了药物在动物口腔内通过缓释而掩味的目的,避免了普通恩诺沙星颗粒制剂常规包衣掩味顾此失彼的现象出现,具有很大的技术优势;
(2)本发明制备的掩味恩诺沙星可溶性粉,水中溶解度高,可同时满足家禽饮水和家畜拌料的使用需求;
(3)本发明制备的掩味恩诺沙星可溶性粉,通过分子包合和微粒喷涂技术提高了药物性状的稳定性,不降解不变色不结块。
附图说明:
图1为具体实施方式中实验组和对照组于口腔溶液中释放度比较图。
具体实施方式:
实施例1:
若生产100kg掩味恩诺沙星可溶性粉,包含以下步骤:
(1)称取恩诺沙星10kg,倍他环糊精84.5kg(按有效成分计),碳酸钠3kg、甜菊糖苷0.5kg,海藻酸钠0.5kg,辛烯基琥珀酸淀粉钠1.5kg,备用;
(2)恩诺沙星和倍他环糊精混合均匀,投入80~83℃热水中不断搅拌,水料比2:1,为分子包合液;
(3)待步骤(2)中分子包合液温度稳定在80~83℃范围时投入碳酸钠、甜菊糖苷使溶液澄清,保温1h后离心喷雾干燥,进风温度175~180℃,出风温度80±2℃,雾化盘转速3000~3200r/min,得到恩诺沙星粉末制剂,粒径控制在120~160μm;
(4)将海藻酸钠和辛烯基琥珀酸淀粉钠混合均匀配制成5%的水溶液,温度保持在50~55℃,剪切并通过高压均质机制备成均质胶体;
(5)将步骤(3)中得到的恩诺沙星粉末制剂通过带有喷涂装置的振动流化床,边喷涂步骤(4)中均质胶体边干燥,直至干燥完全,螺杆泵双气流喷嘴压缩空气进量为0.82~0.85m3/min,喷雾压力为0.5~0.55Pa,然后过80目筛,即得掩味恩诺沙星可溶性粉。
实施例2:
若生产100kg掩味恩诺沙星可溶性粉,包含以下步骤:
(1)称取恩诺沙星12kg,倍他环糊精81.4kg(按有效成分计),碳酸钠和碳酸氢钠各2kg、甜菊糖苷0.6kg,羧甲基纤维素钠和羟丙基甲基纤维素各0.25kg,辛烯基琥珀酸淀粉钠1.5kg,备用;
(2)恩诺沙星和倍他环糊精混合均匀,投入80~83℃热水中不断搅拌,水料比2:1,为分子包合液;
(3)待步骤(2)中分子包合液温度稳定在80~83℃范围时投入碳酸钠、碳酸氢钠、纽甜和阿斯巴甜使溶液澄清,保温1h后离心喷雾干燥,进风温度175~180℃,出风温度80±2℃,雾化盘转速3000~3200r/min,得到恩诺沙星粉末制剂,粒径控制在120~160μm;
(4)将羧甲基纤维素钠、羟丙基甲基纤维素和辛烯基琥珀酸淀粉钠混合均匀配制成5%的水溶液,温度保持在50~55℃,剪切并通过高压均质机制备成均质胶体;
(5)将步骤(3)中得到的恩诺沙星粉末制剂通过带有喷涂装置的振动流化床,边喷涂步骤(4)中均质胶体边干燥,直至干燥完全,螺杆泵双气流喷嘴压缩空气进量为0.82~0.85m3/min,喷雾压力为0.5~0.55Pa,然后过80目筛,即得掩味恩诺沙星可溶性粉。
实施例3:
若生产100kg掩味恩诺沙星可溶性粉,包含以下步骤:
(1)称取恩诺沙星15kg,羟丙基倍他环糊精77.2kg(按有效成分计),碳酸钠和碳酸氢钠分别为2kg和2.5kg、甜菊糖苷0.8kg,羟丙基甲基纤维素和海藻酸钠各0.5kg,辛烯基琥珀酸淀粉钠1.5kg,备用;
(2)恩诺沙星和羟丙基倍他环糊精混合均匀,投入80~83℃热水中不断搅拌,水料比2:1,为分子包合液;
(3)待步骤(2)中分子包合液温度稳定在80~83℃范围时投入碳酸钠、碳酸氢钠、甜菊糖苷使溶液澄清,保温1h后离心喷雾干燥,进风温度175~180℃,出风温度80±2℃,雾化盘转速3000~3200r/min,得到恩诺沙星粉末制剂,粒径控制在120~160μm;
(4)将羟丙基甲基纤维素、海藻酸钠和辛烯基琥珀酸淀粉钠混合均匀配制成5%的水溶液,温度保持在50~55℃,剪切并通过高压均质机制备成均质胶体;
(5)将步骤(3)中得到的恩诺沙星粉末制剂通过带有喷涂装置的振动流化床,边喷涂步骤(4)中均质胶体边干燥,直至干燥完全,螺杆泵双气流喷嘴压缩空气进量为0.82~0.85m3/min,喷雾压力为0.5~0.55Pa,然后过80目筛,即得掩味恩诺沙星可溶性粉。
对照实验1:
本发明制备的掩味恩诺沙星可溶性粉和常规工艺制备的恩诺沙星可溶性粉性状稳定性验证。
实验组:实施例1制备的10%掩味恩诺沙星可溶性粉;
对照组:按《国家兽药标准》2015年版制备10%掩味恩诺沙星可溶性粉,即取80目以下恩诺沙星原料10g,无水葡萄糖和碳酸钠分别为87g和3g,混合均匀,即得。
实验方法:(1)实验组和对照组样品各称取100g,每组分5等份,每份20g分别封装于阴阳袋中;(2)所有阴阳袋阳面朝上平置于恒温光照培养箱内,确保样品均匀平铺于袋中,互不覆盖遮挡,24h不间断光照,温度设定至30℃;(3)每7d观察一次各样品色泽变化和结块情况,并抽取其中一袋检测含量,持续至35d实验结束。
实验结果:
表1恩诺沙星可溶性粉性状稳定性比较结果
实验结论:本实验结果显示,35d内实验组掩味恩诺沙星可溶性粉色泽无变化,十分稳定,而对照组仅7d色泽变化为微黄色,21d后为黄色,色泽不稳定。实验组和对照组含量都稳定,稳定性相当,而对照组28d观察略有结块,不太稳定。色泽稳定性从一个侧面说明恩诺沙星经包合和喷涂两步固定后性质更加稳定,这也是掩味效果好的一个重要原因。
对照实验2:
本发明制备的掩味恩诺沙星可溶性粉模拟口腔溶液中释放度实验,并与药典描述常规工艺恩诺沙星可溶性粉做释放度比较,从而说明产品的掩味效果。
实验方法:
(1)按ISO/TR10271标准配制人工唾液:精确称取NaCl 0.4g,KCl 0.4g,CaCl2~2H2O 0.795g,NaHPO4~2H2O 0.78g,Na2S~2H2O0.005g,Urea 1.0g,分别加入1000ml蒸馏水中,搅拌充分溶解澄清,用0.001mol/l HCl或NaOH溶液调PH值至7.0,水浴至37℃,备用。
(2)精确称取实验组中掩味恩诺沙星可溶性粉和对照组常规工艺恩诺沙星可溶性粉各3份,每份50mg(约含恩诺沙星5mg),分别加入50ml带塞试管中,实验组编号为E1,E2,E3,对照组编号为C1,C2,C3。
(3)两名实验人员同时分别在实验组E1和对照组C1试管中加入50ml人工唾液。以1次/s的速度每颠倒5次用移液管吸取10ml溶液于10ml试管中,直到第25次(25s),得到E1和C1各5管溶液,然后分别用450nm水系滤膜过滤,滤液摇晃均匀后在271nm下用吸光度法测定恩诺沙星浓度,以表示制剂在口腔中的释放度。按照上述方法依次完成实验组和对照组剩余编号释放度测定,各时间点取平均值。
实验结果:
表2实验组E和对照组C恩诺沙星可溶性粉各时间点在口腔溶液中的释放度比较
实验结论:实验结果及图1表明,实验组掩味恩诺沙星可溶性粉在25s时平均释放度仅为5.202ug/ml,而对照组恩诺沙星可溶性粉达20.532ug/ml,远高于实验组。资料显示,家畜动物对恩诺沙星苦味的阈值是人的几百分之一,及其敏感,所以恩诺沙星可溶性粉在口腔溶液中释放度越低掩味效果越明显,说明本发明生产的恩诺沙星可溶性粉掩味效果良好。
对照实验3:
通过动物饲喂试验对本发明恩诺沙星可溶性粉掩味效果进行评价。
试验地点:浙江湖州某猪场。
试验方法:(1)选择60头50kg的健康肉猪,分成A、B、C 3组,每组20头;(2)实验组和对照组均按10g/t药量混饲各180kg,另备无药饲料180kg;(3)肉猪A、B、C 3组分别隔离饲喂实验组、对照组和无药饲料60kg,1h后清扫食槽并称量剩余饲料重量,通过余料比较采食效果;(4)隔天再重复上述试验两次,采食量取平均值。
试验结果:
表3动物饲喂试验采食量比较
试验结论:实验组与无药饲料组采食量基本接近,而对照组采食量仅36.9%,显著下降,说明本发明恩诺沙星可溶性粉掩味效果理想。
以上所述仅为本发明的较佳实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
Claims (8)
1.一种掩味恩诺沙星可溶性粉,其特征在于:每100质量份数的掩味恩诺沙星可溶性粉中含有恩诺沙星10~15份,包合剂75.5~84.5份,助溶剂3~5份,矫味剂0.5~1.5份,成膜缓释剂2~3份。
2.根据权利要求1所述的一种掩味恩诺沙星可溶性粉,其特征在于:所述包合剂为倍他环糊精和羟丙基倍他环糊精中的一种或两种组合。
3.根据权利要求1所述的一种掩味恩诺沙星可溶性粉,其特征在于:所述助溶剂为碳酸钠和碳酸氢钠中的任意一种或两种组合。
4.根据权利要求1所述的一种掩味恩诺沙星可溶性粉,其特征在于:所述矫味剂为甜菊糖苷。
5.根据权利要求1所述的一种掩味恩诺沙星可溶性粉,其特征在于:所述成膜缓释剂为羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠中的一种或数种组合及辛烯基琥珀酸淀粉钠的混合物,羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠中的一种或数种组合为组合1,辛烯基琥珀酸淀粉钠为组合2,组合1和组合2的质量比为1:3。
6.根据权利要求1所述的一种掩味恩诺沙星可溶性粉的制备方法,其特征在于包括以下几个步骤:
a、按所述质量份数分别称取恩诺沙星、包合剂、助溶剂、矫味剂、成膜缓释剂备用;
b、恩诺沙星和包合剂混合均匀,投入80~83℃热水中不断搅拌,水料比2:1,为分子包合液;
c、待步骤b中分子包合液温度稳定在80~83℃范围时投入助溶剂和矫味剂使分子包合液澄清,保温1h后离心喷雾干燥,得到恩诺沙星粉末制剂,恩诺沙星粉末制剂的粒径控制在120~160μm;
d、将成膜缓释剂配制成5%的水溶液,温度保持在50~55℃,剪切并通过高压均质机制备成均质胶体;
e、将步骤c中得到的恩诺沙星粉末制剂通过带有喷涂装置的振动流化床,边喷涂步骤d中的均质胶体边干燥,直至干燥完全,然后过80目筛,即得掩味恩诺沙星可溶性粉。
7.根据权利要求6所述的一种掩味恩诺沙星可溶性粉的制备方法,其特征在于:所述步骤c中离心喷雾干燥参数为进风温度175~180℃,出风温度80±2℃,雾化盘转速3000~3200r/min。
8.根据权利要求6所述的一种掩味恩诺沙星可溶性粉的制备方法,其特征在于:所述步骤e中喷涂装置为螺杆泵双气流喷嘴,压缩空气进量为0.82~0.85m3/min,喷雾压力为0.5~0.55Pa。
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