CN105902499B - 恩诺沙星可溶性粉及其制备方法 - Google Patents
恩诺沙星可溶性粉及其制备方法 Download PDFInfo
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- CN105902499B CN105902499B CN201610425381.7A CN201610425381A CN105902499B CN 105902499 B CN105902499 B CN 105902499B CN 201610425381 A CN201610425381 A CN 201610425381A CN 105902499 B CN105902499 B CN 105902499B
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- enrofloxacin
- acid
- soluble powder
- dihydrogen phosphate
- sodium dihydrogen
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- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229960000740 enrofloxacin Drugs 0.000 title claims abstract description 83
- 239000000843 powder Substances 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
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- 235000019799 monosodium phosphate Nutrition 0.000 claims abstract description 22
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims abstract description 22
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- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 9
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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
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- Bioinformatics & Cheminformatics (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供一种恩诺沙星可溶性粉,它包括下述质量百分数的原料:恩诺沙星5%~10%、有机酸助溶剂5%~20%、磷酸二氢钠1.5%~5%,余量为载体。本发明还提供一种上述恩诺沙星可溶性粉的制备方法,它包括对上述质量百分数的原料进行混合、分装、密封的步骤。本发明提供的恩诺沙星可溶性粉组分简单、易于储存、稳定性好、用药方便、适口性好,而且制备步骤简单,适于工业化生产。
Description
技术领域
本发明涉及一种兽用抗菌类药物,具体的说,涉及了一种恩诺沙星可溶性粉及其制备方法。
背景技术
作为动物专用的第三代喹诺酮类抗菌药物,恩诺沙星首先由德国Bayer公司在1987年开发成功,并于1996年获得美国FDA批准。恩诺沙星又名乙基环丙沙星、恩氟沙星,为淡黄色结晶性粉末、无臭、味苦、不溶于水,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,口服吸收好,能广泛分布于组织中。本品代谢产物为环丙沙星,代谢产物仍有强大抗菌作用。研究表明,恩诺沙星抗菌机制是它可以作用于细菌细胞的DNA,从而干扰细菌DNA复制、转录和修复重组,细菌因不能正常繁殖而死亡。近年来,国内外许多学者对恩诺沙星在不同家畜体内的代谢作了大量研究,结果表明其在牛、绵羊、马、猪、犬、兔、鸭和鱼等体内均显示出优良的药动学特征。因此,恩诺沙星被广泛用于畜禽细菌性疾病和支原体感染,如猪支原体肺炎、巴氏杆菌病、大肠杆菌病、沙门氏菌病、链球菌病、放线菌性胸膜肺炎、乳腺炎等;犬、猫敏感菌所致皮肤、呼吸道、泌尿道感染等;并具有起效迅速、增强畜禽对感染的抵抗力、治疗量与中毒量相差数十倍等优点。
虽然恩诺沙星具有诸多优点,但由于恩诺沙星在水中不溶,导致较差的生物利用度,大大限制了其在临床上的应用。目前市场中,恩诺沙星主要有注射剂、溶液剂、混悬剂、可溶性粉剂等。但由于注射剂给药麻烦,溶液剂、混悬剂又不够稳定,而现有的可溶性粉剂因需要添加的大量的辅料造成成本高且工艺复杂,不适于工业化大规模生产;另一方面,可溶性粉剂在饮用水中溶解度低、临床应用顺应性不好、稳定性差、在贮存期间容易受到外界温度、湿度的影响,造成粉剂的变色,有效成分失效等缺点。
例如CN102038643A公开了一种恩诺沙星可溶性粉及其制备方法和应用,其采用固体无机碱类或有机碱类作为有机酸助溶剂,虽具有良好的增溶效果,但该方法制备的产品在辅料筛选方面直接以无机碱类或有机碱类作为辅料,筛选安全性能低且碱性过强、适口性很差,口服给药禽畜不喜摄入,影响了治疗效果。再例如CN105412111A提供了一种恩诺沙星葡甲胺制剂及其制备方法,通过以葡甲胺、乙酰胺作为恩诺沙星的有机酸助溶剂,增加恩诺沙星在水中的溶解性。但有资料显示,乙酰胺有一定的致癌性,吸入、吞食、皮肤及眼部接触均有毒,可经皮肤吸收,强烈刺激眼、皮肤和黏膜,其毒性比二甲基甲酰胺强。现场操作必须穿戴好防护用品,即使是极其小量的乙酰胺渗入地下也会对饮用水造成危险,且该发明组成成份众多,生产成本高,制备工艺繁琐复杂,不利于工业化生产。因此开发一种新的恩诺沙星可溶性粉剂就显得意义重大且十分有必要。
发明内容
所以,本发明的目的是针对现有技术的不足,从而提供一种组分简单、易于储存、稳定性好、用药方便、适口性好且制备工艺简单的恩诺沙星可溶性粉及其制备方法。
为了实现上述目的,本发明所采用的技术方案是:一种恩诺沙星可溶性粉,它包括下述质量百分数的原料:恩诺沙星5%~10%、有机酸助溶剂5%~20%、磷酸二氢钠1.5%~5%、余量为载体。优选地,所述恩诺沙星的质量百分数为5%、6%、8%和10%;所述有机酸助溶剂的质量百分数为5%、8%、10%、12%、14%、15%和20%。
基于上述,所述有机酸助溶剂为甲磺酸、牛磺酸、烟酸、丁二酸、半乳糖醛酸、枸橼酸、酒石酸、月桂基硫酸、苹果酸、色氨酸、葡萄糖酸和谷氨酸中的一种或几种的组合。
基于上述,所述载体为葡萄糖、麦芽糊精、可溶性淀粉、乳糖、半乳糖、加益粉、蔗糖、右旋糖酐、山梨醇、玄明粉中的一种或几种的组合。
本发明还提供一种所述的恩诺沙星可溶性粉的制备方法,它包括以下步骤:
(1)按照上述质量百分数的恩诺沙星可溶性粉原料计算,将所述恩诺沙星、所述有机酸助溶剂、所述磷酸二氢钠和所述载体加入混合罐中进行混合,制得混合料;
(2)将所述混合料按照规格进行分装、密封即得所述恩诺沙星可溶性粉成品。
本发明相对现有技术具有突出的实质性特点和显著的进步,具体的说,本发明中所采用的有机酸助溶剂、磷酸二氢钠和富含糖分的载体均具有良好的稳定性,不易因受到外界温度、湿度的影响从而造成原料的变色、有效成分失效;另外,原料中的有机酸助溶剂能提高恩诺沙星在水中的溶解率;同时所述有机酸助溶剂会与原料中的磷酸二氢钠形成缓冲溶液,起到调节恩诺沙星水溶液的pH值的作用,同时结合富含糖分的载体,使得到的恩诺沙星粉体能够较好的溶于水中且具有适口性好等特点;本发明所提供的产品为粉体结构,相比液体制剂更易于储存、稳定性好、用药方便等优点。本发明所提供的恩诺沙星可溶性粉是通过各种粉体原料的直接混合所制得的,整个制备步骤简单、适于大规模生产。
具体实施方式
下面通过具体实施方式,对本发明的技术方案做进一步的详细描述。
实施例1
本实施例提供一种恩诺沙星可溶性粉,它包括下述质量百分数的原料:恩诺沙星5Kg、甲磺酸5 Kg、磷酸二氢钠1.5 Kg和可溶性淀粉88.5 Kg组成。
本实施例还提供一种上述恩诺沙星可溶性粉的制备方法,其步骤包括:
(1)依次称取恩诺沙星5 Kg、甲磺酸5 Kg、磷酸二氢钠1.5 Kg和可溶性淀粉88.5Kg,然后将上述质量的原料加入混合罐中均匀混合10分钟,制得混合物料;
(2)将所述混合物料按照规格分别分装成小袋并进行密封处理,即得恩诺沙星可溶性粉。
实施例2
本实施例提供一种恩诺沙星可溶性粉,它包括下述质量百分数的原料:恩诺沙星10 Kg、牛磺酸10 Kg、色氨酸8 Kg、磷酸二氢钠5 Kg和乳糖67 Kg组成。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例3
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星8Kg、葡萄糖酸5 Kg、苹果酸5 Kg、半乳糖醛酸5 Kg、磷酸二氢钠5 Kg、蔗糖52 Kg和山梨醇20Kg组成。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例4
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星5Kg、丁二酸3 Kg、半乳糖醛酸3 Kg、枸橼酸14 Kg、磷酸二氢钠3 Kg、蔗糖32 Kg和山梨醇40Kg组成。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例5
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星5Kg、磷酸二氢钠5 Kg、甲磺酸5 Kg、牛磺酸5 Kg、烟酸3 Kg、丁二酸2 Kg、半乳糖醛酸5 Kg、葡萄糖10 Kg、麦芽糊精10 Kg、可溶性淀粉15 Kg、乳糖10 Kg、半乳糖10 Kg和加益粉15 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例6
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星10Kg、磷酸二氢钠5 Kg、半乳糖醛酸2 Kg、枸橼酸2 Kg、酒石酸2 Kg、苹果酸2 Kg、色氨酸2 Kg、葡萄糖酸10 Kg、可溶性淀粉15 Kg、乳糖20 Kg、半乳糖5 Kg、加益粉5 Kg、蔗糖5 Kg、右旋糖酐5 Kg、山梨醇5 Kg、玄明粉5 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例7
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星8Kg、磷酸二氢钠5 Kg、烟酸5 Kg、丁二酸5 Kg、半乳糖醛酸5 Kg、葡萄糖5 Kg、麦芽糊精32Kg、可溶性淀粉25 Kg、乳糖10 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例8
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星10Kg、磷酸二氢钠5 Kg、甲磺酸10 Kg、麦芽糊精25 Kg、可溶性淀粉50 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例9
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星9Kg、磷酸二氢钠5 Kg、酒石酸11 Kg、牛磺酸5 Kg、烟酸4 Kg、可溶性淀粉11 Kg、乳糖20 Kg、半乳糖15 Kg、葡萄糖10 Kg、麦芽糊精10 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
实施例10
本实施例提供一种恩诺沙星可溶性粉,它由下述质量百分数的原料:恩诺沙星10Kg、磷酸二氢钠5 Kg、牛磺酸5 Kg、烟酸12 Kg、丁二酸3 Kg、半乳糖醛酸20 Kg、葡萄糖10Kg、麦芽糊精10 Kg、可溶性淀粉15 Kg、乳糖10 Kg。本实施例所提供的恩诺沙星可溶性粉的制备方法同实施例1中的制备方法。
药物稳定性中的加速试验验证:此项试验是在超常的条件下进行。其目的是通过加速药物的化学或物理变化,预测药物的稳定性。试验条件为将试验药物在温度为60±2℃、相对湿度为75±5%的条件下放置六个月。
分别对实施例1~10制得的恩诺沙星可溶性粉进行药物稳定性中的加速试验,试验步骤为:分别将实施例1~10制得的恩诺沙星可溶性粉0.5g溶解于100 mL饮用水中,得到十组试验溶液,并将十组所述试验溶液置于温度为60±2℃、相对湿度为75±5%的条件下放置,分别在试验期间的开始第一天、第五天和第十天对加速试验中恩诺沙星可溶性粉的性状、鉴别、干燥失重、外观均匀度、溶解性、含量进行检查;其中实施例1~5制得的恩诺沙星可溶性粉第十天的稳定性加速试验检查结果如表1所示;
表1实施例1~5加速试验中恩诺沙星可溶性粉第十天检测结果
项目 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 |
性状 | 白色粉末 | 白色粉末 | 白色粉末 | 白色粉末 | 白色粉末 |
鉴别 | 主斑点相同 | 主斑点相同 | 主斑点相同 | 主斑点相同 | 主斑点相同 |
失重 | 4.0% | 4.2% | 4.3% | 3.9% | 4.3% |
外观 | 合格 | 合格 | 合格 | 合格 | 合格 |
溶解性 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 |
含量 | 99.7% | 99.5% | 99.4% | 99.5% | 99.5% |
结论 | 合格 | 合格 | 合格 | 合格 | 合格 |
其中实施例6~10制得的恩诺沙星可溶性粉第十天的稳定性加速试验检查结果如表2所示:
表2实施例6~10加速试验中恩诺沙星可溶性粉第十天检测结果
项目 | 实施例6 | 实施例7 | 实施例8 | 实施例9 | 实施例10 |
性状 | 白色粉末 | 白色粉末 | 白色粉末 | 白色粉末 | 白色粉末 |
鉴别 | 主斑点相同 | 主斑点相同 | 主斑点相同 | 主斑点相同 | 主斑点相同 |
失重 | 3.9% | 4.1% | 4.0% | 3.8% | 4.2% |
外观 | 合格 | 合格 | 合格 | 合格 | 合格 |
溶解性 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 | 溶液澄清透明稀释无异常 |
含量 | 99.3% | 99.1% | 99.2% | 99.4% | 99.0% |
结论 | 合格 | 合格 | 合格 | 合格 | 合格 |
从表中可以看出:本发明实施例1~10提供的恩诺沙星可溶性粉稳定性好,不易因受到外界温度、湿度的影响从而造成粉剂的变色、有效成分失效等,且最终产品为粉体,相比液体制剂更易于储存和运输;在普通的饮用水中就有很好的溶解性,产生的溶液澄清,进行任意比例稀释均无异常出现,无需纯化用水,大大方便了养殖者用药,适口性很好,口服给药易被禽畜摄入吸收。
最后应当说明的是:以上实施例仅用以说明本发明的技术方案而非对其限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技术人员应当理解:依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换;而不脱离本发明技术方案的精神,其均应涵盖在本发明请求保护的技术方案范围当中。
Claims (8)
1.一种恩诺沙星可溶性粉,其特征在于,它包括下述质量百分数的原料:恩诺沙星5%~10%、有机酸助溶剂5%~20%、磷酸二氢钠1.5%~5%,余量为载体。
2.根据权利要求1所述的恩诺沙星可溶性粉,其特征在于,所述有机酸助溶剂为甲磺酸、牛磺酸、烟酸、丁二酸、半乳糖醛酸、枸橼酸、酒石酸、月桂基硫酸、苹果酸、色氨酸、葡萄糖酸和谷氨酸中的一种或几种的组合。
3.根据权利要求1或2所述的恩诺沙星可溶性粉,其特征在于,所述载体为葡萄糖、麦芽糊精、可溶性淀粉、乳糖、半乳糖、加益粉、蔗糖、右旋糖酐、山梨醇、玄明粉中的一种或几种的组合。
4.根据权利要求3所述的恩诺沙星可溶性粉,其特征在于,它包括下述质量百分数的原料:恩诺沙星5%、甲磺酸5%、磷酸二氢钠1.5%和可溶性淀粉88.5%。
5.根据权利要求3所述的恩诺沙星可溶性粉,其特征在于,它包括下述质量百分数的原料:恩诺沙星10%、牛磺酸10%、色氨酸8%、磷酸二氢钠5%和乳糖67%。
6.根据权利要求3所述的恩诺沙星可溶性粉,其特征在于,它包括下述质量百分数的原料:恩诺沙星8%、葡萄糖酸10%、谷氨酸5%、磷酸二氢钠3%、右旋糖24%和山梨醇50%。
7.根据权利要求3所述的恩诺沙星可溶性粉,其特征在于,它包括下述质量百分数的原料:恩诺沙星5%、丁二酸3%、半乳糖醛酸3%、枸橼酸14%、磷酸二氢钠3%、蔗糖32%和山梨醇40%。
8.一种恩诺沙星可溶性粉的制备方法,它包括以下步骤:
(1)按照权利要求1~7任一项所述质量百分数的原料计算,将所述恩诺沙星、所述有机酸助溶剂、所述磷酸二氢钠和所述载体加入到混合罐中进行混合,制得混合料;
(2)将所述混合料按照规格进行分装、密封即得所述恩诺沙星可溶性粉成品。
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