CN112516076B - 一种头孢噻呋注射用原位凝胶及其制备方法 - Google Patents
一种头孢噻呋注射用原位凝胶及其制备方法 Download PDFInfo
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- CN112516076B CN112516076B CN202011484438.3A CN202011484438A CN112516076B CN 112516076 B CN112516076 B CN 112516076B CN 202011484438 A CN202011484438 A CN 202011484438A CN 112516076 B CN112516076 B CN 112516076B
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- ceftiofur
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- situ gel
- solid dispersion
- poloxamer
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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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
本发明属于动物用药物制剂技术领域,涉及一种头孢噻呋注射用原位凝胶及其制备方法。所述头孢噻呋注射用原位凝胶包括头孢噻呋固体分散体、温敏型原位凝胶基质、高分子阻滞剂、注射用水,其中所述温敏型原位凝胶基质由泊洛沙姆407和泊洛沙姆188组成;所述头孢噻呋注射用原位凝胶各组分的质量分数为:4‑20%头孢噻呋固体分散体、12‑28%泊洛沙姆407、0.2‑10%泊洛沙姆188、0.05~5%高分子阻滞剂,余量为注射用水。本发明将固体分散体与注射用原位凝胶相结合,增加了原位凝胶的胶凝强度,能明显延迟原位凝胶的溶蚀,缓释效果更为明显。
Description
技术领域
本发明属于动物用药物制剂技术领域,涉及一种头孢噻呋注射用原位凝胶及其制备方法。
背景技术
头孢噻呋为类白色至淡黄色粉末。在丙酮中极微溶解,在水或乙醇中几乎不溶,其钠盐具有引湿性,在水中易溶;其盐酸盐为白色或类白色结晶性粉末,在N,N-二甲基乙酰胺中易溶,在甲醇中微溶,在水中不溶。
头孢噻呋属于动物专用的第三代头孢菌素,具有光谱杀菌作用。对革兰氏阳性菌(包括产β-内酰胺酶)、革兰氏阴性菌的活性较强。敏感菌主要有多杀性巴氏杆菌、溶血性巴氏杆菌、胸膜肺炎放线杆菌、沙门菌、大肠杆菌、链球菌、葡萄球菌等。抗菌活性比氨苄西林强,对链球菌的抗菌作用比氟喹诺酮类药物强。主要用于治疗牛的急性呼吸系统感染,尤其是溶血性巴氏杆菌或多杀性巴氏杆菌引起的支气管肺炎、牛乳腺炎;猪放线杆菌性胸膜肺炎;1日龄雏鸡的大肠杆菌、沙门菌感染等。
头孢噻呋内服不吸收,肌内和皮下注射吸收迅速。体内分布广泛,但不能通过血脑屏障。注射给药后,在血液和组织液中的药物浓度高。本品在牛和猪体内迅速生成具有活性的代谢物-脱氧呋喃甲酰头孢噻呋,并进一步代谢为无活性的产物从尿和粪中排泄。在马、牛、羊、猪、犬、鸡和火鸡体内的半衰期分别是3.2h、7.1h、2.2-3.9h、14.5h、4.1h、6.8h及7.5h。钠盐与盐酸头孢噻呋的半衰期相似。
我国已批准上市的用于注射给药的头孢噻呋制剂有:注射用头孢噻呋钠,规格为4.0g、1g、0.5g、0.2g、0.1g;盐酸头孢噻呋注射液,规格为10ml:1g、20ml:1g、20ml:2g、100ml:5g、100ml:10g;头孢噻呋注射液,规格为10ml:0.5g、20ml:1g、20ml:2g、50ml:2.5g、50ml:5g、100ml:5g、100ml:10g。
目前已上市的注射用头孢噻呋钠和盐酸头孢噻呋注射液,一个疗程需要重复给药多次,给药期间的血药“波峰、波谷”不利于药效的发挥。频繁抓捕动物,费时费力,造成动物应激也不利于疾病转归。头孢噻注射液靶动物猪的使用方法是三日1次,连用2次,具有一定的缓释效果。但盐酸头孢噻呋注射液和头孢噻呋注射液均为油剂,相对水剂,有刺激性较大的不足。
注射用温敏型原位凝胶是将药物和可供机体注射用的具有受热反向胶凝性质的聚合物分散于适宜的溶剂中,局部肌肉或皮下注射,在药部位温度下胶凝,形成透明、柔软、润滑的凝胶,药物随着聚合物的不断降解、溶蚀缓慢释放,达到长效。该制剂所选溶媒为水,基质为泊洛沙姆,生物相容性好,安全性高;常规注射给药,一次注射给药可持效3-7d,缓释长效作用明显,很好的提高了动物应用的顺应性,增加了经济效益。
发明内容
本发明的目的在于提供一种头孢噻呋注射用原位凝胶,将固体分散体与注射用原位凝胶相结合,增加了原位凝胶的胶凝强度,能明显延迟原位凝胶的溶蚀,缓释效果更为明显。
本发明的另一目的在于提供一种头孢噻呋注射用原位凝胶的制备方法,制备工艺更简单,重复性好,适用于工业化生产。
为实现上述目的,本发明采用以下技术方案:
本发明提供一种头孢噻呋注射用原位凝胶,所述头孢噻呋注射用原位凝胶包括头孢噻呋固体分散体、温敏型原位凝胶基质、高分子阻滞剂、注射用水,其中所述温敏型原位凝胶基质由泊洛沙姆407和泊洛沙姆188组成;所述头孢噻呋注射用原位凝胶各组分的质量分数为:4-20%头孢噻呋固体分散体、12-28%泊洛沙姆407、0.2-10%泊洛沙姆188、0.05~5%高分子阻滞剂,余量为注射用水。
优选地,所述头孢噻呋固体分散体的制备步骤如下:取处方量的固体分散体脂质材料熔融,加入处方量的头孢噻呋,搅拌均匀;迅速置于-20℃下冷却固化;低温粉碎获得头孢噻呋固体分散体;所述头孢噻呋和固体分散体脂质材料的质量比为1:(0.5-10)。
优选地,述固体分散体脂质材料选自硬脂酸、月桂酸、肉豆蔻酸、马来棕榈蜡、巴西棕榈蜡、微晶蜡、虫白蜡、棕榈酸甘油酯、单硬脂酸甘油酯、卵磷脂、大豆磷脂、二棕榈酸磷脂酰胆碱、氢化大豆磷脂、磷脂酸乙醇胺、磷脂先丝氨酸、胆固醇、二氨胆固醇、大豆甾酰糖苷、大豆甾醇或麦角固醇中的任意一种或多种。
优选地,所述高分子阻滞剂选自聚乙二醇、聚维酮、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、卡波姆、透明质酸、黄原胶、壳聚糖或海藻酸钠中的任意一种或多种。
优选地,所述头孢噻呋注射用原位凝胶的成凝胶温度为31℃~35℃。
优选地,所述头孢噻呋的颗粒粒径均不大于15μm且90%颗粒粒径小于5μm。
本发明还提供一种上述头孢噻呋注射用原位凝胶的制备方法,包括以下步骤:
步骤1:取处方量的头孢噻呋固体分散体、高分子阻滞剂和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解;
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
相比现有技术,本发明的有益效果在于:
1、本发明头孢噻呋注射用原位凝胶中头孢噻呋固体分散体为脂质体,分散于原位凝胶基质中,可有效提高头孢噻呋的稳定性。
2、本发明将固体分散体与注射用原位凝胶相结合,增加了原位凝胶的胶凝强度,能明显延迟原位凝胶的溶蚀,缓释效果更为明显。
3、本发明与脂质体、微球、微囊等制剂相比,制备工艺更简单,重复性好,适用于工业化生产。
4、本发明采用的高分子材料均生物相容性好,安全性高,头孢噻呋制备为固体分散体后分散于凝胶体系中,与油剂相比,能明显降低给药刺激性。
附图说明
图1为本发明实施例1~5头孢噻呋注射用原位凝胶的体外释放度曲线。
图2为本发明实施例1~5头孢噻呋注射用原位凝胶的溶蚀曲线。
具体实施方式
以下实施例用于说明本发明,但不用来限定本发明的保护范围。若未特别指明,实施例中所用技术手段为本领域技术人员所熟知的常规手段。下述实施例中的试验方法,如无特别说明,均为常规方法。
实施例1
头孢噻呋固体分散体处方:
头孢噻呋固体分散体的制备:(1)取处方量的硬脂酸、大豆磷脂和胆固醇在70℃下熔融,加入处方量的头孢噻呋,搅拌均匀;(2)迅速置于-20℃下冷却固化;(3)低温粉碎获得头孢噻呋固体分散体。
注射用原位凝胶制备处方:
头孢噻呋注射用原位凝胶的制备方法:
步骤1:取处方量的头孢噻呋固体分散体、甲基纤维素和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解。
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
对头孢噻呋注射用原位凝胶进行体外性能评价,包括性状、通针性、胶凝温度、胶凝时间、热可逆性、释放度、溶蚀性的测定。体外释放度曲线如图1所示。溶蚀曲线如图2所示。体外性能评价结果如表1所示。测定方法如下:
通针性测定:用12号针头考察制剂的通针性,“+”代表通针性好,“+”越多代表通针性越好;“-”代表通针性差,“-”越多代表通针性越差。
胶凝温度测定:采用试管倒转法。取4℃条件下冷藏的头孢噻呋注射用原位凝胶5ml,至于试管中,并插入用于测温的温度计。将试管置于水浴中,水浴液面需高出试管内容物液面,缓慢加热升温,升温速率保持在每分钟升高1℃。水温达到30℃以后,每分钟将试管取出倾斜90度,观试管内容物不流动时,记录温度,即为相变温度。每个处方样品按本方法测定3次,结果取平均值。
胶凝时间测定:取药液,25℃放置0.5h后,置于已预热至37℃的试管中并保温,记录相变时间。
热可逆性测定:将凝胶加热至特定温度(30,35,40,45,50,55,60,70℃),然后缓慢冷却至室温,即算作一次加热循环,检验直至凝胶不再具备温敏性或者成分发生改变,若重复10次仍具有温敏性,记做循环次数>10。
释放度测定:采用透析袋法研究头孢噻呋注射用原位凝胶的体外释药特性。精密量取头孢噻呋注射用原位凝胶2ml,放于实现在蒸馏水中浸泡24h的透析袋中,两端用透析夹夹紧,置于150ml的烧杯中,加入100ml的透析介质,将烧杯放在恒温磁力搅拌器上,转速50r/min,调节温度值37±0.5℃,分别于0.5、1、2、3、6、8、12、24、36、48、60、72、84、96、108、120、132、144、156、168、180h取5ml透析液,随即补加介质5ml,以保证透析环境不变。取出的透析液过滤,HPLC法测定头孢噻呋的浓度,计算累积释放率。
溶蚀性的测定:
精密称取10g头孢噻呋注射用原位凝胶,置于预先已称重的平底具塞刻度试管中,再行称重。将该试管置于37.0±0.2℃的恒温水浴振荡器中平衡10min,使聚合物溶液完全形成凝胶。小心加入经37℃预热的PBS溶液5ml作为释放介质,在50次/min恒温水浴振荡,分别在0.5、1、2、4、6、12、24、48、60、72、84、96、108、120、144、168、180h立即倾出全部释放介质,将容器内外表面用滤纸吸干,迅速称量并纪录,然后重新放入恒温水浴振荡器中平衡10min,再补充释放介质5ml。如此反复操作,直至试验结束。
实施例2
头孢噻呋固体分散体处方:
头孢噻呋固体分散体的制备:(1)取处方量的单硬脂酸甘油酯、氢化大豆磷脂和胆固醇在85℃下熔融,加入处方量的头孢噻呋,搅拌均匀;(2)迅速置于-20℃下冷却固化;(3)低温粉碎获得头孢噻呋固体分散体。
注射用原位凝胶制备处方:
制备方法:
头孢噻呋注射用原位凝胶的制备方法:
步骤1:取处方量的头孢噻呋固体分散体、聚维酮K30和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解,头孢噻呋固体分散体分散均匀。
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
对其进行体外性能评价,包括性状、通针性、胶凝温度、胶凝时间、热可逆性、释放度的测定。体外性能评价方法同实施例1。体外释放度曲线如图1所示。溶蚀曲线如图2所示。体外性能评价结果如表1所示。
实施例3
头孢噻呋固体分散体处方:
头孢噻呋 200.0g
棕榈酸甘油酯 350.0g
大豆甾醇 100.0g
制备方法:
头孢噻呋固体分散体的制备:(1)取处方量的棕榈酸甘油酯、大豆甾醇在80℃下熔融,加入处方量的头孢噻呋,搅拌均匀;(2)迅速置于-20℃下冷却固化;(3)低温粉碎获得头孢噻呋固体分散体。
注射用原位凝胶制备处方:
头孢噻呋注射用原位凝胶的制备方法:
步骤1:取处方量的头孢噻呋固体分散体、羟丙基甲基纤维素和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解,头孢噻呋固体分散体分散均匀。
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
对其进行体外性能评价,包括性状、通针性、胶凝温度、胶凝时间、热可逆性、释放度的测定。体外性能评价方法同实施例1。体外释放度曲线如图1所示。溶蚀曲线如图2所示。体外性能评价结果如表1所示。
实施例4
头孢噻呋固体分散体处方:
头孢噻呋固体分散体的制备:(1)取处方量的微晶蜡、磷脂酸乙醇胺、胆固醇在75℃下熔融,加入处方量的头孢噻呋,搅拌均匀;(2)迅速置于-20℃下冷却固化;(3)低温粉碎获得头孢噻呋固体分散体。
注射用原位凝胶制备处方:
头孢噻呋注射用原位凝胶的制备方法:
步骤1:取处方量的头孢噻呋固体分散体、羧甲基纤维素钠和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解,头孢噻呋固体分散体分散均匀。
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
对其进行体外性能评价,包括性状、通针性、胶凝温度、胶凝时间、热可逆性、释放度的测定。体外性能评价方法同实施例1。体外释放度曲线如图1所示。溶蚀曲线如图2所示。体外性能评价结果如表1所示。
实施例5
头孢噻呋固体分散体处方:
头孢噻呋 250.0g
硬脂酸 250.0g
麦角固醇 100.0g
头孢噻呋固体分散体的制备:(1)取处方量的硬脂酸、麦角醇在75℃下熔融,加入处方量的头孢噻呋,搅拌均匀;(2)迅速置于-20℃下冷却固化;(3)低温粉碎获得头孢噻呋固体分散体。
注射用原位凝胶制备处方:
头孢噻呋注射用原位凝胶的制备方法:
步骤1:取处方量的头孢噻呋固体分散体、羟丙基甲基纤维素和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解,头孢噻呋固体分散体分散均匀。
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
对其进行体外性能评价,包括性状、通针性、胶凝温度、胶凝时间、热可逆性、释放度的测定。体外性能评价方法同实施例1。体外释放度曲线如图1所示。溶蚀曲线如图2所示。体外性能评价结果如表1所示。
表1体外性能评价结果
注:+代表通针性,+越少代表通针性越好。
以上所述之实施例,只是本发明的较佳实施例而已,仅仅用以解释本发明,并非限制本发明实施范围,对于本技术领域的技术人员来说,当然可根据本说明书中所公开的技术内容,通过置换或改变的方式轻易做出其它的实施方式,故凡在本发明的原理上所作的变化和改进等,均应包括于本发明申请专利范围内。
Claims (5)
1.一种头孢噻呋注射用原位凝胶,其特征在于,所述头孢噻呋注射用原位凝胶包括头孢噻呋固体分散体、温敏型原位凝胶基质、高分子阻滞剂、注射用水,其中所述温敏型原位凝胶基质由泊洛沙姆407和泊洛沙姆188组成;所述头孢噻呋注射用原位凝胶各组分的质量分数为:4-20%头孢噻呋固体分散体、12-28%泊洛沙姆407、0.2-10%泊洛沙姆188、0.05~5%高分子阻滞剂,余量为注射用水;
所述头孢噻呋固体分散体的制备步骤如下:取处方量的固体分散体脂质材料熔融,加入处方量的头孢噻呋,搅拌均匀;迅速置于-20℃下冷却固化;低温粉碎获得头孢噻呋固体分散体;所述头孢噻呋和固体分散体脂质材料的质量比为1:(0.5-10);所述固体分散体脂质材料选自硬脂酸、月桂酸、肉豆蔻酸、马来棕榈蜡、巴西棕榈蜡、微晶蜡、虫白蜡、棕榈酸甘油酯、单硬脂酸甘油酯、卵磷脂、大豆磷脂、二棕榈酸磷脂酰胆碱、氢化大豆磷脂、磷脂酸乙醇胺、磷脂先丝氨酸、胆固醇、二氨胆固醇、大豆甾酰糖苷、大豆甾醇或麦角固醇中的任意一种或多种。
2.根据权利要求1所述的一种头孢噻呋注射用原位凝胶,其特征在于,所述高分子阻滞剂选自聚乙二醇、聚维酮、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、卡波姆、透明质酸、黄原胶、壳聚糖或海藻酸钠中的任意一种或多种。
3.根据权利要求1所述的一种头孢噻呋注射用原位凝胶,其特征在于,所述头孢噻呋注射用原位凝胶的成凝胶温度为31℃~35℃。
4.根据权利要求1所述的一种头孢噻呋注射用原位凝胶,其特征在于,所述头孢噻呋的颗粒粒径均不大于15μm且90%颗粒粒径小于5μm。
5.权利要求1~4任一项所述的一种头孢噻呋注射用原位凝胶的制备方法,其特征在于,包括以下步骤:
步骤1:取处方量的头孢噻呋固体分散体、高分子阻滞剂和泊洛沙姆188混合均匀后,加入处方量80%的水中,搅拌至泊洛沙姆188完全溶解;
步骤2:取处方量的泊洛沙姆407加入步骤1中,搅拌直至得到无团块、分散均匀的药液,加水定容,即得。
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