CN115518039A - 一种兽用托芬那酸固体脂质纳米混悬液及其制备方法 - Google Patents
一种兽用托芬那酸固体脂质纳米混悬液及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种兽用托芬那酸固体脂质纳米混悬液及其制备方法；所述纳米混悬液包括如下质量比的原料：托芬那酸原料药2％‑5％，固体脂质8％‑20％，表面活性剂2％‑4％，抗氧化剂0.1‑1％，防腐剂0.1‑0.5％，余量为灭菌水；所述固体脂质由山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成；所述表面活性剂包括聚乙烯吡咯烷酮K30、泊洛沙姆188和聚乙烯醇中的一种与椰油酸二乙醇酰胺复配而成。本发明通过各组分的协同作用及结合热熔乳化超声法制成的托芬那酸固体脂质纳米混悬液不仅具有缓释效果好、溶解度大、生物利用度高的特点，克服了BCSⅡ类药物低溶解性的缺陷；且减少了药物的毒副作用、成本较低、制备方法简单，能满足犬、猫关节炎症和牛、猪等呼吸道疾病的药学应用。
Description
技术领域
本发明属于制备兽药制剂技术领域，具体是一种兽用托芬那酸固体脂质纳米混悬液及其制备方法。
背景技术
托芬那酸(Tolfenamic acid)属于非甾体类抗炎药，主要具有抗炎，解热镇痛作用，在非甾体抗炎药中效果优于同类其它药物，且副作用小。由法国威隆公司将该药开发成兽药产品，主要缓解犬、猫骨关节相关的炎症和疼痛，还被用于猪、牛等家畜上呼吸道疾病的辅助治疗。虽然托芬那酸副作用小，但在后期研究发现托芬那酸对胃肠道还是有一定损伤。托芬那酸几乎不溶于水，水溶性和溶解速率较差。难溶性药物在胃肠液中溶出度小、溶出速率慢，导致吸收缓慢且不完全，从而影响药物的吸收和生物利用度。
固体脂质纳米(SLN)是以生物相容的高熔点脂质为骨架材料制成的纳米球。SLN载体基质由可生物降解和生物相容的固体脂质组成，SLN载体可以改善药物的溶解性,提高药物的渗透性和缓释性能。同时还可以防止药物破坏胃肠道的酸和酶,减少药物对胃肠道的刺激等优点。与其他制剂技术相比SLN载体更具有各种优势，如可将亲脂性和亲水性药物结合起来、提高药物有效性、杀菌性、提高物理稳定性、成本低、易于放大生产等。
为了解决现有托芬那酸制剂存在的问题，本发明提供了一种兽用托芬那酸固体脂质纳米混悬液及其制备方法。
发明内容
本发明针对托芬那酸溶解度差、生物利用度低等不足，提供一种兽用托芬那酸固体脂质纳米混悬液及其制备方法。本发明通过加入固体脂质、表面活性剂、抗氧化剂、防腐剂辅料及结合热熔乳化超声法制成的托芬那酸固体脂质纳米混悬液不仅具有缓释效果好、溶解度大、生物利用度高的特点，且无毒副作用、成本较低、制备方法简单，能满足犬、猫关节炎症和牛、猪等呼吸道疾病的药学应用。
为了实现以上目的，本发明采用的技术方案如下：
一种兽用托芬那酸固体脂质纳米混悬液，所述纳米混悬液包括如下质量比的原料：托芬那酸原料药2％-5％，固体脂质8％-20％，表面活性剂2％-4％，抗氧化剂0.1-1％，防腐剂0.1-0.5％，余量为灭菌水；所述固体脂质由山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成；所述表面活性剂包括聚乙烯吡咯烷酮K30、泊洛沙姆188和聚乙烯醇中的一种与椰油酸二乙醇酰胺复配而成。
优选地，所述抗氧化剂为焦亚硫酸钠和/或亚硫酸氢钠。
优选地，所述防腐剂为尼泊金乙酯和/或尼泊金甲酯。
优选地，所述固体脂质中山嵛酸甘油酯、硬脂酸和巴西棕榈蜡的质量比为3-5:1-3:1。
本发明的另一目的在于提供所述兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)按照配方称取各原料，将托芬那酸与固体脂质混合，并加热至95-105℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将表面活性剂加热至95-105℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将抗氧剂和防腐剂加至托芬那酸初乳中，利用细胞超声破碎仪超声，补全余量灭菌水，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
优选地，所述超声处理是在50-200W的功率下超声10-15min。
与现有技术相比，本发明的优点及有益效果为：
1、本发明通过加入固体脂质、表面活性剂、抗氧化剂、防腐剂辅料及结合热熔乳化超声法制成的托芬那酸固体脂质纳米混悬液不仅具有缓释效果好、溶解度大、生物利用度高的特点，克服了BCSⅡ类药物低溶解性的缺陷；且未使用有机试剂，且无毒、无害、无刺激性、减少了药物的毒副作用，降低了药物对胃肠的刺激性，成本较低，制备方法简单，能满足犬、猫关节炎症和牛、猪等呼吸道疾病的药学应用。
2、本发明采用山嵛酸甘油酯、硬脂酸和巴西棕榈蜡作为固体脂质，由于三者的协同作用，制得的托芬那酸纳米混悬液的包封率达到92.65％，载药量达到27.16％。
3、本发明采用聚乙烯吡咯烷酮K30、泊洛沙姆188或聚乙烯醇与椰油酸二乙醇酰胺复配组成表面活性剂，能够很好改善混悬液的分散性及各组分相容性，使得固体脂质纳米混悬液的多分散指数为0.15-0.45，沉降系数为0.9-1.0。
附图说明
图1为托芬那酸固体脂质纳米混悬液粒径分布图。
图2为托芬那酸固体脂质纳米混悬液和市售注射液在PH＝7.4的PBS缓冲液中体外释放度曲线图。
图3为托芬那酸固体脂质纳米混悬液和市售注射液在猪体内的药时曲线图。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，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，都属于本发明保护的范围。
实施例1
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g固体脂质混合，所述固体脂质由质量比为5:2:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液20mL、聚乙烯醇溶液10mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
实施例2
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取3g托芬那酸与12g固体脂质混合，所述固体脂质由质量比为4:3:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液30mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.2g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声15min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
实施例3
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取4g托芬那酸与12g固体脂质混合，所述固体脂质由质量比为3:2:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将泊洛沙姆188 30mL、聚乙烯醇溶液20mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.3g亚硫酸氢钠和0.4g尼泊金甲酯加至托芬那酸初乳中，利用超声破碎仪在150W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
实施例4
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取5g托芬那酸与20g固体脂质混合，所述固体脂质由质量比为3:1:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯醇溶液40mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.3g亚硫酸氢钠和0.4g尼泊金甲酯加至托芬那酸初乳中，利用超声破碎仪在150W的功率下超声15min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
对比例1
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g固体脂质混合，所述固体脂质由质量比为5:3的山嵛酸甘油酯、硬脂酸组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液20mL、聚乙烯醇溶液10mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
对比例2
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g巴西棕榈蜡固体脂质混合，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液20mL、聚乙烯醇溶液10mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
对比例3
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g固体脂质混合，所述固体脂质由质量比为5:2:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液20mL和聚乙烯醇溶液20mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
对比例4
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g固体脂质混合，所述固体脂质由质量比为5:2:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将椰油酸二乙醇酰胺40mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，利用超声破碎仪在100W的功率下超声10min，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
对比例5
一种兽用托芬那酸固体脂质纳米混悬液的制备方法，包括如下步骤：
(1)称取2g托芬那酸与8g固体脂质混合，所述固体脂质由质量比为5:2:1的山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成，加热至100℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将聚乙烯吡咯烷酮K30溶液20mL、聚乙烯醇溶液10mL和椰油酸二乙醇酰胺10mL加热至100℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将0.1g焦亚硫酸钠和0.1g尼泊金乙酯加至托芬那酸初乳中，补全灭菌水至100mL，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
一、托芬那酸固体脂质纳米混悬液理化性质测试
1、试验药物：将实施例1-4和对比例1-5所制得的固体脂质纳米混悬液进行理化性质测试。
2、试验方法：根据《中华人民共和国兽药典》2015版相关要求进行外观性状、沉降体积比、重分散性等试验。利用马尔文激光粒度仪进行纳米混悬液的粒径大小、多分散系数、电位进行测定，利用高效液相色谱仪(HPLC)对固体脂质纳米混悬液进行包封率和载药量的测定。
3、试验结果
固体脂质纳米混悬液的外观性状、沉降体积比、重分散性、粒径大小、多分散系数、电位以及包封率和载药量的结果如表1所示。其中实施例1托芬那酸固体脂质纳米混悬液的粒径分布如图1所示，达到纳米级别。
从上述测试结果得知，本发明方案制得的托芬那酸固体脂质纳米混悬液的沉降系数为1、粒径在389-438nm，电位为-20mV至--23.3mV，多分散系数在0.291-0.341，包封率在86.27-92.65％，载药量在23.65-27.16％。
二、体外释放度试验
1、试验药物：将实施例1所制得的固体脂质纳米混悬液和市售托芬那酸注射液进行体外释放度试验
2、试验方法：参照《中华人民共和国兽药典》2015版第二部附录中的相关要求，采用“转桨法”测定托芬那酸固体脂质纳米混悬液在PBS缓冲液(pH＝7.4)中的释放度。溶出杯的温度设置为37±0.5℃，转速设置为50r/min。量取经脱气处理的PBS溶液500mL，加入到每个溶出杯内，托芬那酸固体脂质纳米混悬液注入3个溶出杯内，即3个平行。取市售托芬那酸注射液作为对照组，设置3个平行。加入样品后，分别于0.25、0.5、1、2、3、4、6、8、12、24、48、72、96和120h时间点采集样品1ml，取样后向溶出杯内添加同体积和同温度的PBS溶液。样品经0.22um的滤膜过滤，利用高效液相色谱仪(HPLC)测定浓度，绘制体外释放曲线。
3、试验结果
托芬那酸注射液和托芬那酸固体脂质纳米混悬在PBS缓冲液中的累积释放百分率如表2所示，体外释放度结果如图2所示，市售托芬那酸注射液在2h释放了80.01％的药物，释放速度快，在12h基本释放完全。而托芬那酸固体脂质纳米混悬液在72h才释放71.85％的药物，释放速度慢，在120h才基本释放完。通过两者制剂的体外释放曲线对比，固体脂质纳米混悬液能显著延长托芬那酸的释放时间。
表2托芬那酸注射液和托芬那酸固体脂质纳米混悬液在PBS(pH＝7.4)缓冲液中各个时间点释放百分比(n＝3)
注：ND未检测到
三、在猪体内的药代动力学试验
1、试验药物：将实施例1所制得的固体脂质纳米混悬液和市售托芬那酸注射液进行猪体内的药代动力学试验
2、试验动物：选取健康猪6头，公母各半，体重15kg左右，每日饲养商品维持饲料(不含目标药物)两次，自由饮水。
3、动物试验：6头健康猪适应环境一周后，按4mg/kg肌肉注射托芬那酸固体脂质纳米混悬液和市售托芬那酸注射液。对6头猪进行二个周期的交叉试验，每个周期间隔7天，给药后分别与0、0.13、0.25、0.5、0.75、1、2、4、6、8、12、24、36、48、72、96和120h从前腔静脉采血5ml，按建好的血浆处理方法处理后，用HPLC进行含量测定。
4、数据处理：选用Winnonlin软件，用非房室模型拟合托芬那酸的主要药动学参数，结果如表3所示。
表3托芬那酸固体脂质纳米混悬液和市售注射液给猪肌注主要药动学参数
注明：*与市售托芬那酸注射液相比呈显著性差异p＜0.05。
5、试验结果
托芬那酸固体脂质纳米混悬液和市售托芬那酸注射液在猪体内的药时曲线如图3所示。固体脂质纳米混悬液肌肉注射后，托芬那酸在4.00h达到最高血药浓度1.68±0.06ug/mL，之后血药浓度缓慢下降，到120h后低于检测限。市售托芬那酸注射液在0.91h达到最高血药浓度3.31±0.47ug/mL，之后血药浓度缓慢下降，到48h后低于检测限。药动学参数表明，固体脂质纳米混悬液经肌肉注射能提高托芬那酸的生物利用度。上述结果表明本发明的制剂能在猪体内消除缓慢，能延长药物的作用时间，具有较好的缓释作用。托芬那酸固体脂质纳米混悬液的相对于托芬那酸注射液的生物利用度为185.33％。
以上内容是结合具体的/优选的实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，其还可以对这些已描述的实施例做出若干替代或变型，而这些替代或变型方式都应视为属于本发明的保护范围。
Claims (6)
1.一种兽用托芬那酸固体脂质纳米混悬液，其特征在于：所述纳米混悬液包括如下质量比的原料：托芬那酸原料药2％-5％，固体脂质8％-20％，表面活性剂2％-4％，抗氧化剂0.1-1％，防腐剂0.1-0.5％，余量为灭菌水；所述固体脂质由山嵛酸甘油酯、硬脂酸和巴西棕榈蜡组成；所述表面活性剂包括聚乙烯吡咯烷酮K30、泊洛沙姆188和聚乙烯醇中的一种与椰油酸二乙醇酰胺复配而成。
2.根据权利要求1所述兽用托芬那酸固体脂质纳米混悬液，其特征在于：所述抗氧化剂为焦亚硫酸钠和/或亚硫酸氢钠。
3.根据权利要求1所述兽用托芬那酸固体脂质纳米混悬液，其特征在于：所述防腐剂为尼泊金乙酯和/或尼泊金甲酯。
4.根据权利要求1所述兽用托芬那酸固体脂质纳米混悬液，其特征在于：所述固体脂质中山嵛酸甘油酯、硬脂酸和巴西棕榈蜡的质量比为3-5∶1-3∶1。
5.如权利要求1-4任一项所述兽用托芬那酸固体脂质纳米混悬液的制备方法，其特征在于：包括如下步骤：
(1)按照配方称取各原料，将托芬那酸与固体脂质混合，并加热至95-105℃，不断搅拌使其成为熔融透明状态下的托芬那酸溶液；
(2)将表面活性剂加热至95-105℃，趁热加入至托芬那酸溶液，不断搅拌，形成水包油的托芬那酸初乳；
(3)再将抗氧剂和防腐剂加至托芬那酸初乳中，利用细胞超声破碎仪超声，补全余量灭菌水，搅拌均匀，制得托芬那酸固体脂质纳米混悬液。
6.根据权利要求5所述兽用托芬那酸固体脂质纳米混悬液的制备方法，其特征在于：所述超声处理是在50-200W的功率下超声10-15min。
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| CN105796540A (zh) * | 2016-03-18 | 2016-07-27 | 沈阳药科大学 | 托芬那酸在制备治疗亨廷顿氏症药物中的应用 |
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| CN105796540A (zh) * | 2016-03-18 | 2016-07-27 | 沈阳药科大学 | 托芬那酸在制备治疗亨廷顿氏症药物中的应用 |
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