CN118557518A - 一种消旋卡多曲纳米混悬液及其制备方法 - Google Patents
一种消旋卡多曲纳米混悬液及其制备方法 Download PDFInfo
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- CN118557518A CN118557518A CN202410694874.5A CN202410694874A CN118557518A CN 118557518 A CN118557518 A CN 118557518A CN 202410694874 A CN202410694874 A CN 202410694874A CN 118557518 A CN118557518 A CN 118557518A
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- Prior art keywords
- racecadotril
- nanosuspension
- cyclodextrin
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- water
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Abstract
本发明提供一种消旋卡多曲纳米混悬液及其制备方法，以质量百分比计，包含以下原料：消旋卡多曲0.1‑0.6％、助溶剂10‑40％、β‑环糊精10‑35％、稳定剂10‑25％、矫味剂0.5‑3％和水适量。本发明选用无毒的助溶剂，采用溶剂‑反溶剂法制备消旋卡多曲纳米混悬剂，提高了药物的溶解度，采用环糊精包合技术有效掩盖了药物的不良气味，采用高速均质联合高压均质法制备纳米混悬液，使制剂粒径大幅度减小，粒径范围较窄，有利于提高药物的稳定性和剂量精确度。
Description
技术领域
本发明涉及药物制剂领域，尤其涉及一种消旋卡多曲纳米混悬液及其制备方法。
背景技术
小儿腹泻是一种常见的儿科疾病，多发于不到2岁的婴幼儿。症状是大便频次变多、大便性状变化等。症状轻时没有明显表现，严重时患儿可能发生肠道外症状，如重度脱水、酸碱平衡、电解质紊乱等，甚至危及生命。服用常规止泻药，常出现便秘、肠道菌群失调等副作用。
消旋卡多曲为强效脑啡肽酶抑制剂，通过保护内源性脑啡肽免受降解而显示出固有的肠分泌抑制作用。目前常用剂型为颗粒剂和片剂，婴幼儿以颗粒剂为主，颗粒剂最小包装规格为10mg，对于体重较低或月龄较小的幼儿，服用剂量很难控制，另外颗粒剂服用过程中极易出现服用不完全情况。
消旋卡多曲的半衰期为3-4小时，常规制剂需每日服用三次，以确保全天不间断地完全抑制靶向肽酶。但是对于服药困难的婴幼儿患者，每日给药两次是优选的。
中国专利CN103338749B提供了一种消旋卡多曲的混悬液制剂，包括活性成分、增稠剂、助悬剂、防腐剂、矫味剂、pH调节剂等，由于消旋卡多曲具有极重的苦味，仅通过添加甜味剂很难达到掩味效果，制剂的粒径在1μm-750μm之间，生物利用度虽有提高，但是仍无法达到每天服用两次。
混悬剂在给药途径上优于片剂和粉剂，但由于消旋卡多曲溶解度较差，普通混悬剂的生物利用度依然很低。消旋卡多曲的低溶解性和生物利用度严重制约了其在临床上的应用，因而利用新制剂技术提高其生物利用度非常必要。纳米混悬液是将水难溶性药物在稳定剂作用下分散于介质中，通常为水，利用机械研磨、高压均质或控制析晶等纳米化技术，将药物颗粒尺寸降至1μm以下，形成药物纳米胶体分散体系，可显著改善难溶性药物的溶解度和生物利用度。因此，制成纳米混悬液能有效解决难溶性药物临床应用的问题，有利于药物在胃肠道内吸收并延长药物的体内作用时间，从而提高难溶性药物的生物利用度。
发明内容
为了解决现有技术中消旋卡多曲液体制剂掩味效果差、生物利用度不高的问题，本发明提供一种满足婴幼儿给药，掩味效果良好，可减少给药次数的消旋卡多曲纳米混悬液制剂及其制备方法；
为实现上述目的，本发明采用如下的技术方案:一种消旋卡多曲纳米混悬液，以质量百分比计，包含以下原料：消旋卡多曲0.1-0.6％、助溶剂10-40％、β-环糊精10-35％、稳定剂10-25％、矫味剂0.5-3％和水适量。
消旋卡多曲在水中几乎不容，水中溶解度仅约10μg/ml，易溶于甲醇、乙腈、丙酮、二甲基亚砜等有机溶剂，但是这些有机溶剂均具有一定毒性，不适合作为儿童用药的溶剂，因此寻找一种无毒、热稳定性好的绿色溶剂尤为重要。本发明所述助溶剂为相对分子量为200-600范围内的聚乙二醇，消旋卡多曲在聚乙二醇中溶解度较大，满足制剂需求。
消旋卡多曲具有强烈的苦味，在水溶液中易被水解或氧化为低活性的化合物，极大的限制了消旋卡多曲液体制剂的应用，β-环糊精是由淀粉经微生物酶作用后提取制成的由7个葡萄糖残基以β-1,4-糖苷键结合构成的环状物，可与多种化合物形成包合复合物，使化合物更加稳定、增溶、缓释、抗氧化、抗分解，并具有掩蔽异味等作用。本发明选用β环糊精包合技术，达到较好的掩味效果，并能提高消旋卡多曲在溶液中的稳定性。本发明中所述环糊精为β-环糊精或其衍生物，优选羟丙基-β-环糊精、羟乙基-β-环糊精、羧甲基-β-环糊精或磺丁基醚-β-环糊精，更优选羧甲基-β-环糊精。
本发明中稳定剂可选用十二烷基磺酸钠、十二烷基硫酸钠、泊洛沙姆、聚乙烯基吡咯烷酮、吐温80、聚乙烯醇、聚山梨酯等中的一种或多种，优选的稳定剂选用十二烷基硫酸钠和聚乙烯基吡咯烷酮，其中十二烷基硫酸钠和聚乙烯基吡咯烷酮的质量比为1:1-2。
本发明所述矫味剂可选用蔗糖、山梨醇、木糖醇、葡萄糖、果糖、麦芽糖醇、阿斯巴甜、糖精、糖精钠、液体麦芽糖醇、三氯蔗糖、草莓香精、甜橙香精、苹果香精中的任意一种或几种。
本发明还提供一种消旋卡多曲纳米混悬剂的制备方法，其制备步骤如下：
F.将消旋卡多曲微粉化，粒径D90≤20μm；
G.将称取处方量的消旋卡多曲，加入到助溶剂中，充分搅拌溶解，得到溶液A；
H.称取处方量的β-环糊精，加入到一定量水中，水温控制在80-100℃，搅拌30-60min，直至得到澄清溶液B；
I.将溶液A缓慢加入到溶液B中，并加入稳定剂和矫味剂混合，进行高速均质，得到初级混悬液；
J.将得到的初级混悬液加水定容后进行高压均质，得到消旋卡多曲纳米混悬液。
本发明使用潜溶剂法进行纳米混悬剂的制备，其中溶液A中助溶剂与溶液B中水的体积比为1:2-10，优选的助溶剂与水的体积比为1:2-6。
本发明先采用高速均质法得到初级混悬液，所述高速均质法中转速采用6000-10000rpm/min，优选8000rpm/min；均质10-15min，得到粒径范围为350-800nm的初级混悬液；
本发明采用高速均质法联合高压均质法制备消旋卡多曲纳米混悬液，将所得初级纳米混悬液再进行高压均质，所述高压均质法的压力为40-250Mpa，优选80-120Mpa，均质循环10-15次，最终所得消旋卡多曲纳米混悬液的粒径范围为100-250nm。
综上所述，本发明的有益效果为：
本发明采用环糊精包合技术，可以有效掩盖药物的不良气味，并能达到稳定化合物的作用可有效降低有关物质的含量。
本发明采用高速均质联合高压均质的制备方法，可使制剂粒径达到100-200nm，粒径范围较窄，可有效提高制剂剂量精确度。
本发明制备的消旋卡多曲纳米混悬液粒径可控制在200nm以下，药代动力学研究表明，本发明所得制剂T1/2明显延长，生物利用度明显提高，可为减少服药次数提供可靠依据，有利于提高婴幼儿服药的依从性。
附图说明
图1为本发明实施例1-3的沉降容积曲线示意图
具体实施方式
下面将结合发明实施例，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。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1消旋卡多曲纳米混悬液(2mg/ml)的制备
| 物料组成 | 处方配比 |
| 消旋卡多曲 | 0.2g |
| 聚乙二醇400 | 10ml |
| 羧甲基-β-环糊精 | 10g |
| 十二烷基硫酸钠 | 5g |
| 聚乙烯基吡咯烷酮 | 5g |
| 三氯蔗糖 | 1g |
| 草莓香精 | 0.05g |
| 水 | 适量 |
制备工艺：
A.将微粉化的消旋卡多曲0.2g加入到10ml聚乙二醇400中，充分搅拌溶解，得到溶液A。
B.称取10g羧甲基-β-环糊精，加入60ml纯净水，水温控制在80℃，搅拌30-60min，直至得到澄清溶液B。
C.将溶液A缓慢加入到溶液B中，并加入十二烷基硫酸钠5g、聚乙烯基吡咯烷酮5g、三氯蔗糖1g、草莓香精0.05g，以8000rpm/min的转速高速均质15min，得到初级混悬液。
D.将步骤C中所得初级混悬液加入纯净水至100ml，进行高压均质，均质压力为80Mpa，循环均质10次，得到消旋卡多曲纳米混悬剂。
实施例2消旋卡多曲纳米混悬液(4mg/ml)的制备
| 物料组成 | 处方配比 |
| 消旋卡多曲 | 0.4g |
| 聚乙二醇200 | 20ml |
| 羟丙基-β-环糊精 | 20g |
| 十二烷基硫酸钠 | 5g |
| 聚乙烯基吡咯烷酮 | 10g |
| 三氯蔗糖 | 1.5g |
| 草莓香精 | 0.05g |
| 水 | 适量 |
制备工艺同实施例1，区别在于，高压均质条件为压力100Mpa，循环均质10次。
实施例3消旋卡多曲纳米混悬液(6mg/ml)的制备
| 物料组成 | 处方配比 |
| 消旋卡多曲 | 0.6g |
| 聚乙二醇600 | 30ml |
| 羧甲基-β-环糊精 | 30g |
| 十二烷基硫酸钠 | 7g |
| 聚乙烯基吡咯烷酮 | 14g |
| 三氯蔗糖 | 1.5g |
| 草莓香精 | 0.05g |
| 水 | 适量 |
制备工艺同实施例1，区别在于，高压均质条件为压力120Mpa，循环均质15次。
对比例1消旋卡多曲混悬液的制备
采用专利CN103338749B实施例1中的制剂处方及制备方法，制得消旋卡多曲混悬液。
对比例2未采用环糊精包合技术的消旋卡多曲纳米混悬液
将实施例1中的羧甲基-β-环糊精去除，将所得溶液A直接缓慢加入到60ml水中，并加入其他辅料，进行高速均质和高压均质，得到未采用环糊精包合的消旋卡多曲纳米混悬液。
制剂口感评估
取实施例1、对比例1和对比例2所制得混悬液制剂各5ml，选择10名20-40岁健康成年男女作为评估者，要求评估者将5ml液体制剂分三次服用，评估液体制剂的味道，评估结果见表1。
从评估者的口感评价可知，实施例1的口感香甜，对比例均有不同程度的苦味，掩味效果较差，本发明采用环糊精包合技术能够起到较好的掩味效果，制剂口感香甜，有利于提高患者服用的依从性。
制剂稳定性评价
吸取实施例1、实施例2和对比例1制得的混悬液各1ml，采用激光粒度分析仪测定产品的平均粒径和PDI，并对其进行不同放置时间粒径、PDI考察，分析其稳定性，检测结果如表2所示。
本发明采用溶剂-反溶剂法联合高速和高压均质法制得纳米混悬液，从实验结果可知本发明制得的纳米混悬液粒径在200nm以下，且粒径分布较窄，有利于提高液体制剂的稳定性和单位计量的精确度，提高了婴幼儿用药剂量的可控性。
沉降容积比考察
将实施例1、实施例2和实施例3所得纳米混悬剂放于量筒中，混匀，测定混悬剂的总容积V0，静置一段时间后,观察沉降面不再改变时沉降物的容积Vu，公式F＝(Hu/H0)*100％。结果见图1。
本发明实施例所得的纳米混悬液放置30min未见分层，放置3h后，沉降体积比为0.993，沉降曲线比较平和，缓慢降低，所得制剂稳定性良好。
药代动力学实验
使用本发明实施例1制得的消旋卡多曲纳米混悬液和市售消旋卡多曲散进行体内药动学和生物利用度研究，对服用消旋卡多曲散和消旋卡多曲纳米混悬液后不同时间点进行血药浓度测定，从而对比两种剂型产品在体内生物利用度。
实验材料：消旋卡多曲散(Bioprojet pharma生产，10mg规格)，自制消旋卡多曲纳米混悬液(实施例1制备的消旋卡多曲纳米混悬液)；
试验动物：健康家兔，体质量2kg±0.2kg，共8只(雄4只，雌4只)
试验方法：将家兔按照雌雄随机分两组，每组2只雄兔和2只雌兔，按照1.5mg/kg剂量给两组家兔分别服用旋卡多曲散和消旋卡多曲纳米混悬液。服药前0.5h试验动物完成进食，服药后于0.25、0.5、1、1.5、2、2.5、3、4、6、8、12、24h共计12个时间点分别从家兔耳缘静脉取血2.5ml，进行离心处理后得到血浆样品。
采用LC-MS测定血药浓度，采用Phoenix1.3软件计算给药后的药代动力学参数，体内药代动力学测试结果见表3。
家兔体内的药代动力学和相对生物利用度实验结果表明，口服本发明所制备的消旋卡多曲纳米混悬剂在家兔体内的Cmax较散剂增加1.61倍，AUC0-t较散剂增加2.35倍，纳米混悬剂相对于散剂的相对生物利用度F为214％。上述结果表明，本发明制备的消旋卡多曲纳米混悬剂较散剂在药效的发挥上更具优势，具有更高的生物利用度。纳米混悬剂的T1/2相比于散剂明显延长，已接近5小时，为临床减少服药次数给出了依据。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种消旋卡多曲纳米混悬液，其特征在于，以质量百分比计，包含以下原料：消旋卡多曲0.1-0.6％、助溶剂10-40％、β-环糊精10-35％、稳定剂10-25％、矫味剂0.5-3％和水适量。
2.按照权利要求1所述的一种消旋卡多曲纳米混悬液，其特征在于，所述助溶剂为相对分子量为200-600范围内的聚乙二醇。
3.按照权利要求1所述的一种消旋卡多曲纳米混悬液，其特征在于，所述β-环糊精为羟丙基-β-环糊精、羟乙基-β-环糊精、羧甲基-β-环糊精或磺丁基醚-β-环糊精中的一种。
4.按照权利要求1所述的一种消旋卡多曲纳米混悬液，其特征在于，所述稳定剂可选用十二烷基磺酸钠、十二烷基硫酸钠、泊洛沙姆、聚乙烯基吡咯烷酮、吐温80、聚乙烯醇、聚山梨酯等中的一种或多种。
5.按照权利要求4所述的一种消旋卡多曲纳米混悬液，其特征在于，所述稳定剂选用十二烷基硫酸钠和聚乙烯基吡咯烷酮，十二烷基硫酸钠和聚乙烯基吡咯烷酮的质量比为1:1-2。
6.按照权利要求1所述的一种消旋卡多曲纳米混悬液，其特征在于，所述矫味剂可选用蔗糖、山梨醇、木糖醇、葡萄糖、果糖、麦芽糖醇、阿斯巴甜、糖精、糖精钠、液体麦芽糖醇、三氯蔗糖、草莓香精、甜橙香精、苹果香精中的任意一种或几种。
7.一种如权利要求1所述消旋卡多曲纳米混悬液的制备方法，其特征在于，包含以下制备步骤：
A.将消旋卡多曲微粉化，粒径D90≤20μm；
B.将称取处方量的消旋卡多曲，加入到助溶剂中，充分搅拌溶解，得到溶液A；
C.称取处方量的β-环糊精，加入到一定量水中，水温控制在80-100℃，搅拌30-60min，直至得到澄清溶液B；
D.将溶液A缓慢加入到溶液B中，并加入稳定剂和矫味剂混合，进行高速均质，得到初级混悬液；
E.将得到的初级混悬液加水定容后进行高压均质，得到消旋卡多曲纳米混悬液。
8.按照权利要求7所述的一种消旋卡多曲纳米混悬液的制备方法，其特征在于，溶液A中助溶剂与溶液B中水的体积比为1:2-10，优选的助溶剂与水的体积比为1:2-6。
9.按照权利要求7所述的一种消旋卡多曲纳米混悬液的制备方法，其特征在于，所述高速均质法中转速采用6000-10000rpm/min，优选8000rpm/min；均质10-15min，得到粒径范围为350-800nm的初级混悬液。
10.按照权利要求7所述的一种消旋卡多曲纳米混悬液的制备方法，其特征在于，所述高压均质法的压力为40-250Mpa，优选80-120Mpa，均质循环10-15次，最终所得消旋卡多曲纳米混悬液的粒径范围为100-250nm。
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