CN102805731B - 泊沙康唑干混悬剂及其制备方法 - Google Patents
泊沙康唑干混悬剂及其制备方法 Download PDFInfo
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- 229960001589 posaconazole Drugs 0.000 title claims abstract description 38
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 34
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 18
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Abstract
本发明涉及一种泊沙康唑干混悬剂及其制备方法，该干混悬剂包括泊沙康唑20%～40%、填充剂5%～50%、助悬剂10%～40%、阴离子表面活性剂0.5%～3%、防腐剂0.01%～1.5%、pH调节剂0.1%～10%、遮光剂1%～5%和絮凝剂1%～5%。本发明提供的泊沙康唑干混悬剂以固体形式储存，而以混悬液形式供口服，给运输带来了方便，特别适用于儿童、老人和部分有吞咽困难的患者服用。
Description
技术领域
本发明涉及治疗真菌的药物制剂，尤其涉及一种泊沙康唑干混悬剂及其制备方法。
背景技术
泊沙康唑(posaconazole)是2006年9月15日由美国FDA批准的一种广谱三唑类抗真菌药,用于难治性疾病或其他药物耐药所引起的真菌感染(如曲霉菌病、结核菌病和镰刀菌病等),该药由美国Schering-Plough公司研制上市,商品名为Noxafil。泊沙康唑是一种新的化学分子实体，是第一个被FDA批准的用于预防由侵袭性曲霉菌引起病变的抗菌药物，属于高亲脂性第二代抗真菌药，与其他唑类抗菌药物相同，该药也是通过与羊毛甾醇14α-脱甲基酶(CYP51或Erg11p)活性部位的血红素辅助因子结合，抑制真菌麦角甾醇的生物合成，破坏细胞膜的形成和完整性而起到抗菌作用。泊沙康唑克服了第一代三唑类药物抗菌谱窄、生物利用度低及耐药性等问题，其抗真菌的作用无论是在体内和体外都已经被证实具有广谱的活性，对念珠菌、各种曲霉菌及其他常见的和非常见的致病真菌均有较大活性。
本品安全性好，无明显的肝、肾毒性，耐受性好，可用于需长期治疗的患者。在预防免疫功能缺陷（粒细胞缺乏、移植后使用免疫抑制剂或HIV感染）患者的深部真菌感染方面，本品疗效优于氟康唑或伊曲康唑。
发明内容
泊沙康唑由于在水中溶解度极低，因此制成的片剂生物利用率很低，目前只有口服混悬剂。但是口服悬浮剂采用玻璃包装，易碎，不易运输，且受温度影响较大，低温时候易冻凝，不易保存。因此，临床需要开发出一种新的剂型，即干混悬剂。干混悬剂既有制剂（颗粒）的特点，方便携带，运输方便，稳定性好，又有液体制剂的优势（方便服用，适合于吞咽有困难的患者，如老人与儿童）。
本发明的目的是就是提供一种泊沙康唑干混悬剂及其制备方法，包括泊沙康唑、至少一种助悬剂、至少一种阴离子表面活性剂、至少一种遮光剂、至少一种防腐剂、一组缓冲体系及其一些常用辅料填充剂、矫味剂、甜味剂等等。
本发明泊沙康唑干混悬剂中的泊沙康唑几乎不溶于水，故需要对其微粉化，使其粒径99%的小于或等于20μm，重重95%小于或等于10μm，其用量为总重量的20%～40%。
所述助悬剂有黄原胶、羧甲纤维素钠、阿拉伯胶、海藻酸钠、羟丙甲基纤维素、羟甲基纤维素、聚乙烯吡咯烷酮中的一种或多种混合，其用量为10%～40%。
适合的表面活性剂是聚山梨酯、脂肪酸山梨坦、十二烷基硫酸钠，其中优选的是十二烷基硫酸钠，在干混悬剂中表面活性剂与总质量比是0.5%～3%，其中优选的是1%。
适合的填充剂包含淀粉、乳糖、蔗糖、微晶纤维素、木糖醇、甘露醇中的一种或多种混合，干混悬剂中填充剂与总质量比是5%～50%。
适合的遮光剂为含金属离子的二氧化钛，占总质量比为1%～5%，优选为2%。
适合的防腐剂包含苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、苯扎氯铵和一些药学上可接受的水溶性的防腐剂，我们选择苯甲酸钠，干混悬剂中防腐剂与总质量比为0.01%～1.5%，优先选择1%。
适合的pH调节剂为枸橼酸、酒石酸中的一种或多种，其用量为0.1%～10%。
适合的絮凝剂为枸橼酸钠或酒石酸钾，其用量1%～5%。
选择矫味剂为草莓味香精、奶油味香精等等，用量为0.1%～2%，适量即可。
本发明还公开了泊沙康唑干混悬剂的制备方法：将所述的配比的已微粉化的泊沙康唑、助悬剂、填充剂、絮凝剂、甜味剂、pH调节剂、防腐剂、遮光剂和矫味剂干燥混匀后，过100～200目筛，分装即可。
具体实施方式：
下面以具体实施例对本发明进行进一步详细说明，但本发明包括但不限于这些实施例。
实施例1
| 处方 | mg/袋 | %wt |
| 泊沙康唑 | 200 | 40 |
| 羟丙甲基纤维素 | 200 | 40 |
| 蔗糖 | 62.5 | 12.5 |
| 十二烷基硫酸钠 | 5 | 1 |
| 枸橼酸钠一水合物 | 10 | 2 |
| 枸橼酸一水合物 | 3.5 | 0.7 |
| 苯甲酸钠 | 5 | 1 |
| 二氧化钛 | 10 | 2 |
| 草莓味香精 | 4 | 0.8 |
| 500 | 100 |
制成1000袋。
制备方法：将所述的配比的已微粉化的泊沙康唑、羟丙甲基纤维素、蔗糖、枸橼酸钠一水合物、枸橼酸一水合物、十二烷基硫酸钠、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
实施例2
| 处方 | mg/袋 | %wt |
| 泊沙康唑 | 200 | 40 |
| 果原胶 | 200 | 40 |
| 木糖醇 | 62.5 | 12.5 |
| 十二烷基硫酸钠 | 5 | 1 |
| 枸橼酸钠一水合物 | 10 | 2 |
| 枸橼酸一水合物 | 3.5 | 0.7 |
| 苯甲酸钠 | 5 | 1 |
| 二氧化钛 | 10 | 2 |
| 草莓味香精 | 4 | 0.8 |
| 500 | 100 |
制成1000袋。
制备方法：将所述的配比的已微粉化的泊沙康唑、果原胶、木糖醇、枸橼酸钠一水合物、枸橼酸一水合物、十二烷基硫酸钠、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
实施例3
| 处方 | mg/袋 | %wt |
| 泊沙康唑 | 200 | 40 |
| 羟丙甲基纤维素 | 200 | 40 |
| 蔗糖 | 62.5 | 12.5 |
| 十二烷基硫酸钠 | 5 | 1 |
| 酒石酸 | 8 | 1.6 |
| 酒石酸钾 | 5.5 | 1.1 |
| 苯甲酸钠 | 5 | 1 |
| 二氧化钛 | 10 | 2 |
| 草莓味香精 | 4 | 0.8 |
| 500 | 100 |
制成1000袋。
制备方法：将所述的配比的已微粉化的泊沙康唑、羟丙甲基纤维素、蔗糖、酒石酸、酒石酸钾、十二烷基硫酸钠、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
实施例4
| 处方 | mg/袋 | %wt |
| 泊沙康唑 | 100 | 20 |
| 羟甲基纤维素 | 150 | 30 |
| 蔗糖 | 162.5 | 32.5 |
| 微晶纤维素 | 50 | 10 |
| 十二烷基硫酸钠 | 5 | 1 |
| 枸橼酸钠一水合物 | 10 | 2 |
| 枸橼酸一水合物 | 3.5 | 0.7 |
| 苯甲酸钠 | 5 | 1 |
| 二氧化钛 | 10 | 2 |
| 草莓味香精 | 4 | 0.8 |
| 500 | 100 |
制成1000袋。
制备方法：将所述的配比的已微粉化的泊沙康唑、羟甲基纤维素、蔗糖、枸橼酸钠一水合物、枸橼酸一水合物、十二烷基硫酸钠、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100-200目筛，分装即可。
实施例5
| 处方 | mg/袋 | %wt |
| 泊沙康唑 | 150 | 30 |
| 羟丙甲基纤维素 | 150 | 30 |
| 蔗糖 | 62.5 | 12.5 |
| 微晶纤维素 | 105 | 21 |
| 十二烷基硫酸钠 | 5 | 1 |
| 枸橼酸钠一水合物 | 10 | 2 |
| 枸橼酸一水合物 | 3.5 | 0.7 |
| 二氧化钛 | 10 | 2 |
| 奶油味香精 | 4 | 0.8 |
| 500 | 100 |
制成1000袋。
制备方法：
（1） 将所述的配比的已微粉化的泊沙康唑、羟丙甲基纤维素、蔗糖、微晶纤维素、枸橼酸钠一水合物、枸橼酸一水合物和十二烷基硫酸钠干燥混匀后，过100～200目筛；
（2） 将步骤（1）的混合物加入适量水，制软材，然后用18目筛制粒，烘干成为干燥颗粒；
（3） 将步骤（2）的干燥颗粒再与处方量的苯甲酸钠、二氧化钛、奶油味香精混匀后，分装即可。
质量评定
1、按照《中国药典》2010年版二部附录口服混悬剂的要求，应检查沉降体积比，具体方法如下：取供试品5袋，倒出内容物置50ml具塞比色管中，加入水50ml，强力振摇，应均匀分散，记录起始高度H0，静置1小时、3小时、5小时、7小时、24小时记录溶液的高度H，H/H0应不低于0.9，即可判断符合规定。
24小时的沉降体积比的数据
| 时间（h） | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 |
| 0 | 0.97 | 0.95 | 0.94 | 0.97 | 0.96 |
| 1 | 0.96 | 0.95 | 0.94 | 0.97 | 0.96 |
| 3 | 0.94 | 0.94 | 0.93 | 0.95 | 0.95 |
| 5 | 0.94 | 0.93 | 0.92 | 0.95 | 0.95 |
| 7 | 0.94 | 0.93 | 0.92 | 0.94 | 0.95 |
| 24 | 0.93 | 0.93 | 0.92 | 0.94 | 0.94 |
2、我们选择实施例1～5供试品除去内包装，直接用泊沙康唑干混悬剂的按照影响因素试验各条件放置10天。
考察项目：性状、吸湿增重（高湿条件下考察）、沉降体积比、有关物质、含量
实施例1影响因素试验记录结果
实施例2影响因素试验记录结果
实施例3影响因素试验记录结果
实施例4影响因素试验记录结果
实施例5影响因素试验记录结果
实施例1-5 样品在影响因素试验下各条件下，除了在高湿条件下，吸湿增重比较明显外，其余指标与0天比较，均没有什么变化趋势，只要在包装考虑防潮即可，因此我们选择铝塑包装。
Claims (2)
1.泊沙康唑干混悬剂，其特征在于每袋的处方为泊沙康唑200mg，羟丙甲基纤维素200mg，蔗糖62.5mg, 十二烷基硫酸钠5mg，枸橼酸钠一水合物10mg，枸橼酸一水合物3.5mg，苯甲酸钠5mg， 二氧化钛10mg，草莓味香精4mg，每袋500mg，将所述的配比的已微粉化的泊沙康唑、羟丙甲基纤维素、蔗糖、十二烷基硫酸钠、枸橼酸钠一水合物、枸橼酸一水合物、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
2.泊沙康唑干混悬剂，其特征在于每袋的处方为泊沙康唑200mg，果原胶200mg，木糖醇62.5mg, 十二烷基硫酸钠5mg，枸橼酸钠一水合物10mg，枸橼酸一水合物3.5mg，苯甲酸钠5mg， 二氧化钛10mg，草莓味香精4mg，每袋500mg，将所述的配比的已微粉化的泊沙康唑、果原胶、木糖醇、十二烷基硫酸钠、枸橼酸钠一水合物、枸橼酸一水合物、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
3. 泊沙康唑干混悬剂，其特征在于每袋的处方为泊沙康唑200mg，羟丙甲基纤维素200mg，蔗糖62.5mg, 十二烷基硫酸钠5mg，酒石酸8mg，酒石酸钾5.5mg，苯甲酸钠5mg， 二氧化钛10mg，草莓味香精4mg，每袋500mg，将所述的配比的已微粉化的泊沙康唑、羟丙甲基纤维素、蔗糖、十二烷基硫酸钠、酒石酸、酒石酸钾、苯甲酸钠、二氧化钛和草莓味香精干燥混匀后，过100～200目筛，分装即可。
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