CN115300460B - 一种泊沙康唑口服混悬液及其制备方法 - Google Patents
一种泊沙康唑口服混悬液及其制备方法 Download PDFInfo
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- CN115300460B CN115300460B CN202211237570.3A CN202211237570A CN115300460B CN 115300460 B CN115300460 B CN 115300460B CN 202211237570 A CN202211237570 A CN 202211237570A CN 115300460 B CN115300460 B CN 115300460B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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Abstract
本发明公开了一种泊沙康唑口服混悬液及其制备方法，属于医药制剂技术领域，具体包括泊沙康唑，稳定剂，助稳定剂，增溶剂，助悬剂，pH调节剂，甜味剂，甘油和水；所述稳定剂为羟基乙基淀粉钠，辛酸癸酸聚乙二醇甘油酯，月桂酸聚乙二醇甘油酯中的一种或几种，所述助稳定剂为脱氧胆酸钠；所述混悬液的pH为4‑5.4。本发明泊沙康唑口服混悬液不易沉降，长期储存物理稳定性好，载药量高，药物均一性好，制备工艺简单，保证患者服用的安全有效，适合工业大规模生产。
Description
技术领域
本发明属于医药制剂技术领域，具体地说，涉及一种泊沙康唑口服混悬液及其制备方法。
背景技术
泊沙康唑是第二代三唑类抗真菌药物，为伊曲康唑的衍生物，适用于深层真菌感染(如侵袭性曲霉菌、镰刀菌、酵母菌、分枝菌、球孢子菌)的治疗，也适用于13岁和13岁以上因重度免疫缺陷而导致这些感染风险增加的患者。这些患者包括接受造血干细胞移植(HSCT)后发生移植物抗宿主病(GVHD)的患者或化疗导致长时间中性粒细胞减少症的血液系统恶性肿瘤患者。泊沙康唑的作用机理主要是减少麦角甾醇的合成而发挥作用。麦角甾醇是真菌细胞合成的过程中必不可少的物质，其参与细胞上一些重要蛋白质的合成，是真菌细胞中必须的物质。当泊沙康唑作用于真菌细胞后，与真菌内羊毛甾醇14α-去甲基化酶相竞争作用，降低其活性，使细胞内羊毛甾醇积累而麦角甾醇缺少，导致细胞膜无法合成，从而发挥泊沙康唑药效。
泊沙康唑，化学名称为4-[4-[4-[4-[[(3R,5R)-5-(2,4- 二氟苯基) 四氢-5-(1H-1,2,4 三唑-1- 基甲基)-3- 呋喃] 甲氧基] 苯基]-1- 哌嗪基] 苯基]-2-[(1S,2S)-1-乙基-2- 羟基丙基]-2,4- 二氢-3H-1,2,4- 三唑-3- 酮，其结构式为：
泊沙康唑难溶于水，一般制成口服混悬液。目前上市销售的泊沙康唑口服混悬液（商品名Noxafil），其辅料包括：吐温80、聚二甲硅氧烷、苯甲酸钠、柠檬酸钠二水合物、柠檬酸一水合物、甘油、黄原胶、液体葡萄糖、二氧化钛、人造樱桃芳香剂和水，该制剂处方重现性差，且存在物理稳定性较差等缺陷。
混悬液体系的热力学存在不稳定性的问题，开发难度大，因此，需要进一步研究泊沙康唑口服混悬液，得到一种物理稳定的泊沙康唑口服混悬液。
发明内容
鉴于此，本发明提供一种泊沙康唑口服混悬液，旨在解决泊沙康唑口服混悬液载药量低，容易沉降，均一性差的问题。本发明泊沙康唑口服混悬液不易沉降，长期储存物理稳定性好，载药量高，药物均一性好，制备工艺简单，保证患者服用的安全有效，适合工业大规模生产。
本发明提供一种泊沙康唑口服混悬液，该口服混悬液具体包括泊沙康唑，稳定剂，助稳定剂，增溶剂，助悬剂，pH调节剂，甜味剂，甘油和水；其中，所述稳定剂为羟基乙基淀粉钠，辛酸癸酸聚乙二醇甘油酯，月桂酸聚乙二醇甘油酯中的一种或几种，所述助稳定剂为脱氧胆酸钠；所述混悬液的pH为4-5.4。
泊沙康唑溶解呈pH依赖性，在酸性条件下溶解性高，碱性条件下溶解性低，本发明为了增加泊沙康唑的溶解性，采用pH调节剂将混悬液体系调节pH为4-5.4，然而随着泊沙康唑溶解性增加，体系中的物理稳定性和均一性受到挑战，这给泊沙康唑口服混悬液体系开发增加了难度。为了保证泊沙康唑口服混悬液体系有较大的载药量，同时还要兼顾混悬液的沉降性能，使其长期储存稳定，发明人经过大量研究，发现当稳定剂为羟基乙基淀粉钠，辛酸癸酸聚乙二醇甘油酯，月桂酸聚乙二醇甘油酯中的一种或几种以及助稳定剂为脱氧胆酸钠能够显著提高泊沙康唑口服混悬剂的长期储存稳定性。
上述的泊沙康唑口服混悬液中，所述稳定剂为羟基乙基淀粉钠和辛酸癸酸聚乙二醇甘油酯；其中，羟基乙基淀粉钠和辛酸癸酸聚乙二醇甘油酯可以为任意用量比例，优选的，羟基乙基淀粉钠和辛酸癸酸聚乙二醇甘油酯的质量用量比为1:0.5-2。
上述的泊沙康唑口服混悬液中，所述稳定剂与助稳定剂的质量用量比为1-4:1。
上述的泊沙康唑口服混悬液中，所述增溶剂为卵磷脂，大豆磷脂、吐温80，聚氧乙烯氢化蓖麻油，泊洛沙姆中的一种或几种。
为了增加泊沙康唑口服混悬液的均一性，所述助悬剂为西黄蓍胶，魔芋胶中的一种或两种。
上述的泊沙康唑口服混悬液中，所述的pH调节剂为本领域常规物质，pH 调节剂可将混悬液体系的pH调节为4-5.4，优选的，pH调节剂为柠檬酸和柠檬酸钠。
上述的泊沙康唑口服混悬液中，所述甜味剂为薄荷香精，甘草甜素，香蕉香精，菠萝香精，橙味香精，柠檬香精，蓝莓香精，甜菊糖，安赛蜜中的一种或几种。
上述的泊沙康唑口服混悬液中，所述泊沙康唑口服混悬液中含有各组分的用量为：泊沙康唑为40-80mg/mL，稳定剂为5-15 mg/mL，助稳定剂为3-10mg/mL，增溶剂为7-15mg/mL，助悬剂为2-6 mg/mL，pH调节剂为将混悬液调节至4-5.4的量，甜味剂为2-6mg/mL，甘油为80-120mg/mL，水适量。
上述的泊沙康唑口服混悬液中，所述泊沙康唑口服混悬液中含有各组分的用量为：泊沙康唑为50-80mg/mL，稳定剂为5-15 mg/mL，助稳定剂为3-10mg/mL，增溶剂为7-15mg/mL，助悬剂为2-6 mg/mL，pH调节剂为将混悬液调节至4-5.4的量，甜味剂为2-6mg/mL，甘油为80-120mg/mL，水适量。
本发明还提供一种上述泊沙康唑口服混悬液的制备方法，方法包括以下步骤：
（1）将泊沙康唑加到甘油中混合均匀，再加入增溶剂，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入助悬剂，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入pH调节剂，混合均匀使溶解完全，再加入稳定剂和助稳定剂混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入甜味剂，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
与现有技术相比，本发明的有益效果为：
本发明通过pH调节剂控制口服混悬液的体系pH为4-5.4，增加了泊沙康唑的溶解度，并通过加入稳定剂和助稳定剂的配合，使口服混悬液体系在较大载药量情况下还会保持较好的长期储存稳定性，不易沉降，保证患者服用的安全有效。
具体实施方式
实施例1
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入吐温80，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入西黄蓍胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入羟基乙基淀粉钠、辛酸癸酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入香蕉香精，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
实施例2
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入聚氧乙烯氢化蓖麻油，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入魔芋胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入羟基乙基淀粉钠、辛酸癸酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入香蕉香精，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
实施例3
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入泊洛沙姆，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入西黄蓍胶和魔芋胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入羟基乙基淀粉钠、辛酸癸酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入蓝莓香精，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
实施例4
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入卵磷脂，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入西黄蓍胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入月桂酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入柠檬香精，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
实施例5
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入大豆磷脂，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入魔芋胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入羟基乙基淀粉钠、月桂酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入橙味香精，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
实施例6
制备方法：
（1）将泊沙康唑加到甘油中混合均匀，再加入吐温80和卵磷脂，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入西黄蓍胶，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入柠檬酸和柠檬酸钠，混合均匀使溶解完全，再加入羟基乙基淀粉钠、辛酸癸酸聚乙二醇甘油酯和脱氧胆酸钠混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入安赛蜜，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
对比例
制备方法同实施例1。
稳定性考察
将实施例和对比例样品，置于相对湿度（RH）为65%±5%、温度为30℃±2℃培养箱中连续放置24个月，分别于0月、6月、24月观察溶液稳定性情况，观察时将样品振摇后静置2.5h，观察样品的沉降情况。具体如下：
对上述实施例和对比例得到的样品进行长期储存稳定性考察得出，本发明实施例1-6以及对比例7-8中加入稳定剂以及助稳定剂，通过稳定剂和助稳定剂的配合，可以使得到的混悬液具有较好的沉降性能，长期储存的物理稳定性好，保证患者的用药安全。
均一性考察
将实施例和对比例制得的样品，振摇15秒，分别于瓶子的上部、中间和底部取样，照含量测定项下的实验结果如下，每一部位含泊沙康唑应为标示量的95.0-105.0%。
由上述实验结果可知，本发明加入助悬剂为西黄芪胶和/或魔芋胶能显著改善泊沙康唑口服混悬液的均一性，保证患者的用药安全。
Claims (6)
1.一种泊沙康唑口服混悬液，其特征在于，包括泊沙康唑，稳定剂，助稳定剂，增溶剂，助悬剂，pH调节剂，甜味剂，甘油和水；其中，所述稳定剂为羟基乙基淀粉钠，辛酸癸酸聚乙二醇甘油酯，月桂酸聚乙二醇甘油酯中的一种或几种，所述助稳定剂为脱氧胆酸钠；所述混悬液的pH为4-5.4；所述稳定剂与助稳定剂的质量用量比为1-4:1；所述助悬剂为西黄蓍胶，魔芋胶中的一种或两种；所述增溶剂为卵磷脂，大豆磷脂，吐温80，聚氧乙烯氢化蓖麻油，泊洛沙姆中的一种或几种；所述泊沙康唑口服混悬液中含有各组分的用量为：泊沙康唑为40-80mg/mL，稳定剂为5-15 mg/mL，助稳定剂为3-10mg/mL，增溶剂为7-15 mg/mL，助悬剂为2-6mg/mL，pH调节剂为将混悬液调节至4-5.4的量，甜味剂为2-6mg/mL，甘油为80-120mg/mL，水适量。
2.根据权利要求1所述的泊沙康唑口服混悬液，其特征在于，所述稳定剂为羟基乙基淀粉钠和辛酸癸酸聚乙二醇甘油酯。
3.根据权利要求1所述的泊沙康唑口服混悬液，其特征在于，所述pH调节剂为柠檬酸和柠檬酸钠。
4.根据权利要求1所述的泊沙康唑口服混悬液，其特征在于，所述甜味剂为薄荷香精，甘草甜素，香蕉香精，菠萝香精，橙味香精，柠檬香精，蓝莓香精，甜菊糖，安赛蜜中的一种或几种。
5.根据权利要求1所述的泊沙康唑口服混悬液，其特征在于，所述泊沙康唑口服混悬液中含有各组分的用量为：泊沙康唑为50-80mg/mL，稳定剂为5-15 mg/mL，助稳定剂为3-10mg/mL，增溶剂为7-15 mg/mL，助悬剂为2-6 mg/mL，pH调节剂为将混悬液调节至4-5.4的量，甜味剂为2-6mg/mL，甘油为80-120mg/mL，水适量。
6.一种权利要求1所述泊沙康唑口服混悬液的制备方法，其特征在于，方法包括以下步骤：
（1）将泊沙康唑加到甘油中混合均匀，再加入增溶剂，混合均匀，得主药溶液；
（2）将步骤（1）中的主药溶液在快速搅拌下加入水中，得主药混悬液；
（3）将步骤（2）得到的主药混悬液研磨，形成均一乳状混悬液；
（4）向步骤（3）中得到的均一乳状混悬液中加入助悬剂，使充分溶胀，得胶液；
（5）向步骤（4）得到的胶液中加入pH调节剂，混合均匀使溶解完全，再加入稳定剂和助稳定剂混合均匀，得混合体系；
（6）向步骤（5）得到的混合体系中加入甜味剂，混合均匀及分散匀化处理，得泊沙康唑口服混悬液。
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