CN106236732A - 一种依维莫司软胶囊的制备方法 - Google Patents
一种依维莫司软胶囊的制备方法 Download PDFInfo
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- CN106236732A CN106236732A CN201610769371.5A CN201610769371A CN106236732A CN 106236732 A CN106236732 A CN 106236732A CN 201610769371 A CN201610769371 A CN 201610769371A CN 106236732 A CN106236732 A CN 106236732A
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- everolimus
- soft capsule
- utricule
- acid
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Abstract
本发明涉及一种依维莫司软胶囊的制备方法。步骤：以明胶、硬酯酸、大豆蛋白、甘油和纯水为囊体原料，制作得到囊体；根据处方得到混合均匀的内容物；将内容物及囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到软胶囊。本发明制备得到的依维莫司软胶囊具有稳定性好，性状稳定的优点。本发明的治疗肿瘤、免疫抑制剂的药物组合，配比合理，可以快速释放药物，对所述病症能产生很好的疗效。
Description
技术领域
本发明属于医药技术领域，具体涉及一种依维莫司软胶囊的制备方法。
依维莫司(Everolimus)，化学名：40-O-(2-羟乙基)-雷帕霉素，分子式:C53H83NO14，分子量：958.2244。是用于治疗肿瘤、免疫抑制剂的三类新药，目前正在进行临床前研究。
背景技术
依维莫司临床上主要用来预防肾移植和心脏移植手术后的排斥反应。其作用机制主要包括免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用。常与环孢素等其他免疫抑制剂联合使用以降低毒性。
与西罗莫司相比，依维莫司的药物代谢动力学更加优越。
依维莫司由瑞士诺华公司（Novartis）最先研制开发，有片剂和分散片等剂型。商品名Certican。2003年首次在瑞典上市，在2006年已全面占领欧洲市场。
依维莫司(Everolimus)是一种大环内酯类药物，结构上属于雷帕霉素(rapamycin)的衍生物，故又称为40-O-(2-羟乙基)-雷帕霉素，功能上其属于mTOR激酶抑制剂，作用机制主要是与细胞内蛋白FKBP-12结合形成抑制复合物，从而抑制mTOR激酶的活性，降低mTOR的下游效应物S6核糖体蛋白激酶(S6K1)和真核延伸因子4E结合蛋白(4E-BP)的活性，干扰癌细胞的生长、分化和代谢，发挥抗肿瘤效应。研究显示，依维莫司具有免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用等。目前，临床上依维莫司主要用来预防有轻中度免疫排斥风险的肾脏移植患者出现的肾脏移植的排异反应，以及用于舒尼替尼或索拉非尼治疗无效的晚期肾癌患者。此外，依维莫司在美国也获批共计6个适应症（晚期乳腺癌、内分泌肿瘤、肾细胞癌、肾血管肌脂肪瘤和结节性硬化症）。
此外，除了肾细胞癌，依维莫司也正在进行对神经内分泌肿瘤、淋巴瘤、其他癌症以及结节性硬化症的研究，可作为单一制剂或者与现有的癌症治疗方法合用。 作为研究药物，依维莫司的安全性和有效性还没有在肿瘤领域完全建立起来，现在正处于严格控制和监测进行的临床试验阶段。这些试验的设计是为了更好地理解该化合物的潜在效益以及相应的风险。由于临床试验的不确定性，现在还不能确保依维莫司可以作为肿瘤适应症的药品在全球范围商业出售。
【专利及市场分析】依维莫司化合物及其制剂专利于2016年过期，国内申报家数较少，原料药存在合成技术壁垒。依维莫司已批准用于晚期乳腺癌、内分泌肿瘤、肾细胞癌、肾血管肌脂肪瘤和结节性硬化症等。后续还在继续开发其他适应症，应用前景非常广泛。2010年该药的销售额为297.1百万美元，2011年销售额为492.4百万美元。销售额增长较快，预测前景较好。
发明内容
本发明的目的是：提供一种稳定性好的依维莫司软胶囊的制备方法，主要是通过加入稳定性组分来实现上述目的。
技术方案是：
一种依维莫司软胶囊的制备方法，包括如下步骤：
第1步，制作囊体：按重量份计，以明胶15～25份、硬酯酸3～6份、大豆蛋白2～3份、甘油10～25份和纯水10～15份为囊体原料，将甘油和纯水注入溶胶罐内，加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：配制内容物：按重量份计，将大豆油30～90份、不饱和脂肪酸4～9份、依维莫司1～5份及甘油5～20份进行混合，过胶体磨，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
所述的第1步中，搅拌加热的温度是60～70℃。
所述的第2步中，不饱和脂肪酸选自二十二碳六烯酸、二十碳五烯酸、鱼油、亚麻籽油、琉璃苣油、α-亚麻酸、γ-亚麻酸、共轭亚油酸或者锯叶棕提取物。
所述的第2步中，混合时的温度50～70℃，混合时间20～40min，过胶体磨的次数是1～3次。
本发明制备得到的依维莫司软胶囊具有稳定性好，性状稳定的优点。
具体实施方式
本发明的软胶囊的内容物，除了上述的成分之外，根据实际的应用需要，还可以包含其它的添加物组分，所述的添加物组分可以包含一种或多种适合食物的其他组分。这些包括抗氧化剂、乳化剂、防腐剂、甜味剂、香精、pH调节剂等。添加物组分在与组合物混合后的混合物所占的重量百分比范围可以为最大89wt%，例如10～89wt%，更优选是20～75wt%。
抗氧化剂的可以采用生育酚类如α-生育酚、α-生育酚棕榈酸酯、α-生育酚乙酸酯，叔丁基羟基甲苯，叔丁基羟基茴香醚，抗坏血酸、其盐和酯，例如抗坏血酸钠、抗坏血酸钙、抗坏血酰磷酸酯、抗坏血酸的脂肪酸酯如抗坏血酰硬脂酸酯和抗坏血酰棕榈酸酯以及乙氧基喹。
乳化剂的实例尤其是亲油性分散剂，例如是抗坏血酸的脂肪酸酯如抗坏血酰棕榈酸酯，聚甘油脂肪酸酯如聚甘油-3-聚蓖麻醇酸酯，脱水山梨醇脂肪酸酯，尤其是脱水山梨醇C10～C28脂肪酸酯。
作为pH调节剂，可被包括在本发明的制剂组合物中以提高或降低本发明的制剂组合物的pH。所述制剂组合物的pH可被降低或提高，用于感官觉察的作用，或者用于改善理化特性，例如增加溶解的化合物的溶解度。pH调节剂可以是指酸化剂或碱化剂。例如，乳酸、柠檬酸、苹果酸、氢氧化钾、氢氧化钙和氢氧化镁。
防腐剂，可任选地包括在本发明的制剂组合物中的防腐剂的非限定性实例包括：醋酸、柠檬酸、苯甲酸、山梨酸、二氧化硫、苯甲酸钾、山梨酸钾。
作为香精，优选使用1种或2种以上天然香精、合成香精等油脂香精和粉末香精，但并无特别限定。例如，冬青油、肉桂油、薄荷醇油、绿薄荷油、酸橙油、薰衣草油、草莓油、香兰酮。
作为甜味剂，优选常用甜味剂，例如从麦芽糖醇、蔗糖、葡萄糖、葡聚糖选出的至少1种。
实施例1
依维莫司软胶囊的制备方法，步骤：
第1步，制作囊体：按重量份计，以明胶15份、硬酯酸3份、大豆蛋白2份、甘油10份和纯水10份为囊体原料，将甘油和纯水注入溶胶罐内，60℃加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：配制内容物：按重量份计，将大豆油85份、γ-亚麻酸4份、依维莫司1份、及甘油20份在50℃下进行混合，混合时间20min，过胶体磨3次，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
实施例2
依维莫司软胶囊的制备方法，步骤：
第1步，制作囊体：按重量份计，以明胶25份、硬酯酸6份、大豆蛋白3份、甘油25份和纯水15份为囊体原料，将甘油和纯水注入溶胶罐内，70℃加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：配制内容物：按重量份计，将大豆油85份、γ-亚麻酸4份、依维莫司1份、及甘油20份在50℃下进行混合，混合时间20min，过胶体磨3次，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
实施例3
依维莫司软胶囊的制备方法，步骤：
第1步，制作囊体：按重量份计，以明胶20份、硬酯酸5份、大豆蛋白3份、甘油20份和纯水12份为囊体原料，将甘油和纯水注入溶胶罐内，65℃加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：配制内容物：按重量份计，将大豆油90份、γ-亚麻酸4份、依维莫司1份、及甘油15份在50℃下进行混合，混合时间20min，过胶体磨3次，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
实施例4
依维莫司软胶囊的制备方法，步骤：
第1步，制作囊体：按重量份计，以明胶20份、硬酯酸5份、大豆蛋白3份、甘油20份和纯水12份为囊体原料，将甘油和纯水注入溶胶罐内，65℃加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：配制内容物：按重量份计，将大豆油90份、γ-亚麻酸4份、依维莫司1份、及甘油15份在50℃下进行混合，混合时间20min，过胶体磨3次，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
Claims (4)
1.一种依维莫司软胶囊的制备方法，其特征在于，包括如下步骤：
第1步，制作囊体：按重量份计，以明胶15～25份、硬酯酸0～6份、大豆蛋白0～3份、甘油10～25份和纯水10～15份为囊体原料，将甘油和纯水注入溶胶罐内，加热搅拌，再加入明胶、硬酯酸和大豆蛋白，继续搅拌均匀后真空脱泡，制作得到囊体；
第2步：按重量份计，将大豆油30～90份、不饱和脂肪酸4～9份、依维莫司1～5份及甘油5～20份进行混合，过胶体磨，得到混合均匀的内容物；
第3步：将第2步得到的内容物及第1步得到囊体经过压丸、定型、洗丸、干燥、拣丸和分装步骤，制备得到依维莫司软胶囊。
2.根据权利要求1所述的依维莫司软胶囊的制备方法，其特征在于：所述的第1步中，搅拌加热的温度是60～70℃。
3.根据权利要求1所述的依维莫司软胶囊的制备方法，其特征在于：所述的第2步中，不饱和脂肪酸选自二十二碳六烯酸、二十碳五烯酸、鱼油、亚麻籽油、琉璃苣油、α-亚麻酸、γ-亚麻酸、共轭亚油酸或者锯叶棕提取物。
4.根据权利要求1所述的依维莫司软胶囊的制备方法，其特征在于：所述的第2步中，混合时的温度50～70℃，混合时间20～40min，过胶体磨的次数是1～3次。
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