CN110913914A - 固体挤出形式的药物组合物 - Google Patents
固体挤出形式的药物组合物 Download PDFInfo
- Publication number
- CN110913914A CN110913914A CN201880051506.1A CN201880051506A CN110913914A CN 110913914 A CN110913914 A CN 110913914A CN 201880051506 A CN201880051506 A CN 201880051506A CN 110913914 A CN110913914 A CN 110913914A
- Authority
- CN
- China
- Prior art keywords
- cellulose
- pharmaceutical composition
- carboxymethyl
- hydroxypropyl
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 239000007787 solid Substances 0.000 title claims abstract description 17
- 239000000905 isomalt Substances 0.000 claims abstract description 17
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims abstract description 16
- 235000010439 isomalt Nutrition 0.000 claims abstract description 16
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims abstract description 14
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- 235000021436 nutraceutical agent Nutrition 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 23
- 239000003826 tablet Substances 0.000 claims description 18
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 13
- -1 carboxymethyl ethylcellulose Chemical compound 0.000 claims description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
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- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 3
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 240000007472 Leucaena leucocephala Species 0.000 claims description 3
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- 239000005913 Maltodextrin Substances 0.000 claims description 3
- 229920002774 Maltodextrin Polymers 0.000 claims description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 3
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Abstract
提供了一种药物组合物,其包括被挤出的固体和一种或多种药物或营养品。被挤出的固体包括醋酸羟丙基甲基纤维素琥珀酸酯和益寿糖。
Description
相关申请
本申请要求来自2018年7月26日提交的美国非临时申请号16/046,488和2017年8月7日提交的美国临时申请号62/541,928的优先权,其公开内容通过引用以其整体并入本文。
发明领域
本发明涉及固体挤出形式的药物组合物,其中挤出可以在较低温度下进行并且所得挤出物具有较高的可压缩性。
发明背景
许多药物和营养品使用熔体挤出方法以固体形式提供。通常,挤出机包含具有螺杆的桶,所述螺杆迫使包括聚合物材料和活性药物成分(API)的材料通过成形模。通常加热挤出机以软化聚合物材料并降低其熔体粘度。这样的熔体挤出方法通常用于将难溶性API配制成固体分散体。在该方法中,非活性聚合物通常处于无定形状态或半结晶状态,以及API从其初始结晶状态转化为其无定形状态以提高其溶解度。一旦挤出,通常将固体形式进行研磨,并随后压制成片剂、丸剂或颗粒剂。
粘度是熔体挤出的重要方面,并且通常通过增加热量来降低。然而,许多API是热敏的,因此必须避免过度的热量以防止对API活性的不利影响。在挤出后,可压缩性是重要的方面,并且固体形式必须足够硬以能够将挤出物压制成其所需形式。
因此,本发明提供了表现出较低熔体粘度的药物组合物和表现出较高可压缩性的固体挤出形式(挤出物)。
发明概述
提供了药物组合物,并且其包括可挤出的固体和一种或多种药物或营养品。可挤出的固体包含醋酸羟丙基甲基纤维素琥珀酸酯和益寿糖。
附图简述
图1说明了根据实施例1使用TBH 125 (Erweka)测试仪的片剂硬度。
图2说明了根据实施例1的抗拉强度。
图3说明了根据实施例3A和3B的溶出测试结果。
本发明的实施方案的详细描述
现在将参照本文提供的描述和方法更详细地描述本发明的前述和其它方面。应当理解,本发明可以以不同的形式体现,并且不应当被解释为限于这里阐述的实施方案。相反,提供这些实施方案是为了使本公开透彻和完整,并且将向本领域技术人员充分传达本发明的范围。
本文中,在本发明的描述中使用的术语仅是为了描述特定实施方案的目的,而不是要限制本发明。如在本发明的实施方案的描述和所附权利要求中所使用的,单数形式"一"、"一个"和"该"旨在也包括复数形式,除非上下文另有明确指出。此外,如本文所用,"和/或"是指并涵盖一个或多个相关的所列项目的任何和所有可能的组合。此外,如本文所用,在提及可测量值,例如化合物的量、剂量、时间、温度等时,术语"约"意在涵盖指定量的20%、10%、5%、1%、0.5%或甚至0.1%的变化。
将进一步理解,在本说明书中使用时,术语"包含(comprises)"和/或"包含(comprising)"指定所陈述的特征、整数、步骤、操作、元件和/或组分的存在,但不排除一个或多个其它特征、整数、步骤、操作、元件、组分和/或其组的存在或添加。除非另有定义,否则所有术语,包括在描述中使用的技术和科学术语,具有与本发明所属领域的普通技术人员通常理解的相同的含义。
如本发明中所应用的术语"基本上由……组成"(和语法上的变体)是指方法或组合物可以包含另外的步骤或组分,只要另外的步骤或组分不会实质上改变本发明的基本和新颖的一个或多个特征。
术语"由……组成"排除权利要求中未指定的任何另外的步骤或组分。
除非上下文另外指出,否则特别旨在本文所述的本发明的各种特征可以以任何组合使用。
此外,本发明还预期在本发明的一些实施方案中,本文中阐述的任何特征或特征的组合可被排除或省略。
本文提及的所有专利、专利申请和出版物均通过引用以其整体并入。在术语冲突的情况下,以本说明书为准。
如本领域普通技术人员可以理解的,本文所述的参数可以根据方法和/或制剂以及最终产品的所需性质而极大地变化。
本发明涉及新型药物组合物,其包含可挤出的固体(即挤出物)和与可挤出的固体混合的药物或营养品。可挤出的固体包含醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)和益寿糖。
在一个实施方案中,HPMCAS是市售可得的,例如来自Shin-Etsu Chemical Co.,Ltd.(日本)的Shin-Etsu AQOAT®、来自Dow Chemical (USA)的AffiniSol®和来自Ashland(USA)的AquaSolveTM。在一个实施方案中,益寿糖是从BENEO GmbH (德国)获得的galenIQTM。益寿糖是包含两种立体异构体α-吡喃葡萄糖基-1-1-D-甘露醇(GPM)和α-D-吡喃葡萄糖基-1,6-D-山梨醇(GPS)的等量混合物的糖醇。
任选地,可以包括通常用作药物或营养品组合物中的添加剂或赋形剂的其它材料。示例性的其它组分包括控制释放剂,如羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、甲基丙烯酸酯-丙烯酸甲酯-甲基丙烯酸甲酯共聚物、聚醋酸乙烯邻苯二甲酸酯和虫胶。可以包括组合物的约1至约50重量%的量的这些其它组分。
待挤出的可挤出固体组合物包含约10至约80%的HPMCAS、约3至50%的益寿糖和约10至约80%的API。挤出物(片剂)包含约10至约100%的用于挤出的可挤出固体组合物、约0至约20%的崩解剂、约0至约80%的填充剂、约0至约80%的粘合剂和约0至约1%的润滑剂/助流剂。
合适的崩解剂包括羟丙基纤维素(HPC)、低取代的HPC (L-HPC)、羧甲基纤维素(CMC)、CMC钠、CMC钙、交联聚维酮、交联羧甲基纤维素钠;淀粉(例如,羧甲基淀粉、羟丙基淀粉、改性淀粉);结晶纤维素、淀粉羟乙酸钠;海藻酸或其盐(如海藻酸钠)或它们的等同物和其混合物。
合适的填充剂包括乳糖、乳糖一水合物、拉克替醇、蔗糖、山梨醇、甘露醇、葡萄糖结合剂、糊精、右旋糖、麦芽糖糊精、交联羧甲基纤维素钠、硅化微晶纤维素、微晶纤维素、羟丙基纤维素、低取代的羟丙基纤维素、羟丙基甲基纤维素聚合物、羟乙基纤维素、羧甲基纤维素钠、羧亚甲、羧甲基羟乙基纤维素和其它纤维素衍生物、淀粉或改性淀粉(包括马铃薯淀粉、玉米淀粉(corn starch)、玉米淀粉(maize starch)和大米淀粉)及其混合物。
合适的粘合剂包括聚乙烯吡咯烷酮(也称为聚维酮)、聚乙二醇、阿拉伯胶、海藻酸、琼脂、角叉菜胶钙、纤维素衍生物(如乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠)、糊精、明胶、阿拉伯树胶、瓜尔胶、黄芪胶、海藻酸钠或其混合物或任何其它合适的粘合剂。
合适的润滑剂/助流剂包括硬脂酸及其药学上可接受的盐或酯(例如,硬脂酸镁、硬脂酸钙、硬脂富马酸钠或其它金属的硬脂酸盐)、滑石、微晶蜡、甘油酯、轻质矿物油、聚乙二醇、硅酸及其药学上可接受的盐或酯(例如硅酸盐、二氧化硅、胶体二氧化硅)、脂肪酸的蔗糖酯、氢化植物油(例如氢化蓖麻油)或其混合物。
整个组合物可以包括约65至约95%水重量作为分散剂以提供含水形式的组合物。
其它添加剂可包括吸收增强剂、溶出改良剂、着色助剂、调味剂和稳定剂(例如磷酸氢二钠)。
挤出形式可以形成片剂、丸剂和颗粒剂。
在操作中,API可以与醋酸羟丙基甲基纤维素琥珀酸酯和益寿糖在高速混合机中混合0至60分钟。在一个实施方案中,可以在100至200℃的温度和100至1000 rpm的螺杆速度下通过双螺杆挤出机挤出共混物。挤出物的特定成形可以如本领域技术人员已知的那样进行。然后可以使用常规压片机将挤出物压制成片剂、丸剂或颗粒剂。然后,任选地,可以使用常规的包衣设备对所得的片剂、丸剂或颗粒剂进行包衣以改善外观或味道,或者用含水或有机聚合物组合物进行膜包衣。
活性药物成分(API)可以是药物或营养品。本文所用的"药物"定义为任何意在用于医学诊断、治愈、治疗或预防疾病的化学物质,例如非处方药(OTC)和处方药(POM)。示例性的活性药物组分列于美国专利号6,723,358第9列第25行至第13列第25行,其公开内容通过引其整体并入本文。
如本文所用,"营养品"补充剂包括可提供健康和医学益处(包括疾病的预防和治疗)的任何营养物。实例包括但不限于维生素、矿物质、益生菌、酶、草药和其它植物提取物、氨基酸、浓缩物、代谢物、成分等。
示例性的维生素和矿物质包括但不限于维生素A (例如以棕榈酸酯或β胡萝卜素的形式)、B-复合物(例如B-1、B-2、B-6和B-12)、C、D、E和K;烟酸;酸性维生素,如泛酸和叶酸;生物素;矿物质,如铁、钙、镁、碘、铜、磷、锌、锰、钾、铬、钴、钼、硒、镍、锡、硅、钒和硼;营养品补充剂,如氟和氯;等等。各种草药和草药疗法可用作营养品补充剂。草药通常选自具有各种药用或饮食补充性质的那些。草药通常是可在药学上使用或用于调味的芳香植物或植物部分。实例包括银杏、雷公根(gotu kola)、松果菊(echinacea)、圣约翰草(St. John'swort)、人参(ginseng)、缬草(valerian)等。合适的草药可以单独或以各种混合物用于本文所述的填料中。
本发明将通过以下非限制性实施例进一步说明。
实施例1
通过将HPMCAS (Shin-Etsu AQOAT® AS-MMP)、益寿糖和API (硝苯地平)混合20分钟来制备挤出物。加入5、10和20%水平的从Beneo,德国可获得的GalenIQTM益寿糖720和益寿糖721。
甘露醇(Pearlitol®)、羟丙基纤维素(等级:HPC-L)和共聚维酮(Kollidon®)用作益寿糖的比较添加剂。还制备了不含益寿糖或其它添加剂的对照。
在挤出方法期间,测试每个的最大扭矩的百分比。挤出机是Pharma-11双螺杆挤出机(Thermo Scientific, 德国),主桶温度为175℃。结果在表1中提供。
表1:挤出方法期间最大扭矩的百分比
没有添加剂的对照具有58%的最大扭矩。
使用Handtab-200单站台式压力机(Ichihashiseki,日本)在15、20或25 KN下压制包含20%添加的可挤出组合物。使用TBH 125 (Erweka,德国)硬度测试仪记录片剂硬度。结果提供在图1中。进一步计算抗拉强度并示于图2中。
实施例2
使用Pharma-11双螺杆挤出机(Thermo Scientific,德国),挤出API (硝苯地平)(20%)、HPMCAS (AS-MMP,75或60%)和益寿糖720 (5或20%)的混合物。主桶温度设定为155℃或175℃,以及螺杆速度设定为100或400 rpm。根据23阶乘Plackett-Burman设计设定参数以进行12个实验。将挤出物研磨并使用单冲压片机(Handtab-200,Ichihashiseki,日本)在25 kN下压制成片剂,并使用TBH 125硬度测试仪(Erweka,德国)测量硬度。结果总结在表2中。
表2:加工参数和益寿糖对片剂的抗拉强度的影响
实验编号 | 螺杆速度(rpm) | 主桶温度(℃) | 益寿糖(%) | 片剂的抗拉强度(MPa) |
1 | 100 | 155 | 20 | 18.91 |
2 | 100 | 155 | 5 | 10.12 |
3 | 400 | 155 | 20 | 14.94 |
4 | 400 | 155 | 5 | 14.72 |
5 | 400 | 175 | 5 | 16.84 |
6 | 400 | 175 | 20 | 24.64 |
7 | 100 | 175 | 20 | 22.19 |
8 | 100 | 175 | 5 | 17.81 |
9 | 100 | 155 | 20 | 25.99 |
10 | 100 | 155 | 5 | 16.39 |
11 | 400 | 175 | 5 | 15.15 |
12 | 400 | 175 | 20 | 24.92 |
结果清楚地表明,益寿糖的含量越高,提供的抗拉强度越高。
实施例3A和3B
使用Pharma-11双螺杆挤出机(Thermo Scientific,德国),在175℃的主桶温度下挤出API (伊曲康唑(20%))和HPMCAS (AS-MMP,80%)的混合物(实施例3A)。将挤出物研磨并使用单冲压片机(Handtab-200,Ichihashiseki,日本)在8 kN的压实力下压制成片剂(直径:1cm,重量:400 mg)。使用TBH 125硬度测试仪(Erweka,德国)测量的片剂硬度为90N。以相同的方式,挤出API (伊曲康唑(20%))、HPMCAS (AS-MMP,65%)和益寿糖721 (15%)的混合物(实施例3B)。155℃的主桶温度是实现与没有益寿糖的挤出相同的挤出扭矩所必需的。片剂硬度为230N,其显著高于不含益寿糖的制剂。使用溶出测试仪(Model 2500, Distek, USA)进行实施例3A和3B的两种片剂的溶出测试。伊曲康唑的分析使用Agilent 1100 HPLC(USA)进行。溶出结果示于图3中。图3说明实施例3A和3B的两种片剂的溶出模式是相同的,并且与各成分的仅物理混合物相比,两者都具有显著更好的溶出。这清楚地表明,益寿糖在通过熔体挤出的HPMCAS固体分散体的加工和性能方面具有益处,而不会对API的溶出提供任何实质上的负面影响。
因此已经描述了本发明的某些实施方案,应当理解,由所附权利要求限定的本发明不受以上描述中阐述的特定细节的限制,因为在不背离如所附要求保护的本发明的精神或范围的情况下,本发明的许多明显变化是可能的。
Claims (18)
1.一种药物组合物,其包含可挤出的固体和一种或多种药物,其中所述可挤出的固体包含醋酸羟丙基甲基纤维素琥珀酸酯和益寿糖。
2.权利要求1的药物组合物,其为片剂、丸剂或颗粒剂的形式。
3.根据权利要求1所述的药物组合物,其进一步包含控制释放剂。
4.根据权利要求3所述的药物组合物,其中所述控制释放剂选自羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、甲基丙烯酸酯-丙烯酸甲酯-甲基丙烯酸甲酯共聚物、聚醋酸乙烯邻苯二甲酸酯和虫胶。
5.根据权利要求1所述的药物组合物,其进一步包含崩解剂。
6.根据权利要求5所述的药物组合物,其中所述崩解剂选自羟丙基纤维素、低取代的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联聚维酮、交联羧甲基纤维素钠、淀粉、结晶纤维素、淀粉羟乙酸钠和海藻酸或其盐。
7.根据权利要求1所述的药物组合物,其进一步包含填充剂。
8.根据权利要求7所述的药物组合物,其中所述填充剂包含乳糖、乳糖一水合物、拉克替醇、蔗糖、山梨醇、甘露醇、葡萄糖结合剂、糊精、右旋糖、麦芽糖糊精、交联羧甲基纤维素钠、硅化微晶纤维素、微晶纤维素、羟丙基纤维素、低取代的羟丙基纤维素、羟丙基甲基纤维素聚合物、羟乙基纤维素、羧甲基纤维素钠、羧亚甲和羧甲基羟乙基纤维素及其混合物。
9.根据权利要求1所述的药物组合物,其进一步包含粘合剂。
10.根据权利要求9所述的药物组合物,其中所述粘合剂选自聚乙烯吡咯烷酮、聚乙二醇、阿拉伯胶、海藻酸、琼脂、角叉菜胶钙、纤维素衍生物、糊精、明胶、阿拉伯树胶、瓜尔胶、黄芪胶、海藻酸钠及其混合物。
11.根据权利要求1所述的药物组合物,其进一步包含润滑剂。
12.根据权利要求11所述的药物组合物,其中所述润滑剂选自硬脂酸及其药学上可接受的盐或酯、滑石、微晶蜡、甘油酯、轻质矿物油、聚乙二醇、硅酸及其药学上可接受的盐或酯和其混合物。
13. 一种药物组合物,其包含:
a) 10至90%的可挤出的固体,其包含醋酸羟丙基甲基纤维素琥珀酸酯和益寿糖;以及
b) 10至90%的药物或营养品。
14.权利要求13所述的药物组合物,其进一步包含:
c) 0至20%的崩解剂;
d) 0至80%的填充剂;
e) 0至80%的粘合剂;以及
f) 0至1%的润滑剂。
15.根据权利要求14所述的药物组合物,其中所述崩解剂选自羟丙基纤维素、低取代的HPC、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联聚维酮、交联羧甲基纤维素钠、淀粉、结晶纤维素、淀粉羟乙酸钠和海藻酸或其盐。
16.根据权利要求14所述的药物组合物,其中所述填充剂包含乳糖、乳糖一水合物、拉克替醇、蔗糖、山梨醇、甘露醇、葡萄糖结合剂、糊精、右旋糖、麦芽糖糊精、交联羧甲基纤维素钠、硅化微晶纤维素、微晶纤维素、羟丙基纤维素、低取代的羟丙基纤维素、羟丙基甲基纤维素聚合物、羟乙基纤维素、羧甲基纤维素钠、羧亚甲和羧甲基羟乙基纤维素及其混合物。
17.根据权利要求14所述的药物组合物,其中所述粘合剂选自聚乙烯吡咯烷酮、聚乙二醇、阿拉伯胶、海藻酸、琼脂、角叉菜胶钙、纤维素衍生物、糊精、明胶、阿拉伯树胶、瓜尔胶、黄芪胶、海藻酸钠及其混合物。
18.根据权利要求14所述的药物组合物,其中所述润滑剂选自硬脂酸及其药学上可接受的盐或酯、滑石、微晶蜡、甘油酯、轻质矿物油、聚乙二醇、硅酸及其药学上可接受的盐或酯和其混合物。
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US20190038754A1 (en) | 2019-02-07 |
JP7047064B2 (ja) | 2022-04-04 |
US20210113700A1 (en) | 2021-04-22 |
JP2020530842A (ja) | 2020-10-29 |
WO2019032319A1 (en) | 2019-02-14 |
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KR20200037252A (ko) | 2020-04-08 |
EP3664853A1 (en) | 2020-06-17 |
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