CN105828807A - 用于在治疗肠病症中口服施用薄荷醇的释放改变的治疗系统 - Google Patents
用于在治疗肠病症中口服施用薄荷醇的释放改变的治疗系统 Download PDFInfo
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- CN105828807A CN105828807A CN201480067078.3A CN201480067078A CN105828807A CN 105828807 A CN105828807 A CN 105828807A CN 201480067078 A CN201480067078 A CN 201480067078A CN 105828807 A CN105828807 A CN 105828807A
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- hydroxypropyl methyl
- menthol
- methyl cellulose
- cellulose
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Abstract
公开了结肠特异性延迟释放药物组合物，包含：a)基质，其中分散了粒度分布为100nm至1200μm的微粉化薄荷醇；b)基质a)的具有滞后时间的胃抵抗性或抗酸性pH独立的包衣。
Description
本发明涉及装载到具有胃抵抗型包衣的整体式系统中的含有掺入在羟丙基甲基纤维素亲水基质中的薄荷醇的释放改变的组合物。
本发明的组合物调节薄荷醇的活性，减少其施用频率和调控其在胃肠道的特定位置的释放。
本发明的组合物可用于治疗炎性、免疫性和/或全身性来源的肠病症，特别是治疗肠易激惹综合征。
现有技术
近年来，欧薄荷在治疗肠易激惹综合征(IBS)的症状、特别是胃肠道痛性痉挛、气胀和腹痛中的应用已经通过大量研究得以验证和证实。欧薄荷油对消化道平滑肌的解痉作用是熟知的。所述作用已经在体外和体内被不同地证实，尤其是对结肠平滑肌纤维。主要负责欧薄荷油的作用的成分是薄荷醇，其呈现出可归于以下活性机制的显著解痉作用：
-抑制在收缩机制中牵涉的、存在于平滑肌细胞上的Ca2+通道；
-结肠性激活TRPM8(瞬时受体电位通道)受体，该受体引起对结肠肌的长效放松作用(已知为清凉受体)；
-抑制TRPA1受体，该受体引起结肠近端和远端收缩。
鉴于这些性质，一个特别期望的目标是薄荷醇的具有适宜滞后时间直至到达小肠的远端部分、从远端回肠开始的结肠特异性释放，由此确保了产品在整个结肠道中缓慢、逐渐和恒定的释放。
以胃抵抗性包衣为特征的薄荷精油制剂是已知的和在市场上已经是可获得的。但是，已知制剂的释放性质是不满意的，因为它没有保证在整个结肠道中均匀释放。
US2012/207842公开了具有胃抵抗性包衣的多颗粒延迟释放系统(2小时，pH1.2)，其在中性pH快速释放(2小时内最多超过80％薄荷醇)。核不呈现出释放改变的系统，而是立即释放或适度释放控制(45分钟至2小时)。所述文献要求在核和底包衣中使用羟丙基甲基纤维素，但目的不是控制释放，而是作为粘合剂以获得颗粒和在薄膜包衣中作为包衣剂。
WO01/76392公开了含有大蒜作为活性成分以及肠溶包衣的组合物。该活性成分在小肠中立即释放。该组合物可以含有欧薄荷提取物(不是纯薄荷醇)作为除臭剂。薄荷油存在于外层肠溶薄膜衣中，因此未进行任何在肠环境中的释放控制，因此提取物在肠环境中被立即释放。因此，该文献没有公开薄荷醇的结肠特异性延迟释放制剂，也没有公开其中薄荷醇分散于亲水基质中的制剂。
CN102008547公开了用丙烯酸树脂包衣的含有圆叶薄荷(Mentharotundifoliae)油(其具有非显著的薄荷醇含量)的胶囊。因此，其不仅没有涉及结晶薄荷醇，而且该文献中所述的制剂不具有活性成分在结肠中延迟释放的任何作用，仅仅是胃抵抗性的。
发明描述
现在已经发现，采用包含如下的整体式药物组合物可以获得最适宜的薄荷醇结肠特异性缓慢释放：
a)含有羟丙基甲基纤维素的核，其中分散了研磨、共研磨或微粉化形式的薄荷醇，粒度为100nm至1200μm；
b)核a)的胃抵抗型包衣。
以具有整体式基质的核为特征的本发明的制剂能够调控、控制和减缓活性成分在8-24小时内的释放。核的胃抵抗型包衣在pH<1.2-5.5的条件下阻止了体外释放达至少2小时。
胃抵抗型包衣通常由纤维素衍生物、邻苯二甲酸纤维素、琥珀酸酯、甲基丙烯酸或聚甲基丙烯酸聚合物、虫胶或海藻酸组成，优选由虫胶和羟丙基甲基纤维素、或乙基纤维素连同海藻酸、或聚甲基丙烯酸(pH-依赖性)、或简单的乙基纤维素和/或羟丙基甲基纤维素(pH-独立/滞后时间)组成。虫胶和羟丙基甲基纤维素的混合物是特别优选的。
基质核包涂了足以保证其在从核释放活性成分之前在胃液和肠液中保持完整达至少2-4小时(滞后时间)的量的聚合物/树脂。为了减少胃排空时间差异的影响，制剂可以在基质核(pH-独立)外和在纤维素膜包衣(pH-独立)外包括另外的胃抵抗型包衣(pH-依赖性)以进一步延迟生物流体与释放改变的核之间的接触(延时释放)。
在这种方式中，该系统阻止了胃-空肠通过时间期间的早期释放，获得了一直到24小时的缓慢释放以确保药物在大肠的上升束、横向束和下行束的均匀分布。
因此，本发明的组合物与通常的延迟释放形式(胃抵抗型和/或具有滞后时间)是不同的，后者可以到达回肠的远端部分和/或结肠的开始部分，但是然后快速释放活性组分而没有在结肠道中均匀分布。
基质核使用具有不同流变学特征(粘度/膨胀性质)的羟丙基甲基纤维素允许以逐渐的程序方式调控释放达8-24小时。根据本发明可以使用的羟丙基甲基纤维素具有3-200,000mPs、优选30-150,000、更优选50-100,000的表观粘度，所述表观粘度于20℃在2％水性溶液中测定。可以使用单一类型的羟丙基甲基纤维素或者至少两种类型的具有不同粘度的羟丙基甲基纤维素的混合物。羟丙基甲基纤维素在市场上可以从DowChemical以商标Methocel获得，或者从Ashland以商标Benecel获得。羟丙基甲基纤维素的优选实例有具有与市售产品MethocelK100lv、K15M、K4M和K100M相同的特征的那些。特别优选使用具有与MethocelK100lv相似的78至117mPas的粘度的羟丙基甲基纤维素。
本发明的组合物通常将含有10-1200mg薄荷醇、优选50-200mg薄荷醇的单位剂量。
薄荷醇和亲水基质的重量比为1:5至4:1(优选1:3)。
本发明的组合物还可以含有其它赋形剂，例如湿润剂、离子或非离子型表面活性剂、崩解剂、超崩解剂、交联聚合物、络合剂和润滑剂。
所述赋形剂的实例包括磷脂、卵磷脂、月桂硫酸钠、山梨坦酯、蔗糖棕榈酸酯、月桂肌氨酸钠、胆酸、泊洛沙姆、环糊精、淀粉、淀粉羟乙酸钠、交联羧甲基纤维素和交联聚乙烯吡咯烷酮。
羟丙基甲基纤维素的亲水基质可以任选地通过添加亲脂性成分(脂肪酸、脂肪醇、甘油三酯)、水溶性成分(多元醇、甘露醇、乳糖、海藻糖)、水可分散性成分(微晶纤维素)或水不溶性成分(磷酸氢钙、钙和镁盐)进行修饰以调控释放动力学。
本发明的组合物使得薄荷醇在治疗肠易激惹综合征中的药理学作用最大化，这是因为它们能够将活性成分运送到结肠中和特别是在结肠中释放活性成分。胃抵抗性包衣必须保证结构在pH1.2保持约1-2小时，并且在随后8-2小时在pH7.2保证控释性质，由此确保从结肠的上行束至横向和下行束的药理学覆盖区。
对于预期应用，重要的是保证从回肠末端通道开始并在整个结肠道继续的控制释放。还有必要保证随时间推移释放的量的一定均匀性，同时当已经释放一定比例的活性成分时允许其在局部和全身水平的活性。因此，本发明的组合物可特别用于治疗急性和慢性胃肠病症如肠易激惹综合征(IBS)、腹泻、便秘、节段性回肠炎、溃疡性结肠炎和一般性的炎性肠病(IBD)。
常规技术如直接压片、湿法制粒、干法压片/制粒和熔融制粒可用于制备本发明的组合物。
由于薄荷醇作为大结晶存在，所以它不能原样用于制备和生产不同的药物形式，因此必须通过研磨和/或微粉化和/或共研磨单独或装载在一些惰性稀释赋形剂中的产品而进行活化步骤。
将产品(最初以数厘米尺寸的半透明晶体的形式存在)适宜地研磨、微粉化和/或与其它功能性赋形剂如纤维素、淀粉、糊精、磷酸钙、多元醇、胶体二氧化硅和其它稀释剂共研磨，以获得具有100nm至1200μm、优选50至700μm尺寸的产品。
因此，采用适宜的湿法或干法制粒技术、直接分配、直接压片、共研磨、熔融制粒或挤出制粒在加入赋形剂如湿润剂、表面活性剂、崩解剂、超崩解剂、助流剂、无粘性物质或润滑剂的情况下将产品掺入亲水基质中。
然后将由具有胃抵抗性和/或在不同肠pH的释放性质(pH-依赖性)和/或pH-独立的滞后时间性质(延迟释放)的材料组成的外包衣应用于如此获得的核。根据本发明的一般实施方案，首先制备了含有一种或多种类型的羟丙基甲基纤维素的亲水基质，其中分散了微粉化、研磨或共研磨的薄荷醇。然后通过不同药物方法加入稀释产品和使其可操作所需的任意功能性赋形剂。活性成分:基质的比例可以为1:1至1:9，活性成分:赋形剂的比例应当通常不超过1:4；最佳量为0.1％至50％。
可以向该混合物中加入可变量的至多50％的稀释剂、润滑剂(0.5-3％)、助流剂(0.5-3％)、崩解剂和超崩解剂(0.1-40％)和络合剂(0.1-40％)。
本发明的组合物还可以含有其它具有协同、补充或在其它方面有用的活性的活性成分。所述活性成分的实例包括益生菌(乳杆菌属(lactobacilli),双歧杆菌属(bifidobacteria))、消化酶(肠液)、益生元(丁酸盐、丙酸盐、中长链脂肪酸、ω-3脂肪酸或酯)、纤维(欧车前、瓜尔胶、阿拉伯纤维、聚卡波非钙)、解痉药(曲美布汀及其盐、奥替溴铵及其它盐、双环胺及其盐、替罗拉胺、丙胺太林及其盐、比哌立登及其盐、辛托品及其盐、美金刚和尿多灵(ditropan))、在IBS和IBD中具有活性的药物如抗炎剂(美沙拉嗪、皮质类固醇、硫唑嘌呤、巯嘌呤、α-硫辛酸)、在IBS中具有活性的药物(卢比前列通、利那洛肽(linaclotide))、植物来源的提取物或活性成分(洋蓟、虾青素、洋甘菊、姜黄素、乳香属、绿茶、紫锥花属)、乳铁蛋白和具有局部作用的抗生素如利福昔明和利福霉素。
就溶出性质而言，上述组合物与水或肠生物流体之间的接触产生了活性成分的延迟、位置特异性的释放。结构中存在的赋形剂和聚合物调节了系统的可润湿性和薄荷醇在有限释放范围内的均匀溶出，由此促进了其在胃肠道中的局限性活性和连续逐渐的吸收。
以下实施例更详细地解释了本发明。
实施例1
将50g活化的薄荷醇与200g磷酸氢钙、200mg微晶纤维素和150g甘露醇一起加入混合器/造粒机中。
向相同体系中依次加入2g交聚维酮、8g卵磷脂和150g羟丙基甲基纤维素(HPMCK100lv)。
将各成分混合直至基质均匀分散，然后依次加入5g硬脂酸镁和5g胶体二氧化硅。
将最终混合物压制成770mg/片的单位重，以施用50mg活性成分/片。
然后将所得片剂用基于30g虫胶(25％)、12g羟丙基甲基纤维素和6g甘油的胃抵抗性溶液/混悬液进行薄膜包衣，获得平均重为818mg的片剂。
当于pH1.2进行崩解实验时，片剂保持完整达至少2小时。当于pH7.2进行溶出试验时，它们呈现出以下释放性质：在60分钟后不超过20％，在240分钟后不超过60％，在480分钟后不超过80％；在任何事件中，该值在24小时后必须>70％。
实施例2
将50g活化的薄荷醇装入造粒机/匀化器中，加入55g甘露醇。
将100g羟丙基甲基纤维素(HPMCK100lv)、55g羟丙基甲基纤维素(K4M)和50mg微晶纤维素加入相同造粒机中。
将各成分混合直至基质均匀分散，然后依次加入210g磷酸钙、3g硬脂酸镁和5g胶体二氧化硅。
将最终混合物压制成530mg/片的单位重，以施用50mg活性成分/片。
然后将所得片剂用基于20g虫胶(25％)20、8g羟丙基甲基纤维素和2g甘油的胃抵抗性溶液/混悬液进行薄膜包衣，获得平均重为560mg的片剂。
当于pH1.2进行崩解实验时，片剂保持完整达至少2小时。当于pH7.2进行溶出试验时，它们呈现出以下释放性质：在60分钟后不超过10％，在240分钟后不超过40％，在480分钟不超过70％；在任何事件中，该值在24小时后必须>70％。
实施例3
将800g薄荷醇装入造粒机/匀化器中，加入200g羟丙基甲基纤维素(K100lv)、200g羟丙基甲基纤维素(K15M)、480g甘露醇和252g微晶纤维素。
将各成分混合至少15分钟以获得均匀混合物。
然后依次加入8g交联羧甲基纤维素、40g卵磷脂、40g胶体二氧化硅和20g硬脂酸镁。
将最终混合物压制成510mg/片的单位重，以施用200mg活性成分/片。
然后将所得核用500g虫胶(aquagold25％)、50g羟丙基甲基纤维素和25g甘油进行包衣。获得具有约50mg包衣/片的胃抵抗性薄膜包衣。
当于pH1.2、然后于pH7.2进行溶出试验时，该片剂呈现出以下释放性质：pH1.2:在120分钟后0％；pH7.2：在60分钟后不超过25％、在180分钟后不超过50％和在8小时后不超过80％；在12小时后>80％。实施例4
将800g薄荷醇装入造粒机/匀化器中，加入200g羟丙基甲基纤维素、200g聚氧乙烯氧化物(PEO-20NF)、480g甘露醇和252g微晶纤维素。
将各成分混合至少15分钟以获得均匀基质。
然后依次加入8g交联羧甲基纤维素、40g卵磷脂、40g胶体二氧化硅和20g硬脂酸镁。
将最终混合物压制成510mg/片的单位重，以施用200mg活性成分/片。
然后将所得核用含有80g乙基纤维素、16g海藻酸钠、2g二氧化钛和2g硬脂酸的水性分散液进行包衣。获得具有约25mg包衣/片的薄膜包衣。
当进行溶出实验时，片剂呈现出以下释放性质：pH1.2：在120分钟后<10％；pH7.2：在60分钟后不超过25％、在180分钟后不超过60％和在8小时后不超过80％；在24小时后>80％。
实施例5
将500g活化的薄荷醇与350g磷酸氢钙一起装入混合器/造粒机中。
向相同系统中依次加入2g交聚维酮和150g亲水基质羟丙基甲基纤维素(HPMCK15M)。
将各成分混合直至基质均匀分散，然后依次加入5g硬脂酸镁、5g胶体二氧化硅和8g山嵛酸甘油酯。
将最终混合物压制成1020mg/片的单位重，以施用500mg活性成分/片。
然后将所得片剂用基于160g虫胶(25％)、20g羟丙基甲基纤维素和8g甘油的胃抵抗性溶液/混悬液进行薄膜包衣。
当于pH1.2进行崩解实验时，片剂保持完整达至少2小时。当于pH7.2进行溶出试验时，它们呈现出以下释放性质：在60分钟后不超过35％，在240分钟后不超过65％，在480分钟后不超过80％；在任何事件中，该值在24小时后必须>80％。
Claims (12)
1.整体式结肠特异性延迟释放药物组合物，包含：
a)含有羟丙基甲基纤维素的核，其中分散了研磨、共研磨或微粉化形式的薄荷醇，粒度为100nm至1200μm；
b)核a)的胃抵抗性包衣。
2.根据权利要求1的组合物，其中核中的羟丙基甲基纤维素具有3-200,000mPas的表观粘度，所述表观粘度于20℃在2％水溶液中测定。
3.根据权利要求1或2的组合物，其中所述核包含至少两种具有不同表观粘度值的羟丙基甲基纤维素的混合物。
4.根据权利要求1的组合物，包含仅一种具有80至120mPas的表观粘度的羟丙基甲基纤维素，所述表观粘度于20℃在2％水溶液中测定。
5.根据权利要求1-3中一项或多项的组合物，其中胃抵抗性包衣包含纤维素衍生物、甲基丙烯酸聚合物、虫胶、海藻酸或其混合物。
6.根据权利要求4的组合物，其中胃抵抗性包衣由虫胶和羟丙基甲基纤维素、或乙基纤维素和海藻酸、或聚甲基丙烯酸酯或乙酰邻苯二甲酸纤维素组成。
7.根据上述权利要求中一项或多项的组合物，包含50-1200mg薄荷醇。
8.根据上述权利要求中一项或多项的组合物，其中薄荷醇:羟丙基甲基纤维素的重量比为1:5-4:1、优选1:3。
9.上述权利要求中一项或多项的组合物，还包含选自湿润剂、离子或非离子型表面活性剂、水溶性稀释剂、水可分散性稀释剂、水不溶性稀释剂、崩解剂、润滑剂、助流剂和着色剂的赋形剂。
10.根据权利要求9的组合物，其中所述赋形剂选自磷脂、卵磷脂、月桂硫酸钠、山梨坦酯、蔗糖棕榈酸酯、月桂肌氨酸钠、胆酸、泊洛沙姆、环糊精、淀粉、淀粉羟乙酸钠、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、多元醇、微晶纤维素、磷酸氢钙、钙和镁盐。
11.根据权利要求1-10的组合物，还包含选自如下的一种或多种成分：益生菌、消化酶、益生元、纤维、解痉药、抗炎剂、IBS-和IBD-活性药物、植物来源的提取物或活性成分、局部抗生素。
12.用于治疗炎性肠综合征(IBS)和肠病的权利要求1-11的组合物。
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2014
- 2014-12-10 CN CN201480067078.3A patent/CN105828807B/zh not_active Expired - Fee Related
- 2014-12-10 US US15/103,192 patent/US10328035B2/en not_active Expired - Fee Related
- 2014-12-10 JP JP2016539146A patent/JP6471165B2/ja not_active Expired - Fee Related
- 2014-12-10 ES ES14830618T patent/ES2698132T3/es active Active
- 2014-12-10 KR KR1020167015412A patent/KR102296850B1/ko active IP Right Grant
- 2014-12-10 CA CA2933309A patent/CA2933309A1/en not_active Abandoned
- 2014-12-10 WO PCT/IB2014/066763 patent/WO2015087258A1/en active Application Filing
- 2014-12-10 RU RU2016122897A patent/RU2683645C1/ru active
- 2014-12-10 EP EP14830618.6A patent/EP3079673B1/en active Active
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| CN110772502A (zh) * | 2019-12-06 | 2020-02-11 | 上海市肺科医院 | 一种用于治疗过敏性鼻炎的组合物及制备方法和应用 |
| CN110772502B (zh) * | 2019-12-06 | 2023-03-28 | 上海市肺科医院 | 一种用于治疗过敏性鼻炎的组合物及制备方法和应用 |
| CN111297889A (zh) * | 2020-02-28 | 2020-06-19 | 奥纳斯(北京)医药科技有限公司 | 一种对胃肠道痉挛和胆道系统痉挛均具有抑制作用的组合物、其水溶液及其制法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2698132T3 (es) | 2019-01-31 |
| JP6471165B2 (ja) | 2019-02-13 |
| RU2683645C1 (ru) | 2019-04-01 |
| ITMI20132066A1 (it) | 2015-06-12 |
| WO2015087258A8 (en) | 2015-10-29 |
| JP2016540019A (ja) | 2016-12-22 |
| KR102296850B1 (ko) | 2021-09-01 |
| KR20160094977A (ko) | 2016-08-10 |
| US20180133166A1 (en) | 2018-05-17 |
| WO2015087258A1 (en) | 2015-06-18 |
| CA2933309A1 (en) | 2015-06-18 |
| CN105828807B (zh) | 2021-02-02 |
| EP3079673B1 (en) | 2018-09-19 |
| EP3079673A1 (en) | 2016-10-19 |
| US10328035B2 (en) | 2019-06-25 |
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