CN106265482B - 一种橄榄苦苷栓剂 - Google Patents
一种橄榄苦苷栓剂 Download PDFInfo
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Abstract
本发明公开了一种橄榄苦苷栓剂，该栓剂的药物成分为橄榄苦苷，通过调整栓剂基质的组分和比例，可获得速释栓剂和中等释放速度的栓剂。本发明栓剂经阴道给药可用于治疗阴道炎、盆腔炎及宫颈糜烂等妇科疾病，经直肠给药可用于治疗直肠炎及直肠癌，也可经直肠粘膜下血管进入全身血液循环，发挥全身性的抗炎、改善骨质疏松症状等作用。
Description
技术领域
本发明涉及一种栓剂，特别是涉及一种橄榄苦苷栓剂。
背景技术
阴道炎、盆腔炎及宫颈糜烂是妇科常见病和多发病，感染阴道、盆腔的微生物包括细菌、念珠菌及滴虫等，临床上常用的治疗方法为口服抗厌氧菌药物如甲硝唑、替硝唑及克林霉素结合局部栓剂治疗，常用的栓剂包括甲硝唑栓剂、咪康唑栓剂、制霉菌素栓剂与克霉唑栓剂。然而，阴道炎、盆腔炎和宫颈糜烂均易复发，复发与个人卫生不洁、性生活不洁或阴道与盆腔环境菌群失调相关，复发后的重复用药易引起细菌产生耐药性，只能通过增大剂量改善疗效，当给药量已达到最大值时，炎症将难以控制，给病人带来痛苦与精神负担。
橄榄苦苷为裂环烯醚萜类化合物，主要存在于油橄榄叶中。研究发现，橄榄苦苷具有很强的抗氧化和抗菌作用，可有效抑制大肠杆菌、金黄色葡萄球菌及白色念珠菌等细菌、真菌的生长。橄榄苦苷结构及抑菌机理与常用的阴道药物甲硝唑、克霉唑等有很大差异，为阴道与盆腔疾病患者提供了一新的选择，避免了因重复用药产生的耐药性问题。将橄榄苦苷制备为栓剂，释放后的橄榄苦苷可杀灭病人阴道与盆腔中的各种细菌、真菌及其他微生物，有效治疗盆腔炎、阴道炎及宫颈糜烂等妇科疾病。
另外，橄榄苦苷具有抗癌活性，对结肠癌及直肠癌有一定的治疗与改善作用。采用栓剂局部给药的形式，可用在直肠炎、直肠癌及结肠癌的治疗上。橄榄苦苷还能增加成骨细胞密度，改善骨质疏松症状。经直肠给药的橄榄苦苷栓剂可通过直肠下毛细血管吸收进入全身血液循环，发挥其对抗骨质疏松及全身性感染的治疗作用，避免肝脏首过效应。
本发明人通过实验发现橄榄苦苷的溶解度高达50mg/mL，脂水分配系数为5.44，故推断它对皮肤与粘膜应有很好的穿透能力，适合运用于粘膜给药系统。目前还没有橄榄苦苷栓剂的报道。
发明内容
本发明的目的在于提供一种橄榄苦苷栓剂，该栓剂经阴道给药能治疗阴道炎、盆腔炎及宫颈糜烂等妇科疾病，经直肠给药能治疗直肠炎及直肠癌，也可经直肠粘膜下血管进入全身血液循环，发挥全身性的抗炎、改善骨质疏松症状等作用。
为达到上述目的，本发明提供的橄榄苦苷栓剂，由橄榄苦苷和栓剂基质制成，每粒栓剂中含橄榄苦苷10-50mg。
进一步地，所述栓剂基质由占栓剂基质重量20％-80％的PEG6000、PEG4000、PEG1000中的一种或一种以上的组合和占栓剂基质重量20-80％的PEG200、PEG300、PEG400或PEG600组成，或由占栓剂基质重量80％-95％的PEG6000、PEG4000、PEG1000中的一种或一种以上的组合和占栓剂基质重量5％-20％的水凝胶组成，采用上述栓剂基质制成的橄榄苦苷栓剂为速释栓剂。所述速释栓剂是指按2015年版中国药典四部0931溶出度与释放度测定法操作，转速设置为50rpm，至60min溶出可达60％以上的栓剂。速释栓剂主要用于炎症急性期的治疗。
进一步地，所述栓剂基质由占栓剂基质重量60％-90％的PEG6000、PEG4000、PEG1000中的一种或一种以上组合和占栓剂基质重量5％-20％的脂溶性基质及占栓剂基质重量5％-20％的水凝胶组成，采用该栓剂基质制成的橄榄苦苷栓剂为中等释放速度的栓剂。所述中等释放速度栓剂是指按2015年版中国药典四部0931溶出度与释放度测定法操作，转速设置为50rpm，至2h溶出在30％-60％范围的栓剂。中等释放速度栓剂用于炎症控制后的巩固治疗，减少给药次数。
进一步地，所述水凝胶采用浓度为0.2-2％的卡波姆溶液、1-10％的羧甲基纤维素钠溶液、1-10％的甲基纤维素溶液、1-10％的羟丙甲纤维素溶液或1-15％的海藻酸钠溶液。
进一步地，所述脂溶性基质为月桂酸甘油酯、单硬脂酸甘油酯、棕榈酸酯或硬脂酸丙二醇酯。
本发明不仅研制了速释的橄榄苦苷栓剂，同时经过反复试验，还得到了中等释放速度的栓剂，该栓剂2h释药在50％左右，至6h释药可达90％以上，不仅对急性期炎症有治疗作用，同时与速释栓剂比较，作用时间延长，用药次数可减少为每日2-3次。此外，本发明还在基质中引入了水凝胶，水凝胶具有一定的润滑作用，但易引起栓剂发软，成型性差，本发明通过将脂溶性基质与水凝胶联用，可使栓剂既具有良好的润滑效果，又硬度适中，不易变形，同时还具有一定的韧性，病人用药舒适，释药速度适中，能达到理想的疗效。
本发明栓剂经阴道给药可用于治疗阴道炎、盆腔炎及宫颈糜烂等妇科疾病，经直肠给药可用于治疗直肠炎及直肠癌，也可经直肠粘膜下血管进入全身血液循环，发挥全身性的抗炎、改善骨质疏松症状等作用。
附图说明
图1为实施例1制得的速释橄榄苦苷栓剂的溶出曲线。
图2为实施例2制得的速释橄榄苦苷栓剂的溶出曲线。
图3为实施例3制得的具有中等释放速度的橄榄苦苷栓剂的溶出曲线。
具体实施方式
为了更好地理解本发明，下面结合具体实施例对本发明作进一步详细描述，但本发明的保护范围不限于此。
实施例1 速释橄榄苦苷栓剂
(1)取卡波姆0.3g，加水29.7g，静置4h，制得浓度为1％的卡波姆溶液即水凝胶；
(2)取橄榄苦苷，研细，过100目筛后称取3g，将3g橄榄苦苷分多次加入水凝胶中，搅拌均匀；
(3)称取PEG4000198g，将其在80℃加热熔融后，再置于60℃保温；
(4)称取步骤(2)制得的混有橄榄苦苷的水凝胶22g，将其加至熔融的PEG4000中，保温搅拌20min，使其混合均匀；
(5)将步骤(4)获得的含有橄榄苦苷的基质趁热倒入栓模中，制得速释橄榄苦苷栓剂100粒，每粒重量为2.2g，每粒含橄榄苦苷20mg，含基质2.18g，基质中PEG4000占90.83％，水凝胶占9.17％。
取6粒制得的橄榄苦苷栓剂测定硬度，平均硬度为7.54±0.06kg；按2015版中国药典四部0931溶出度与释放度测定法第二法测定栓剂的溶出，转速50rpm，溶出曲线见图1。本品60min溶出达94％，属橄榄苦苷速释栓剂。
实施例2 速释橄榄苦苷栓剂
(1)取PEG400 109g，加入橄榄苦苷2g，超声或略加热使橄榄苦苷溶解；
(2)称取PEG4000 99g，将其在80℃加热熔融后，再置于60℃保温；
(3)将步骤(1)获得的含有橄榄苦苷的PEG400分多次加入熔融的PEG4000中，边加入边搅拌，加毕，继续搅拌30min；
(4)将步骤(3)获得的含有橄榄苦苷的基质趁热倒入栓模中，制得速释橄榄苦苷栓剂100粒，每粒重量为2.1g，每粒含橄榄苦苷20mg，含基质2.08g，基质中PEG4000占47.60％，PEG400占52.4％。
取6粒制得的橄榄苦苷栓剂测定硬度，平均硬度为1.70±0.22kg；按2015版中国药典四部0931溶出度与释放度测定法第二法测定栓剂的溶出，转速50rpm，溶出曲线见图2。本品60min溶出达71％，属橄榄苦苷速释栓剂。
实施例3 中等释放速度的橄榄苦苷栓剂
(1)取羧甲基纤维素钠0.3g，加水29.7g，静置4h，制得浓度为1％的羧甲基纤维素钠溶液即水凝胶；
(2)取橄榄苦苷，研细，过100目筛后称取3g，将3g橄榄苦苷分多次加入水凝胶中，搅拌均匀；
(3)称取PEG4000 176g和单硬脂酸甘油酯22g，将其在80℃加热熔融后，再置于60℃保温；
(4)称取步骤(2)制得的混有橄榄苦苷的水凝胶22g，将其加至熔融的PEG4000和单硬脂酸甘油酯中，保温搅拌20min，使其混合均匀；
(5)将步骤(4)获得的含有橄榄苦苷的基质趁热倒入栓模中，制得中等释放速度橄榄苦苷栓剂100粒，每粒重量为2.2g，每粒含橄榄苦苷20mg，含基质2.18g，基质中PEG4000占80.73％，单硬脂酸甘油酯占10.09％，水凝胶占9.17％。
取6粒制得的橄榄苦苷栓剂测定硬度，平均硬度为4.50±0.17kg；按2015版中国药典四部0931溶出度与释放度测定法第二法测定栓剂的溶出，转速50rpm，溶出曲线见图3。本品60min溶出达38％，2h溶出46％，经6h溶出达92％，属中等释放速度的橄榄苦苷栓剂。
实施例4 中等释放速度的橄榄苦苷栓剂
本实施例制得的中等释放速度的橄榄苦苷栓剂每粒重3.44g，每粒含橄榄苦苷40mg，含基质3.4g，基质中PEG6000占73.53％，月桂酸甘油酯占14.71％，水凝胶占11.76％。水凝胶为浓度为5％的甲基纤维素溶液。
实施例5 中等释放速度的橄榄苦苷栓剂
本实施例制得的中等释放速度的橄榄苦苷栓剂每粒重3.8g，每粒含橄榄苦苷50mg，含基质3.75g，基质中PEG6000占43％，PEG1000占20％，硬脂酸丙二醇酯占18％，水凝胶占19％。水凝胶为浓度为10％的海藻酸钠溶液。
实施例6 中等释放速度的橄榄苦苷栓剂
本实施例制得的中等释放速度的橄榄苦苷栓剂每粒重2.8g，每粒含橄榄苦苷10mg，含基质2.79g，基质中PEG1000占88％，棕榈酸酯占6％，水凝胶占6％。水凝胶为浓度为10％的卡波姆溶液。
实施例7 速释橄榄苦苷栓剂
本实施例制得的速释橄榄苦苷栓剂每粒重3.0g，每粒含橄榄苦苷40mg，含基质2.96g，基质中PEG6000占82％，水凝胶占18％。水凝胶为浓度为5％的甲基纤维素溶液。
实施例8 速释橄榄苦苷栓剂
本实施例制得的速释橄榄苦苷栓剂每粒重2.6g，每粒含橄榄苦苷10mg，含基质2.59g，基质中PEG6000占65％，PEG1000占30％，水凝胶占5％。水凝胶为浓度为8％的海藻酸钠溶液。
实施例9 速释橄榄苦苷栓剂
本实施例制得的速释橄榄苦苷栓剂每粒重2.8g，每粒含橄榄苦苷10mg，含基质2.79g，基质中PEG6000占22％，PEG200占78％。
实施例10 速释橄榄苦苷栓剂
本实施例制得的速释橄榄苦苷栓剂每粒重3.2g，每粒含橄榄苦苷30mg，含基质3.17g，基质中PEG1000占35％，PEG600占45％，PEG400占20％。
实施例11 速释橄榄苦苷栓剂
本实施例制得的速释橄榄苦苷栓剂每粒重3.2g，每粒含橄榄苦苷40mg，含基质3.16g，基质中PEG4000占38％，PEG1000占40％，PEG300占22％。
以上所述仅是本发明较好的实施方式，但本发明的保护范围并不局限于此，任何基于本发明的方案和构思进行的改进和替换都应涵盖在本发明的保护范围内。
Claims (2)
1.一种橄榄苦苷栓剂，由橄榄苦苷和栓剂基质制成，每粒栓剂中含橄榄苦苷10-50mg，所述栓剂基质由占栓剂基质重量80％-95％的PEG6000、PEG4000、PEG1000中的一种或一种以上的组合和占栓剂基质重量5％-20％的水凝胶组成，所述水凝胶采用浓度为0.2％-2％的卡波姆溶液、1％-10％的羧甲基纤维素钠溶液、1％-10％的甲基纤维素溶液、1％-10％的羟丙甲纤维素溶液或1％-15％的海藻酸钠溶液，采用上述栓剂基质制成的橄榄苦苷栓剂为速释栓剂。
2.一种橄榄苦苷栓剂，由橄榄苦苷和栓剂基质制成，每粒栓剂中含橄榄苦苷10-50mg，所述栓剂基质由占栓剂基质重量60％-90％的PEG6000、PEG4000、PEG1000中的一种或一种以上组合和占栓剂基质重量5％-20％的脂溶性基质及占栓剂基质重量5％-20％的水凝胶组成，所述水凝胶采用浓度为0.2％-2％的卡波姆溶液、1％-10％的羧甲基纤维素钠溶液、1％-10％的甲基纤维素溶液、1％-10％的羟丙甲纤维素溶液或1％-15％的海藻酸钠溶液,所述脂溶性基质为月桂酸甘油酯、单硬脂酸甘油酯、棕榈酸酯或硬脂酸丙二醇酯，采用该栓剂基质制成的橄榄苦苷栓剂为中等释放速度的栓剂。
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