CN114569564B - 戈舍瑞林缓释微球组合物 - Google Patents
戈舍瑞林缓释微球组合物 Download PDFInfo
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Abstract
本发明公开了一种戈舍瑞林缓释微球组合物,所述戈舍瑞林缓释微球组合物的起始原料包括戈舍瑞林或其可药用盐,以及乙交酯丙交酯共聚物;所述乙交酯丙交酯共聚物分子量分布为:分子量≥40000Da的占0.1‑2%、15000Da≤分子量<40000Da的占25‑30%、8000Da≤分子量<15000Da的占33‑37%、5000Da≤分子量<8000Da的占18‑22%、2000Da≤分子量<5000Da的占14‑16%、500Da≤分子量<2000Da的占1‑3%。本发明显著提高了药物包封率的同时,明显降低辅料用量,显著减少患者体内不必要的辅料摄入,进一步提高人体安全性。
Description
技术领域
本发明涉及药物制剂生产技术领域,特别涉及一种戈舍瑞林缓释微球组合物。
背景技术
戈舍瑞林是人工合成的十肽,也是***释放激素(LHRH)类似物,与LHRH相比,其稳定性更加优越、与LHRH受体亲和力更强,效价是LHRH百倍以上。戈舍瑞林功效因给药方式和剂量的不同具体表现为正向促进和负向调节,当发生短期、低剂量给药时,对垂体-性腺轴起到促进作用,临床上可治疗性功能低下、不***、***延后等症状。长期使用则抑制垂体-性腺轴分泌LHRH,从而引起男性血清睾酮和女性血清***的下降,临床上用于治疗性激素依赖性疾病,如***癌、乳腺癌、子宫肌瘤、子宫内膜异位症、性早熟等,停药后作用可逆转。
戈舍瑞林缓释制剂体内给药后,载体表面药物会引起血药浓度急剧上升,对垂体-性腺轴起到顺时兴奋作用,这个过程中体内性激素水平短暂上升,随后将进入持续释放期,对垂体-性腺轴起到长期抑制作用,具体表现为性激素分泌能力下降。在每28天用药一次治疗中,睾酮浓度将一直保持在去势后的浓度范围,从而持续发挥治疗效果。因此,适当的前期突释是很有必要的,将引发负反馈调节机制,前期血药浓度提升至一定水平后,才能够保证后期睾酮浓度一直保持在去势后的浓度范围。
目前市售戈舍瑞林长效制剂商品名(诺雷德),是由阿斯利康开发销售的植入剂,作用时间可维持一个月,1987年在法国获准上市,1989年获FDA批准上市,剂量3.6mg/支,适应症为闭经前的晚期乳腺癌、子宫内膜异位症和***癌。该植入剂为直径1.2mm、长度1cm的圆筒形颗粒,需要特殊设备和专业人员进行给药,注射前药栓预置于一次性针筒内,采用16号针(外径1.61mm、长30mm)进行注射。植入剂对患者创伤较大,注射引起疼痛程度大,所以顺应性差。除此之外,/>是热熔挤出(HME)制成的戈舍瑞林植入剂,其简要工艺流程为:戈舍瑞林与PLGA分别溶于醋酸→溶液混匀→过滤除菌→冷冻干燥→加热挤压→切割装配→包装,这种连续生产工艺,也存在诸多优点:连续生产、步骤少、放大效应小(无液中干燥等溶剂去除步骤),但采用HME技术包封多肽类药物,挤出时高温及醋酸一元的残留将不可避免的增加多肽有关物质至较高水平(总杂>2%,醋酸戈舍瑞林植入剂质量回顾与分析《药物分析杂质》)。
因此,开发一种有关物质水平低、顺应性更好的醋酸戈舍瑞林长效缓释剂是很有必要的。
目前国内多家企业纷纷投入戈舍瑞林微球的开发,山东绿叶采用S/O/W方法制备戈舍瑞林微球(CN104107434B),该方法API制粒技术对药物活性、释放行为影响均较大,API批间粒度分布差异很容易造成微球体内释放行为不稳定。根据其披露的API粒度分布d50(实施例0.067~3.44μm)及微球D(4,3)(体积四次矩平均径)(实施例88.5~157.4)可推测,微球粒度分布中位径为75~150μm(根据D(4,3)与d50关系换算),需要20~21G针给药。
赛乐医药披露一种戈舍瑞林植入剂的制备方法(CN102755627B),其制备原理与基本一致,只是改进了溶剂残留,并未解决植入剂注射时带来的疼痛效应。
齐鲁制药披露一种醋酸戈舍瑞林微球的制备方法(CN109692325A),这里复凝聚法的种种弊端(粒度分布宽、溶剂残留高、环境压力大、成本高、批量小)不再赘述。
丽珠医药采用复乳法制备戈舍瑞林微球(CN104840429B),复乳法已成功应用到上市产品亮丙瑞林微球(抑那通)中,突释高、包封率低是复乳法中最常见的问题,专利中通过改进液中干燥过程,在液中干燥后期升温至超过微球玻璃化转变温度(Tg)来达到闭孔效应,从而降低液中干燥过程中药物迁移引起的突释效应,这样改进带来的后果是微球包封率下降,只能通过增加投药量方式获得较高的载药量,具体见其实施例,包封率仅为90%左右(包封率=实际载药量百分比/理论投药量百分比×100%)。
发明内容
本发明的目的在于提供一种戈舍瑞林缓释微球组合物,显著提高了药物包封率的同时,明显降低辅料用量,显著减少患者体内不必要的辅料摄入,进一步提高人体安全性。
本发明解决其技术问题所采用的技术方案是:
一种戈舍瑞林缓释微球组合物,所述戈舍瑞林缓释微球组合物的起始原料包括戈舍瑞林或其可药用盐,以及乙交酯丙交酯共聚物;
所述乙交酯丙交酯共聚物分子量分布为:分子量≥40000Da的占0.1-2%、15000Da≤分子量<40000Da的占25-30%、8000Da≤分子量<15000Da的占33-37%、5000Da≤分子量<8000Da的占18-22%、2000Da≤分子量<5000Da的占14-16%、500Da≤分子量<2000Da的占1-3%。
该分子量分布的共聚物可通过商业购买各分子量范围的PLGA进行混合获得,或按常规手段纯化制备混合获得。或根据CN112694605所述技术方案获得。
聚合物的分子量分布对微球释放行为学的影响重大,本发明意外通过优化聚合物分子量分布,在提高稳定性,获得极为理想释放行为的微球组合物的同时,获得小粒径范围微球制剂,优化微球粒度分布,显著提高了药物包封效率(高达95%以上),保证达到1个月有效释放周期同时降低注射疼痛。
在此基础上本发明意外发现,通过添加一定量的冰醋酸,能够进一步显著提高药物包封率(甚至可达>100%)的作用,本发明加入冰醋酸目的是增加包封效率。
作为优选,所述戈舍瑞林缓释微球组合物的起始原料还包括冰醋酸。所述戈舍瑞林缓释微球组合物的起始原料还可以包括冻干保护剂。
作为优选,冰醋酸用量与戈舍瑞林摩尔比为0.1~1.1:1。更优选,冰醋酸用量与戈舍瑞林摩尔比为0.3~0.7:1。
作为优选,所述戈舍瑞林缓释微球组合物的粒度分布为d10 1~3μm,d50 5~50μm,d90 15~100μm。更优选,微球组合物粒度分布为d10 1~2μm,d50 5~10μm,d90 15~30μm。
作为优选,所述乙交酯丙交酯共聚物的乳酸单元和乙醇酸单元的摩尔比为85:15-50:50。更优选乙交酯丙交酯共聚物的乳酸单元和乙醇酸单元的摩尔比为75:25。
作为优选,所述乙交酯丙交酯共聚物的重均分子量范围为10000-20000Da,数均分子量范围为6000-9000Da。更优选乙交酯丙交酯共聚物的重均分子量范围为10000~15000Da,数均分子量范围为7000~8500Da。
作为优选,所述乙交酯丙交酯共聚物的末端为羧基末端。
作为优选,所述戈舍瑞林缓释微球组合物中,戈舍瑞林重量含量为8~12%,乙交酯丙交酯共聚物重量含量为73~80%,冻干保护剂重量含量为12~15%。当戈舍瑞林原料为其盐时,可以根据分子量进行折算。
作为优选,制备方法如下:
(1)将戈舍瑞林或其可药用盐溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
作为优选,制备方法如下:
(1)将戈舍瑞林或其可药用盐和冰醋酸溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
醋酸是内水相配制过程中重要的一部分,但在微球成品中已除去,去除过程主要通过液中干燥步骤。醋酸的加入可增强戈舍瑞林与聚合物之间的分子作用力,增加包封效率。此外,醋酸的作用还包括调节微球内药物分布水平。
所述的表面活性剂在外水相中浓度范围是0.1g/L-20g/L,更优选1g/L-10g/L,表面活性剂优选聚乙烯醇(PVA),其分子量范围不做特别限定。
所述液中干燥过程中,料液温度始终处于微球的玻璃化转变温度(Tg)之下。
所述的冻干保护剂这里不做特别要求,主要作用是防止微球冻干期间絮凝,成分包括但不限于甘露醇、乳糖、葡萄糖、氨基酸(甘氨酸),更优选的,可以是甘露醇。
本发明所述的微球组合物,主要应用于***癌、乳腺癌、子宫内膜异位症、子宫肌瘤、性早熟、***症。
本发明提供的微球组合物可以制备成无菌粉末形式,所述无菌粉末含有戈舍瑞林缓释微球组合物和甘露醇,其制备方法为:各相料液除菌过滤后在经过无菌验证的生产线上进行无菌生产、冻干、过筛、转移、粉末分装、轧盖。在给药前,将无菌粉末分散在无菌溶媒中。
本发明提供的无菌戈舍瑞林缓释微球给药方式为皮下注射和肌肉注射。
本发明提供的戈舍瑞林缓释微球适用针头为25G~26G针头。
本发明提供的戈舍瑞林缓释微球可提供至少30天释放周期,释放周期内能够以有效剂量释放戈舍瑞林。
本发明的有益效果是:本发明体内给药后,起效作用时间不低于28d,其载药量高、给药剂量低、粒径小、极大降低注射疼痛,提高病人顺应性。
附图说明
图1不同PLGA分子量分布的戈舍瑞林微球体外释放曲线对比;
图2内水相中添加和不添加醋酸的戈舍瑞林微球体外释放曲线对比;
图3是实施例1戈舍瑞林微球狗体内药时曲线,其中3a时间轴为0-35d,3b时间轴为0-1d;
图4是实施例1戈舍瑞林微球狗体内睾酮去势水平;
图5是实施例1戈舍瑞林微球显微镜图。
具体实施方式
下面通过具体实施例,对本发明的技术方案作进一步的具体说明。
本发明中,若非特指,所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法,如无特别说明,均为本领域的常规方法。
总实施方案:
一种戈舍瑞林缓释微球组合物,所述戈舍瑞林缓释微球组合物的起始原料包括戈舍瑞林或其可药用盐,以及乙交酯丙交酯共聚物;
所述乙交酯丙交酯共聚物分子量分布为:分子量≥40000Da的占0.1-2%、15000Da≤分子量<40000Da的占25-30%、8000Da≤分子量<15000Da的占33-37%、5000Da≤分子量<8000Da的占18-22%、2000Da≤分子量<5000Da的占14-16%、500Da≤分子量<2000Da的占1-3%。
所述戈舍瑞林缓释微球组合物的起始原料还包括冰醋酸。冰醋酸用量与戈舍瑞林摩尔比为0.1~1.1:1。
所述戈舍瑞林缓释微球组合物的粒度分布为d10 1~3μm,d50 5~50μm,d90 15~100μm。
所述乙交酯丙交酯共聚物的乳酸单元和乙醇酸单元的摩尔比为85:15-50:50。
所述乙交酯丙交酯共聚物的重均分子量范围为10000-20000Da,数均分子量范围为6000-9000Da。
所述乙交酯丙交酯共聚物的末端为羧基末端。
所述戈舍瑞林缓释微球组合物中,戈舍瑞林重量含量为8~12%,乙交酯丙交酯共聚物重量含量为73~80%,冻干保护剂重量含量为12~15%。
第一种制备方法如下:
(1)将戈舍瑞林或其可药用盐溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
第二种制备方法如下:
(1)将戈舍瑞林或其可药用盐和冰醋酸溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
定义:温升是至温度变化范围,即最高温度减去最低温度。
以下实施例中,“40000Da以上分子量占比、15000~40000Da占比、8000~15000Da占比、5000~8000Da占比、2000~5000Da占比、500~2000Da占比”为简化表述,实际表达的意思是:分子量≥40000Da的占比、15000Da≤分子量<40000Da的占比、8000Da≤分子量<15000Da的占比、5000Da≤分子量<8000Da的占比、2000Da≤分子量<5000Da的占比、500Da≤分子量<2000Da的占比。
实施例1
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw12000,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为9.59%,pH7.4PBS中,1d突释10.46%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上分子量占比0.47%、15000~40000Da占比27.02%、8000~15000Da占比34.66%、5000~8000Da占比20.70%、2000~5000Da占比14.81%、500~2000Da占比2.32%。
实施例2
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw13500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量9.66%,pH7.4PBS中,1d突释11.52%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上占比0.50%、15000~40000Da占比29.98%、8000~15000Da占比34.17%、5000~8000Da占比18.46%、2000~5000Da占比14.21%、500~2000Da占比1.68%。
实施例3
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw11200,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例(导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为9.58%,pH7.4PBS中,1d突释10.06%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上占比1.18%、15000~40000Da占比25.54%、8000~15000Da占比35.36%、5000~8000Da占比21.88%、2000~5000Da占比15.39%、500~2000Da占比1.65%。
实施例4(超出要求保护的PLGA分子量上限限度,后期释放变慢)
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw13500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为10.1%,pH7.4PBS中,1d突释9.31%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上占比1.34%、15000~40000Da占比31.18%、8000~15000Da占比35.74%、5000~8000Da占比20.01%、2000~5000Da占比11.59%、500~2000Da占比0.14%。
实施例5(超出要求保护的PLGA分子量下限限度,前期突释加快)
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw10500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为9.66%,pH7.4PBS中,1d突释13.63%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上占比0.67%、15000~40000Da占比17.71%、8000~15000Da占比28.22%、5000~8000Da占比35.29%、2000~5000Da占比15.35%、500~2000Da占比2.76%。
实施例6(加冰醋酸)
称取1.11g戈舍瑞林、0.0008mol冰醋酸加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw12500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/LPVA)按1:150体积比例在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为10.5%,pH7.4PBS中,1d突释9.95%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上分子量占比0.69%、15000~40000Da占比28.33%、8000~15000Da占比35.28%、5000~8000Da占比20.73%、2000~5000Da占比15.01%、500~2000Da占比2.54%。
实施例7(加冰醋酸)
称取1.11g戈舍瑞林、0.0004mol冰醋酸加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw12500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/LPVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为10.2%,pH7.4PBS中,1d突释10.77%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上分子量占比0.69%、15000~40000Da占比28.33%、8000~15000Da占比35.28%、5000~8000Da占比20.73%、2000~5000Da占比15.01%、500~2000Da占比2.54%。
实施例8
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(7525,Mw12500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例(导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为9.79%,pH7.4PBS中,1d突释10.83%,平稳释放28d。
其中上述PLGA分子量分布如下:40000Da以上分子量占比0.69%、15000~40000Da占比28.33%、8000~15000Da占比35.28%、5000~8000Da占比20.73%、2000~5000Da占比15.01%、500~2000Da占比2.54%。
实施例9(其它型号PLGA)
称取1.11g戈舍瑞林加热溶解于1.00g水配成内水相,冷却至室温;称取10.0gPLGA(5050,Mw17500,羧基末端)溶解于16.0g二氯甲烷配制成油相;将油相加入到内水相中预混1min(3000rpm),剪切3min(12000rpm),快速降温;将初乳和外水相(2.5g/L PVA)按1:150体积比例导入在线剪切机(IKA,7000rpm)制备复乳;随后进行液中干燥,干燥过程中控制料液温升不超过5℃,离心收集微球浓缩液,加入湿微球固含量16.3wt%的甘露醇,冷冻干燥,收集微球成品。获得戈舍瑞林微球载药量为9.55%,pH7.4PBS中,1d突释20.56%,平稳释放28d。
实施例10
微球中醋酸检测方法:
采用气相色谱(Shimadzu GC-2014)对实施例1-9进行醋酸残留分析,样品制备方法为:精密称取干燥后的微球20mg,加入1mL二甲基亚砜充分溶解,进样1μL。色谱条件如下:色谱柱:Rtx-1301(0.32mm×30m,1.8μm,GC-004)
柱温:起始80℃,10℃/min升温至110℃,30℃/min升温至180℃。
检测结果见表1
表1实施例微球醋酸残留检测结果
实施例 | 微球醋酸残留/% |
实施例1 | 未检出 |
实施例2 | 未检出 |
实施例3 | 未检出 |
实施例4 | 未检出 |
实施例5 | 未检出 |
实施例6 | 未检出 |
实施例7 | 未检出 |
实施例8 | 未检出 |
实施例9 | 未检出 |
醋酸为工艺助剂,内水相中添加一定比例醋酸均会在后续步骤去除。
实施例11
微球粒度分布检测方法:
采用粒度分析仪(Mastersizer3000)对实施例1-9进行粒度分布分析,选择湿法测定,介质选用0.5%SDS溶液,样品进样前超声30s。
检测结果见表2
表2实施例微球粒度分布检测结果
实施例 | D10/μm | D50/μm | D90/μm | span | D(4,3) |
实施例1 | 2.23 | 7.50 | 25.0 | 3.036 | 11.5 |
实施例2 | 2.19 | 7.20 | 25.2 | 3.196 | 11.4 |
实施例3 | 2.35 | 7.38 | 27.1 | 3.354 | 12.1 |
实施例4 | 2.19 | 8.33 | 27.7 | 3.062 | 8.81 |
实施例5 | 1.99 | 5.11 | 16.1 | 2.761 | 7.87 |
实施例6 | 2.38 | 10.5 | 29.7 | 2.602 | 12.9 |
实施例7 | 2.61 | 8.05 | 28.6 | 3.228 | 9.27 |
实施例8 | 2.66 | 7.95 | 24.9 | 2.797 | 9.85 |
实施例9 | 2.50 | 11.32 | 33.7 | 2.756 | 13.7 |
实施例12
微球中戈舍瑞林含量检测方法:
采用HPLC(Agilent1260 infinity II)对实施例1-9进行载药量测定,并根据投药量计算包封率,样品制备方法为:精密称取干燥后的微球10mg,加入2mL乙腈充分溶解,过0.22μm滤膜,进样10μL。
20%乙腈(含0.05%三氟乙酸)为流动相,色谱柱:C18(150mm×4.6mm×5μm),220nm处检测戈舍瑞林峰面积,根据标曲计算药物含量:
载药量(%)=实测药物含量/微球质量×100;
包封率(%)=实测载药量百分比/理论投药量百分比×100。
检测结果见表3
表3实施例微球包封率和载药量检测结果
实施例 | 包封率/% | 载药量/%(戈舍瑞林) | 载药量/%(醋酸戈舍瑞林) |
实施例1 | 95.9 | 9.59 | 10.07 |
实施例2 | 96.6 | 9.66 | 10.14 |
实施例3 | 95.8 | 9.58 | 10.06 |
实施例4 | 97.7 | 9.77 | 10.25 |
实施例5 | 96.6 | 9.66 | 10.14 |
实施例6 | 105.0 | 10.5 | 11.02 |
实施例7 | 102.0 | 10.2 | 10.71 |
实施例8 | 97.9 | 9.79 | 10.28 |
实施例9 | 95.5 | 9.55 | 10.02 |
液中干燥过程中,少量药物会向外水相进行迁移,随着有机溶剂的去除,部分低分子量PLGA也会迁移至外水相中,故药物包封率存在超过100%的现象。
此外,醋酸的加入会继续增加戈舍瑞林与聚合物之间的分子作用力,使包封率上升。
实施例13
戈舍瑞林微球体外释放检测方法:
释放介质:pH7.4等渗PBS,含0.02%叠氮化钠,37℃静止测试。取样点1h、2h、6h、1d、4d、7d、14d、21d、28d、35d、42d。料液取出后过滤进HPLC。
检测结果见图1-图2,图1表明只有在本发明保护范围内的分子量才能够得到满意的释放曲线,超出范围,不是过快就是过慢。
图2表明醋酸加或不加对药物释放影响不大,还会提高包封率。
图3-图4展示了本发明最佳实施例的体内给药情况及各药代指标变化情况。
图5戈舍瑞林微球显微镜图表明微球粒度小且均一。
以上所述的实施例只是本发明的一种较佳的方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (5)
1.一种戈舍瑞林缓释微球组合物,其特征在于,所述戈舍瑞林缓释微球组合物的起始原料包括戈舍瑞林或其可药用盐,以及乙交酯丙交酯共聚物;
所述乙交酯丙交酯共聚物分子量分布为:分子量≥40000Da的占0.1-2%、15000Da≤分子量<40000Da的占25-30%、8000Da≤分子量<15000Da的占33-37%、5000Da≤分子量<8000Da的占18-22%、2000Da≤分子量<5000Da的占14-16%、500Da≤分子量<2000Da的占1-3%;
所述戈舍瑞林缓释微球组合物的粒度分布为d10 1~2.66μm,d50 5~10.5μm,d90 15~29.7μm;
所述戈舍瑞林缓释微球组合物的起始原料还包括冰醋酸,冰醋酸用量与戈舍瑞林摩尔比为0.1~1.1:1;
所述乙交酯丙交酯共聚物的重均分子量范围为10000-20000Da,数均分子量范围为6000-9000Da;
所述戈舍瑞林缓释微球组合物中,戈舍瑞林重量含量为8~12%,乙交酯丙交酯共聚物重量含量为73~80%,冻干保护剂重量含量为12~15%。
2.根据权利要求1所述的戈舍瑞林缓释微球组合物,其特征在于,所述乙交酯丙交酯共聚物的乳酸单元和乙醇酸单元的摩尔比为85:15-50:50。
3.根据权利要求1所述的戈舍瑞林缓释微球组合物,其特征在于,所述乙交酯丙交酯共聚物的末端为羧基末端。
4.根据权利要求1所述的戈舍瑞林缓释微球组合物,其特征在于,制备方法如下:
(1)将戈舍瑞林或其可药用盐溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
5.根据权利要求1所述的戈舍瑞林缓释微球组合物,其特征在于,制备方法如下:
(1)将戈舍瑞林或其可药用盐和冰醋酸溶解于水配成内水相;将乙交酯丙交酯共聚物溶解于有机溶剂配成油相;
(2)将内水相和油相预混后剪切形成初乳;
(3)将初乳和含有表面活性剂的外水相剪切形成复乳;
(4)复乳在液中干燥罐内干燥除溶剂后进行连续收集;
(5)清洗微球,连续收集,加冻干保护剂,冷冻干燥。
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