CN115475148A - 一种阿昔莫司缓释片及其制备方法 - Google Patents
一种阿昔莫司缓释片及其制备方法 Download PDFInfo
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- CN115475148A CN115475148A CN202110663860.3A CN202110663860A CN115475148A CN 115475148 A CN115475148 A CN 115475148A CN 202110663860 A CN202110663860 A CN 202110663860A CN 115475148 A CN115475148 A CN 115475148A
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- acipimox
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- 229960003526 acipimox Drugs 0.000 title claims abstract description 47
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- 239000000945 filler Substances 0.000 claims description 14
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- 235000012211 aluminium silicate Nutrition 0.000 claims description 8
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
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Abstract
本发明属于缓释制剂领域,具体涉及一种阿昔莫司缓释片及其制备方法,所述的阿昔莫司缓释片由片芯和缓释包衣层组成,片芯包含阿昔莫司、填充剂、崩解剂、助流剂、润滑剂以及骨架材料,缓释包衣层包含缓释膜控材料、增塑剂、消泡剂、抗粘剂。本发明采用骨架型和膜控型双重结合控制,释药徐缓,避免峰谷现象,优选辅料配比,使药品长期稳定性高,有关物质含量低,制备工艺简单,技术难度低,批间差异小,工业化生产。
Description
技术领域
本发明属于缓释制剂领域,具体涉及一种阿昔莫司缓释片及其制备方法。
背景技术
阿昔莫司,英文名称:Acipimox,化学名称为:5-甲基吡嗪-2-甲酸4-氧化物。分子式为C6H6N2O3。化学结构式为
阿昔莫司由意大利Farmitalia Carlo Erba公司研制开发,用于各种原发性和继发性高脂血症,可降低血浆总胆固醇、甘油三酯、低密度脂蛋白和极低密度脂蛋白含量,提高高密度脂蛋白含量。它可抑制脂肪组织释放游离脂肪酸,降低极低密度脂蛋白和低密度脂蛋白的血中浓度,导致血中甘油三醇和总胆固醇水平的降低,同时可以提高高密度脂蛋白——胆固醇量,通常在服药一个月之内即可改善血中脂质的含量。因此,阿昔莫司是一种很有市场前景的降血脂药。并且药物吸收迅速完全,1次口服后2h血浆浓度达峰值,部分药物与血浆蛋白相结合。药物在血液中半减期为4h,药物在体内很少代谢,绝大部分以原形通过肾脏排出体外。
缓释制剂是指在规定介质中,按要求缓慢的非恒速释放药物,与相应的普通制剂比较,给药频率减少一半或有所减少,且能显著增加患者依从性的制剂。其特点在于活性药物释放缓慢,吸收入血后可维持较长时间的有效治疗血药浓度。
与普通制剂相比,缓释制剂具有以下优点:(1)降低给药频率,方便给药,提高患者的顺应性。(2)减少血药浓度波动,吸收完全,提高药物疗效。(3)降低毒副作用,降低药物对胃肠道的刺激(4)全程治疗费用降低。
中国专利CN103211785A公开了一种阿昔莫司膜控缓释微丸胶囊,公开了丸芯处方和缓释衣膜处方,该制剂前期释放较慢,但后期有明显的突释现象,导致后期释放较快,释放不稳定,且药物释放时间较短。
发明内容
克服现有技术不足,本发明提供了一种骨架型和膜控型双重结合的阿昔莫司缓释片剂。通过优选亲水性凝胶骨架材料和膜控包衣材料配合使用,调节制剂的释药速率,释药徐缓,能有效避免峰谷现象,制备工艺简单,技术难度低,批次间的差异小,释放曲线重现性好,适合放大生产。
本发明的第一个目的是提供一种阿昔莫司缓释片,所述的阿昔莫司缓释片由片芯和缓释包衣层组成,片芯包含阿昔莫司、填充剂、崩解剂、助流剂、润滑剂以及骨架材料,缓释包衣层包含缓释膜控材料、增塑剂、消泡剂、抗粘剂,所述的填充剂为微晶纤维素、乳糖、预胶化淀粉、糊精、磷酸氢钙、白陶土中的一种或多种。
具体的,所述的处方按重量份计算组成如下:
片芯处方:
缓释包衣膜处方:
优选为:
片芯处方:
缓释包衣膜处方:
进一步的,所述的填充剂优选为白陶土、预胶化淀粉、微晶纤维素。
具体的,填充剂按重量份计算为:
白陶土 5-15份
预胶化淀粉 15-25份
微晶纤维素 100-280份;
优选为,白陶土、预胶化淀粉、微晶纤维素的重量份比为1:2:15。
进一步的,所述的缓释骨架材料为羟丙甲纤维素、羟乙基纤维素、海藻酸钠、聚氧乙烯、乙基纤维素、聚丙烯中的一种或多种;所述的崩解剂为交联羧甲基纤维素钠、干淀粉、低取代羟丙纤维素、交联聚维酮中的一种或多种;所述的粘合剂为羟丙基纤维素、聚维酮、明胶中的一种或多种;所述的助流剂为二氧化硅、滑石粉、微粉硅胶中的一种或多种;所述的润滑剂为硬脂酸镁、滑石粉、淀粉、聚乙二醇中的一种或多种。
进一步的,所述的缓释膜控材料为Eudragit RL 30D和Eudragit RS 30D,重量份比为1:5-12,优选为Eudragit RL 30D和Eudragit RS 30D的重量份比为1:9。
进一步的,所述的增塑剂为丙二醇、蓖麻油、邻苯二甲酸二乙酯、硅油、聚乙二醇、三乙酸三乙酯、油酸、柠檬酸三乙酯中的一种或多种;所述消泡剂为二甲基硅油;抗粘剂为聚乙二醇、滑石粉、硬脂酸镁、单硬脂酸甘油酯中的一种或多种。
进一步的,包衣的重量为片芯的10-20%,优选为15%。
本发明的第二个目的在于提供一种阿昔莫司缓释片的制备方法,其特征在于,包括如下步骤:
(1)粉碎混合:阿昔莫司原料经粉碎后过筛,将填充剂、崩解剂、骨架材料和阿昔莫司置于制粒机中,混合均匀;
(2)制粒:向步骤(1)混合物中加入适量2%的聚维酮K30溶液,制粒,干燥,整粒;
(3)总混:步骤(2)所得颗粒中加入助流剂和润滑剂,混合均匀;
(4)压片;
(5)包衣片芯。
具体的,阿昔莫司缓释片的制备方法包括如下步骤:
(1)阿昔莫司原料粉碎后过60目筛。
(2)称取处方量填充剂、崩解剂、骨架材料和阿昔莫司置于湿法混合制粒机中,混合均匀。
(3)向步骤(2)所得混合物中加入2%聚维酮K30溶液适量,制粒,于流化床制粒包衣机中进行干燥,干燥结束后用摇摆式颗粒机进行整粒,整粒机筛网目数为20目。
(4)向步骤(3)颗粒中加入处方量的助流剂和润滑剂,混合均匀。
(5)选择直径10mm的浅凹冲进行压片,调节充填深度和压片压力,制得素片。
(6)包衣:使用高剪切匀化机按缓释包衣膜处方配置包衣液,滑石粉和柠檬酸三乙酯加入水中,用匀浆机匀化,然后倒入Eudragit RL 30D和Eudragit RS30D的分散体中,搅拌,40目筛过滤,加入二甲基硅油作为消泡剂。在包衣锅中进行包衣,控制进风温度55-65℃,片床温度38-42℃。
与现有技术相比,本发明的有益效果在于:
(1)优选缓释膜控材料Eudragit RL 30D和Eudragit RS 30D以及比例,同时优化骨架材料,共同控制药物释放,使得药效平稳长效;
(2)优选填充剂的种类和配比,使得药物长期稳定性提高,有关物质降低,提高药物品质及用药安全性。
附图说明
图1实施例1-5体外累积释放度
图2对比实施例1-6体外累积释放度
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:(1000片)(单位:g)
制备方法:
(1)阿昔莫司粉碎后过60目筛,称取阿昔莫司、填充剂、崩解剂、骨架材料与阿昔莫司一同置于湿法混合制粒机中,混合均匀;
(2)向步骤(1)所得混合物中加入2%的聚维酮K30溶液适量,制粒,于流化床制粒包衣机中进行干燥,干燥结束后用摇摆式颗粒机进行整粒,筛网目数为20目;
(3)向步骤(3)制粒完的颗粒加入处方量的助流剂和润滑剂,混合均匀;
(4)选择直径10mm的浅凹冲装压片机,控制硬度为200N-300N,制得素片;
(5)使用高剪切匀化机按缓释包衣膜处方配置包衣液:将抗粘剂和增塑剂加入水中,用匀浆机匀化,倒入缓释材料水分散体中,搅拌,40目筛过滤,加入消泡剂,在包衣锅中进行包衣,控制进风温度55-65℃,片床温度38-42℃,包衣增重为15%。
实施例2:(1000片)(单位:g)
制备方法:
同实施例1。
实施例3:(1000片)(单位:g)
制备方法:
同实施例1。
实施例4:(1000片)(单位:g)
制备方法:
包衣增重10%,其他同实施例1。
实施例5:(1000片)(单位:g)
制备方法:
包衣增重20%,其他同实施例1。
对比实施例1:(1000片)(单位:g)
制备方法:
同实施例1。
对比实施例2:(1000片)(单位:g)
制备方法:
同实施例1。
对比实施例3:(1000片)(单位:g)
制备方法:
同实施例1。
对比实施例4:(1000片)(单位:g)
制备方法:
同实施例1。
对比实施例5:(1000片)(单位:g)
制备方法:
同实施例1。
对比实施例6:(1000片)(单位:g)
制备方法:
同实施例1。
验证实施例
含量、有关物质和释放度的检测
含量及含量均匀度测定照紫外-可见分光光度法(中国药典2020年版四部通则0401)测定。供试品溶液:取本品20片,研细,混匀,精密称取细粉适量(约相当于阿昔莫司50mg),置250ml量瓶中,加水适量,超声使阿昔莫司溶解,用水稀释至刻度,摇匀,滤过,精密量取续滤液2ml,置50ml量瓶中,用水稀释至刻度,摇匀。对照品溶液:取阿昔莫司对照品适量,精密称定,加水溶解并定量稀释制成每1ml中含8μg的溶液。测定法:取供试品溶液与对照品溶液,在264nm的波长处分别测定吸光度,计算。
有关物质照高效液相色谱法(通则0512)测定。供试品溶液:取本品内容物,精密称定,加流动相使阿昔莫司溶解并定量稀释制成每1ml中约含阿昔莫司0.2mg的溶液,摇匀,滤过,取续滤液。对照溶液:精密量取供试品溶液适量,用流动相定量稀释制成每1ml中约含阿昔莫司1μg的溶液。对照品溶液:取杂质I对照品适量,精密称定,加流动相溶解并定量稀释制成每1ml中约含1μg的溶液。系统适用性溶液:取阿昔莫司与杂质I对照品各适量,加流动相溶解并稀释制成每1ml中分别约含200μg与2μg的混合溶液。色谱条件:用十八烷基硅烷键合硅胶为填充剂;甲醇-0.01mol/L四丁基氢氧化铵溶液(15:85)(用磷酸调节pH值至6.0)为流动相,检测波长为264nm;进样体积20μl。系统适用性要求:系统适用性溶液色谱图中,理论板数按阿昔莫司峰计算不低于6000,阿昔莫司峰与杂质I峰之间的分离度应符合要求。测定法:精密量取供试品溶液、对照溶液与对照品溶液,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的2倍。限度:供试品溶液色谱图中,如有与杂质I峰保留时间一致的色谱峰,按外标法以峰面积计算,不得过阿昔莫司标示量的0.5%;其他单个杂质峰面积不得大于对照溶液主峰面积的0.4倍(0.2%),其他各杂质峰面积的和不得大于对照溶液的主峰面积(0.5%)。
参照溶出度与释放度测定法(中国药典2020年版四部通则0931第一法)测定。采用第一法装置,以盐酸溶液(取氯化钠2g,加盐酸7ml,用水稀释至1000ml)900ml为溶出介质,转速为每分钟50转,依法操作,经1小时、2小时、4小时、6小时、8小时、10小时、12小时时分别取样10ml。滤过,并及时在操作容器中补充相同温度的溶出介质10ml,精密量取续滤液5ml,置100ml量瓶中,用0.1mol/L的盐酸溶液稀释至刻度,作为供试品溶液;取阿昔莫司对照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中约含10μg的溶液,作为对照品溶液。分别取供试品溶液和对照品溶液,照紫外-可见分光光度法(中国药典2020年版四部通则0401),在270nm的波长处分别测定吸收度,计算每片在不同时间的释放量。
表1实施例1-5体外累积释放度
表2对比实施例1-6体外累积释放度
将实施例1-3、对比实施例1-6所制的样品铝塑包装后进行加速考察(40℃、75%RH),于1个月、3个月、6个月末取样进行检测含量、有关物质。其他实施例的效果与实施例1-3相同或类似,在此不一一列举。
表3稳定性长期考察结果
通过对比实施例与对比实施例的体外累积释放度以及长期稳定性考察结果,本发明技术方案具体的实施例1-5体外释放平缓长效,避免剂量突释现象,保证临床用药安全性,且实施例1-5有效成分含量高,有关物质含量度,长期稳定。
Claims (10)
1.一种阿昔莫司缓释片,其特征在于,所述的阿昔莫司缓释片由片芯和缓释包衣层组成,片芯包含阿昔莫司、填充剂、崩解剂、助流剂、润滑剂以及骨架材料,缓释包衣层包含缓释膜控材料、增塑剂、消泡剂、抗粘剂,所述的填充剂为微晶纤维素、乳糖、预胶化淀粉、糊精、磷酸氢钙、白陶土中的一种或多种。
4.根据权利要求1所述的阿昔莫司缓释片,其特征在于,所述的填充剂优选为白陶土、预胶化淀粉、微晶纤维素。
5.根据权利要求4所述的阿昔莫司缓释片,其特征在于,所述的填充剂按重量份计算为白陶土5-15份、预胶化淀粉15-25份、微晶纤维素100-280份,优选为白陶土、预胶化淀粉、微晶纤维素的重量份比为1:2:15。
6.根据权利要求1所述的阿昔莫司缓释片,其特征在于,所述的缓释骨架材料为羟丙甲纤维素、羟乙基纤维素、海藻酸钠、聚氧乙烯、乙基纤维素、聚丙烯中的一种或多种;所述的崩解剂为交联羧甲基纤维素钠、干淀粉、低取代羟丙纤维素、交联聚维酮中的一种或多种;所述的粘合剂为羟丙基纤维素、聚维酮、明胶中的一种或多种;所述的助流剂为二氧化硅、滑石粉、微粉硅胶中的一种或多种;所述的润滑剂为硬脂酸镁、滑石粉、淀粉、聚乙二醇中的一种或多种。
7.根据权利要求1所述的阿昔莫司缓释片,其特征在于,所述的缓释膜控材料为Eudragit RL 30D和Eudragit RS 30D,重量份比为1:5-12,优选为Eudragit RL 30D和Eudragit RS 30D的重量份比为1:9。
8.根据权利要求1所述的阿昔莫司缓释片,其特征在于,所述的增塑剂为丙二醇、蓖麻油、邻苯二甲酸二乙酯、硅油、聚乙二醇、三乙酸三乙酯、油酸、柠檬酸三乙酯中的一种或多种;所述消泡剂为二甲基硅油;抗粘剂为聚乙二醇、滑石粉、硬脂酸镁、单硬脂酸甘油酯中的一种或多种。
9.根据权利要求1所述的阿昔莫司缓释片,其特征在于,包衣的重量为片芯的10-20%,优选为15%。
10.一种制备权利要求1-9任一项所述阿昔莫司缓释片的方法,其特征在于,包括如下步骤:
(1)粉碎混合:阿昔莫司原料经粉碎后过筛,将填充剂、崩解剂、骨架材料和阿昔莫司置于制粒机中,混合均匀;
(2)制粒:向步骤(1)混合物中加入适量2%的聚维酮K30溶液,制粒,干燥,整粒;
(3)总混:步骤(2)所得颗粒中加入助流剂和润滑剂,混合均匀;
(4)压片;
(5)包衣。
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