CN114246836A - 一种普瑞巴林缓释片及其制备方法 - Google Patents
一种普瑞巴林缓释片及其制备方法 Download PDFInfo
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- CN114246836A CN114246836A CN202210074776.2A CN202210074776A CN114246836A CN 114246836 A CN114246836 A CN 114246836A CN 202210074776 A CN202210074776 A CN 202210074776A CN 114246836 A CN114246836 A CN 114246836A
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- pregabalin
- polyoxyethylene
- carbomer
- release tablet
- povidone
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 44
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
本发明提供的一种稳定的普瑞巴林缓释片,由含有活性成分普瑞巴林或其其药学上可接受的盐或水合物,乙基纤维素,交联聚维酮,聚氧乙烯,卡波姆,粘合剂和润滑剂组成。该片剂在胃酸介质下漂浮性能、溶胀迅速且直径大于13mm、溶胀后刚性良好,可以实现在胃内的长时间滞留,释放曲线及各项质量属性均与已上市原研制剂相似。
Description
技术领域
本发明属于药物制剂技术领域,尤其涉及普瑞巴林缓释片及其制备方法。
背景技术
普瑞巴林(Pregabalin),化学名为(S)-3-(氨基甲基)-5-甲基己酸,是第二代钙离子通道调节剂,其增强了与α2-δ亚基的亲和力,并且涉及与脑神经元活性的调节相关的内源抑制性神经传递质γ-氨基丁酸(GABA)有关,临床可以用于治疗糖尿病性末梢神经病变、疱疹后的神经痛以及作为成人局部癫痫发作的辅助治疗。
普瑞巴林缓释片最早由Pfizer研发并在美国上市,相较于每日2次或更多次给药的普瑞巴林速释制剂,普瑞巴林缓释片仅需每日服药一次,尤其对于年长患者和服用多种药物的患者而言,其可改善患者的服药依从性,也可以减轻或避免与剂量有关的不良反应(通过降低峰血药浓度Cmax),并提高疗效(通过增加有效血药浓度维持的时间)。然而,在开发每日给药一次的普瑞巴林剂型时存在一些问题。因为普瑞巴林是通过L-氨基酸输送***进行吸收,其并不显示均匀的胃肠道吸收。临床研究表明,普瑞巴林在小肠和升结肠吸收良好,但是超过结肠肝曲以后,其吸收非常差。这表示普瑞巴林的平均吸收窗为6小时或更短,如果开发成普通缓释制剂,当其约6小时后转移至结肠肝曲,这些药物将被浪费,不能发挥任何作用。
根据普瑞巴林的化合物特性,原研制剂即选择聚醋酸乙烯酯和聚乙烯基吡咯烷酮作为缓释骨架,聚醋酸乙烯酯为水不溶性骨架,经口服进入胃内后,通过溶胀剂使片剂膨胀后的尺寸大于贲门孔径,且由于骨架本身漂浮性能和刚性良好,可以确保片剂在胃内较长时间的滞留,从而起到缓慢起药效的作用。
Pfizer在中国专利号ZL200680041140.7,公开了一种含普瑞巴林、基质形成剂和溶胀剂并适用于每日口服一次的固体药用组合物,其基质形成剂包含聚醋酸乙烯酯和聚乙烯基吡咯烷酮(聚维酮),该基质形成剂的商品名为kollidon SR,溶胀剂包含交联聚乙烯基吡咯烷酮,其实施例采用粉末直压技术。
中国专利号zl201510275818.9,公布了一种含活性成分普瑞巴林的药物组合物,采用赋形剂包括基质形成剂和溶胀剂,其基质形成剂为聚醋酸乙烯酯和聚乙烯吡咯烷酮的混合物,溶胀剂选择交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙纤维素、聚氧乙烯之一或其任意组合,实施例中提到的制备方法为直压压片和干法制粒工艺。其特点是采用了与原研不一致的溶胀剂,避免交联聚乙烯吡咯烷酮的过氧化物带来的稳定性问题,提高了产品的稳定性。
中国专利号ZL201510252515.5,公布了一种普瑞巴林胃漂浮缓释片剂及其制备方法,赋形剂采用骨架材料、膨胀剂、助漂剂、稀释剂,骨架材料选自羟丙甲基纤维素、海藻酸钠、聚氧乙烯的一种或几种,膨胀剂选自交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素中的一种或几种,助漂剂选自十六寸、十八醇、山嵛酸甘油酯、硬脂酸中的一种或几种,稀释剂选择乳糖、微晶纤维素、磷酸氢钙、甘露醇、淀粉中的一种或几种。工艺为骨架材料、助漂剂、填充剂混合均匀后制软材,干燥过筛后,加入普瑞巴林和膨胀剂和润滑剂,并压片。其特点是采用了与原研不一致的基质形成剂(骨架材料),但工艺上采用湿法制粒,增加了制造成本。
中国专利申请号202010735998.5,公布了一种普瑞巴林胃漂浮缓释制剂,赋形剂采用的凝胶骨架材料含有海藻酸盐、溶胀材料含有聚氧乙烯,其中海藻酸盐的平均分子量为1*104至2×105,聚氧乙烯的分子量为1×105至1×107。其特点是采用了与原研不一致的基质形成剂(骨架材料)。
中国专利申请号202110604834.3,公布了一种普瑞巴林胃漂浮缓释片及其制备方法,采用羟乙纤维素或乙基纤维素的一种或两种(优选为羟乙纤维素),聚氧乙烯和卡波姆均聚物A型为清水凝胶骨架,以聚维酮为致孔剂,以交联聚维酮为溶胀剂。其特点是采用了与原研不一致的基质形成剂(骨架材料)。
中国专利申请号202110170974.4,公布了一种普瑞巴林组合物及其制备方法,首先将缓释材料完全溶解于溶剂中,然其特点是采用湿法制备普瑞巴林缓释微丸,后加入粘合剂,搅拌至完全溶解,再加入普瑞巴林和抗粘剂,搅拌均匀后,以基地微丸丸芯上药得普瑞巴林缓释微丸,继续与赋形剂或润滑剂混合制备成不片剂或胶囊机。其特点是采用空白丸芯上药方式制备普瑞巴林缓释微丸。
中国专利申请号201810608326.0,公开了一种普瑞巴林缓释组合物及其制备方法,组合物包含活性成分、基质形成剂、溶胀剂和凝胶剂。其特点是基质形成剂与原研产品一致,但溶胀剂和凝胶剂与参比制剂一致。
普瑞巴林化合物通常情况下稳定性均良好,其主要降解产物为内酰胺杂质(见下图)。综上所述,现有技术大多采用聚氧乙烯或卡波姆作为释放阻滞剂或溶胀剂,但本发明人的研究结果表明普瑞巴林与聚氧乙烯、卡波姆或kollidon SR在40℃高温、60℃高温或加速条件40℃/RH75%下条件下,内酰胺杂质均会明显增长,比如原研制剂其0时刻的杂质含量为0.45%,因此,依然需要开发一种制备工艺简单、生产效率高、稳定性好且经济效益好的普瑞巴林缓释片。
发明内容
针对现有技术的不足,本发明的目的是提供一种稳定的普瑞巴林缓释片及其制备方法,该片剂在胃酸介质下漂浮性能、溶胀迅速且直径大于13mm、溶胀后刚性良好,可以实现在胃内的长时间滞留,释放曲线及各项质量属性均与已上市原研制剂相似。
为实现发明目的,本发明采取如下的技术方案:
一种稳定的普瑞巴林缓释片,由含有活性成分普瑞巴林或其其药学上可接受的盐或水合物,乙基纤维素,交联聚维酮,聚氧乙烯,卡波姆,粘合剂和润滑剂组成。
作为优选,所述的粘合剂选自聚维酮,羟丙基纤维素,羟丙甲基纤维素中的一种或多种;润滑剂选自硬脂酸镁,滑石粉,硬脂酸钙,硬脂酸锌或硬脂酸富马酸钠中的一种或多种。
进一步地,所述的普瑞巴林缓释片各组分的量为:活性成分普瑞巴林330mg,乙基纤维素200mg,交联聚维酮265mg,聚氧乙烯180mg,卡波姆135mg,粘合剂20mg,润滑剂10mg;
或活性成分普瑞巴林165mg,乙基纤维素295mg,交联聚维酮335mg,聚氧乙烯180mg,卡波姆135mg,粘合剂20mg,润滑剂10mg。
作为优选,所述的乙基纤维素的粘度为10cPs,交联聚维酮型号为XL,聚氧乙烯分子量为6500000-7500000,卡波姆的粘度为4000cps-10000cps。
作为优选,所述的粘合剂为聚维酮K30,润滑剂为硬脂酸镁。
作为优选,所述活性成分普瑞巴林的粒径采用D90为400μm~500μm,D10大于150μm。
本发明的另一目的在于提供一种稳定的普瑞巴林缓释片的制备方法,采取如下的技术方案:
一种稳定的普瑞巴林缓释片的制备方法,包括如下步骤:
(1)称量及过筛:先后称取配方量的聚氧乙烯、卡波姆、交联聚维酮共同过40目,得聚氧乙烯卡波姆交联聚维酮混合物;称取配方量乙基纤维素过24目;称取配方量普瑞巴林过40目;
(2)隔离层包衣:取配方量的聚维酮K30,加水配置成固含量为10%的粘合剂溶液;取配方量的普瑞巴林,置流化床中,用粘合剂溶液进行底喷包衣,得普瑞巴林聚维酮隔离层物料;
(3)混合:依次将步骤(1)的聚氧乙烯卡波姆交联聚维酮混合物,步骤(2)的普瑞巴林聚维酮隔离层物料,步骤(1)的乙基纤维素先后加入到混合机中,混合;
(4)润滑:经步骤(3)得到的混合物中加入硬脂酸镁混合,取样检测中间体含量;
(5)压片:将步骤(4)得到的中间体安装于模具中,并根据中间体含量结果计算应压片重,控制片重差异在±3%,硬度在200N~240N;
(6)包装:采用HPDE瓶包装或双铝包装。
作为优选,所述步骤(3)和步骤(4)中的混合机的转数均为10转/分钟~20转/分钟。
本发明的一种稳定的普瑞巴林缓释片,其片芯重量设计为1133mg,除去普瑞巴林活性成分,需要辅料的用量较大,而本发明所用的乙基纤维素的粘度为10cPs,交联聚维酮型号为XL,聚氧乙烯分子量为6500000-7500000,卡波姆的粘度为4000cps-10000cps;其用量均在FDA非活性成分数据库(Inactive Ingredient Search for Approved DrugProducts)公布的范围内。
乙基纤维素是片剂优良的填充剂,广泛应用于口服和外用制剂中。乙基纤维素具有化学性质稳定,用量范围广,在水中及生理pH范围内均不会溶解的特点,其和原研制剂采用的聚醋酸乙烯酯聚维酮混合物具有非常相似的制剂学特性,本发明采用的乙基纤维素粘度为10cPs,粘度小,对影响药物的溶出释放也影响较小,在聚氧乙烯和卡波姆的凝胶化下,可以使片剂在溶液中漂浮的存在时间延长。
聚氧乙烯是将环氧乙烷在适宜的催化剂的作用下聚合而成,主要作为制剂中的黏附剂、片剂阻滞剂、增稠剂(助悬剂)。浓度为5~85%的聚氧乙烯可作为片剂黏合剂,聚氧乙烯的功能性发挥与分子量有关,大分子量的聚氧乙烯通过亲水性骨架溶胀而延缓药物释放。本发明采用的聚氧乙烯分子量为6500000-7500000,具有分子量较大、用量范围广、胶凝速度快、助悬性能好、是控制药物溶出释放主要成分之一,可以使片剂在溶液中漂浮的存在时间延长。
卡波姆是合成的高分子量的丙烯酸交联聚合物,主要作为助悬剂或增黏剂应用于液体或半固体的药物剂型,作为亲水凝胶剂,可改变(例如延长)剂型的药物释放,可以用于口服制剂,混悬剂、片剂、或缓释片剂。本发明采用的卡波姆的粘度为4000cps-10000cps,具有粘度较大、用量范围广、胶凝速度快、助悬能好、是控制药物溶出释放主要成分之一,可以使片剂在溶液中漂浮的存在时间延长。
交联聚维酮是水不溶性的片剂崩解剂或溶出剂,交联聚维酮可迅速表现出高的毛细管活性和优异的水化能力,几乎无凝胶的倾向,在缓释制剂中其可作为溶胀剂,充当制剂进入胃中从胃液中快速吸水膨胀,延长制剂在胃内的滞留时间。本发明采用的交联聚维酮型号为XL,具有用量范围广、溶胀性好,是控制药物溶出释放主要成分之一。
本发明是使用的粘合剂选自聚维酮、羟丙基纤维素、羟丙甲基纤维素中的一种或多种;优选的粘合剂为所述的粘合剂优选为聚维酮K30,主要作为固体制剂的溶出助剂、助悬剂、片剂黏合剂。
本发明公开的制备本发明缓释片的方法,主要体现在首先将普瑞巴林活性成分用聚维酮K30水溶液进行隔离层包衣,其最大的作用是在不影响活性成分释放的同时,避免了普瑞巴林与聚氧乙烯、卡波姆的直接接触,极大的提高了产品的稳定性。
本发明的普瑞巴林缓释片不含原研制剂的缓释骨架(kollidon SR),采用乙基纤维素为骨架填充物与聚氧乙烯和卡波姆共同形成水不溶性的骨架,可维持片剂在溶剂中长时间的漂浮;另一方面,本发明通过对活性成分进行隔离层包衣,有效提高了产品的稳定性。
附图说明
图1是试验3中自制制剂与参比制剂在不容溶出介质下的曲线对比示意图。
具体实施方式
下面结合实施例对本发明做进一步说明。
实施例1
一种普瑞巴林缓释片的制备方法方法,其生产10,00片时,包括如下步骤:
(1)称量:按照重量配比称取各原料及辅料,普瑞巴林330mg,乙基纤维素200mg,交联聚维酮265mg,聚氧乙烯180mg,卡波姆135mg,聚维酮K30 20mg,硬脂酸镁10mg;其中,普瑞巴林的粒径采用D90为4μm-100μm;乙基纤维素的粒径采用D90小于50μm。乙基纤维素的粘度为10cPs(规格为premium 10cp)、交联聚维酮型号为XL、聚氧乙烯分子量为6500000-7500000(规格为WSR LEO NF 303)、卡波姆的粘度为4000cps-10000cps(规格为980NF Polymer);
(2)过筛:先后称取配方量的聚氧乙烯、卡波姆、交联聚维酮共同过40目,得聚氧乙烯卡波姆交联聚维酮混合物;称取配方量乙基纤维素过24目;称取配方量普瑞巴林过40目;
(3)取配方量的聚维酮K30,加水配置成固含量为10%的粘合剂溶液;取配方量的普瑞巴林,置流化床中,用粘合剂溶液进行底喷包衣,得普瑞巴林聚维酮隔离层物料;
(4)混合:依次将步骤(1)的聚氧乙烯、卡波姆、交联聚维酮混合物,步骤(2)的普瑞巴林聚维酮隔离层物料,步骤(1)的乙基纤维素先后加入到混合机中,以15转/分钟,混合30分钟;
(5)润滑:经步骤(3)得到的混合物中加入硬脂酸镁,以15转/分钟,混合3分钟,取样检测中间体含量;
(6)压片:将步骤(4)得到的中间体安装22mm*10.8mm椭圆形模具,并根据中间体含量结果计算应压片重,控制片重差异在±3%,硬度在200N~240N;
(7)包装:采用铝铝包装。
实施例2
一种普瑞巴林缓释片的制备方法方法,其生产10,00片时,包括如下步骤:
(1)称量:按照重量配比称取各原料及辅料,普瑞巴林165mg,乙基纤维素295mg,交联聚维酮335mg,聚氧乙烯180mg,卡波姆135mg,粘合剂20mg,润滑剂10mg;其中,普瑞巴林的粒径采用D90为4μm-100μm;乙基纤维素的粒径采用D90小于50μm。乙基纤维素的粘度为10cPs(规格为premium 10cp)、交联聚维酮型号为XL、聚氧乙烯分子量为6500000-7500000(规格为WSR LEO NF 303)、卡波姆的粘度为4000cps-10000cps(规格为980NFPolymer);
(2)过筛:先后称取配方量的聚氧乙烯、卡波姆、交联聚维酮共同过40目,得聚氧乙烯卡波姆交联聚维酮混合物;称取配方量乙基纤维素过24目;称取配方量普瑞巴林过40目;
(3)取配方量的聚维酮K30,加水配置成固含量为10%的粘合剂溶液;取配方量的普瑞巴林,置流化床中,用粘合剂溶液进行底喷包衣,得普瑞巴林聚维酮隔离层物料;
(4)混合:依次将步骤(1)的聚氧乙烯、卡波姆、交联聚维酮混合物,步骤(2)的普瑞巴林聚维酮隔离层物料,步骤(1)的乙基纤维素先后加入到混合机中,以15转/分钟,混合30分钟;
(5)润滑:经步骤(3)得到的混合物中加入硬脂酸镁,以15转/分钟,混合3分钟,取样检测中间体含量;
(6)压片:将步骤(4)得到的中间体安装22mm*10.8mm椭圆形模具,并根据中间体含量结果计算应压片重,控制片重差异在±3%,硬度在200N~240N;
(7)包装:采用铝铝包装。
试验1
通过对上述实施例1-2中的原辅料进行相容性实验。用量较大的稀释剂乙基纤维素,按主药:辅料=1:5的比例混合;交联聚维酮、聚氧乙烯、卡波姆,按主药:辅料=10:1的比例混合粘合剂聚维酮K30、润滑剂硬脂酸镁,按主药:辅料=20:1的比例混合,按稳定性影响因素试验方法,分别在高温(60℃)、高湿(90%±5%RH,25℃)和光照(4500lx±500lx,90μW/cm2),放置30天,考察放置前后有关物质变化,同时观察外观性状、含量等的变化。实验结果显示,高温条件:普瑞巴林+聚氧乙烯样品在高温60℃下放样30天时,含量明显降低,有关物质增加也比较明显;普瑞巴林+卡波姆样品在高温60℃下放样10天和30天时,有关物质明显增加;普瑞巴林+薄膜包衣预混剂、普瑞巴林全处方样品高温30天时均可检测处未知杂质,总杂明显增加,分析可能为包衣粉、聚氧乙烯与普瑞巴林在60℃下可能存在部分化学反应的情况。
试验2
通过对实施例1-2制备的样品进行多介质溶出曲线测定,在0.06M盐酸溶液、pH4.5缓冲液、pH6.8缓冲液介质、900ml下下,采用中国药典溶出度装置2在37℃测定。实验结果显示,本发明的自制制剂溶出曲线在不同介质下均与参比制剂相似。
试验3
通过对实施例1-2制备的样品进行漂浮时间及溶胀尺寸测定:在0.06M盐酸介质、900ml下,采用中国药典溶出度装置2在37℃下测定。实验结果显示,本发明的自制制剂漂浮时间优于参比制剂,溶胀速率与参比制剂相似。
试验4
对上述实施例1和实施例2产品与原研上市产品同时进行影响因素(高温40℃、光照4500±500lux/h、高湿RH75%)放置30天研究、加速稳定性试验(40℃/75%)放置6个月和长期稳定性试验(30℃/65%)放置6个月,性状、有关物质、含量的对比。结果自制产品各时间点的性状、含量均与原研上市产品一致,有关物质变化趋势优于原研上市产品,见下表:
自研产品质量符合标准草案要求,且与原研产品相似,稳定性良好,自制制剂稳定性在各稳定性试验条件下(高温、高湿、光照、加速等条件)均优于原研产品。
该片剂在胃酸介质下漂浮性能、溶胀迅速且直径大于13mm(可从试验3中得到)、溶胀后刚性良好,可以实现在胃内的长时间滞留,释放曲线及各项质量属性均与已上市原研制剂相似。
Claims (8)
1.一种稳定的普瑞巴林缓释片,其特征在于由含有活性成分普瑞巴林或其其药学上可接受的盐或水合物,乙基纤维素,交联聚维酮,聚氧乙烯,卡波姆,粘合剂和润滑剂组成。
2.根据权利要求1所述的一种稳定的普瑞巴林缓释片,其特征在于所述的粘合剂选自聚维酮,羟丙基纤维素,羟丙甲基纤维素中的一种或多种;润滑剂选自硬脂酸镁,滑石粉,硬脂酸钙,硬脂酸锌或硬脂酸富马酸钠中的一种或多种。
3.根据权利要求1或2所述的一种稳定的普瑞巴林缓释片,其特征在于各组分的量为:活性成分普瑞巴林330mg,乙基纤维素200mg,交联聚维酮265mg,聚氧乙烯180mg,卡波姆135mg,粘合剂20mg,润滑剂10mg;
或活性成分普瑞巴林165mg,乙基纤维素295mg,交联聚维酮335mg,聚氧乙烯180mg,卡波姆135mg,粘合剂20mg,润滑剂10mg。
4.根据权利要求3所述的一种稳定的普瑞巴林缓释片,其特征在于所述的乙基纤维素的粘度为10cPs,交联聚维酮型号为XL、聚氧乙烯分子量为6500000-7500000,卡波姆的粘度为4000cps-10000cps。
5.根据权利要求3所述的一种稳定的普瑞巴林缓释片,其特征在于所述的粘合剂为聚维酮K30,润滑剂为硬脂酸镁。
6.根据权利要求1所述的一种稳定的普瑞巴林缓释片,其特征在于所述活性成分普瑞巴林的粒径采用D90为400μm~500μm,D10大于150μm。
7.如权利要求1至6任一所述的一种稳定的普瑞巴林缓释片的制备方法,其特征在于包括如下步骤:
(1)称量及过筛:先后称取配方量的聚氧乙烯、卡波姆、交联聚维酮共同过40目,得聚氧乙烯卡波姆交联聚维酮混合物;称取配方量乙基纤维素过24目;称取配方量普瑞巴林过40目;
(2)隔离层包衣:取配方量的聚维酮K30,加水配置成固含量为10%的粘合剂溶液;取配方量的普瑞巴林,置流化床中,用粘合剂溶液进行底喷包衣,得普瑞巴林聚维酮隔离层物料;
(3)混合:依次将步骤(1)的聚氧乙烯卡波姆交联聚维酮混合物,步骤(2)的普瑞巴林聚维酮隔离层物料,步骤(1)的乙基纤维素先后加入到混合机中,混合;
(4)润滑:经步骤(3)得到的混合物中加入硬脂酸镁混合,取样检测中间体含量;
(5)压片:将步骤(4)得到的中间体安装于模具中,并根据中间体含量结果计算应压片重,控制片重差异在±3%,硬度在200N~240N;
(6)包装:采用HPDE瓶包装或双铝包装。
8.如权利要求7所述的普瑞巴林缓释片的制备方法,其特征在于步骤(3)和步骤(4)中的混合机的转数均为10转/分钟~20转/分钟。
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