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标题: 质量源于设计(QbD)在设计处方中的运用-以多潘立酮片为例 [打印本页]

作者: aiyao 时间: 2017-9-13 09:59 AM
标题: 质量源于设计(QbD)在设计处方中的运用-以多潘立酮片为例

摘要

研究背景：近年来，仿制药的比例在全球处于增长趋势，中国是仿制药大国，多潘立酮作为一种促胃动力药，是一种在我国运用较广泛的仿制药，生产厂家很多，然而原研产品杨森的吗丁啉占据最大的市场，然而从各厂家的体外溶出度来看，不同厂家的溶出度存在差异。在国家即将进行的固体制剂一致性评价中，多潘立酮作为国家的基药品种也即将要开展一致性的质量研究，很多仿制药为达到体外溶出度一致的情况需要进行处方和工艺的改进。

研究目的：为提高处方和工艺的开发的质量和效率，有必要采用ICH Q8的

QbD理念进行开发出一个稳定的多潘立酮片处方。

研究方法：本论文中先采用QbD的风险分析工具对产品的CQA进行初步分析，然后通过Minitab的DOE实验对API粒径、预交化淀粉用量、羧甲基淀粉钠用量、微晶纤维素用量、乳糖用量等因素对处方的影响进行研究，最后通过标准化效应的Pareto 图、标准化效应的正态图确认出对溶出有显著影响的因素是预交化淀粉用量、羧甲基淀粉钠用量；考虑到后续压片中的对片剂成型的影响，又采用DOE的实验方法通过标准化效应的Pareto图、标准化效应的正态图确认出对硬度有显著影响的因素是微晶纤维素和乳糖的用量；最后通过溶出度和硬度的影响因素叠加图得到了处方变量的设计空间，确定了处方。为对效果进行确认，新设计的处方制备的产品与原研药体外释放的4种溶出介质相比，相似因子大于50%或15分钟内溶出大于85%，证明该处方和参比制剂体外溶出行为相似。

研究结论：以确定的处方制备多潘立酮片，模拟市售包装在60℃/RH75%的条件下进行加速稳定性试验，对产品外观、溶出速释、有关物质、含量进行了30天的考察，结果表明，开发的多潘立酮片有较好的稳定性，在加速试验过程中各项关键质量指标无显著变化，适宜于商业化的生产。对该处方进行连续三个批次的中试放大，证明该处方稳定可靠，适合商业化的生产。

关键词：多潘立酮；溶出曲线；风险评估；DOE；稳定性

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Product DevelopmentUsingQualitybyDesignApproach

--FormulationDevelopmentofDomperidoneTablets

Abstract

Studybackground:Recentyearshavewitnessedarapidgrowthofthegenericdrugintheglobalmarketdrugsshare.Chinaisamajorproductionmarketintheworld.DomperidoneiswidelyusedasgastricdynamictreatmentdruginChina.AlthoughtherearealotofgenericproducersinChina,Xi'anJanssenpharmaceuticalfactory-thepatentproducerofMadinglin(thecommercialbrandnameofDomperidone)isstilldominatingthemarket.Accordingtotheresultsofthedissolutioninvitrobytheproducers,therestillexistthedifferencesamongthem.Sinceconformityassessmentsrequestedbythestateforthesoliddosageformsaretoberesumedshortly,andthequalitystudyoftheessentialdrug,Domperidone,isalsoneedtobedone.Therecipeandprocessofmanygenericdrugsshouldbeimprovedtomeetthevitrodissolutionconformityrequirements.

Studyobjectives:TheconceptofICHQ8andQbDshouldbeadoptedtoimprovethedevelopmentqualityandefficiencyoftherecipeandprocesstodevelopastablerecipeforDomperidone.

Studyapproach:ThispaperwastoconductaprimaryanalysesfortheCQAofthisproductwiththeassistanceoftheriskassessmenttoolofQbD,thenstudiedthepossibleimpactstotherecipebythefactorssuchasAPI’sparticlesize,thequantityofstarchquantity,PregelatinisedStarch,Carboxymethylstarchsodium,MicrocrystallineCellulose,andlactosethroughDOEtestofMinitab.Afterthat,itwasconfirmedthattheobviouseffectingfactorstothedissolutionwerethequantityofPregelatinisedStarch,CarboxymethylstarchsodiumbythemeansoftheParetochartandnormalplotofthestandardizedeffects.C**ideringtheimpactstothetabletsforminginthefollowingprocess,theDOEtestingmethodaswellastheParetochartandnormalplotofthestandardizedeffectswasadopted,anditwasassuredthatobviouscausestothehardnessarethequantityoftheMicrocrystallineCelluloseandlactose;andinlaststep,thedesignspaceoftherecipevariableswasderivedfromthelayoutchartsofthedissolutionandhardness,andtherecipehadbeenfixed.Inordertoverifytheeffectsofthedrug,4

8 f0 @& B! h I9 }! Y e

typesofthevitrodissolutionmediumoftheproductsofthenewlydesignrecipeandthepatentdrugistocontrasted.Ifthesimilarfactorismorethan50% orthesolutionisover85%within15minutes,theresolutionbehaviorofthenewrecipeofdomperidoneandthereferencedrugareverifiedthesame.

Studyconclusion:Itwassimulatedthemarketingpackagingofthenewrecipeundertheconditionof60℃/RH75%fortheacceleratedstabilitytest,andtheproductappearance,

immediateresolution,relatedsubstances,andassaywereobservedaslongas30days.Theresultsprovedthatthenewlydevelopeddomperidonecharacterizedwiththeimprovedstability,andthekeyqualit**catorsduringthestabilitytestwerenotfoundobviouschanges.Andathreecontinuousscale-upbatchtestprovedthatthisrecipeisstableandreadyforcommercialproduction.