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二甲双胍片资料调研一、品种概述盐酸二甲双胍研发历史:1950年,格华止公司开发了苯乙双胍及多种双胍类药物。1957年,二甲双 胍首次在临床上使用,被批准用于治疗糖尿病。2000年,二甲双胍缓释片(格 华止)在美国批准上市,并研发出一些双胍类药物与其他药物的复合制剂。化学信息:中文名称:盐酸二甲双胍英文名称:Metformin HC1日本名称:塩酸具卜7才儿分子式:叽CN分子量:165.61、原研及美、欧、日上市信息FDAN020357ABYesMETFORMINHYDROCHLORIDETABLET;ORAL1GMGLUCOPHAGEBRISTOL MYERSSQUIBBN020357ABNoMETFORMINHYDROCHLORIDETABLET;ORAL500MG GLUCOPHAGEBRISTOL MYERSSQUIBBN020357ABNoMETFORMINHYDROCHLORIDETABLET;ORAL850MGGLUCOPHAGEBRISTOL MYERSSQUIBB日本XT汐。標準販売名会社名含量単位薬価後発品規格公示 承認5大b八二八錠2 5 0 mg日本新薬250mg1錠9.60公的b公示日本新薬生产的二甲双胍片250mg为参比制剂,日本共有26家上市公司上市, 规格 250mg ,500mg 片。2、国内生产上市情况目前SFDA共批准122个批件用于盐酸二甲双胍片生产,规格为:250mg 和 500mg。3、进口情况产品名称生产厂家规格商品名二甲双胍片澳大利亚,默克500mgDiaformin迪化唐锭二、原料药理化性质1、关键理化信息理化项目性质描述性状本品为白色或类白色粉末或结晶性粉末。溶解度易溶于水,在甲醇中溶解,在乙醇中微溶,不溶于乙醚和氯仿。比旋度+285。至+298熔点222-226(分解)解离常数(pKa)pKa = 12.4立体构型NH NH (I II.NCNHCNF-L HCl hL晶型/粒度/将用于制剂生产的物理形态/2、在各种溶出介质中的溶解度及稳定性在各溶出介质中的溶解度(37 C):pH1.2: 333mg/mlpH4.0: 353mg/mlpH6.8: 355mg/ml水:346mg/ml在各溶出介质中的稳定性:水:未测定。在各pH值溶出介质中:未测定。光:未测定。2、生物药剂学分类统(BCS)二甲双胍:三类,盐酸二甲双胍:无。三、制剂1、制剂处方美国百时美施贵宝公司参比制剂处方:500mg2、溶出方法方法一(中国):【检苫】容出廈収丰帛朋落川履匀障械慶鬪宦注(:通轴意).口术】0皿曲为粘;U介质.转理为饵分轴100 轻.依迭槪怖咼45分悴时*血请膛试煥洼世捍夬初就液 IDmh帮嶄憾取竦冏灌适比.阳水足fit祁海制咸毎巾卜中岬舍 亦口的第谁.黑章剧宜项下的方法嚣定.计肓卿川的磨出 最隈咸肖折爪駄儕应符咅規应.方法二(日本):取本品,照溶出度测定法(桨板法)以水900ml为溶剂,转速为每分钟50转,依法操作,经120分钟(A型)或15分钟(B型)时, 取溶液适量滤过,弃去至少10ml初滤液,精密量取续滤液适量,加水稀释制成 每1ml中含5.6 “g的溶液,作为供试品溶液。另精密称取预经105C干燥3小 时的盐酸二甲双胍对照品0.028g,置200ml量瓶中,加水溶解并稀释至刻度, 摇匀,精密量取4ml,置100ml量瓶中,加水稀释至刻度,摇匀,作为对照品溶 液。取上述两种溶液照紫外-可见分光光度法,分别在233nm波长处测定吸光度, 计算每片的溶出量,限度为标示量的85% (A型)或80% (B型),应符合规定。方法三(美国):b-uffer 10C0 mL Dis-WLinMHi (7T1) lest 1 Medium; pH Apparatusi 1; Timbt 45 minStandard wlution; U5P Metformin Hydrochlande R5 in Met/iumSample solution;卩型巧 “ portion oi tie salulhtn under test through a suliable filter.In5tnjrnntl conditians(Seetomeffy and UghUmt伽吨(351.)An冃匕1 気冃I wavekogth; WiiVekngth of maKimuni )L- 50 r Ba nee at - HCI) tii55olved by using UV absorp- Uiun of filtered purtirjns cf the Sample wfutio diluted with Meiurn, if necessaryf in comparison with lbs JtonJcrM wfton.Toler flrices; MLT FO 開(Q) of the labeleJ j mount of rnetfbrrnin hydrcchbrid? (QHnNs - HCI) is dissolved.MnTes-t 2 II the product comp lies, with this test, the labeling indicates- Ihat it meets USP Drjsolution hst 2,For products labeled to contain 50Q mg of mBtformin hydrochlorideMedium; pH .&phosphabe buffer; 1000 mL Apparatus 2; 50 rpmTim-er 30 mlnStandard wlutn, 5-iirnple slutiQn, Instrumental onditi-on5, jnd AnalysiK Proceed as dinected in estTclerjinces: MLT 80fe (Q) uf the labeled amount of medofmln hydrcchhrkfe fG4 li iN - HCI) is di5wlved.For 卩r-oducts labeled to rontain B501 DOO mg ofmetformin hydrochlorideMedium; pH 6.8 phosphate bufl曰;1000 mL Apparatus Zr 75 rpimTim-er 10 ktiinStandard wlutian, Sflmple solution, Instrumcrtal ionditions,! “nd Analysis; Proceed as d inected in Tej/Tolerances: MLT 75 (Q) of the labeled amount of metformin hydrochloride (C4 li iNj. - HCI) is disolved.Ml - - j. ij. - n ” 6,8 phosphate buffer; 1000 mL1 00 rpmTime; 60 minTest 3: If the product complies with this test the labeling incikatea Iheil it meets U5P Ufjsci/utjoin i. MBuffer Dlve 1. ij of rnQncbask wdiurn phos- pheite in abcut 1800 mL erf water. Add 3 J84 g of1-pentane3uhfQnic acid sodium sa.ltL Adjust with diluted phophork afid to a pH of 3.00 0.05. Dilute with water to 2000 m L. 口 ai n tr=r i*来源溶出介质溶出方法介质体积取样点限度CP2015水100r/min、桨法1000ml45min70%USP36 (lg,850mg)0.01M磷酸二氢钠溶液(pH6.8)75r/min、桨法1000ml30min75%USP36 (500mg)0.01M磷酸二氢钠溶液(pH6.8)50r/min、桨法1000ml30min80%日本水50r/min、桨法900ml45min70%3溶岀曲线图来源日本厚生省药品体外溶出试验信息库四条标准溶出曲线溶出度试验条件:桨板法/50 转、溶出介质中不添加 表面活性剂。 A 型溶出曲線測定例血酸; A錠250mg枠準製剤a標準製剤a!.冇効威分乞:弗密;金八-:-2。剤鬆:錠題1 .合亶:溶出率应试纔滋nE4.: -HC.E, /?5 .回云帚铢沖 B型溶出曲線測定例 塩酸y bzh/lz 錠250mg標準製剤b標準頼剤b1 .有効成分名:塩酸;2 .剤形:錠剤 3 .含畳:250mg4.試験液:pHi.2、pH4,0. pH6,8.水 5.回転数:50rpm6 .界面活性劑:使用乜于四、标准收载情况1、标准情况剂型标准收载情况二甲双胍CP2015, USP36, EP8.0, BP2016, IP2010, JP16二甲双胍片CP2015, USP36,BP2016, IP2010, JP162、有关物质项目名称标准来源杂质控制二甲双胍CP2015双氰胺W0.02%,其他单个杂质W0.1%,总杂质w 0.5%。USP36Individual impurities: NMT 0.02% for metformin related compou nd A; NMT 0.1% for any other impurity.Total impurities: NMT 0.5%EP8.0Impurity A : not more than the area of the corresponding peak in the chromatogram obtained with reference solution(a)(0.02percent);一 unspecified impurities : for each impurity, not more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05percent);- total : maximum 0.2 per cent; 一 disregard limit : 0.3 times the area of the principal peak in the chromatogram obtained with referencesolution (b) (0.03percent);do not disregard the peak due to impurity A二甲双胍片CP2015双氰氨W0.02%,单个杂质W1.0%,总杂质W0.6%。EP8.0无USP39二甲双胍相关复合物AW0.02%,单个杂质W0.1%,总杂质W0.6%。
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