CN1726909A - 丁苯酞自乳化释药体系及其制备方法和应用 - Google Patents
丁苯酞自乳化释药体系及其制备方法和应用 Download PDFInfo
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- CN1726909A CN1726909A CNA2004100750682A CN200410075068A CN1726909A CN 1726909 A CN1726909 A CN 1726909A CN A2004100750682 A CNA2004100750682 A CN A2004100750682A CN 200410075068 A CN200410075068 A CN 200410075068A CN 1726909 A CN1726909 A CN 1726909A
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- butyphthalide
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- releasing medicine
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Abstract
本发明涉及丁苯酞新型药物传递与释放系统——自乳化释药体系及其制备工艺以及在药物制剂中的应用，该释药体系以1％～65％丁苯酞、10％～65％乳化剂为必要组成部分，再加以各种依托剂型所需的适宜赋形剂制成各种依托剂型，本发明大大提高了丁苯酞与胃肠壁的接触面积从而加快药物的吸收速率。
Description
技术领域
本发明涉及丁苯酞新型药物传递与释放系统——自乳化释药体系及其制备工艺以及在药物制剂中的应用。
技术背景
自乳化药物传递系统(Self-EmulsifyingDrugDeliverySystem，简称SEDDS)是包含油相、表面活性剂和助表面活性剂的固体或液体剂型，这一系统的基本特征是在胃肠道内或在环境温度(通常指体温37℃)及温和搅拌的情况下能自发形成水包油乳剂。随着乳化剂用量的增多，这种自乳化系统可在胃肠道内自发形成微乳，被称之为自微乳化药物传递系统(Self-MicroemulsifyingDrugDeliverySystem，SMEDDS)。SEDDS进入胃肠道后，先自乳化成乳滴。快速分散于胃肠道中，减少了由于药物与胃肠壁的直接接触引起的刺激，乳剂微粒在胃肠道内结构会改变或被破坏。破坏后形成的微米级或纳米级微粒能渗透进入胃肠道的粘膜层，经消化的油滴渗透进入血液循环。极大的提高了药物的生物利用度。自乳化释药体系主要用于脂溶性及水难溶性药物，增加药物的稳定性，提高生物利用度。
丁苯酞是芹菜及其籽中主要成分，它既可以从天然植物芹菜籽油中提取直接得到，也可以通过合成获得，在中国专利98125618.X中，公开了左旋丁苯酞在制备抗血栓形成及抗血小板凝聚药物中的应用，清楚地表明本品具有调节NOS-NO-cGMP系统功能及脑缺血后神经细胞花生四烯酸代谢的作用。在中国专利93117148.2中，公开了芹菜甲素在制备预防和治疗哺乳动物或人类脑缺血引起的疾病的药物中的应用，芹菜甲素即为无旋光活性的丁苯酞。本品为油状液体，具有浓烈的芹菜香味，化学结构式如下：
目前丁苯酞上市产品仅有软胶囊剂，即将药物以植物油分散后中直接灌封软胶囊，该剂型虽可掩盖药物的不良气味，但其内容物在水相中分散较差，体外溶出程度无法直接测得，不仅影响到产品生产过程中的质量控制，且很大程度上影响到药物吸收的速率。
另外，中国专利02123000.5是本公司采用环糊精衍生物包合改善丁苯酞水溶性的一项技术，此技术的使用不仅改善了本品的不良气味，更增加了其在水中的溶解度，但包合物制备过程中所使用主分子的用量受剂型容量所限制，不能完全满足患者对各种剂型的需求，如硬胶囊剂的制备受装量限制，片剂制备受片形大小适宜度限制，包合物主分子用量不宜太大；另外，包合技术动力消耗较大，且工艺操作多较为复杂，工艺控制点较多(如温度、研磨方式与力度、时间、搅拌速度与时间等)，使得该产品包合技术产业化进程较慢。
发明内容
本发明的目的是解决上述丁苯酞制剂产品在临床应用方面的缺欠，旨在公开一种新的丁苯酞释药体系—丁苯酞自乳化释药体系。
本发明针对丁苯酞特有的理化性质，通过大量实验设计的丁苯酞自乳化释药体系以重量百分比1％～65％丁苯酞、10％～65％乳化剂为必要组成部分，再加以各种依托剂型所需的适宜赋形剂形成各种制剂。
丁苯酞是指其消旋体、左旋体或右旋体。
本自乳化释药体系同样适用于油溶性丁苯酞衍生物。
本发明中SEDDS乳化剂主要为非离子乳化剂。非离子乳化剂比离子乳化剂毒性低，它们只引起胃肠道壁渗透性的可逆性转变。本发明中SEDDS乳化剂选自下列乳化剂中的一种物质，或两种或两种以上物质的混合物：不同种类的液体或固体乙氧基聚氧乙烯甘油酯、聚氧乙烯油酸酯、液态卵磷脂(如Ophase31，HLB＝4.0)、聚氧乙烯蓖麻油(CremophorEL，HLB＝13.5)、椰子油C8/C10聚乙二醇甘油酯(LabrafacCM10，HLB＝10)、杏仁油油酸聚乙二醇甘油酯(LabrafilM1944CSD，HLB＝3～4)、杏仁油油酸聚乙二醇(HLB＝3～4)甘油酯(LabrafilM2125CS)、聚氧乙烯(25)甘油三油酸酯(TagatTO，HLB＝11.3)、聚氧乙烯(20)山梨醇油酸酯(Tween80，HLB＝11.0)、聚乙二醇-8甘油辛酸/葵酸酯(Labrasol，HLB＝14)等。
制备过程：20～60℃水浴中使乳化剂充分融溶并混匀后，搅拌下加入丁苯酞混匀，加入赋形剂，制得制得具有丁苯酞自乳化释药体系的依托剂型。
取所得药液0.2ml，轻微搅拌下滴至100ml37℃人工胃液中，旋即自发形成均一水包油乳剂，显微镜观察结果乳滴粒径＜5μm者约占98.7％(见附图1)，与马尔文粒径分布检测结果基本一致(附图1)，属微乳范畴，故根据本剂型特点，称为丁苯酞自乳化(自微乳化)释药体系。
本发明在丁苯酞自乳化释药体系基础上，研制开发了系列丁苯酞自乳化释药制剂及采用自乳化释药机理的各种丁苯酞的剂型，加以各种依托剂型所需的适宜赋形剂，如丁苯酞自乳化释药片剂、软胶囊、颗粒剂、硬胶囊、口服液等口服制剂。
本发明丁苯酞自乳化释药体系尤其适用于软胶囊剂型，其内容物为具备自乳化特征的油状液，其组成为丁苯酞和乳化剂，还可加入赋形剂，赋形剂选自可口服的植物油，如麻油、玉米油、花生油、豆油、杏仁油、桃仁油、棉籽油、葵花籽油、橄榄油中的一种物质，或两种或两种以上物质的混合物，也可加入抗氧剂和亲脂性的矫味剂。
本发明所涉及的自乳化软胶囊中赋形剂可为常用的本发明丁苯酞自乳化释药体系同样适用于口服液剂型，它是具备自乳化特征的油状液，用水稀释后服用。其组成为丁苯酞、乳化剂，在前述丁苯酞自乳化释药体系制备基础上，还可加入助溶剂及适宜的矫味剂，直接制成口服液。
本发明丁苯酞自乳化释药体系同样适用于口服固体粉末或颗粒，本发明中丁苯酞自乳化释药体系所依托的口服固体制剂如片剂(包括缓、控释片)、胶囊剂(含缓、控释)、颗粒剂等，在前述丁苯酞自乳化释药体系制备基础上，加入口服固体剂型所需赋形剂，如崩解剂、粘合剂、矫味剂、及高分子骨架材料等，经常规工艺制备成具有自乳化特征的固体粉末或颗粒。
本发明中丁苯酞自乳化释药体系所依托的片剂，由具备自乳化特征的固体粉末或颗粒加适宜增塑剂、崩解剂及润滑剂混匀后采用适宜大小的冲模压制而成，必要时可包以适宜的衣膜如胃溶衣、肠溶衣、或醋酸纤维素及乙基纤维素等可延缓或控制药物释放的衣膜。
本发明中丁苯酞自乳化释药体系所依托的硬胶囊，由具备自乳化特征的固体粉末或颗粒加常规的润滑剂、缓控释材料，制得普通硬胶囊或控、缓释硬胶囊。
本发明所述自乳化软胶囊中内容物为具自乳化能力的油状液，其在水中崩解同时药物迅速向水中分散形成水包油乳剂，不仅可通过溶出度测定对产品质量进行评价，且大大提高了丁苯酞与胃肠壁的接触面积从而加快药物的吸收速率。自乳化释药体系不仅制备工艺简单，可操作性强，且具有生产或制备过程中动力消耗小，工业化程度较高等优点。
本批三批样品溶出度及粒度测定结果见表1：
表1 本批三批样品溶出度及粒度测定结果
| 031201 | 031202 | 031203 | 备注 | ||
| 粒径μm | ＞51～5＜1 | 2.784.6492.68 | 3.055.6491.31 | 2.545.0192.45 | 每批次计数总量为300个 |
| 结论1 | 三批样品均为自微乳化释药体系 | ||||
| 溶出度(％) | 自乳化(45min)普通软胶囊(60min) | 100.0195.4 | 99.696.8 | 98.992.5 | 遇水自成均一乳剂崩解时油滴贴于杯壁不能分散，溶出介质中需加入乳化剂方可测定 |
| 结论2 | 自乳化释药体系溶出度明显优于普通软胶囊 | ||||
丁苯酞自乳化软胶囊除具普通软胶囊可掩盖其强烈的特殊气味且服用方便，易于吞咽、病人依从性好等特点外，更可使油状活性成分在与胃液接触时迅速分散并形成水包油乳剂而提高吸收的程度和速度。本品经加速试验和长期实验结果表明：尽管在加热条件下软胶囊壳老化现象明显，崩解时间有所延长，但仍小于60分钟，符合中国药典有关规定，变化较明显，但外观、含量、降解物、自乳化时间及体外释放度崩各项指标均无明显变化。实验数据如表2：
表2 丁苯酞自乳化软胶囊初步稳定性考察
| 考察条件 | 外观 | 含量(％) | 降解物(％) | 自乳化时间(秒) | 体外释放度(％) | 崩解时限 | |
| 时间(月) | |||||||
| 初始 | 0 | 黄色透明软胶囊 | 100.3 | 0.61 | 2.33 | 99.3 | 5’50？ |
| 加速试验 | 1 | 黄色透明软胶囊 | 101.1 | 0.66 | 2.67 | 100.2 | 6’45？ |
| 2 | 黄色透明软胶囊 | 99.3 | 0.63 | 3.33 | 99.6 | 14’10？ | |
| 3 | 黄色透明软胶囊 | 98.4 | 0.62 | 3.5 | 100.2 | 28’30？ | |
| 6 | 黄色透明软胶囊 | 99.0 | 0.58 | 3.33 | 98.5 | 49’52？ | |
| 室温留样 | 1 | 黄色透明软胶囊 | 100.1 | 0.63 | 2.50 | 100.5 | 6’15？ |
| 3 | 黄色透明软胶囊 | 101.0 | 0.67 | 2.50 | 98.9 | 8’35？ | |
| 6 | 黄色透明软胶囊 | 99.4 | 0.66 | 2.67 | 100.1 | 9’45？ | |
| 12 | 黄色透明软胶囊 | 99.1 | 0.62 | 2.83 | 99.7 | 17’50？ | |
附图说明
附图1为激光粒度分布仪所测丁苯酞自乳化粒径分布结果，由图可知，粒径小于5μm的乳滴已超过98％，属自微乳化释药体系范畴，且由图中体积不足百分率曲线可知本体系中粒子分布范围比较集中、均匀。
具体实施方式
本发明选用软胶囊作为丁苯酞自乳化释药体系的优选依托剂型。
本发明中自乳化释药软胶囊内容物由丁苯酞与乳化剂组成，优选的重量百分比是：丁苯酞为10％～50％，乳化剂为15％～60％，亦可在药液油中加入适宜的抗氧剂二丁基羧基甲苯及矫味剂薄荷油、青苹果油等。
乳化剂优选聚氧乙烯蓖麻油与聚乙二醇-8甘油辛酸/葵酸酯的混合物，混合重量比例优选1∶0.5～1.5。丁苯酞与表面活性剂比例优选1∶0.5～1.5。
优选的制备工艺：25～50℃水浴中使氢化蓖麻油充分融溶，搅拌下加入聚乙二醇-8甘油辛酸/葵酸酯混合，得均一澄明油状液，室温搅拌下加入丁苯酞混匀，即得软胶囊内容物。
本发明中自乳化释药软胶囊囊材基本由胶料、增塑剂、水组成，三者重量比例为：1∶0.2～0.4∶0.8～1.3，还可以在囊材中加入适宜的防腐剂尼泊金乙酯或尼泊金甲酯及其混合物。
胶料可以是明胶、阿拉伯胶中的一种或二者混合物。
增塑剂可以是甘油、山梨醇中的一种或两者混合物。
本发明丁苯酞软胶囊可以采用常规的软胶囊制备工艺制得。如手工模压法、旋转模压法或滴制法。一般选用压制法如旋转模压法，使用自动旋转轧囊机，温度控制在40～50℃之间，使每个软胶囊中含有可药用量的丁苯酞。
为更好地说明本发明的技术方案，特给出以下实施例，但本发明并不仅限于此。
实施例1 丁苯酞自乳化软胶囊的制备
明胶液的制备：明胶100g，甘油30g，水130g和200mg尼泊金乙酯。取明胶加入适量的水使其吸水膨胀。另将甘油、尼泊金乙酯及余下的水置溶胶锅中加热至70-80℃，混合均匀，加入膨胀的明胶搅拌，熔融，保温1～2小时，静置，使泡沫上浮，刮去上浮的泡沫，以洁净白布过滤，保温待用。配成胶液粘度一般为2.8～3.2度；
药液油的制备：称取丁苯酞100g，聚乙二醇-8甘油辛酸/葵酸酯与聚氧乙烯蓖麻油各50g，充分搅匀即得；
压制软胶囊：将已制好的明胶甘油和丁苯酞装入自动旋转轧囊机中，温度控制在40～50℃，压制出每粒含200mg药液油的软胶囊。
药液油按此比例压制的软胶囊，外形大小适中，经检验含量均匀度好。
实施例2 丁苯酞软胶囊的制备
称取丁苯酞100g，聚乙二醇-8甘油辛酸/葵酸酯与聚氧乙烯蓖麻油各50g，；其余步骤与实施例1相同，只是在药液油的制备步骤中另加入潜溶剂丙二醇20g，充分搅匀即得，最后压制的软胶囊每个含220mg的药液油。
实施例3 丁苯酞软胶囊的制备
明胶液的制备：明胶100g，甘油40g、水120g和尼泊金乙酯200mg，其余明胶液制备步骤与实施例1相同；
药液油的制备：称取丁苯酞500g与聚乙二醇-8-甘油辛酸600g及鲜橙浊500mg，充分搅匀即得；
软胶囊压制：其余步骤与实施例相同，只是最后压制的软胶囊每个包含220mg的药液油。
实施例4 丁苯酞自乳化颗粒的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸120g，乙醇20g、薄荷油100mg，甜橙香精100mg、混匀作为粘合剂，加至450g糖粉与5g低取代纤维素(L-HPC)的混合物中，制粒，烘干即得。
实施例5 丁苯酞自乳化颗粒的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸50g，氢化蓖麻油50g，薄荷油100mg，青苹果油100mg、混匀作为粘合剂，加至400g糖粉、100gPVP与5g低取代纤维素(L-HPC)的混合物中，20目筛制粒，烘干，分装入袋，即得。
实施例6 丁苯酞自乳化片剂的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸50g，氢化蓖麻油40g，混匀作为粘合剂，加至100g糖粉、40g羧甲基淀粉钠、150g微晶纤维素的混合物中，32目筛制粒，45℃烘干后，外加入5g硬脂酯镁作为润滑剂，以青苹果固体粉末香精为矫味剂，混匀后压片，即得，每片片重约0.49g。
实施例7 丁苯酞自乳化片剂的制备
片芯：丁苯酞100g，聚乙二醇-8-甘油辛酸50g，混匀作为粘合剂，加至100g糖粉、40g羧甲基淀粉钠、150g微晶纤维素的混合物中，32目筛制粒，45℃烘干后，外加入5g硬脂酯镁作为润滑剂，混匀后压片，即得，每片片重约0.49g。
衣膜：羟丙甲基纤维素60g溶于80％乙醇溶液1000ml中，加入0.5g食用绿色素，混匀，采用滚转包衣法，片床温度35～45℃，进行包衣，得淡绿色薄膜衣片。
实施例8 丁苯酞自乳化缓释片的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸50g，氢化蓖麻油50g，薄荷油100mg，混匀作为粘合剂，缓缓加至100g羟丙基甲基纤维素(HPMCK100M)、80个羟丙甲纤维素(HPMCK4M)及10g乙基纤维素的混合物中，搅拌均匀，32目筛制粒，45℃烘干后，20目整粒，加入5g硬脂酯镁作为润滑剂，压片，即得。
实施例9 丁苯酞自乳化控释片的制备
片芯：丁苯酞100g，聚乙二醇-8-甘油辛酸50g，混匀后加入至120g淀粉、180g微晶纤维素、100g乳糖，20g泊洛沙姆-188的混合粉中，搅拌均匀，32目筛制粒，45℃烘干后，20目整粒，加入5g硬脂酯镁作为润滑剂，压片，包以0.1～0.3mm的羟丙基纤维素聚醋酸乙烯复合膜，即得。
实施例10 丁苯酞自乳化硬胶囊的制备
丁苯酞50g，聚乙二醇-8-甘油辛酸20g，混匀用100g淀粉作为吸收、稀释剂，10g聚乙烯吡咯烷酮(PVP)作为粘合剂，10g低取代纤维素(L-HPC)作为崩解剂，32目筛制粒，烘干，20目筛整粒，加入硬脂酸镁作为润滑剂，分装入1#胶囊壳，即得
实施例11 丁苯酞自乳化硬胶囊的制备丁苯酞50g，聚乙二醇-8-甘油辛酸20g，以泊洛沙姆40g、麦芽糖糊精60g、微晶纤维素60g及羧甲基淀粉钠8g等吸附后，以32目筛制粒，45～50℃烘干，20目筛整粒后，加入滑石粉作为润滑剂，混匀分装入2#胶囊壳
实施例12 丁苯酞自乳化缓释胶囊的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸50g，氢化蓖麻油50g，薄荷油100mg，青苹果油100mg、混匀作为粘合剂，缓缓加至100g羟丙基甲基纤维素(HPMCK100M)、80g羟丙甲纤维素(HPMCK4M)及10g乙基纤维素的混合物中，搅拌均匀，32目筛制粒，45℃烘干后，20目整粒，加入5g硬脂酯镁作为润滑剂，混匀后分装入1#胶囊壳中即得。
实施例13 丁苯酞自乳化口服液(油)的制备
丁苯酞100g，聚乙二醇-8-甘油辛酸50g，氢化蓖麻油50g，鲜橙浊0.1g及薄荷油0.1g混匀后，加入至5L含1％天冬甜精、及0.01％对羟基苯甲酸乙酯钠的水溶液中所形成的水包油乳剂(虽已属乳剂，但其制备工艺属自乳化机理，故本说明中列入)，依患者不同需求分装入5ml、10ml、20ml或50ml口服液瓶中。
实施例14 丁苯酞自乳化口服液油的制备
配制处方基本同实施例12，只是在药液油配制时就加入抑菌剂如尼泊金乙酯及阿斯巴甜(阿斯巴甜可先以微量酒精分散后混入)，混匀后得无色澄清油状液，直接分装入具刻度口服液瓶，即得。用时定量取出可加入水使成水包油乳剂服用；亦可直接服用遇体液后自成水包油乳剂。
实施例15、丁苯酞自乳化软胶囊大鼠口服后药物动力学实验
以实施例1所制备丁苯酞自乳化软胶囊大鼠口服后药物动力学试验结果与普通软胶囊比较结果见表2
表2 大鼠灌胃给药后不同时间内血浆中药物浓度
| 取样点(hr) | 血药浓度(μg/ml) | |
| 普通软胶囊 | 自乳化软胶囊 | |
| 0.080.170.50.812357912 | 5.326.798.067.0210.154.224.314.049.55.162.5 | 13.6216.1712.259.39.326.617.434.362.541.921.36 |
由表可见，自乳化释药体系给药后达峰明显快于普通油状内容物，其tmax分别为0.1和1.0h，且达峰浓度亦高于普通软胶囊内容物，且个体差异较小。
这正说明SEDDS进入胃肠道后，先自乳化成乳滴，随之快速分散于胃肠道中，减少了因油滴分散较差造成的个体吸收差异，同时减少了由于药物与胃肠壁的直接接触引起的刺激，乳剂微粒在胃肠道内结构会改变或被破坏。综上所述，自乳化释药体系应用于脂溶性及水难溶性油状药物—丁苯酞，将有较大的临床使用价值。
Claims (12)
1、一种丁苯酞自乳化释药体系，其特征是含有重量百分比1％～65％丁苯酞和10％～65％乳化剂，余量为赋形剂。
2、按照权利要求1所述的丁苯酞自乳化释药体系，其特征在于优选的重量百分比是：丁苯酞为10％～50％，乳化剂为15％～60％。
3、按照权利要求1或2所述的丁苯酞自乳化释药体系，其特征在于丁苯酞是指其消旋体、左旋体或右旋体。
4、按照权利要求1或2所述的丁苯酞自乳化释药体系，其特征在于乳化剂选自下列一种物质，或两种或两种以上物质的混合物：不同种类的液体或固体乙氧基聚氧乙烯甘油酯、聚氧乙烯油酸酯、液态卵磷脂、聚氧乙烯蓖麻油、椰子油、聚乙二醇甘油酯、杏仁油油酸聚乙二醇甘油酯、杏仁油油酸聚乙二醇甘油酯、聚氧乙烯甘油三油酸酯、聚氧乙烯山梨醇油酸酯、聚乙二醇-8甘油辛酸/葵酸酯。
5、按照权利要求1或2所述的丁苯酞自乳化释药体系，其特征在于还可以加入水、助溶剂及矫味剂，制得口服液。
6、按照权利要求1或2所述的丁苯酞自乳化释药体系，其特征在于赋形剂选自可口服的植物油，制得软胶囊剂型的内容物。
7、按照权利要求6所述的丁苯酞自乳化释药体系，其特征在于植物油选自下列一种物质，或两种或两种以上物质的混合物：麻油、玉米油、花生油、豆油、杏仁油、桃仁油、棉籽油、葵花籽油、橄榄油。
8、按照权利要求1、2或3所述的丁苯酞自乳化释药体系，其特征在于乳化剂优选聚氧乙烯蓖麻油与聚乙二醇-8甘油辛酸/葵酸酯的混合物，混合重量比例优选1∶0.5～1.5。
9、按照权利要求1所述的丁苯酞自乳化释药体系，其特征在于赋形剂选自崩解剂、粘合剂、矫味剂、及高分子骨架材料，制得口服固体粉末或颗粒。
10、按照权利要求9所述的丁苯酞自乳化释药体系，其特征在于加入常规的增塑剂、崩解剂、润滑剂、缓控释材料，制得普通片剂或控、缓释片剂。
11、按照权利要求9所述的丁苯酞自乳化释药体系，其特征在于常规的润滑剂、缓控释材料，制得普通硬胶囊或控、缓释硬胶囊。
12、一种丁苯酞自乳化释药体系的制备方法，其特征在于20～60℃水浴中使乳化剂充分融溶并混匀后，搅拌下加入丁苯酞混匀，添加赋形剂，制得具有丁苯酞自乳化释药体系的依托剂型。
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| CN1375288A (zh) * | 2002-05-13 | 2002-10-23 | 周桂荣 | 一种治疗脑血管疾病的药物组合物 |
| BR0215848A (pt) * | 2002-08-21 | 2005-06-21 | Shijiazhuang Pharma Group | Complexos de inclusão de butilfitalida com ciclodextrina ou seus derivados, processo para preparação destes e uso dos mesmos |
| JP4215633B2 (ja) | 2002-12-19 | 2009-01-28 | Ｊｆｅケミカル株式会社 | 複合黒鉛粒子の製造方法 |
| CN1233317C (zh) | 2003-07-07 | 2005-12-28 | 西安利君制药有限责任公司 | 水飞蓟素自乳化微乳组合物及其制备工艺 |
-
2004
- 2004-08-27 CN CNB2004100750682A patent/CN100361656C/zh not_active Expired - Lifetime
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2005
- 2005-08-26 ES ES05781769T patent/ES2341265T4/es active Active
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- 2005-08-26 KR KR1020077006741A patent/KR100887034B1/ko active IP Right Grant
- 2005-08-26 RU RU2007111120/15A patent/RU2371176C2/ru active
- 2005-08-26 DE DE602005020317T patent/DE602005020317D1/de active Active
- 2005-08-26 AU AU2005276811A patent/AU2005276811B8/en active Active
- 2005-08-26 CA CA2578130A patent/CA2578130C/en active Active
- 2005-08-26 EP EP05781769A patent/EP1787638B1/en active Active
- 2005-08-26 AT AT05781769T patent/ATE462410T1/de not_active IP Right Cessation
- 2005-08-26 US US11/574,313 patent/US8728518B2/en active Active
- 2005-08-26 WO PCT/CN2005/001332 patent/WO2006021160A1/zh active Application Filing
- 2005-08-26 MX MX2007002335A patent/MX2007002335A/es active IP Right Grant
- 2005-08-26 JP JP2007528562A patent/JP4653810B2/ja active Active
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2007
- 2007-03-12 NO NO20071354A patent/NO336917B1/no unknown
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342152B (zh) * | 2007-07-10 | 2010-10-13 | 石药集团中奇制药技术（石家庄）有限公司 | 丁苯酞片及其制备方法 |
| CN101579323B (zh) * | 2008-05-16 | 2012-01-25 | 石药集团中奇制药技术（石家庄）有限公司 | 丁苯酞缓释片及其制备方法 |
| CN102178643A (zh) * | 2011-04-29 | 2011-09-14 | 石药集团恩必普药业有限公司 | 一种丁苯酞或其衍生物的微乳透皮凝胶剂及其制备方法 |
| CN102178643B (zh) * | 2011-04-29 | 2014-05-14 | 石药集团恩必普药业有限公司 | 一种丁苯酞或其衍生物的微乳透皮凝胶剂及其制备方法 |
| CN103784424A (zh) * | 2012-10-30 | 2014-05-14 | 石药集团中奇制药技术（石家庄）有限公司 | 一种丁苯酞经皮贴剂及其制备方法 |
| CN103784424B (zh) * | 2012-10-30 | 2018-04-27 | 石药集团中奇制药技术（石家庄）有限公司 | 一种丁苯酞经皮贴剂及其制备方法 |
| CN105796486A (zh) * | 2016-03-17 | 2016-07-27 | 南京天翔医药科技有限公司 | 丁苯酞脂肪乳注射剂及其制备工艺 |
| CN110856712A (zh) * | 2018-08-06 | 2020-03-03 | 刘超 | 丁苯酞自微乳组合物及其制备方法和用途 |
| CN110856712B (zh) * | 2018-08-06 | 2021-11-30 | 刘超 | 丁苯酞自微乳组合物及其制备方法和用途 |
| CN114073694A (zh) * | 2020-08-14 | 2022-02-22 | 北京科莱博医药开发有限责任公司 | 丁苯酞制剂及其制备方法 |
| CN114073694B (zh) * | 2020-08-14 | 2024-03-12 | 北京科莱博医药开发有限责任公司 | 丁苯酞制剂及其制备方法 |
| WO2022143631A1 (zh) * | 2020-12-29 | 2022-07-07 | 中国科学院上海药物研究所 | 经口腔黏膜递送的丁苯酞组合物及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1787638B1 (en) | 2010-03-31 |
| RU2371176C2 (ru) | 2009-10-27 |
| BRPI0515070B8 (pt) | 2021-05-25 |
| US8728518B2 (en) | 2014-05-20 |
| EP1787638A4 (en) | 2008-12-03 |
| NO20071354L (no) | 2007-05-29 |
| BRPI0515070B1 (pt) | 2020-09-08 |
| AU2005276811B2 (en) | 2008-11-13 |
| RU2007111120A (ru) | 2008-10-20 |
| AU2005276811B8 (en) | 2009-01-22 |
| ES2341265T4 (es) | 2011-04-27 |
| WO2006021160A8 (en) | 2006-04-13 |
| KR20070046948A (ko) | 2007-05-03 |
| ATE462410T1 (de) | 2010-04-15 |
| KR100887034B1 (ko) | 2009-03-04 |
| AU2005276811A1 (en) | 2006-03-02 |
| CA2578130C (en) | 2010-08-31 |
| MX2007002335A (es) | 2007-10-10 |
| NO336917B1 (no) | 2015-11-23 |
| ES2341265T3 (es) | 2010-06-17 |
| US20080319056A1 (en) | 2008-12-25 |
| DE602005020317D1 (de) | 2010-05-12 |
| JP4653810B2 (ja) | 2011-03-16 |
| EP1787638A1 (en) | 2007-05-23 |
| CN100361656C (zh) | 2008-01-16 |
| CA2578130A1 (en) | 2006-03-02 |
| JP2008510737A (ja) | 2008-04-10 |
| WO2006021160A1 (fr) | 2006-03-02 |
| BRPI0515070A2 (pt) | 2009-08-04 |
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