Kuorinka_1997_International-Journal-of-Industrial-Ergonomics
群落内物种多样性发生与维持的一个假说
生物多样性 1997,5(3):161~167CHIN ESE BIODIV ERSIT Y群落内物种多样性发生与维持的一个假说3张大勇 姜新华(兰州大学生物系干旱农业生态国家重点实验室, 兰州 730000)摘 要 本文根据作者对竞争排除法则的研究而提出了一个新的群落多样性假说。
按照作者的观点,占用相同生态位的物种可以稳定共存;这样,群落内物种多样性将受到4个基本因子所控制。
它们分别是:(Ⅰ)生态位的数量;(Ⅱ)区域物种库的大小;(Ⅲ)物种迁入速率,以及(Ⅳ)物种灭绝速率。
该假说强调区域生物地理过程与局域生态过程共同决定了群落内种多样性的大小及分布模式。
关键词 局域物种多样性,物种分化,区域物种库,生态位,竞争排除法则A hypothesis for the origin and maintenance of within2community species diversity/Zhang Dayong,JiangXinhu a//CHINESE BIODIVERSIT Y.—1997,5(3):161~167This paper formulates a novel hypothesis of community diversity on the basis of rejecting the competitive exclu2 sion principle.Since we accept the view that many species could occupy the same niche,local s pecies diversity is considered to be controlled by four fundamental factors,which are,res pectively,(Ⅰ)the number of niches in the community,(Ⅱ)the size of regional species2pool,(Ⅲ)species immigration rate,and(Ⅳ)species extinc2 tion rate.The hypothesis suggests that both regional biogeographic processes and local ecological processes will play an important role in determining the magnitude and pattern of community diversity.K ey w ords local species diversity,speciation,regional species2pool,niche,competitive exclusion principle Author’s address Department of Biology&State K ey Laboratory of Arid Agroecology,Lanzhou Univer2sity,Lanzhou 7300001 引言由于环境污染和生境破坏等人类活动的影响,大规模物种灭绝已成为当今社会所密切关注的一个焦点。
可靠性增长
random nature of the wave loading in a typical offshore environment. An essential step to maintain the structural integrity is to make an initial prediction about the safety of the structure over its life and to plan inspections based on it. An inspection may result in sizing of cracks in a joint and, thereby, provides the means to take suitable measures for the repair of the joint. In the assessment of the integrity of a joint, the main concern is to predict the remaining life, which is dictated by crack growth. Fracture mechanics principles are best suited for this purpose. Deterministic fracture mechanics analyses typically produce conservative results, since limiting assumptions are to be made on key input parameters. However, some of the key parameters of the problem can exhibit considerable scatter and, therefore, have to be modeled as random quantities. The fundamentals of reliability assessment, if properly applied, can provide immense insight into the performance of the structural system. 2. Literature survey Wisch [1] presented a detailed account of the development of design practices of fixed offshore structures. The paper predicts that reliability fundamentals coupled with risk assessments will provide a two-stage design approach for such structures.This will result in a more consistent and better-known safety margins upon which the risks associated with the structure can be evaluated. Kam [2] detailed the application of the principles of reliability fatigue fracture mechanics to assess the integrity of offshore tubular members. It is indicated that inservice inspection combined with integrity analysis forms the basis for a reliable tool to ensure the integrity of joints of an offshore platform structure. Macias et al. [3] reported probabilistic fracture mechanics analysis of a cracked plate. The study follows an approach by coupling a mechanical model defined using finite element method to model the geometry and the material and a reliability model defined using first order reliability method (FORM)/second order reliability method (SORM). The principles of linear elastic fracture mechanics have been employed in the mechanical model. An example problem of a rectangular plate with a center crack has been analyzed. The probability of failure has been defined as pf ϭ Prob[KIՆKIC], (1) where KI and KIC are, respectively, the stress intensity factor (SIF) of the cracked plate and fracture toughness of the material of the plate. A parametric study has been conducted to investigate the relative significance of the different parameters modeled in the study. Kam et al. [4] studied the fatigue fracture mechanics modeling and structural integrity assessment techniques
柯里拉京调节自噬影响巨噬细胞源性泡沫细胞形成的研究
柯里拉京调节自噬影响巨噬细胞源性泡沫细胞形成的研究*吴静宜, 邓欣, 姜丙通, 胡蒙蒙, 李志杰, 张雅琼, 赵毅, 车彦云△(云南省药食同源饮品工程研究中心,云南中医药大学,云南 昆明 650500)[摘要] 目的:探讨柯里拉京(Cor )通过自噬抑制巨噬细胞源性泡沫细胞的形成及其机制。
方法:以THP -1和J774A.1巨噬细胞为研究对象,分别设正常组、泡沫细胞模型组(ox -LDL+LPS 组/ox -LDL 组)和不同浓度Cor 处理组(Cor 组)。
油红O 染色观察各组细胞内脂滴沉积情况,ELISA 法检测各组细胞内总胆固醇(TC )和游离胆固醇(FC )含量及细胞上清液白细胞介素6(IL -6)、单核细胞趋化蛋白1(MCP -1)、IL -1β、肿瘤坏死因子α(TNF -α)的表达;分子对接建模预测Cor 与自噬和炎症相关靶点的作用;Western blot 检测各组细胞中自噬和炎症相关蛋白的表达水平,试剂盒检测caspase -1活性。
结果:与模型组比较,Cor 中、高剂量组可显著减少THP -1和J774A.1两种巨噬细胞内的红色脂滴;Cor 可减少细胞脂滴沉积,呈浓度依赖性降低胆固醇酯(CE )/TC (P <0.05或P <0.01),显著降低IL -6、MCP -1、IL -1β和TNF -α的含量(P <0.01);Cor 与受体哺乳动物雷帕霉素靶蛋白(mTOR )的结合亲和力最好,最佳结合亲和力是−9.8 kcal/mol ;同时Cor 高剂量组可显著上调磷酸化AMP 活化蛋白激酶(p -AMPK )/AMPK 的蛋白表达水平(P <0.01),显著下调磷酸化mTOR (p -mTOR )/mTOR 、P62、核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)、含caspase 募集结构域的凋亡相关斑点样蛋白(ASC )和caspase -1的蛋白表达水平(P <0.05或P <0.01),beclin -1和LC3的蛋白表达无显著性差异(P >0.05);此外,Cor 也显著抑制了caspase -1的活性(P <0.05)。
Low-K Gate Spacer and Formation Thereof
专利名称:Low-K Gate Spacer and Formation Thereof发明人:Bo-Cyuan Lu,Chunyao Wang,Jr-HungLi,Chung-Ting Ko,Chi On Chui申请号:US16203814申请日:20181129公开号:US20190148239A1公开日:20190516专利内容由知识产权出版社提供专利附图:摘要:Gate structures and gate spacers, along with methods of forming such, are described. In an embodiment, a structure includes an active area on a substrate, a gate structure on the active area and over the substrate, and a low-k gate spacer on the activearea and along a sidewall of the gate structure. The gate structure includes a conformal gate dielectric on the active area and includes a gate electrode over the conformal gate dielectric. The conformal gate dielectric extends vertically along a first sidewall of the low-k gate spacer. In some embodiments, the low-k gate spacer can be formed using a selective deposition process after a dummy gate structure has been removed in a replacement gate process.申请人:Taiwan Semiconductor Manufacturing Co., Ltd.地址:Hsinchu TW国籍:TW更多信息请下载全文后查看。
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【doc】利福霉素类药物国内外研究情况综述
利福霉素类药物国内外研究情况综述利福霉素类药物国内外研究情况综述口安蠢省合肥制药有限公司(230025)贺芝红结核病对人类的危害已有数千年历史.80年代初.由于开展对结核病的短程化疗,使结核病受到很大程度的控制.但近年来,随着人免疫缺陷病毒(HIv)感染以及多药耐药菌的产生,使结核病再度蔓延.WHO宣布肺结核已处于一十全球的紧急状态,并号召制药行业多投资于寻找对付该痍病的新药的研究,WHO的P.Nunn博士说,有效的新药中,利福霉素急需进一步开发.我国6O年代着手对利福霉素类药物进行研究.在临床应用研究方面领先于国外.先后研究成功并已上市的有利福平,利福定,利福喷丁,对利福哌啶,利福苯噻唑等品种的研究取得了较大的进展.本文对利福霉素类抗结核药物国内外研究情况予以综述.利福霉素(Rifamyeins)是1957年意大利利培提公司从地中海锤霉菌培养液中分离而得到的混合物.由其成分利福霉素B转化的利福霉素SV是一种高效的主要抗革兰氏阳性菌及结核分枝杆菌的抗菌素,但由于利福霉素sv口服不吸收,同时对革兰氏阴性菌的抗菌作用不理患,因此进行了芈合成的研究近年来开发的新利福霉素衍生物不仅抗菌作用强,抗菌谱广,而且半衰期延长.WHO认为,新型利福素类药物治疗结核病的费用低,易被病人接受.因此,自从开展利福霉素衍生物的研究工作以来,在合成手段及衍生物效果考寨等方面正在不断发展,抗感染方面正沿着长效,高效,广谱,抗耐药等方向努力.1利福平(RFP)RFP是开发摄早的利福霉素类抗结核药,由意大利利培提公司与瑞士汽巴?嘉基公司合作开发,1062年上市,我国1974年通过鉴定.由于它较链霉素.异烟肼具有更强的杀灭结核菌的活性而成为治疗结核病的主要药物.并成为当时世界医学临床评价最高,应用最广的一十新品种固其疗效确切,价格低.长期以来,一直是治疗肺结核病的基本药物1997年成为国内本类产品中的畅销品种RFP是广谱的利福霉素类半合戒抗生素,它不仅能杀灭代谢旺盛期的结核菌,还能彖灭静止期的结核菌它与依赖于DNA的RNA多聚酶的B亚单位牢固结合-抑制细菌RNA的合成,防止该酶与DNA连接,从而阻断RNA转录过程.RFP单独用于治疗结核病时可能迅速产生细菌耐药性,因此本品必须与其它抗结核药合用.同时以RFP为主药的联合用药方案可缩短结核病的疗程. RFP与异烟肼间歇疗法曾成功地用于结核病的治疗,但间璩疗法的副作用可能较多见且严重,尤其当RFp的剂量较大时,美国的《内科医师参考书》指出RFP不宜间耿使用.目前国内RFP剂型有片剂,胶囊剂,滴限刺.软胶囊,复方制剂等,但无供辖注用粉针(此剂型为美国药典收载,采用粉针剂常规制备工艺,配方中应器加增溶剂),开发此剂型可增加临床可选用的品种,并可填补国内空白.2利福定(RFD)1973年瑞士汽巴?嘉基公司合成并专利化,但没有进一步开发-我国研制的RFD于1981年5月通过鉴定.RFD是利福霉素的半合成衍生物,作用机理与RFP相同.对结核杆菌的抑菌作用是RFP的三倍,与RFP有交叉耐药性.动物实验发现:如用RFP等量的RFD,动物肝眈和血液等的毒性反应不仅小于RFp,且无RFP的致畸作用.RFD有四种晶型,其中I型和lv型有良好的生物有效性,在贮藏过程中本品可以变为无效晶■述报告型,且复发率高,故已有学者提出对RFD的应用应持慎重态度.本品种有胶囊和片剂两种剂型.3利福喷丁(RPE)本品为新型,高效,长效利福霉素类抗生素,1975年意大利利培提公司首先报道本品,我国率先完成研制t并于1987年6月通过国家级评审,1989年批准上市本品为RFP的环戊基衍生物,作用机理与RFP相同,与RFp之间无交叉耐药性.对结核杆菌的活性2~4倍于RFP.血清抑菌有效浓度维持时间招小时以上,为RFp的4~6倍与RFP相比, RPE具有RFP的所有优点,而在长效和高效上更具优越性t本品在结核病的治疗中可取代RFP.每周2次培药和每日连续使用RFP的疗效一致.也可与异烟肼合并每周口服一次.适用于何戢给药治疗啼结核,这样既有利于给药,叉能节约医疗费用.是较为理想的化疗药物.RPE也存在不同晶型问题,但其稳定性好,在密闭避光干燥阴暗处保存,不会改变晶型.本品种仅肢囊一种剂型4利福布丁(RBU)198]年由意大利的Farmita]Ja公司开发,1982年报道它有抗RFP耐药结核菌株的作用,奉品已于1992年在意大利和美国上市. 本品属于新型螺旋哌啶基利福霉素,抗菌谱广对革兰氏阳性胡性菌的活性与RFP相似,对结核杆菌的活性比RFP强2倍, 体内活性比RFP强6~7倍,特别适宜何歇给药.对耐RFP的结核杆菌具有抗菌活性.并能部分抑制耐RFP的菌株,对RFP耐药结核杆菌的活力在于干涉菌株DNA合成,所需浓度仅为RFP的1 /40.与乙胺丁醇联合使用能增加或有效地协同抑制和杀灭马型结核杆菌复合体,有报道将奉品用于艾滋病治疗奉品毒性低于R5利福嘱啶(FCE--22250)由意大利Farmit~lia公司开发,我国在],986年开始研究.本品为偶氨甲基利福毒案类新衍生物之一.抗结核菌活性比RPP强l4倍.且需每3周口脬欢,也船,皂的绪药时闻长两倍,根据国内外有关的药理试验结果,本品可望每3周或2罔给药1 次,每次口服剂量与RPE每周服用量相仿.其满疗程的服用总量仅为RPE的l/2~1/S,费用将比E大幅度降低.因此本品是超长效的抗结核病药物,并可降低患者的医疗费用它除对结核病有显着疗效外,对麻风向等亦可能有良好疗效.此外.对芟滋病也可能有一定的防止作用.6利福苯喀唑(RabeI1lI血∞neR-7S—1)本品为我国首创的第一十利福霉素类抗结桩新药,由四川抗菌素研究所研究.日本微生物研究所报道了本品的作用机理是抑制RNA的合成,作用比利福平强10倍本品体内吸收较差,血浆蛋白结合率较高,但本品抗结核病疗效显着且毒副作用小.若能提高其生物利用度将会成为一十非常有前途曲药物参考文献1国末医两昔理局抗生素睛报中-站等.1949~1986年囤内鉴定过的抗生素原井药品种汇蝙.1988.109~1]62四川抗菌素工业研究所.利瓶霉素的化学改遣.见:1969~1972年国外抗茸素发展功态1972.96~98.57?环丙沙星的剂型开发与临床应用口羹口长囊团公司职工医院药剂科(长●13001])膏越光王颤晃胜红机薯厂卫生所(长●130000)膏嗣环丙沙星是第三代哇诺酮类抗菌药物,抗菌谱广,杀翦作用强,尤其对大脑扦菌,肺炎克雷伯氏茁有较强的抗菌活性研究证明: F)【抗绿脓杆菌的话性可与第三代头孢菌素魏美.根据临束需要,现已研制出多种剂型.它们是:口服剂,注射剂,眼用荆,耳用剂,浦鼻剂,口腔,皮肤及其它制荆,现对上述剂型及临床应用进行综述.-I口曩荆口服荆是应用最广迂的一种荆型.健康人口服盐酸环丙沙星200rag,1~2小时即可达到高峰浓度,半衰期约为4小时,对太多数适应症可口服两趺剂量.本品主要分布于胆汁,牯液,唾液,骨以及前列腺中,可在肝脏中部分被代谢,并经肾脏排于尿中,可在尿中保持较高药物诹度,它对由敏感致扁菌引起的各种感染疾患有明显疗效.适用于上呼嗳遭藤染,下呼吸道感染,泌尿系和肠道感染,皮肤及外伤感染等.左扬橙等推疗绿脓杆菌引起下呼吸道感染,口服剂量750rag,每l2小时1砍,疗程7~24天,结果有效率81.3,细菌阴转率71.2,治疗慢性支气管炎总有效率为8O%,发热白细胞升高好转率100.镣攫等口服环丙涉垦治疗外科感染也取得明显疗效.在治疗急性淋病98例观察中,结合洁尔阴局部冲洗.结果总有数率为91.8,治愈率达88.8【2注射剂处方组成t乳酸环丙抄星12.7,氯化钠45.00g,乳酸适量,注射用水加至5000ml.崩备.将乳酸环丙沙星,蒸化钠,乳酸用适量蒸馏水潜解,注射用水加至5000ml,过滤,{l装,灭菌即得.呈无色或几乎无色澄明液体.氯化钠用来调节等渗.静脉jI薯注后血峰浓度可达4-14~g/ II1I,半寰期3.35小时,脆迅速分布到各种体液和脏器,75药物由尿中排出.临床适用于敏感细菌引起的中,重度呼吸系统,泌尿系统以及皮肤软组织感染,败血症与瘦睦内感染等.苏思仁等静滴治疗急性呼吸道细菌感染50倒,泌尿系感染50倒和消化道感染25倒,结果显示临床疗效迭86,T%,细菌转暇率迭866%,无严重不良反应,显示其安全,有数的治疗效果.有资料显示,用于治疗尿路蒜染效果最佳-,有效率可达10OL6J.l■用■荆处方组成{乳酸环丙抄星5.Ig,EDTA-2Na0?Ig,硼砂0?15g,硼酸21.5g,PVP-K3020a,对羟基苯甲馥甲酯0.2g,对羟基苯甲魏丙矗O.1fig,燕馏水加至1000ml.制备t取处方中环丙抄星乳酸盐祁EDTA-2Na溶于适量热水中为I液l取对羟基苯甲馥甲酯和丙醋,PVP-K30,硼砂,硼酸加水适量搅拌溶解,为l号液.将I号液和I号液合并,搅拌均匀后添加蒸馏水至全量,搅匀,过滤,灭菌,分装即得.可用于治疗急慢性结膜炎,角膜炎,睫状体炎,泪囊炎,有效率高达90~100t耳用翩荆处方组成:盐酸环丙抄垦5s,氢化可的橙0.5g,乙醇100ml,燕馏水加至l000ml.取盐酸环丙沙星溶于适量蒸馏水中,另取氢化可的松溶于乙醇中,再将其缓缓加入上述盐酸环丙沙星溶液中, 混匀,过滤,自摅器上添加蒸馏水至全量,搅匀邵得.临床治疗54倒患者,显效44例,有效9倒,无效l倒,总有效率为98.2.经一周治疗,耳部细菌培养,灭菌宰达96.5.5滴鼻荆目前采用复方制剂,与麻黄碱配伍,麻黄碱有收缩鼻粘膜血管作用.处方组成:环丙沙星0.3g,麻黄碱lg,加蒸馏水配成100ml溶液,分装即得.用于治疗鼻炎,鼻窦炎,鼻粘膜阻塞等效果显着.这种复方制剂配制简单.快速易行,很适合一般医院制剂室配制. B口腔用睽剂处方组成:环丙氟暇酸lg.灭敌灵lg,棱黄素0.O6g,浓鱼肝油滴剂2ml,甘油4ml,吐温80Iml,地卡固0.4g,冰硼散lg,糖精钠适量,PV A05-889g,PV AI7—883g,CMC-Na3g.蒸馏水加至22i)ml.制备方法:(1)药膜的制备:聚乙烯醇经85%乙醇授泡处理二次烘干,加适量蒸馏水溶胀,水浴(90"C左右)加热使溶,制成溶液IoCMC-Na加适量蒸馏水浸泡.糖精钠,地卡因加适量水溶解,加入上述液体中,髑成I号液.滩鱼肝油滴剂加吐温80在研诈中研磨均匀后加入甘油,再将灭敌灵,环丙沙星,冰硼散细粉加入砑匀,制成m号液,将I号液滤入CMC-Na液中,水潜上加搅拌成均匀腔液.加入m号液放置,以驱除气泡.在消毒过的玻璃板上铺成4.2crnX28crn的均匀薄膜,于{0~60"C干燥3小时,控崩药膜厚度0.1mm待用.(2)复台膜崩备加适量蒸馏水浸泡PVA,充分膨胀后,加热溶解,冷却后均匀倒在已干燥的药膜上,推板,干燥后即成复合膜,紫外灯下灭菌,于净化台上割成2.5锄×B.5cm药膜.分装即得选用无毒无味的高分子多聚物制成复合膜主要是防止药膜被唾液澜湿而掉膜,从而使药物局部作用时间长,充分发挥药物治疗作用.临床用于口腔牯戚溃疡,齿龈溃疡,剖伤性渍痔,鼓果较好,无副作用.7皮肤制剂7.1乳膏剂≈处方组成:环丙沙星3.0g,十八醇76.5g,白凡士林50.0g,液状石蜡16O.0g,十二烷基硫酸钠&5g,甘油50.0g,蒸馏水652-0a, 崩备方法:取十八酵,白凡士林,液状石螬加热熔化.70℃~80℃保温.另取十二烷基硫馥钠,甘油溶于赫水,70℃~80"C保温,加3四川抗茸童工生拜览所.善奏抗生膏的研觅进晨.见}1979~l983年田'卜抗生毒品种均盎奉拜宄避^'惨改蕾).19R3.~934膏玉英f.利辐霉童真蔚轴的进晨.见圆内外医药工业水平调研报告桌(卉桌).北京,圆掌医琦量重屑匮琦工业情矗中心站,1990.15~215束明.抗培棱琦撕厦其直属越势.见罔内'卜医药工业水平调研报告橐(羊九集)-北京:固李医琦蕾理屑医药工业情量中一站,1993. 58?65~676日牢计委科技司等田棼妊他荦匡茼嘶产品开发括^,[99hl3~147回车妊井垂备料挂司午.圆誊艇蔚转.j荆新产品开置精南(羊一辑) 1993.38lg上海琦赛甩手册-支汇由牲枉,1992.16|一l7l9中单凡民共和田蔚彝(羊二卑).1995年版.北索≈他学工业由版枉, l996.508~6ll车方^募一●。
气相色谱法在有机磷农药残留量分析中的应用与进展_钱莹
第13卷第2期 广西科学院学报 Vol.13,No.2 1997年5月 Jo ur nal o f Guang xi Academ y o f Sciences May1997气相色谱法在有机磷农药残留量分析中的应用与进展Application and Development of GasChromatography in the Analysis ofOrganophosphorous Pesticide Residues钱 莹 苏小川Qia n Ying Su Xiaochuan(广西建筑工程学校基础科南宁530003) (广西卫生防疫站南宁530021)(Guang xi Architecture Engineering School (Guang xi Anti-Epidemic andBasic Course Section,Na nning,530003) Sa nita ry Center,Nanning,530021)摘要 介绍了气相色谱法的发展及其作为1种常用的仪器分析方法的特点,讨论了该方法在有机磷农药残留量分析应用方面的3个关键问题,即:样品的提取、色谱柱的选择、检测器的灵敏度。
并详述了国内外有关气相色谱法分析有机磷农药残留量的研究进展及其未来的发展方向。
关键词 气相色谱法 有机磷农药残留量 分析 应用 进展Abstract We descrie the development o f GC and its trait as a co mmo n in-strum ental analystical metho d.Th ree key pro blems o f this method in OPpesticide residues analy sis and applica tion hav e been discussed.They arethe collectio n o f samples,the selection of chroma tog raphy co lum n and thesensitiv ity of detector.The dev elopment o f resea rch and dev elo ping direc-tion o n GC analysis fo r O P pesticide residues a t ho me and abroad w as de-scribed.Key words g as ch ro matog raphy,o rg ano phosphoro us pesticide residues,analysis,a pplicatio n,dev elopment中图法分类号 O657.7 有机磷农药(Org ano phosphoro us Pesticides)是30年代末问世的第二代人工合成农药[1],由于它具有广谱、高效、品种多和残毒期短等许多优越的特点,问世不久便得到了迅速的发展,至50、60年代已在世界范围内广泛推广。
A generalized friction correlation for louver fin geometry
a
Energy and Resources Laboratories, Industrial Technology Research Institute, D500 ERL/ITRI, Bldg. 64, 195 H 6 Section 4, Chung Hsing Road, Chutung 310, Hsinchu, Taiwan b Department of Mechanical Engineering, Yuan-Ze University, Tauyuan, Taiwan Received 6 June 1999; received in revised form 14 September 1999
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Y.-J. Chang et al. / Int. J. Heat Mass Transfer 43 (2000) 2237±2243
Nomenclature A Ac Dh Dm f f 1, f 2, f 3 Fd Fl Fp Ft Gc Kc Ke Lh Ll Lp M total surface area [m2] minimum ¯ow area [m2] hydraulic diameter of ®n array [mm] major tube diameter [mm] Fanning friction factor dimensionless correlation parameter ®n depth [mm] ®n length [mm] ®n pitch [mm] ®n thickness [mm] rmVc, mass ¯ux at minimum ¯ow area [kg mÀ2] abrupt contraction coecient, dimensionless abrupt expansion coecient, dimensionless louver height [mm] louver length [mm] louver pitch [mm] number of test data point ReDh ReLp Th Tp Td Vc DP r1 r2 rm s y Reynolds number based on hydraulic diameter, dimensionless Reynolds number based on louver pitch, dimensionless TpÀDm [mm] tube pitch [mm] tube depth [mm] maximum velocity [m sÀ1] pressure drop [Pa] inlet air density [kg mÀ3] outlet air density [kg mÀ3] mean density [kg mÀ3] contraction ratio, dimensionless louver angle [deg]
CO2-ECBM field tests in the Ishikari Coal Basin of Japan
CO 2-ECBM field tests in the Ishikari Coal Basin of JapanMasaji Fujioka a ,⁎,Shinji Yamaguchi b ,Masao Nako ca Resources Department,Japan Coal Energy Center 3-14-10Mita,Minato-ku,Tokyo 108-0073,Japanb Department of Earth Science and Technology,Faculty of Engineering and Resource Science,Akita University 1-1Tegata Gakuenmachi,Akita 010-8502,Japan cGeneral Environmental Technos Co.,Ltd.1-3-5Azuchimachi,Chuo-ku,Osaka 541-0052,Japana b s t r a c ta r t i c l e i n f o Article history:Received 8December 2009Received in revised form 8January 2010Accepted 9January 2010Available online 25January 2010Keywords:CO 2-ECBMIshikari Coal Basin Hydraulic fracturingCO 2injection and sequestration N 2flooding test Coal swellingThe feasibility of extracting gas from coal seam while storing carbon dioxide underground was evaluated in Japan.A CO 2-ECBM project had begun near the town of Yubari on the island of Hokkaido in northern Japan.The primary coal seam of interest was a 5–6m thick Yubari coal seam located at the depth of 900m.A micro-pilot test with a single well and multi-well CO 2injection tests,involving an injection and production wells,were carried out in the period between May 2004and October 2007.There were a variety of tests conducted in the injection well,including an initial water injection fall-off test and a series of CO 2injection and fall-off tests.Although gas production rate was obviously enhanced by CO 2injection,water production rate was not clearly affected by CO 2injection.Several injection tests suggested that injectivity of CO 2into the virgin coal seam saturated with water was eventually increased as the water saturation near the injector was decreased by the injected CO 2.It was estimated that low injectivity of CO 2was caused by the reduction in permeability induced by coal swelling.N 2flooding test was performed in 2006to evaluate the effectiveness of N 2injection on improving well injectivity.The N 2flooding test showed that daily CO 2injection rate was boosted,but only temporarily.Moreover,the permeability did not return to the initial value after CO 2and N 2were repeatedly injected.It was also indicated that the coal matrix swelling might create a high stress zone near to the injection well.©2010Elsevier B.V.All rights reserved.1.Introduction and geologyThe Yubari field test at the southern part of the Ishikari Coal Basin of Hokkaido represents Japan's first CO 2-ECBM field trial (Yamaguchi et al.,2005).The project was carried out in the period from 2002and 2007as part of the “Technology Development for Carbon Dioxide Sequestration in Coal Seam ”project supported by the Ministry of Economy,Trade and Industry of Japanese Government.The pilot site was selected after a careful assessment of the suitability for CO 2storage of coal mining areas throughout Japan.The pilot test involved the drilling of a vertical injection well (IW-1)and a slant production well (PW-1)located 67m up dip of the injection well.The site location and conceptual design of the pilot test are shown in Figs.1and 2.Ishikari Coal Basin is located in the middle of Hokkaido,covering approximately 800km 2,with its width ranging from 7to 20km east to west,and its length 80km north to south,which is the largest coal basin in Japan.The Ishikari coal-bearing series was deposited during Eocene and Oligocene epoch overlying Cretaceous strata in the state of para-unconformity.At Yubari area,all of Cretaceous system,Ishikari series have been deformed by the tremendous pressure from the east producing numerous overthrusts,inverted folds,and recumbent foldsalong the north –south axis.In addition to all these irregularities,nearly all of this area is covered with the homogeneous Horonai Shale,which plays the role of cap rock.The principal target for CO 2injection is one of coal seams of Tertiary deposit.2.Drilling methodsThe site itself is bounded by N –S and NE –SW faults destroying the lateral continuity of the coal seams.The exact locations of the wells were mainly de fined by spatial constraints at the rugged surface.The first well (IW-1)was drilled in autumn 2003as an injection well.The well was vertical and completed with full-hole cementing.Three coal seams in the Yubari formation were con firmed by the well.Geological formation at the injection well is presented in Table 1.The principal target for CO 2injection was the Yubari Lower coal seam of Tertiary deposit,which is the thickest coal seam among three seams.A 6-1/4in (158.8mm)hole was drilled to the total depth of 932.60m.A core barrel of 83mm inner diameter was set in the hole and all cores between 667m and 932.60m were obtained.Open-hole log data such as natural gamma ray,spontaneous potential,electrical logging,neutron porosity,bulk density,x –y caliper and temperature logging were acquired from 650m to 932m.After cement slurry was pumped into the annulus between the casing and open-hole,cement bond log tool was run in the well.The Yubari Lower seam was perforated from 890m to 895m.The casing pro file of IW-1well is shown in Fig.3.International Journal of Coal Geology 82(2010)287–298⁎Corresponding author.Tel.:+81364005196;fax:+81364005207.E-mail address:fujioka@jcoal.or.jp (M.Fujioka).0166-5162/$–see front matter ©2010Elsevier B.V.All rights reserved.doi:10.1016/j.coal.2010.01.004Contents lists available at ScienceDirectInternational Journal of Coal Geologyj o u r n a l ho m e p a g e :w w w.e l s ev i e r.c o m /l o c a t e /i j c o a l g e oWater injection fall-off test was carried out on 26and 28November 2003in order to determine in-situ permeability to water,reservoir pressure,near-well bore damage,and fracture opening and closing pressure in the target coal seam.Then the well was shut-in until spring 2004.The second well (PW-1)was drilled at 196m apart on the surface from IW-1well in autumn 2004as a production (observation)well.PW-1well was deviated from the depth of 420m so as to close to IW-1well resulting to reduce the amount of CO 2required to achieve the breakthrough.Horizontal distance between penetrated points of both wells (IW-1and PW-1)at the target coal seam was about 67m.After a 8-1/2in (215.9mm)hole had been drilled to the measuring depth of 856m;7in (177.8mm)casing was set in the hole and cement slurry was pumped into the annulus between the casing and open-hole.A 6-1/4in (158.8mm)hole was drilled to the total measuring depth of 930m.The depth from 872.5m to 930m was then reamed by 8-1/2in (215.9mm)cutting bit.A 4-1/2in (114.3mm)casing and slotted liner were installed from the total depth of the well to above the top of the production casing.The strainer pipe was set in the hole from 854.9m to916.31m.The same open-hole log data as those at IW-1well were acquired from 854.2m to 930m.No core was obtained from PW-1well.Open-hole log data indicated that measuring depth of the Yubari main seam and the Yuabri lower seam were from 837.6m to 841.3m and from 877.4m to 884m,respectively.The casing pro file of PW-1well is also shown in Fig.3.3.Coal properties,gas content and storageDesorbed gas volume of eight-core samples retrieved from IW-1well was measured using canisters.The direct method was used to determine the lost gas volume from core samples.As shown in Fig.4,the result from five-core samples shows a very strong relationship between organic content and desorbed gas content.Two samples taken from the roof side does not show the same relationship.It is considered that some gas might be contained in ash (and/or coaly shale)involved in two samples.Gas content on dry ash-free-basis was estimated at 24.86m 3/t by the regression line shown in Fig.4.Fig.1.Site location of the CO 2-ECBM pilot test at the Yubari area in the Ishikari CoalBasin.Fig.2.Conceptual well design of the CO 2-ECBM pilot test.288M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298There might be insuf ficient variation in the composition in the core samples to determine a statistically signi ficant relationship between gas content and inorganic content (sum of the moisture,ash andsulfur content).Therefore the relationship shown in Fig.4was not used to estimate gas content from ash content determined from open-hole log data.However,the relationship was used to estimate the initial condition of gas saturation.Gas composition for each core sam-ple is listed in Table 2.Table 1Geological formations at the injection well (IW-1).Formation (coal)Depth (interval)LithofaciesHoronai0.00–678.00m (678.00m)Dark gray to dark brown mudstone,dark bluish med-fine sandstone,coarse sandstone (with glauconitic)Yubari678.00–916.20m (238.20m)Dark brownish mudstone,dark gray siltstone,bluish graysandstone ∼very fine sandstone,coal,coaly shale,black shale(Upper coal seam)742.00–743.75m Appearance thickness (1.01m/1.75m)Net thickness (0.87m/1.52m)(Main coal seam)851.20–853.70m Appearance thickness (2.50m/2.50m)Net thickness (2.35m/2.35m)(Lower coal seam)890.08–896.30m Appearance thickness (5.32+m/6.22m)Net thickness (4.83+m/5.64m)Horokabetsu916.20–932.60mGraymudstoneFig.3.Casing pro file of IW-1well (left)and PW-1well (right);IW-1well is an injection well and PW-1well is a productionwell.Fig.4.Desorbed gas content anic content and ash plus moisture content of core samples from IW-1well;red squares correspond to core samples taken from the middle part of the Yubari lower seam and blue dots correspond to core samples taken from the roof side of the Yubari lower seam.(For interpretation of the references to colour in this figure legend,the reader is referred to the web version of this article.)289M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298Proximate and ultimate analyses were implemented for core samples being used to measure the gas content.Table 3summarizes gas content and coal characterization data that were determined on samples from the Yubari lower seam.The coal rank was high volatile bituminous based on the moisture,ash-free calori fic value and vitrinite re flectance data.The averaged value of gas content is 22.2m 3/t,which is excellent for this rank of coal.Adsorption isotherms of CO 2,CH 4and N 2were measured on the Yubari lower coal seam at a temperature of 30°C.As listed in Table 4,Langmuir volume and Langmuir pressure were derived from measured adsorption isotherms.Isotherm curves of CO 2,CH 4and N 2on the basis of Langmuir properties are shown in Fig.5.Storage capacity of CO 2,CH 4and N 2at the reservoir pressure of 102bars (10.2MPa)was estimated at 40.22m 3/t,23.84m 3/t and 13.34m 3/t,respectively.On the basis of Langmuir properties listed in Table 4and assumed gas composition (97.6%CH 4,2.03%CO 2,0.57%N 2),in-situ gas storage capacity of dry ash-free base can be calculated at 24.35m 3/t using the extended Langmuir isotherm relationship,which is very close to the estimation (24.86m 3/t)made by the relationship between in-situ gas content and organic content.It was also recognized that the reservoir was saturated with gas.The saturated conditions were supported by the production history that gas production started just after the production process had begun.Water injection fall-off test at IW-1well was conducted twice in November 2003.A multi-step injection rate schedule was used to determine the permeability.After water was injected for 120min at the rate of 2.0l/min,then the well was shut-in at in flatable packer.The pressure during the test had been recorded with bottom-hole ing 5.64m of net pay,pressure analysis with a single-phase pressure transient program based on a radial composite model resulted in an inner radius of 5.97m having permeability to water of 0.93mD (0.92×10−15m 2).The outer permeability was estimated at 1.66mD (1.64×10−15m 2)with 40.62m radius from the well.Thecalculated skin at the well was estimated at 0.24.A micro-fracture test was conducted after getting the conclusion of the fall-off test to ascertain fracture opening pressure and provide additional estimation of reservoir permeability.As shown in Figs.6and 7,the test yielded a fracture opening pressure of 15800kPa and a fracture closing pressure of 10900kPa.From the analysis of the fall-off pressure following the micro-fracture test,initial reservoir pressure was estimated at 10246kPa and average reservoir permeability to water was estimated at 1.10mD (1.09×10−15m 2).4.Test results4.1.Micro-pilot test with a single well (from November 2003to September 2004)Since PW-1well was not completed during the period from November 2003to September 2004,micro-pilot test with a single well (IW-1)was conducted.Activities occurred at IW-1well which include:a)primary production from 8May to 26June 2004,b)CO 2injection on 22July,and c)production from 14August to 13September.IW-1well had been shut-in from November 2003to spring 2004.When the well was reopened,the well was filled with water that flowed into the well from the coal seam.The water was pumped up from the well on 8May 2004,and the gas production started just after the production had begun.From this production history,it was estimated that the coal seam was saturated with gas.Water and gas production data during the early period could not be recorded due to electrical noise generated by the pump unit and pressure gauges.Fig.8shows the primary production data from 27May to 25June 2004.Early gas production rate ranged 30–35m 3/day and water production ranged 300–400l/day.It turned out that the capacity of the selected progressing cavity (PC)pump was 20times larger than actual water production volume.Injection of CO 2into almost virgin coal seam was tried twice in 2004.Prior to the first CO 2injection,water in the well was lifted outTable 2Produced gas composition (in mole fraction,%).Core sample Methane Ethane +propane n/i-Butane Nitrogen CO 2Lower 196.58 1.480.060.19 1.68Lower 298.220.080.000.15 1.55Lower 394.42 1.020.10 1.60 2.85Lower 494.600.990.06 1.61 2.73Lower 597.890.070.000.37 1.66Lower 695.76 1.170.060.31 2.70Lower 796.97 1.130.060.30 1.55Lower 898.330.060.000.06 1.55Average96.600.750.040.572.03Table 3Gas content and coal characterization of Yubari lower coal seam.ParameterUnit Lower Yubari 1Lower Yubari 2Lower Yubari 3Lower Yubari 4Lower Yubari 5Lower Yubari 6Lower Yubari 7Lower Yubari 8Ave.or total Top depth m 890.08890.23891.57892.33892.75893.25895.50896.00No data Bottom depth m 890.23890.50891.72892.50892.95893.47895.62896.15No data Thicknessm 0.150.170.150.170.200.220.120.15 1.33Sample weight g895.01132.0946.0911.01211.0978.0897.0958.0991.0In-situ gas content cm 3/g 19.927.020.523.819.421.222.723.322.2Moisture content wt frac 0.0090.0080.0090.0090.0090.0090.0080.0100.0089Ash contentwt frac 0.1480.0450.0440.0160.0560.0380.0270.0180.0490Volatile matter content wt frac 0.3540.3990.3870.3800.3640.3930.3840.3820.3804Fixed carbon content wt frac 0.4890.5480.5600.5950.5720.5600.5810.5900.5619Air-dry calori fic value J/g 30,60034,74034,53035,71033,45034,99035,16035,33034,314Moisture,ash-free calori fic valueJ/g 35,59236,08635,79435,96435,11536,04535,84735,61835,758Mean vitrinite re flectance %0.750.740.750.790.810.750.780.800.77Crucible swelling index No unit 7.07.58.09.08.58.09.09.08.3Total moisture wt frac 0.0950.0130.1450.1010.1570.1720.0660.0180.096True densityg/cm 31.4071.3301.3181.3141.3461.3281.3101.3401.337wt frac =weight fraction.Table 4Langmuir properties of Yubari lower coal seam at 30°C.Source of data:Prof.Tamon,Kyoto University.Langmuirvolume (m 3/t)Langmuirpressure (1/bar)Storage capacity at 102bar (m 3/t)Ratio of CH 4storage CO 244.050.102940.22 1.68CH 428.010.056023.84 1.00N 221.930.0152413.340.56290M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298by nitrogen circulation.On 8July 2004,the first CO 2injection test was performed without packer in the well and terminated due to leaks at the wellhead.The injected CO 2was released from the well into the atmosphere.After the leakage portion of the casing head flange was repaired,the second CO 2injection test was conducted on 22July 2004with a down-hole packer.The casing –tubing annulus was filled with water.Since it was most likely that there was a small leak through the down-hole packer seals,surface casing –tubing annulus pressure increased.Some amount of the injected CO 2was released to the atmosphere from the well annulus to protect the casing head flange.Although gross amount of injected CO 2was 7.5t,it was presumed that 2–3t of CO 2was injected into the coal seam.The well was shut-in during the period from 23July to the early morning of 8August 2004.After pumping and measuring tools for water and gas production were installed at IW-1well,water and gas rates as well as composition of produced gas were measured during the micro-pilot production period from 13August to 31August 2004.Fig.9shows the production rates of gas and water as well as gas composition during the micro-pilot paring with primary production (30–40m 3/day),gas production was obviously enhanced by CO 2injection.4.2.Multi-well pilot test (From October 2004to March 2008)The pilot test using an injection and a production well had been conducted since the completion of the production well (PW-1)in October 2004.Because there were a heavy fall of snow and rugged hills at the test site,the field activities were con fined to the period from spring to autumn due to economical and safety reasons.The fracture opening pressure made the upper limit of the bottom-hole injection pressure.During the period from October 2004to March 2005,activities occurred at IW-1and PW-1wells which include:a)First continuous CO 2injection test at IW-1well between 9and 25November.A total of 35.7t of CO 2was injected;b)primary and pilot production test at PW-1well from 1October to 21December.The tubing was mech-anically stuck while pulling out of the well.The tubing was released in June 2005.Fig.10shows the daily gas and water rates as well as CO 2injection rate during this period.A 15m 3CO 2storage tank was installed next to the injection pump skid as shown in Fig.2.The injection skid comprised of a compressor having a capacity of 16.0MPa outlet pressure with maximum 1000kg/h flow rate,and a boiler being capable to heat CO 2up to 90°C.The operation was controlled by an inverter motor (frequency control),which maintained a setting of outlet pressure.Prior to the first continuous CO 2injection,injection rate of CO 2was predicted from 15.5to 25.3t/day by a simulation model in case of no effect of coal swelling.However,actual CO 2injection rate ranged from 1.8to 2.8t/day.It seemed that the reasons for this low CO 2injectivity were flow restriction (positive skin factor)and/or low permeability caused by CO 2adsorption.CO 2injection rate was gradually increased.Because the hole of IW-1well was filled with water before CO 2injection,water was pushed into the coal seam together with CO 2.As water saturation near to the well decreased by injected CO 2,effective permeability to CO 2increased so that CO 2injection rate could be increased.Primary production was performed from 1to 30October 2004at PW-1well prior to the first continuous CO 2injection at IW-1well.Since the coal seam was saturated with gas,production of gas started soon after water production.During the primary production period,gas production rate was decreased from 300to 50m 3/day.After the primary production,the tubing was tried to remove to retrievetheparison of adsorption isotherm curves for CO 2,CH 4and N 2.Fig.6.Analysis of micro-fracture step rate test at IW-1well;fracture opening pressure was estimated.291M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298transducer and to install a surface readout transducer for extended bottom-hole pressure and temperature monitoring.However,the tubing was mechanically stuck while pulling out operation.It was decided that the pilot production was performed under the conditions that the tubing had been stuck.The pilot production commenced on 13November 2004and terminated on 20December 2004.It was likely that gas production rate was enhanced by CO 2injection at IW-1well.During the period from April 2005to June 2005,activities occurred at IW-1and PW-1wells which include:a)micro-pilot production from 29April to 24May after the first continuous CO 2injection test to measure gas composition,b)water injection fall-off test on 11May to identify skin factor and permeability,and c)recovering stuck tubing from PW-1well in June.Flow back gas composition during the micro-pilot production at IW-1well is shown in Fig.11.During the period from July 2005to March 2006,activities occurred at IW-1and PW-1wells which include:a)perforation to improve flow conditions at IW-1well,b)measuring temperature pro file in IW-1well,c)recovering the tubing to replace thermal tubing,d)the second continuous CO 2injection at IW-1well from 26August to 6October,resulting a total 115t of CO 2injection,and e)pilot production at PW-1well from 31July to 11December.The results of injection and production during this period are shown in Fig.12.When the second continuous CO 2injection was commenced on 26August,the tubing was filled with water.Like the first continuous CO 2injection test,CO 2was injected into the coal seam together with water at the beginning stage.As shown in Fig.12,injection rate ranged from 1.6to 3.5t/day and increased with time.The reasons for lower injection rate at the beginning period were considered that;a)free CO 2in coal cleats might move away from the injection well along with steep dipping of coal seam due to buoyancy during a relative long inactivity time,and b)effective permeability to CO 2was low due to high water saturation.Pilot production at PW-1well was performed from 31July to 11December.A baseline of the primary production prior to CO 2injection (26August)was from 75to 80m 3/day.As shown in Fig.12,gas production sensitively responded to CO 2injection.Gas production increased immediately after the commencement of CO 2injection and decreased just after the termination of CO 2injection.It is considered that this quick response to CO 2injection was caused by injection pressure of CO 2and water saturation in the cleats.At the later stages of the pilot production,the injection had a lagged in fluence on the gas production rate.The rate culminated in 370m 3/day when CO 2continuous injection was terminated,which was around 5times higher than primary production rate.After the termination of CO 2injection,the production rate gradually stabilized at 130m 3/day.During the period from April 2006to March 2007,activities occurred at IW-1and PW-1wells which include:a)short term CO 2injection from 11April to 10May,b)N 2flooding test from 11to 19May,c)the third (post-N 2flooding)continuous CO 2injection from 25May to 11September,in the meantime intermittent N 2injection from 18to 26August,d)installation of thermal tubing in the well to replace the normal tubing pipe on 2May and 26October,e)short term CO 2injection from 1to 15November,and f)pilot production at PW-1well from 13April to 16November.Daily injection and production rate during this period are shown in Fig.13.N 2flooding test was performed to evaluate the effectiveness of N 2flooding on improving well injectivity as indicated (Mavor et al.,2004;Reeves and Oudinot,2004;Shi et al.,2008).Fig.7.Analysis of micro-fracture fall off test at IW-1well;fracture closing pressure wasestimated.Fig.8.Primary production rate of micro-pilot test with a single well IW-1in 2004.292M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298Prior to the start of N 2flooding,intermittent CO 2injection into IW-1well was carried out to establish the baseline of CO 2injectivity.A total 23t of CO 2was injected in three separate terms over a 30-day period.Daily CO 2injection rate as well as daily production rate of water and gas is shown in Fig.14.The peak injection rate reached 4.3t/day and the average rate for the first two injection periods was more than 3.0t/day.This injection rate was consistent with the injection rate in 2005.During the last CO 2injection period,just prior to the N 2flooding,the injection rate dropped to around 1.7t/day.The reason for this substantial reduction in the injection rate was likely caused by the well work to replace the tubing with thermal tubing pipe.N 2flooding started on 11May 2006,immediately after the last CO 2injection term.The injection rate increased steadily from 354kg/day (284Nm 3/day)to 7195kg/day (5770Nm 3/day).Because an ade-quate injection pump for N 2flooding was not available at that time,the pump skid was intermittently operated under manual control so as to maintain the bottom-hole pressure lower than the fracture opening pressure of 15.8MPa.The hourly pressure variations are presented in Fig.15.The injection pressure for N 2was lower than the injection pressure for CO 2.Gas mole fractions of CH 4,CO 2and N 2contained in the produced gas are shown in Fig.16.A clear N 2breakthrough was observed on 20May,right after the end of the N 2flooding.The N 2mole fraction increased steadily with time and likely leveled off at 7.5%around the end of August.Two wells were opened and some amount of gas was released from these wells in September,so gas mole fraction data did not make sense after this time.After a five-day break from the end of N 2flooding,a further 39.6t of CO 2was injected into IW-1well over 11day period from 25May to 4June.During the injection,the hourly injection rate was recorded as shown in Fig.17.It can be seen that after reaching an early peak of 12.85t/day,injection rate declined rapidly,then leveled off at around 2.5t/day after day 5.It is noted that stabilized injection ratewasFig.9.Production rate and produced gas composition after CO 2injection of micro-pilot test with a single well IW-1in2004.Fig.10.Production and injection rates of multi well pilot test in 2004;gas and water were produced from PW-1well and CO 2was injected from IW-1well.293M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298within the range of 1.5to 3.5t/day observed in the 2005test.The N 2flooding test showed that daily CO 2injection rate was boosted by up to 4-fold by the N 2injection,but only temporarily.N 2flooding test indicated that adsorption volume on the coal could affect the permeability and well injectivity.The swelling of coal matrix by the sorption of CO 2seemed to be a major reason for the low CO 2injection rates observed at the Yubari pilot test (Yamaguchi et al.,2009).N 2flooding could be used to reverse the permeability reduction due to matrix swelling.Daily injection rate eventually increased from 2.5t/day to around 3.0t/day except the period of intermittent N 2injection from 18to 26August.This injection rate was obviously less than those during the test in 2005as well as CO 2short term injection before N 2flooding.It seems that the injectivity after N 2flooding was not recovered during the course of the cyclic injection of CO 2,N 2and CO 2.It may be estimated that the permeability might be lost by plugging of cleats with coal fines or change of cleat geometry.The gas rate produced from PW-1well during the pre-N 2flooding CO 2injection was broadly comparable to those recorded in 2004and 2005,but water rate was much higher.With the start of N 2flooding,Fig.11.Flow back gas composition at IW-1well after the first continuous CO 2injection in2004.Fig.12.Production and injection rates of multi well pilot test in2005.Fig.13.Production and injection rates of multi well pilot test in 2006;gas and water were produced from PW-1well and CO 2or N 2was injected from IW-1well.294M.Fujioka et al./International Journal of Coal Geology 82(2010)287–298。
the new issues puzzle
The New Issues Puzzle:Testing the Investment-Based ExplanationEvgeny Lyandres ∗Jones Graduate School of ManagementRice UniversityLe Sun †William E.Simon Graduate School of Business AdministrationUniversity of Rochester and GSAMLu Zhang ‡Stephen M.Ross School of BusinessUniversity of Michigan and NBERNovember 2006§AbstractAn investment factor,long in low investment stocks and short in high investment stocks,helpsexplain the new issues puzzle.Adding this factor into standard factor regressions reduces sub-stantially the magnitude of the underperformance following equity and debt offerings and thecomposite issuance effect.The reason is that issuers invest more than nonissuers,and the low-minus-high investment factor earns a significant average return of 0.57%per month.Our evi-dence lends support to the real options theory,in which investment extinguishes risky expansionoptions,and the q -theory of investment,in which firms with low costs of capital invest more.i li1IntroductionEquity and debt issuers underperform matching nonissuers with similar characteristics during the three tofive post-issue years(e.g.,Ritter1991;Loughran and Ritter1995;and Spiess and Affleck-Graves1995,1999).We explore empirically the investment-based hypothesis of this underper-formance.The q-theory of investment and real options theory imply a negative relation between investment and expected returns.If the proceeds from equity and debt issues are used tofinance in-vestment,then issuers should invest more and earn lower average returns than matching nonissuers.Our centralfinding is that a new investment factor,long in low investment stocks and short in high investment stocks,explains a substantial part of the new issues puzzle.Specifically:•We construct the investment factor by buying stocks with the bottom30%investment-to-asset ratios and selling stocks with the top30%investment-to-asset ratios,while using a triple sort to control for size and book-to-market.From January1970to December2005,the investment factor earns an average return of0.57%per month(t-statistic=7.13).•Most importantly,adding the investment factor into standard factor regressions reduces the magnitude of the underperformance for new equity issues portfolios.The equally-weighted portfolio offirms that have conducted seasoned equity offerings(SEOs)in the prior36months earns an alpha of−0.41%per month(t-statistic=−2.43).Adding the investment factor makes the CAPM alpha insignificant and reduces its magnitude by82%to−0.07%per month.The equally-weighted portfolio offirms that have conducted initial public offerings(IPOs)in the prior36months earn an alpha of−0.71%per month(t-statistic=−2.60).Adding the investment factor makes the CAPM alpha insignificant and reduces its magnitude by59%to −0.29%.The results from the Fama-French(1993)model are quantitatively similar.•The investment factor also helps explain the underperformance following debt offerings.The equally-weighted portfolio offirms that have conducted convertible debt offerings in the prior 36months earn an alpha of−0.63%per month(t-statistic=−4.20).Adding the invest-ment factor makes reduces the CAPM alpha by46%in magnitude to−0.34%,albeit still significant(t-statistic=−2.04).The underperformance following straight debt offerings is largely insignificant in our sample.The only exception is the equally-weighted alpha from the Fama-French(1993)model,−0.26%per month(t-statistic=−2.35).Controlling for the investment factor makes the alpha weakly positive,0.029%per month(t-statistic=0.27).•The results from using buy-and-hold abnormal returns(BHARs)are largely consistent with factor regressions.The BHARs of the SEO portfolio from matching on size and book-to-market over thefirst two and three post-issue years are−21.9%and−34.6%,respectively.Matching further on investment-to-asset ratios reduces the BHARs to−16.1%and−25.2%, respectively,about26%drop in magnitude.The BHARs of the IPO portfolio from matching on size and book-to-market are significantly negative after about six post-issue months,and the BHARs of the convertible debt portfolio are significantly negative after about18post-issue months.Matching on investment-to-asset makes this underperformance largely insignificant.•The investment factor also explains part of Daniel and Titman’s(2006)finding.A zero-cost portfolio that buys stocks in the bottom30%and sells stocks in the top30%of their composite equity issuance measure earns an equally-weighted alpha of−0.56%per month (t-statistic=−4.38)from the CAPM.Adding the investment factor reduces the alpha to −0.40%(t-statistic=−3.18),a drop in magnitude of28%.The value-weighted alpha from the Fama-French(1993)model is−0.36%per month(t-statistic=−3.57),and it drops by 57%in magnitude to−0.16%(t-statistic=−1.49)when we include the investment factor.Our evidence lends support to the investment-based explanation of the new issues puzzle(e.g., Zhang2005;Carlson,Fisher,and Giammarino2006).In their real options model,Carlson et al. argue thatfirms have expansion options and assets in place prior to equity issuance.This compo-sition is levered and risky.If real investment isfinanced by equity,then risk and expected returns must decrease because investment extinguishes the risky expansion options.2Inspired by the negative relation between real investment and expected returnsfirst derived by Cochrane(1991),Zhang(2005)argues that investment is likely to be the main driving force of the new issues puzzle.Intuitively,real investment increases with the net present values(NPVs)of new projects(e.g.,Brealey,Myers,and Allen2006,chapter6).The NPVs of new projects are inversely related to their costs of capital or expected returns,controlling for their expected cashflows.If the costs of capital are high,then the NPVs are low,giving rise to low investment.If the costs of capital are low,then the NPVs are high,giving rise to high investment.The average costs of equity forfirms that take many new projects are reduced by the low costs of capital for the new projects.Further,firms’balance-sheet constraint implies that the sources of funds must equal the uses of funds.Therefore,firms raising capital are likely to invest more and earn lower expected returns,andfirms distributing capital are likely to invest less and earn higher expected returns.Consistent with this theoretical prediction,we document that issuers invest more than matching nonissuers.The investment-to-asset spread between issuers and nonissuers is the highest in the IPO sample,followed by the SEO and convertible debt sample,and is the lowest in the straight debt sample.The relative magnitudes of the investment-to-asset spreads are consistent with the relative magnitudes of the underperformance across the four samples.We alsofind that high composite issuancefirms invest more than low composite issuancefirms.Our paper brings the insights from the literature on investment-based asset pricing to the liter-ature on the new issues puzzle.Our use of investment-to-asset as a key matching characteristic is motivated by the partial equilibrium models of Cochrane(1991,1996)and Berk,Green,and Naik (1999).Our use of the investment factor as a common factor of stock returns is motivated by the general equilibrium models of Gala(2005)and P´a stor and Veronesi(2005a,b).Several papers document the negative relation between investment and average returns.Cochrane (1991)is among thefirst to show this relation in the time series.Titman,Wei,and Xie(2004) and Cooper,Gulen,and Schill(2006)find a similar relation in the cross section but interpret the evidence as investors underreacting to overinvestment.Xing(2005)shows that real investment3helps explain the value effect.Anderson and Garcia-Feij´o o(2006)find that investment growth classifiesfirms into size and book-to-market portfolios.Anderson and Garcia-Feij´o o also anticipate our analysis:“Many studies examine long-run returns tofirms subsequent to new security offerings and report negative abnormal returns.Benchmarking long-run returns to changes in investment spending that may coincide withfinancing events might attenuate abnormal returns(p.191).”Brav and Gompers(1997)and Brav,Geczy,and Gompers(2000)document that equity issuers are concentrated among small-growthfirms,and suggest that their underperformance reflects the Fama-French(1993)size and book-to-market factors.Our evidence supports this argument because both equity issuers and small-growthfirms invest more than other types offirms.We suggest that real investment is likely to be the common link and the more fundamental driving force of their underperformance.Eckbo,Masulis,and Norli(2000)show that a six-factor model can explain the new issues puzzle,but we show that controlling for the investment factor is often sufficient.The rest of the paper is organized as follows.Section2develops the testable hypothesis.Section 3describes our data.Section4reports our empirical results,and Section5concludes.2Hypothesis DevelopmentThe investment-based explanation of the new issues puzzle argues that the post-issue underperfor-mance arises from the negative relation between real investment and expected returns.First,the relation between real investment and expected returns is negative.Second,iffirms issue new equity and debt tofinance real investment,then issuers should earn lower expected returns than nonissuers.2.1Theoretical MotivationFigure1illustrates the negative relation between real investment and expected returns,a central prediction in recent theoretical literature on investment-based asset pricing.Cochrane(1991,1996) derives the negative investment-return relation from the q theory of investment.In his models,firms invest more when their marginal q—the net present value of future cashflows generated from4one additional unit of capital—is high.Controlling for expected cashflows,a high marginal q is associated with a low cost of capital.In the real options model of Berk,Green,and Naik(1999),firms invest more when they have access to many low risk projects.Investing in these projects lowersfirm level risk and expected returns.In Carlson,Fisher,and Giammarino(2004),expansion options are riskier than assets in place.Real investment transforms riskier expansion options into less risky assets in place,thereby reducing risk and expected returns.1Figure1:The Investment-Based Explanation of the New Issues PuzzleTExpected return1The basic mechanisms in the real options and the q-theory models are similar because the two approaches are equivalent(e.g.,Abel,Dixit,Eberly,and Pindyck1996).5Gala(2005)constructs a general equilibrium production economy with heterogeneousfirms.In his model,afirm’s ability to provide consumption insurance depends on its ability to mitigate ag-gregate business cycle shocks through capital investment.In bad times,low investment,valuefirms want to disinvest and sell offtheir capital stocks.But they are prevented from doing so because of binding irreversibility constraints.Thesefirms thus earn high expected returns because their returns covary more with economic downturns.In contrast,in the face of negative shocks,high investment, growthfirms can easily lower their positive investment without facing the irreversibility constraints. Thesefirms thus earn low expected returns as they provide consumption insurance to investors.P´a stor and Veronesi(2005a)develop a general equilibrium model of optimal timing of initial public offerings,in which IPO waves are partially caused by declines in expected market returns.In their model,entrepreneurs choose the optimal timing of taking their privatefirms public,and then immediately investing part of the equity proceeds.Entrepreneurs prefer to postpone their IPOs until favorable market conditions such as low expected market return and high expected aggregate profitability.As a result,real investment of IPOfirms can serve as a state variable:high investment suggests low expected market returns,high aggregate profitability,or both.P´a stor and Veronesi(2005b)develop a general equilibrium model in which returns offirms investing in new technologies can define new systematic factors.Their model has two sectors:the “new economy”and the“old economy.”The old economy implements existing technologies on a large scale and its output determines a representative agent’s terminal wealth.The new economy implements the new technology on a small scale that does not affect the terminal wealth.The agent optimally chooses to experiment with the new technology on a small scale to learn about its unobservable productivity.If the productivity turns out to be sufficiently high,the new technology is adopted on a large scale.The nature of the risk associated with new technologies changes over time.The risk is initially idiosyncratic because of the small scale of production.Once adopted on a large scale,the risk becomes systematic because the new economy now affects the terminal wealth.6Figure1also shows that issuers are located at the right end of the curve,where expected re-turns are low,and nonissuers are located at the left end of the curve,where expected returns are high.Intuitively,the balance-sheet constraint requires that the uses of funds must equal the sources of funds,implying that issuers are likely to invest more than nonissuers.Based on this insight, Zhang(2005)and Carlson,Fisher,and Giammarino(2006)argue that SEOfirms must earn lower expected returns than matching nonissuers.The same intuition also applies to the underperfor-mance following IPOs(e.g.,Ritter1991)and convertible and straight debt offerings(e.g.,Spiess and Affleck-Graves1999),as well as the composite issuance effect(e.g.,Daniel and Titman2006).The investment-based explanation of the new issues puzzle,and more generally,the negative investment-return relation are conditional on a given level of profitability.High investment can be caused not only by low costs of capital,but also by high expected cashflows(profitability). More profitablefirms earn higher average returns than less profitablefirms(e.g.,Piotroski2000; Fama and French2006).Our results show that the difference in investment between issuers and nonissuers,rather than the difference in profitability,drives the new issues puzzle.2.2Empirical DesignOur choice of empirical methods echoes the theme of the theoretical motivation by complementing the use of a zero-cost low-minus-high investment factor as a common factor of stock returns and the use of investment as a matching characteristic.Motivated by the partial equilibrium models(e.g.,Cochrane1991;Berk,Green,and Naik1999), we examine the performance of security issuers relative to matchingfirms with similar characteris-tics including prior investment-to-asset ratios.The theoretical prior is that matching on investment should reduce the magnitude of buy-and-hold abnormal returns documented in previous studies(in which investment is not one of the control characteristics).Motivated by the general equilibrium models(e.g.,Gala2005;P´a stor and Veronesi2005a,b),we augment standard factor regressions with the investment factor constructed by sortingfirms on their investment-to-asset ratios.The7theoretical prior is that doing so should reduce the magnitude of the post-issue underperformance.Following Fama and French(1993,1996),we interpret the investment factor as a common fac-tor.While Fama and French go further and interpret their similarly constructed SMB and HML factors as risk factors motivated from ICAPM or APT,we do not take a stance on the risk inter-pretation of our investment factor.Arguments supporting the risk interpretation are clear.None of the theoretical papers that we use to motivate the investment factor assumes any form of over-and under-reaction.And unlike size and book-to-market,investment-to-asset does not involve the market value of equity,and is less likely to be affected by mispricing,at least directly.However,general equilibrium models with behavioral biases(e.g.,Barberis,Huang,and Santos 2001)can also motivate the investment factor.2Moreover,investor sentiment can presumably affect investment policy through shareholder discount rates(e.g.,Polk and Sapienza2006).Perhaps more importantly,covariance-based and characteristic-based explanations of the average-return variations are not mutually exclusive,in contrast to the position taken by Daniel and Titman(1997) and Davis,Fama,and French(2000).Under certain conditions,there exists a one-to-one mapping between covariances and characteristics,implying that they can both serve as sufficient statistics for expected returns(e.g.,Zhang2005).Our goal is thus to search for a theoretically motivated and empirically parsimonious factor specification that can explain anomalies in asset pricing tests. 3DataWe examine four types of security offerings:IPOs,SEOs,convertible debt issues,and straight debt issues.All four samples are obtained from Thomson Financial’s SDC database.The samples of the IPOs,SEOs,and convertible debt offerings are from1970to2005.Due to data availability,the sample of the straight debt offerings is from1983to2005.We obtain monthly returns from the Center for Research in Security Prices(CRSP).The monthly returns of Fama and French’s(1993)three factors and the risk-free rate are from Kenneth French’s website.Accounting information is from the COMPUSTAT Annual Industrial Files.Our sample selection largely follows previous studies.3To be included in a sample,a security offering must be performed by a U.S.firm that has returns on CRSP at some point during the three post-issuance years.We exclude unit offerings and secondary offerings of SEOs,in which new shares are not issued.For SEOs,our results are also robust to the exclusion of mixed offerings.4We also exclude equity and debt offerings offirms that trade on exchanges other than NYSE,AMEX, and NASDAQ.Similar to Brav,Geczy,and Gompers(2000)and Eckbo,Masulis,and Norli(2000), but different from Loughran and Ritter(1995)and Spiess and Affleck-Graves(1995,1999),we include utilities in our sample.Following Loughran and Ritter,we define utilities asfirms with SIC codes ranging between4,910and4,949.Excluding utilities does not materially impact our results,likely because the fraction of utilities in each sample is small:6%for SEOs,0.4%for IPOs, 2%for convertible debt issues,and8%for straight debt issues.Further,manyfirms issue multiple tranches of debt on the same date.We deal with this issue by aggregating the amount issued on a given day but separating straight and convertible debt issues.Table1reports for each of the four samples the number of offerings for each year,the number of offerings by non-utilities,and the number of offerings with valid data on size,book-to-market,and investment-to-asset ratio.These characteristics are used to select matching nonissuers.Our samples include10,084SEOs,7,732IPOs,1,215convertible debt offerings,and2,969straight debt offerings. Because of the long sample period(22years for straight debt offerings and36years for all others), our samples are among the largest in the literature.For comparison,Eckbo,Masulis,and Norli’s (2000)sample includes4,766SEOs,Loughran and Ritter’s(1995)sample consists of3,702SEOs and 4,753IPOs,and Brav,Geczy,and Gompers’s(2000)sample includes4,526SEOs and4,622IPOs.Inaddition,Spiess and Affleck-Graves’s(1995)sample consists of1,247SEOs,and Spiess and Affleck-Graves’s(1999)samples contain1,557straight debt offerings and672convertible debt offerings.To study the frequency distribution of issuers across size and book-to-market quintiles,we as-sign issuers to quintiles using the breakpoints from Kenneth French’s website.Forfirms that have issued in the period from July of year t to June of year t+1,we determine the size and book-to-market quintiles at thefiscal yearend of calendar year t−1.If size or book-to-market is missing at that time(frequently in the IPO sample),we use thefirst available size and book-to-market if the available date is no later than12months after the offering(24months for IPOs).We measure the market value as the share price at the end of June times shares outstanding. Book equity is stockholder’s equity(item216)minus preferred stock plus balance sheet deferred taxes and investment tax credit(item35)if available,minus post-retirement benefit asset(item330) if available.If stockholder’s equity is missing,we use common equity(item60)plus preferred stock par value(item130).If these variables are missing,we use book assets(item6)less liabilities(item 181).Preferred stock is preferred stock liquidating value(item10),or preferred stock redemption value(item56),or preferred stock par value(item130)in that order of availability.To compute the book-to-market equity,we use December closing price times number of shares outstanding.Table2presents the frequency distribution of issuingfirms and the relative amount of capital raised in the offerings.From the left four panels,smallfirms are more likely than largefirms to issue equity and convertible debt,but are less likely to issue straight debt.Growthfirms are more likely than valuefirms to issue equity and convertible debt,and to a lesser extent,straight debt. From Panel A,small-growthfirms perform19%of SEOs,while big-valuefirms account for only 0.52%of SEOs.The spread in issuing frequency is even wider for IPOs:32%of IPOs are conducted by small-growthfirms,in contrast to only0.11%by big-valuefirms.The frequency distribution of the convertible debt offerings sample is similar to that of the SEO sample.12%of the convertible debt issues are performed by small-growthfirms,in contrast to only0.58%undertaken by big-value firms.Prior studies show that small-growthfirms have higher investment-to-asset ratios than other10firms(e.g.,Xing2005;Anderson and Garcia-Feijoo2006).Our evidence that small-growthfirms are also the most frequent equity and convertible debt issuers is therefore suggestive of the role of real investment in explaining the underperformance following the offerings.5The right four panels of Table2report the median new issue-to-asset ratios of issuers by size and book-to-market quintiles.We measure the new issue-to-asset ratio as the proceeds of a new issue from SDC divided by the book value of assets at thefiscal yearend preceding an SEO or convertible or straight debt offering.Because of data limitations,we use the book value of assets at thefiscal yearend of an IPO.The distribution of the median new issue-to-asset across size and book-to-market quintiles is similar to the frequency distribution reported in the left panels of the table.Not only small-growthfirms issue securities much more frequently than big-valuefirms,but they also issue much more as a percentage of their book assets.From Panel A,the median new seasoned equity-to-asset ratio of small-growthfirms is0.89.In contrast,the median ratio of big-valuefirms is only 0.01.Dispersions of similar magnitudes are also evident in the convertible and straight debt samples (Panels C and D).From Panel B,the IPO sample displays an even wider spread:the median new equity-to-asset ratio for small-growthfirms is1.75,much higher than that for big-valuefirms,0.05. 4Empirical ResultsWe study the role of investment in driving the new issues puzzle using factor regressions(Section 4.1)and buy-and-holding abnormal returns(Section4.2).Section4.3examines the investment and profitability behavior for issuers and matching nonissuers.Inspired by Daniel and Titman(2006), Section4.4studies the link between investment and the returns of composite issuance portfolios.4.1Factor RegressionsEvidence on the New Issues PuzzleWe measure the post-issue underperformance as Jensen’s alphas in factor regressions.Lyon,Barber and Tsai(1999)argue that factor regressions are one of the two methods that yield well-specifiedtest statistics.(The other approach is Buy-and-Hold Abnormal Returns,see Section4.2.) We use the CAPM and the Fama and French(1993)three-factor model.The dependent variables in the factor regressions are the new issues portfolio returns in excess of the one-month Treasury bill rate.The new issues portfolios,including the SEO,IPO,convertible debt,and straight debt portfolios,consist of allfirms that have issued seasoned equity,gone public,issued convertible debt, and issued straight debt in the past36months,respectively.6Loughran and Ritter(2000)argue that the power of the tests can be increased if we weight eachfirm equally,instead of weighting each period equally.Following Spiess and Affleck-Graves(1999),we thus estimate factor regressions using Weighted Least Squares(WLS),where the weight of each month corresponds to the number of eventfirms having non-missing returns during that month.7Table3reports strong evidence of underperformance following equity issuance(Panels A and B).From Panel A,the equally-weighted alpha from the CAPM regression of the SEO portfolio is −0.41%per month(t-statistic=−2.43),and that from the Fama-French(1993)model is−0.39% per month(t-statistic=−3.52).The value-weighted alphas are similar in magnitude.From Panel B,the post-issue underperformance of IPOs from the CAPM is larger in magnitude than that of SEOs.The equally-weighted and value-weighted CAPM alphas of the IPO portfolio are−0.71% and−0.82%per month with t-statistics−2.60and−3.03,respectively.The alphas of the IPO portfolios from the Fama-French model are close to those of the SEO portfolios.Table3also reports reliable evidence of post-issue underperformance of convertible debt issuers, but not of straight debt issuers(Panels C and D).Convertible debt issuers show comparable under-performance to equity issuers.The convertible debt portfolio earns equally-weighted alphas from the CAPM and the Fama-French(1993)model of−0.63%and−0.54%per month,respectively. Both have t-statistics above four.The value-weighted alphas are smaller in magnitude,−0.44% and−0.26%,but still significant(t-statistics−3.38and−2.00),respectively.In contrast,only the equally-weighted alpha from the Fama-French model,−0.26%,is significant for the straight debtportfolio(t-statistic=−2.35).All the other alphas are insignificantly different from zero.Our evidence that convertible debt issuers display higher post-issue underperformance than straight debt issuers is consistent with Spiess and Affleck-Graves(1999).The Investment FactorAs a direct test of the investment hypothesis,we augment traditional factor models with a common factor based on real investment.We construct the investment factor as the zero-cost portfolio from buying stocks with the lowest30%investment-to-asset ratios and selling stocks with the highest 30%investment-to-asset ratios,while controlling for size and book-to-market.We measure investment-to-asset as the annual change in gross property,plant,and equipment (COMPUSTAT annual item7)plus the annual change in inventories(item3)divided by the lagged book value of assets(item6).We use property,plant,and equipment to measure real investment in long-lived assets used in operations over many years such as buildings,machinery,furniture, computers,and other equipment.We use inventories to measure real investment in short-lived assets used in a normal operating cycle such as merchandise,raw materials,supplies,and work in process.We do a triple sort on size,book-to-market,and investment-to-asset`a la Fama and French (1993).We independently sort stocks in each June on size,book-to-market,and investment-to-asset into three groups,the top30%,the medium40%,and the bottom30%.By taking intersections of these nine portfolios,we classify stocks into27portfolios.The investment factor,denoted INV, is defined as the average return of the nine low investment-to-asset portfolios minus the average return of the nine high investment-to-asset portfolios.8In untabulated results,the investment factor earns an average return of0.57%per month (t-statistic=7.13)from January1970to December2005.This average return is economically meaningful.For comparison,the average market excess return over the same period is0.50%per month(t-statistic=2.28)and the average HML return is0.48%per month(t-statistic=3.24).。
Factors affecting the size distribution of liposomes produced by freeze–thaw extrusion
International Journal of Pharmaceutics188(1999)87–95Factors affecting the size distribution of liposomes producedby freeze–thaw extrusionJonathan D.Castile,Kevin M.G.Taylor*Department of Pharmaceutics,School of Pharmacy,Uni6ersity of London,Brunswick Square,London WC1N1AX,UK Received22March1999;received in revised form25May1999;accepted9June1999AbstractThis paper describes the development of a protocol for the production of liposomes using a freeze–thaw extrusion ser diffraction particle size analysis showed that the median diameter of freeze–thawed egg phosphatidylcholine multilamellar vesicles(eggPC MLVs)was increased when cholesterol was included in the ing a freeze–thaw cycle of3min freezing in liquid nitrogen at−196°C followed by3min thawing at 50°C resulted in an anomalously large particle size for eggPC/cholesterol formulations.When liposomes were repeatedly freeze–thawed a maximum size was achieved afterfive freeze–thaw cycles.Dispersion of liposomes in sodium chloride solutions promoted size increases following freeze–thawing,suggesting that vesicles had aggregated or fused.Poloxamers P338and P407inhibited the size increases observed during freeze–thawing for eggPC MLVs dispersed in1.0M NaCl,probably through steric prevention of aggregation and fusion.©1999Elsevier Science B.V. All rights reserved.Keywords:Extrusion;Freeze–thaw;Liposome;Particle size;Poloxamer/locate/ijpharm1.IntroductionMuch of the potential damage to liposomes during freezing and subsequent thawing is directly related to the behaviour of water in the disper-sions(Talsma et al.,1991).Repeated freezing and thawing of multilamellar vesicles(MLVs)pro-duces physical disruption of the liposomal phos-pholipid bilayers,probably due to ice crystals formed during the freezing process.This also serves to break apart the closely spaced lamellae of the vesicles thereby raising the trapping effi-ciency by increasing the ratio of aqueous solute to lipid(Hope et al.,1985;Mayer et al.,1985). Extrusion of frozen and thawed MLVs(FATM-LVs)results in production of unilamellar lipo-somes more readily than those made by conventional techniques(Mayer et al.,1986). Elorza et al.(1993)showed,using5,6car-boxyfluorescein as an aqueous marker,that frozen and thawed extruded liposomes were a monodispersed population with an internal vol-ume higher than LUVs prepared solely by extru-sion of MLVs through polycarbonatefilters of equivalent pore size.*Corresponding author.Tel.:+44-171-753-5853;fax:+44-171-753-5920.E-mail address:ktaylor@(K.M.G.Taylor)0378-5173/99/$-see front matter©1999Elsevier Science B.V.All rights reserved. PII:S0378-5173(99)00207-0J.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–95 88Cooling rate,liposome size,phospholipid con-centration and localisation of any additives,all affect the crystallization behaviour of water in liposome dispersions(Talsma et al.,1991).Fast freezing rates impose a greater force of stress on liposomes than slower rates because intra-liposo-mal ice formation is likely at freezing rates greater than10°C/min,leading to expansion of vesicles’aqueous phase(O zer et al.,1988).For cooling rates faster than20°C/min,the probabil-ity of intra-liposomal ice formation is100%. Thawing is also an important parameter because the freeze–thawing is only effective at improving MLV swelling,and hence aqueous entrapment values,if the sample is thawed at temperatures above the temperature of the phospholipid main transition(T c)of the liposome suspension(Hope et al.,1986;MacDonald and MacDonald,1993). Little has been published about the effect of varying the number of freeze–thaw cycles on the structure of liposomes.31P NMR has been used to demonstrate the influence of the number of freeze–thaw cycles on distribution of lipid within liposomes,with an equilibrium distribution be-tween lipid and solute(Mn2+)being observed afterfive cycles(Mayer et al.,1985).Hope et al. (1986)demonstrated that the trapped volume of egg phosphatidylcholine(eggPC)MLVs in-creased in relation to the number of freeze–thaw cycles.A maximum trapped volume of9m l wa-ter per m mol of lipid was recorded after nine cycles,after which no further increase in trapped volume was observed.No data have been pub-lished reporting the effect of varying the time length of each freeze–thaw cycle.However, Fransen et al.(1986)observed a time-dependent leakage of a drug from a liposome suspension at −30°C,but below−40°C(homogeneous nucle-ation temperature of water)the dispersion was shown to be stable over a long period. Cryoprotective agents such as trehalose(and other disaccharides),dimethyl sulphoxide and glycerol are known to protect phospholipid bi-layers from damage during freeze–thawing and freeze–drying.Cryoprotectants are thought to depress the phospholipid T c,bind water,and in-teract with polar head groups of phospholipids.Water molecules associated with polar head groups of hydrated phospholipid bilayers may be replaced by sugar molecules which protect lipo-somes from aggregation and fusion during freeze–thawing or freeze–drying by holding indi-vidual vesicles in a vitrified matrix(Crowe et al., 1987,1988).Certain cryoprotectants,such as tre-halose,have also been shown to maintain phos-pholipids in afluid-like state in the absence of water,avoiding passage through the gel to liq-uid-crystalline phase transition and subsequent bilayer disruption during freeze–drying(Crowe et al.,1987),and may prevent fusion of vesicles by decreasing the surface tension at the liposome surface(Koster et al.,1994).The purpose of this study was to systemati-cally develop a protocol for the production of freeze–thaw extruded MLVs.The inclusion in the liposome dispersions of sodium chloride and poloxamer surfactants was also investigated. Poloxamers are non-ionic surface active ABA block copolymers having two hydrophilic poly-oxyethylene(POE)moieties and a hydrophobic polyoxypropylene(POP)moiety.They reduce phagocytosis when included in model colloidal systems(Illum et al.,1987;Rudt and Mu¨ller, 1993),and interact with the bilayers of liposomes to some extent,although the nature of the inter-action is not well understood(Jamshaid et al., 1988;Moghimi et al.,1991;Kostarelos et al., 1995;Castile et al.,1999).2.Materials and methods2.1.De6elopment of a freeze–thaw protocol for liposome preparationEggPC(Lipoid,Italy)was refined by chro-matographic purification(Bangham et al.,1974). MLVs were prepared as previously described (Castile et al.,1999)by weighing appropriate amounts of eggPC(up to300mg),with or without cholesterol(99%+purity,Sigma,UK) at a1:1mol ratio,into a round-bottomedflask, and adding chloroform(HiPerSolv,BDH,UK) to dissolve the phospholipid.Chloroform was removed by rotary evaporation under vacuum,J.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–9589in a water bath at55°C for15min.Theflask was thenflushed with nitrogen for1–2min to remove traces of residual solvent.An appropriate volume offiltered(100-nm porefilter[Poretics, USA]),bi-distilled,deionised water(Model WP 700,Whatman,UK),further purified by passing through an Elgastat Ultra High Quality Purifica-tion System(Elga,UK)was added to the dry film in theflask to give afinal phospholipid concentration of10mg/ml.Glass beads were added to aid dispersion,theflaskflushed with nitrogen,gently rotated for30min in the water bath,and shaken to produce MLVs.The suspen-sion was annealed for a further2h in the water bath before storage under nitrogen in a refrigera-tor at4°C.2.2.The effect of repeated heating and cooling on the thermal profile of liposomesEggPC and eggPC/chol(1:1)MLVs were ex-truded10times through a2-m m polycarbonate filter(Cyclopore,UK),held in a25-mm syringe filter holder,to standardize the size of the lipo-some population,and sized by laser Fraunhofer diffraction using a magnetically stirred cell and a 63-mm lens(Malvern2600C,Malvern Instru-ments,UK).The instrument’s software expresses particle size as the volume median diameter (VMD),i.e.the equivalent sphere diameter above and below which50%of the volume of particles lies and the size distribution is expressed as a span value[(90%undersize−10%undersize)/50% undersize)].Sizing data are presented as the mean9S.D.of three independent analyses. Aliquots from each dispersion(4ml)were dis-pensed into20-ml liquid scintillation vials(FBG-Trident,UK.)and quench frozen in liquid nitrogen at−196°C for the specified duration (1–5min).The vials were transferred immedi-ately to a water bath and held at50°C for an equal duration.The freezing and thawing process was repeated for a specified number of cycles. The FATMLVs were kept at room temperature in sealed containers for1h before size analysis by laser diffraction.All experiments were per-formed in triplicate.2.3.Standardised freeze–thaw procedure Subsequent experiments used a standardised freeze–thaw protocol to investigate the influence of external agents on the size distribution of freeze–thawed liposomes.MLVs were extruded through polycarbonatefilters,as described in Section 2.1.Each dispersion(4ml)was frozen for3min at−196°C in liquid nitrogen and then thawed for3min at50°C in a water bath.The cycle was repeated a further four times.In addi-tional experiments eggPC or eggPC/chol MLVs, produced by dispersion of lipid mixtures in aqueous sodium chloride(BDH,UK)solutions at concentrations of0.1,0.5and1.0M NaCl, were subjected to the freeze–thaw protocol.2.4.The effect of poloxamer concentration on the size distribution of FATMLVsEggPC MLVs were produced using 1.0M NaCl solution as the aqueous phase,and ex-truded through a2-m m porefilter as described in Section2.1.Poloxamers P338(ICI,France)and P407(Blagden Chemicals,UK)were added to some formulations at concentrations of0.05,0.1, 0.2,0.3,0.5and1.0%w/v and incubated at25°C for2h in a shaking water bath(Grant Instru-ments,UK)before being subjected tofive freeze–thaw cycles,as described in Section2.2.3.Results and discussion3.1.Parameters associated with freeze–thaw extrusionThe mean VMD of eggPC MLVs was not altered by freeze–thawing,and the duration of each freeze–thaw cycle had no clear effect on the mean VMD of eggPC FATMLVs(Fig.1).Small but significant increases in diameter were de-tected following1-and3-min freeze–thaw cycles but not at other cycle lengths(P B0.05).The mean VMD of all eggPC/chol MLVs sig-nificantly increased following repeated freeze–thawing(P B0.05)(Fig.1),with the greatest size increase observed for samples subjected to tenJ.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–95 90‘3-min’freeze–thaw cycles.The analysis was re-peated an additionalfive times for this data point (i.e.n=8),and the observed increase in size was reproduced,suggesting that the presence of cholesterol resulted in the formation of larger liposomes or aggregates during freeze–thawing, particularly with a3-min cycle.Cholesterol modifies the physical structure of phospholipid bilayers,restricting bilayer permeability and the movement of the hydrocarbon chains at tempera-tures above the T c(Oldfield and Chapman,1972). Therefore eggPC/chol bilayers are more rigid than eggPC bilayers.The inclusion of cholesterol re-duces the water permeability and compressibility of liposome bilayers(Finklestein and Cass,1967), decreasing their ability to withstand internal ex-pansion due to ice formation during fast-freezing (Morris and McGrath,1981;MacDonald and MacDonald,1993;van Winden et al.,1997),and causing bilayers to rupture during freeze–thaw-ing,with new liposomes forming as bilayer frag-ments re-assemble.In addition,cholesterol has been reported to induce aggregation and fusion on freeze–thawing of DPPC liposomes(Henry-Michellard et al.,1985).The observed increase in mean size for eggPC MLVs when cholesterol was included indicates that larger structures were formed,which may have been due to aggregation and subsequent fusion of vesicles.It was observed macroscopically,that samples exposed to1-and2-min freeze–thaw cycles did not completely melt during the thaw stage of each cycle.Consequently,a proportion of vesicles may not have been exposed to damaging conditions during re-freezing.Preparations exposed to3-min freeze–thaw cycles did melt completely during each thaw stage.However,the preparations may not have been warmed completely,with incom-plete mixing,possibly resulting in insufficient time for disrupted bilayers to re-anneal.Therefore lipo-some fragments may have suffered further freeze–thaw damage before re-assembling.Vesicles exposed to4-and5-min freeze–thaw cycles had more time to re-assemble during each thaw stage and this may have been reflected by smaller in-creases in mean diameter.Extruded liposomes had a relatively homoge-neous size distribution,with small distribution span values of0.8390.02and0.9990.03for eggPC and eggPC/chol preparations respectively. Freeze–thawing increased polydispersity,with the mean distribution spans of freeze–thawed eggPC and eggPC/chol MLVs significantly higher(P B 0.05)than those of non-freeze–thawed prepara-tions,with the exception of preparations subjected to the‘2-min’freeze–thaw protocol.Span values for eggPC preparations ranged from1.36to1.61 and for eggPC/chol MLVs from1.36to1.77. 3.2.Effect of changing the number offreeze–thaw cyclesThe mean VMDs of eggPC MLVs increased after one freeze–thawing cycle,but did not change significantly(P B0.05)between one and 20cycles.However,the mean VMD of eggPC/ chol MLVs increased following the process up to five cycles(Fig.2).Subsequent increases in the number of cycles produced no significant change in vesicle diameter(P B0.05),indicating an equi-librium situation after which further freeze–thaw cycles had little or no effect on the mean diameter for these liposomes.After one freeze–thawing cycle,the mean dis-tribution spans of eggPC and eggPC/chol MLVsFig. 1.Influence of freeze–thaw cycle length on the mean VMD of MLVs extruded10times through a2-m m porefilter then freeze–thawed10times. ,eggPC; ,eggPC/chol(1:1). Freeze–thaw cycle length is the number of minutes prepara-tions were held at−196°C and subsequently at50°C(n=39 S.D.).J.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–9591Fig.2.Influence of the number of‘3-min’freeze–thaw cycles on the mean VMD of MLVs(previously extruded10times through a2-m m porefilter). ,eggPC; ,eggPC/chol(1:1) (n=39S.D.).oleoylphosphatidylcholine MLVs for10cycles in 0.1M NaCl solutions has previously been re-ported to result in their fragmentation into a population of smaller vesicles having a mean size less than200nm(MacDonald et al.,1994).Such fragmentation was not observed when water was used as the aqueous phase,suggesting that an osmotic removal of water from the vesicles,in the presence of electrolyte solutions,was responsible for the dehydration and subsequent fragmenta-tion of bilayers.Such fragmentation,though to a lesser extent,has also been described for other phospholipids(Morris and McGrath,1981), whilst loss of the barrier properties of bilayers during freeze–thawing,without major fragmenta-tion has also been reported(Oku and MacDon-ald,1983;Mayer et al.,1985).Freeze–thawing eggPC in the presence of high concentrations(\1 M)of some alkali metal chlorides has been re-ported to result in the production of‘giant’uni-and oligolamellar liposomes having diameters greater than10m m(Oku and MacDonald,1983). The tendency for large liposomes to be formed depends on the alkali metal chloride being used, such vesicles being most prevalent with KCl and RbCl,and on the eutectic temperature of the frozen alkali metal chloride solutions.‘Giant’liposomes of eggPC were produced in the pres-ence of NaCl,but at higher concentrations ofextruded through2-m m porefilters were signifi-cantly increased(P B0.05)from0.8390.02to 1.3990.05for eggPC MLVs and from0.999 0.03to 1.5190.05for eggPC/chol MLVs.The eggPC/chol liposomes exhibited greater increases in mean distribution span between one and20 freeze–thaw cycles than the eggPC MLVs.Span values after20cycles were1.6090.04and1.999 0.26for eggPC and eggPC/chol preparations re-spectively.Thus the increased rigidity of eggPC bilayers due to the inclusion of cholesterol seemed to have a destabilizing effect during freeze–thaw-ing,causing the liposomes to rupture and subse-quently re-assemble to form a new population of liposomes with a higher mean VMD and wider and more variable size distribution.3.3.Effect of preparing liposomes in sodium chloride solutionsThe mean VMD of eggPC MLVs dispersed in NaCl solutions increased afterfive freeze–thaw-ing cycles by a greater extent than liposomes dispersed in water(P B0.05)(Fig.3).Mean distri-bution spans of all preparations dispersed in NaCl solutions increased significantly;the increase indistribution span for MLVs dispersed in0.5M NaCl(for instance,an increase from0.8290.06 before freeze–thawing to1.5590.15after freeze–thawing was typical).Freeze–thawing di-Fig.3.Influence of NaCl concentration on the mean VMD of eggPC MLVs before and afterfive freeze–thaw cycles. , before freeze–thawing;b,after freeze–thawing(n=39 S.D.).J.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–95 92both salt and phospholipid than used in the presentstudies(Oku and MacDonald,1983).EggPC MLVs reversibly aggregate in the pres-ence of alkali metal cations,including Na+(Na-gata et al.,1986;Mosharraf et al.,1995).Hydration forces(due to adsorption of hydroxylgroups)are the main repulsive force in dispersionsof eggPC MLVs(Lis et al.,1982;Mosharraf et al.,1995).Close association is a prerequisite of vesiclefusion.These results may indicate that liposomessuspended in NaCl can locate in closer proximityto neighbouring vesicles than those dispersed inbi-distilled water due to reduction of the netnegative charge by the presence of Na+ions.When bilayer damage occurs during freeze–thawing, damaged vesicles will aggregate and possibly fuse with vesicles with which they come into contact (Lasic,1988).Additionally,exposure to high tem-peratures during thawing provides thermal energy for liposomes to become closely associated,and thus would be more likely to overcome repulsive, hydration forces and so be more likely to aggre-gate.Addition of electrolyte after liposome manufac-ture provides an osmotic gradient and promotes an efflux of water from the aqueous compartments of vesicles.Even though liposomes were hydrated in NaCl solutions,an osmotic gradient may exist because phospholipid bilayers are semi-permeable membranes in which the outer bilayers hinder the progress of solutes to the inner aqueous compart-ments resulting in non equilibrium solute distribu-tions and an osmotic gradient across the bilayer (Gruner et al.,1985).Freeze–thawing of MLVs produces equilibrium distributions of solute,and consequently enhances vesicle swelling(Mayer et al.,1985).Efflux of water due to solute imbalances prior to freeze–thawing could cause osmotic shrinkage of vesicles,producing areas where the bilayer dilates or shrinks,causing local changes to the area occupied by each phospholipid molecule with a significant effect on bilayer stability.3.4.Effect of poloxamer concentration on the size distribution of FATMLVsA1.0M NaCl solution was used as the aqueous phase in this study since it enhanced the freeze–Fig.4.Effect of poloxamer concentration on the mean VMD of eggPC MLVs followingfive freeze–thaw cycles. ,P338; ,P407(n=39S.D.).thaw induced increase in mean diameter eggPC MLVs(Fig.3).Following extrusion through2-m m filters,and prior to freeze–thawing,all samples had mean VMDs of between2.4and3.2m m.The mean VMD of poloxamer-free samples was slightly higher than all poloxamer-containing samples, possibly due to aggregation before freeze–thawing. Differences,though small,were significant at all concentrations of P407and\0.1%w/v P338 (P B0.05).Fig.4shows the mean VMDs of eggPC FATM-LVs afterfive freeze–thaw cycles.The poloxamer-free sample had a mean VMD of8.090.4m m following freeze–thawing.Inclusion of poloxamer P338or P407inhibited the size increase associated with freeze–thawing.Low poloxamer concentra-tions were less effective than higher concentrations at inhibiting the size increase,but the median sizes of all poloxamer-containing formulations were sig-nificantly smaller than the poloxamer-free prepara-tions(P B0.05).There was no significant difference(P B0.05)in the mean VMD of formu-lations containing0.5and 1.0%w/v of either poloxamer.The size distribution of FATMLVs was less polydispersed as poloxamers concentrations were increased from0to0.3%w/v,but then the distri-bution span increased as poloxamer concentra-tions were increased further(Fig.5).On closerJ.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–9593analysis of the data(not presented),it was appar-ent that this was due to a reduction of the10% undersize value(the diameter below which10%of the volume of particles lies).The90%undersize value of these formulations was similar to that of samples containing lower concentrations of polox-amers,which indicates that the increase in span at higher poloxamer concentrations is caused by the formation of smaller vesicles.The presence of poloxamer molecules within liposome bilayers may sterically inhibit contact between two vesicles and subsequently prevent aggregation and fusion.As poloxamer concentra-tion was increased,vesicles may have been in-creasingly inhibited from associating with other vesicles during bilayer repair.This would account for the correlation between the increasing pres-ence of small vesicles at higher poloxamer concen-tration.It is also possible that higher poloxamer concentrations may destabilize phospholipid membranes,making them more susceptible to freeze–thaw damage although still inhibited from fusing with other liposomes.Jamshaid et al. (1988)showed that bilayer permeability of eggPC SUVs was increased by the presence of poloxam-ers,possibly due to the formation of‘pores’or regions of enhanced membranefluidity caused by inclusion of poloxamer within the bilayer.4.ConclusionThe median size and size distribution of2m m eggPC MLVs increased following freeze–thawing, suggesting that a new population of liposomes had been formed.Inclusion of cholesterol further enhanced these increases,possibly due to aggrega-tion and fusion of vesicles,indicating that it had a destabilizing influence on eggPC bilayers during the freeze–thaw procedure.Liposome bilayers are damaged by internal ice formation during freezing.Bilayers may break off or partially fragment.Damaged bilayers will re-assemble due to the‘hydrophobic effect’and form new liposomes possibly of a different size.Refor-mation may involve fusion with other liposomes (Lasic,1988).Each freeze–thaw cycle would provide an opportunity for this process to occur, both in previously unaffected liposomes and those damaged by a previous freeze–thaw cycle.How-ever,the proportion of vesicles that are affected and the extent of the damage to each bilayer cannot be determined from size analysis. Preparations dispersed in NaCl solutions in-creased in diameter following freeze–thawing to a greater extent than those dispersed in water.It seems likely that if there was any repulsion be-tween liposomes dispersed in bi-distilled water (from hydration or electrostatic forces),it was inhibited by NaCl,resulting in increased aggrega-tion and fusion of vesicles as bilayers recovered from freeze–thaw damage.Significantly,NaCl may have caused an osmotic gradient across lipo-some bilayers resulting in areas of bilayer instabil-ity due to osmotic shrinkage of vesicles.These areas may be more susceptible to freeze–thaw damage.Poloxamers P338and P407inhibited the size increases observed during freeze–thawing for eggPC MLVs dispersed in 1.0M NaCl.This suggests that the poloxamers may have sterically stabilized the liposome formulations.Poloxamers may associate with the surface of liposomes,pos-sibly through penetration of the POP moiety into the hydrophobic region of the phospholipid bi-layer or by adsorption to the liposome surface (Castile et al.,1999).Liposomes may still have been disrupted during freeze–thawing,but the presence of strongly hydrated POE groups ex-Fig.5.Effect of poloxamer concentration on the mean distri-bution span of eggPC MLVs followingfive freeze–thaw cycles. ,P338; ,P407(n=39S.D.).J.D.Castile,K.M.G.Taylor/International Journal of Pharmaceutics188(1999)87–95 94tending from the liposome surface may have steri-cally inhibited contact between vesicles.Subse-quently aggregation and fusion associated with freeze–thawing may then be inhibited.A greater proportion of small vesicles was detected as the poloxamer concentration was increased,suggest-ing that vesicles were still disrupted by freeze–thawing,but may have been increasingly inhibited from associating with other vesicles during bilayer repair.AcknowledgementsThe authors wish to thank BBSRC forfinancial support.ReferencesBangham,A.D.,Hill,M.W.,Miller,N.G.A.,1974.Prepara-tion and use of liposomes as models of biological mem-branes.Methods Membr.Biol.1,56–57.Castile,J.D.,Taylor,K.M.G.,Buckton,G.,1999.A high sensitivity differential scanning calorimetry study of the interaction between poloxamers and dimyristoylphos-phatidylcholine and dipalmitoylphosphatidylcholine lipo-somes.Int.J.Pharm.182,101–110.Crowe,J.H.,Crowe,L.M.,Carpenter,J.F.,Wistrom,C.A., 1987.Stabilization of dry phospholipid bilayers and proteins by sugars.Biochem.J.242,1–10.Crowe,J.H.,Crowe,L.M.,Carpenter,J.F.,Rudolph,A.S., Wistrom, C.A.,Spargo, B.J.,Anchordoguy,T.J.,1988.Interactions of sugars with membranes.Biochim.Biophys.Acta947,367–384.Elorza,B.,Elorza,M.A.,Sainz,M.C.,Chantrez,J.R.,1993.Comparison of particle size and encapsulation parameters of three liposomal preparations.J.Microencapsul.10, 237–248.Finklestein,A.,Cass,A.,1967.The effect of cholesterol on the water permeability of thin lipid membranes.Nature216, 717–718.Fransen,G.J.,Salemink,P.T.M.,Crommelin,D.J.A.,1986.Critical parameters in freezing of liposomes.Int.J.Pharm.33,27–35.Gruner,S.M.,Lenk,A.S.,Janoff,A.S.,Ostro,M.J.,1985.Novel multilayered lipid vesicles:comparison of physical characteristics of multilamellar liposomes and stable pluril-amellar vesicles.Biochemistry24,2833–2842.Henry-Michellard,S.,Ter-Minassian-Saraga,L.,Poly,P.A., Delattre,J.,Pusieux,F.,1985.Lyophilization and rehydra-tion of liposomes.Colloids Surfaces14,269–276.Hope,M.J.,Bally,M.B.,Webb,G.,Cullis,P.R.,1985.Pro-duction of large unilamellar vesicles by a rapid extrusion procedure.Characterisation of size distribution,trapped volume and ability to maintain a membrane potential.Biochim.Biophys.Acta812,55–65.Hope,M.J.,Bally,M.B.,Mayer,L.D.,Janoff,A.S.,Cullis, P.R.,1986.Generation of multilamellar and unilamellar phospholipid vesicles.Chem.Phys.Lipids40,89–107. Illum,L.,Jacobsen,L.O.,Mu¨ller,R.H.,Mak,E.,Davis,S.S., 1987.Surface characteristics and the interaction of colloid particles with mouse peritoneal macrophages.Biomaterials 8,113–117.Jamshaid,M.,Farr,S.J.,Kearney,P.,Kellaway,I.W.,1988.Poloxamer sorption on liposomes:comparison with polystyrene latex and influence on solute efflux.Int.J.Pharm.48,125–131.Kostarelos,K.,Luckham,P.F.,Tadros,T.F.,1995.Addition of block copolymers to liposomes prepared using soybean lecithin.Effects on formation,stability and the specific localisation of the incorporated surfactants investigated.J.Liposome Res.5,117–130.Koster,K.,Webb,M.S.,Bryant,G.,Lynch, D.V.,1994.Interactions between soluble sugars and POPC(1-palmi-toyl-2-oleoylphosphatidylcholine)during dehydration:vit-rification of sugars alters the phase behaviour of the phospholipid.Biochim.Biophys.Acta1193,143–150. 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MacDonald,R.C.,MacDonald,R.I.,1993.Applications of freezing and thawing in liposome technology.In:Gregori-adis,G.(Ed.),Liposome Technology,vol.1.CRC Press, Boca Raton,FL,pp.209–228.MacDonald,R.C.,Jones,F.D.,Qiu,R.,1994.Fragmentation into small vesicles of dioleoylphosphatidylcholine bilayers during freezing and thawing.Biochim.Biophys.Acta1191, 362–370.Mayer,L.D.,Hope,M.J.,Cullis,P.R.,1986.Vesicles of variable sizes produced by a rapid extrusion procedure.Biochim.Biophys.Acta858,161–168.Mayer,L.D.,Hope,M.J.,Cullis,P.R.,Janoff, A.S.,1985.Solute distributions and trapping efficiencies observed in freeze–thawed multilamellar vesicles.Biochim.Biophys.Acta817,193–196.Moghimi,S.M.,Porter,C.J.H.,Illum,L.,Davis,S.S.,1991.The effect of poloxamer-407on liposome stability and targeting to bone marrow:comparison with polystyrene microspheres.Int.J.Pharm.68,121–126.Morris,G.J.,McGrath,J.J.,1981.The response of multilamel-lar liposomes to freezing and thawing.Cryobiology18, 390–398.Mosharraf,M.,Taylor,K.M.G.,Craig,D.Q.M.,1995.Effect of calcium ions on the surface charge and aggregation of phosphatidylcholine liposomes.J.Drug Target.2,541–545.。
叶下珠属植物活性成分柯里拉京研究进展(综述)
叶下珠属植物活性成分柯里拉京研究进展(综述)张树峰;明艳林;林毅;陈良华;童庆宣【摘要】柯里拉京(Corilagln)是从植物中分离得到的一种天然多酚类物质,主要来源于叶下株属植物,是该属植物的主要活性成分.研究表明,柯里拉京具有抗肿瘤、治疗心血管疾病、抗氧化等多种生物活性,且不良反应低,近年来受到研究者的广泛关注,值得进一步研究开发.本文对柯里拉京的基本性质、提取分离和主要活性进行详细综述.【期刊名称】《亚热带植物科学》【年(卷),期】2010(039)004【总页数】5页(P79-83)【关键词】叶下珠属;柯里拉京;抗肿瘤;心血管疾病【作者】张树峰;明艳林;林毅;陈良华;童庆宣【作者单位】华侨大学,化工学院,福建,厦门,361021;厦门华侨亚热带植物引种园,药用植物与植物药研究中心,福建,厦门,361002;厦门华侨亚热带植物引种园,药用植物与植物药研究中心,福建,厦门,361002;华侨大学,化工学院,福建,厦门,361021;厦门华侨亚热带植物引种园,药用植物与植物药研究中心,福建,厦门,361002;厦门华侨亚热带植物引种园,药用植物与植物药研究中心,福建,厦门,361002【正文语种】中文【中图分类】Q949.95大戟科(Euphorbiaceae)叶下珠属(Phyllanthus)植物在全世界约有600种,广泛分布于热带和亚热带地区。
我国有33种,其中4个变种,主要分布于长江以南各省。
该属植物具有重要的药用价值,民间常用来治疗肠炎、肾炎水肿、黄疸性肝炎、尿路感染和小儿疳积等疾病[1]。
研究发现,该属植物的主要活性成分为化合物柯里拉京(Corilagin)。
柯里拉京(Corilagin,Beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-glucose)是多酚的新成员。
目前研究发现,柯里拉京存在于6科10属14种植物中,如叶下珠(Phyllanthus reticulatus)[2]、榄李(Lumnitzera racemosa)[3]、余甘子(Phyllanthus emblica)[4]、老鹳草(Geranium wilfordii)[5]、橄榄(Canarium album)[6]、蜜柑草(Phyllanthus matsumurae)[7,8]、龙眼(Dimocarpus longana)[9,10]等。
第十九届安子介国际贸易研究奖评选结果
中国社会科学
Journal of Development
Economics
世界经济
倪鹏飞 中国社会科学院 葛嬴 对外经济贸易大学 鲍晓华 上海财经大学
学术鼓励奖(10 名)
序号 1 2 3 4 5 6 7 8 9 10
获奖者 任婉婉 刘啟仁 孙南翔
李靓 李斌 杨连星 杨修 周记顺 诸竹君 蒋为
所在单位 浙江大学 厦门大学 西南政法大学 中国农业大学 对外经济贸易大学 中国人民大学 北京师范大学 中南财经政法大学 浙江大学 南开大学
中国社会科学出版 赵果庆 云南财经大学
中国财政经济出版社 聂名华 中南财经政法大学中国社会科学出版社 起凡浙江大学 宁波理工学院
南京大学出版社 谢建国
南京大学
优秀论文奖(18 篇)
论文题目
一 等 奖(1 篇)
发表刊物
申请人
工作单位
总贸易核算法:官方贸易统计与全球价值链的度量
中国社会科学 祝坤福 对外经济贸易大学
管理世界
中国投资协议实体保护标准的自由化和多边化演进
法学研究
全球价值链降低了劳动收入份额吗——来自中国行业面板数 据的实证研究
经济学动态
申请人 毛其淋
工作单位 南开大学
冯辉 对外经济贸易大学
全毅 福建社会科学院
李玉梅 对外经济贸易大学
沈伟
上海交通大学
张少军
厦门大学
什么决定国家标准制定的话语权:技术创新还是政治关系
附件:
第十九届“安子介国际贸易研究奖”评选结果
优秀著作奖(8 部)
一 等 奖(空缺)
二 等 奖(2 部)
著作题目
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工作单位
葡萄球菌,链球菌与中毒性休克症候群
葡萄球菌、鏈球菌與中毒性休克症候群1疾病管制局研究檢驗中心、2現代中醫聯合診所、3衛生署基隆醫院蘇勳璧1 、鄧振華2、蘇治原3一、前言中毒性休克症候群(Toxic Shock Syndrome, TSS)是一種與金黃色葡萄球菌(Staphylococcal aureus)和A型β溶血性鏈球菌(Group A Streptococcal, GAS)等產生外毒素感染有關的症候群。
金黃色葡萄球菌和A型β溶血性鏈球菌主要可經由皮膚、粘膜、腸道等處侵入,即使很小的皮膚傷口,均可能引起細菌感染而產生毒素。
引起中毒性休克症候群的毒素屬於超級抗原毒素(superantigen toxins)。
金黃色葡萄球菌的超級抗原毒素包括SEA、SEB、SEC1、SEC2、SEC3、SED、SEE、SEG、SEH、SEI、SEJ、SEK、SEL、SEM、SEP,及原來命名為SEF,現改稱為Toxic shock syndrome toxin-1(TSST-1)(Bergdoll,1983:Spero,1988)等。
A型β溶血性鏈球菌的超級抗原毒素包括SpeA、SpeC、SpeG、SpeH、SpeI、SpeJ、SpeL、SpeM、SSA、SMEZn等。
由動物實驗與臨床觀察得知超級抗原毒素有以下幾種作用:1.發熱2.加重內毒素致死作用3.降低宿主網狀內皮系統細胞對異物的清除作用4.對T細胞具有分裂原作用,使T 細胞大量增殖,釋放多種細胞激素,干擾並降低宿主個體的免疫 5.改變毛細血管壁通透性,使血漿外滲,導致血容量不足、低血壓、休克。
二、金黃色葡萄球菌葡萄球菌中以金黃色葡萄球菌(Staphylococcal aureus)產生毒素最強,和人類疾病最有相關性(Elek,1959),能引起食物中毒(Food poisoning)、骨髓炎(Osteomyelitis)、中毒性休克症候群(Toxic shock syndrome)、敗血症(Septicaemia)等(Shah & Watanakunakorn,1979)。
金的等离子共振等综述
a b s t r a c t
This review describes the fundamental aspects of laser–gold nanoparticle (Au NP) interaction that leads to nanoscale energy deposition to the surroundings through light amplification and heat generation. Besides the importance of the primary process in physics and chemistry, application of the light–NP interaction has attracted significant interest from various areas ranging from analytical chemistry to material chemistry and biomedicine. Here we consider both mechanistic and application aspects. Our attention is focused on pulsed-laser-induced fast processes that revealed the heating–cooling dynamics of electrons, lattice (particle), and particle’s environment. On the application side, we focus on material fabrication and processing that beat diffraction-limited resolution. Together, we will shed a light on the essence of research activities carried out in the past 10 years. In addition to an abundance of latest information obtained from currently available literature, this review includes figures obtained by our own calculations to provide readers with a better understanding of the basics of the optical properties and energy and heat-transfer processes of Au NPs, which are not familiar to photochemists. © 2012 Elsevier B.V. All rights reserved.
Binding structure of calender and the like
专利名称:Binding structure of calender and the like发明人:川口 裕申请号:JP実願2000-4472(U2000-4472)申请日:20000627公开号:JP実用新案登録第3074397号(U3074397)U公开日:20010112专利内容由知识产权出版社提供专利附图:摘要:(57)< Abstract > < Topic > Binding generation of the calender form which you pile up hotAdhesion with the adhesive of melt type, the calender form sameAs adhesion binding power of the loyal retainer is raised, the calender form and the backmosquitoOffering the binding structure of the calender and the like which raises theadhesiveness of the barDo. Solutions The form of the calender form 1,2 and the like which you pile upIn binding generation, in the notch which is opened in the edge of particular form 1,2 aThe tsu te, width of the aforementioned open part from width inside maximum of this notch it is smallRectangle string facilities to do the notch 3 which is formed, in each notch 3 hot melPut back cover 6 to the binding generation which inserted to adhesive 5With, the aforementioned form and adhesion back cover 6.申请人:川口 裕地址:神奈川県川崎市川崎区台町18番8号国籍:JP代理人:樋口 盛之助 (外1名)更多信息请下载全文后查看。
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The sociotechnical principles of work organization demonstrated the need and usefulness of participation in modern industrial production (e.g., Daniellou and Garrigou, 1992). Several tendencies can be identified; in the past, the main themes focused on autonomy, self-development, etc. Finally, ergonomics itself is moving towards a systems approach, i.e., macroergonomics (Hendrick, 1994). Understanding and identifying the organizational, technological and individual component roles in an industrial production has shifted the emphasis to systemic issues, 'Just-in-time', 'design for manufacturing' and other trends in industry have influenced the need for participatory ergonomics. They have also changed the role of an ergonomist from a specialist to a change agent, which in turn influences the practice of participatory ergonomics. In the framework of a case study, Wilson (1995a) has discussed the relative merits of a participatory and specialist approach. Participatory ergonomics is defined here as practical ergonomics with participation of the necessary actors in problem solving. The participation is not limited to 'worker participation' nor to formal, representative participation. It covers, in principle, all levels of the hierarchy, inviting the participation of those who may have first-hand experience about the problem in question.
Relevance to industry
Participatory approaches, including ergonomics, help management to deal with uncertainty and to manage complex situations in designing manual tasks. Participation adds value to product design and adds realism to complex systems design.
Keywords:
Participatoryergonomics;Participation; Methodology;Problem-solving beyond the scope of this article. Shipley (1990), for example, has discussed these issues in a larger context. The following text is based on the author's experience with participatory ergonomics tools rather than on a theoretical review of participatory issues. Before exploring the tools, participatory ergonomics should itself be defined. Participatory ergonomics is an approach resulting from several trends: Participation in society, organization of production according to sociotechnical principles, and the development of ergonomics from 'micro' to 'macro'. The societal aspect goes back to debates in the nineteen sixties about industrial democracy (e.g., ILO, 1981). The main issues concern participation in the capital of the enterprises, co-determination, etc. These issues have little practical influence on participatory ergonomics.
Ilkka Kuorinka
Institut de Recherche en Sant~ et en S~curit~ du Travail du Qugbec (IRSST), 505, boul. de Maisonneuue Ouest, Montrgal, Qugbec Canada H3A 3C2
Abstract
A review of the techniques used in participatory ergonomic projects is presented. The emphasis is on pragmatic tools and the means often used in the context of occupational safety and health. Few methods stem from the domain of participatory ergonomics itself but come from organizational development, rationalization, etc. It is emphasized that these methods should be used in a systemic context and they should respect the participants' needs and expectations.
3. Methods used to concretize the workplace and process The simulation of full-scale workplaces is an established design tool which has been used for the simple exploration of workplace components as well as for testing the dimensioning of space vehicles. But the simulation has another quality in a participatory context: It allows a workplace a n d / o r work process that does not exist yet to be visualized and explored. In a conventional design, it is usually the project leader who has a mental image of the future state of the design object. In participatory design, this image must be shared with and enriched by the participants. Constructing a simulated lay-out, for example, is one way of sharing the image. Simulation may take different forms: Full-size or scale mock-ups are classical means of concretizing and testing a finite object. An example is the design of the cockpit of a police car (C6t~ et al., 1991). Simple, readily available means, scrap material, cardboard boxes marking furniture, and tapemarks on the floor showing the boundaries of a machine are effective ways to show the future situation. Several other methods have been used to concretize and illustrate a design object or situation (e.g. Wilson, 1991). Innovative production games have been used in training at work, which may also be useful in participatory design (Vartiainen et al., 1985). Imada (1991) enumerates several categories of tools, which may be employed in a participatory process. Actually, the goal of the simulation is to bring the