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1、药 剂 学,第 三 章 液体制剂,第四节 输 液,输液(infusion solution)是指由静脉滴注输入体内的大剂量(100ml)注射液.,一、概 述,输液种类,电解质输液营养输液 胶体输液 药物输液,1.电解质输液 用以补充体内水份、电解质，纠正体内酸碱平衡等.如氯化钠注射液、乳酸钠注射液等.,2.营养输液 营养输液有糖类输液、氨基酸输液、脂肪乳剂输液等.,3.胶体输液 胶体输液有多糖类、明胶类、高分子聚合物等,4.药物输液 临床治疗输液.,严格要求无菌、无热原及澄明度含量、色泽、pH渗透压:等渗或偏高渗不能有产生过敏反应的异性蛋白不含降压物质输液中不得添加任何抑菌剂在贮存过程中质量稳
2、定,质量要求较高！,水洗,原辅料注射用水,成品入库,输液瓶,胶塞,酸碱处理,原水清洗,清洁剂处理,配制,过滤,原水清洗,纯化水清洗,灌装,放膜,注射用水洗,上胶塞,轧铝盖,灭菌,贴签,质检,纯水煮沸,乙醇浸泡,纯水清洗,包装,注射用水洗,隔离膜,注射用水洗,纯水清洗,容器、材料处理,三、输液的制备,一）制备工艺流程,1.输液瓶的质量要求和清洁处理,输液玻璃瓶 酸洗：用硫酸重铬酸钾清洁液洗涤效果较好.碱洗：是用2%氢氧化钠溶液(50-60）冲洗，也可用1%-3%的碳酸钠溶液 直接水洗：药厂生产输液瓶，制瓶车间洁净度较高，瓶子出炉后，立即密封，使用时只要用过滤注射用水冲洗即可.聚丙烯塑料瓶 无毒、
3、轻质、耐腐蚀、耐热、机械强度高,二）输液容器准备,2.输液瓶所用橡胶塞,富于弹性及柔软性；针头刺入和拔出后应立即闭合，能耐受多次穿刺而无碎屑脱落；具耐溶性，不致增加药液中的杂质；可耐受高温灭菌；有高度化学稳定性；对药液中药物或附加剂的吸附作用应达最低限度；无毒性，无溶血作用.,四、输液的质量检查,1.澄明度与微粒检查2.热原无菌检查3.酸碱度及含量测定,1.澄明度与微粒检查,全自动微粒检查仪,2.热原无菌检查,HTY一次性使用全封闭集菌培养器,STV6无菌检查薄膜滤器,3.酸碱度及渗透压测定,4.含量测定,二、主要存在的问题及解决办法,输液存在的问题染菌热原反应澄明度与不溶性微粒的问题原因原辅
4、料质量问题 橡胶塞与输液容器质量问题 工艺操作中的问题 医院输液操作及静脉滴注装置问题,解决办法严格控制原辅料的质量；提高橡胶塞及输液容器质量；合理安排工序，采取单向层流净化空气，采用微孔滤膜滤过和生产联动化等措施；使用无菌无热原的一次性全套输液器，在输液器中安置终端过滤器（0.8 m孔径的薄膜）；尽量减少生产过程中微生物的污染，同时严格灭菌，严密包装,葡萄糖注射液(glucose injection)处 方注射用葡萄糖 50g 100g1%盐酸 适量 适量注射用水加至 1000ml 1000ml制 法 按处方量将葡萄糖投入煮沸的注射用水内，使成50-60%的浓溶液，加盐酸适量，同时加浓溶液量
5、的0.1%(g/ml)的活性炭，混匀，加热煮沸约15分钟，趁热滤过脱炭.滤液加注射用水稀释至所需量，测定pH及含量合格后，反复滤过至澄明即可灌装封口，11530分钟热压灭菌.,处方及工艺分析1.浓配、加盐酸、煮沸，使糊精水解，中和胶粒电荷使蛋白质凝聚.2.颜色变黄、pH下降，生成5-羟甲基呋喃甲醛,第五节 注射用无菌粉末,定义,应用方法,适合药物,配制后注射，或用静脉输液配制后静脉滴注.,注射用无菌粉末系指药物制成的供临用前用适宜的无菌溶液配制成澄清溶液或均匀混悬液的无菌粉末或无菌块状物，也称粉针剂.,抗生素类药物及酶或血浆等生物制品，如头孢菌素类及一些酶制剂（胰蛋白酶、辅酶A等）.,一、注射
6、用无菌分装制品,易发生的问题：装量差异，澄明度与无菌问题.,无菌的粉末原料,分装于灭菌容器,无菌分装制品,密封,无菌操作条件,药粉,重结晶法或喷雾干燥法,制备方法：,二、注射用冻干制品的制备工艺,定义,适用对象,极不稳定的药物,采用冷冻干燥的方法，使已滤除微生物的溶液在低温下冻结，再使其在真空条件下形成固体状态，这类制剂称为注射用冻干制品.,分装,再干燥,升华干燥,药液,安瓿或小瓶,预冻,封口,质检,成品,注射用冻干制品的制备工艺,冷冻干燥机,冷冻干燥用冻干机,冷冻干燥中存在的问题、原因及处理办法,第六节 眼用制剂,定义,分类,眼用液体制剂系指供洗眼、滴眼或眼内注射用以治疗或诊断眼部疾病的液体
7、制剂.,滴眼剂眼内注射溶液,药物吸收途径1,药物吸收途径2,影响眼用药物吸收的因素,1.药物从眼睑缝隙的损失2.药物外周血管消除3.pH与pKa4.刺激性5.表面张力6.粘度,无菌澄明度pH值：5.09.0 渗透压：与泪液等渗粘度：4.05.0mPas,眼用液体制剂的质量要求,第五章 注射剂和眼用液体制剂,一、眼用液体制剂的附加剂,pH值调节剂等渗调节剂 抑菌剂粘度调节剂稳定剂、增溶剂与助溶剂,二、眼用液体制剂的制备工艺流程,洗涤,配液,质量检查,灭菌,滴眼瓶、帽塞,过滤,无菌灌装,成品,主药和附加剂,灭菌,封口,印字包装,第七节 其他灭菌与无菌制剂,一、植入药物传递系统(IDDS),置入泵高
8、分子聚合物植入系统原位凝胶,植入制剂,渗透泵控制释药模式图,片心=药物+渗透活性物质,水,水,水,药 物 溶 液,释药孔（Orifice),半透性衣膜CA,以溶液状态给药后立即在用药部位发生相转变,形成的非化学交联的半固体制剂.原位凝胶能够以液体状态自由加载各种性质及分子量的药物.原位凝胶具有凝胶制剂的亲水性三维网络结构及良好的组织相容性，独特的溶液-凝胶转变性质使其兼有制备简单、使用方便、与用药部位特别是黏膜组织亲和力强、滞留时间长等优点广泛的用途和良好的控制释药性能,原位凝胶给药系统已成为药剂学领域的一个研究热点.包括热敏型凝胶、离子敏感型、pH敏感型、光聚合可生物降解型水凝胶等.,原位凝
9、胶(in situ gel)技术,溃疡、烧伤、及外伤用溶液剂、软膏剂溃疡、烧伤、及外伤用气雾剂、粉雾剂 要求严格灭菌,二、创面用制剂,三、手术用制剂,止血海绵淀粉、明胶、纤维、蛋白骨腊骨止血，蜂蜡,第八节 灭菌与无菌制剂新进展,脂质体纳米粒微乳无针注射器,LiposomesAn aqueous suspension of vesicles enclosing an aqueous solution with bilayer membranes of phospholipids.,Fig 1.1 Schematic diagram of the structure of liposomes.,D
10、iscovery of liposomes,By A.Bangham,M.Standish,J.Watkins.Diffusion of univalent ions across the lamellae of swollen phospholipids.J.Mol.Biol.13(1965)238252.Was eventually awarded a Citation Classic(1989).In 1961 Babraham acquired an electron microscope.R.W.Horne,Discovery of liposomes,First observati
11、on,Fig.1 TEM of lecithin dispersions dispersed in 2%potassium phosphotungstate.,Phospholipid spherules(liposomes)as a model for biological membranes G.Sessa&G.Weissmann.1968.J.Lipid Res.9:310-318.Weissmann took the model back to New York.Renamed them liposomes.,Discovery of liposomes,The phospholipi
12、d spherules was first named liposomes,FIG.1.Electron nlicrograph of artificial lipid sphcrulcs,Composition&Structure of liposomes,Different categories of liposomes,Conventional liposomesMacrophage targeting Local depot VaccinationLong-circulating liposomesTargeting to pathological areas Circulating
13、microreservoirImmunoliposomesSpecific targetingCationic liposomesGene delivery,Classification of liposomes based on composition and application.,Liposomal products on markets,Liposomes as drug carriers,Liposomal drugsAmBisome(Gilead,Fujisawa 1989)Abelcet(Liposome company 1989)Amphocil(Alza 1995)Epax
14、al(Swiss S&V Institute 1995)Inflexal(Swiss S&V Institute 1995)Doxil/Caelyx(Alza 1995)DaunoXome(Gilead 1995)Myocet(Elan,Europe 2000)DepoCyt(SkyePharm,1999)DepoDur(SkyePharm,2004)Visudyne(Vovartis 2000),AmBisome(NeXstar,Gilead,Fujisawa 1989),Liposomes as drug carriers,Liposomal drugs on markets,AmBiso
15、me for Injection is a sterile,non-pyrogenic lyophilized product for intravenous infusion.Amphotericin B 50 mgHSPC 213 mg Cholesterol 52 mgDSPG 84 mgAlpha tocopherol 0.64 mg Sucrose 900 mgNa2H4C4O4 27 mgpH 56,DaunoXome(NeXstar 1995),Liposomes as drug carriers,Liposomal products on markets,A sterile a
16、queous suspension of liposomes containing citrate salt of daunorubicin with a mean diameter of about 45 nm.DSPC/Cholesterol/daunorubicin(10:5:1 molar ratio),Each vial(25 mL)contains Daunorubicin citrate 50 mg DSPC 704 mgCholesterol 168 mgSucrose 2 125 mgGlycine 94 mgCaCl2H2O 7 mgThe pH 4.9 6.0.,Lipo
17、somal drugs on markets,Liposomes as drug carriers,Doxil/Caelyx(Alza,Tibotec 1995)is provided as a sterile,translucent,red liposomal dispersion in 10-mL or 30-mL glass,single use vials.,Doxorubicin HCl 2 mg/mL PEG2000-DSPE 3.19 mg/mLHSPC 9.58 mg/mL Cholesterol 3.19 mg/mL(NH3)2SO4 2 mg/mL Histidine&Su
18、crose,Doxil/Caelyx(Sequus),Liposomes as drug carriers,Liposomal drugs on markets,DepoDur is morphine sulfate extended-release liposome injection and is administered as a single dose epidural injection at the lumbar level prior to surgery.The particles are 10-30 microns in diameter.Phospholipids/Trig
19、lycerides2 ml/vial 10 mg/ml,DepoDur(Skye Pharma,2004),Solid Lipid Nanoparticles,The first generation,the solid lipid nanoparticles(SLN)were developed more or less in parallel by Prof.Rainer H.Mller and Dr.Jrg-Stefan Lucks(at this time both at the Kiel University,North Germany)and Prof.Dr.Maria Gasco
20、(Turin University/Italy)at the beginning of the 1990s.At the turn of the millennium,the second generation of the lipid nanoparticles was developed,the nanostructured lipid carriers(NLC).,The lipid nanoparticles can be used for very different application routes including drug targeting.Articles are i
21、ncluded covering topical application,oral and pulmonary administration including one about targeting to the brain,a side of high therapeutic interest.A delivery system can also be characterised in terms of its ability to encapsulate important groups of drugs.Due to the lipophilic nature of the parti
22、cle matrix,lipid nanoparticles are predestined for incorporation of poorly water-soluble,lipophilic compounds such as many anti-cancer drugs.Peptides and proteins are also in the focus of interest,but due to their mostly hydrophilic nature they are more difficult to incorporate.,In the year 2005 the
23、 lipid nanoparticles(in form of NLC)were present in the first cosmetic products.As lipid nanoparticles are patent protected worldwide as Lipopearls or Nanopearls,Now the future needs to show if we are going to find lipid nanoparticles also in pharmaceutical products to finally judge the degree of success of this delivery system.,
