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1、李博士提供的毒性试验常用配方：Table 2: Vehicles for the administration of DS in animals. Vehicles are arranged so that the hydrophilic ones are at the top and the most lipophilic ones at the bottom of the table. VehiclesTo have “on the bench”RoutesHumanUseRemarks: Hydroxypropyl cellulose (Klucel HF) or Methylcellu
2、lose, up to 1% (w/w) in waterOrally (as a suspension medium)YesFor po suspensions of insoluble cpd. Addition of Tween 80 (2% of final conc.) possible. Prepare it freshly or store it sterilised by heat (121C/15 minutes)Physiological saline solution (NaCl 0.9% (w/w) in water)Orally,parenterallyYesFor
3、hydrophilic cpd. Issue: salting out of DS. Acidic buffer:D-Tartaric acid in water, down to final pH of 3-4;is an alternative to HCl, 0.1NOrally,parenterallyYesFor basic hydrophilic cpd. Mix cpd and acid in 1:1.5 molar ratio and dissolve in water. Addition of small amount of Ethanol possible (see bel
4、ow). Basic buffer1 M Tris pH 8.8 15 %Water 85 % (w/w)Is an alternative to NaOH 0.1NOrally,parenterallyYesFor acidic hydrophilic cpd. It might be necessary to dissolve cpd first in a concentrated Tris solution and further dilute it. Increasingly lipophilic Ethanol 94% Orally,parenterallyYesFor lipoph
5、ilic cpd up to 20% (w/w). Check for solvent effects, dilute with water or saline. PEG 300 neat or diluted with water.Orally,parenterallyYesWidely used solvent for lipophilic cpd. Has an antiinflammatory potential! Tween 80, up to 20% (w/w), (= Polysorbate 80)Orally (20%, w/w),Parenterally (2%, w/w)Y
6、esSurfactant for dissolving lipophilic cpd. Dilute with water or saline. Widely used wetting agent and surfactant. Has an immuno-suppressive potential. To be prepared freshly. Pluronic F68 (Poloxamer 188)Orally and parenterally (5% (w/w)YesSurfactant for dissolving lipophilic cpd. Of spe As a “matri
7、x” for solid dispersions see special chapter in this document. Solid dispersions always need to be further formulated.Cremophor EL (650 mg) plus Ethanol 94% ad 1 ml (965 mg)Orally,Parenterally after dilution, micellar based systemYes, parenteralIn house supply. Dissolve cpd in vehicle, dilute with s
8、aline / 5% glucose. Dilution for mice /rats 1:3（相当于5%Cremophor EL,15% Ethanol） for monkeys 1:20: Toxic in dogs! Interferences with LC-MS have been noted.SpeciesWeight (kg)Blood volume(ml)Administration Volumes (ml/kg except *ml/site) (values in () are max. values)posc*multiple sites pos-sibleipim*iv
9、 bolusiv slow in-jectioniv in-fusion rate ml/kg/h over 24hid*multiple sites pos- sibleMouse0.0251.810 (20) 5(0.5) 10 (10) 0.05(0.05) 5(3)2540.05Rat0.251610 (10) 5 (1)10 (25) 0.1(0.1) 5(3)2020.05Rabbit422410 (5) 1(1.5) 4 (10)0.25(2) 2(3)1010.1Hamster0.053.520(10)5(0.5)10(25)0.1(0.1)5(3)-Guinea Pig0.3
10、2120(5)5(1)5(30)0.1 (0.5) 1(3)-Dog10850 5 1 1 0.25 2.5520.1Macaque (Cynomolgus)5325 5 0.5 - 0.25 2-0.1Marmoset0.352510 - 0.25 2.510-0.05Baboon 251750102-0.52.5-Minipig15975 5 1 1 0.25 2.5510.1Humans50(FDA value)3500 (f)3900(m)2502-3No!3502.5 L/24hMinimally 100ml/h-VehiclesTo have “on the bench”Route
11、sHumanUseRemarks: More information can be obtained in the extended excipient list including ordering numbers (see Annex ).Miglyol 812 (mid chain triglyceride（中链甘油三脂） of caprylic/capronic acid)Orally, parenterally but not i.v.YesFor oily and/or oil containing solutions and suspensions. Orally adminis
12、tered oils have the disadvantage to slow down the depletion of the stomach and therefore to influence Tmax and Cmax (to be carefully evaluated) 可注射表面活性剂1、 泊洛沙姆188（F68）：可用作静脉注射脂肪乳的乳化剂。安全性：泊洛沙姆被用于一系列的口服、注射和局部用药物制剂，通常被认为无毒、无刺激性，它在体内不被代谢。LD50（小鼠，IV）：1g/kgLD50（小鼠，SC）：5.5g/kgLD 50（大鼠，IV）：7.5g/kg推荐浓度：5%(w/
13、w)（依据见上表）法规：被收载于FDA非活性成分指南用于静脉注射剂，吸入、眼用制剂，口服散剂、溶液剂、混悬剂、糖浆剂、局部用制剂，英国许可用于非注射和注射用制剂。2、 聚山梨酯80（吐温80）安全性：聚山梨酯广泛用于化妆品、食品以及口服、非胃肠道和局部给药的制剂，通常认为是无毒、无刺激性材料。聚山梨酯80：静注毒性中等、胃肠道摄取毒性中等。对眼有刺激性。为实验性致癌物，对生殖有影响。有致突变的报道。LD50（小鼠，IP）：7.6g/kgLD50（小鼠，IV）：4.5g/kgLD 50（大鼠，IP）：6.8g/kgLD50（大鼠，IV）：1.8g/kg推荐浓度：2%(w/w)（依据见上表）法规：
14、聚山梨酯80收载入FDA非活性成分指南，用于肌注、静注，口服，局部、直肠，阴道用制剂中，英国准许在注射和非注射用制剂中使用。3、 聚氧乙烯蓖麻油衍生物安全性： 聚氧乙烯蓖麻油衍生物应用于口服、局部和注射等各种给药途径，在动物体中的急性和慢性毒性试验表明其基本上无毒、无刺激性。但在人体和动物上静注本产品有较严重的致敏性。聚氧乙烯35蓖麻油（Cremophor EL）已作为地西泮、丙泮尼地等专利注射剂的溶剂；LD50（狗，IV）：0.64g/kgLD50（小鼠，IV）：2.5g/kg推荐浓度：5%(w/w)（依据见上表）法规：已收载入FDA非活性组分指南用于静脉注射和眼用溶液，在英国准许用在注射制剂。4、 Solutol HS 15（Polyethylene glycol 660 12-hydroxystearate）BASF新辅料应用
