DX-9065A HCl hydrate

Factor Xa (FXa) (Ki = 41 nM)

合成化合物DX-9065a代表了一种低分子量、直接、竞争性的因子Xa（FXa）抑制剂，对酶具有高亲和力和选择性。在实验条件下，DX-9065a在体外具有很强的抗凝血作用，在各种血栓形成模型中具有抗血栓作用。它抑制细胞培养系统中血管平滑肌细胞的增殖。作为一种小分子抑制剂，DX-9065a可以灭活游离和纤维蛋白结合的FXa。通过这种机制，它有效地影响了血栓相关的促凝血活性，促凝血活性可能是血管内血栓传播以及溶栓后复发性血栓形成和血栓再闭塞的原因。[1]

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合成化合物DX-9065a是一种低分子量的FXa直接抑制剂，对酶具有高亲和力和选择性。首次动力学研究揭示，DX-9065a以41 nM的抑制常数Ki竞争性抑制人FXa，而其他丝氨酸蛋白酶没有或仅受到微弱影响（Ki值单位：凝血酶>2000，胰蛋白酶=0.62，胰凝乳蛋白酶>2000，纤溶酶=23，tPA=21，血浆激肽释放酶=2.3，组织激肽释放蛋白酶=1000）。在以下研究中，发现抑制人FXa的Ki值略有不同，范围为3.1和7.8 nM（14）至24 nM。[1]

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强效和选择性的FXa抑制剂，如DX-9065a，不会影响预形成的凝血酶，但基于凝血级联中的扩增机制和凝血酶原酶复合物的重要作用，预计可以有效抑制凝血酶的产生，这可能是这些药物抗血栓形成效力的最重要机制。凝血酶介导的反馈反应，如扩增凝血酶形成的辅因子V和VIII的激活，以及凝血酶对血小板和其他细胞元件的影响也将发生改变。DX-9065a对凝血酶生成的抑制作用在人全血中得到了证实，它导致凝血酶生成的时间和浓度依赖性延迟或抑制，在生化凝血酶生成试验中，DX-9065a延迟和减少了凝血酶的生成，导致血浆中凝血酶的量减少。[1]

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DX-9065a是新开发的Xa因子合成和选择性抑制剂系列中的第一个成员。DX 9065A以剂量依赖的方式抑制人Xa因子，其K iota值为3.1+/-0.5nM。稳态研究表明，DX 9065A是Xa因子的竞争性抑制剂。DX 9065A在体外通过外源性和内源性途径抑制凝血酶的产生。[2]

对血小板活化后形成的血小板衍生微粒的研究表明，这些微粒表面的凝血酶原酶活性和由此产生的体内血栓前作用都受到直接（DX-9065a）和直接（五糖）FXa抑制剂的抑制。这些抗FXa药物的抑制作用基于对存在于微粒表面的FXa的抑制、凝血酶爆发的延迟和对微粒表面触发的凝血级联的抑制。开发FXa小分子抑制剂的一个重要方面是，它们不仅能灭活血浆中的凝血酶，还能在与凝块内的纤维蛋白结合时灭活凝血酶，这是抗凝血酶和抗凝血酶依赖性抑制剂所没有的效果。由于血管内和壁血栓中存在FXa和活性凝血酶原酶复合物（10,11,39），FXa的失活和由此导致的凝血酶形成的抑制可能是影响血栓相关抗凝剂活性的有效方法，血栓相关抗凝血剂活性被认为是血管内血栓传播和成功溶栓后复发血栓形成的原因。作为一种对酶具有高亲和力的小分子量抑制剂，DX-9065a抑制游离和结合凝血酶前体的FXa，能够渗透到凝块中并抑制凝块结合酶[1]。

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静脉注射给兔子后，DX-9065a显示出延长的抗Xa因子活性和抑制凝血酶生成。用DX-9065a预处理小鼠，剂量依赖性地提高了注射致死剂量组织因子（ED50=1.1+/-0.2mg/kg）的小鼠的存活率。口服给药后，DX 9065A导致组织因子诱导的小鼠死亡率降低，ED50值为56+/-7mg/kg。当静脉注射给大鼠时，DX 9066A对Xa+因子淤滞诱导的静脉血栓形成表现出剂量依赖性的抗血栓作用（ED50=1.2+/-0.7mg/kg静脉注射），但在动静脉分流血栓形成模型中（ED50=8.1+/-3.5mg/kg静脉静脉注射）也没有显著影响出血时间。皮下注射或口服给药后也获得了类似的效果。在兔子中，静脉注射、皮下注射或口服给药后，DX 9065A抑制了注射组织因子后淤滞诱导的血栓形成，ED50值分别为0.03+/-0.01、0.3+/-0.07和50.5+/-19mg/kg（n=10）。DX 9065A以剂量依赖的方式抑制内毒素诱导的兔静脉血栓形成（ED50=0.25+/-0.1mg/kg静脉注射）（n=5），并在组织因子诱导的弥散性血管内凝血实验模型中减少血小板数量和循环纤维蛋白原水平的降低。与标准肝素相比，DX-9065a显示出良好的抗血栓/出血比率，因此表明它可能被认为是治疗和预防各种血栓性疾病的有前景的化合物。[2]

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抗凝作用[1]
注射给药后，DX-9065a的给药剂量与其抗凝和抗FXa活性之间存在可预测的定量关系。口服抑制剂后，APTT和PT测定中的凝血时间也出现了剂量依赖性延长。口服和静脉内有效剂量的DX-9065a之间的直接比较表明，口服抗凝和/或抗血栓作用所需的剂量至少是静脉内给药的5到10倍（见表1）。同样明显的是，DX-9065a在仅适度增加离体测量的凝血时间APTT和PT的剂量下抑制了实验性血栓形成。值得一提的是，DX-9065a的抗凝和抗Xa活性是物种依赖性的。DX-9065a在延长人类和普通松鼠猴血浆PT方面几乎同样有效。相比之下，在大鼠血浆中，抑制剂的效力比在人血浆中低40倍。猴、狗、兔和小鼠血浆对DX-9065a的抗凝反应介于人和鼠血浆之间。

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对血小板功能的影响[1]
浓度高达100μM的DX-9065a不会抑制ADP、胶原蛋白或凝血酶诱导的血小板聚集。DX-9065直接灭活Xa因子并不能阻止花生四烯酸、TRAP或α-凝血酶等激动剂诱导的人全血血小板活化。然而，DX-9065a对组织因子或Xa因子介导的血小板活化表现出时间和浓度依赖性的抑制作用。DX-9065a的抗血小板作用似乎主要是由于抑制凝血酶的产生，众所周知，凝血酶是血小板活化和聚集最重要的生理抑制剂。

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抗血栓作用[1]
各种实验研究清楚地表明，DX-9065a是一种静脉注射、皮下注射或口服的有效抗血栓药物。DX-9065a抑制或预防几种类型的血管血栓形成，如静脉和动脉血栓形成、血管分流闭塞和弥散性血管内凝血。由于实验模型、血栓形成刺激、药物给药类型以及使用的物种存在很大差异，因此很难评估DX-9065a对确定的血栓性疾病的有效性。根据DX-9065a的作用机制，预计该抑制剂可能对血栓形成过程具有更大的抑制作用，其中潜在的病理生理机制主要涉及凝血级联的激活，最终将纤维蛋白原转化为纤维蛋白，如静脉血栓形成。表1给出了用DX-9065a进行的血栓研究的实验总结。

PHARMACOKINETICS [1]
Animal studies
Pharmacokinetics and pharmacodynamics of FXa inhibitors are closely related becausethe circulating blood is the primary site of action for a compound that inactivates clottingenzymes. For the long-term clinical use of anticoagulants/antithrombotics the oral admin-istration is the preferred route. DX-9065a is a low molecular weight FXa inhibitor thatwas designed to overcome the limitations of peptide compounds, especially the lack oforal bioavailability. The effectiveness of DX-9065a after oral administration was demon-strated in animal and human studies. DX-9065a caused strong anticoagulant and/or anti-thrombotic effects after either parenteral or oral administration (Table 1). However, com-parative studies revealed that for antithrombotic effects much (at least 10 times) higheroral than intravenous doses are required (Table 1). This is in accordance withpharmacokinetic studies in baboons where the oral bioavailability was estimated to be ap-proximately 5 to 12%. Studies on the time course of action of DX-9065a in ratsshowed that after i.v. injection of the inhibitor the anti-FXa activity was maximal immedi-ately after the injection and persisted for approximately 30 min. After oral administrationthe maximal anti-Xa activity was reached at 15 to 30 min after administration and per-sisted for about 90 min. The same time course was observed fot the antithrombotic action,i.e., the effect was transient after i.v. injection lasting for 10 to 20 min and was observedfor more than 3 h after oral administration. Other authors found that the peak activityof DX-9065a after oral administration to rats occurred at about 1 h after treatment and per-sisted for 4 h. After i.v. injection of DX-9065a to baboons plasma half-lives of6.3 min for the á-phase and 99 min for the â-phase were found. After oral administrationpeak plasma levels of DX-9065a were seen at 30 min and then gradually declined overabout 6 to 8 h.

Human studies
The pharmacokinetics of DX-9065a in humans differs from that in animals. This couldbe based on species differences which were clearly demonstrated in studies on the antico-agulant/antithrombotic effects of this inhibitor (see above). It is of special interest that theduration of action of DX-9065a in humans is much longer than in rats or baboons. Inregard to the possible clinical use of DX-9065a in the prevention or treatment of thrombo-embolic disorders, its longer duration of action is highly desirable. After a single i.v. bolusinjection (0.625–2.5 mg) of DX-9065a or a 1 h i.v. infusion (total dose 5 to 30 mg) to malehuman volunteers a biexponential or triexponential decrease of DX-9065a plasmaconcentrations was seen. At i.v. bolus injection of 2.5 mg the terminal phase t1/2 was10.7 h, whereas after i.v. infusion for 60 min the t1/2 was in the range of 22.8 to 26.1 h.The plasma protein binding rates ranged from 64.6 to 83%, and cumulative urinary ex-cretion ranged between 32.3 and 40.9%. Concentrations of DX-9065a in feces were belowthe quantification limit. At the dose range studied the pharmacokinetics of DX-9065a inhuman subjects after either i.v. bolus injection or continuous i.v. infusion for 1 h waslinear, independent of the dose administered and there were no statistically significant dif-ferences between the two treatment groups.After a single i.v. dose of 10 mg [14 C]DX-9065a, administered as 1 h infusion to ahealthy male Caucasian volunteer, plasma concentration of the drug decreased in a biexponential manner and was below the detection limit at 48 h after dosing. The half-lifefor the distribution phase was 6.93 h. The major route of excretion was via urine, ac-counting for more than 77.6% of the dose. A renal tubular secretion might contribute tothe urinary excretion of DX-9065a. Biotransformation of DX-9065a does not seem to playa significant role in the elimination of DX-9065a in humans.In the XaNADU-IB (Xa Neutralization for Atherosclerotic Disease Understanding)trial patients with stable coronary artery disease received DX-9065a at 1 mg i.v. bolus, fol-lowed by infusion at 4 different doses (see below) for 72 h. The half-life values ofDX-9065a were: t1/2á = 0.14 to 0.30 h, t1/2â = 1.93 to 3.20 h, t1/2ã = 76.57 to 98.86 h. Inter-individual differences increased at higher doses.In a double-blind, placebo-controlled study DX-9065a, 2.5, 5, or 10 mg, was adminis-tered s.c. to healthy male subjects. The peak plasma levels of the drug were reached at 1 hafter injection and declined to below the detection limit at 4 to 8 h after treatment.

Hemorrhagic Effects in Animal Studies [1]
The main side effects of anticoagulant/antithrombotic drugs during their therapeuticuse are hemorrhagic complications. At antithrombotically effective doses the risk ofbleeding should be as low as possible. Data on anti-FXa agents regarding the impairmentof primary hemostasis pointed out that FXa inhibitors might cause less bleeding complica-tions than thrombin inhibitors. As a competitive inhibitor DX-9065a does not suppress theproduction of thrombin completely so that trace amounts of thrombin are still generated.Because of the much higher affinity of thrombin for platelets than for fibrinogen, thesesmall amounts of thrombin are sufficient to form the platelet-dependent hemostatic plugand, thus, to avoid bleeding. In various preclinical studies DX-9065a was shown to sup-press experimental thrombosis without causing hemorrhagic complications. In different models of bleeding time measurement, such as the tail transec-tion or the gastrointestinal hemorrhagic model in rats or the ear bleeding model in rabbits,DX-9065a did not prolong bleeding time at antithrombotically effective doses by eitherparenteral or oral administration. A direct comparison between the thrombin inhibitorargatroban, the low molecular weight heparin fragmin, unfractionated heparin andDX-9065a showed that argatroban as well as the antithrombin III-dependent anticoagu-lants prolonged bleeding time in rats at slightly higher doses than the antithromboticallyeffective doses, whereas DX-9065a at ten times higher doses did not affect the bleedingtime.

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Side Effects in Humans [1]
In human volunteers DX-9065a, either by i.v. injection (0.625 to 2.5 mg) or by infusion(5 to 30 mg/60 min), produced no serious adverse effects either during or after the study. There were no clinically significant changes in serum chemistry, hematology, bleedingtime or urinary testsIn the XaNADU-IB trial DX-9065a was well tolerated in patients with stable coronaryartery disease. There were no discernable adverse effects on renal or hepatic function,platelet count, or hemoglobin. There were no major bleeding complications and only asmall, non-significant, dose-related increase in the incidence of minor bleeding in thehighest dose group as compared with placebo.

[1]. Brigitte Kaiser. DX-9065a, a direct inhibitor of factor Xa. Cardiovasc Drug Rev. 2003 Summer;21(2):91-104.

[2]. DX 9065A a novel, synthetic, selective and orally active inhibitor of factor Xa: in vitro and in vivo studies. J Pharmacol Exp Ther. 1996 Mar;276(3):1030-8.

In recent years great progress has been achieved in the development of small molecule,direct inhibitors of coagulation enzymes which interrupt the clotting process at differentsites of the coagulation cascade. Highly potent and selective inhibitors of activated clott-ing factors such as thrombin and FXa are expected to overcome the still existing limita-tions of the currently used antithrombotic regimens with heparin or vitamin K antagonists.The synthetic, low molecular weight FXa inhibitor DX-9065a which inactivates theenzyme without requiring any endogenous cofactor represents a new class of anticoagu-lant/antithrombotic drugs with a promising therapeutic potential. Under experimentalconditions DX-9065a exerts strong anticoagulant actions in vitro and in vivo, is antithrom-botically effective in various thrombosis models and also inhibits the proliferation of vas-cular smooth muscle cells in cell culture systems as well as in in vivo models. As a smallmolecule anti-FXa agent it inhibits both free and clot-bound FXa. This action, togetherwith the inhibition of thrombin generation, may be an effective way to control the clot-as-sociated procoagulant activity. However, despite of the demonstrated effectiveness of DX-9065aa general assessment of its therapeutic potential has to consider various addi-tional aspects.The development of an active-site directed inhibitor of FXa has to focus not only onoptimal binding to the target enzyme but also to its physico-chemical properties which de-termine the pharmacokinetic and pharmacodynamic behavior of the compound. One of themain goals in the development of a synthetic FXa inhibitor is to find a drug which can beused intravenously for acute thrombotic indications and then the therapy can be continuedwith an oral formulation of the same drug for chronic out-patient treatment. However,many of the small-molecule FXa inhibitors are highly basic moieties causing poor phar-macokinetic properties and especially a limited oral bioavailability. The intestinal ab-sorption of synthetic anti-factor Xa agents which is mainly accomplished by passive dif-fusion can be improved by more lipophilic molecules. A good example is the discovery ofDPC423, a highly potent, selective and orally bioavailable inhibitor of factor Xa. In aseries of 3-trifluoromethylpyrazole derivatives the replacement of the highly basic benz-amidine moiety by a less basic benzylamine moiety and the further optimization of themolecule resulted in a compound with a good pharmacokinetic and pharmacodynamicprofile. DPC423 showed an oral bioavailability of 57% and a plasma half-life of 7.5 h indogs and was antithrombotically effective in a rabbit arterio-venous shunt throm-bosis. DX-9065a, which has a basic naphthamidine moiety in its molecule, is oneof the few FXa inhibitors which, in experimental studies, are also effective by oral admin-istration. However, its oral bioavailability is relatively low and may not be adequate for itslong-term therapeutic use. Nevertheless, first clinical trials in healthy volunteers as well asin patients with cardiovascular diseases demonstrated at least predictable pharmacodyna-mic and pharmacokinetic profiles of DX-9065a by i.v. bolus injection and constant in-fusion. Intravenously administered DX-9065a is shown to be an efficacious anticoagu -lant/antithrombotic agent which has the advance of a greater safety than other drugs suchas heparin or warfarin. Furthermore, it was expected that specific FXa inhibitors mightalso be superior to direct thrombin inhibitors, such as hirudin, in providing selective inhi-bition of thrombus formation without compromising the hemostatic responses of platelets.As shown in preclinical and first clinical studies DX-9065a presents a promising alternative for the prevention or treatment of thrombotic events without hemorrhagic side ef-fects. Thus, it might be used as an adjunctive drug for thrombolytic therapy or togetherwith antiplatelet agents without increasing the bleeding risk.Another important point to be discussed with the use of a given FXa inhibitor iswhether and how its effect can be monitored in clinical practice, i.e., is there an easy andreproducible assay. A dose-dependent increase in the plasma concentrations of DX-9065a has been correlated with a prolongation of coagulation times measured in global clottingassays, such as PT and APTT. It is not yet clear whether at therapeutic doses and plasmalevels DX-9065a will prolong coagulation parameters, which marker is most sensitive forthis drug and whether it should be routinely used for monitoring of DX-9065a effec-tiveness. Furthermore, at present nothing is known about a possible way to neutralize theeffect of the compound in case of overdose or occurrence of undesired side effects.Results from experimental studies indicate a role of FXa in the complex pathogenesisof restenosis and atherosclerosis. Both thrombin and FXa appear to affect proliferation ofvascular smooth muscle cells in vivo. However, the precise role of the serine proteases andespecially the significance of their mitogenic activities for restenosis and atherosclerosis,as well as the practical significance of the inactivation of the enzymes by specific inhib-itors, have still to be clarified. For the thrombogenesis in the arterial system not onlyplatelet activation and aggregation but also thrombin generation is critical. Therefore, thedirect inhibition of FXa by DX-9065a appears to be a safe and effective new approach forpreventing the thrombotic complications of atherosclerotic disease.A general assessment of the therapeutic potential of DX-9065a has to consider variousadditional aspects. In addition to pharmacokinetic characteristics, such as oral bioavail-ability, biological half-life, metabolic transformations and excretory routes, interactionswith other drugs or endogenous factors have to be also investigated. The most promisingclinical indications for DX-9065a have to be defined just as the usefulness of combinationwith other drugs with different mechanisms or sites of action. Such a combination mightbe synergistic for the therapeutic effect, but could also enhance undesired side effects suchas bleeding complications.In conclusion, the FXa inhibitor DX-9065a represents a promising drug for the prophy-laxis and/or therapy of various thromboembolic disorders. Further experimental studiesand especially comprehensive clinical trials are likely to demonstrate the inhibitory profileof this compound, its effectiveness and especially its superiority over other drug regimensused for cardiovascular indications. [1]

C26H39CLN4O8

571.068

570.246

C, 54.68; H, 6.88; Cl, 6.21; N, 9.81; O, 22.41

155204-81-2

150612-55-8;150611-74-8 (HCl);155204-81-2 (HCl hydrate);201933-30-4 (racemic); 155204-80-1 (R-isomer);

122128

Typically exists as solid at room temperature

632.9ºC at 760mmHg

336.6ºC

6.9E-17mmHg at 25°C

5.303

169.64

10

10

8

39

720

2

CC(=N)N1CC[C@@H](C1)OC2=CC=C(C=C2)[C@H](CC3=CC4=C(C=C3)C=CC(=C4)C(=N)N)C(=O)O.Cl.O.O.O.O.O

LJCBAPRMNYSDOP-LVCYMWGESA-N

InChI=1S/C26H28N4O3.ClH.5H2O/c1-16(27)30-11-10-23(15-30)33-22-8-6-19(7-9-22)24(26(31)32)13-17-2-3-18-4-5-20(25(28)29)14-21(18)12-17;;;;;;/h2-9,12,14,23-24,27H,10-11,13,15H2,1H3,(H3,28,29)(H,31,32);1H;5*1H2/t23-,24-;;;;;;/m0....../s1

(2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;pentahydrate;hydrochloride

DX9065A; DX 9065A; dx-9065a; 155204-81-2; DX 9065-a; DX-9065-A HCl hydrate; QXQVEPEVI2; 155204-81-2 (HCl, hydrate); (2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; (2S)-3-(7-Carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;pentahydrate;hydrochloride; DX-9065A

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。