Lemborexant (E-2006)   中文名称: 莱博雷生

Orexin (hypocretin) receptor

Orexin (hypocretin) 神经肽与觉醒/睡眠控制有关，之前已经证明拮抗食欲素信号通路可以促进动物和人类的睡眠。这一机制开辟了一种新的治疗方法，可以抑制失眠患者的过度觉醒，而不是促进与睡眠相关的信号传导。在这里，我们描述了双食欲素受体拮抗剂（DORA）lemborexant（（1R，2S）-2-{[（2,4-二甲基嘧啶-5-基）氧基]甲基}-2-（3-氟苯基）-N-（5-氟吡啶-2-基）环丙烷甲酰胺）的临床前体外和计算机药理学特征，它是一种用于失眠症状治疗的新型实验性治疗剂，并将其特性与其他两种DORA，即阿米氧嘧啶和suvorexant进行了比较。Lemborexant与食欲素受体结合，并以低纳摩尔效力的竞争方式在功能上抑制它们，在人类、大鼠和小鼠受体之间没有明显的物种差异。两种食欲素受体的结合和解离动力学都很快。Lemborexant对食欲素受体的选择性超过了其他88种具有重要生理功能的受体、转运蛋白和离子通道。将lemborexant模拟为食欲素受体的计算机模拟表明，它在受体结合袋内与suvorexant具有相同类型的构象，即π堆叠的马蹄形构象[2]。

Lemborexant阻止了食欲素促进的大鼠促肾上腺皮质激素的增加，因此证明了食欲素信号通路的抑制。此外，lemborexant促进了野生型小鼠和大鼠的睡眠。Lemborexant以相等的速率促进REM和非REM睡眠（REM睡眠比率没有变化）。相比之下，唑吡坦减少了REM睡眠。lemborexant的睡眠促进作用是通过食欲素肽信号通路介导的，食欲素神经元缺陷小鼠缺乏睡眠促进作用就证明了这一点。长期给药与给药后即刻效应大小或睡眠结构的变化无关。Lemborexant不会增加乙醇的镇静作用或损害运动协调，在动物身上显示出良好的安全裕度。小鼠和大鼠的药代动力学/药效学数据非常一致[1]。

通过受体结合试验测量亲和力[2]
使用96孔Flashplate通过受体结合分析（RBA）测定结合亲和力。膜组分由表达人OX1R（hOX1R）或人OX2R（hOX2R）的中国仓鼠卵巢（CHO）细胞制备。将hOX1R或hOX2R（5µg蛋白质/测定）的膜悬浮液与测试拮抗剂[lemborexant（0.6-200 nmol/l）、almorexant（0.2-200 nmol/l）或suvorexant（0.2–60 nmol/1）]以及OXA（10µmol/l）溶液或载体和[125I]OXA溶液（0.2 nmol/l）混合。将混合物（最终体积为100µl）在96孔闪存盘上于室温下孵育30分钟。丢弃所有反应混合物，然后用200µl含有525 mmol/l NaCl的25 mmol/l HEPES缓冲液进行两次洗涤。通过TopCount测量每个孔的剩余放射性（以dpm为单位），并使用以下公式计算试验拮抗剂的抑制活性：
其中，在存在试验拮抗剂（试验）的情况下，T以dpm表示，在存在10µmol/l OXA（非特异性结合）的条件下，N以dpm表达，在不存在化合物（对照）的情况中，C以dpm表述。
实验中的值分为三份（lemborexant、almorexant）或四份（suvorexant）。以相同的方式进行了三次lemborexant实验，在计算最终IC50值及其S.E.M.的平均值之前，计算了每个实验的IC50值。almorexant和suvorexant的实验进行了一次，每个值表示为平均值±S.E.M.进行统计分析。

基于细胞的功能报告酶测定[1]
HEK293细胞用人或小鼠OX1R或OX2R以及报告系统（Chen等人，1995；Durocher等人，2000）稳定转染，其中报告酶[胎盘碱性磷酸酶（PLAP）]（Goto等人，1996）可以通过细胞内Ca2+依赖性报告单元在功能性OXR激活后诱导。
将细胞以10000/孔的密度接种到96孔板中，并在培养基中培养过夜。第二天，将5µl的lemborexant溶液加入96孔板中的培养细胞中，使最终培养基体积为115µl（23倍稀释），从而得到1、3、10、30、100、300和1000 nmol/l的终浓度，用于细胞培养。
在加入lemborexant并在室温下孵育约2-3小时后，将食欲素肽激动剂人/小鼠OXA、人OXB（hOXB）、小鼠OXB（mOXB）或修饰的[Ala11，d-Leu15]-OXB在Dulbecco的修饰Eagle培养基（含0.1%牛血清白蛋白和3.45µmol/l福司可林）中稀释，并将10µl加入细胞孔中，得到115-µl的最终体积。肽激动剂的最终浓度范围为0.01至1000 nmol/l。搅拌平板混合后，将细胞在37°C下孵育约20小时，将lemborexant和肽激动剂各自的浓度组合应用于四个细胞孔。hOXB和mOXB之间有两种不同的氨基酸。因此，hOX2R被hOXB激活，小鼠OX2R（mOX2R）被mOXB激活。[Ala11，d-Leu15]-OXB已被描述为对OX2R的选择性高于天然OXB（Asahi等人，2003）。

Rodent (wild-type rats and wild-type and orexin neuron-deficient [orexin/ataxin-3 Tg/+] mice) studies were performed to evaluate the effects of single-dose oral lemborexant (1–300 mg/kg) on orexin-induced increases in plasma adrenocorticotropic hormone (ACTH), locomotor activity, vigilance state measures (wakefulness, nonrapid eye movement [non-REM] sleep, rapid eye movement [REM] sleep), ethanol-induced anesthesia, and motor coordination, and the effects of multiple-dose oral lemborexant (30 mg/kg) on vigilance state measures. Active comparators were almorexant and zolpidem. Pharmacokinetics were assessed after single-dose lemborexant in mice and rats.[1]

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lemborexant, almorexant, and zolpidem were suspended as free bases in the vehicle solution specified for each study. Doses for each compound in the mouse experiments were set based on the minimum necessary dose for sleep promotion in mice, and are therefore different for each compound.[1]

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Effect of single-dose lemborexant on the orexin-induced increase in ACTH in rats.[1]
Male F344 rats (age: 5 weeks; body weight: 85.8–103.5 g) were implanted with infusion cannulae into the left lateral ventricle for intracerebroventricular (i.c.v.) injection. Four to five days after surgery, rats were habituated for oral administration (p.o.) and handling once before the study. Six to seven days after cannula implantation, rats received p.o. vehicle (5% [v/v] dimethyl sulfoxide, 9.5% [v/v] cremophor in saline; n = 10) or lemborexant (5 mL/kg suspended in vehicle) 1, 3, 10, or 30 mg/kg (n = 5, 6, 6, and 5, respectively). One hour later, vehicle control rats received 5 µL of phosphate buffered saline (PBS) or [Ala11, D-Leu15]-orexin B (1 nmol/head, 0.2 mmol/L in PBS) via i.c.v. injection (n = 5 each). All lemborexant pretreated rats received [Ala11, D-Leu15]-orexin B via i.c.v. injection. Fifteen minutes later, rats were decapitated and blood samples were collected with Na2EDTA (100 mg/mL, 100 µL). Blood samples were then centrifuged (1000 × g, 10 min at 4°C) and supernatant plasma was stored at −80°C for later measurement of ACTH and lemborexant concentrations. After decapitation, blue ink was injected i.c.v. to confirm the correct placement of cannulae. Coronal cross-sections were made near the cannulae; placement was judged (by an experienced observer) to be correct if blue ink was visible in the lateral ventricle(s). Data from 3 out of 32 rats with incorrect cannula placement were excluded from analysis.

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Effect of single-dose lemborexant on spontaneous locomotor activity in wild-type and orexin neuron-deficient mice[1]
Wild-type male mice (age: 9 weeks; body weight: 19.4–22.5 g) were dosed p.o. with vehicle (5% [v/v] dimethyl sulfoxide, 10% [v/v] cremophor in 10 mmol/L HCl; 10 mL/kg; n = 16) or lemborexant (30 [n = 8] or 100 mg/kg [n = 7]) at Zeitgeber time 3:40 or 5:30. One hour after dosing, mice were placed in an open field arena and locomotor activity was automatically recorded as infrared light beam breaks as previously described. For activity values, all horizontal and vertical infrared light beam break counts were summed over 1 h after the start of locomotor activity recording.[1]
In a separate study, orexin neuron-deficient mice (age: 18–26 weeks; body weight: 27.9–36.0 g) were dosed p.o. with vehicle (as above; n = 8) or 100 mg/kg lemborexant (n = 8), the maximum dose tested in wild-type mice, at Zeitgeber time 3:40 or 5:30. Thirty minutes later, locomotor activity was recorded and summed over 1 h as described above.

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Effect of single-dose lemborexant on vigilance state measures in wild-type and orexin neuron-deficient mice[1]
Mice were allowed to recover and to habituate to the recording room for 1 week while being housed in recording cages, and were then divided into body-weight matched groups and habituated to p.o. dosing with vehicle (10 mL/kg 0.5% [w/v] methylcellulose 400) at Zeitgeber time 3:30–4:10 for 2 consecutive days. The next day, mice were dosed p.o. with vehicle (n = 5), lemborexant (1 [n = 5] or 10 mg/kg [n = 4]), almorexant (10 [n = 5] or 100 mg/kg [n = 4]), or zolpidem (3 [n = 5] or 30 mg/kg [n = 4]) at Zeitgeber time 3:30–4:10.

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Effect of single-dose lemborexant on vigilance state measures in rats[1]
Under deep sodium pentobarbital anesthesia, male Sprague Dawley rats (age: 7–10 weeks; body weight: 311–449 g) were intraperitoneally implanted with battery-driven, wireless telemetry devices (TL11M2-F40-EET) for EEG/EMG measurements. Two silver screws were fixed 2.0 mm left and right of lambda through the skull bone so as to touch the dura mater. EEG leads were knotted to the screws, while EMG leads were placed intranuchally into pockets formed by blunt dissection of neck muscle left and right of midline. After 9–11 days of recovery in home cages, rats were habituated to the recording room and p.o. dosing procedure for 2 days, while still being housed in the same home cages throughout the experiment. A total of 12 rats were then selected for the study and assigned to body-weight matched groups for five dosing and recording sessions. The sessions were conducted with 2–3 days of intermittent wash-out periods, with p.o. dosing taking place at Zeitgeber time 2:00–3:00 and subsequent recording of EEG/EMG signals for 4 h using a telemetry system for later off-line analysis. Continuous recordings were divided into 10-s epochs and automatically analyzed via an algorithm that determined vigilance states. Automated analysis results were then verified and, if necessary, corrected by a trained observer blinded to treatment. No animal received the same test compound at the same dose twice. There were a total of 10 treatment groups in the study; vehicle (10 mL/kg 0.5% [w/v] methyl-cellulose 400 [n = 6]), lemborexant (3, 10, 30, 100, or 300 mg/kg [all n = 6]), and zolpidem (3, 10, 30, or 100 mg/kg [all n = 6]).

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Effect of chronic-dose lemborexant on vigilance state measures in rats[1]
Male Sprague Dawley rats, fully habituated to experimental conditions from the previously described single-dose study, were used after a 5-day washout period. All rats were dosed p.o., once-daily at Zeitgeber time 2:00–3:00, with vehicle (0.5% [w/v] methylcellulose 400) on day 1–3, then vehicle (n = 2), lemborexant 30 mg/kg (n = 5), or zolpidem 100 mg/kg (n = 5) from day 4 to 24, and finally vehicle on days 25 and 26. EEG/EMG signals were recorded (as already described for the single-dose study) on days 1 and 2 (pretreatment), days 4, 7, 11, 14, 18, 21, and 24 (treatment), and days 25 and 26 (posttreatment) for nearly 3 hours. Lemborexant and zolpidem doses were chosen based on the maximum effects in the previous single-dose experiment.

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Effect of single-dose lemborexant on ethanol-induced anesthesia in wild-type mice[1]
Wild-type male mice (age: 13 weeks; body weight: 21.8–28.1 g) were dosed p.o. with vehicle (10 mL/kg 0.5% [w/v] methylcellulose 400), lemborexant (1, 3, or 10 mg/kg), almorexant (30, 100, or 300 mg/kg), or zolpidem (3, 10, or 30 mg/kg) (all groups, n = 6) during the light phase. After 5 min, mice received intraperitoneal injections of 3.0 g/kg ethanol (20% [w/v] in saline). The almorexant and zolpidem doses were based on those used in a previous rat study, where almorexant up to 300 mg/kg did not show interaction with ethanol, but zolpidem from 10 mg/kg upwards showed interaction with ethanol.

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Effect of single-dose lemborexant on motor coordination in wild-type mice [1]
For this study, male wild-type mice (age: 14 weeks; body weight: 22.1–29.1 g), previously trained on the treadmill for 3 consecutive days with subsequent 14 days rest, were allocated to body-weight equivalent groups to receive single p.o. dosing of vehicle (10 mL/kg 0.5% [w/v] methylcellulose 400), lemborexant (30, 100, or 300 mg/kg), or zolpidem (100 mg/kg) (all groups, n = 11). The starting lemborexant dose (30 mg/kg) was selected as this is approximately threefold the sleep-promoting dose, while zolpidem 100 mg/kg has previously been reported to impair motor coordination in rats

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Plasma and CSF concentrations of lemborexant after single dosing in rats[1]
Male Sprague Dawley rats (age: 9 weeks; body weight: 337–355 g) were dosed p.o. with lemborexant 30 mg/kg in 0.5% (w/v) methylcellulose 400 (5 mL/kg) at Zeitgeber time 4:30–5:00. Two hours later, rats were anesthetized and plasma and CSF samples were obtained from the abdominal aorta and cisterna magna, respectively, for the measurement of lemborexant concentrations by LC-MS/MS.

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Plasma concentrations of lemborexant after single dosing in mice[1]
Male C57BL/6N mice (age: 14 weeks; body weight: 26.7–31.7 g) were dosed p.o. with lemborexant 10 or 300 mg/kg in 0.5% [w/v] methylcellulose 400 (10 mL/kg) at Zeitgeber time 3:00–9:15. At 0.25, 0.5, 1, 3, 5, 6, 18, and 24 h after dosing, mice were anesthetized and plasma samples were obtained from the abdominal aorta for measurement of lemborexant concentrations by LC-MS/MS.

Absorption, Distribution and Excretion
Animal model studies have shown that lemfranzene is rapidly absorbed after oral administration. The time to peak concentration (Tmax) of lemfranzene is approximately 1–3 hours, or 3–5 hours after ingestion of a high-fat, high-calorie meal. The rate of increase in Cmax and AUC0-24h is slightly lower than the proportion of the administered dose. After ingestion of a high-fat, high-calorie meal, Cmax decreases by 23%, and AUC0-inf increases by 18%. In moderate hepatic impairment, AUC, Cmax, and terminal half-life all increase; in mild hepatic impairment, AUC (but not half-life) increases. Following oral administration, 57.4% of the dose is excreted in feces, and 29.1% in urine. Less than 1% of the drug recovered in urine is in its original form, indicating extensive metabolism. The volume of distribution of lemfranzene is 1970 liters, indicating extensive tissue distribution.

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Metabolism/Metabolites
Given that less than 1% of the drug dose recovered in urine is in its original form, rumoredex is likely extensively metabolized—this has been confirmed in rat and monkey models, but its metabolism in humans is not fully elucidated. Prescribing information indicates that rumoredex is primarily metabolized via CYP3A4, with a smaller contribution from CYP3A5. The major circulating metabolite is the M10 metabolite of rumoredex, which is pharmacologically active and binds to orexin receptors with a similar affinity to the original drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, exhibits weak inhibition of CYP3A enzymes, and is a substrate for the P-gp transporter.

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Biological Half-Life
The half-lives of rumoredex at 5 mg and 10 mg doses are 17 hours and 19 hours, respectively.

Hepatotoxicity
In multiple clinical trials, lemborexa was found to be well-tolerated. Less than 1% of subjects in the treatment group experienced serum ALT elevations exceeding three times the upper limit of normal, and a similar incidence was observed in the placebo group. These elevations were transient and asymptomatic, requiring no dose adjustment or discontinuation, and were not accompanied by concurrent increases in serum bilirubin. Therefore, no clinically significant liver injury was reported in lemborexa's registration trials. While lemborexa has a limited market presence, its wider clinical application has not yet been associated with clinically significant liver injury. Probability Score: E (Unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation The concentration of lemborexa in breast milk appears to be very low. This is not a reason to discontinue breastfeeding if the mother requires lemborexa. However, infant sedation should be monitored, especially in breastfed newborns or preterm infants, until more data are available.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Lemborase binds to approximately 94% of proteins in vitro, but the specific proteins it binds to in plasma are not yet clear.

[1]. Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation. Sleep. 2019 Mar 29;42(6):zsz076.

[2]. In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist. J Pharmacol Exp Ther . 2017 Aug;362(2):287-295.

[3]. OREXIN\nRECEPTOR ANTAGONIST PROVEN EFFECTIVE FOR BOTH SLEEP ONSET AND SLEEP\nMAINTENANCE IN CLINICAL DEVELOPMENT PROGRAM OF MORE THAN 2,000 PATIENTS.\n2019.

[4]. HIGHLIGHTS OF PRESCRIBING INFORMATION

Lemborexant is a Schedule IV controlled substance under the U.S. Drug Enforcement Administration (DEA). Schedule IV controlled substances are less likely to be abused compared to Schedule III controlled substances. It is a sedative. Lemborexant is a novel dual orexin receptor antagonist used to treat insomnia characterized by difficulty falling asleep and/or maintaining sleep. Recent research in the field of sleep disorders suggests that the cause of insomnia may not be the brain's inability to "turn on" sleep-related circuits, but rather its inability to "turn off" arousal circuits. Previously used insomnia medications (such as zopiclone, zolpidem, and benzodiazepines) primarily enhance sleep drive by modulating GABA and melatonin receptors, while lemborexant and other orexin antagonists (such as lemborexant) work by counteracting inappropriate arousal. This novel mechanism of action offers potential advantages over traditional hypnotics, including a better spectrum of adverse reactions and potentially higher efficacy, and may mark the beginning of a new era in the treatment of insomnia. Lemborexant is an orexin receptor antagonist. Lemborexant's mechanism of action is as an orexin receptor antagonist and cytochrome P450 2B6 inducer. Lemborexant is an orexin receptor antagonist used to treat insomnia and sleep disorders. Treatment with lemborexant has been associated with rare, transient elevations of serum enzymes, but no clinically significant cases of liver injury have been found. Indications: Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulty falling asleep and/or difficulty maintaining sleep. FDA Label: Mechanism of Action: The orexin neuropeptide signaling system is involved in various physiological functions, including sleep/wake control. Orexin A and orexin B activate postsynaptic G protein-coupled orexin 1 receptors (OX1R) and orexin 2 receptors (OX2R), which are located on hypothalamic neurons and project to numerous nuclei controlling wakefulness. The activity of each receptor differs slightly—activation of OX1R appears to inhibit rapid eye movement (REM) sleep, while activation of OX2R appears to inhibit non-rapid eye movement (NREM) sleep. Leboresen is a competitive antagonist of both OX1R and OX2R. Leboresen promotes sleep by blocking the binding of the wakefulness hormones orexin A and B to these receptors, inhibiting arousal drive.

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Pharmacodynamics
Leboresen promotes sleep by antagonizing the effects of wakefulness-promoting chemicals in the brain. Patients taking Leboresen have reported complex sleep behaviors (such as eating, sexual activity, phone calls)—these events can occur in both patients who have never used hypnotics and those who have, and patients typically do not remember these events. Patients experiencing complex sleep behaviors should immediately discontinue Leboresen. Leboresen may pose an abuse risk; patients with a history of alcohol or drug addiction should use it with caution. Its controlled substance list is currently under review by the U.S. Drug Enforcement Administration.

C22H20F2N4O2

410.4248

410.155

1369764-02-2

1369764-02-2

56944144

Typically exists as solid at room temperature

1.3±0.1 g/cm3

596.1±50.0 °C at 760 mmHg

314.3±30.1 °C

0.0±1.7 mmHg at 25°C

1.619

3.16

77

1

7

6

30

612

2

O=C([C@H]1[C@@](C2=CC=CC(F)=C2)(COC3=CN=C(C)N=C3C)C1)NC4=NC=C(F)C=C4

MUGXRYIUWFITCP-PGRDOPGGSA-N

InChI=1S/C22H20F2N4O2/c1-13-19(11-25-14(2)27-13)30-12-22(15-4-3-5-16(23)8-15)9-18(22)21(29)28-20-7-6-17(24)10-26-20/h3-8,10-11,18H,9,12H2,1-2H3,(H,26,28,29)/t18-,22+/m0/s1

(1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide

E-2006; Dayvigo; E 2006; 1369764-02-2; Dayvigo; UNII-0K5743G68X; 0K5743G68X; (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide; E2006; Lemborexant

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。