Broad-spectrum antiviral; RNA-dependent RNA polymerase

The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects; however, biochemical data of molnupiravir-induced mutagenesis have not been reported. Here we studied the effects of the active compound NHC 5’-triphosphate (NHC-TP) against the purified severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase complex. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12,841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate in the RNA primer strand. When embedded in the template strand, NHC-monophosphate supported the formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand [3].

Molnupiravir is a potent antiviral that can stop SARS-CoV replication and illness when taken orally every 12 hours for three days at a dose of 50–500 mg/kg[1].
Molnupiravir (7 mg/kg; p.o. ; twice daily for 3.5 days) dramatically lowers the amount of shed virus and shortens the fever's duration[2].Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N4-hydroxycytidine-5'-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs [1].

Protein expression and purification[3]
The SARS-CoV-2 RdRp complex was produced by expressing nsp-5, -7, -8, and -12 as a polyprotein by employing a baculovirus expression system and purifying the nsp-7-8-12 complex through Ni-NTA affinity chromatography on nsp-8 N-terminal histidine tag as described.

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NTP incorporation and the effect of primer- or template-embedded NHC-MP on viral RNA synthesis[3]
NTP incorporation by SARS-CoV-2 RdRp and data acquisition and quantification were done as reported by us. Enzyme concentration was 100 or 200 nM for single and multiple nucleotide incorporation assays, respectively. RNA synthesis incubation time was 10 min. Data from single nucleotide incorporation assays were used to determine the preference for the natural nucleotide over NHC-TP. The selectivity value is calculated as a ratio of the incorporation efficiencies of the natural nucleotide over the nucleotide analogue. The efficiency of nucleotide incorporation is determined by the ratio of Michaelis–Menten constants Vmax over Km. The substrate for nucleotide incorporation is a 5-nt primer generated by incorporation of [α-32P]NTP into a 4-nt primer. Formation of the 5-nt primer is maximal at a given time point; however, its precise concentration is unknown. Hence, the product generated in the reaction is measured by quantifying the signal corresponding to the 6-nt primer product and dividing it to the total signal in the reaction (5-nt primer and 6-nt primer). This defines the product fraction. The product fraction is commonly multiplied by the total substrate concentration in order to determine the molar units of the Vmax, which is here not possible as explained above. Therefore, the unit of Vmax is reported as product fraction over time. The selectivity value is unitless as it is the ratio of two Vmax/Km measurements with the same units. RNA templates with embedded NHC-MP were produced as described by us. NHC-related protocol modifications are explained in Fig. S1.

Madin-Darby canine kidney (MDCK) cells (ATCC CCL-34) were grown at 37°C and 5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 7.5% fetal bovine serum (FBS). Normal primary human bronchial tracheal epithelial cells (HBTECs) from a 30-year old healthy female donor were grown in BronchiaLife cell culture medium. These cells were obtained by the vendor under informed consent and adheres to the Declaration of Helsinki, The Human Tissue Act (UK), CFR Title 21, and HIPAA regulations. All regulatory approval lies with the vendor. Immortalized cell lines used in this study were routinely checked for microbial contamination (in approximately 6-month intervals). HBTECs were tested for microbial contamination on July 25, 2017 by LifeLine Cell Technology. Only HBTECs with a passage number 1-4 were used for this study [2].

Animal Model: C57BL/6 mice (intranasal infection with SARS-CoV)[1]
Dosage: 50, 150, 500 mg/kg
Administration: Oral; every 12 hours for 3 days
Result: Body weight loss is significantly diminished or prevented.

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PK in cynomolgus macaques[2]
Non-naïve cynomolgus macaques (4 males, 4 females; 2 to 6 years of age) retrieved from the colony stock at Concord Biosciences and originally received from Chares River Laboratories were each dosed orally with 100 mg/kg of NHC dissolved in 240 mM citrate buffer, followed by blood collection from the femoral vein at the specified time points. After a 7-day washout period, each animal was dosed orally with 130 mg/kg of EIDD-2801 dissolved in 80% (v/v) PEG-400, 20% (v/v) N,N-Dimethylacetamide, followed by blood collection from the femoral vein at the specified time points. In a separate study, non-naïve cynomolgus macaques (3 males, 3 females; 2 to 6 years of age) retrieved from the colony stock at MPI, Inc and originally received from Chares River Laboratories were each dosed intravenously with 10 mg/kg of NHC dissolved in 0.9% sterile sodium chloride, followed by blood collection from the femoral vein at the specified time points. For all samples, plasma was separated from heparinized blood and stored at −80°C before analysis as described in NHC. For calibration, standard curves were prepared in blank plasma (concentrations range 10 to 10,000 ng/ml). Quality-control samples of 30, 500, and 5000 ng/ml in blank plasma were analyzed at the beginning of each sample set. Calibration showed linearity with R2 values >0.99.

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PK and PD in ferrets[2]
Female ferrets (6 to 8 months of age) received from Marshall BioRescoursces were rested for one week, assigned randomly to study groups and dosed orally with EIDD-2801 dissolved in 1% methylcellulose, followed by blood collection from the anterior vena cava and tissue sampling at the specified time points. Three animals per groups were sampled for PK analyses and 2-3 animals for PD testing. Plasma was separated from heparinized blood, and tissue samples snap-frozen and stored at −80°C before analysis as described in NHC. For calibration, standard curves were prepared in blank plasma (concentrations range 10 to 100,000 ng/ml) and blank tissue lysate (concentration range 1.56 to 3,130 ng/ml), respectively. Quality-control samples of 30, 500 and 5,000 ng/ml in blank plasma were analyzed at the beginning of each sample set. Calibration in each matrix showed linearity with R2 values >0.99.

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Influenza infection studies in ferrets[2]
Female ferrets (6 to 8 months of age) were received from Marshall BioRescoursces and housed in an ABSL-2 (animal biosafety level) facility. Ferrets were rested for 1 week, weighed, assigned randomly to groups, anesthetized with dexmedetomidine/ketamine, and infected intranasally with 1 × 105 (A/California/07/2009 (H1N1)) or 1 × 106 pfu (A/Wisconsin/67/2005 (H3N2)); infection volume 200 μl. Treatment with EIDD-2801 was initiated 3 hours before infection (prophylactic regimen), 12 hours post-infection (post-exposure prophylactic regimen), or 24 hours post-infection (therapeutic regimen), and continued for 3.5 days b.i.d. Compound was administered orally in 3.5 ml doses in 1% methylcellulose formulation and chased with 3.5 ml high-calorie liquid dietary supplement. Control groups received vehicle (1% methylcellulose in water) volume equivalents. Body temperature was monitored continuously (readings every 2-15 minutes) using implanted telemetric sensors. Bodyweight of animals was measured at start and end of each experiment, and for some experiments daily; no changes in body weight were detected. Additional monitoring of phenotypically appreciable adverse effects included assessment of animals for changes in overall composure, activity level or vocation and occurrence of diarrhea, vomiting or reduced food uptake. Viral load was measured from nasal lavages (collected in 12-hour intervals) and nasal turbinates (upper respiratory tract), harvested 3.5 days after infection if not specified otherwise.

[1]. An orally bioavailable broad-spectrum antiviral inhibits\nSARS-CoV-2 in human airway epithelial cell cultures and multiple\ncoronaviruses in mice. Sci Transl Med. 2020 Apr 6. pii: eabb5883.

[2]. Characterization of orally efficacious influenza drug with\nhigh resistance barrier in ferrets and human airway epithelia. Sci\nTransl Med. 2019 Oct 23;11(515). pii: eaax5866.

[3]. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. Biol Chem. 2021 Jul; 297(1): 100770.

Molnupiravir is a nucleoside analogue that is N(4)-hydroxycytidine in which the 5'-hydroxy group is replaced by a (2-methylpropanoyl)oxy group. It is the prodrug of the active antiviral ribonucleoside analog N(4)-hydroxycytidine (EIDD-1931), has activity against a number of RNA viruses including SARS-CoV-2, MERS-CoV, and seasonal and pandemic influenza viruses. It is currently in phase III trials for the treatment of patients with COVID-19. It has a role as a prodrug, an anticoronaviral agent and an antiviral drug. It is a nucleoside analogue, an isopropyl ester and a ketoxime. It is functionally related to a N(4)-hydroxycytidine. ChEBI

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Molnupiravir (EIDD-2801, MK-4482) is the isopropylester prodrug of [N4-hydroxycytidine]. With improved oral bioavailability in non-human primates, it is hydrolyzed in vivo, and distributes into tissues where it becomes the active 5’-triphosphate form. The active drug incorporates into the genome of RNA viruses, leading to an accumulation of mutations known as viral error catastrophe. Recent studies have shown molnupiravir inhibits replication of human and bat coronaviruses, including SARS-CoV-2, in mice and human airway epithelial cells. A [remdesivir] resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine. Molnupiravir was granted approval by the UK's Medicines and Health products Regulatory Agency (MHRA) on 4 November 2021 to prevent severe outcomes such as hospitalization and death due to COVID-19 in adults. Molnupiravir was also granted emergency use authorization by the FDA on December 23, 2021; however, it is not yet fully approved. DrugBank

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Molnupiravir is a ribonucleoside analogue and antiviral agent that is used in the therapy the severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection, the cause of the novel coronavirus disease, 2019 (COVID-19). Molnupiravir therapy is given orally for 5 days early in the course of SARS-CoV-2 infection and has not been linked to serum aminotransferase elevations or to clinically apparent liver injury. LiverTox

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Molnupiravir is an orally bioavailable prodrug of EIDD-1931, the synthetic ribonucleoside derivative N4-hydroxycytidine and ribonucleoside analog, with potential antiviral activity against a variety of RNA viruses. Upon oral administration, molnupiravir, being a prodrug, is metabolized into its active form EIDD-1931 and converted into its triphosphate (TP) form. The TP form of EIDD-1931 is incorporated into RNA and inhibits the action of viral RNA-dependent RNA polymerase. This results in the termination of RNA transcription and decreases viral RNA production, and viral RNA replication.

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[N4-hydroxycytidine] and its prodrug molnupiravir are being studied for its activity against a number of viral infections including influenza, MERS-CoV, and SARS-CoV-2. Molnupiravir is approved in the UK for reducing the risk of hospitalization and death in mild to moderate COVID-19 cases for patients at increased risk of severe disease (eg. with obesity, diabetes mellitus, heart disease, or are over 60 years old). In the US, molnupiravir is authorized for emergency use for the treatment of high-risk adults With mild to moderate COVID-19.

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Molnupiravir is a ribonucleoside analogue and antiviral agent that is used in the therapy the severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection, the cause of the novel coronavirus disease, 2019 (COVID-19). Molnupiravir therapy is given orally for 5 days early in the course of SARS-CoV-2 infection and has not been linked to serum aminotransferase elevations or to clinically apparent liver injury.

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Absorption: After an 800 mg oral dose of molnupiravir every 12 hours, the active compound (N4-hydroxycytidine) reaches a Cmax of 2970 ng/mL, with a Tmax of 1.5 hours, and an AUC0-12h of 8360 h\*ng/mL.
Route of Elimination: ≤3% of an oral molnupiravir dose is eliminated in the urine as the active metabolite N4-hydroxycytidine. DrugBank Metabolism / Metabolites: Molnupiravir is hydrolyzed to [N4-hydroxycytidine], which distributes into tissues. Once inside cells, N4-hydroxycytidine is phosphorylated to the 5'-triphosphate form.
Biological Half-Life: The half life of the active metabolite, N4-hydroxycytidine, is 3.3 hours.

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Mechanism of Action: Molnupiravir is hydrolyzed _in vivo_ to N4-hydroxycytidine, which is phosphorylated in tissue to the active 5’-triphosphate form, and incorporated into the genome of new virions, resulting in the accumulation of inactivating mutations, known as viral error catastrophe. A [remdesivir] resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine.

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Hepatotoxicity: In preregistration clinical trials, serum aminotransferase elevations were uncommon and mild, and were no more frequent with molnupiravir than with placebo. Furthermore, among more than 900 patients treated with molnupiravir (800 mg twice daily) for 5 days in prelicensure studies, there were no reported episodes of clinically apparent liver injury. Confounding the issue is that serum aminotransferase elevations are common during symptomatic SARS-CoV-2 infection, present in up to 70% of patients and are more frequent in patients with severe disease and in those with the known risk factors for COVID-19 severity such as male sex, older age, higher body mass index and diabetes. Thus, molnupiravir has not been shown to cause liver injury, but the total clinical experience with its use is limited.

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◈ What is molnupiravir?
Molnupiravir is an investigational antiviral medication. Investigational (or experimental) drugs are ones that are being studied to see if they work. Molnupiravir is being studied for the treatment of SARS-CoV-2 (which causes COVID-19). Molnupiravir is given by mouth (orally). A brand name for molnupiravir is Lagevrio®. For this medication to be effective, it must be started within 5 days of having symptoms of COVID-19.Because molnupiravir is still being studied, there is limited information about whether or not it is safe and/or effective. However, the U.S. Food and Drug Administration (FDA) gave emergency permission for molnupiravir to be used to treat some patients with mild-to-moderate COVID-19 infection. COVID-19 infection can increase the chance of pregnancy complications. For more information about COVID-19, please the see the MotherToBaby fact sheet at https://mothertobaby.org/fact-sheets/covid-19/.According to the emergency use label, the use of molnupiravir is not recommended during pregnancy based on animal data that suggests a possible concern. However, your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

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◈ I am taking molnupiravir, but I would like to be finished with taking it before becoming pregnant. How long does the drug stay in my body?
People eliminate medication at different rates. In non-pregnant adults, it takes up to 1 day, on average, for most of the molnupiravir to be gone from the body. However, it is recommended by the emergency use label that females avoid trying to get pregnant during the time they are taking molnupiravir and for 4 days after the last dose of molnupiravir.

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◈ I take molnupiravir. Can it make it harder for me to get pregnant?
Studies have not been done to see if molnupiravir can make it harder to get pregnant. It is recommended by the emergency use label that females who can get pregnant use effective contraception correctly and consistently while they are taking molnupiravir and for 4 days after the last dose of molnupiravir.

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◈ Does taking molnupiravir increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Animal studies suggested an increased chance for miscarriage. Studies have not been done in humans to see if molnupiravir increases the chance for miscarriage. It is not known whether COVID-19 infection itself increases the chance of miscarriage.

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◈ Does taking molnupiravir increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have not been done in humans to see if molnupiravir does or does not increase the chance for birth defects above the background risk. Animal studies by the manufacturer suggest an increase in birth defects when molnupiravir was given at 8 times the human dose. These birth defects involved the eyes, kidneys, and some bones. It is not known whether COVID-19 infection can increase the chance of birth defects.

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◈ Does taking molnupiravir in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done in humans to see if molnupiravir increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). An animal study reported lower fetal weight and a lower amount of mineralized bone (delayed ossification) when molnupiravir was given at 3 times the human dose. At this dose, other effects on fetal development, miscarriage, or stillbirth were not seen.There is evidence to suggest that COVID-19 infection increases the chance of stillbirth or the mother dying during childbirth. Other negative pregnancy outcomes that appear to be related to COVID-19 include spontaneous preterm delivery, fetal growth restriction, and bleeding in the mother after birth (postpartum hemorrhage).

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◈ Does taking molnupiravir in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if molnupiravir can cause behavior or learning issues for the child.

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◈ Breastfeeding while taking molnupiravir:
The emergency use label for molnupiravir recommends people who are breastfeeding not use this medication. But, the benefit of using molnupiravir while breastfeeding may outweigh possible risks. People who are breastfeeding may consider pumping and discarding breast milk during treatment with molnupiravir and for 4 days after the last dose. Your healthcare providers can talk with you about using molnupiravir and what treatment is best for you and your baby. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

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◈ If a male takes molnupiravir, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if molnupiravir could affect male fertility or increase the chance of birth defects. The product label notes that, while the risk is considered to be low, it is recommended that males use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose of molnupiravir. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

C13H19N3O7

329.3059

329.12

C, 47.42; H, 5.82; N, 12.76; O, 34.01

2349386-89-4

3258-02-4 (EIDD-1931);2492423-29-5

145996610

White to off-white solid powder

-0.8

141Ų

O[C@@H]([C@H]([C@H](N1C(N/C(C=C1)=N/O)=O)O2)O)[C@H]2COC(C(C)C)=O

HTNPEHXGEKVIHG-QCNRFFRDSA-N

InChI=1S/C13H19N3O7/c1-6(2)12(19)22-5-7-9(17)10(18)11(23-7)16-4-3-8(15-21)14-13(16)20/h3-4,6-7,9-11,17-18,21H,5H2,1-2H3,(H,14,15,20)/t7-,9-,10-,11-/m1/s1

((2R,3S,4R,5R)-3,4-dihydroxy-5-((E)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate

Molnupiravir; MK-4482; MK4482; MK 4482; EIDD-2801; EIDD 2801; EIDD2801; prodrug-EIDD-1931; prodrug-EIDD 1931; prodrug-EIDD1931; molnupiravirum;

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)