HCV 1a (EC50 = 1 nM); HCV 1b (EC50 = 0.21 nM); SARS-CoV 3CL^pro (IC50 = 1.31 μM)
Paritaprevir (also named ABT-450) targets hepatitis C virus (HCV) NS3/4A protease; EC50 values are 1.0 nM (genotype 1a), 0.21 nM (genotype 1b), 5.3 nM (genotype 2a), 19 nM (genotype 3a), 0.09 nM (genotype 4a), 0.69 nM (genotype 6a) against stable HCV replicons with NS3 protease [2]
Paritaprevir is an NS3/4A protease inhibitor [1]

Paritaprevir inhibits in vitro the p-glycoprotein (p-gp)[1]. With 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively, ABT-450 is an effective inhibitor of HCV NS3/4A protease. With a CC50 greater than 37 μM, ABT-450 exhibits an in vitro selectivity index of approximately 37,000 times. ABT-450 has an EC50 of 5.3 nM against the genotype 2a JFH-1 subgenomic replicon, indicating activity against various HCV genotypes[2].

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1. Paritaprevir (ABT-450) exhibited potent inhibitory activity against HCV NS3/4A protease from different genotypes in stable HCV replicon assays: EC50 values were 1.0 nM (1a), 0.21 nM (1b), 5.3 nM (2a), 19 nM (3a), 0.09 nM (4a), and 0.69 nM (6a) [2]
2. In vitro resistance selection assays of Paritaprevir (ABT-450) in genotype 1 HCV replicons showed that the most common amino acid variants were located in NS3 at positions 155, 156, and 168; the D168Y variant conferred the highest resistance (219-fold for 1a, 337-fold for 1b) [2]

Paritaprevir achieves maximum concentrations after oral administration in a mean of 4-5 hours, with exposure increases exceeding dose proportionality. Approximately 50% of the total bioavailability occurs when food is administered. It exhibits high plasma protein binding (between 97-99.9%) and 16.7 liters of apparent volume of distribution. Paritaprevir is metabolized primarily by CYP3A4 and CYP3A5[1].

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Phenotypic evaluation of in vivo resistance development. [2]
Phenotypic analyses of viral isolates from baseline (before the first dose was administered) and at the end of 3 days of ABT-450/r monotherapy were performed in order to characterize the selection of resistant variants. The development of phenotypic resistance to ABT-450 during 3 days of dosing was assessed by calculating the fold change in EC50 at the end of the 3-day monotherapy compared to baseline (Table 4). Thirteen of the 24 patients (12 of 19 infected with genotype 1a and 1 of 5 infected with genotype 1b) had a viral load level sufficient (≥500 IU/ml) to allow amplification of the target gene at the end of the 3-day dosing period (5, 3, and 5 patients in the ABT-450/r 200/100-, 100/100-, and 50/100-mg treatment groups, respectively). [2]

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Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased[3].

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1. In a 3-day monotherapy clinical study (Phase II) of HCV genotype 1-infected patients, Paritaprevir (ABT-450) was coadministered with ritonavir (a CYP3A4 inhibitor); a mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses [2]
2. In phase II/III clinical trials, the fixed-dose combination of Paritaprevir/ombitasvir/ritonavir plus dasabuvir (± ribavirin) achieved high rates of sustained virological response (SVR12) in adults with chronic HCV genotype 1 infection (including 1a/1b, compensated cirrhosis, liver transplant recipients, HIV-1 co-infection) [1]
3. Resistant variants selected in Paritaprevir (ABT-450)-treated patients were R155K and D168V (genotype 1a) and D168V (genotype 1b); selection of resistant variants was significantly reduced at the highest Paritaprevir dose compared to lower doses [2]

Paritaprevir exhibits antiviral activity in vitro against HCV GT1-4 and GT6 (EC50 range: 0.09 to 19 nM), while its EC50 against GT4a is 0.09 nM.

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Antiviral activity against a panel of resistant mutants. [2]
The 1a-H77 and 1b-Con1 subgenomic replicon shuttle vector constructs used for introduction of mutations of interest in the NS3 gene were similar to the replicon cell line constructs described above, but in both cases the Neo gene was not present, and the HCV NS2 gene was inserted between the EMCV IRES and the NS3 gene (Fig. 2B). In addition, the 1a-H77 replicon construct had the adaptive mutation in NS3 protease encoding E1202G replaced with one encoding P1496L in NS3 helicase. An AscI restriction site was introduced into the NS2 gene 62 nucleotides upstream of the 5′ end of the NS3 gene, and a BstBI restriction site was introduced within the helicase domain of NS3 after the NS3 amino acid 251 codon. The introduction of these restriction sites did not result in an amino acid insertion or change in either the genotype 1a or 1b replicon. Mutations encoding resistance-associated variants were introduced by site-directed mutagenesis and confirmed by sequence analysis. Subgenomic replicon RNA was generated by linearization of plasmid DNA followed by in vitro transcription. Replicon RNA was transfected into Huh7-derived cells, and inhibition of replication of the HCV replicon by ABT-450 was measured using the luciferase assay as described above, except that cells were incubated for 4 days rather than 3 days prior to lysis. Replication efficiency was calculated as a percentage of wild-type replication using the following equation: 100 ×[(mutant 4-day luciferase activity/wild-type 4-day luciferase activity)/(mutant 4-h luciferase activity/wild-type 4-h luciferase activity)][2].

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1. HCV NS3/4A protease inhibition assay: Stable HCV replicon cell lines (with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, 6a) and transient replicon assays were used to evaluate the inhibitory activity of Paritaprevir (ABT-450); the 50% effective concentration (EC50) values for each genotype were determined by measuring viral replication inhibition at different drug concentrations [2]
2. Resistance profile assay of Paritaprevir: In vitro resistance selection experiments were conducted on genotype 1 HCV replicons treated with Paritaprevir (ABT-450); amino acid variations in NS3 protease were identified, and the resistance level of key variants (e.g., D168Y) was quantified by measuring EC50 fold changes [2]

Antiviral activity in cell culture.[2]
Replicon cell lines were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with 100 IU/ml penicillin, 100 μg/ml streptomycin, and 200 μg/ml G418, all of which were from Invitrogen, as well as 10% (vol/vol) fetal bovine serum (FBS). The inhibitory effect of ABT-450 was evaluated by incubating replicon-containing cells in the presence of a series of ABT-450 dilutions for 3 days in the same medium containing 5% FBS, followed by measurement of firefly luciferase activity using the luciferase assay system. In assays measuring inhibitory activity in the presence of human plasma, the medium contained 40% human plasma and 5% FBS. The percent inhibition of HCV RNA replication was calculated for each compound concentration, and the 50% effective concentration (EC50) was calculated using nonlinear regression sigmoidal dose-response variable slope curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software. The cytotoxicity of ABT-450 was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. The 50% cytotoxicity concentration (CC50) was calculated using nonlinear regression sigmoidal dose-response variable slope curve fitting as described above.

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1. HCV replicon cell assay: Stable HCV replicon cell lines expressing NS3 protease from different genotypes (1a, 1b, 2a, 3a, 4a, 6a) were cultured with different concentrations of Paritaprevir (ABT-450); viral replication levels were detected to calculate EC50 values; transient replicon assays were also used to confirm the inhibitory activity [2]
2. Resistance selection cell assay: Genotype 1 HCV replicon cells were exposed to Paritaprevir (ABT-450) to induce resistant variants; NS3 protease gene sequencing was performed to identify amino acid mutations, and the replication capacity of variant-containing replicons was assessed to determine resistance levels [2]

In this study, 75 patients meeting all eligibility criteria and none of the exclusion criteria were randomized to receive various doses of ABT-450/r, dasabuvir, or ABT-072. Only data from the 24 patients treated with ABT-450/r are discussed in this report. Eligibility criteria for study M11-602 included the following: age of 18 to 65 years, body mass index (BMI) of ≥18 and <35 kg/m2, chronic HCV genotype 1 infection for at least 6 months prior to study enrollment, plasma HCV RNA level of ≥100,000 IU/ml at screening, liver biopsy within the past 3 years with histology consistent with HCV-induced liver damage, and no evidence of cirrhosis. Exclusion criteria included the following: liver biopsy with a METAVIR fibrosis score of 3 or 4, positive test result for hepatitis B surface antigen or anti-HIV antibodies, history of major depression within the 2 years prior to enrollment, history of disease precluding the use of pegIFN or RBV, and unresolved clinically significant diseases other than HCV.[2]
Patients were randomized to receive 1 of 3 doses of ABT-450/r (50/100 mg, 100/100 mg, or 200/100 mg) or placebo once daily (QD). Following 3 days of monotherapy, pegIFN alfa-2a at 180 μg/week and weight-based RBV at 1,000 to 1,200 mg/day were added, and the same dose of ABT-450/r or placebo was continued to complete a total of 12 weeks. At week 12, ABT-450/r or placebo was discontinued, and patients received pegIFN/RBV alone for up to 36 additional weeks.[2]

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1. Clinical trial protocol (3-day monotherapy): HCV genotype 1-infected patients received Paritaprevir (ABT-450) coadministered with ritonavir at different doses for 3 days; plasma trough concentrations of Paritaprevir were measured, and HCV RNA levels were monitored to evaluate antiviral efficacy and resistance selection [2]
2. Phase II/III clinical trial protocol: Adults with chronic HCV genotype 1 infection were treated with Paritaprevir/ombitasvir/ritonavir (fixed-dose tablet) plus dasabuvir (± ribavirin); SVR12 (sustained virological response 12 weeks post-treatment) was the primary efficacy endpoint, and safety/tolerability was monitored [1]

Absorption, Distribution and Excretion
The time to peak concentration (Tmax) is approximately 4 to 5 hours, and the maximum concentration (Cmax) is 194 ng/mL. Following a single dose of 14C-palipvir combined with 100 mg ritonavir, approximately 88% of the radioactive material is recovered in feces, with limited radioactivity in urine (8.8%); 1.1% of the radioactive material in feces is unmetabolized palipvir, and 0.05% in urine. The steady-state volume of distribution is approximately 10³ liters. Metabolism/Metabolites Palipvir is primarily metabolized via CYP3A4, with a small amount metabolized via CYP3A5.

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Biological half-life
5.5 hours

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1. When ritonavir (a cytochrome P450 3A4 inhibitor) is used in combination with palipvir (ABT-450), it significantly increases the peak plasma concentration, trough concentration and total plasma exposure of palipvir [2]

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
No studies have been conducted on paliprevir in breastfeeding women receiving treatment for hepatitis C virus infection. Because it binds to maternal plasma proteins at a rate exceeding 97%, its concentration in breast milk may be very low. Some sources suggest that breastfeeding should not be performed when paliprevir is used in combination with ribavirin.
Ritonavir has been studied as a booster in several studies involving breastfeeding women. It is excreted into breast milk at measurable concentrations, and low concentrations of ritonavir have been detected in the blood of some breastfed infants. No adverse reactions have been reported in breastfed infants. For more information, please refer to the ritonavir documentation on the LactMed website.
Hepatitis C is not transmitted through breast milk, and breast milk has been shown to inactivate the hepatitis C virus (HCV). However, the U.S. Centers for Disease Control and Prevention (CDC) recommends that mothers infected with hepatitis C virus (HCV) should consider discontinuing breastfeeding if they experience cracked or bleeding nipples. It is unclear whether this warning applies to mothers undergoing hepatitis C treatment. Infants born to mothers infected with HCV should be tested for HCV; nucleic acid testing is recommended because maternal antibodies are present in the infant for the first 18 months after birth and until the infant develops an immune response. ◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on breastfeeding and breast milk
No published information found as of the revision date.

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Protein binding
Binding rate with human plasma proteins is 97% to 98.6%.

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1. In clinical trials, the combination of palipvir/obitavir/ritonavir and dasabuvir was generally well tolerated; the most common adverse reactions included nausea, insomnia, weakness, pruritus, other skin reactions and fatigue[1]

[1]. Drugs . 2015 Jun;75(9):1027-38.

[2].Antimicrob Agents Chemother . 2015 Feb;59(2):988-97.

[3]. Arch Pharm Res. 2023 Jun;46(6):564-572.

Paritaprevir is a direct-acting antiviral drug often used in combination with other medications to treat chronic hepatitis C. Chronic hepatitis C is an infectious liver disease caused by infection with the hepatitis C virus (HCV). HCV is a single-stranded RNA virus with nine different genotypes, of which genotype 1 is the most common in the United States, accounting for approximately 72% of all chronic hepatitis C cases. Since 2011, significant progress has been made in treatment options for chronic hepatitis C with the development of direct-acting antiviral drugs (DAAs) such as Paritaprevir. As a new generation of direct-acting antiviral drugs, Paritaprevir products offer higher sustained virological response (SVR) rates, a higher resistance barrier, fewer side effects, and a lighter medication burden compared to older generation drugs (such as [DB08873], [DB05521], [DB00008], [DB00022], and [DB00811]). By combining multiple antiretroviral drugs into a fixed-dose formulation, targeted therapy can be administered against multiple stages of the viral life cycle while reducing the risk of developing drug-resistant viral strains. In Canada and the United States, paretamivir is currently marketed in three fixed-dose formulations: Viekira Pak (approved by the U.S. Food and Drug Administration), Technivie (approved by both the U.S. Food and Drug Administration and Health Canada), and Holkira Pak (approved by Health Canada). More specifically, paretamivir inhibits viral replication by inhibiting the NS3/4A serine protease of hepatitis C virus (HCV). After HCV genetic material replicates and is translated into a single polypeptide chain, non-structural protein 3 (NS3) and its activating cofactor non-structural protein 4A (NS4A) are responsible for cleaving the genetic material into structural and non-structural proteins essential for the assembly of a mature virus: NS3, NS4A, NS4B, NS5A, and NS5B. Therefore, paretamivir inhibits viral replication and function by inhibiting the viral protease NS3/4A. In 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) jointly published guidelines recommending paritaprevir as a first-line treatment for genotypes 1a, 1b, and 4, and it can be used in combination with other antiviral drugs. Depending on the genotype, paritaprevir is typically used in combination with other antiviral drugs (such as [DB09296], [DB09183], [DB00503], and [DB00811]) to achieve a cure or sustained virological response (SVR), which is typically achieved after 12 weeks of daily treatment. SVR and eradication of hepatitis C virus (HCV) infection are associated with significant long-term health benefits, including reduced liver-related damage, improved quality of life, reduced incidence of hepatocellular carcinoma, and reduced all-cause mortality. Side effects from direct-acting antiviral therapy with paritaprevir are minimal; the most common side effects are headache and fatigue. Compared to previous interferon-based treatment regimens, paritaprevir offers fewer side effects and a shorter treatment duration, a significant advantage. Previous interferon regimens have been limited by infusion site reactions, decreased blood cell counts, and neuropsychiatric side effects. Paritaprevir was initially marketed as a fixed-dose combination formulation with [DB09296], [DB09183], and [DB00503], namely the FDA-approved Viekira Pak. Viekira Pak was first approved in December 2014 for the treatment of HCV genotype 1b infection in patients with or without cirrhosis or compensated cirrhosis; when used in combination with [DB00811], it is also indicated for the treatment of HCV genotype 1a infection in patients with or without cirrhosis or compensated cirrhosis. Palipvir can also be formulated as a fixed-dose combination with [DB09296] and [DB00503], namely the FDA-approved Technivie. Technivie was first approved in July 2015 for use in combination with [DB00811] for the treatment of patients with chronic hepatitis C virus (HCV) genotype 4 infection without cirrhosis or with compensated cirrhosis. In Canada, paritaprevir is also available as a fixed-dose combination with [DB09296], [DB09183], and [DB00503], namely the commercially available product Holkira Pak, approved by Health Canada. Holkira Pak was first approved in January 2015 for the treatment of HCV genotype 1b infection with or without cirrhosis, and in combination with [DB00811] for the treatment of HCV genotype 1a infection with or without cirrhosis. Paritaprevir is a hepatitis C virus NS3/4A protease inhibitor. Paretamivir's mechanism of action involves its role as an inhibitor of hepatitis C virus NS3/4A protease, organic anion transporter 1B1, organic anion transporter 1B3, breast cancer resistance protein, UGT1A1, and P-glycoprotein. Paretamivir is a highly bioavailable synthetic acylsulfonamide that inhibits the hepatitis C virus (HCV) protease complex composed of non-structural proteins 3 and 4A (NS3/NS4A), exhibiting potential activity against HCV genotype 1. After administration, paretamivir reversibly binds to the active site and binding site of the HCV NS3/NS4A protease, thereby preventing NS3/NS4A protease-mediated polyprotein maturation. This interferes with viral protein processing and the formation of the viral replication complex, thus inhibiting viral replication in HCV genotype 1 infected host cells. NS3 is a serine protease crucial for proteolytic cleavage at multiple sites within the HCV polyprotein and plays a key role in HCV ribonucleic acid (RNA) replication. NS4A is an activator of NS3. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family. Its infection is closely related to the development and progression of hepatocellular carcinoma (HCC).
See also: Ombitavir; Paritavir; Ritonavir (components)...See more...

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Drug Indications
When used in combination with [DB09296], [DB09183], and [DB00503] in a fixed-dose combination formulation (i.e., the FDA-approved Viekira Pak), palipvir is indicated for the treatment of HCV genotype 1b infection in patients with or without cirrhosis or compensated cirrhosis; when used in combination with [DB00811], it is indicated for the treatment of HCV genotype 1a infection in patients with or without cirrhosis or compensated cirrhosis. When used in combination with [DB09296] and [DB00503] in a fixed-dose combination product, namely Technivie, a product approved by the U.S. Food and Drug Administration (FDA) and Health Canada, palipvir, in combination with [DB00811], is indicated for the treatment of patients with chronic hepatitis C virus (HCV) genotype 4 infection without cirrhosis or with compensated cirrhosis. When used in combination with [DB09296], [DB09183], and [DB00503] in a fixed-dose combination formulation (i.e., Holkira Pak, a commercially available product approved by Health Canada), palipvir is indicated for the treatment of HCV genotype 1b infection with or without cirrhosis; when used in combination with [DB00811], it is indicated for the treatment of HCV genotype 1a infection with or without cirrhosis.
FDA Label

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Mechanism of Action
Palipuvir is a potent inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. After the hepatitis C virus (HCV) genetic material replicates and is translated into a single polypeptide, non-structural protein 3 (NS3) and its activating cofactor non-structural protein 4A (NS4A) are responsible for cleaving it into the following structural and non-structural proteins, which are essential for the assembly of the mature virus: NS3, NS4A, NS4B, NS5A, and NS5B. Paritaprevir inhibits viral replication and function by suppressing the viral proteases NS3/4A.

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1. Paritaprevir (ABT-450) is an NS3/4A protease inhibitor (direct antiviral drug, DAA) used to treat HCV infection; the rapid emergence of resistance is a major challenge for DAAs and may lead to cross-resistance within the same drug class[2]
2. Paritaprevir is a fixed-dose tablet composed of ombitasvir (NS5A replication complex inhibitor) and ritonavir (CYP3A4 inhibitor), and is used in combination with dasabuvir (NS5B polymerase inhibitor) to treat chronic HCV genotype 1 infection; this regimen does not contain interferon and has been approved in the United States (Viekira Pak™) and the European Union (Viekirax® + Exviera®)[1]
3. A 3-day monotherapy study of paritaprevir (ABT-450) provided a reference for subsequent clinical trials of HCV-infected patients in combination with other direct-acting antiviral agents (DAAs) [2]
4. Combination therapies containing paritaprevir are effective in a variety of HCV genotype 1 infected populations, including compensated cirrhosis, liver transplant recipients, or patients co-infected with HIV-1 [1]

C40H43N7O7S

765.88

765.294

C, 62.73; H, 5.66; N, 12.80; O, 14.62; S, 4.19

1216941-48-8

Paritaprevir dihydrate;1456607-71-8

45110509

White to off-white powder

6.346

3

10

7

55

1600

5

S(C1([H])C([H])([H])C1([H])[H])(N([H])C([C@@]12C([H])([H])[C@@]1([H])C([H])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@]([H])(C(N1C([H])([H])[C@@]([H])(C([H])([H])[C@]1([H])C(N2[H])=O)OC1C2=C([H])C([H])=C([H])C([H])=C2C2=C([H])C([H])=C([H])C([H])=C2N=1)=O)N([H])C(C1C([H])=NC(C([H])([H])[H])=C([H])N=1)=O)=O)(=O)=O

UAUIUKWPKRJZJV-QPLHLKROSA-N

InChI=1S/C40H43N7O7S/c1-24-21-42-33(22-41-24)35(48)43-32-16-6-4-2-3-5-11-25-20-40(25,39(51)46-55(52,53)27-17-18-27)45-36(49)34-19-26(23-47(34)38(32)50)54-37-30-14-8-7-12-28(30)29-13-9-10-15-31(29)44-37/h5,7-15,21-22,25-27,32,34H,2-4,6,16-20,23H2,1H3,(H,43,48)(H,45,49)(H,46,51)/b11-5-/t25-,26-,32+,34+,40-/m1/s1

(1S,4R,6S,7Z,14S,18R)-N-cyclopropylsulfonyl-14-[(5-methylpyrazine-2-carbonyl)amino]-2,15-dioxo-18-phenanthridin-6-yloxy-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxamide

ATB450; ABT 450; ABT-450; Veruprevir; Paritaprevir; Brand name: VIEKIRA PAK; 1216941-48-8; Veruprevir; ABT-450; Veruprevir anhydrous; ABT450; 1221573-85-8; Paritaprevir(ABT-450);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (2.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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