IC50: 66-410 nM (HIV-1 isolates)[1]

HIV-1 protease (PR) dimerization and enzymatic activity inhibition. [1]

Tipranavir (PNU-140690) exhibits strong action against a broad range of wild-type and multi-PI-resistant HIV-1 variants, inhibits the enzymatic activity of HIV-1 protease, and prevents the dimerization of protease subunits. HIV11MIX, a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (including HIVB and HIVC), quickly develops high-level Tipranavir (PNU-140690) resistance and replicates at high concentrations of Tipranavir (PNU-140690) after being selected against Tipranavir (by 10 passages [HIV11MIXP10]). With IC50s of 2.9 and 3.2 μM, respectively, which represent 11- and 12-fold increases in comparison to the IC50 against cHIVB, cHIVBI54V and cHIVBI54V/V82T are considerably resistant to Tipranavir (PNU-140690)[1].

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Tipranavir exerts potent activity against multi-PI-resistant HIV-1 isolates. A mixture of 11 multi-PI-resistant clinical isolates (HIV_11MIX) was selected against TPV, and by passage 10 (HIV_11MIX^P10), the virus acquired high-level TPV resistance and replicated at TPV concentrations up to 15 µM. The IC₅₀ of TPV against wild-type clinical strain HIV_104pre was 0.16 µM, while against multi-PI-resistant strains, IC₅₀ values ranged from 0.066 µM to 0.41 µM. [1]
Introduction of I54V/V82T into cHIV_B (cHIV_B^I54V/V82T) compromised TPV's dimerization inhibition and conferred significant TPV resistance, with an IC₅₀ of 3.2 µM (12-fold increase). [1]
L24M substitution in cHIV_C conferred moderate resistance to TPV, with IC₅₀ increasing from 0.9 µM to 2.2 µM. [1]
L33I substitution in cHIV_B did not significantly alter TPV susceptibility, but in combination with I54V or I54V/V82T, it increased resistance. [1]

To increase the bioavailability of dipranavir (PNU-140690), it is necessary to combine it with low-dose ritonavir (RTV) when given orally twice a day. The abundance of Tipranavir (PNU-140690) in the liver, spleen, and eyes is considerably higher in Tipranavir/r-cotreated mice than in Tipranavir-treated animals. In the Tipranavir-alone group, 31 and 38% of the serum and liver, respectively, are made up of metabolites of tipranavir (PNU-140690). In the serum and liver of mice cotreated with tipranavir (PNU-140690) and tipranavir (TPV/r), respectively, only 1 and 2% of metabolites are found. One dose of [14C]Tipranavir (PNU-140690) is given to Sprague-Dawley rats in conjunction with RTV. Feces include a lot of oxidation-related metabolites. There isn't a single metabolite that is discovered to be substantially present in urine[2].

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Mice were orally administered Tipranavir (40 mg/kg or 100 mg/kg) with or without RTV (40 mg/kg). TPV and its metabolites were found in feces but not in urine. Eight TPV metabolites were identified in mouse feces, including three monohydroxylated, three desaturated, one dealkylated, and one dihydroxylated metabolites. [2]
Co-administration of RTV significantly inhibited all eight TPV metabolic pathways in mice. [2]
TPV tissue distribution was highest in the liver, followed by kidney, spleen, and lung. Low levels were detected in brain and eyes. RTV co-treatment increased TPV abundance in liver, spleen, and eyes. [2]

An intermolecular FRET-based HIV-1 expression system was used to assess protease dimerization inhibition. CFP- and YFP-tagged HIV-1 protease monomers were co-expressed in COS7 cells. FRET signals were measured using confocal microscopy. A CFP^A/B ratio >1 indicates dimerization, while <1 indicates inhibition. [1]
In the presence of 1 µM and 10 µM TPV, the CFP^{A/B ratios for wild-type protease were 0.85 and 0.64, respectively, indicating dimerization inhibition. [1]
Substitutions such as L24M, L33I, L33F, and E34D were shown to compromise TPV's dimerization inhibition activity. [1]}

Drug susceptibility assays were performed using PHA-stimulated PBMCs or MT-4 cells. Cells were infected with HIV-1 isolates (50 TCID₅₀) and cultured in the presence of serial dilutions of TPV. After 7 days, p24 Gag protein production was measured using a chemiluminescent enzyme immunoassay. IC₅₀ values were calculated based on p24 inhibition. [1]
Selection experiments were conducted by passaging HIV-1 in MT-4 cells with escalating TPV concentrations (starting from 0.4 µM up to 15 µM). Viral replication was monitored by p24 production, and proviral DNA was sequenced to identify mutations. [1]

Mice[2] All mice (2-4 months old) are maintained under a standard
12-h dark and 12-h light cycle with water and chow provided ad libitum.
For metabolomic analysis, Tipranavir (40 mg/kg) is administered via
ball-tipped gavage needles, and the mice are housed in separate
metabolic cages for 18 h. Urine and feces samples are collected and
stored at 20°C for further analysis. For tissue distribution and
inhibition studies, three groups of mice are used and are orally treated
with Tipranavir (100 mg/kg), RTV (40 mg/kg), and Tipranavir/r (100
mg/kg Tipranavir and 40 mg/kg RTV), respectively. Tissues including the
liver, brain, lung, kidney, spleen, and eyes are collected 30 min after
treatment and stored at 20°C for further analysis.

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Mice (2–4 months old) were orally administered Tipranavir at 40 mg/kg (for metabolomic analysis) or 100 mg/kg (for tissue distribution study) using ball-tipped gavage needles. [2]
For the inhibition study, mice were treated with TPV (100 mg/kg), RTV (40 mg/kg), or TPV/r (100 mg/kg TPV + 40 mg/kg RTV). [2]
Animals were housed in metabolic cages for 18 hours post-dose for urine and feces collection. Tissues (liver, brain, lung, kidney, spleen, eyes) were collected 30 minutes after treatment. [2]

Absorption, Distribution and Excretion
While absolute quantitative absorption data are currently unavailable, teplanavir absorption is limited. Teplanavir has a high binding rate to plasma proteins (>99.9%). It binds to human serum albumin and α-1 acid glycoprotein. In clinical samples from healthy volunteers and HIV-1 positive patients, the mean free fraction of teplanavir (not in combination with ritonavir) in plasma was similar. The total plasma concentration of teplanavir in these samples ranged from 9 to 82 μM. Within this concentration range, the free fraction of teplanavir appeared to be independent of the total drug concentration. In (14)C-teplanavir administration to subjects (n=8) who had received Aptivus/ritonavir 500/200 mg doses to steady state, the results showed that most of the radioactivity (median 82.3%) was excreted in feces, with only a median of 4.4% of the administered dose recovered in urine. Furthermore, most of the radioactivity (56%) was eliminated within 24 to 96 hours after administration. In healthy volunteers (n=67) and HIV-1 infected adult patients (n=120), the effective mean elimination half-life of tepranavir/ritonavir at steady state was approximately 4.8 hours and 6.0 hours, respectively, at twice-daily doses of 500/200 mg with food. This study characterized the pharmacokinetics and metabolites of the antiretroviral drug tepranavir (TPV) in combination with ritonavir (RTV) in nine healthy male volunteers. Subjects received 500 mg TPV capsules and 200 mg RTV capsules twice daily for six consecutive days. On day 7, they received a single oral dose of 551 mg TPV (containing 90 microcuries [(14)C]TPV) and 200 mg RTV, followed by unlabeled 500 mg TPV and 200 mg RTV twice daily for up to 20 days. Blood, urine, and fecal samples were collected for mass balance and metabolite analysis. Metabolite analysis and identification were performed using a flow scintillation analyzer combined with liquid chromatography-tandem mass spectrometry. The median radioactivity recovery rate was 87.1%, with 82.3% of the radioactive material excreted in feces and less than 5% in urine. Most of the radioactive material was excreted within 24 to 96 hours after administration of ((14)C)TPV. The radioactive material in the blood was mainly found in plasma, not in red blood cells. Unmetabolized TPV accounted for 98.4% to 99.7% of plasma radioactivity. Similarly, the most common radioactive material in feces was also unmetabolized TPV, accounting for an average of 79.9% of fecal radioactivity. The most abundant metabolite in feces was hydroxyl metabolite H-1, accounting for 4.9% of fecal radioactivity. Tepranavir glucuronide metabolite H-3 was the most abundant drug-related component in urine, accounting for 11% of urinary radioactivity. In summary, when tepranavir and ritonavir are used in combination, unmetabolized tepranavir is the predominant circulating and excreted form, primarily via feces. Tepranavir exhibits very high in vitro plasma protein binding (>99.9%) in all species, including humans, with only a slight saturation trend in the 10–100 μM concentration range. Tepranavir (whether or not used in combination with ritonavir) is primarily distributed in the liver, small intestine, large intestine, kidneys, and lungs. Tepranavir does not cross the blood-brain barrier and does not readily enter erythrocytes. Following intravenous administration, tepranavir clearance is low, at 0.08 L/hr/kg in dogs and 1.15 L/h/kg in mice. The steady-state volume of distribution (Vss) is 0.13 L/kg in dogs and 0.51 L/kg in rats. Tepranavir is rapidly eliminated, with a terminal half-life (t1/2) of 0.93 hours in dogs and 5.43 hours in rats. The mean time to peak concentration (Tmax) of tepranavir after oral administration ranged from 0.5 to 8 hours across all species. Oral bioavailability of tepranavir was low or moderate in all species due to inadequate absorption and/or intestinal metabolism. In rats, the bioavailability of tepranavir was 28.0%, which was moderate; while in dogs (6.5% and 7.7%), mice (11%), and rabbits (9.9%), bioavailability was extremely low. Food had no significant effect on the oral bioavailability of tepranavir in dogs. A ritonavir combination study was conducted to investigate the benefits of combination therapy. However, due to the different ritonavir doses used for oral and intravenous administration of tepranavir, a definitive comparison of the bioavailability of tepranavir in the presence or absence of ritonavir was not possible. Following intravenous administration, teplanavir clearance in combination with ritonavir was low to moderate, at 0.0182 L/hr/kg in rats and 3.00 L/hr/kg in mice. In rats and dogs, ritonavir-teplanavir combination resulted in a 4- to 5-fold reduction in teplanavir clearance, consistent with ritonavir's mechanism of inhibiting drug-metabolizing enzymes. Metabolism/Metabolites: Hepatic metabolism. In vitro human liver microsomal metabolism studies have shown that CYP 3A4 is the major CYP enzyme involved in teplanavir metabolism. Teplanavir (TPV) is the first non-peptide protease inhibitor used to treat drug-resistant HIV infection. Clinically, TPV is used in combination with ritonavir (RTV) to improve blood drug concentrations and efficacy. The mechanism by which RTV enhances TPV metabolism-mediated drug interactions is not fully elucidated. This study used metabolomics to investigate TPV metabolism in mice. TPV and its metabolites were detected in mouse feces but not in urine. Principal component analysis of the fecal metabolome revealed eight TPV metabolites, including three monohydroxylated metabolites, three desaturated metabolites, one dealkylated metabolite, and one dihydroxylated metabolite. In vitro human liver microsomal studies reproduced five TPV metabolites, all of which were inhibited by RTV. CYP3A4 was identified as the major enzyme in the formation of four TPV metabolites (metabolites II, IV, V, and VI), including an unusual dealkylated product resulting from carbon-carbon bond cleavage. Multiple cytochrome P450s (2C19, 2D6, and 3A4) were involved in the formation of one monohydroxylated metabolite (metabolite III). In vivo experiments showed that combined RTV treatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomics analysis identified two known and six novel TPV metabolites in mice, all of which were inhibited by RTV. This study provides conclusive evidence that the ritonavir (RTV)-mediated synergistic effect of teplanavir (TPV) is due to the regulation of P450-dependent metabolism. This study characterized the pharmacokinetics and metabolites of ritonavir (RTV) in combination with the antiretroviral drug teplanavir (TPV) in nine healthy male volunteers. Subjects received 500 mg TPV capsules and 200 mg RTV capsules twice daily for six consecutive days. On day 7, subjects received a single oral dose of 551 mg TPV (containing 90 μCi [(14)C]TPV) and 200 mg RTV. Subsequently, subjects received unlabeled 500 mg TPV and 200 mg RTV twice daily for up to 20 days. …The most abundant metabolite in feces was the hydroxyl metabolite H-1, accounting for 4.9% of fecal radioactivity. The teplanavir glucuronide metabolite H-3 was the most abundant drug-related component in urine, accounting for 11% of urinary radioactivity. …In vitro metabolic studies have shown that CYP3A4 is the major CYP isoenzyme involved in the metabolism of tepranavir in humans. In rats, the CYP3A isoenzyme has also been identified as the major CYP isoenzyme involved in the metabolism of tepranavir. To evaluate the metabolites, studies were conducted in rats and humans administered tepranavir in combination with ritonavir. Unmetabolized tepranavir was predominantly present in plasma (>85.7%). Unmetabolized tepranavir was also the main form of excretion in feces and urine. The total excretion of metabolites in feces and urine was approximately 4.8% in male rats and 7.4% in female rats. Only trace amounts of glucuronide were observed in feces. For more complete metabolite/metabolite data on tepranavir (6 metabolites), please visit the HSDB record page. Biological half-life: 5–6 hours. Tepranavir and its metabolites are primarily excreted in feces, not urine. [2]
In mice, teplanavir is mainly distributed in the liver. Combined administration with ritonavir increases teplanavir levels in the liver, spleen, and eyes. [2]
In mice treated with teplanavir alone, metabolites accounted for 31% and 38% of total teplanavir-related substances in serum and liver, respectively. In mice treated with teplanavir/ritonavir combination therapy, metabolites accounted for only 1-2%. [2]
This study indicates that TPV metabolism is primarily mediated by CYP3A4, with CYP2C19 and CYP2D6 also contributing to the metabolism of some metabolites. [2]

Hepatotoxicity
A significant proportion of patients taking antiretroviral regimens containing teplanavir experience some degree of elevated serum transaminases. Moderate to severe elevations (more than 5 times the upper limit of normal) occur in 3% to 10% of patients, with an even higher incidence in patients co-infected with HIV-HCV. These elevations are usually asymptomatic and self-limiting, resolving with continued use. Clinically significant liver injury caused by teplanavir is rare, and its clinical patterns, latency, and recovery are not well understood. Some protease inhibitors are associated with acute liver injury, which typically occurs 1 to 8 weeks after administration, with varying patterns of liver enzyme elevation, ranging from hepatocellular to cholestatic. Immune allergic reactions (rash, fever, eosinophilia) and autoantibody formation are uncommon. Acute liver injury caused by teplanavir is usually self-limiting but can be severe; the sponsor has received reports of isolated cases of acute liver failure. In patients with co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), some cases appear to be due to exacerbation of pre-existing chronic liver disease, possibly due to a sudden immune remodeling. There is no clear association between tepranavir treatment and lactic acidosis and acute fatty liver, conditions commonly seen with many nucleoside analogue reverse transcriptase inhibitors. Therefore, tepranavir is associated with higher rates of elevated serum enzymes, generally higher than other protease inhibitors, and is thus considered a second-line HIV protease inhibitor. Probability Score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no publicly available information regarding the use of tepranavir during lactation. It is not recommended to take tepranavir during lactation. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of breast milk transmission to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load, breastfeeding should be supported if chosen. If viral load is not suppressed, pasteurized donated breast milk or formula is recommended.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
Gynecomastia has been reported in men receiving highly active antiretroviral therapy. Gynecomastia is initially unilateral, but approximately half of cases develop into bilateral gynecomastia. No changes in serum prolactin levels have been observed, and it usually resolves spontaneously within one year even with continued treatment. Some case reports and in vitro studies suggest that protease inhibitors may cause hyperprolactinemia and galactorrhea in some male patients, but this conclusion remains controversial. The implications of these findings for lactating women are unclear. Prolactin levels in established lactating mothers may not affect their ability to breastfeed. Protein Binding: Broadly bound (>99.9%), binding to both human serum albumin and α1-acid glycoprotein. Interactions: Pharmacokinetic interactions exist with fluconazole (increased tepranavir concentrations; no change in fluconazole concentrations and AUC). If ritonavir-enhanced tepranavir and fluconazole are used concurrently, no adjustment of the fluconazole dose is necessary, but a daily fluconazole dose exceeding 200 mg is not recommended. If high-dose fluconazole is required, alternative classes of HIV protease inhibitors or other antiretroviral drugs should be considered. Possible Pharmacokinetic Interactions with Carbamazepine, Phenobarbital, or Phenytoin: Decreases tepranavir concentrations, potentially reducing antiretroviral efficacy; alters carbamazepine concentrations. If used concomitantly with carbamazepine or phenytoin, some experts recommend monitoring anticonvulsant and tepranavir concentrations; alternatively, other anticonvulsants may be considered. It may have pharmacokinetic interactions with valproic acid (decreasing valproic acid plasma concentrations); the efficacy of anticonvulsants may be reduced. It may have pharmacokinetic interactions with warfarin (altering warfarin concentrations). If warfarin is used concomitantly with ritonavir-enhanced tepranavir, the international normalized ratio (INR) should be monitored, especially when initiating or discontinuing antiretroviral therapy; the warfarin dose should be adjusted as needed. Concomitant use of ritonavir-enhanced tepranavir with anticoagulants may increase the risk of bleeding; caution should be exercised when using these two drugs together. It may have pharmacokinetic interactions with amiodarone, benprimidil (discontinued in the US), flecainide, propafenone, or quinidine (increasing plasma concentrations of antiarrhythmic drugs). There is a risk of serious and/or life-threatening adverse reactions (e.g., arrhythmias). Concomitant use with ritonavir-enhanced tepranavir is contraindicated.
For more complete data on drug interactions of teplanavir (35 items in total), please visit the HSDB record page.

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The literature indicates that teplanavir/ritonavir combination therapy is associated with intracranial hemorrhage and hepatotoxicity. More than 10 cases of intracranial hemorrhage and 12 cases of liver-related death have been reported. [2]
Teplanavir is highly concentrated in the liver, especially when used in combination with ritonavir. Biliary dysfunction may increase the risk of liver injury caused by teplanavir. [2]

[1]. Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1. J Virol. 2012 Dec;86(24):13384-96.

[2]. Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. Drug Metab Dispos. 2010 May;38(5):871-8.

[3]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.

Therapeutic Uses

Anti-HIV Drugs

Tepllanavir, in combination with low-dose ritonavir (ritonavir-boosted tepranavir) and other antiretroviral agents, is used to treat human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and children aged 2 years and older. These patients must have evidence of viral replication, have received prior antiretroviral therapy, and be infected with an HIV-1 strain resistant to multiple HIV protease inhibitors (PIs). /US Product Label Contains/
Drug Warnings
/Black Box Warning/ Warning: Hepatotoxicity and Intracranial Hemorrhage. Hepatotoxicity: Clinical hepatitis and liver decompensation (including some deaths) have been reported. Extra caution should be exercised in patients with concurrent chronic hepatitis B or hepatitis C, as these patients have an increased risk of hepatotoxicity. Intracranial Hemorrhage: Fatal and non-fatal intracranial hemorrhage have been reported. Post-marketing surveillance has shown that HIV-1 infected patients receiving protease inhibitor therapy have experienced new-onset diabetes, exacerbation of pre-existing diabetes, and hyperglycemia. Some patients required initiation of insulin or dose adjustments to manage these adverse events. Diabetic ketoacidosis occurred in some cases. Hyperglycemia persisted in some patients who discontinued protease inhibitor therapy. Because these events were reported voluntarily in clinical practice, their frequency cannot be estimated, and a causal relationship between protease inhibitor therapy and these events has not been established. Patients with known hypersensitivity to sulfonamides should use Aptivus with caution. Teppranavir contains a sulfonamide fraction. Cross-sensitivity between sulfonamides and Aptivus is unknown. Patients receiving ritonavir-enhanced tepranavir have reported rashes, including maculopapular rash, urticaria, and possible photosensitivity. In clinical studies, the incidence of rash in women, men, and children receiving ritonavir-enhanced tepranavir was 10%, 8%, and 21%, respectively. The median time to rash appearance in adults was 53 days, and the median duration was 22 days. Rash may occur after taking teplanavir, accompanied by joint pain or stiffness, a tightness in the throat, or generalized itching. If a severe rash occurs, teplanavir should be discontinued.
For more complete data on teplanavir warnings (16 in total), please visit the HSDB record page.

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Pharmacodynamics
Teprananavir is a non-peptide HIV protease inhibitor (PI). Protease inhibitors block the protease portion of HIV. The HIV-1 protease is an enzyme responsible for hydrolyzing the viral polyprotein precursor protein into the various functional proteins in infectious HIV-1. Nefernavir binds to the active site of the protease, inhibiting its activity. This inhibition prevents the cleavage of the viral polyprotein, thereby preventing the formation of immature, non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

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Tepranavir is a non-peptide protease inhibitor used in combination with antiretroviral therapy for HIV-1 infection, particularly for patients with multi-protease inhibitor-resistant variants. [1]
Tepranavir inhibits the enzymatic activity and dimerization of HIV-1 proteases. Its dimerization inhibitory activity is reduced by single or two amino acid substitutions (e.g., L24M, L33I/F, E34D, I54V, V82T), which may explain its relatively low genetic barrier to resistance compared to darunavir. [1]
HIV-1 variants screened for tepranavir remain sensitive to darunavir, with an IC50 of 0.034 µM against HIV_11MIX^P10. [1]

C31H33N2O5F3S

602.66432

602.206

174484-41-4

Tipranavir-d4;1217819-15-2

54682461

White to off-white solid powder

1.313g/cm3

680ºC at 760mmHg

86-89ºC

365.1ºC

0mmHg at 25°C

1.579

8.479

2

10

11

42

1050

2

CCC[C@]1(CC(=C(C(=O)O1)[C@H](CC)C2=CC(=CC=C2)NS(=O)(=O)C3=NC=C(C=C3)C(F)(F)F)O)CCC4=CC=CC=C4

SUJUHGSWHZTSEU-FYBSXPHGSA-N

InChI=1S/C31H33F3N2O5S/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34/h5-14,18,20,25,36-37H,3-4,15-17,19H2,1-2H3/t25-,30-/m1/s1

N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide

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)

DMSO : ~200 mg/mL (~331.86 mM)
Ethanol :≥ 50 mg/mL (~82.97 mM)

Solubility in Formulation 1: 5 mg/mL (8.30 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 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: ≥ 5 mg/mL (8.30 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 2.5 mg/mL (4.15 mM) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH 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 4: 2.5 mg/mL (4.15 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix well.
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.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (4.15 mM) (saturation unknown) in 10% EtOH + 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 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: 2.5 mg/mL (4.15 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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