Oxazolidinone antibacterial; MAO-A/B

Tedizolid (formerly known as torezolid, TR-700, or DA-7157, trade name Sivextro), is an oxazolidinone-class antibiotic against Gram-positive bacteria. The mechanism of action is to inhibit protein synthesis by binding to the 50S ribosomal subunit of the G+ bacteria. Tedizolid phosphate is a phosphate ester prodrug of the active compound tedizolid. It was developed by Cubist Pharmaceuticals, following acquisition of Trius Therapeutics (formerly Dong-A Pharmaceuticals in Korea), and is approved in 2014 by the US-FDA for the treatment of acute bacterial skin and skin structure infections (also known as complicated skin and skin-structure infections (cSSSIs)).

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Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone Tedizolid against a collection of 44M. abscessus clinical isolates. The MIC50s and MIC90s of Tedizolid (2 and 8μg/mL, respectively) were 2- to 16-fold lower than those of linezolid. There was no difference between the 3M. abscessus subspecies. Time-kill assays did not show any bactericidal activity at 4- and 8-fold the MIC. Combination of tedizolid with clarithromycin was synergistic against 1 out of 6 isolates, while indifferent interactions were observed for tedizolid combined with tigecycline, ciprofloxacin, and amikacin [2].

Male ICR mice (weight, 18 to 20 g) are inoculated intraperitoneally with 1 of 4 PRSP isolates (DR9, DR10, DR11, or DR14) suspended in 10% mucin, to induce a systemic S. pneumoniae infection. The suspension contained sufficient bacteria to kill 100% of untreated control mice. At 1 h postinfection, mice receives a single dose of either tedizolid phosphate or linezolid, and survival is assessed daily for 7 days postinfection. Treatments are delivered both orally and intravenously at each of four doses (40 mg/kg of body weight, 13.33 mg/kg, 4.44 mg/kg, and 1.48 mg/kg), with 8 mice per group defined by dose, delivery method, and infecting strain. The 50% effective dose (ED50), i.e., the dose allowing survival of 50% of the infected mice, is calculated for each delivery route using probit analysis.

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In mice infected systemically with a lethal inoculum of PRSP 1 h prior to a single administration of either antimicrobial, oral Tedizolid phosphate was equipotent to linezolid (1 isolate) to 2-fold more potent than linezolid (3 isolates) for survival at day 7, with tedizolid phosphate 50% effective dose (ED50) values ranging from 3.19 to 11.53 mg/kg of body weight/day. In the PSSP pneumonia model, the ED50 for survival at day 15 was 2.80 mg/kg/day for oral tedizolid phosphate, whereas it was 8.09 mg/kg/day for oral linezolid following 48 h of treatment with either agent. At equivalent doses (10 mg/kg once daily tedizolid phosphate or 5 mg/kg twice daily linezolid), pneumococcal titers in the lungs at 52 h postinfection were approximately 3 orders of magnitude lower with tedizolid phosphate treatment than with linezolid treatment or no treatment. Lung histopathology showed less inflammatory cell invasion into alveolar spaces in mice treated with tedizolid phosphate than in untreated or linezolid-treated mice. These results demonstrate that tedizolid phosphate is effective in murine models of PRSP systemic infection and PSSP pneumonia [1].

Susceptibility testing. [1]
PRSP (penicillin G MICs ≥ 2 μg/ml) clinical isolates were collected between 2002 and 2004 from patients at a South Korean tertiary-care hospital. The species were identified by conventional methods or by using either the ID 32 GN or the ATB 32A system. MIC values of Tedizolid (active form) and linezolid against the 28 PRSP isolates were determined in agar dilution assays in accordance with NCCLS guidelines using Mueller-Hinton agar supplemented with 5% sheep blood. Serial 2-fold dilutions of stock solutions of Tedizolid or linezolid were made to yield 10× solutions that were mixed with 9 parts Mueller-Hinton agar, supplemented with 5% sheep blood, at 45 to 50°C. Final concentrations of antimicrobials were from 128 μg/ml to 0.0313 μg/ml. Agar was poured into 10-cm plastic petri dishes at a depth of 3 to 4 mm and allowed to solidify at room temperature. Inocula were prepared from single colonies of an overnight growth of PRSP isolates by suspending in broth, adjusting the turbidity to match that of the 0.5 McFarland standard, and applying 104 CFU, using a Steers replicator, onto prepared plates, starting with drug-free control plates and ending with the highest concentration of drug. Plates were incubated at 35°C for 16 to 20 h before inspection for growth. S. pneumoniae ATCC 49619 was used as a control. The MIC for each isolate was determined as the minimum concentration at which there was no growth.

MIC Determination [2]
MICs of Tedizolid/TZD and LZD were determined using the broth microdilution method according to CLSI guidelines in cation-adjusted Mueller-Hinton broth (CaMHB). Briefly, TZD was solubilized in dimethylsulfoxyde (DMSO) at a concentration of 1.2 mg/L, and subsequent dilutions were performed in culture medium. Bacteria (ca. 5 × 105 CFU/mL) were inoculated into CaMHB containing 2-fold dilutions of antibiotics (0.06–64 μg/mL) in 96-well microplates. DMSO was added to LZD-containing wells at the same concentration as in TZD-containing wells (maximum concentration 5%vol/vol). MICs were determined after 3 to 5 days of incubation at 30 °C, depending on the growth of the control wells containing no antibiotic, which varied between the isolates. All MICs were performed in triplicate, and the median values are reported. Reference strain S. aureus CIP 4.83 (ATCC 6538) was used as control.

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Time-Kill Assays [2]
Time-kill assays were performed for Tedizolid/TZD as previously described (Lefebvre et al., 2016). A bacterial suspension of M. abscessus subsp. abscessus CIP 104536T was diluted 1/1000 in fresh CaMHB and incubated for 2 h at 30 °C in a shaker incubator (180 rpm) to reach a bacterial density of 105–106 CFU/mL. TZD was then added at concentrations corresponding to 4 or 8 times its MIC, and cultures were incubated at 30 °C in an incubator shaker (180 rpm) for 72 h. CFU counts were determined at 0, 24, 48, and 72 h, using 10−1 to 10−8 dilutions plated on CaMH agar and incubated at 30 °C for 72 h. Time-kill curves were performed in duplicate.

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Synergy Studies [2]
Synergy testing was performed using a 2-dimensional microdilution checkerboard method, as previously described (Bolhuis et al., 2014). Growth conditions were similar to those used for MIC determination, except for the Tedizolid/TZD–clarithromycin combination, for which results were read again at day 14 to monitor induction of resistance according to CLSI recommendations. The fractional inhibitory concentration index (FICI) was calculated as follows: FICI = (MICdrug A in combination/MICdrug A alone) + (MICdrug B in combination/MICdrug B alone), where drug A was TZD and drug B was clarithromycin, tigecycline, ciprofloxacin, or amikacin. Interaction between the 2 compounds was defined as synergistic when FICI value was ≤0.5, indifferent when FICI value was between 0.5 and 4, and antagonistic when FICI was >4.

\n\nPneumococcal systemic lethal infection. [1]
\nTo induce a systemic S. pneumoniae infection, male ICR mice (weight, 18 to 20 g) were inoculated intraperitoneally with 1 of 4 PRSP isolates (DR9, DR10, DR11, or DR14) suspended in 10% mucin. The suspension contained sufficient bacteria to kill 100% of untreated control mice. At 1 h postinfection, mice received a single dose of either Tedizolid phosphate or linezolid, and survival was assessed daily for 7 days postinfection. Treatments were delivered both orally and intravenously at each of four doses (40 mg/kg of body weight, 13.33 mg/kg, 4.44 mg/kg, and 1.48 mg/kg), with 8 mice per group defined by dose, delivery method, and infecting strain. The 50% effective dose (ED50), i.e., the dose allowing survival of 50% of the infected mice, was calculated for each delivery route using probit analysis.\n

\nPneumococcal lower respiratory infection. [1]
\nA PSSP type III clinical isolate found to be highly virulent in mice when introduced into the lungs was used to compare the in vivo efficacy of oral Tedizolid and oral linezolid in a subacute murine pneumonia model. Specific-pathogen-free 5-week-old female C57BL/6 mice (18 to 20 g) were adapted to standardized environmental conditions for 3 days before inoculation. PSSP type III was grown to logarithmic phase in brain heart infusion broth with 10% horse serum, collected by centrifugation, washed twice, and resuspended in phosphate-buffered saline. Mice anesthetized with ketamine and xylazine were inoculated by intranasal instillation of a 25-μl suspension containing 2.5 × 107 CFU of PSSP. Animals were held in a vertical position for 5 min to facilitate distal migration of the bacteria to the alveoli by gravity. The size of the inoculum was confirmed by serial dilution and quantitative subculture. Treatments were initiated at 4 h postinfection (time zero) by oral gavage in groups of 20 mice each using the appropriate dose of Tedizolid phosphate or linezolid in 0.2 ml distilled water.\n

\nTo study effects on survival, infected mice (n = 10 per dose group) received either Tedizolid phosphate at doses of 2.5, 5, 10, and 20 mg/kg once daily (QD) for 48 h or linezolid at doses of 2.5, 5, 10, and 20 mg/kg twice daily (BID) for 48 h. Untreated infected mice served as controls. Survival was recorded daily for 15 days, and cumulative survival rates were calculated. The mean survival day was defined as [f(d − 1)]/N, where f is the number of mice recorded to have expired on day d (survivors at day 15 were included in f for that day), and N is the number of mice in a group. The ED50 was determined as the dose of antibiotic (mg/kg/day) required for survival of 50% of infected mice at day 15, calculated as described above.\n

\nTo study the clearance of PSSP bacteria from the lungs, infected mice received either Tedizolid phosphate at 10 mg/kg QD or linezolid at 5 mg/kg BID, as described above. At 24 and 48 h after initiating treatments (28 and 52 h postinfection), five mice per treatment group were sacrificed by CO2 asphyxiation and exsanguinated by cardiac puncture, and lungs were removed from each mouse and homogenized in 10 ml of saline at 4°C. Untreated infected mice were sacrificed at time zero, 24 h, and 48 h to serve as controls (n = 5 at each time point). Total CFU counts in whole-lung homogenates were determined by plating 10-fold serial dilutions onto agar containing 5% horse serum and incubating the plates for 18 h at 37°C. The results are expressed as the mean log10 number of CFU (± standard deviation) per lung for each treatment group.\n

\nTwo mice per treatment group (Tedizolid phosphate at 10 mg/kg QD, linezolid at 5 mg/kg BID, infected untreated controls, and uninfected controls) were sacrificed at 48 h for histology. Lungs were perfused with saline, fixed in formalin, embedded in paraffin, and sectioned. Sections were stained with hematoxylin-eosin and scored for inflammation and edema, using a scale of from 0 to 3 for each (0, absent; 1, mild; 2, moderate; and 3, severe). One pathologist, blinded to the treatment group, scored all slides.

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40 mg/kg of body weight, 13.33 mg/kg, 4.44 mg/kg, and 1.48 mg/kg; i.p.

Male ICR mice (weight, 18 to 20 g) are inoculated intraperitoneally with 1 of 4 PRSP isolates (DR9, DR10, DR11, or DR14) suspended in 10% mucin, to induce a systemic S. pneumoniae infection.

Absorption, Distribution and Excretion
Following oral administration of tetizolam, peak plasma concentrations are reached within three hours; following intravenous administration, peak plasma concentrations are reached within one hour; oral bioavailability is approximately 91%. Food has no effect on absorption. Steady-state plasma concentrations are reached approximately three days after once-daily oral or intravenous administration of tetizolam. The peak plasma concentration (Cmax) after a single oral dose is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL, and after intravenous administration, it is 2.3 ± 0.6/3.0 ± 0.7 mcg/mL. Similarly, the median Tmax (range) for oral administration is 2.5 (1.0–8.0)/3.5 (1.0–6.0) hours, and the median Tmax (range) for intravenous administration is 1.1 (0.9–1.5)/1.2 (0.9–1.5) hours. The AUC for oral administration was 23.8 ± 6.8/25.6 ± 8.4 mcghr/mL, and the AUC for intravenous administration was 26.6 ± 5.2/29.2 ± 6.2 mcghr/mL. Following a single oral dose, approximately 82% of tepidozide is excreted in feces and 18% in urine. The majority exists as an inactive sulfate conjugate, with only 3% excreted unchanged. Over 85% of the drug is eliminated within 96 hours. The volume of distribution after a single intravenous injection of 200 mg tepidozide is 67 to 80 L. In a study of oral administration of 200 mg tepidozide to steady state, the volume of distribution was 108 ± 21 L, while the apparent volume of distribution for a single oral dose of 600 mg was 113.3 ± 19.3 L. Teldizolide has been observed to penetrate the interstitial space of adipose tissue and skeletal muscle tissue, and has also been found in alveolar epithelial lining fluid and alveolar macrophages. The apparent clearance of teldizolide after a single oral dose is 6.9 ± 1.7 L/hr, and the steady-state clearance is 8.4 ± 2.1 L/hr. Following a single dose, systemic clearance is 6.4 ± 1.2 L/hr, and the steady-state clearance is 5.9 ± 1.4 L/hr. Metabolites/Metabolites: Teldizolide is administered as a phosphate prodrug and is converted in vivo to teldizolide (the active ingredient in circulation). Prior to excretion, most teldizolide is converted to an inactive sulfate conjugate in the liver, but this process is unlikely to involve the action of cytochrome P450 family enzymes. Biological Half-Life: The half-life of teldizolide is approximately 12 hours.

Hepatotoxicity
Teldizolide treatment has been associated with mild, transient increases in serum transaminase and alkaline phosphatase levels in 1% to 4% of patients, although similar elevations have been observed in patients treated with similar drugs, including linezolid, for infections. In all cases, these elevations were asymptomatic or without jaundice and returned to normal upon discontinuation of the drug. While teldizolide has not been associated with clinically evident liver disease with jaundice, linezolid (a similar oxazolidinone antibiotic) has been associated with cases of lactic acidosis and systemic injury. This syndrome typically develops 1 to 8 weeks after treatment and is sometimes accompanied by evidence of liver damage and jaundice. Lactic acidosis is usually due to mitochondrial dysfunction or loss, leading to microvesicular steatosis and liver dysfunction (not necessarily accompanied by jaundice, and even elevated ALT or alkaline phosphatase). Other serious side effects associated with mitochondrial damage include peripheral neuropathy and optic neuropathy, pancreatitis, serotonin syndrome, and kidney damage. Mitochondrial damage is thought to be caused by inhibition of mitochondrial ribosome function, consistent with the known effects of oxazolidinones on bacterial ribosome function. Lactic acidosis typically appears 1 to 8 weeks after treatment, can be severe, but resolves rapidly upon discontinuation of the drug. In contrast, optic neuropathy and peripheral neuropathy caused by these antibiotics resolve more slowly and may be permanent. Lactic acidosis can be fatal; in severe cases caused by linezolid, liver dysfunction and jaundice have been reported. The association of this syndrome with teidazole treatment has not been definitively established.
Probability score: E (Unproven but suspected cause of liver damage).
Pregnancy and lactation effects
◉ Overview of medication use during lactation
There is currently no information regarding the use of teidazole during lactation. Teidazole binds to 70% to 90% in maternal plasma, therefore, a significant amount of the drug is not expected to enter breast milk. If the mother needs to take tepidozide, this is not a reason to stop breastfeeding. However, since there is currently no published experience regarding the use of tepidozide during breastfeeding, it may be preferable to choose other medications, especially when breastfeeding newborns or premature infants.
◉ 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
Approximately 70% to 90% of tepidozide is bound to human plasma proteins.

[1]. Activity of Tedizolid Phosphate (TR-701) in Murine Models of Infection with Penicillin-resistant and Penicillin-sensitive Streptococcus pneumoniae.Antimicrob Agents Chemother.2012 Sep;56(9):4713-7.

[2]. In vitro activity of tedizolid against the Mycobacterium abscessus complex. Diagn Microbiol Infect Dis. 2018 Mar;90(3):186-189.

Pharmacodynamics
Teldizolamide is an oxazolidinone antibiotic whose mechanism of action is through the inhibition of bacterial ribosome protein synthesis. However, oxazolidinone antibiotics can also bind to human mitochondrial ribosomes, but not cytoplasmic ribosomes. Inhibition of mitochondrial protein synthesis is associated with adverse reactions such as neurological, hematologic, and gastrointestinal toxicities, although teldizolamide is better tolerated than its related drug linezolid. Alternative treatment options should be considered when treating patients with neutropenia and acute bacterial skin and skin structure infections (ABSSSI). Clostridium difficile-associated diarrhea has been reported in patients treated with teldizolamide. Teldizolamide phosphate is a phosphate monoester formed by the condensation of an equimolar amount of phosphate with the hydroxyl group of teldizolamide. It is a prodrug of teldizolide and is used to treat acute bacterial skin infections caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-sensitive strains), various Streptococcus spp., and Enterococcus faecalis. It has a dual function as an antibacterial agent, protein synthesis inhibitor, and prodrug. It is a carbamate, organofluorine compound, oxazolidinone, pyridine compound, tetrazolium compound, and monophosphate ester. Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae, pose a significant threat to public health. Teldizolamide belongs to the oxazolidinone class of antibiotics, which also includes the previously approved linezolid, and is generally effective against multidrug-resistant Gram-positive bacteria. Teldizolamide is indicated for the treatment of acute bacterial skin and soft tissue infections (ABSSSI), and its efficacy and tolerability are generally superior to linezolid. On June 20, 2014, the U.S. Food and Drug Administration (FDA) approved teldizolamide for marketing, manufactured by Cubist Pharmaceuticals, under the brand name teldizolamide phosphate (SIVEXTRO®). This product is currently available in oral tablets and intravenous powder formulations.
Teldizolide phosphate is the phosphate form of teldizolide, an oxazolidinone antibacterial drug used to treat acute bacterial skin and soft tissue infections caused by certain Gram-positive bacteria. After intravenous injection, teldizolide targets and binds to the 50S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis.
Teldizolide phosphate is a small molecule drug, with its clinical trial phase up to Phase IV (covering all indications). It was first approved in 2014 for the treatment of skin diseases caused by bacterial infections, and has seven investigational indications.

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Mechanism of Action
Despite increased efforts to combat the spread of antibiotic resistance, multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, remain a threat. Oxazolidinones are a relatively new class of antibacterial drugs that work by inhibiting protein synthesis, often overcoming bacterial resistance to other protein synthesis inhibitors. Protein synthesis involves the role of ribosomes, which are multi-subunit complexes composed of proteins and substituents of ribosomal RNA (rRNA). The translocation of messenger RNA and the accompanying protein synthesis require the action of the A, P, and E sites of the peptidyl transferase center (PTC), which accept charged aminoacyl-tRNAs and catalyze the formation of peptide bonds between them. The bacterial 70S ribosome consists of a small (30S) subunit and a large (50S) subunit. Early studies on the mechanism of action of oxazolidinone antibiotics indicated that they inhibited the initiation step of protein synthesis. However, this mechanism did not align with identified resistance mutations. Subsequent crosslinking and direct structural determination of the binding site revealed that oxazolidinone drugs, including linezolid and tedeszolid, bind to the A site of the peptidyl transferase center (PTC) through interaction with the 23S rRNA component. Structural studies also revealed that the binding of oxazolidinone drugs alters the conformation of a conserved nucleotide in 23S rRNA (U2585 in E. coli), preventing PTC from forming peptide bonds. Therefore, tedecozide exerts its effect by inhibiting bacterial protein synthesis.

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Drug Indications
Tedecozide is indicated for the treatment of acute bacterial infections of the skin and soft tissues (ABSSSI). To prevent resistance, tedecozide should only be used for infections caused by susceptible bacteria.
Sivextro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults and adolescents aged 12 years and older.

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In summary, this study demonstrates that tedecozide is 4 times more potent than linezolid in vitro against drug-resistant Streptococcus pneumoniae (PRSP) isolates, and that oral or intravenous tedecozide phosphate is effective in treating systemic infections caused by PRSP isolates in mice. Oral tedecozide phosphate is also effective in treating pneumonia caused by PSSP strains. These results suggest that further research is needed on the pharmacodynamics of tedeszolid phosphate in the respiratory tract, as well as clinical evaluation of tedeszolid phosphate in the treatment of pneumococcal infections. [1]

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This study showed that tedeszolids (TZDs) were more effective than linezolids (LZDs) in vitro against Mycobacterium abscesses. The accumulation of intracellular thiazolidinediones (TZDs) and their synergistic effect with clarithromycin on certain isolates warrants further investigation. However, plasma drug concentrations at the recommended dose of 200 mg were insufficient (Cmax ≈ 2 μg/mL) (Flanagan et al., 2014), which casts doubt on the efficacy of TZDs in treating Mycobacterium abscesses, although higher doses may overcome this problem. Further research is needed to explore the efficacy and toxicity of higher doses of TZDs. [2]

C17H16FN6O6P

450.32

450.085

C, 45.34; H, 3.58; F, 4.22; N, 18.66; O, 21.32; P, 6.88

856867-55-5

Tedizolid;856866-72-3;(S)-Tedizolid;1431699-67-0; Tedizolid phosphate;856867-55-5; Tedizolid-13C,d3; 856867-39-5 (disodium); 856867-39-5 (disodium)

11476460

White to off-white solid powder

1.8±0.1 g/cm3

725.6±70.0 °C at 760 mmHg

392.6±35.7 °C

0.0±2.5 mmHg at 25°C

1.739

0.69

2

11

6

31

702

1

O=C1O[C@@H](COP(O)(O)=O)CN1C1C=CC(C2C=NC(C3=NN(C)N=N3)=CC=2)=C(F)C=1

QCGUSIANLFXSGE-GFCCVEGCSA-N

InChI=1S/C17H16FN6O6P/c1-23-21-16(20-22-23)15-5-2-10(7-19-15)13-4-3-11(6-14(13)18)24-8-12(30-17(24)25)9-29-31(26,27)28/h2-7,12H,8-9H2,1H3,(H2,26,27,28)/t12-/m1/s1

(R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl dihydrogen phosphate

DA7157; TR700; DA-7157; Tedizolid phosphate; 856867-55-5; Torezolid phosphate; Sivextro; TR-701FA; TR-701 FA; (R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl dihydrogen phosphate; Tedizolid (phosphate); TR-700; TR701-FA; Tedizolid; TR-701-FA; TR 701-FA; Torezolid phosphate. Trade name: Sivextro

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 : 22~36 mg/mL (48.85~79.94 mM)
H2O : ~0.1 mg/mL (~0.22 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.62 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 (4.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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 3: ≥ 2.08 mg/mL (4.62 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.)