Quinolone； DNA gyrase

Delafloxacin/ABT-492 is a novel quinolone with potent activity against gram-positive, gram-negative, and atypical pathogens, making this compound an ideal candidate for the treatment of community-acquired pneumonia. Researchers therefore compared the in vitro pharmacodynamic activity of ABT-492 to that of levofloxacin, an antibiotic commonly used for the treatment of pneumonia, through MIC determination and time-kill kinetic analysis. ABT-492 demonstrated potent activity against penicillin-sensitive, penicillin-resistant, and levofloxacin-resistant Streptococcus pneumoniae strains (MICs ranging from 0.0078 to 0.125 micro g/ml); beta-lactamase-positive and beta-lactamase-negative Haemophilus influenzae strains (MICs ranging from 0.000313 to 0.00125 micro g/ml); and beta-lactamase-positive and beta-lactamase-negative Moraxella catarrhalis strains (MICs ranging from 0.001 to 0.0025 micro g/ml), with MICs being much lower than those of levofloxacin. Both ABT-492 and levofloxacin demonstrated concentration-dependent bactericidal activities in time-kill kinetics studies at four and eight times the MIC with 10 of 12 bacterial isolates exposed to ABT-492 and with 12 of 12 bacterial isolates exposed to levofloxacin. Sigmoidal maximal-effect models support concentration-dependent bactericidal activity. The model predicts that 50% of maximal activity can be achieved with concentrations ranging from one to two times the MIC for both ABT-492 and levofloxacin and that near-maximal activity (90% effective concentration) can be achieved at concentrations ranging from two to five times the MIC for ABT-492 and one to six times the MIC for levofloxacin. [2]

Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0-∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens. [1]

MIC determination. [2]
The MIC for each isolate was determined by broth microdilution techniques as outlined by the National Committee for Clinical Laboratory Standards, and testing was performed in duplicate. Control strains (S. pneumoniae ATCC 49619 and H. influenzae ATCC 49247) were used to validate the MIC results. The inoculum was prepared by suspending S. pneumoniae organisms grown on blood agar plates or H. influenzae and M. catarrhalis organisms grown on chocolate agar plates, which had been incubated for a full 24 h, in 2 ml of sterile saline. Suspensions were adjusted to a 0.5 McFarland turbidity standard by using a spectrophotometer and diluted in broth to obtain a final inoculum of approximately 5 × 105 CFU/ml for each well. Inoculum checks were performed via colony counts. The microtiter plates were incubated overnight at 35°C in humidified air, and the results were read at 24 h. The lowest concentration of antibiotic in the wells showing no visible growth was defined as the MIC.

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Dose-effect response. [2]
To compare the concentration-effect relationships at 2, 4, 6, 12, and 24 h of Delafloxacin (ABT-492; WQ-3034; RX-3341) and levofloxacin against S. pneumoniae, H. influenzae, and M. catarrhalis, the mean time-kill data at each time point for each bacterial isolate were combined according to bacterial species. The net change (log10 numbers of CFU per milliliter) in bacterial density at each time point for each concentration was fitted by multivariate nonlinear-regression analysis with a four-parameter sigmoidal Hill (Emax) model by using SigmaPlot 2000 for Windows. In this model, effect (the net change in the log10 number of CFU per milliliter) is equal to E0 − (Emax × Cn)/(EC50n + Cn), where E0 is the baseline effect (bacterial growth for the control), Emax is the maximal bacterial-kill effect, C is the concentration of interest (a multiple of the MIC), EC50 is the antibacterial concentration that produced 50% of the maximal effect, and n is the sigmoidicity factor that gives flexibility to the shape of the curve. E0, EC50, Emax, and n were given in the regression output. The concentration that produced the EC90 between E0 and Emax was calculated.

Animal Model: Mice with a neutropenic murine lung infection model (four S. aureus , four S. pneumoniae, and four K. pneumoniae strains)[1]
Dosage: The total daily doses vary from 0.156 to 640 mg/kg/24 h
Administration: 0.03 to 160 mg/kg are administered every 6 h (q6h) to infected mice by subcutaneous injection
Result: Inhibited S. aureus strains ATCC 29213, ATCC 33591, MW2, R2527 with MICs of 0.008, 0.008, 0.004, and 0.004 mg/L, respectively. Inhibited S. pneumoniae strains ATCC 10813, ATCC 49619, 145, and 1329 with MICs of 0.03, 0.125, 0.016, and 0.016 mg/L, respectively. Inhibited K. pneumonia strains ATCC 43816, 4105, 4110, and 81-1260A with MICs of 0.06, 1, 0.5, and 0.06 mg/L, respectively.

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Drug pharmacokinetics. [1]
Single-dose plasma pharmacokinetics of Delafloxacin (ABT-492; WQ-3034; RX-3341) were performed in neutropenic mice. Animals were administered single subcutaneous doses (0.2 ml/dose) of Delafloxacin (ABT-492; WQ-3034; RX-3341) at dose levels of 2.5, 10, 40, and 160 mg/kg. Groups of three mice were sampled at each time point (seven time points, consisting of 1, 2, 4, 6, 8, 12, and 24 h) and dose level. [1]
Plasma concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) by the sponsor. Briefly, a stock calibration standard of Delafloxacin (ABT-492; WQ-3034; RX-3341) meglumine salt (RX-3341-83-008) was prepared in dimethyl sulfoxide (DMSO) at a concentration of 1,000 μg/ml (corrected for salt form) to prepare working calibration standards and quality controls (QCs). Working calibration standards were prepared by serial dilution of working stock solution with methanol-water (50:50, vol/vol) over a range of 100 ng/ml to 500,000 ng/ml. Working QCs were prepared in methanol-water (50:50, vol/vol) at three concentration levels: high (300,000 ng/ml), middle (15,000 ng/ml), and low (300 ng/ml). Twenty microliters of each working QC was added to 180 μl of blank mouse plasma, vortex mixed, and run in duplicate. Standards in matrix were prepared with 5 μl of working calibration standard added to 45 μl of control blank mouse plasma in a 96-well collection plate. Fifty microliters of unknown mouse plasma or QC was added to the plate. For blanks and blanks with an internal standard, 50 μl of control blank mouse plasma was added. Twenty microliters of working internal standard (WIS) (1,000 ng/ml RX-4039, a closely related analog, in methanol-water [50:50, vol/vol]) was added to standards, unknowns, and control blanks. Twenty microliters of methanol-water was added to blanks without WIS. Samples were extracted by adding 300 μl of acetonitrile (ACN) to all samples in a 96-well collection plate and vortex mixed for 4 min. Samples were centrifuged for 10 min at 3,200 × g at 4°C. Fifty microliters of supernatant was transferred to 450 μl of ACN-water (50:50, vol/vol) in a 96-well autosampler plate and mixed with a multichannel pipette. Samples were analyzed for Delafloxacin (ABT-492; WQ-3034; RX-3341) using LC-MS/MS. The assay lower limit of quantification was 10 ng/ml. The assay coefficient of variation was less than 10%.

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Murine lung infection model. [1]
Six-week-old, specific-pathogen-free, female ICR/Swiss mice weighing 24 to 27 g were used for all studies. Mice were rendered neutropenic (neutrophils of <100/mm3) by injecting cyclophosphamide intraperitoneally 4 days (150 mg/kg) and 1 day (100 mg/kg) before lung infection. Broth cultures of freshly plated S. aureus and K. pneumoniae were grown to logarithmic phase overnight to an absorbance of 0.3 at 580 nm using a Spectronic 88 spectrophotometer. S. pneumoniae isolates were grown overnight on sheep blood agar. A sterile loop was then used to transfer organisms to sterile saline, and absorbance was adjusted as described above. After a 1:10 dilution, bacterial counts of the inoculum ranged from 108.1 to 108.2 CFU/ml, 108.1 to 108.4 CFU/ml, and 108.0 to 108.3 CFU/ml for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. Lung infections with each of the strains were produced by administration of 50 μl of inoculum into the nares of isoflurane-anesthetized mice. Mice were then held upright to allow for aspiration into the lungs. Therapy with Delafloxacin (ABT-492; WQ-3034; RX-3341) was initiated 2 h after induction of infection.

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Pharmacodynamic target associated with treatment efficacy. [1]
In vivo treatment studies were performed in the murine lung model for each isolate. Seven (S. aureus and S. pneumoniae) and five (K. pneumoniae) 4-fold-increasing dosing regimens of Delafloxacin (ABT-492; WQ-3034; RX-3341) were administered to groups of three neutropenic infected mice per dose level. The total daily doses of Delafloxacin (ABT-492; WQ-3034; RX-3341) varied from 0.156 to 640 mg/kg/24 h. Zero-hour and untreated control animals were included for each strain. Drug was fractionated for an administration schedule of every 6 h and given by the subcutaneous route. Therapy was initiated 2 h after infection. Animals were euthanized at 24 h after infection, and the lungs were aseptically removed for CFU count determination.

Absorption, Distribution and Excretion
The median time to peak plasma concentration for orally administered Delafloxacin is 0.75 (0.5-4.0) hours after a single dose and 1.00 (0.5-6.0) hours for steady state dosing. The median time to peak plasma concentration for intravenously administered Delafloxacin is 1.00 (1.0-1.2) hours for a single dose and 1.0 (1.0-1.0) hour for steady state dosing. The absolute bioavailability for orally administed Delafloxacin is 58.8%.
After a single intravenous dose, 65% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 28% excreted unchanged in the feces. After a single oral dose, 50% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 48% excreted unchanged in the feces.
The steady sate volume of distrubution of Delafloxacin is 30-48 liters.
The mean total clearance of Delafloxacin is 16.3 liters per hour. Renal clearance accounts for 35-45% of total clearance.

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Metabolism / Metabolites
Delafoxacin is primarily metabolized via glucuronidation mediated by UDP glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1-3, and UDP-glucuronosyltransferase 2B15. Less than 1% is metabolized via oxidation.

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Biological Half-Life
The mean half life of elimination of Delafloxacin is 3.7 hours after a single intravenous administration. The mean half life of elimination for multple oral administrations is 4.2-8.5 hours.

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Drug pharmacokinetics.[1]
Single-dose pharmacokinetics of delafloxacin are shown in Fig. 1. At the doses studied, exposure to delafloxacin increased in a dose-dependent manner across the dose range. Cmax concentrations ranged from 2 to 71 mg/liter. AUC0–∞ values ranged from 2.8 to 152 mg · h/liter and were linear across the 2.5- to 160-mg dosing range (R2 of 0.99). The elimination half-life ranged from 0.7 to 1 h.

Hepatotoxicity
Delafloxacin, like other fluoroquinolones, is associated with a low rate (3% to 4%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. ALT elevations above 5 times the upper limit of normal occur in 1% or less of subjects. Although delafloxacin may not have been clearly linked to cases of clinically apparent liver injury, the other fluoroquinolones, such as ciprofloxacin, levofloxacin and moxifloxacin, rank among the 25 most common causes of drug induced liver injury in many case series. Estimates of the frequency of liver injury from fluoroquinolones have been 1:15,000 to 1:25,000 exposed persons. Delafloxacin has been in clinical use for a short time only, but is likely to have a similar frequency and pattern of liver injury as the other fluoroquinolones.
The typical presentation of fluoroquinolone associated liver injury is with a short latency (1 day to 3 weeks) and abrupt onset with nausea, fatigue, abdominal pain and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic, cases with the shorter times to onset usually being more hepatocellular. In addition, the onset of illness may occur a few days after the medication is stopped. Many (but not all) cases have prominent allergic manifestations with fever and rash, and the liver injury may occur in the context of a generalized hypersensitivity reaction. Autoantibodies are usually not present. Most reported cases of liver injury from fluoroquinolones have been mild and self-limited, with recovery in 4 to 8 weeks from onset. However, the fatality rate of cases with jaundice has been greater than 10%. In addition, cases with a cholestatic pattern of serum enzymes may run a prolonged course and, in rare instances, have progressed to chronic vanishing bile duct syndrome leading to liver failure. Nevertheless, delafloxacin is a relatively recently introduced antibiotic and has yet to be convincingly linked to instances of acute hepatitis or jaundice.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of delafloxacin during breastfeeding. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk. The calcium in milk might prevent absorption of fluoroquinolones in milk, but insufficient data exist to prove or disprove this assertion. Use of delafloxacin is acceptable in nursing mothers. However, it is preferable to use an alternate drug for which safety information is available.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Delafloxacin is 84% bound to human plasma proteins. It primarily binds to serum albumin.

[1]. In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model. Antimicrob Agents Chemother. 2016 Jul 22;60(8):4764-9.

[2]. In vitro pharmacodynamic activities of ABT-492, a novel quinolone, compared to those of levofloxacin against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother.2004 Jan;48(1):203-8.

Delafloxacin is a fluoroquinolone antibiotic which has been used in trials studying the treatment and basic science of Gonorrhea, Hepatic Impairment, Bacterial Skin Diseases, Skin Structure Infections, and Community Acquired Pneumonia, among others. It was approved in June 2017 under the trade name Baxdela for use in the treatment of acute bacterial skin and skin structure infections.
Delafloxacin is a Fluoroquinolone Antibacterial.
Delafloxacin is a fourth generation fluoroquinolone with expanded activity against gram-positive bacteria as well as atypical pathogens. Delafloxacin has been linked to mild ALT elevations during therapy, but has yet to be linked to instances of idiosyncratic acute liver injury with symptoms and jaundice as have been described with other fluoroquinolones.
See also: Delafloxacin Meglumine (active moiety of).

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Drug Indication
Delafloxacin is indicated for the treatment of acute bacterial skin and skin structure infections caused by the Gram-positive organisms Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis as well as the Gram-negative organisms Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
FDA Label
Quofenix is indicated for the treatment of the following infections in adults: acute bacterial skin and skin structure infections (ABSSSI),community-acquired pneumonia (CAP), when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the initial treatment of these infections (see sections 4. 4 and 5. 1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Treatment of community-acquired pneumonia
Treatment of local infections of skin and subcutaneous tissues
Treatment of local infections of skin and subcutaneous tissues

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Mechanism of Action
Delafloxacin inhibits the activity of bacterial DNA topoisomerase IV and DNA gyrase (topoisomerase II). This interferes with bacterial DNA replication by preventing the relaxation of positive supercoils introduced as part of the elongation process. The resultant strain inhibits further elongation. Delafloxacin exerts concentration-dependent bacteriocidal activity.

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Pharmacodynamics
Delafloxacin is a fluoroquinolone antibacterial drug which kills bacterial cells.

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In conclusion, delafloxacin exhibited potent in vitro and in vivo efficacy against three important respiratory pathogen groups, including S. aureus (MSSA and MRSA), S. pneumoniae, and K. pneumoniae. Efficacy against the former two pathogen groups was particularly robust compared to that of other fluoroquinolones. At maximal drug exposures, a >4-log10 kill was observed against these groups, and free-drug AUC/MIC targets were <10 whether one examined stasis or bactericidal endpoints. When combined with human PK results, these studies suggest that the current twice-daily dosing regimens in development should achieve drug exposures that exceed the stasis targets identified in this study for each of the pathogen groups and, perhaps most importantly, against MRSA. The data presented will be useful for delafloxacin dosing regimen optimization for the treatment of respiratory tract infections and for setting the preliminary breakpoints. [1]

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This study demonstrates that ABT-492 is a potent concentration-dependent antibiotic with in vitro activity similar to that of levofloxacin. The compound's very low MICs for gram-positive, gram-negative, and levofloxacin-resistant S. pneumoniae respiratory pathogens warrant further investigation. Sigmoidal Emax models were constructed to validate the time-kill pharmacodynamic analysis. The relationship between EC50 and EC90 became closer over time, supporting concentration-dependent pharmacodynamic activity. The models demonstrated that 50% maximal activity occurred between one and two times the MIC, and 90% maximal activity was observed at one to six times the MIC. Knowledge of the concentrations that are needed to achieve near-maximal activity of an antibiotic can help determine a goal for free antibiotic concentrations in serum in vivo.[2]

C18H12CLF3N4O4

440.76

440.049

C, 49.05; H, 2.74; Cl, 8.04; F, 12.93; N, 12.71; O, 14.52

189279-58-1

Delafloxacin meglumine;352458-37-8;Delafloxacin-d5

487101

White to off-white solid powder.

1.8±0.1 g/cm3

698.5±55.0 °C at 760 mmHg

376.2±31.5 °C

0.0±2.3 mmHg at 25°C

1.717

0.81

3

11

3

30

755

0

ClC1=C2C(C(C(C(=O)O[H])=C([H])N2C2=C(C([H])=C(C(N([H])[H])=N2)F)F)=O)=C([H])C(=C1N1C([H])([H])C([H])(C1([H])[H])O[H])F

DYDCPNMLZGFQTM-UHFFFAOYSA-N

InChI=1S/C18H12ClF3N4O4/c19-12-13-7(1-9(20)14(12)25-3-6(27)4-25)15(28)8(18(29)30)5-26(13)17-11(22)2-10(21)16(23)24-17/h1-2,5-6,27H,3-4H2,(H2,23,24)(H,29,30)

1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Trade name. Baxdela; ABT-492; RX 3341; WQ-3034; ABT 492; RX3341; WQ3034; ABT492; RX-3341; WQ 3034

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 : 88~100 mg/mL ( 199.65~226.88 mM )

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.)