Quinolone

Delafloxacin is very effective against S. aureus; total daily doses range from 0.156 to 640 mg/kg/24 h, subcutaneous injection. Even at the lowest dose tested, a reduction in the organism burden from untreated controls of 1.5 to 2.2 log10 CFU is seen against all four strains, and for two strains (MW2 and R2527), there is net bactericidal activity at the lowest dose. All S. aureus strains have a >4-log10 kill from initial burden at the maximum doses examined[1]. The moderate terminal elimination half-life of delafloxacin (2.5, 10, 40, and 160 mg/kg; subcutaneous injection, 24 h) is [1] (t1/2=0.68 h, 0.79 h, 0.69 h, and 1.0 h for 2.5 mg/kg, 10 mg/kg, 40 mg/kg, and 160 mg/kg, respectively).

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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/Disease Models: neutropenic mice [1]
Doses: 2.5, 10, 40, 160 mg/kg; 0.2 mL
Route of Administration: subcutaneous injection; 24-hour
Experimental Results: Maximum drug concentration (Cmax) concentration range is 2 to 71 mg/L. AUC0-∞ values ranged from 2.8 to 152 mg·h/L and were linear over the dose range of 2.5 to 160 mg. Elimination half-life (t1/2) ranges from 0.7 to 1 hour.\n

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\n\nDrug pharmacokinetics. [1]
\nSingle-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.\n[1]
\nPlasma 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%.\n

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\n\nMurine lung infection model. [1]
\nSix-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.\n

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\nPharmacodynamic target associated with treatment efficacy. [1]
\nIn 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.\n\n\n

Absorption, Distribution and Excretion
The median time to peak plasma concentration after a single oral dose of delafloxacin is 0.75 (0.5–4.0) hours, and 1.00 (0.5–6.0) hours after steady-state administration. The median time to peak plasma concentration after a single intravenous dose of delafloxacin is 1.00 (1.0–1.2) hours, and 1.0 (1.0–1.0) hours after steady-state administration. The absolute bioavailability of oral delafloxacin is 58.8%. Following a single intravenous injection, 65% of delafloxacin is excreted unchanged or as a glucuronide metabolite in the urine, and 28% is excreted unchanged in the feces. Following a single oral dose, 50% of delafloxacin is excreted unchanged or as a glucuronide metabolite in the urine, and 48% is excreted unchanged in the feces. The steady-state volume of distribution 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 the total clearance.

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Metabolism/Metabolites
Delafloxacin is primarily metabolized via glucuronidation mediated by UDP-glucuronyltransferase 1-1, UDP-glucuronyltransferase 1-3 and UDP-glucuronyltransferase 2B15. Less than 1% of the drug is metabolized by oxidation.

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Biological Half-Life
The mean elimination half-life of delafloxacin after a single intravenous injection is 3.7 hours. After multiple oral administrations, the mean elimination half-life is 4.2-8.5 hours.

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Pharmacokinetics. [1]
The single-dose pharmacokinetics of delafloxacin are shown in Figure 1. Within the dose range studied, exposure to delafloxacin increased in a dose-dependent manner. The Cmax concentration ranged from 2 to 71 mg/L. The AUC0–∞ values ranged from 2.8 to 152 mg·h/L, exhibiting a linear relationship (R² = 0.99) over a dose range of 2.5 to 160 mg. The elimination half-life ranged from 0.7 to 1 hour.

Hepatotoxicity
Like other fluoroquinolones, delafloxacin can cause elevated serum enzymes during treatment, but the incidence is low (3% to 4%). These abnormalities are usually mild, asymptomatic, and transient, resolving spontaneously with continued treatment. The proportion of patients with ALT elevations exceeding five times the upper limit of normal is 1% or less. While delafloxacin may not yet be clearly associated with clinically significant liver injury, other fluoroquinolones, such as ciprofloxacin, levofloxacin, and moxifloxacin, are among the 25 most common causes of drug-induced liver injury in numerous case series studies. The estimated incidence of fluoroquinolone-induced liver injury is 1 in 15,000 to 25,000 exposed individuals. Although delafloxacin has a relatively short history of clinical use, the incidence and pattern of liver injury it causes may be similar to those of other fluoroquinolones. The typical presentation of fluoroquinolone-related liver injury is a short incubation period (1 day to 3 weeks), with a sudden onset of symptoms including nausea, fatigue, abdominal pain, and jaundice. Elevated serum enzymes can be hepatocellular or cholestatic, with hepatocellular being more common in cases with a shorter onset. Symptoms may also appear within days of discontinuation of the drug. Many (but not all) cases involve significant allergic reactions, such as fever and rash, and liver injury may occur against a background of systemic hypersensitivity. Autoantibodies are usually absent. Most reported cases of fluoroquinolone-related liver injury are mild and self-limiting, typically recovering within 4 to 8 weeks of onset. However, the mortality rate in cases with jaundice exceeds 10%. Furthermore, cases with a cholestatic pattern of serum enzymes may have a prolonged course, and in rare cases, may even develop into chronic disappearance of bile duct syndrome, ultimately leading to liver failure. However, delafloxacin is a relatively new antibiotic, and there is currently no conclusive evidence linking it to cases of acute hepatitis or jaundice.
Probability Score: E (Unconfirmed, but suspected cause of clinically significant liver damage).

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Use during Pregnancy and Lactation
◉ Overview of Use during Lactation
There is currently no information regarding the use of delafloxacin during lactation. Due to concerns about adverse effects of fluoroquinolones on developing joints in infants, their use in infants is traditionally not recommended. However, recent studies suggest the risk is minimal. Calcium in breast milk may prevent the absorption of fluoroquinolones in breast milk, but there is currently insufficient data to confirm or refute this claim. Delafloxacin can be used by breastfeeding women. However, it is best to use alternative medications with available safety information.
◉ 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
Delafloxacin binds to 84% of 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 previously used for the treatment and basic scientific research of gonorrhea, liver dysfunction, bacterial skin diseases, soft tissue infections, and community-acquired pneumonia. It was approved for marketing in June 2017 under the brand name Baxdela for the treatment of acute bacterial skin and soft tissue infections. Delafloxacin is a fourth-generation fluoroquinolone antibiotic with broader antibacterial activity against Gram-positive bacteria and atypical pathogens. Delafloxacin has been associated with mild ALT elevation during treatment, but no specific cases of acute liver injury, accompanied by symptoms and jaundice, have been found associated with other fluoroquinolone drugs. See also: Delafloxacin meglumine (active ingredient).

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Drug Indications
Delafloxacin is indicated for the treatment of acute bacterial skin and skin-soft tissue infections caused by Gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant and methicillin-sensitive strains), hemolytic Staphylococcus, Staphylococcus ludens, Streptococcus agalactiae, Streptococcus pharyngiosum (including Streptococcus pharyngiosum, Streptococcus intermedia, and Streptococcus constellations), Streptococcus pyogenes, and Enterococci. It is also indicated for Gram-negative bacteria such as 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 other antimicrobial agents typically recommended for initial treatment of these infections are deemed inappropriate (see Sections 4.4 and 5.1). Official guidelines on the rational use of antimicrobial agents should be consulted.

Treatment of community-acquired pneumonia
Treatment of local skin and subcutaneous tissue infections
Treatment of local skin and subcutaneous tissue infections

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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, preventing the relaxation of positive supercoils introduced during elongation. The resulting strain inhibits further elongation. Delafloxacin has concentration-dependent bactericidal activity.

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

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In summary, delafloxacin exhibits potent antibacterial activity against three important respiratory pathogens, both in vitro and in vivo, including Staphylococcus aureus (MSSA and MRSA), Streptococcus pneumoniae, and Klebsiella pneumoniae. Compared with other fluoroquinolones, delafloxacin shows particularly significant antibacterial activity against the first two pathogens. At maximum drug exposure, the bactericidal rate against these pathogens exceeded 4 log10, and the AUC/MIC target value of the free drug was less than 10 regardless of whether the antibacterial endpoint or the bactericidal endpoint was examined. Combined with human pharmacokinetic results, these studies indicate that the twice-daily dosing regimen currently under development should enable drug exposure exceeding the antibacterial target value determined in this study for each pathogen (especially MRSA). The data provided in this paper will help optimize the dosing regimen of delafloxacin for the treatment of respiratory tract infections and set preliminary dose breakpoints. [1] This study shows that ABT-492 is a potent concentration-dependent antibiotic with in vitro activity similar to levofloxacin. The compound exhibits extremely low minimum inhibitory concentrations (MICs) against Gram-positive bacteria, Gram-negative bacteria, and levofloxacin-resistant Streptococcus pneumoniae respiratory pathogens, which warrants further investigation. An S-type Emax model was constructed to validate time-bactericidal pharmacodynamic analysis. The relationship between EC50 and EC90 becomes closer over time, supporting concentration-dependent pharmacodynamic activity. Models show that 50% of the maximum activity occurs between 1 and 2 times the MIC, and 90% of the maximum activity occurs between 1 and 6 times the MIC. Understanding the antibiotic concentration required to achieve near-maximal activity helps determine the target concentration of free antibiotic in serum in vivo. [2]

C25H29CLF3N5O9

635.986

635.16

C, 47.21; H, 4.60; Cl, 5.57; F, 8.96; N, 11.01; O, 22.64

352458-37-8

Delafloxacin;189279-58-1

11578213

Off-white to yellow solid powder

9

17

9

43

889

4

O=C(C1=CN(C2=NC(N)=C(F)C=C2F)C3=C(C=C(F)C(N4CC(O)C4)=C3Cl)C1=O)O.O[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)CNC

AHJGUEMIZPMAMR-WZTVWXICSA-N

InChI=1S/C18H12ClF3N4O4.C7H17NO5/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;1-8-2-4(10)6(12)7(13)5(11)3-9/h1-2,5-6,27H,3-4H2,(H2,23,24)(H,29,30);4-13H,2-3H2,1H3/t;4-,5+,6+,7+/m.0/s1

(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

Trade name. Baxdela; ABT-492; Delafloxacin meglumine; 352458-37-8; Delafloxacin (meglumine); RX-3341 meglumine; meglumine; ABT 492 meglumine; ABT492; RX-3341; WQ-3034; RX3341; WQ3034; RX 3341; WQ 3034 meglumine

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, avoid exposure to moisture.

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

DMSO : 6.4~100 mg/mL ( 10.06~157.24 mM )
Water : 50~100 mg/mL(78.62 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.)