Macrolide;Toxoplasma

Treatment with spiramycin (24 hours; 1-1000 μM; T. gondii-infected HeLa cells and HeLa cells) decreases the cytotoxicity and exhibits anti-Toxoplasma gondii activity, with IC50 values of 189 μM for HeLa cells and 262 μM for T. gondii-infected HeLa cells[3].

Treatment with spiramycin (100 mg/kg; intraperitoneal injection; daily; for 4 days; female KM mice) decreases tachyzoites, hepatotoxicity, and greatly increases antioxidative effects. Treatment with piramycin also lessens the liver's granulomatous inflammation[3].

Cell Line: T. gondii infected HeLa cells and HeLa cells
Concentration: 1-1000 μM
Incubation Time: 24 hours
Result: Reduced the cytotoxicity.

Animal Model: 36 female KM mice with T.gondii[3]
Dosage: 100 mg/kg
Administration: Intraperitoneal injection; every day; for 4 days
Result: Tachyzoites were considerably fewer in number. decreased hepatotoxicity and markedly increased antioxidative benefits. Formation of cysts and granulomas was inhibited.

Absorption, Distribution and Excretion
The extent of absorption of Spiramycin was shown to be incomplete. Oral bioavailability ranges from 30-39%. Spiramycin has slower rate of absorption than Erythromycin. It has a high pKa (7.9) which could be a result of high degree of ionization in acidic medium of the stomach.
Fecal-biliary route is the primary route of elimination. The secondary route is renal-urinary route.
The tissue distribution of spiramycin is extensive. The volume of distribution is in excess of 300 L, and concentrations achieved in bone, muscle, respiratory tract and saliva exceed those found in serum. Spiramycin showed high concentrations in tissues such as: lungs, bronchi, tonsils, and sinuses.
80% of the administered dose excreted in the bile, which makes the fecal-biliary route is the most important route of elimination. Enterohepatic recycling could also occur. Only 4 to 14% of an administered dose is eliminated through renal-urinary excretion route.
Spiramycin is well absorbed in humans after oral administration. Oral administration of 15-30 mg/kg bw to healthy young male adults resulted in peak plasma levels in 3-4 hours and plasma concentrations of 0.96-1.65 mg/l. After intravenous dosing (7.25 mg/kg b.w.) a large volume of distribution (Vdss 5.6 l/kg) was observed indicating extensive tissue distribution. Biotransformation did not appear to be important. Biliary excretion was the main route of excretion; only 7-20% of an oral dose was excreted in the urine. Spiramycin is known to achieve high tissue:serum concentrations in pulmonary and prostatic tissues, and in skin.
Spiramycin crosses the placenta to the fetus. Concns of the antibiotic in maternal serum, cord blood, & the placenta after a dosage regimen of 2 g/day were 1.19 ug/ml, 0.63 ug/ml, & 2.75 ug/ml, respectively. When the maternal dose was increased to 3 g/day, the levels were 1.69 ug/ml, 0.78 ug/ml, & 6.2 ug/ml, respectively. Based on these results, the cord:maternal serum ratio is approx 0.5. Moreover, at these doses, spiramycin is concentrated in the placenta with levels approx 2-4 times those in the maternal serum. ... Spiramycin is excreted into breast milk. Nursing infants of mothers receiving 1.5 g/day for 3 days had spiramycin serum concns of 20 ug/ml. This concn was bacteriostatic.
/MILK/ Spiramycin is a macrolide antibiotic that is active against most of the microorganisms isolated from the milk of mastitic cows. This work investigated the disposition of spiramycin in plasma & milk after iv, intramuscular & subcutaneous admin. Twelve healthy cows were given a single injection of spiramycin at a dose of 30,000 IU/kg by each route. Plasma & milk were collected post injection. Spiramycin concn in the plasma was determined by a high performance liquid chromatography method, & in the milk by a microbiological method. The mean residence time after iv admin was significantly longer (P<0.01) in the milk (20.7 +/- 2.7 h) than in plasma (4.0 +/- 1.6 h). An average milk-to-plasma ratio of 36.5 +/- 15 was calculated from the area concn-time curves. Several pharmacokinetic parameters were examined to determine the bioequivalence of the two extravascular routes. The dose fraction adsorbed after intramuscular or subcutaneous admin was almost 100% & was bioequivalent for the extravascular routes, but the rates of absorption, the max concns & the time to obtain them differed significantly between the two routes. Spiramycin quantities excreted in milk did not differ between the two extravascular routes but the latter were not bioequivalent for max concn in the milk. However, the two routes were bio-equivalent for the duration of time the milk concn exceeded the minimal inhibitory concn (MIC) of various pathogens causing infections in the mammary gland.
Plasma protein binding ranges from 10 to 25%. An oral dose of 6 million units produces peak blood concentrations of 3.3 ug/mL after 1.5 to 3 hours; the half life is about 5 to 8 hours. High tissue concentrations are achieved and persist long after the plasma concentration has fallen to low levels.
For more Absorption, Distribution and Excretion (Complete) data for SPIRAMYCIN (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Spiramycin is less metabolised than some of the other macrolides. Metabolism has not been well studied. It is mainly done in the liver to the active metabolites.
In cattle, the metabolite neospiramycin, the demycarosyl derivative, is formed. Concentrations of neospiramycin in muscle and kidney were marginally higher than those of spiramycin 14-28 days after dosing; in muscle, levels of neospiramycin and spiramycin were approximately equal.
Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.

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Biological Half-Life
Intravenous: Young persons (18 to 32 years of age): Approximately 4.5 to 6.2 hours. Elderly persons (73 to 85 years of age): Approximately 9.8 to 13.5 hours. Oral: 5.5-8 hours, Rectal in children: 8 hours
An oral dose of 6 million units produces ... /a/ half life is about 5 to 8 hours.

Toxicity Summary
IDENTIFICATION AND USE: Spiramycin is a macrolide antibiotic used for the treatment and control of a number of bacterial and mycoplasmal infections in animals. It is available as a spiramycin embonate for use in animal feed, and as the adipate, a more soluble form, for administration by other routes. It has also been used in the protozoal infections cryptosporidiosis and toxoplasmosis. HUMAN EXPOSURE AND TOXICITY: Spiramycin is reported to cause contact dermatitis in occupational settings. A man who worked in a feed factory developed allergic contact dermatitis due to airborne spiramycin. The patient suffered recurrent outbreaks of eczematous lesions on uncovered areas during working periods. Spiramycin is also reported to cause hypersensitivity reactions. Rhinoconjunctivitis and spasmodic cough are reported in a 34 year-old female handling spiramycin powder in a pharmaceutical factory. The symptoms appeared within the first few hours of coming into contact with the drug and continued for several hours after leaving her place of work. One year after starting work in the pharmaceutical industry a 35-year-old non-atopic maintenance engineer developed attacks of sneezing, coughing and breathlessness. Inhalation challenge tests carried out in the hospital with gradually increasing quantities of spiramycin reproduced his symptoms and led to the development of late asthmatic reactions. Additionally, two cases of bronchial asthma due to spiramycin in workers of a pharmaceutical factory were reported. The subjects complained of cough, breathlessness and symptoms of asthma at work when coming into contact with spiramycin's powder. The symptoms cleared when away from work for more than 3 or 4 days. ANIMAL STUDIES: Groups of 2 male and 2 female monkeys (Macaca fascicularis) were given daily intravenous injections of 0, 240,000, 360,000, and 540,000 iu/kg bw/day spiramycin adipate for 5 days. Hypersalivation occurred during injection in all dose groups. Muscle hypotonia and nauseous spasticity occurred in several high dose monkeys and in one given the low dose. No abnormalities of body weights occurred but food consumption was reduced in all treated animals. A slight decrease in hemoglobin, red cell numbers and hematocrit was noted in high dose animals. In a short-term dietary study in which rats were given the equivalent of up to 3900 mg/kg bw for 13 weeks, the only major effects noted were a reduction in neutrophil counts in some mid- and high-dose animals, and the dilatation of the caecum. In another dietary study in the rat, animals were given up to the equivalent of 720 mg/kg bw/day for one year. The only notable effects were reductions in the body weights of females receiving the high doses, and increases in relative liver, kidney, and adrenal weights at high dose levels in animals of both sexes. Hepatic glycogen depletion occurred at all dose levels but not in controls. In mongrel dogs given 500 mg/kg bw/day for up to 56 days, reductions in spermatogenesis and testicular atrophy occurred. Kidney damage was also seen. When beagles were given orally spiramycin at up to the equivalent of 150 mg/kg bw/day for two years, testicular damage was not seen although degenerative changes occurred in other organs. In teratogenicity studies in mice, oral doses of spiramycin of up to 400 mg/kg bw given over days 5-15 of gestation had no effects on the outcome of pregnancy. intravenous doses of up to 84 mg/kg bw/day given on days 6-15 of gestation to rats and day 6-19 to rabbits had no effect on developmental, but oral dose of 200 and 400 mg/kg bw/day in rabbit produced caecal enlargement in mothers. Groups of 20 pregnant rats were treated intravenously on days 6-15 of gestation with doses of 0, 90 000, 180 000, and 270 000 iu/kg bw/day with spiramycin adipate. The highest dose given produced brief (5 minutes) ataxia and tremors immediately after dosing. A slight but significant reduction in fetal weight occurred at the intermediate dose but all values were within historical control ranges. There were no increased incidences of any fetal anomaly noted in this study. In a study where male rats were given doses of 30 mg/kg bw/day for 8 days by an unspecified route, mitotic and meiotic abnormalities in spermatogonia were noted. Negative result were obtained with spiramycin adipate and embonate in a forward-mutation test in mammalian cells in vitro, in an in vitro cytogenic assay, and in the mouse micronucleus test.

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Protein Binding
Low level of protein binding (10-25%).

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Interactions
The macrolide antibiotics include natural members, prodrugs & semisynthetic derivatives. These drugs are indicated in a variety of infections & are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metab in the liver by complex formation & inactivation of microsomal drug oxidising enzymes & also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 yrs, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard & not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes & the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin & midecamycin) form complexes to a lesser extent & rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin & azithromycin) do not inactivate cytochrome P450 & are unable to modify the pharmacokinetics of other cmpds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 & the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group & the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decr of the metab of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) & triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids & cholestatic jaundice in those taking oral contraceptives. Erythromycin & its different prodrugs appear to be less potent inhibitors of drug metab. Case reports & controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide & bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these cmpds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined admin should be carried out only with careful patient monitoring.
Reduced plasma concentrations of levodopa have been reported when given with spiramycin.
The authors report the case of a 21 year old woman with a congenital long QT syndrome who had several syncopal attacks at least one of which was caused by torsades de pointes. This sudden complication was attributed to the simultaneous prescription of Spiramycine and Mequitazine over a 48 hour period. These two drugs are not considered to be predisposing factors for torsades de pointes despite the fact that they belong to two families of drugs which can trigger this type of arrhythmia. The withdrawal of this treatment led to the complete regression of the syncopal episodes with a follow-up of two years and a significant shortening of the initial QTc interval which remained, nevertheless, longer than normal. This case underlines the potential risks of drug associations of these two families of drugs, especially in patients with the congenital long QT syndrome.

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Non-Human Toxicity Values
LD50 Rat oral 3550 mg/kg
LD50 Rat ip 575 mg/kg
LD50 Rat sc 1 g/kg
LD50 Rat iv 170 mg/kg
For more Non-Human Toxicity Values (Complete) data for SPIRAMYCIN (23 total), please visit the HSDB record page.

[1]. Post-PKS tailoring steps of the spiramycin macrolactone ring in Streptomyces ambofaciens. Antimicrob Agents Chemother. 2013 Aug;57(8):3836-42.

[2]. Assessment of spiramycin-loaded chitosan nanoparticles treatment on acute and chronic toxoplasmosis in mice. J Parasit Dis. 2018 Mar;42(1):102-113.

[3]. Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents. J Agric Food Chem. 2019 Aug 28;67(34):9630-9642.

Spiramycin is a primarily bacteriostatic macrolide antimicrobial agent with activity against Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium. Spiramycin is a 16-membered ring macrolide discovered in 1952 as a product of Streptomyces ambofaciens that has been available in oral formulations since 1955, and parenteral formulations since 1987. Resistant organisms include Enterobacteria, pseudomonads, and moulds.
Spiramycin is a macrolide originally discovered as product of Streptomyces ambofaciens, with antibacterial and antiparasitic activities. Although the specific mechanism of action has not been characterized, spiramycin likely inhibits protein synthesis by binding to the 50S subunit of the bacterial ribosome. This agent also prevents placental transmission of toxoplasmosis presumably through a different mechanism, which has not yet been characterized.

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Drug Indication
Macrolide antibiotic for treatment of various infections.

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Mechanism of Action
The mechanism of action of macrolides has been a matter of controversy for some time. Spiramycin, a 16-membered macrolide, inhibits translocation by binding to bacterial 50S ribosomal subunits with an apparent 1 : 1 stoichiometry. This antibiotic is a potent inhibitor of the binding to the ribosome of both donor and acceptor substrates. The primary mechanism of action is done by stimulation of dissociation of peptidyl-tRNA from ribosomes during translocation.I

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Therapeutic Uses
Anti-Bacterial Agents; Coccidiostats
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Spiramycin is included in the database.
MEDICATION (VET): Spiramycin is a macrolide antibiotic used for the treatment and control of a number of bacterial and mycoplasmal infections in animals. It is available as a spiramycin embonate for use in animal feed, and as the adipate, a more soluble form, for administration by other routes.
The aim of this study is to evaluate the efficacy of spiramycin in prevention of mother-to-child transmission of Toxoplasma gondii infection. Patients within first trimester of their pregnancy with Toxoplasma IgM positivity (>0.65 index, ELISA, VIDAS) and IgG positivity (>8 IU/ml), who had low IgG avidity (<0.50 index, ELISA, Architet) were considered as having acute toxoplasmosis. These patients who had amniocentesis at the 19th-21st week of pregnancy were examined for the detection of Toxoplasma DNA. Detailed ultrasonographic examinations performed between the 20th and 24th gestational weeks and the mothers and babies were followed for at least one year. ut of 61 patients, 55 (90.2%) had received Spy prophylaxis while 6 (9.8%) cases refused Spy prophylaxis. Toxoplasma PCR test was found to be positive in amniotic fluid of 4 (6.6%) patients obtained by amniocentesis at the 19th-21st week of pregnancy. All four of these patients had refused Spy prophylaxis had positive Toxoplasma PCR in amniotic fluid (p < 0.01). Our results seem to encourage the use of spiramycin in women with toxoplasmosis during pregnancy.
Spiramycin is a macrolide antibacterial that is used similarly to erythromycin in the treatment of susceptible bacterial infections. It has also been used in the protozoal infections cryptosporidiosis and toxoplasmosis.

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Drug Warnings
The most frequent adverse effects are gastrointestinal disturbances. Transient parethesia has been reported during parenteral use.
Spiramycin, a 16-membered lactone ring macrolide, has been in clinical use for the past 15 years with little serious associated toxicity. GI disturbance has usually been mild & no changes in GI motility have been noted either experimentally or in humans, in contrast to other macrolides, such as erythromycin. Allergic reactions have been uncommon & mainly restricted to transient skin eruptions. Although liver injury is a possible complication of most macrolide treatments, no conclusive evidence for spiramycin-induced hepatitis is currently available, and, again in contrast to most other macrolides, the lack of drug interactions with spiramycin has been clearly established in biochemical, pharmacokinetic & clinical studies.
... Allergic drug reactions to macrolides are extremely rare & there is little information in the literature concerning relevant diagnostic tests. ... Twenty-one patients were recently seen for assumed allergies (principally urticaria) to diverse macrolides. Skin tests (prick & intradermal tests) were performed with injectable forms of spiramycin & erythromycin. Seventeen out of 21 patients were provoked under strict hospital surveillance. ... Only 3 patients had a positive provocation test & were thus truly allergic (to spiromycin). They had positive skin tests to both macrolides tested. ... Most hypersensitivity reactions to macrolides are therefore diagnosed with provocation tests.
We recently reported two cases of QT interval prolongation & cardiac arrest in newborns receiving antibiotic therapy with spiramycin, a macrolide agent extensively used for toxoplasmosis prophylaxis. In this study we assessed the effects of this drug on ventricular repolarization & on the potential risk of lethal arrhythmias in 8 newborn infants in whom toxoplasmosis prophylaxis after birth was necessary. Electrocardiograms (ECGs) & echocardiograms were recorded during spiramycin therapy (350,000 i.u./kg/ day) & after its withdrawal. In a control group of 8 healthy newborns matched for age & sex, no differences were found between 2 ECGs analogously recorded. The QT interval corrected for heart rate (QTc) was longer during spiramycin therapy than after drug withdrawal (448 +/- 32 msec vs 412 +/- 10 msec, +9%, p=0.021). QTc dispersion, expressed as the difference between the longest & the shortest value in 12 different leads (QTcmax-min), was also higher during spiramycin therapy (60 +/- 32 msec vs 34 +/- 8 msec, +76%, p=0.021), mainly because of a major lengthening of the longest QTc (QTcmax). QTc & QTc dispersion were markedly increased in the 2 newborns who experienced cardiac arrest after beginning treatment compared with the 6 neonates who had no drug-induced symptoms. During therapy 7 of 8 newborns had a rare abnormality in the thickening of the left ventricular posterior wall similar to that observed in patients with congenital long QT syndrome. This abnormality disappeared after drug withdrawal. Thus antibiotic therapy with spiramycin in the neonatal period may induce QT interval prolongation & incr QT dispersion. When this effect on ventricular repolarization is more marked, it may favor the occurrence of torsades des pointes & lead to cardiac arrest.

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Pharmacodynamics
The absolute bioavailability of oral spiramycin is generally within the range of 30 to 40%. After a 1 g oral dose, the maximum serum drug concentration was found to be within the range 0.4 to 1.4 mg/L.

C43H74N2O14

843.0527

842.513

C, 61.26; H, 8.85; N, 3.32; O, 26.57

8025-81-8

8025-81-8;24916-52-7 (III);67724-08-7 (Embonate);68880-55-7 (adipate);

5289394

White to off-white solid powder

1.2±0.1 g/cm3

913.7±65.0 °C at 760 mmHg

506.4±34.3 °C

0.0±0.6 mmHg at 25°C

1.550

3.06

4

16

11

59

1370

19

O1[C@@]([H])(C([H])([H])[H])[C@@]([H])([C@@]([H])([C@@]([H])([C@@]1([H])O[C@]1([H])[C@]([H])([C@@]([H])(C([H])([H])C(=O)O[C@]([H])(C([H])([H])[H])C([H])([H])C([H])=C([H])C([H])=C([H])[C@@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])[C@]1([H])C([H])([H])C([H])=O)O[C@@]1([H])C([H])([H])C([H])([H])[C@@]([H])([C@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])O[H])OC([H])([H])[H])O[H])N(C([H])([H])[H])C([H])([H])[H])O[C@]1([H])C([H])([H])[C@@](C([H])([H])[H])([C@@]([H])([C@@]([H])(C([H])([H])[H])O1)O[H])O[H] |c:39,43|

ACTOXUHEUCPTEW-AQKFJFIXSA-N

InChI=1S/C43H74N2O14/c1-24-21-29(19-20-46)39(59-42-37(49)36(45(9)10)38(27(4)56-42)58-35-23-43(6,51)41(50)28(5)55-35)40(52-11)31(47)22-33(48)53-25(2)15-13-12-14-16-32(24)57-34-18-17-30(44(7)8)26(3)54-34/h12-14,16,20,24-32,34-42,47,49-51H,15,17-19,21-23H2,1-11H3/b13-12+,16-14+/t24-,25-,26-,27-,28+,29+,30+,31-,32+,34+,35+,36-,37-,38-,39+,40+,41+,42+,43?/m1/s1

2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

HSDB-7027; Rovamycin; HSDB7027; HSDB 7027

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 : 100~157 mg/mL ( 118.62~186.22 mM )
Ethanol : ~157 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.97 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 25.0 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: ≥ 2.5 mg/mL (2.97 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 25.0 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: ≥ 2.5 mg/mL (2.97 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.97 mM)

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