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5g |
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Purity: ≥98%
Mesalamine (also named as 5ASA; Z-206; AJG-501; MAX-002; 5-aminosalicylic acid; Asacol; mesalazine; 5-ASA) orally bioavailable inhibitor of TNFα-induced IKK activity with potential anti-inflammatory activity. Additionally, it stimulates the PPARγ receptor and inhibits both NF-κB and p21-activated kinase 1 (PAK1). It has been approved for the treatment of ulcerative colitis, a type of inflammatory bowel disease.
Targets |
PPARγ; PAK1; p65
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ln Vitro |
5-Aminosalicylic acid (5-ASA) is a specific agonist for PPARγ, and only PPARγ but not PPARα or PPARδ induces p65 degradation. P65 protein is degraded by 5-aminosalicylic acid, demonstrating the E3 ubiquitin ligase activity of PPARγ. Additionally, PAK1 is inhibited by 5-aminosalicylic acid at the mRNA level, suggesting a second mechanism distinct from PPARγ ligand activation. Through PAK1 inhibition, 5-aminosalicylic acid prevents NF-κB from operating in intestinal epithelial cells (IECs). The growth of HT-29 colon carcinoma cells is inhibited by pretreatment with 5-Aminosalicylic acid (5-ASA) or nimesulide at various concentrations (10-1000 mol/L) for 12-96 h in a dose- and time-dependent manner. Nimesulide or 5-Aminosalicylic Acid's suppression, however, has no statistically significant effect. Pretreatment with varying doses of combined 5-Aminosalicylic acid and Nimesulide inhibits the growth of HT-29 colon carcinoma cells in a dose-dependent manner. A combination of 5-Aminosalicylic acid (final concentration 100 μM) and Nimesulide (final concentration 10-1000 μM) has a stronger inhibitory effect than a single dose of Nimesulide on the proliferation of HT-29 colon carcinoma cells. The proliferation of these cells is also inhibited by the combination of nimesulide (final concentration 100 μM) and 5-aminosalicylic acid (final concentration 10-1000 μM) in a dose-dependent manner[2].
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ln Vivo |
5-Aminosalicylic acid (5-ASA) has an antineoplastic effect in a xenograft tumor model. SCID mice engrafted with HT-29 colon cancer cells are given daily treatments for 21 days in a row with 5-Aminosalicylic acid at a concentration of 50 mM to assess the in vivo antineoplasic effect of the compound. Comparing SCID mice receiving 5-Aminosalicylic acid to control mice or mice receiving GW9662 alone at the end of the treatment, a reduction of 80–86% in tumor weight and volume is seen. After 10 days of treatment, the 5-Aminosalicylic Acid's anti-cancer effects are already apparent. Mice given 5-Aminosalicylic acid at 5 mM produced results that were similar. By simultaneously administering GW9662 intraperitoneally, 5-Aminosalicylic acid's antitumorigenic effect is completely eliminated at day 21.
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Enzyme Assay |
5-Aminosalicylic acid (Mesalamine) acts as a specific PPARγ agonist and also inhibits p21-activated kinase 1 (PAK1) and NF-κB.
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Cell Assay |
The MTT assay is used to measure cytostatic effects. A 0.25% trypsin solution is used to separate HT-29 colon cancer cells for 5 minutes. The cells are then seeded onto 96-well plates (1×106 cells/well), supplemented with 10% FCS, and given 24 hours to attach before test chemicals (5-Aminosalicylic acid 10, 50, 100, 500, and 1000 μM; Nimesulide; and their mixtures) are added. In a culture medium devoid of serum, test compounds are diluted. After 48 hours of incubation in a medium or with various drug concentrations, 20 μL of MTT solution (5 g/L) in PBS is added. After four hours, the medium in each well is taken out, and 120 L of muriatic isopropanol (0.04 mM) is added after being lightly concussed for ten minutes. Using an ELISA reader, dye uptake is measured at 490 nm. Each concentration or control group is divided into five wells. The cells, on the other hand, are seeded onto 96-well plates (1×106 cells/well) and allowed to adhere for 24 hours before being exposed to the test chemicals (5-Aminosalicylic acid, Nimesulide, and their combination). It has a 100 μM final concentration. The control group receives the identical medium after which dye uptake is assessed. For each test compound or control group, five wells are used[2].
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Animal Protocol |
Mice: Pathogen-free BALB/c SCID mice that are six to seven weeks old are used. Animals' flanks are implanted subcutaneously with 107 HT-29 human colon cancer cells, which have either been pretreated with GW9662 for 24 hours or not. Mice are given daily peritumoral injections of 5-Aminosalicylic Acid (5 or 50 mM) for 10 or 21 days starting two days after cell inoculation. By injecting GW9662 (1 mg/kg/day) intraperitoneally every day during treatment with 5-Aminosalicylic acid, the impact of PPAR is assessed. In the control group, 5-Aminosalicylic acid is substituted with saline. Three times per week, tumor development in mice is monitored. Tumor volume and size are determined after killing at 10 or 21 days. Prior to paraffin embedding for histological analysis, tumors are weighted.
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ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Depending on the formulation administered, prescribing information for orally administered delayed-released tablets of 2.4g or 4.8g of mesalazine given once daily for 14 days to healthy volunteers was to found to be about 21% to 22% of the administered dose while prescribing information for an orally administered controlled-release capsule formulation suggests 20% to 30% of the mesalazine in the formulation is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalazine is approximately 80% absorbed. Elimination of mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent mesalazine drug in the urine. After the oral administration of the extended-release formulation of mesalazine, of the approximately 21% to 22% of the drug absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. When given the controlled-release formulation, about 130 mg free mesalazine was recovered in the feces following a single 1-g dose, which was comparable to the 140 mg of mesalazine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g F3001]. Elimination of free mesalazine and salicylates in feces increased proportionately with the dose given. N-acetylmesalazine was the primary compound excreted in the urine (19% to 30%) following the controlled-release dosing. In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA. For the extended-release formulation, mesalazine has a Vd of 18 L, confirming minimal extravascular penetration of systemically available drug. For the delayed-release formulation, the apparent volume of distribution was estimated to be 4.8 L. The mean (SD) renal clearance in L/h for mesalazine following the single dose administration of mesalazine delayed-release tablets 4.8g under fasting conditions to young and elderly subjects were documented as 2.05 ± 1.33 in young subjects aged 18 to 35 years old, 2.04 ± 1.16 in elderly subjects aged 65 to 75 years old and 2.13 ± 1.20 in elderly subjects older than 75 years. Following oral administration, low concentrations of mesalamine and higher concentrations of its metabolite, N-acetyl-5-aminosalicylic acid, have been detected in human breast milk. It is not known whether mesalamine or its metabolites are distributed into milk in humans following rectal administration. Mesalamine and N-acetyl-5-aminosalicylic acid cross the placenta following oral administration; however, serum concentrations of mesalamine in umbilical cord and amniotic fluid are very low. It is not known whether mesalamine crosses the placenta following rectal administration. In vitro, mesalamine and N-acetyl-5-aminosalicylic acid are approximately 44-55 and 80% bound, respectively, to plasma proteins. Protein binding of N-acetyl-5-aminosalicylic acid does not appear to be concentration dependent at concentrations ranging from 1-10 ug/mL. It is generally accepted that 5-aminosalicylate (5-ASA; mesalamine), widely used in inflammatory bowel disease therapy, exerts its action from the intraluminal site of the intestine. In addition to local metabolism of 5-ASA, it has been assumed that therapeutic mucosal concentrations of 5-ASA depend on transporter-mediated secretion back to the lumen. ... The hypothesis that 5-ASA represents a substrate of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 2 (MRP2), thereby possibly contributing to variable therapeutic effects /was tested/. Polarized, basal-to-apical transport of [(3)H]5-ASA was studied in monolayers of Caco-2 and L-MDR cells, both of which express P-gp in their apical membrane, as well as in MDCK cells transfected with human MRP2. Moreover, we investigated the influence of 5-ASA on transport of digoxin in Caco-2 cells. In Caco-2 cells a P-gp-mediated efflux of 5-ASA (5-500 muM) could be excluded. Likewise, in L-MDR1 and MRP2 cells no transport differences in either the basal-to-apical or apical-to-basal direction were measurable. 5-ASA (50 muM to 5 mM) had no effect on the transport of digoxin. ... For more Absorption, Distribution and Excretion (Complete) data for MESALAMINE (15 total), please visit the HSDB record page. Metabolism / Metabolites Mesalazine is metabolized both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) principally by NAT-1. Some acetylation also occurs through the action of colonic bacteria. Mesalazine (5-aminosalicylic acid, 5-ASA), an anti-inflammatory agent for the treatment of inflammatory bowel diseases, is metabolized in organism to the principal biotransformation product, N-acetyl-5-ASA. Some other phase II metabolites (N-formyl-5-ASA, N-butyryl-5-ASA, N-beta-d-glucopyranosyl-5-ASA) have also been described. 5-ASA is a polar compound and besides it exhibits amphoteric properties. ... The exact metabolic fate of mesalamine has not been clearly established. The drug undergoes rapid N-acetylation, probably in the liver, to form N-acetyl-5-aminosalicylic acid; mesalamine and N-acetyl-5-aminosalicylic acid also may undergo conjugation with glucuronic acid. Several other, unidentified metabolites also may be formed. It has been suggested that N-acetylation also may occur (to a limited extent) in the intestinal wall and/or the lumen. The intestinal flora probably are involved in this acetylation, and extensive floral acetylation may adversely affect clinical efficacy of the drug. Correlation between acetylator phenotype of patients receiving mesalamine and the degree of N-acetylation does not appear to exist. Although it has been suggested that N-acetyl-5-aminosalicylic acid may be pharmacologically active, therapeutic response has been poor in some patients treated rectally with this metabolite, and the relative contribution of this metabolite to the therapeutic effect of mesalamine remains questionable. N-Acetyl-5-aminosalicylic acid did not inhibit lipoxygenase in vitro. Mesalazine has known human metabolites that include mesalazine, N-acetyl. Biological Half-Life For the delayed-release formulation, after intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the median terminal half life values for mesalamine are usually about 25 hours, but are variable, ranging from 1.5 to 296 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their terminal half-lives following the administration of mesalazine. For the extended-release formulation, following single and multiple doses of mesalazine, the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. The mean elimination half-life was 5 hours (CV=73%) for 5-ASA and 5 hours (CV=63%) for N-acetyl-5-ASA in patients taking 500 mg mesalazine as a rectal suppository every 8 hours for 6 days. For the rectal enema suspension formulation, the elimination half-life was 0.5 to 1.5 hours for 5-ASA and 5 to 10 hours for N-acetyl-5-ASA. Elimination of metabolite: 5 to 10 hr /N-acetyl-5-aminosalicylci acid/ Elimination: 0.5-1.5 hours |
Toxicity/Toxicokinetics |
Interactions
Omeprazole may increase gastrointestinal pH; concurrent use may result in an increase in the absorption of mesalamine. Acidification of the colonic lumen by lactulose may impair release of mesalamine from delayed- or extended-release formulations. |
References |
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Additional Infomation |
Therapeutic Uses
Mesalamine rectal suspension is indicated for the treatment of mild to moderate distal ulcerative colitis, proctosigmoiditis, and proctitis. /Included in US product labeling/ Mesalamine rectal suspension is indicated to help maintain remission of distal ulcerative colitis. /NOT included in US product labeling/ Mesalamine suppositories are indicated for the treatment of active ulcerative proctitis. /Included in US product labeling/ Mesalamine is indicated to treat and to maintain remission of mild to moderate ulcerative colitis or (Crohn's disease). /Included in US product labeling/ Lialda /the first oral once daily mesalamine tablet/ is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Drug Warnings Oral and rectal mesalamine preparations usually are well tolerated. The most common adverse effects of oral or rectal mesalamine are GI effects and headache. In clinical studies, most adverse effects associated with oral or rectal preparations were mild in severity and were transient or reversible. However, adverse effects have been severe enough to require discontinuance of the drug in less than 1% or in up to about 4-5% of patients receiving rectal or oral mesalamine, respectively, although in some studies, the rate of discontinuance of the drug was similar to or less than in those receiving placebo. Most of the adverse effects reported with the use of oral mesalamine delayed-release tablets were similar in short- and long-term studies. Exacerbation of colitis symptoms was reported in 3% of patients receiving oral mesalamine delayed-release tablets. Other adverse GI effects associated with oral mesalamine extended-release capsules and occurring in less than 1% of patients, include abdominal distention, constipation, duodenal ulcer, dysphagia, eructation, esophageal or mouth ulcer, fecal incontinence, GI bleeding (e.g., rectal bleeding), stool abnormalities (e.g., change in color or texture), oral moniliasis, and thirst, although a causal relationship to the drug of many of these adverse effects has not been established. In controlled clinical trials in patients receiving oral mesalamine delayed-release tablets, abdominal pain, eructation, nausea, diarrhea, dyspepsia, vomiting, constipation, flatulence, exacerbation of colitis, abdominal enlargement, gastroenteritis, GI hemorrhage, rectal disorder (e.g., hemorrhage, tenesmus), and stool abnormalities, were the most common adverse GI effects, occurring in about 2-18% of patients; dry mouth, indigestion, stomatitis, and cramping were reported rarely. Frequency of these GI effects did not seem to increase with increased dosages, although in uncontrolled studies, the incidence of abdominal pain, flatulence, and GI bleeding were dose related. The most common adverse GI effects of oral mesalamine extended-released capsules were diarrhea (including melena), nausea, abdominal pain, dyspepsia, vomiting, anorexia, worsening of ulcerative colitis, and rectal urgency, occurring in greater than 0.4-3% of patients. An acute intolerance syndrome (sensitivity reaction), characterized by cramping, abdominal pain, bloody diarrhea, and, occasionally, fever, headache, malaise, conjunctivitis, pruritus, and rash, has occurred in a few patients receiving mesalamine and required prompt discontinuance of the drug. In patients manifesting such intolerance, a history of sulfasalazine intolerance, if any, should be reevaluated. For more Drug Warnings (Complete) data for MESALAMINE (26 total), please visit the HSDB record page. Pharmacodynamics Mesalazine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter responsible for most of the side effects associated with sulphasalazine therapy, while mesalazine is known to be the active moiety in the treatment of ulcerative colitis. Mesalazine is thought to dampen the inflammatory process through its ability to inhibit prostaglandin synthesis, interfere with leukotriene synthesis, and consequent leukocyte migration as well as act as a potent scavenger of free radicals. Regardless of the mode of action, mesalazine appears to be active mainly topically rather than systemically. Intraperitoneally administered mesalazine at 30 and 340 mg/kg daily had similar efficacy in attenuating colitis as prednisolone 4 to 550 mg/kg daily given intraperitoneally or sulphasalazine 0.34 to 5 mg/kg given orally in immune complex-induced colitis mice. Mesalazine at 5 mmol/L and sulphasalazine 1.5 mmol/L also reversed the increase in water and chloride secretion and decrease the sodium in dinitrochlorbenzene-induced colitis guinea pig. |
Molecular Formula |
C7H7NO3
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Molecular Weight |
153.13
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Exact Mass |
153.042
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Elemental Analysis |
C, 54.90; H, 4.61; N, 9.15; O, 31.34
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CAS # |
89-57-6
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Related CAS # |
5-Aminosalicylic acid-d3;1309283-32-6;5-Aminosalicylic Acid-d3 hydrochloride;1346601-18-0;5-Aminosalicylic acid-13C6;1189709-96-3
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PubChem CID |
4075
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Appearance |
Brown to gray solid powder
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Density |
1.5±0.1 g/cm3
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Boiling Point |
380.8±32.0 °C at 760 mmHg
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Melting Point |
275-280 °C (dec.)(lit.)
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Flash Point |
184.1±25.1 °C
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Vapour Pressure |
0.0±0.9 mmHg at 25°C
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Index of Refraction |
1.691
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LogP |
1.14
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Hydrogen Bond Donor Count |
3
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Hydrogen Bond Acceptor Count |
4
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Rotatable Bond Count |
1
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Heavy Atom Count |
11
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Complexity |
160
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Defined Atom Stereocenter Count |
0
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SMILES |
O=C(C1C(O)=CC=C(N)C=1)O
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InChi Key |
KBOPZPXVLCULAV-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C7H7NO3/c8-4-1-2-6(9)5(3-4)7(10)11/h1-3,9H,8H2,(H,10,11)
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Chemical Name |
5-amino-2-hydroxybenzoic acid
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (16.32 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (16.32 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. View More
Solubility in Formulation 3: 7.14 mg/mL (46.62 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 16.67 mg/mL (108.85 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 6.5304 mL | 32.6520 mL | 65.3040 mL | |
5 mM | 1.3061 mL | 6.5304 mL | 13.0608 mL | |
10 mM | 0.6530 mL | 3.2652 mL | 6.5304 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Fenofibrate in Ulcerative Colitis
CTID: NCT05753267
Phase: Phase 2/Phase 3   Status: Recruiting
Date: 2024-04-10