Absorption, Distribution and Excretion
The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 0.55. Cmax is between 5-35 ng/mL and is achieved after 4 hours (Tmax). AUC over an 8 hour dosing interval was reported to be approximately 177 ng.hr/mL.
After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity was excreted in the urine while 14-15% was excreted in the feces. Cyclobenzaprine is highly metabolized, with only approximately 1% of this same radio-labeled dose recovered in the urine as unchanged drug. Metabolites excreted in the urine are likely water-soluble glucuronide conjugates.
The volume of distribution of cyclobenzaprine is approximately 146 L. The combination of high plasma clearance despite a relatively long half-life observed with cyclobenzaprine is suggestive of extensive tissue distribution.
The approximate plasma clearance of cyclobenzaprine is 0.7 L/min.
Cyclobenzaprine is widely distributed into body tissues. ... It is not known if cyclobenzaprine crosses the placenta. The drug is extensively (about 93%) bound to plasma protein.
/MILK/ It is not known if cyclobenzaprine is distributed into milk in humans; however, the drug is distributed into milk in rats.
The absorption, distribution, excretion, and metabolism of 3-(5 H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine (cyclobenzaprine) were investigated in the rat, dog, rhesus monkey, and man. The drug was well absorbed in all species after oral administration. The rat eliminated the drug primarily in the feces, but urinary excretion was predominant in the dog, monkey, and man. The drug was rapidly and widely distributed into rat tissues, highest concentrations being found in the small intestine, lung, kidney, and liver. The drug was highly bound in human plasma. Extensive biliary excretion of the labeled compound was observed in the rat. Major metabolites in the rat were phenolic derivatives but in man the major metabolites were 10,11-dihydroxynortriptyline and cyclobenzaprine glucuronide. Only minor amounts of unchanged drug were present in the urine.
Orally administered cyclobenzaprine is well absorbed. Cyclobenzaprine undergoes enterohepatic circulation, and appears to be metabolized during its first pass through the GI tract and/or liver. Mean oral bioavailability of the drug is estimated to range from 33-55%. Following oral administration of a single 5- or 10-mg dose of cyclobenzaprine hydrochloride, peak plasma concentrations of 4.3 or 8.5 ng/mL, respectively, are attained in about 4 hours. When cyclobenzaprine is administered 3 times daily, steady-state plasma concentrations are attained within 3-4 days that are about fourfold greater than those after a single dose. In healthy individuals receiving the drug 3 times daily, a mean steady-state peak plasma cyclobenzaprine concentration of 14.9 or 25.9 ng/mL was achieved at 4 or 3.9 hours after administration of a 5 or 10 mg dose, respectively.

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Metabolism / Metabolites
Cyclobenzaprine is extensively metabolized in the liver via both oxidative and conjugative pathways. Oxidative metabolism, mainly N-demethylation, is catalyzed primarily by CYP3A4 and CYP1A2 (with CYP2D6 implicated to a lesser extent) and is responsible for the major metabolite desmethylcyclobenzaprine. Cyclobenzaprine also undergoes N-glucuronidation in the liver catalyzed by UGT1A4 and UGT2B10, and has been shown to undergo enterohepatic circulation.
Ten metabolites of cyclobenzaprine, accounting for approximately 50% of the urinary radioactivity, were identified in the urine of dogs to which the labeled drug had been given orally. These included the 1,2-dihydrodiol, three phenolic derivatives, the N-oxide, the 10,11-epoxide, the 10,11-glycol, desmethylcyclobenzaprine, and the glucuronide conjugates of desmethylcyclobenzaprine and cyclobenzaprine. The metabolites were excreted in both the free and conjugated states. Unchanged cyclobenzaprine was present in only minor amounts.
Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine.
The absorption, distribution, excretion, and metabolism of 3-(5 H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine (cyclobenzaprine) were investigated in the rat, dog, rhesus monkey, and man. ... Major metabolites in the rat were phenolic derivatives but in man the major metabolites were 10,11-dihydroxynortriptyline and cyclobenzaprine glucuronide. ...
Cyclobenzaprine is extensively metabolized by both oxidative and conjugative pathways. Hepatic cytochrome P-450 (CYP) 3A4, 1A2, and (to a lesser extent) 2D6 isoenzymes are responsible for oxidative N-demethylation of the drug.Orally administered cyclobenzaprine is excreted in urine principally as inactive glucuronide metabolites; less than 1% of the drug is excreted renally as unchanged drug.
The fungus, Cunninghamella elegans, was used as a microbial model of mammalian drug metabolism to biotransform a tricyclic antidepressant, cyclobenzaprine. Seventy-five percent of this drug at a concentration of 1 mM was metabolized within 72 hr by C. elegans grown on Sabouraud dextrose broth. Milligram amounts of fungal metabolites were isolated by reversed-phase high performance liquid chromatography (HPLC) and their structures were characterized by 1H NMR spectroscopy, mass spectrometry, and UV spectroscopy analyses. The major fungal metabolites of cyclobenzaprine were 2-hydroxycyclobenzaprine (59%), N-desmethylcyclobenzaprine (21%), cyclobenzaprine trans-10,11-dihydrodiol (5%), N-desmethyl-2-hydroxy-cyclobenzaprine (3%), 3-hydroxycyclobenzaprine (3%), and cyclobenzaprine N-oxide (1%). These fungal metabolites were used as standards to investigate the metabolism of cyclobenzaprine by rat liver microsomes. Rat liver microsomes also biotransformed cyclobenzaprine to produce similar metabolites as the fungus. The isotope labeling of 2-hydroxycyclobenzaprine by 18O2 and the trans-configuration of the dihydrodiol suggested that these reactions were catalyzed by cytochrome P-450 monooxygenases in C. elegans. These results also demonstrated that the fungal biotransformation system could be used to predict and synthesize the mammalian drug metabolites.
Cyclobenzaprine has known human metabolites that include N-Desmethylcyclobenzaprine.

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Biological Half-Life
The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18 hours. These values are extended in the elderly and those with hepatic insufficiency, with a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively.
Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18) ... .

Toxicity Summary
IDENTIFICATION AND USE: Cyclobenzaprine (used in the form of cyclobenzaprine hydrochloride tablets) is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. HUMAN EXPOSURE AND TOXICITY: Manifestations of toxicity may develop rapidly after a cyclobenzaprine overdose, and rarely, death may occur. The most common toxic effects associated with cyclobenzaprine overdose are drowsiness and tachycardia; less frequent manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rarely, potentially serious effects may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Serotonin syndrome is another potential side effect. Blood concentration of > or = 0.8 mg/L cyclobenzaprine may be associated with a fatal outcome. In one case of accidental overdose, the victim developed severe hypothermia and then developed cardiac arrest during transport. ANIMAL STUDIES: Ptyalism, emesis, tremors, convulsions and increased respiratory rate developed and death occurred within 1 hour following single oral doses of 180 mg/kg or more by gavage in dogs. Acute exposure to the drug in rats resulted in ataxia, decreased respiratory rate, sedation, flaccid hind legs, loss of the ear flick reflex, loss of the righting reflex with swimming movements, intermittent clonic convulsions, weight loss, lethargy, and then death. The drug was more toxic to infant and weanling rats than to young adults. In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. No evidence of embryo lethality or teratogenicity was revealed following oral doses of 5, 10 or 20 mg/kg/day in studies in mice and rabbits. The reproductive performance and fertility of males and females, and the growth and survival of their offspring were not adversely affected by doses of 5 or 10 mg/kg/day in rats. Litter size, size and survival of the pups, and weight gain of the mothers were decreased by doses of 20 mg/kg/day. Cyclobenzaprine hydrochloride was determined to have no genotoxic effects in several assays, including mouse bone marrow micronucleus assay; Salmonella-Escherichia coli mammalian microsome reverse mutation assay with confirmatory assay; and in a CHO cells chromosomal aberration assay with and without metabolic activation.

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Hepatotoxicity
The product insert for cyclobenzaprine mentions that abnormal liver function, hepatitis, jaundice, and cholestasis occur in
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
Amounts of cyclobenzaprine in milk appear to be very small and two infants apparently tolerated the drug in milk well. If cyclobenzaprine is required by the mother, it is not a reason to discontinue breastfeeding. Monitor the infant for (drowsiness, adequate weight gain, and developmental milestones), especially in neonates and preterm infants and when using combinations of sedating drugs.
◉ Effects in Breastfed Infants
Two mothers were taking chronic cyclobenzaprine therapy. One mother was taking 5 mg once daily for temporomandibular joint pain and the other mother was taking 10 mg twice daily for fibromyalgia pain. The latter mother was also taking unspecified antidepressants, levothyroxine, zolpidem, alprazolam and famotidine. Both mothers were breastfeeding their infants (extent not stated). Neither infant had any noticeable adverse reaction such as sedation.
A search was performed of the shared database of all U.S. poison control centers for the time period of 2001 to 2017 for calls regarding medications and breastfeeding. Of 2319 calls in which an infant was exposed to a substance via breastmilk, 1 of 7 classified as resulting in a major adverse effect involved cyclobenzaprine. A 16-day-old infant was exposed to cyclobenzaprine, acetaminophen and oxycodone in breastmilk. The infant was admitted to the hospital in a noncritical care unit for bradycardia, hypotension, and respiratory arrest. The dosages and extent of breastfeeding were not reported and the infant survived.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Cyclobenzaprine is approximately 93% protein bound in plasma. It has been identified as specifically having a high affinity for human serum albumin.

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Interactions
Concomitant use of cyclobenzaprine with diflunisal or naproxen reportedly was well tolerated and did not appear to result in any unexpected adverse effects. However, concomitant use of cyclobenzaprine with naproxen has been associated with an increased incidence of drowsiness. Plasma concentrations of aspirin or cyclobenzaprine were unaffected when the drugs were administered concomitantly. It has not been established whether combined therapy with cyclobenzaprine and aspirin (or other analgesics) will result in enhanced clinical efficacy.
Cyclobenzaprine and structurally similar tricyclic antidepressants may block the hypotensive effects of guanethidine (no longer commercially available in the US) and other similarly acting drugs.
Cyclobenzaprine and structurally similar tricyclic antidepressants may enhance the risk of seizures in patients receiving tramadol.
Cyclobenzaprine may be additive with or may potentiate the action of other CNS depressants (e.g., alcohol, barbiturates). Cyclobenzaprine, especially when used concomitantly with alcohol or other CNS depressants, may impair the patient's ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).
For more Interactions (Complete) data for Cyclobenzaprine (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 36 mg/kg
LD50 Mouse ip 90 mg/kg
LD50 Mouse oral 250 mg/kg
LD50 Rat oral 425 mg/kg
LD50 Mouse oral 338 mg/kg

Eur J Pharmacol.1996 Sep 5;311(1):29-35;Eur J Pharmacol.2003 Jan 1;458(1-2):91-9.

Therapeutic Uses
Antidepressive Agents, Tricyclic; Muscle Relaxants, Central; Tranquilizing Agents
/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. Cyclobenzaprine is included in the database.
Cyclobenzaprine hydrochloride tablets are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living. Cyclobenzaprine hydrochloride should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. Cyclobenzaprine hydrochloride has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy. /Included in US product label/
Some data suggest that cyclobenzaprine may be useful for the treatment of fibrositis. Cyclobenzaprine is ineffective in the treatment of spasticity associated with cerebral or spinal disease or in children with cerebral palsy. /NOT included in US product label/
EXPL Tinnitus is defined as an intrinsic sound sensation that cannot be attributed to an external sound source. Currently there are no standardized drug therapies for the treatment of tinnitus. Based on the analogy between pain and tinnitus it is suggested that among all antidepressant families that have been used for tinnitus, particular interest should be paid to the tricyclic group of drugs as they have an analgesic effect. The aim of the present study was to investigate the effect of a tricyclic pharmacological agent, namely cyclobenzaprine for the relief of tinnitus complaints. 65 patients, who received the drug treatment, were compared to 30 patients on a waiting list, who received no treatment. Analysis shows that cyclobenzaprine offers some benefit to patients with tinnitus on both tinnitus intensity and tinnitus distress, while a waiting list control group does not demonstrate any improvement: 24% of the tinnitus patients showed a clear response to cyclobenzaprine with a reduction of 53% on tinnitus intensity and 25% had a clear response to cyclobenzaprine with a reduction of 55% on tinnitus distress. It was further demonstrated that particular subgroups, namely pure tone tinnitus patients and unilateral tinnitus patients, respond better to cyclobenzaprine. Our results indicate that cyclobenzaprine is a promising drug to treat tinnitus particularly in certain subgroups. As there is a good risk-benefit ratio and there are currently no well-established, specific treatments for tinnitus, cyclobenzaprine might be worthwhile to further investigate.

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Drug Warnings
The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of Cyclobenzaprine Hydrochloride with MAO inhibitors is contraindicated. Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases.
Dry mouth occurred in 21 or 32% of patients receiving 5 or 10 mg, respectively, of cyclobenzaprine and in 7% of those receiving placebo in controlled studies. Dry mouth also occurred in 27 or 7% of patients receiving 10 mg of the drug in clinical studies or during postmarketing surveillance, respectively. Abdominal pain, acid regurgitation, dyspepsia, constipation, diarrhea, nausea, and unpleasant taste occurred in 1-3% of patients receiving 5 or 10 mg of cyclobenzaprine in controlled studies or during postmarketing surveillance in patients receiving 10 mg of the drug. Vomiting, anorexia, GI pain, gastritis, thirst, edema of the tongue, and flatulence were reported during postmarketing surveillance or in less than 1% of patients receiving 10 mg of the drug in controlled studies. Paralytic ileus, tongue discoloration, stomatitis, and parotid swelling were reported in patients receiving other tricyclic drugs or rarely with cyclobenzaprine, but a causal relationship with cyclobenzaprine could not be established.
Malaise, seizures, ataxia, vertigo, dysarthria, hypertonia, tremors, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking, abnormal dreaming, hallucinations, excitement, paresthesia, and diplopia were reported during postmarketing surveillance or in less than 1% of patients receiving 10 mg of the drug in controlled studies. Other adverse nervous system effects that have been reported in patients receiving other tricyclic drugs or rarely with cyclobenzaprine but for which a causal relationship with the drug could not be established include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal manifestations.
Headache occurred in 5% of those receiving 5 or 10 mg of cyclobenzaprine and in 8% of those receiving placebo in controlled studies; headache occurred in 1-3% of patients receiving 10 mg of the drug in controlled studies and postmarketing surveillance. Irritability, decreased mental acuity, nervousness, asthenia, and confusion occurred in 1-3% of patients receiving 5 or 10 mg of cyclobenzaprine in controlled studies or during postmarketing surveillance in patients receiving 10 mg of the drug.
For more Drug Warnings (Complete) data for Cyclobenzaprine (25 total), please visit the HSDB record page.

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Pharmacodynamics
Cyclobenzaprine is a skeletal muscle relaxant that works on areas of the brainstem to reduce skeletal muscle spasm, though its exact pharmacodynamic behaviour is currently unclear. Despite its long half-life, it is relatively short-acting with a typical duration of action of 4-6 hours. Cyclobenzaprine has been reported to contribute to the development of serotonin syndrome when used in combination with other serotonergic medications. Symptoms of serotonin syndrome may include autonomic instability, changes to mental status, neuromuscular abnormalities, or gastrointestinal symptoms - treatment with cyclobenzaprine should be discontinued immediately if any of these reactions occur during therapy.

C20H21N

275.39

275.167

303-53-7

303-53-7;6202-23-9 (HCl);

2895

Typically exists as solid at room temperature

1.096 g/cm3

405.9ºC at 760 mmHg

177.8ºC

1.7500 (estimate)

4.553

0

1

3

21

365

0

Cl.CN(CC/C=C1\C=C2C=CC=CC2=CC2=CC=CC=C\12)C

JURKNVYFZMSNLP-UHFFFAOYSA-N

InChI=1S/C20H21N/c1-21(2)15-7-12-20-18-10-5-3-8-16(18)13-14-17-9-4-6-11-19(17)20/h3-6,8-14H,7,15H2,1-2H3

N,N-dimethyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)propan-1-amine

MK-130MK130Flexeril

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)