Amphotericin B is an organic compound with the chemical formula Cforty-sevenHseventy-threeNOseventeenIt is a kind of polyene antifungal drug. The fungi sensitive to this product include cryptococcus neoformans, blastoderma dermatitis, histoplasma, coccidiosporum, sporotrichum, candida, etc. Some Aspergillus are resistant to this product, while most dermatophytes and trichophyton are resistant to this product, and have no antimicrobial activity against bacteria, rickettsia, viruses, etc,The drug concentration reached by the commonly used treatment dose has only bacteriostatic effect on fungi.
Chinese name
Amphotericin B
Foreign name
Amphotericin B[3]
chemical formula
Cforty-sevenHseventy-threeNOseventeen
molecular weight
nine hundred and twenty-four point zero seven nine
CAS registration
1397-89-3
EINE
215-742-2
boiling point
1140.4 ℃
Water solubility
Insoluble
atlas
Science popularization in China
Committed to authoritative science communication
The certification expert of this term is
Zhang Zheng|Pharmacist in charge
Pharmacy Department of Beijing Chaoyang Hospitalto examine
Qiu Kui|Deputy Chief Pharmacist
Pharmacy Department of Beijing Chaoyang Hospitalto examine
nine hundred and twenty-four point zero seven nine
CAS login number
1397-89-3
EINECS login number
215-742-2
Boiling point
1140.4 ℃
Water solubility
Insoluble
Density
1.34 g/cm³
Appearance
Yellow crystalline powder
Flash point
643.5 ℃
Security description
S26；S36/37/39；S45
Hazard symbol
Xi
Hazard description
R36/37/38
UN dangerous goods number
one thousand seven hundred and fifty-nine
Compound Introduction
Announce
edit
essential information
Chemical formula: Cforty-sevenHseventy-threeNOseventeen
Molecular weight: 924.079
CAS No.: 1397-89-3
EINECS No. 215-741-2
Physical and chemical properties
Density: 1.34g/cmthree
Boiling point: 1140.4 ℃
Flash point: 643.5 ℃
Appearance: yellow crystalline powder
Solubility: soluble in dimethyl sulfoxide, slightly soluble in dimethyl formamide, very slightly soluble in methanol, insoluble in water, absolute ethanol, chloroform and ether[1]
Molecular structure data
Molar refractive index: 240.24
Molar volume (cmthree/mol）：689.4
Isotonic specific volume (90.2K): January 2006
Surface tension (dyne/cm): 71.6
Polarization (10-24cmthree）：95.24[1]
Calculate chemical data
Drainage parameter calculation reference value (XlogP): 0
Number of hydrogen bond donors: 12
Number of hydrogen bond receptors: 18
Number of rotatable chemical bonds: 3
Number of tautomers: 2
Topological molecular polar surface area: 320
Number of heavy atoms: 65
Surface charge: 0
Complexity: 1670
Number of isotope atoms: 0
Determine the number of atomic structure centers: 19
Number of uncertain atomic structure centers: 0
Determine the number of chemical bond stereocenters: 7
Number of uncertain chemical bond structure centers: 0
Number of covalent bond units: 1[1]
Brief Introduction to Drugs
Announce
edit
indication
It is used for visceral or systemic infection caused by cryptococcus, coccidiosporum, histoplasma capsulatum, blastomyces, sporotrichum, candida, mucor, aspergillus, etc.
Usage and dosage
Announce
edit
1. Static drip:
(1) From a small dose, it is generally increased by 1mg, 3mg, 5mg, 10mg, and gradually increased to 0.7mg/(kg · d).The initial dose increase should be slow, and the incremental speed can be appropriately accelerated when the patient's response is not obvious.
(2) Amphotericin B is dissolved into 500ml of 5% glucose injection each time, and it is dropped within 6-8 hours.Select glucose injection at pH5.5. If it is lower than pH5.3, the stability of the main drug will decline. If the pH is low, adjust its pH value with sodium bicarbonate injection.
(3) When the patient's reaction is obvious during the medication, a small dose of glucocorticoid (such as dexamethasone 1~2mg) can be used to antagonize it.
(4) In order to prevent chills and high fever, 1/3 of indomethacin suppository can be given by rectum 20~30 minutes before medication.
(5) Amphotericin B is unstable to light, and infusion should be conducted in a dark place.
(6) The liver and kidney functions and electrolytes should be monitored during medication.
(7) The total amount of amphotericin B is generally 2-3 g.
2. Atomization inhalation
It is applicable to cases of lung and bronchial infection.5~10mg a day, dissolved in 100~200mL of water for injection, used 4 times;
3. Local focus injection
The concentration is 1~3mg/mL, once every 3~7 days, and a small amount of procaine injection can be added if necessary;For fungal empyema and arthritis, 5~10mg of drug can be injected after local pus extraction, 1-3 times a week.
Adverse reactions
The toxicity is relatively high, which can cause fever, chills, headache, anorexia, nausea, vomiting and other reactions. Intravenous administration can cause thrombophlebitis, and intrathecal injection can cause back and lower limb pain.It can damage the kidney and cause proteinuria and tubular urine. If urea nitrogen>20mg/dl or creatinine>3mg/dl is found in regular inspection, measures should be taken to stop the drug or reduce the dose.There were also leukopenia, anemia, blood pressure decrease or increase, liver damage, diplopia, peripheral neuritis, skin rash and other reactions.During the trial period, the heart rate may be accelerated, even ventricular fibrillation, which is mostly related to the high concentration, fast speed and excessive dosage of the injected solution, as well as the patient's low blood potassium.
matters needing attention
Hypokalemia may occur during the use of this product, which should be paid great attention to and potassium supplement in time.This product is easy to degrade in the solution with strong acidity, and the pH value of glucose injection used is 5.5.This product is highly toxic, and can cause fever, nausea, vomiting and other adverse reactions. Intrathecal injection can cause back and lower limb pain;It can cause kidney damage such as proteinuria, and should be checked regularly. When urea nitrogen>20mg/dl or creatinine>3mg/dl, the drug should be stopped or the dose should be reduced.There are also leukopenia, decreased or increased blood pressure, liver damage, diplopia, peripheral neuritis, skin rashes, etc.During the use, the heart rate may be accelerated, even ventricular fibrillation, which is mostly related to the high concentration, fast speed, excessive dosage of the injected solution, and the patient's low blood potassium.During the treatment period, the blood, urine routine, liver, kidney function, blood potassium, electrocardiogram, etc. shall be followed up regularly and closely. If the blood urea nitrogen or creatinine significantly increases, the treatment shall be reduced or suspended until the kidney function recovers.
Drug contraindication
It is forbidden for people allergic to this product and patients with severe liver disease.Use with caution in patients with liver and kidney dysfunction.
Drug interaction
1. When combined with fluorocytosine, the efficacy of the two drugs is enhanced, but the toxicity of fluorocytosine is enhanced.
2. When combined with adrenocortical hormone, it may aggravate the hypokalemia induced by amphotericin B.
3. The combination of this product with azole antifungal drugs can reduce the antibacterial efficacy.
4. Combined with other nephrotoxic drugs, such as aminoglycosides, anti-tumor drugs, vancomycin, etc., can aggravate nephrotoxicity.
Note: The above contents are only for introduction. Drug use must be carried out by regular hospitals under the guidance of doctors.
Pharmacopoeia information
Announce
edit
essential information
This product is [1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*,18S*,19E,21E,23E,25E,27E,29E,31E,33R*,35S*,36R*,37S*) - 33 - [(3-amino-3,6-dideoxygenation-β-D-mannopyranosyl) oxygen] - 1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxobicyclo [33.3.1] tridecane-19,21,23,25,27,29,31-heptene-36-carboxylic acid, the potency per 1mg of dry product shall not be less than 850 amphotericin B units.
character
This product is a yellow to orange powder, odorless or almost odorless, hygroscopic, easily damaged and ineffective in sunlight.
This product is dissolved in dimethyl sulfoxideN,N-Dimethylformamide is slightly soluble, extremely slightly soluble in methanol, and insoluble in water, absolute ethanol or ether.
identify
1. In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
2. The infrared absorption spectrum of this product should be consistent with the reference spectrum (spectrum collection 176 figure).
inspect
acidity
Take 3% of the suspension of this product and measure it according to the law (general rule 0631). The pH value should be 4.0~6.0.
Related substances
It is determined according to the high performance liquid chromatography (general rule 0512), and is newly prepared for clinical use.
Solvent:N,N-Dimethylformamide water (1:1).
Test solution: take appropriate amount of this product, weigh it accurately, place it in a brown measuring bottle, addN,N-Dimethylformamide is dissolved and quantitatively diluted to make a solution containing about 0.8mg per 1mL. Precisely measure an appropriate amount, and quantitatively dilute with solvent to make a solution containing about 80 µ g per 1mL.
Reference solution: Take an appropriate amount of amphotericin B reference, weigh it precisely, place it in a brown measuring bottle, addN,N-Dimethylformamide is dissolved and quantitatively diluted to make a solution containing about 0.8mg per 1mL. Precisely measure an appropriate amount and quantitatively dilute it with solvent to make a solution containing about 0.8 µ g per 1mL.
System suitability solution: take about 8mg amphotericin B, place it in a 50mL brown measuring bottle, addN,N-Dissolve 5mL of dimethylformamide, dilute it to the scale with methanol, add 0.1mL of hydrochloric acid, shake it up, place it for 1 hour, take 5mL, place it in a 10mL volumetric flask, dilute it with water to the scale, shake it up.
Sensitivity solution: Precisely measure an appropriate amount of the reference solution and dilute it quantitatively with solvent to prepare a solution containing about 0.08 µ g per 1mL.
Chromatographic conditions: use octadecyl silane bonded silica gel as filler (4.6mm × 250mm, 5 µ m or equivalent chromatographic column), acetonitrile phosphoric acid solution (pH1.00 ± 0.05) (300:700) as mobile phase A, acetonitrile phosphoric acid solution (pH1.00 ± 0.05) (500:500) as mobile phase B, and perform linear gradient elution according to the following table, with flow rate of 0.8mL per minute and column temperature of 25 ° C,The detection wavelength is 303nm and 383nm, and the injection volume is 100 µ L.
Time (minutes)
Mobile phase A (%)
Mobile phase B (%)
zero
one hundred
zero
fifty
twenty
eighty
fifty-one
one hundred
zero
sixty
one hundred
zero
System suitability requirements: in the system suitability solution chromatogram (383nm), if necessary, adjust the proportion of mobile phase so that the retention time of amphotericin B is between 25~30 minutes, and the resolution between impurity C peak and impurity B peak should meet the requirements.In the sensitivity solution chromatogram (383nm), the signal-to-noise ratio of the peak height of the main component should be greater than 10.
Determination method: Precisely measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the chromatogram.
Limit: If there is an impurity peak in the chromatogram of the test solution (303nm), the peak area of impurity A (relative retention time is about 0.75) should not be greater than 0.5 times (2.0%) of the amphotericin B peak area (for injection), and the peak area of impurity A should not be greater than 1.25 times (5.0%) of the amphotericin B peak area (for non injection),The peak area of other single impurities shall not be greater than 0.25 times (1.0%) of the peak area of amphotericin B, and the peak area less than 0.025 times of the peak area of amphotericin B shall be ignored (0.1%). If there is an impurity peak in the chromatogram (383nm) of the test solution, the external standard method shall be used to calculate the main peak area of the reference solution. The sum of impurity B and impurity D shall not exceed 4.0%, and the sum of other single impurity peaks shall not exceed 2.0%,The peak smaller than the main peak area of the sensitivity solution is ignored.The total amount of impurities detected at 303nm and 383nm shall not exceed 15.0%.
Loss on drying
Take this product, use phosphorus pentoxide as the desiccant, and dry it at 60 ° C to constant weight, and the weight loss shall not exceed 5.0% (general rule 0831).
Assay
It is determined according to the high performance liquid chromatography (general rule 0512), and is newly prepared for clinical use.
solvent
See related substances.
Test solution
Take an appropriate amount of this product, weigh it precisely, put it in a brown measuring bottle, addN,N-Dissolve dimethylformamide and dilute it quantitatively to make a solution containing about 0.8mg per 1mL, accurately measure 1mL, place it in a 10mL brown measuring bottle, dilute it with solvent to the scale, and shake it up.
Reference solution
Take an appropriate amount of amphotericin B reference substance, precisely weigh it, place it in a brown measuring bottle, addN,N-Dissolve dimethylformamide and dilute it quantitatively to make a solution containing about 0.8mg per 1mL, accurately measure 1mL, place it in a 10mL brown measuring bottle, dilute it with solvent to the scale, and shake it up.
Chromatographic conditions
Octadecylsilane bonded silica gel is used as the filler, acetonitrile phosphoric acid solution (pH1.00 ± 0.05) (370:630) is used as the mobile phase, the flow rate is 0.8mL per minute, the column temperature is 25 ° C, the detection wavelength is 383nm, and the injection volume is 10 µ L.
System suitability requirements
In the chromatogram of reference solution, the resolution between amphotericin B peak and adjacent impurity peak should meet the requirements.
Assay
Accurately measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the chromatogram.Calculate by peak area according to external standard method.C per 1mgforty-sevenHseventy-threeNOseventeenIt is equivalent to 1049 amphotericin B units.
category
Antifungal agents.
Storage
Blackout, tightly sealed, refrigerated.
preparation
Amphotericin B for injection.[2]
security information
Announce
edit
Safety terminology
S26：In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
After eye contact, immediately flush with plenty of water and seek medical advice.
S36/37/39：Wear suitable protective clothing, gloves and eye/face protection.
Wear appropriate protective clothing, gloves and eye/face protection.
S45：In case of accident or if you feel unwell, seek medical advice immediately (show the lable where possible).
In case of an accident or feeling unwell, seek medical advice immediately (show the label if possible).
Risk terminology
R36/37/38：Irritating to eyes, respiratory system and skin.
