Background and overview[1]
Metronidazole disodium phosphate is the precursor of metronidazole. Metronidazole is currently the drug of choice for clinical treatment of anaerobic bacterial infections. In recent years, it has also been used as a radiotherapy sensitizer. Due to the low solubility of metronidazole, the concentration of existing metronidazole injection is only 0.5% (the specification is 0.5g/100ml bottled injection). The commonly used clinical dose for anti-anaerobic bacterial infection is more than 1g. If used as a radiotherapy sensitizer, its dose can reach More than 10g, so the injection volume is large; due to the large bottle volume and low concentration, it can only be dripped but not pushed, which is inconvenient for clinical application; in addition, the production cost of bottled injections is high, and there are problems in packaging, transportation, storage and other links Many inconveniences. In order to solve the solubility problem of metronidazole, the soluble precursor of metronidazole, metronidazole disodium phosphate, has been synthesized at home and abroad. It has high solubility and can be quickly hydrolyzed under the action of phosphatase when entering the body, releasing the parent metronidazole. The azole exerts a therapeutic effect. Existing technologies for metronidazole and metronidazole disodium phosphate: ①0.5% metronidazole injection (100ml:500mg specification), which is now produced and used in China. ② 5% metronidazole disodium phosphate injection was approved by Romania on May 30, 1986. However, there are no literature reports on the efficacy, toxicology, stability and clinical application of this compound, and no product has been marketed. . Prior art ① metronidazole injection has its shortcomings as mentioned above. The main drug of the prior art ② is the same as the main drug of the present invention, but its dosage form is an injection with lower concentration, larger clinical dosage and poor stability; it is inconvenient to transport and store. In addition, the injection prescription contains 5 to 15% polyethylene glycol, which has certain side effects.
Pharmacological effects[2]
Metronidazole disodium phosphate is a derivative of metronidazole, which is easily soluble in water. It is hydrolyzed in the body to produce metronidazole, thereby exerting its powerful anti-anaerobic effect. It is also effective against infections caused by trichomonas, amoeba and other diseases. This product is for injection administration only.
Pharmacokinetics[3]
After this product enters the body, it is quickly hydrolyzed into metronidazole and phosphate. After intravenous injection of 0.915g of this product, the time to reach peak metronidazole in plasma (Tmax) is about 10 to 20 minutes, and the peak plasma concentration (Cmax) is about 50mg/ml. After this product is hydrolyzed into metronidazole, it is widely distributed in various tissues and body fluids, and can pass through the blood-cerebrospinal fluid barrier. Saliva, bile, breast milk, amniotic fluid, semen, urine, pus and cerebrospinal fluid can all reach effective concentrations. The concentration in placenta, milk, and bile is similar to that in plasma. Protein binding rate is less than 20%. Mainly metabolized in the liver. The blood elimination half-life (t1/2b) is 9 to 11 hours, and 60% to 80% is excreted by the kidneys, of which 20% is unchanged and the rest is metabolites (25% is glucuronic acid conjugates and 14% is other metabolic conjugates) things).
10% is excreted in feces and 14% is excreted through skin.
Purpose[2]
Metronidazole disodium phosphate is mainly used for various infections caused by anaerobic bacteria. It can also be used for patients with trichomonas and amoeba infections.
Adverse reactions[3]
1. The most serious adverse reactions of this product are epileptic seizures and peripheral neuropathy at high doses, the latter mainly manifesting as numbness and abnormal sensation in the extremities. In some cases, persistent peripheral neuropathy may occur with long-term medication.
2. Other common adverse reactions include:
(1) Gastrointestinal reactions, such as nausea, loss of appetite, vomiting, diarrhea, abdominal discomfort, taste changes, dry mouth, metallic taste in the mouth, etc.
(2) Reversible neutropenia.
(3) Allergic reactions, rashes, urticaria, itching, etc.
(4) Central nervous system symptoms, such as headache, dizziness, syncope, paresthesias, limb numbness, ataxia and mental confusion.
(5) Local reactions such as thrombophlebitis, etc.
(6) Other symptoms include fever, vaginal candida infection, cystitis, dysuria, dark urine, etc., all of which are reversible and will recover on their own after stopping the drug
Preparation specifications[2]
Injection: 0.915g per bottle (equivalent to 0.5g of metronidazole). Capsules: 0.25g each.
Usage and dosage[2]
Intravenous drip or intravenous injection: 0.915g each time, 2 to 3 times a day; or 1.83g each time, once a day. The amount may be increased as appropriate for special purposes. The dosage for children is 13.7mg per kilogram of body weight. It can be dissolved in normal saline for injection or 5% glucose sodium chloride solution and then injected intravenously or intravenously.
Packaging specifications
Capsules: 10 capsules/box, 300 small boxes/carton. Injections: 10 bottles/box, 60 boxes/carton.
Notes[3]
1． Carcinogenic and mutagenic effects: Animal experiments or in vitro measurements have found that this product is carcinogenic and mutagenic, but this has not been confirmed in humans.
2. If adverse reactions to the central nervous system occur during use, the drug should be discontinued promptly.
3． This product can interfere with the test results of alanine aminotransferase, lactate dehydrogenase, triglycerides, hexokinase, etc., reducing the measured values to zero.
4． Alcoholic beverages should not be consumed during medication, as they can cause the accumulation of acetaldehyde in the body, interfere with the oxidation process of alcohol, and lead to disulfiram-like reactions. Patients may experience abdominal cramps, nausea, vomiting, headaches, facial flushing, etc.
5. In patients with reduced liver function, the metabolism of this product slows down, and the drug and its metabolites are easy to accumulate in the body. The dosage should be reduced and the blood drug concentration should be monitored.
6. This product can be continuously cleared from gastric juice. Some patients who have a gastric tube placed for suction and decompression may cause a decrease in blood concentration. During hemodialysis, this product and metabolism�It is cleared quickly, so there is no need to reduce the dosage when applying this product.
7． If patients with Candida infection use this product, their symptoms will be aggravated and they need to be given antifungal treatment at the same time.
8． For patients with anaerobic bacterial infection and renal failure, the dosing interval should be extended from 8 hours to 12 hours.
9． This product should not come into contact with aluminum-containing needles and cannulas, and avoid infusion with other drugs.
10． Before repeating a course of treatment, a white blood cell count should be performed.
Drug interactions[3]
1． This product can inhibit the metabolism of warfarin and other oral anticoagulants, strengthen their effects, and cause prolongation of prothrombin time.
2. Combined use with drugs that induce liver microsomal enzymes such as phenytoin and phenobarbital can enhance the metabolism of this product, reduce the blood drug concentration, and slow down the excretion of phenytoin.
3． Combined with drugs that inhibit the activity of hepatic microsomal enzymes such as cimetidine, it can slow down the metabolism and excretion of this product in the liver, and prolong the blood elimination half-life (T1/2b) of this product. It should be measured according to the blood drug concentration. Adjust dose as a result.
4． This product can interfere with the metabolism of disulfiram. When the two are used together, patients may develop mental symptoms after drinking alcohol. Therefore, patients who have used disulfiram within 2 weeks should not use this product again.
5. This product can interfere with the measurement results of serum aminotransferase and lactate dehydrogenase, and can reduce cholesterol and triacylglycerol levels.
Drugs for pregnant and lactating women[3]
Metronidazole, the hydrolyzate of this product, can pass through the placenta and quickly enter the fetal circulation. Animal experiments found that intraperitoneal administration was toxic to the fetus, while oral administration was not toxic. There is no sufficient and rigorous controlled observation of the effect of this product on the fetus, so it is contraindicated for pregnant women.
The concentration of metronidazole in breast milk is similar to that in blood. Animal tests have shown that metronidazole is carcinogenic to young rats, so lactating women should not use it. If medication is necessary, breastfeeding should be suspended and breastfeeding should be resumed 24 to 48 hours after the end of the course of treatment.
Preparation[4]
Metronidazole and phosphorus oxychloride undergo esterification and hydrolysis reactions to prepare metronidazole monophosphate, which is converted into sodium salt in methanol to obtain metronidazole disodium phosphate monohydrate, with a total yield of 85%.
1) Metronidazole monophosphate (4)
POCl3 (47ml, 0.51mol) was dissolved in acetonitrile (350ml), added 2 (360g, 0.35mol), stirred at 10-18℃ for 40min, and let stand at 0℃ for 3h. Filter, dissolve the filter cake in water (140 ml), stir for 30 minutes and then evaporate the water under reduced pressure. Add 95% ethanol (350 ml) to the residue, stir for 10 minutes and leave to stand at 0°C for 3 hours to crystallize. Filter and dry the filter cake to obtain white solid 4 (81g, 86%), mp 225~226°C (document [9]: 237~238°C).
2) Metronidazole disodium phosphate (1)
4 (81g, 0.3mol) was dissolved in methanol (1.6L) with stirring, and Na2CO3 (35g, 0.33mol) was added. p-toluenesulfonic anhydride was released without bubbles and then decolorized with activated carbon (4g). The filtrate was evaporated under reduced pressure to remove methanol. The residue was dissolved in water (160 ml), recrystallized with 95% ethanol (850 ml), filtered, and the filter cake was dried under reduced pressure at 50°C to obtain white solid 1 (93g, 99%), mp>300°C. IR(KBr)n(cm-1): 3556, 3217, 1684, 1654, 1545, 1489, 1476, 1370, 1125, 1060. 1HNMR(D2O)d: 2.35(s, 3H, -CH3), 3.83～3.87 (q, 2H, -NCH2-), 4.33~4.36 (t, 2H, -CH2O-), 7.82 (s, H, =CH-N). 13CNMR(D2O)d: 13.7(-CH3), 47.3(NCH2-), 62.5(-CH2O), 132.8(=CH-N), 138.4(=C-NO2), 153.3(-C=N). FAB-MS (m/z): 272 (M+-Na-H2O), 250 (M+-2Na-H2O+H). After drying under reduced pressure at 120°C, the moisture content was 5.93% (theoretical value 5.75%) by thermogravimetric analysis.
Main reference materials
[1] CN93111862.X Metronidazole Phosphate Rohm and Haas Plasticizer Disodium Powder for Injection
[2] Commonly Used New Drugs Handbook
[3] Instructions for Metronidazole Disodium Phosphate for Injection
[4] Synthesis of metronidazole disodium phosphate
