What Is Ganciclovir?

Prevent and treat cytomegalovirus infections in immunocompromised patients, such as AIDS patients, tumor patients undergoing chemotherapy, and organ transplant patients using immunosuppressants.

Chinese name: Ganciclovir
Foreign name: ganciclovir

Formulation specifications: 540 mg lyophilized per vial
Drug alias: Cymevene

Introduction to Ganciclovir Compounds

Ganciclovir Basic Information

Chinese name: Ganciclovir

Chinese alias: 9- (1,3-dihydroxy-2-propoxymethyl) guanine; Ganciclovir hydrate; Gancilovir; Propoxyguanosine

English name: ganciclovir

English alias: biolf62; Ganciclovir; bw-759u; GVC; bwb759u;

CAS number: 82410-32-0

Molecular formula: C ₉ H ₁₃ N ₅ O ₄

Structural formula:

Molecular weight: 255.23100

Exact mass: 255.09700

PSA: 139.28000

Ganciclovir physicochemical properties

Appearance and properties: white powder

Density: 1.81 g / cm ³

Melting point: 250 ° C

Boiling point: 675ºC at 760 mmHg

Stability: Avoid exposure to temperatures above 40ºC. Sterile powders have a validity of 3 years.

Storage conditions: 2-8ºC

Ganciclovir Safety Information

Symbol: GHS08

Signal Word: Danger

Hazard statement: H360

Cautionary statement: P201; P308 + P313

Customs code: 2933990090

WGK Germany: 3

Danger category code: R46; R60; R61

Safety instructions: S53-S36 / 37 / 39-S45

RTECS number: MF8407000

Dangerous goods mark: T ^[1]

Ganciclovir production method

Compound (I) (15 g, 0.088 mo1) was suspended in 200 ml of HMDS (1, 1, 1, 3, 3, 3-hexam. Ethyldisilizane), and 1.5 g of ammonium sulfate was added and refluxed for 2 h. The reaction solution was concentrated under reduced pressure. Mercury cyanide (24 g, 0.095 mo1) and 250 ml of benzene were added to the remaining yellow solid, and heated to reflux. Add 6-chloroguanine (29.93 g, 0.093 mo1) ^[1]

Ganciclovir uses

It is suitable for immunocompromised patients with life-threatening or visual cytomegalovirus (CMV) infection, such as AIDS, patients with exogenous immunosuppression related to organ transplantation and tumor chemotherapy. It is used as an intermediate of antiviral drugs for the treatment of cytomegalovirus (CMV) infection caused by low immunity ^[1] .

Ganciclovir experimental analysis

Method name: Ganciclovir API-determination of ganciclovir-non-aqueous titration

Scope of application: This method uses titration to determine the content of ganciclovir in the ganciclovir API.

This method is applicable to the ganciclovir drug substance.

Principle of the method: After the test product is dissolved in glacial acetic acid, a crystal violet indicator solution is added, and the solution is titrated with a perchloric acid titration solution until the solution becomes green. Wei content.

Reagent: 1. Glacial acetic acid

2. Perchloric acid titrant (0.1mol / L)

3. Crystal violet indicator liquid

4. Reference potassium hydrogen phthalate

equipment:

Sample preparation: 1. Perchloric acid titration solution (0.1mol / L)

Preparation: Take 750mL of anhydrous glacial acetic acid (calculated with water content, add 5.22mL of acetic anhydride per 1g of water), add 8.5mL of perchloric acid (70 ~ 72%), shake well, let cool, add an appropriate amount of anhydrous glacial acetic acid 1000mL, shake well and leave for 24 hours. If the test sample is easily acetylated, the water content of the solution must be determined by the moisture measurement method, and then the water content of the solution is adjusted to 0.01% to 0.2% with water and acetic anhydride.

Calibration: Take about 0.16g of standard potassium hydrogen phthalate dried to constant weight at 105 , accurately weigh, add 20mL of anhydrous glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, and slowly titrate with this solution to Blue, and the titration results are corrected with a blank test. Each 1mL of perchloric acid titration solution (0.1mol / L) is equivalent to 20.42mg of potassium hydrogen phthalate. Calculate the concentration of this solution based on the consumption of this solution and the amount of potassium hydrogen phthalate taken.

Crystal violet indicator liquid

Take 0.5 g of crystal violet and add 100 mL of glacial acetic acid to dissolve.

Operation steps: Weigh accurately about 0.15g of the test sample, add 40mL of glacial acetic acid, heat to dissolve, let cool, add 1 drop of crystal violet indicator solution, titrate with perchloric acid titration solution (0.1mol / L) until the solution becomes green And correct the titration results with a blank test. Each 1mL of perchloric acid titration solution (0.1mol / L) is equivalent to 25.52mg of C9H13N5O4.

Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measurement" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards ^[2] .

Ganciclovir Pharmacopoeia Standard

Ganciclovir source (name), content (potency)

This product is 9-[[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl] guanine. Calculated on dry basis, containing C9H13N5O4 shall not be less than 99.0%.

Ganciclovir traits

This product is white crystalline powder; odorless, tasteless; hygroscopic.

This product is slightly soluble in water or glacial acetic acid, almost insoluble in methanol and insoluble in dichloromethane; slightly soluble in hydrochloric acid solution or sodium hydroxide solution.

Ganciclovir identification

(1) Take an appropriate amount of this product, dissolve and dilute with water to make a solution containing about 10 g per 1 ml, and determine the maximum absorption at a wavelength of 252 nm according to the ultraviolet-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of 2010 Edition) There is minimal absorption at a wavelength of 222 nm.

(2) The infrared absorption spectrum of this product should be the same as that of the reference substance (Appendix IV C of Part Two of the 2010 Pharmacopoeia). If inconsistent, take appropriate amounts of this product and reference product, add water to make a saturated solution, and filter. Take the filtrate and leave it below 10 ° C overnight. After the crystals precipitate, filter, dry the filter residue at 105 ° C, and measure again.

Ganciclovir check

relative substance

Take 15mg of this product, accurately weigh it, place it in a 50ml measuring bottle, add 1ml of 0.4% sodium hydroxide solution to dissolve, dilute to the mark with mobile phase, shake well, and use it as the test solution; take 1ml of precise amount and set it to 100ml In the bottle, dilute to the mark with mobile phase, shake well, and use it as a control solution. Measured by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), using octadecylsilane bonded silica as a filler, methanol-water (5:95) as the mobile phase, and the detection wavelength is 252nm; theoretical plate The number is not less than 3000 calculated by the ganciclovir peak. Take 20 l of the control solution and inject it into the liquid chromatograph to adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 15% of the full scale. Precisely measure 20 l each of the test solution and the control solution, and inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of the main component peak. If there is an impurity peak in the chromatogram of the test solution, the sum of the area of each impurity peak must not be greater than the main peak area (1.0%) of the control solution.

Loss on drying

Take this product and dry it at 105 to constant weight, and the weight loss shall not exceed 6.0% (Appendix L of Part Two of the Pharmacopoeia of 2010 Edition).

Residue on ignition

Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

Heavy metal

Take the residue left under the burning residue and inspect it according to law (Appendix H, the second method of the 2010 edition of the Pharmacopoeia, the second method). The content of heavy metals must not exceed 10 parts per million.

Determination of ganciclovir content

Take about 0.15g of this product, accurately weigh, add 40ml of glacial acetic acid, heat to dissolve, let cool, add 1 drop of crystal violet indicator solution, titrate with perchloric acid titration solution (0.1mol / L) until the solution becomes green, and The results of the titration were corrected with a blank test. Each 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 25.52mg of C ₉ H ₁₃ N ₅ O ₄ ^[3] .

Ganciclovir Categories

Antiviral drugs.

Ganciclovir storage

Shaded and sealed.

Ganciclovir preparation

(1) Ganciclovir sodium chloride injection (2) Ganciclovir for injection

Ganciclovir drug description

Ganciclovir Pharmacology and Toxicology

The intracellular glycoxyguanosine is phosphorylated to the monovalent phosphate of deoxyguanosine by the action of deoxyguanosine kinase. It can also be further phosphorylated to the trivalent phosphate by some cell kinases. Endopropoxyguanosine can be preferentially phosphorylated. The metabolism of propoxyguanosine trivalent phosphate is very slow, and it can still be stored at 60 70% after 18 hours of separation from extracellular fluid. The mechanism of inhibiting viral DNA synthesis is: 1. Competitively inhibits the binding of deoxyguanosine trivalent phosphate to DNA polymerase; 2. The combination of propoxyguanosine trivalent phosphate and viral DNA finally causes the suspension of DNA extension. It has been found that patients with cytomegalovirus infection treated with this drug can develop acute drug resistance. Propoxyguanosine is a chemically synthesized guanine analog that prevents the replication of herpes virus. Viruses that are sensitive to it include CMV, HSV-1, HSV-2, EBV, VZV. Clinical studies are limited to evaluating the efficacy of patients with cytomegalovirus infection.

Ganciclovir pharmacokinetics

The drug is mainly excreted by glomerular filtration. In patients with normal renal function, after continuous injection at a dose of 5 mg / kg body weight for 1 hr, the half-life was 2.9 hr, and the average clearance rate was 3.64 mL / min / kg body weight. At a dose of 5 mg / kg body weight, two injections per day did not cause drug accumulation after 14 days. In patients with renal insufficiency, when the serum creatinine content is & lt; 124 mmoL / L, 125-225 mmol / L, and 226-398 mmoL / L, the plasma clearance and half-life of the drug are 3.64 mL / min / kg body weight and 2.9 hr, 2.01 mL / min / kg body weight and 5.3 hr and 1.11 mL / min / kg body weight and 9.7 hr. In patients with severe renal impairment, hemodialysis can reduce drug concentrations by 50%.

Ganciclovir indication

Blind cytomegalovirus retinitis, AIDS, tube transplantation, malignant tumors, etc. caused by severe immunodeficiency, as well as pneumonia, gastroenteritis, liver and central nervous system CMV infection.

Ganciclovir adverse reactions

Leukopenia and thrombocytopenia are the most common. Anemia, fever, rash, abnormal liver function, edema, infection, and fatigue are rare. Arrhythmia, high / low blood pressure. Abnormal thinking or nightmares, ataxia, coma, dizziness, headache, nervousness, sensory disturbance, psychosis, lethargy, tremor. Nausea, vomiting, diarrhea, gastrointestinal bleeding, abdominal pain. Eosinophils increase and hypoglycemia. Difficulty breathing. Hair loss, itching, hives. Increased hematuria and urea nitrogen. Retinal detachment may occur in AIDS patients with cytomegalovirus-infected retinitis. Infection, pain, and phlebitis can be seen at the injection site.

Ganciclovir drug interactions

Probenecid and other drugs that can inhibit the secretion and reabsorption of renal tubules can reduce the clearance of the drug to the kidney and extend its half-life. The simultaneous use of this drug and drugs that inhibit rapid cell division and replication can produce a synergistic effect. This medicine is used in combination with dapsone, pentanesulfon, flucytosine, vincristine, vinblastine, doxorubicin, amphotericin, trimethoxypyrimidine and some nucleoside drugs, which can increase side effects occur. Most people with AIDS who use this medicine and zidovudine will have severe white blood cell reduction. This drug can be used in combination with imitalen / cilastatin sodium to induce epilepsy.

Ganciclovir dosage

Treatment and prevention of cytomegalovirus infection: 5 mg / kg body weight / time, two intravenous injections per day, each injection time should be more than 1 hr, and maintained for 14 to 21 days. Maintenance period: 6 mg / kg body weight / day, 5 days per week or 5 mg / kg body weight / day, 7 days per week, intravenously. When the patient's retinitis develops further, the induction dose needs to be treated again.

The cytomegalovirus infection-preventive induction amount is 5 mg / kg body weight, which is injected every 12 hr for 7 to 14 days.

When the patient has renal insufficiency, the induction dose should be adjusted as follows: those with serum creatinine <124 moL / L, the dose remains unchanged; when the blood creatinine is 125 225 moL / L, use 2.5 mg / Kg body weight, twice daily dose ; When blood creatinine is 226 to 398 moL / L, the dose is 2.5 mg / kg body weight, once a day; when blood creatinine> 398 moL / L, the dose is 1.25 mg / kg body weight, once a day. The optimal maintenance dose is not clear, and the dosage for dialysis patients is 1.25 mg / kg body weight / day. Medication should be taken immediately after the day of dialysis. Symptoms A single intravenous injection of 500 mg / kg to animals can produce vomiting, excessive salivary secretion, bleeding, late purity, abnormal liver function, elevated urea nitrogen, testicular atrophy, and death. Treatment of hemodialysis and increased fluid replacement can reduce drug plasma concentrations. 10 mL of water for injection should be added to each vial, and its preparation solution concentration is 50 mg / mL. Add the drug to 100 mL of intravenous injection solution, and the injection time should exceed 1 hr. 0.9% physiological saline, 5% glucose, sodium lactate injection and Ringer's solution can be compatible with this medicine, and the antibiotic solution containing parabens is not compatible with this medicine. The diluted injection solution should be refrigerated but not frozen, and must be used within 24 hrs ^[4] .

Ganciclovir notes

Pregnant and lactating women, allergic to this medicine or acyclovir is contraindicated. Preclinical studies on carcinogenicity, teratogenicity and effects on fertility have found that this drug can cause sperm reduction, mutation, teratogenicity and carcinogenesis, and contraception should be taken within 90 days of stopping treatment. Leukopenia occurs in approximately 10 to 40% of patients treated, so this drug should be used with caution in patients with a history of leukopenia. Thrombocytopenia occurred in 10% of patients treated with this drug (less than 50,000 cells / L), and patients treated with immunosuppressive drugs had a lower decline than patients with AIDS. When the patient's platelet count is less than 100,000 cells / L, the risk of developing thrombocytopenia also increases.

Effects on pregnancy and lactation Animal experiments have found that this drug has teratogenic effects, which cannot be used by pregnant women. This medicine can have adverse effects on the offspring of mammals. It is unknown whether this drug can be secreted into human milk, so it cannot be used in breastfeeding women, and breastfeeding can be resumed after using this drug for 72 hr.

Impact on children The clinical experience of applying to children under 12 years is limited, so children should be used with caution. The adverse effects were reported to be similar to those of adults.

The effect on the elderly should be adjusted according to renal function ^[4] .

Production of ganciclovir

Production unit is Shanghai Roche Pharmaceutical Co., Ltd.

Regarding the synthesis of ganciclovir, there are many methods reported in the literature, but the basic synthesis principles are the same. Since 1982, many companies have applied for ganciclovir synthesis process patents, but basically all purines and Derivatives are used as the main raw material to conduct condensation reaction with various protected 2-hydroxymethyl glycerol, and then remove the protection to obtain. There are also reports of ganciclovir produced by cyclization reaction, but the synthesis of ganciclovir by cyclization route is rare, the process conditions are complex, and the yield is low, which loses its industrial significance.

According to different raw materials, there are five main methods for synthesizing ganciclovir, which are held by ENS Biol of Canada, Syntex of the United States, Merck of the United States, Wellcome Fund Limited of the United Kingdom, and Inke of Spain ^[4] .