What Is Carboplatin?

Carboplatin was discovered by Clear et al in 1980, first listed in the United Kingdom in 1986, and approved by the US FDA in 1989, and its applications have gradually been promoted. China approved the production of carboplatin powder and injection in 1990.

Drug Name: Carboplatin
Alias: Carboplatin
Foreign name: Carboplatin
Whether prescription drugs: prescription
Main indications: Tumor

Adverse reactions: Bone marrow suppression, ototoxicity, nephrotoxicity
Dosage form: injection
Athletes use with caution: Inadvertent use
Drug type: chemical
English abbreviations: CBP

Carboline Introduction

Common name: Carboplatin

Chinese alias: carboplatin, carboplatin, platinum, cisplatin, cisplatin, cisplatin

Foreign names: Carboplatin, Paraplatin, Carboplat, Ercar

English abbreviations: CBP, JM-8, CBDCA

Chemical Name: Cis-Diamino (1,1-cyclobutanediacid) Platinum

Chemical formula:

Molecular formula: C ₆ H ₁₂ N ₂ O ₄ Pt ^[1]

Molecular weight: 371.3 ^[2]

Properties: This product is white or off-white powder or crystalline powder. It is odorless, tasteless, slightly soluble in water, insoluble in ethanol, acetone, ether, and chloroform. It is easy to decompose when exposed to light. ^[1]

This product is a second-generation platinum compound. It was marketed in the United Kingdom in 1986. Its biochemical characteristics are similar to cisplatin, but its renal toxicity, ototoxicity, and neurotoxicity, especially the gastrointestinal response, are significantly lower than DDP. New drugs that are valued ^[3] are the same cell cycle non-specific drugs as DDP. It mainly acts on the N7 and O6 atoms of guanine of DNA, causing inter- and intra-chain cross-linking of DNA, destroying DNA molecules, preventing its helical melting, interfering with DNA synthesis, and producing cytotoxic effects.

Carboplatin in vivo processes

This product is not effective orally. After intravenous injection, there is a linear relationship between the total platinum in the plasma and the free platinum concentration that can be considered, and the amount of the subject. The terminal elimination half-life of the non-binding platinum that can be ultrafiltered and the parent drug are 6 hours. And 1.5 hours. In the initial phase, most ultrafiltration-free free platinum exists in its original form. The terminal half-life of total platinum in plasma is 24 hours, and about 87% of the platinum in the plasma evacuates leukocytes about 24 hours after administration. Mainly excreted from urine, excreted by glomerular filtration within 24 hours.

The pharmacokinetics of carboplatin differs from cisplatin in three ways: first, the serum protein binding rate, carboplatin is only 24%, and cisplatin is above 90%; second, the ultra-filterable non-binding platinum half-life, carboplatin is 6 Hours, while cisplatin is very short, and the blood concentration decreases rapidly. The third is urinary excretion. Carboplatin is 6.5% in one day, while cisplatin is 16% to 35%. Therefore, there is a significant difference in liver toxicity between the two. .

Carboplatin clinical application

This drug is a broad-spectrum antitumor drug. It has no cross-resistance with other anti-tumor drugs and cross-resistance with DDP.

Liver cancer (1) It is mainly used for small cell lung cancer, ovarian cancer, testicular tumor, and head and neck squamous cell carcinoma. For small cell lung cancer, the response rate of this product alone is 60%; the total response rate of combination therapy with Vp-16 and IFO is 78%; the response rates of epithelial ovarian cancer and squamous cell carcinoma of the head and neck are 65% and 29%, respectively.

(2) Can be used for non-small cell lung cancer, bladder cancer, cervical cancer, pleural mesothelioma, melanoma and endometrial cancer.

(3) It can also be used for digestive system tumors, liver cancer, etc. and radiotherapy.

Carboplatin dosage

(1) Intravenous infusion or intravenous injection: once administration method, 300 ~ 400mg / m2 each time, repeated on the 28th, children can increase to 560mg / m2; even

Intravenous drip Continue administration for 5 days, 100 mg / time, or 50 ~ 70 mg / m2 each time. Dilute with saline or 5% glucose injection.

(2) Intrathoracic injection: its dose is higher than intravenous administration.

Carboplatin adverse reactions

(1) Bone marrow suppression: It is a dose-limiting toxicity. When long-term high-dose administration, it can reduce platelets, hemoglobin, and leukocytes. It usually occurs on the 14th to 21st days after treatment, and recovers on 3 to 4 weeks after stopping treatment.

Carboplatin (2) Gastrointestinal reactions: loss of appetite, nausea, and vomiting, which are milder than DDP.

(3) There is no significant effect on liver, kidney, and heart function at conventional doses.

(4) Adverse reactions such as neurotoxicity, ototoxicity, hair loss, and dizziness are lower than DDP, with occasional allergies. Neurotoxicity refers to the numbness or tingling sensation in the toes, which has a cumulative effect; ototoxicity occurs first with high-frequency hearing loss, and occasionally tinnitus.

(5) Allergic reactions (rash or itching, occasional wheezing), occurring within minutes after use

Carboplatin

Patients with obvious bone marrow suppression and liver and kidney dysfunction, pregnant women and patients with severe complications, are all contraindicated to this product or other platinum preparations and mannitol.

Carboplatin considerations

(1) Before using this product, dissolve it with 10ml of normal saline or 5% glucose injection, then dilute it with 250-500ml of 5% glucose injection, and inject intravenously for half an hour or 1 hour. When using CBP, although it is not necessary to hydrate, patients should be encouraged to drink more water, and the urine output should be maintained at about 2000ml per day.

(2) After the product is dissolved, it should be used up within 8 hours and protected from light.

(3) This product is for intravenous administration only, and should not be leaked out of blood vessels.

(4) This product should avoid contact with aluminum compounds, and it should not be mixed with other drugs.

(5) Blood images, liver and kidney functions should be checked regularly before and during the medication period.

(6) Patients should be followed up to check hearing, nerve function, blood urea nitrogen, creatinine clearance and serum creatinine measurement, hematocrit, hemoglobin measurement, white blood cell classification and platelet count, serum calcium, magnesium, potassium, sodium content .

Carboplatin formulation specifications

Injection: 100mg / piece. Powder injection: 50mg, 100mg, 150mg, 450mg.

Carboplatin storage

Store at room temperature away from light.

Physical and chemical properties of carboplatin

The solid carboplatin is a white crystalline powder, slightly soluble in water and insoluble in organic solvents such as ethanol. When the temperature is higher than 120 , the appearance gradually changes color, and the decomposition temperature is 247 258 . Solid carboplatin is more stable to light, unstable in aqueous solution, and prone to degradation. The degradation product is diammonium dihydrate dihydrate, which is accelerated by ultraviolet light irradiation [1]. Carboplatin is stable in 5% glucose or 0.45% sodium chloride solution for the first 6 hours, but loses 2% at 24 hours at 25 ° C; 5% is lost for 24 hours in 0.9% sodium chloride solution, and 24 hours at 37 ° C It loses 10%. It should be protected from light and dissolved in carboplatin using a solution containing no chlorine. Carboplatin and aluminum can produce black precipitates and should not be directly contacted.

Carboplatin is a second-generation platinum complex, which is widely used due to its strong antitumor activity, low gastrointestinal response, and low renal toxicity. It can combine with DNA to form cross-bonds, destroy the function of DNA, prevent it from copying and synthesizing, and has killing effect on tumor cells at various stages of growth. It is a cell cycle non-specific drug. Mainly applicable to ovarian cancer, lung cancer, head and neck cancer, germ cell tumor, thyroid cancer, cervical cancer, bladder cancer, etc. Intravenous infusion should avoid direct sunlight, it is best to use black paper for shading, otherwise it will easily break down and fail. Combined with other anticancer drugs, the effect is better.

Carboplatin Instructions for Use

[Drug name] Carboplatin injection

[Alias] carboplatin, carboplatin, cisplatin, cisplatin

[English name] Carboplatin, Paraplatin, CBDCA, JM-8

[Characteristics] It is a second-generation platinum-based antitumor drug. Its biochemical characteristics are similar to cisplatin, but its renal toxicity, digestive tract response, and ototoxicity are low. It is similar to an alkylating agent, which mainly causes intra- and inter-chain cross-linking of DNA, destroys DNA molecules, and causes the helix to disintegrate.

[Indications] It is mainly used for advanced ovarian cancer, testicular cancer, head and neck cancer, lung cancer, etc. that cannot tolerate vomiting caused by cisplatin.

[Usage and Dosage] Intravenous: 40Omg / m2, make a 10mg / ml solution with 5% glucose injection, and then add 5% glucose solution to 250 500ml, and finish dripping within 15 60min. Dosing for 5 consecutive days. The next course should be given at least 4 weeks after the previous course. The existing water injection is more convenient to use.

[Adverse reactions] The main toxicity is bone marrow suppression, such as leukocytes and thrombocytopenia, and a few patients also have hemoglobin decline. This product can cause gastrointestinal reactions such as nausea and vomiting, but it is milder than cisplatin. Individual patients have elevated SGPT and abnormal ECG. Ototoxicity and hair loss are also lower than cisplatin.

Precautions

1. Use with caution if you have a history of allergies to the use of cisplatin or other platinum-containing compounds.

2. Pregnant or lactating women and elderly patients do not use or use with caution.

3. Be used with caution in patients with medical diseases, especially chickenpox, shingles, infections, and impaired renal function.

4. Patients who cannot tolerate mannitol may not be able to tolerate injection of carboplatin due to the mannitol contained in its formula.

5. Follow-up inspection during medication:

(1) Listening;

(2) neural function;

(3) Determination of blood urea nitrogen, creatinine clearance and serum creatinine;

(4) Hematocrit, hemoglobin measurement, white blood cell classification, and platelet count;

(5) Determination of serum calcium, magnesium, potassium and sodium content.

Carboplatin identification

(1) Take about 5mg of this product, add a little thiourea, add an appropriate amount of water, heat, and the solution is yellow.

(2) Take this product, add water to make a solution containing about 1mg per 1ml, add 3 drops of 2mol / L sulfuric acid solution, heat to boiling, add 2 drops of potassium potassium iodide test solution, the solution will turn yellow, and it will become instantaneous Reddish-brown. After standing for 5 minutes, it turned light blue and purple, and black precipitation occurred.

(3) Take 25mg of this product, put it in an evaporation dish, add 2ml of sulfoxide, stir well, put it on a water bath and evaporate to dryness, add 2ml of saturated hydroxylamine hydrochloride in ethanol solution, and then add 0.5% sodium hydroxide ethanol solution to make it alkaline. After heating and cooling, add dilute sulfuric acid to make it acidic. Take the supernatant and add a few drops of ferric chloride test solution. The solution is brownish red or purple.

(4) The infrared absorption spectrum of this product should be consistent with the reference spectrum.

Carboplatin check

Clarity of the solution: Take 80mg of this product. After adding 10ml of water to dissolve, the solution should be clear. The pH is taken from the solution under the clarity of the solution and measured according to the law (Appendix VIH). The pH value should be 5.5 to 7.5. Relevant substances are taken from this product and measured according to the method under content determination. The sum of the peak areas of each impurity must not be greater than 2.0% of the peak area of the main component. Take 80mg of acid-soluble barium salt, add 10ml of water to dissolve, add 2ml of dilute hydrochloric acid, and boil for 5 minutes. After replenishing the evaporated water, let it cool, filter through the filter paper washed with hydrochloric acid solution (1 40), filter residue and funnel Add a small amount of water (about 2ml) for washing, combine the washing solution with the filtrate, add 0.5ml of dilute sulfuric acid, and leave it for 30 minutes without turbidity. Take this product after losing weight and dry it at 105 to constant weight. The weight loss should not exceed 0.5% (Appendix L).

Determined by high performance liquid chromatography (Appendix VD). Chromatographic conditions and system suitability tests use octadecylsilane bonded silica as a filler; water as a mobile phase; flow rate of 2 ml per minute; detection wavelength of 229 nm. The number of theoretical plates calculated based on the carboplatin peak should not be less than 3000, and the resolution of the carboplatin peak and the internal standard substance peak should meet the requirements. Preparation of the internal standard solution Take about 25mg of uridine, accurately weigh it, place it in a 25ml measuring bottle, add water to dissolve and dilute to the mark, and shake well. Take about 25mg of this product by measuring method, accurately weigh, place in a 25ml measuring bottle, add water to dissolve and dilute to the mark, shake well; accurately measure 5ml each of this solution and the internal standard solution, place in another 25ml measuring bottle, and dilute with water To the scale, shake well, take 10l into the liquid chromatograph, record the chromatogram; take another carboplatin reference substance for the same measurement. Calculate the peak area according to the internal standard method.

Carboplatin determination method

Method name: Carboplatin API-Carboplatin-High Performance Liquid Chromatography

Scope of application: This method uses high-performance liquid chromatography to determine the content of carboplatin in carboplatin raw materials.

This method is applicable to carboplatin drug substances.

Principle of the method: The test product is dissolved in water and quantitatively diluted. After the internal standard is added, the sample is quantitatively diluted with water. It enters a high-performance liquid chromatography for chromatographic separation, and the peak area of carboplatin is detected at a wavelength of 229 nm using an ultraviolet absorption detector. Calculate its content.

Reagent: water

Equipment: 1. Instrument

1.1 HPLC

1.2 Column

Octadecylsilane-bonded silica gel is used as a filler, and the theoretical plate number should not be less than 3000 based on the carboplatin peak calculation.

1.3 UV absorption detector

Chromatographic conditions

2.1 Mobile phase: water

2.2 Detection wavelength: 229nm

2.3 Flow rate: 2mL / min

2.4 Column temperature: room temperature

Sample preparation: 1. Preparation of internal standard solution

Weigh approximately 25mg of uridine accurately, place it in a 25mL volumetric flask, add water to dissolve and dilute to the mark, and shake well to obtain the internal standard solution.

2. Preparation of reference solution

Precisely weigh about 25mg of carboplatin reference substance, place it in a 25mL volumetric flask, add water to dissolve and dilute to the mark, shake well, accurately measure 5mL each of this solution and the internal standard solution, place in another 25mL volumetric flask, and dilute to the mark with water , Shake well, that is the reference solution.

3. Preparation of test solution

Precisely weigh about 25mg of the test product, place it in a 25mL volumetric flask, add water to dissolve and dilute to the mark, shake well, accurately measure 5mL each of the solution and the internal standard solution, and place in another 25mL volumetric flask, and dilute to the mark with water. Shake well to prepare the test solution.

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.

Operation steps: Precisely draw 10 mL of each of the reference solution and the test solution, and inject them into a high-performance liquid chromatograph. Use a UV absorption detector to measure the peak area of carboplatin (C6H12N2O4Pt) at a wavelength of 229 nm and calculate its content.

References: Pharmacopoeia of the People's Republic of China, compiled by the National Pharmacopoeia Committee, Chemical Industry Press, 2005 edition, one, p.108.