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Novel anti-tumor epirubicin compound

A compound and composition technology, applied in the field of medicine, can solve problems such as unqualified raw materials, danger to patients, and large increase in related substances, achieve good industrial value or medicinal value, reduce manufacturing costs and costs, facilitate storage and transport effect

Inactive Publication Date: 2020-03-06
刘力
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

What is not known to many professionals is that some APIs that have been industrially produced for many years are even put into the same batch of raw materials in the same workshop and the same equipment under the same process flow, and the product stability of different batches varies greatly. Even under the specified conditions, it can only maintain stability for about 2 to 3 months, and some quality control indicators have obvious changes in varying degrees, which brings confusing or difficult problems, various potential threatening problems continue, and even Although the problematic product may have been listed in the Pharmacopoeia, there is no doubt that there is a great unexpected danger to the patient
Judging from the current actual situation, although epirubicin hydrochloride has been on the market for many years, there are still some problems in the stability of epirubicin hydrochloride anhydrate, for example, the large hygroscopicity, the decline in the storage period, or the related substances The increase range is too large, etc., and these problems have not been solved for many years. There are large differences in the quality control index settings of epirubicin hydrochloride in China, the United States or the Japanese Pharmacopoeia, which may easily lead to unqualified raw materials or problems in the preparation of preparations. Let us seek solutions to compound stability problems
Although it is hoped to obtain valuable results by changing the crystal form on the basis of the unchanged molecular formula of the compound, it has not been significantly improved, and various problems still exist
Moreover, epirubicin hydrochloride 1 hydrate also has a large problem of hygroscopicity
[0006] However, so far, there are no published literature reports at home and abroad for the novel epirubicin hydrochloride compounds of the present invention that are easier to prepare or have better stability, such as epirubicin hydrochloride ν-type crystal compounds, that is, different molecular formulas or structural forms Novel compound of epirubicin hydrochloride and its preparation method and use

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0100] The preparation of embodiment 1 epirubicin hydrochloride 1.5 hydrate (ν type)

[0101]Add 10g of epirubicin and 20ml of dichloromethane to a 250ml three-necked flask at room temperature, pass nitrogen protection, stir, add 5% hydrochloric acid and 95% ethanol solution to adjust the pH value of the solution to about 3.4, and raise the temperature to about 30-40°C , add an appropriate amount of dichloromethane, stir to dissolve, then add 10ml of ethanol, stir, evaporate part of the solvent under reduced pressure, add 80ml of isopropanol, 5ml of ether, cool to 0°C and place it until the precipitate is fully separated, suction filtration, a small amount Wash with ether, filter with suction, dilute the obtained solid in an oven at about 40°C and blow dry for 3 hours to obtain 9.2 g of orange-red crystals; Identification: ①Take this crystal, add methanol to make a solution containing about 15 μg per 1 ml, and irradiate with ultraviolet light -Visible spectrophotometry (2010 e...

Embodiment 2

[0102] The preparation of embodiment 2 epirubicin hydrochloride 1.5 hydrate (v type compound)

[0103] Add 8g of epirubicin hydrochloride to a 250ml three-necked flask, add 40ml of 95% methanol water, protect with nitrogen, stir, stir at about 50-62°C, add an appropriate amount of methanol and stir until completely dissolved, continue stirring for 0.5 hours, Add 40ml of acetonitrile and about 50ml of isopropanol, cool to below 5°C and place it until the crystals are fully separated, then filter with suction, wash the obtained crystals twice with a small amount of ether and ethyl acetate, filter with suction, and dilute the obtained solids in an oven at 35°C. Air-dried for about 2 hours, and air-dried at about 40°C for 1 hour to obtain 7.2 g of orange-red crystalline solids; identification: ① Take this product, add methanol to make a solution containing about 20 mg per 1 ml, and use UV-visible spectrophotometry ( Appendix IV A) measured, there is maximum absorption at the wavel...

Embodiment 3

[0104] Example 3 Preparation of epirubicin hydrochloride crystalline hydrate freeze-dried powder injection (prescription: 1000 bottles)

[0105] Prescription: epirubicin hydrochloride crystalline hydrate (prepared by the method of embodiment 1 or embodiment 2, the weight of the main ingredient is calculated in terms of epirubicin hydrochloride) 10g, sorbitol 40g, disodium EDTA 0.05g, lactic acid of about 1M and Disodium hydrogen phosphate solution, appropriate amount, appropriate amount of water for injection;

[0106] Take the prescribed amount of epirubicin hydrochloride crystalline hydrate, add sorbitol, and disodium EDTA in the liquid preparation tank, add about 400ml of water for injection, stir to dissolve, and adjust the pH with about 1M lactic acid and disodium hydrogen phosphate solution to 4.5~5.5, add activated carbon 0.01% (W / V), stir for 30 minutes, filter with 0.22 micron microporous membrane, pack according to the weight of main drug 10mg / bottle, freeze at -45~-...

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Abstract

The invention relates to a novel anti-tumor epirubicin compound being an epirubicin hydrochloride v-type compound, wherein the novel compound is easy to prepare and has advantages of less hygroscopicity, improved storage stability, good promotion of drug quality control and the like. The novel anti-tumor epirubicin compound is used for application in treatment and preventive drugs for treatment ofthe malignant lymphomam, breast cancer, lung cancer, soft tissue sarcoma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, melanoma, colorectal cancer, ovarian cancer, multiple myeloma, leukemia, and brain glioma, treatment of the superficial bladder cancer and carcinoma in situ by the intravesical administration, and prevention of recurrence after transurethral resection and the like.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to provide anti-tumor drug epirubicin hydrochloride with new molecular formula and new molecular structure and its pharmaceutical composition with better stability. Background technique [0002] The molecular formula of epirubicin hydrochloride (Epirubicin hydrochloride, CAS Registry Number: 56390-09-1) is C 27 h 29 NO 11 HCl, M=579.98, is the main isomer of doxorubicin, which is the trans configuration of the C4 hydroxyl group in the amino sugar part of doxorubicin, and is a semi-synthetic second-generation anthracycline anticancer antibiotic. The main pharmacological effect is that it can be directly embedded in DNA, form a complex with the double helix structure of DNA, block the formation of RNA dependent on DNA, and have the kinetic energy to form superoxide free radicals. Therefore, this drug can act on the nucleus, It can also affect the cell membrane of tumor cells and i...

Claims

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Application Information

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IPC IPC(8): C07H15/252C07H1/06A61P35/00A61P35/02A61K31/704
CPCA61P35/00A61P35/02C07B2200/13C07H1/06C07H15/252
Inventor 刘力
Owner 刘力
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