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A stable and safe idarubicin pharmaceutical composition and preparation method thereof

A technology of idarubicin and compounds, applied in the field of stable idarubicin pharmaceutical composition and its preparation, can solve problems affecting drug stability, drug efficacy or side effects, and achieve increased cardiotoxicity and good stability sexual effect

Active Publication Date: 2020-03-31
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of impurities may not only affect the stability of the drug, but may also affect the efficacy or side effects of the drug.

Method used

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  • A stable and safe idarubicin pharmaceutical composition and preparation method thereof
  • A stable and safe idarubicin pharmaceutical composition and preparation method thereof
  • A stable and safe idarubicin pharmaceutical composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of embodiment 1 impurity A (hydrochloride)

[0032] (1) Preparation of compound 1

[0033] Dissolve 10 g of idarubicin hydrochloride in 100 ml of dichloromethane, add 10 g of triethylamine and 7.5 g of ethyl trifluoroacetate, and stir at room temperature for 4 h; add 100 ml of dichloromethane to dilute the reaction solution, wash twice with water, spin dry the organic phase, 10.4 g of solid was obtained (yield 94%, HPLC purity 97%).

[0034] (2) Preparation of Compound 2

[0035] Under anhydrous and oxygen-free conditions, 8g of compound 1 was dissolved in anhydrous dichloromethane (80ml), and trifluoromethanesulfonic anhydride (2eq) and triethylamine (2.2eq) were added under ice-cooling conditions, and reacted for 2 hours. Dilute the reaction solution with 80ml of methyl chloride, wash twice with water, and spin dry the organic phase to obtain 8.1g of solid (83% yield)

[0036] (3) Preparation of Compound 3

[0037] Dissolve 7g of compound 2 in diox...

Embodiment 2

[0040] Example 2 Toxicity studies of impurity A

[0041] Select 30 adult female Wistar rats, randomly divide them into blank group, positive drug group, and impurity A group, 10 rats in each group, administer once a week, and collect serum to detect brain natriuretic peptide (BNP) after 6 weeks of continuous administration and troponin I (cTnI) levels. Impurity A is prepared from Example 1. Idarubicin hydrochloride is self-made by the company, and its HPLC purity is 99.91%. The result is as follows:

[0042]

[0043] *P<0.05

[0044] It can be seen from the above table that compared with the blank group, the BNP and cTnl contents of the positive drug group and the impurity A group were significantly increased, and the value of the impurity A group was higher than that of the positive drug group, and the results were statistically different. This shows that both idarubicin and impurity A have certain cardiotoxicity, and the cardiotoxicity of impurity A is greater than th...

Embodiment 3

[0045] Example 3 Stability investigation

[0046] Composition samples with different contents of impurity A were subjected to accelerated test investigation under the conditions of temperature 40±2°C and relative humidity 75%±5%, left for 30 days, and samples were taken on day 0, day 10 and day 30, Investigate changes in product appearance and purity. The compositions whose mass ratios of idarubicin hydrochloride and impurity A are 1:0.2%, 1:0.3%, 1:0.4%, 1:0.5%, 1:0.6% are compositions 1, 2, 3, 4, 5. The purity of idarubicin hydrochloride is 99.9%, impurity A is prepared by embodiment 1. The results are shown in the table below:

[0047]

[0048]

[0049] The above results show that when the content of impurity A in the composition does not exceed 0.3%, idarubicin hydrochloride can maintain high stability, and when the content of impurity A reaches 0.4%, 0.5%, and 0.6%, the color of the product gradually becomes darker , the content of other impurities increases, and ...

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Abstract

The invention discloses a stable and safe idarubicin pharmaceutical composition and a preparation method thereof. The pharmaceutical composition contains idarubicin or a pharmaceutically acceptable salt thereof and a compound of formula A or a pharmaceutically acceptable salt thereof in an amount of no more than 0.3%. According to the method, an impurity A in idarubicin is separated and confirmed.Prior to this, there is no report that the impurity A is present in the idarubicin. The impurity A is fully researched, it is found that the existence of the impurity A affects the physical and chemical stability of idarubicin and increases cardiac toxicity of idarubicin. The pharmaceutical composition enables idarubicin to maintain good stability. The invention further provides a method for preparing the impurity A. The high-purity impurity A can be acquired to serve as a reference sample or a standard sample for controlling the content of the impurity A in idarubicin and preparations thereof.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a stable idarubicin pharmaceutical composition and a preparation method thereof. Background technique [0002] Idarubicin, namely 4-demethoxydaunorubicin, is a semi-synthetic anthracycline antineoplastic drug, which is clinically used to treat acute myelogenous leukemia (AML) and was launched in the United States in 1990. Its mechanism of action is that idarubicin with a rigid structure inserts into DNA to interfere with nucleic acid synthesis, and idarubicin can also interact with topoisomerase II to further interfere with nucleic acid synthesis. At present, the combination of idarubicin and cytarabine is the first choice for the treatment of AML. The hydrochloride salt of idarubicin is clinically used, as shown in the following structure: [0003] [0004] Studies have shown that idarubicin has some cardiotoxicity manifested as early (i.e. acute) or late (i.e. del...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/704C07H15/252C07H1/00A61P35/00
CPCA61K31/704C07H1/00C07H15/252
Inventor 刘丹苏进财代清宇吴舰王华萍柴雨柱徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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