WO2023155320A1

WO2023155320A1 - Method for synthesizing anti-tumor drug afatinib

Info

Publication number: WO2023155320A1
Application number: PCT/CN2022/094836
Authority: WO
Inventors: 李小维
Original assignee: 上海龙翔生物医药开发有限公司
Priority date: 2022-02-15
Filing date: 2022-05-25
Publication date: 2023-08-24
Also published as: CN114452290A

Abstract

A method for synthesizing an anti-tumor drug afatinib, the method comprising the following steps: S1: preparing raw materials; S2: preparing a drug; S3: carrying out inspection; S4: carrying out a clinical test; and S5: carrying out a subsequent treatment. The present invention aims to improve the drug property of the drug and increase the clearance rate of tumor cells by means of performing continuous detection and clinical tests during the preparation process of the drug, analyzing obtained data and changing the administration of the drug on the basis of an analysis result. Moreover, the present invention also reduces the decline in the drug property of the drug caused by external factors by means of sampling and inspecting drugs in storage.

Description

A kind of synthetic method of antineoplastic drug Afatinib

technical field

The invention relates to the technical field of synthesis of antitumor drugs, in particular to a method for synthesizing the antitumor drug afatinib.

Background technique

Malignant tumors are one of the most serious diseases that threaten human health and social development today. Among the 184 countries and regions in the world, the incidence of malignant tumors in China is generally at the upper-middle level, accounting for about 21.8% of the global incidence of malignant tumors. Afatinib, whose trade name is Gilotrif, and its English name is afatinib, works by irreversibly blocking ErbB family receptors. Unlike other targeted therapies (such as erlotinib, which is reversible and specifically targets EGFR (ErbB1)), afatinib provides sustained and selective blockade of the entire ErbB receptor family, effectively inhibiting The growth of tumor cells is an important anti-tumor disease drug.

However, the current existing anti-tumor drug synthesis technology still has the problem that the simple drug detection steps lead to strong drug resistance after a period of use of the drug, which makes the tumor cell clearance rate of the drug low. Therefore, we propose an anti-tumor drug A The synthetic method of fatinib is used to solve the above problems.

Contents of the invention

The purpose of the present invention is to solve the problem that the current existing anti-tumor drug synthesis technology still has simple drug detection steps, which leads to strong drug resistance after a period of use of the drug, and makes the tumor cell clearance rate of the drug low, etc., and proposes a Synthesis method of antineoplastic drug afatinib.

In order to achieve the above object, the present invention adopts the following technical solutions:

A kind of synthetic method of antineoplastic drug Afatinib, comprises the following steps:

S1: Preparation of raw materials: prepare the raw materials required for the preparation of drugs;

S2: Prepare the drug: prepare the anti-tumor drug afatinib by mixing the selected raw materials and auxiliary materials;

S3: Perform inspection: inspect the prepared medicine, and process the medicine according to the inspection result;

S4: Clinical trials: select drugs that meet the criteria for clinical trials;

S5: Subsequent processing: the prepared drugs are packaged, coded, stored, and regularly sampled;

Preferably, in the S1, select (2E)-N-[4-(3-chloro-4-fluoroanilino)-7-{[(3S)-oxuron-3-yl]oxy}quinone Azoline-6-yl]-4-(dimethylamino)but-2-enamide is used as a raw material, and cosolvents, preservatives, flavoring agents, surfactants and emulsifiers are selected as auxiliary materials, wherein the cosolvents It is sodium benzoate, the preservative is paraben, the flavoring agent is sweetener and mucilage, the surfactant is monoglyceride fatty acid ester, and the emulsifier is gum arabic;

Preferably, in said S2, the anti-tumor drug afatinib is prepared by mixing the selected raw materials and auxiliary materials by professionals, wherein when preparing the drug, the mass ratio of raw materials and auxiliary materials is 5:2, And the mass component ratio in the excipients is co-solvent: preservative: flavoring agent: surfactant: emulsifier is 1:2:1:2:3, and the prepared medicine is extruded into tablets with equal specifications, wherein the The above specifications include 20mg, 30mg, 40mg and 50mg, and the specifications are selected by professionals;

Preferably, in said S3, the prepared medicine is inspected by a professional, wherein the inspection content includes whether the composition of the medicine has changed, the proportion of the medicine composition, the toxicity of the medicine, and whether the medicine meets the pharmaceutical standards, and the medicine is checked by the test results. For processing, the sampling inspection method of the same specification is adopted during drug inspection, wherein the sampling inspection method of the same specification is to simultaneously extract drugs of the same quality from drugs of different specifications for inspection at the same time period, and the number of sampled drugs: the total number of drugs of the same specification It is 1:50. The test result shows that the drug composition has changed and should be reported immediately, and the changed drug composition is tested, and the test result is processed. If the test result shows that the drug changed composition is a harmful component, all the drugs prepared in the same batch will be processed. Carry out centralized destruction treatment. If the test results show that the changed ingredients of the drug are harmless ingredients, it will not be processed, and the changed ingredients will be added to the instructions. If the test results show that the proportion of the drug ingredients does not meet the set requirements, it will be reported and judged by the superior And issued a processing order, if the test results show that the proportion of drug ingredients meets the set requirements, no processing will be carried out. If there is no toxicity, it will not be processed; if the test result shows that the drug meets the pharmaceutical standard, it will not be processed; if the test result shows that the drug does not meet the pharmaceutical standard, all the drugs prepared in the same batch will be destroyed in a centralized manner;

Preferably, in said S4, clinical trials will be carried out on drugs that have no harmful changes in the composition after the drug test, the proportion of the drug components remains unchanged, the drug is non-toxic, and the drug meets the pharmaceutical standards, and the tumor is tested on the patient before the clinical trial. Cell screening, and record the number of tumor cells. During clinical trials, professionals will set the dosage of drugs and the time interval of drug replenishment. After 2 hours of each medication, the patient will be screened for tumor cells, and the number of tumor cells will be recorded. The recorded data is entered into the computer, and the data is drawn and calculated by the computer. The data drawing includes a histogram of data changes and a line chart of data changes. Change the amount of drug administered to the patient and the interval between drug refills;

Preferably, in said S5, the prepared drugs are packaged, coded, and put into storage, wherein the same batch number is stacked together and stacked separately, and the ambient temperature of the warehouse is kept at 10-20°C. The distance between the wall, the medicine and the roof is not less than 30cm, the distance between the warehouse radiator and the heating pipe is not less than 30cm, and the distance between the ground and the ground is not less than 10cm. The XRD analyzer conducts regular sampling inspections on the same batch of drugs, and the number of tablets sampled during the sampling inspection: the total number of tablets of the same batch number is 1:200, and the interval between two sampling inspections is two months.

Compared with prior art, the beneficial effect of the present invention is:

1. Through continuous detection and clinical trials in the process of drug preparation, and analysis of the obtained data, the drug is changed according to the analysis results, the drug properties of the drug are improved, and the tumor cell clearance rate is enhanced.

2. Through the sampling inspection of the medicines put into the warehouse, the decline of medicine properties caused by external factors is reduced.

The purpose of the present invention is to improve the drug properties of the drug and enhance the tumor cell clearance rate by performing continuous detection and clinical trials in the drug preparation process, and analyzing the obtained data, and changing the drug use from the analysis results. Drugs are sampled and tested to reduce the decline in drug properties caused by external factors.

Description of drawings

Fig. 1 is a flow chart of the synthetic method of a kind of antitumor drug afatinib that the present invention proposes.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them.

Embodiment one

With reference to Fig. 1, a kind of synthetic method of antineoplastic drug Afatinib comprises the following steps:

S1: Raw material preparation: select (2E)-N-[4-(3-chloro-4-fluoroanilino)-7-{[(3S)-oxuronamide-3-yl]oxy}quinazoline- 6-base]-4-(dimethylamino)but-2-enamide as raw material, and choose cosolvent, preservative, flavoring agent, surfactant and emulsifier as adjuvant, wherein said cosolvent is sodium benzoate , the preservative is paraben, the flavoring agent is sweetener and mucilage, the surfactant is monoglyceride fatty acid ester, and the emulsifier is gum arabic;

S2: Preparation of drug: The anti-tumor drug afatinib is prepared by mixing the selected raw materials and auxiliary materials by professionals. When preparing the drug, the mass ratio of raw materials and auxiliary materials is 5:2, and the auxiliary materials in The mass-component ratio is co-solvent: preservative: flavoring agent: surfactant: emulsifier is 1:2:1:2:3, and the prepared medicine is extruded into tablets with equal specifications, wherein the equal specifications Including 20mg, 30mg, 40mg and 50mg, the specifications are selected by professionals;

S3: Inspection: The prepared drug is inspected by professionals, and the inspection content includes whether the composition of the drug has changed, the proportion of the drug ingredient, the toxicity of the drug, and whether the drug meets the pharmaceutical standards, and the drug is processed according to the inspection results. The sampling inspection method of the same specification is used for drug inspection, wherein the sampling inspection method of the same specification is to simultaneously extract drugs of the same quality from drugs of different specifications for inspection at the same time period, and the number of sampling drugs: the total number of drugs of the same specification is 1: 50. The inspection results show that the composition of the drug has changed, which needs to be reported immediately, and the changed composition of the drug is tested, and the test result is processed. If the test result shows that the changed composition of the drug is harmful, all the drugs prepared in the same batch will be destroyed in a centralized manner. Processing, if the test results show that the changed ingredients of the drug are harmless ingredients, no processing will be carried out, and the changed ingredients will be added to the instructions. If the test results show that the proportion of drug ingredients does not meet the set requirements, it will be reported, and the superior will judge and issue a treatment Command, if the test result shows that the proportion of the drug ingredients meets the set requirements, it will not be processed. If the test result shows that the drug is toxic, it needs to be reported, and all the drugs prepared in the same batch will be destroyed in a centralized manner. The test result shows that the drug is not toxic. If the test result shows that the drug meets the pharmaceutical standard, it will not be processed; if the test result shows that the drug does not meet the pharmaceutical standard, all the drugs prepared in the same batch will be destroyed in a centralized manner;

S4: Clinical trial: After the drug test, the ingredients have no harmful changes, the proportion of the drug ingredients remains unchanged, the drug is non-toxic, and the drug meets the pharmaceutical standards for clinical trials. Before the clinical trial, the tumor cells of the patients are screened, And record the number of tumor cells. During the clinical trial, professionals will set the dosage of drugs and the time interval of drug replenishment. After 2 hours of each drug, the patient will be checked for tumor cells, and the number of tumor cells will be recorded. The data recorded each time will be recorded. Computer input, data drawing and calculation by the computer, wherein the data drawing includes a data change histogram and a data change line chart, which is analyzed by professionals through the drawn graphs and calculated data, and changes the results of the analysis to patients The amount of drug used and the interval between drug refills;

S5: Subsequent processing: the prepared drugs are packaged, coded, and put into the warehouse. The same batch number is stacked together and stacked separately when put into the warehouse. The ambient temperature of the warehouse is kept at 10-20°C. The distance between the medicine and the roof is not less than 30cm, the distance between the radiator and the heating pipe in the warehouse is not less than 30cm, and the distance between the ground and the ground is not less than 10cm. After entering the warehouse, the XRD analyzer must be used by professionals if the medicine has not been released within two months. Regular sampling inspections are carried out on the same batch of drugs, and the number of tablets sampled during the sampling inspection: the total number of tablets of the same batch number is 1:200, and the interval between two sampling inspections is two months.

Embodiment two

S1: Raw material preparation: select (2E)-N-[4-(3-chloro-4-fluoroanilino)-7-{[(3S)-oxuronamide-3-yl]oxy}quinazoline- 6-yl]-4-(dimethylamino)but-2-enamide as a raw material, and selecting cosolvents, preservatives, flavoring agents, surfactants and emulsifiers as auxiliary materials;

Embodiment three

S3: Inspection: The prepared drug is inspected by professionals, and the inspection content includes whether the composition of the drug has changed, the proportion of the drug ingredient, the toxicity of the drug, and whether the drug meets the pharmaceutical standards, and the drug is processed according to the inspection results. The sampling inspection method of the same specification is used for drug inspection, wherein the sampling inspection method of the same specification is to simultaneously extract drugs of the same quality from drugs of different specifications for inspection at the same time period, and the number of sampling drugs: the total number of drugs of the same specification is 1: 50;

Embodiment four

S4: Clinical trial: After the drug test, the ingredients have no harmful changes, the proportion of the drug ingredients remains unchanged, the drug is non-toxic, and the drug meets the pharmaceutical standards for clinical trials. Before the clinical trial, the tumor cells of the patients are screened, And record the number of tumor cells. During clinical trials, professionals will set the dosage of drugs and the time interval of drug replenishment. After 2 hours of each drug, the patients will be checked for tumor cells and the number of tumor cells will be recorded;

Embodiment five

S4: Clinical trial: After the drug test, the ingredients have no harmful changes, the proportion of the drug ingredients remains unchanged, the drug is non-toxic, and the drug meets the pharmaceutical standards for clinical trials. Before the clinical trial, the tumor cells of the patients are screened, And record the number of tumor cells. During the clinical trial, professionals will set the dosage of drugs and the time interval of drug replenishment. After 2 hours of each drug, the patient will be checked for tumor cells, and the number of tumor cells will be recorded. The data recorded each time will be recorded. Computer input, data drawing and calculation by the computer, wherein the data drawing includes a histogram of data changes and a line chart of data changes, which are analyzed by professionals through the drawn graphs and calculated data, and the results of the analysis are changed to treat patients. The amount of drug used and the interval between drug refills;

S5: Subsequent processing: the prepared drugs are packaged, coded, and put into the warehouse. The same batch number is stacked together and stacked separately when put into the warehouse. The ambient temperature of the warehouse is kept at 10-20°C. The distance between the medicine and the roof shall not be less than 30cm, the distance between the radiator and the heating pipe of the warehouse shall not be less than 30cm, and the distance between the medicine and the ground shall not be less than 10cm.

The synthetic method of a kind of antineoplastic drug Afatinib in embodiment one, embodiment two, embodiment three, embodiment four and embodiment five is tested, draws the result as follows:

Embodiment one, embodiment two, embodiment three, embodiment four and the synthetic method of the antineoplastic drug afatinib that embodiment five makes have significantly improved compared with existing method tumor cell clearance rate, and embodiment one is best practice.

The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope disclosed in the present invention, according to the technical solution of the present invention Any equivalent replacement or change of the inventive concepts thereof shall fall within the protection scope of the present invention.

Claims

A kind of synthetic method of antineoplastic drug Afatinib, is characterized in that, comprises the following steps:

S1: Preparation of raw materials: prepare the raw materials required for the preparation of drugs;

S2: Prepare the drug: prepare the anti-tumor drug afatinib by mixing the selected raw materials and auxiliary materials;

S3: Perform inspection: inspect the prepared medicine, and process the medicine according to the inspection result;

S4: Clinical trials: select drugs that meet the criteria for clinical trials;

S5: Subsequent processing: the prepared medicine is packaged, coded, stored, and regularly sampled.
The synthetic method of a kind of antitumor drug afatinib according to claim 1, is characterized in that, in described S1, select (2E)-N-[4-(3-chloro-4-fluoroanilino) -7-{[(3S)-oxuronamide-3-yl]oxyl}quinazolin-6-yl]-4-(dimethylamino)but-2-enamide as raw material, and select cosolvent, Preservatives, flavoring agents, surfactants and emulsifiers are used as excipients.
The synthetic method of a kind of antineoplastic drug Afatinib according to claim 2, is characterized in that, described solubilizer is sodium benzoate, preservative is paraben, and flavoring agent is sweetener and Mucilage agent, surfactant is monoglyceride fatty acid ester, and emulsifier is gum arabic.
The synthetic method of a kind of antineoplastic drug Afatinib according to claim 1, characterized in that, in said S2, said antineoplastic drug Afatinib is prepared by mixing the selected raw materials and auxiliary materials by professionals. Tini, in which the mass ratio of raw materials and excipients is 5:2 during drug preparation, and the mass component ratio in the excipients is cosolvent: preservative: flavoring agent: surfactant: emulsifier is 1:2:1 :2:3, and the prepared drug is pressed into tablets with equal specifications, wherein the equal specifications include 20mg, 30mg, 40mg and 50mg, and the specifications are selected by professionals.
A method for synthesizing the antineoplastic drug afatinib according to claim 1, characterized in that in said S3, the prepared drug is tested by professionals, wherein the test content includes whether the composition of the drug has changed , the proportion of drug ingredients, drug toxicity, and whether the drug meets the pharmaceutical standards, and the drug is processed according to the test results. The same specification sampling test method is used for drug testing. Drugs of the same quality are sampled for testing at the same time period, and the number of sampled drugs: the total number of drugs of the same specification is 1:50.
A method for synthesizing the antineoplastic drug afatinib according to claim 5, wherein the test result shows that the drug composition changes and needs to be reported immediately, and the changed composition of the drug is detected, and the detection result is used for processing, If the test results show that the changed ingredients of the medicine are harmful ingredients, all the medicines prepared in the same batch will be destroyed in a centralized way. If the test results show that the changed ingredients of the medicine are harmless ingredients, they will not be processed. If the results show that the proportion of drug ingredients does not meet the set requirements, it will be reported, and the superior will make a judgment and issue a processing order. If the test results show that the proportion of drug ingredients meets the set requirements, it will not be processed. If the test results show that the drug is toxic, it needs to be reported. And all the drugs prepared in the same batch will be destroyed in a centralized manner. If the test results show that the drugs do not have toxicity, they will not be processed. If the test results show that the drugs meet the pharmaceutical standards, they will not be processed. All the drugs prepared in batches will be destroyed in a centralized manner.
The synthetic method of a kind of antineoplastic drug afatinib according to claim 1, characterized in that, in said S4, no harmful change occurs in the components after the drug test, the proportion of the drug components remains unchanged, and the drug is non-toxic And the drug is a drug that meets the pharmaceutical standards for clinical trials. Before the clinical trial, the tumor cells of the patients are screened and the number of tumor cells is recorded. During the clinical trial, professionals set the dosage of the drug and the time interval for drug replenishment. 2 hours after the first dose of medication, the patient was screened for tumor cells, and the number of tumor cells was recorded, and the data recorded each time was input into the computer, and the data was drawn and calculated by the computer, wherein the data drawing included a data change histogram and a data change broken line Diagrams are analyzed by professionals through the drawn diagrams and calculated data, and the dosage of drugs for patients and the time interval of drug replenishment are changed through the analysis results.
A method for synthesizing the antineoplastic drug afatinib according to claim 1, characterized in that in said S5, the prepared drug is packaged, coded, and put into storage, wherein the same batch number is carried out when putting into the warehouse. Centrally stacked and stacked separately, and the ambient temperature of the warehouse is kept at 10-20°C. At the same time, the distance between the medicine and the wall, medicine and the roof is not less than 30cm, and the distance between the warehouse radiator and heating pipe is not less than 30cm, and the distance between the ground and the ground Not less than 10cm. After entering the warehouse, if the medicine has not been released within two months, the professional staff should use the XRD analyzer to conduct regular sampling inspections on the same batch of drugs. The number of samples taken during the sampling inspection: the total number of tablets of the same batch number is 1: 200, and the interval between two sampling inspections is two months.