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A pharmaceutical composition comprising gefitinib and histone deacetylase inhibitors, its liposome formulation and its pharmaceutical use

A technology of gefitinib and its composition, which is applied in the direction of drug combination, liposome delivery, and medical preparations containing active ingredients, etc., which can solve problems such as narrow therapeutic window, failure of molecular targeted therapy, and limited clinical benefit , to achieve the effect of increasing accumulation

Active Publication Date: 2021-03-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, 50% of patients will undergo a mutation from threonine (T) to methionine (M) at the 790th amino acid on exon 20 after receiving treatment, resulting in the ability of EGFR to bind ATP Significantly enhanced, resistance to gefitinib, resulting in failure of molecular targeted therapy
Although the second-generation TKI afatinib was later developed, which is an irreversible inhibitor, it cannot effectively control EGFR due to its narrow therapeutic window. T790M Drug resistance due to mutation, limited clinical benefit
In March 2017, the third-generation TKI osimertinib was approved for marketing in China. It targets EGFR T790M The resulting drug-resistant patients have significant clinical benefits. However, it has been widely reported that EGFR C797S mutations will occur after patients receive osimertinib treatment, and they are resistant to osimertinib.
[0007] However, for the combined use of molecularly targeted drugs, there are few studies on dosage form modification in pharmacy, and the monoclonal antibody Herceptin is used as a targeting ligand to modify the surface of the drug delivery system with HER2 as the target in non-small cell lung cancer. research has not yet been reported

Method used

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  • A pharmaceutical composition comprising gefitinib and histone deacetylase inhibitors, its liposome formulation and its pharmaceutical use
  • A pharmaceutical composition comprising gefitinib and histone deacetylase inhibitors, its liposome formulation and its pharmaceutical use
  • A pharmaceutical composition comprising gefitinib and histone deacetylase inhibitors, its liposome formulation and its pharmaceutical use

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Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0068] Preparation of dual-targeted co-loaded liposomes

[0069] (a) Weigh an appropriate amount of mannose isothiocyanate and dissolve it in dichloromethane, add an appropriate amount of triethylamine to adjust the pH to alkaline, and use mannose isothiocyanate / DSPE-PEG 2000 -NH 2 The molecular ratio is 3 / 1, and then add an appropriate amount of DSPE-PEG to it 2000 -NH 2 , react at room temperature for 4 hours, remove the organic solvent by rotary evaporation, add an appropriate amount of water, shake well, centrifuge at 15,000 rpm for 5 minutes, take the supernatant and freeze-dry to obtain mannose-modified DSPE-PEG 2000 , call it DSPE-PEG 2000 -Man.

[0070] (b) Weigh egg yolk lecithin (PC 98T), cholesterol, DSPE-PEG 2000 、DSPE-PEG 2000 -Man and DSPE-PEG 2000 -NHS was dissolved in chloroform and added to the round bottom flask according to the molecular ratio of 10 / 2 / 1 / 0.1 / 0.1. Weigh gefitinib and vorinostat, dissolve them in methanol, add them into a round bottom f...

experiment Embodiment 1

[0090] in vitro cellular uptake

[0091] The green fluorescent probe coumarin 6 was introduced into liposomes at a mass ratio of gefitinib / coumarin 6 of 10 / 1 to prepare dual-targeted co-drug-loaded lipids loaded with coumarin 6 Plastids and unmodified drug-loaded liposomes, using a fluorescence spectrophotometer to quantify the coumarin 6 contained in the liposomes under the condition of an excitation wavelength of 466nm and an emission wavelength of 504nm, the amount of coumarin 6 entering the cell To characterize the cell entry efficiency of liposomes. details as follows:

[0092] HER2-positive cell line H1975 and M2 macrophages were used at 8x10 per well 4 Cells were seeded in a 12-well cell culture plate at 37°C, 5% CO 2 After culturing under the same conditions for 24 hours, 0.1 μg of coumarin 6 per well was added to dual-targeted co-drug-loaded liposomes and unmodified co-drug-loaded liposomes. Cells were collected after liposome treatment for 4 hours for flow cytomet...

experiment Embodiment 2

[0095] In vitro antitumor activity

[0096] The in vitro toxicity of drugs and dual-targeted co-loaded liposomes in HER2-positive H1975 cells was detected by MTT method to characterize the impact of targeted modification and co-loading on the synergistic efficiency of combined drugs. The specific experiment is as follows:

[0097] at 5x10 3 Cells per well were planted in a 96-well plate at a density of 37°C, 5% CO 2After culturing for 24 hours under the same conditions, the cells were treated with different concentrations of gefitinib (the mass ratio of vorinostat to gefitinib was 0.12:1, and the mass ratio of TMP 195 to gefitinib was 1:1). Set up 6 auxiliary wells, and set up a negative control without drug addition at the same time. After culturing for 48 hours, 20 μL of 5 mg / mL MTT solution was added to each well, and cultured for another 4 hours. The liquid in each well was removed with a syringe, and 200 μL of dimethyl sulfoxide was added to each well. For the absorba...

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Abstract

The present invention relates to a pharmaceutical composition comprising gefitinib and a histone deacetylase inhibitor, its liposome formulation and their preparation for the treatment of EGFR T790M Use in medicine for mutation-resistant non-small cell lung cancer, wherein the histone deacetylase inhibitor is preferably vorinostat and TMP195. Specifically, the present invention also relates to a dual-target co-loading liposome, which is a liposome whose surface is modified by Herceptin and mannose and contains the above-mentioned pharmaceutical composition. The dual-targeted co-loaded liposomes can be used to regulate the polarization of macrophages and can be used to treat cells with EGFR T790M Mutant non-small cell lung cancer.

Description

technical field [0001] The invention belongs to the field of biomedicine, more specifically, the invention relates to a pharmaceutical composition comprising gefitinib and a histone deacetylase inhibitor, its liposome preparation and their preparation for the treatment of EGFR T790M Use of a drug in mutation-resistant non-small cell lung cancer. Background technique [0002] Lung cancer is a type of cancer with the highest morbidity and mortality in China and even in the world. With the intensification of my country's industrialization and urbanization process, resulting in serious air pollution and high smoking rate, the harm of lung cancer will be further aggravated. Among all malignant tumors, lung cancer is one of the most deeply studied pathogenesis. The main cause of non-small cell lung cancer (NSCLC) is the deletion of the 19th exon or the 21st exon of the epidermal growth factor receptor (EGFR). The 858th amino acid on the exon is mutated from leucine (L) to argini...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/5377A61K31/167A61K9/127A61P37/02A61P35/00
Inventor 黄永焯彭会歌
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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