An oral gefitinib complex with enhanced anti-cancer effect, and its preparation method and application

Abstract

The present invention belongs to the field of biotechnology and discloses an orally-administered gefitinib complex with enhanced anti-cancer effects, as well as its preparation method and application. The gefitinib complex of the present invention is formed by combining at least one of nicotinamide and 3-aminothioamino-butyric-2-one oxime with gefitinib or a pharmaceutically acceptable salt thereof. The present invention also provides the use of the gefitinib complex in the preparation of a drug for the prevention and / or treatment of lung cancer, particularly in the preparation of a drug for the prevention and / or treatment of non-small cell lung cancer. The gefitinib complex of the present invention has significantly improved solubility and dissolution rate, exhibiting enhanced therapeutic effects on cancer; it can increase its uptake by cancer cells, exhibiting a stronger ability to inhibit cancer cell proliferation, and has a better anti-cancer effect.

Description

Technical Field

[0001] The present invention belongs to the field of biotechnology, and particularly relates to an orally-administered gefitinib complex with enhanced anti-cancer effects, and a preparation method and application thereof. Background Art

[0002] Lung cancer is the most common cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancer types. Most NSCLC patients are diagnosed in the advanced stages of the disease, with chemotherapy the only treatment option to improve their quality of life and prolong their lives.

[0003] Gefitinib (GEF) is a semi-synthetic derivative of camptothecin, with the molecular formula: C 22 H 24 ClFN4O3, molecular weight: 446.9, its chemical structure is as follows:

[0004]

[0005] Gefitinib is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor. By inhibiting EGFR, it can hinder tumor growth and metastasis and enhance tumor cell apoptosis. It is commonly used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) that has previously received chemotherapy to increase tumor sensitivity to the drug. However, GEF, as a first-line anti-NSCLC drug, has significant drawbacks in clinical use: poor water solubility, high binding to human hemoglobin, and low free drug concentrations in tumor tissue, resulting in low bioavailability. Consequently, GEF's clinical application is significantly limited. Reports have also suggested that long-term use of GEF may cause adverse reactions such as diarrhea.

[0006] Oral drug formulations have the advantages of safe and convenient administration and high patient compliance, but the drug's efficacy is affected by factors such as the drug's water solubility, dissolution rate, drug permeability, first-pass effect, pre-systemic metabolism, and sensitivity to efflux mechanisms. Although GEF has high intestinal permeability, its solubility and dissolution rate are both low, which seriously limits the drug's efficacy. Pharmaceutical cocrystal technology is a method of specifically changing the physicochemical properties of the active pharmaceutical ingredient (API) by selecting a suitable cocrystal conformer (CCF). Compared to methods that reduce the particle size of the drug by changing the drug formulation process or by changing the chemical properties of the drug, cocrystal technology not only has the advantages of simple preparation and good stability, but also can form multi-drug cocrystals by combining two or more APIs to achieve synergistic or adjuvant combination therapy.

[0007] Therefore, it is expected that the above-mentioned problems of low solubility and dissolution rate of GEF can be overcome through eutectic technology, thereby greatly improving the pharmaceutical effect of GEF. Summary of the Invention

[0008] In order to overcome the above-mentioned shortcomings and deficiencies of the prior art, improve the solubility and dissolution rate of GEF, and enhance its therapeutic effect on lung cancer, the primary purpose of the present invention is to provide an orally administrable gefitinib complex with enhanced anti-cancer effect.

[0009] The gefitinib complexes of the present invention utilize nicotinamide (NCA) and 3-thiosemicarbano-butan-2-oneoxime (TSBO) as cocrystal formers, respectively, to form cocrystals with GEF. A series of cell and animal experiments confirmed that the gefitinib complexes of the present invention exhibited enhanced solubility and dissolution rate, significantly improving their inhibitory effects on lung cancer both in vitro and in vivo.

[0010] Another object of the present invention is to provide a method for preparing the gefitinib complex.

[0011] Another object of the present invention is to provide applications of the gefitinib complex.

[0012] Another object of the present invention is to provide the use of the gefitinib complex in the preparation of drugs for preventing and / or treating lung cancer, particularly in the preparation of drugs for preventing and / or treating non-small cell lung cancer.

[0013] The purpose of the present invention is achieved through the following solutions:

[0014] An orally administered gefitinib complex with enhanced anti-cancer effects is formed by combining at least one of nicotinamide (NCA) and 3-thiosemicarbano-butan-2-oneoxime (TSBO) with gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0015] Furthermore, in the gefitinib complex, the molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to nicotinamide may be 1:3-3:1.

[0016] Furthermore, in the gefitinib complex, the molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to 3-aminothioamino-butan-2-one oxime may be 1:3-3:1.

[0017] Furthermore, the molecular formula of niacinamide is C6H6N2O, the molecular weight is 122.1, and its chemical structure is as follows:

[0018]

[0019] Furthermore, the molecular formula of 3-aminothioamino-butan-2-one oxime is C5H 10 SN4O, molecular weight 174.2, its chemical structure is as follows:

[0020]

[0021] Furthermore, an orally administrable gefitinib complex (GEF@NCA) with enhanced anti-cancer effects is formed by combining nicotinamide (NCA) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0022] Furthermore, the orally administrable gefitinib complex (GEF@NCA) with enhanced anti-cancer effect uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed by the 2θ diffraction angle has characteristic peaks at 6.17±0.2°, 7.10±0.2°, 9.55±0.2°, 12.40±0.2°, 14.2±0.2°, 18.20±0.2°, 18.40±0.2°, 18.80±0.2°, 19.7±0.2°, 21.10±0.2°, 22.30±0.2°, 23.4±0.2°, 24.80±0.2°, and 25.90±0.2°.

[0023] Furthermore, an orally available gefitinib complex (GEF@TSBO) with enhanced anti-cancer effects is formed by combining 3-thiosemicarbano-butan-2-oneoxime (TSBO) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0024] Furthermore, the orally administrable gefitinib complex (GEF@TSBO) with enhanced anti-cancer effect has characteristic peaks at 7.13±0.2°, 9.40±0.2°, 11.30±0.2°, 14.10±0.2°, 15.9±0.2°, 17.80±0.2°, 18.61±0.2°, 19.50±0.2°, 20.70±0.2°, 22.61±0.2°, 24.53±0.2°, and 26.8±0.2° in an X-ray powder diffraction pattern expressed by 2θ diffraction angles using Cu-Kα radiation.

[0025] The gefitinib complex of the present invention can be obtained by a recrystallization method.

[0026] The present invention also provides applications of the gefitinib complex.

[0027] The present invention also provides the use of the gefitinib complex in preparing drugs for preventing and / or treating lung cancer, particularly in preparing drugs for preventing and / or treating non-small cell lung cancer.

[0028] The gefitinib complex of the present invention has significantly improved solubility and dissolution rate, showing enhanced therapeutic effect on cancer; it can increase its uptake by cancer cells, showing stronger ability to inhibit cancer cell proliferation, and has better anti-cancer effect.

[0029] Furthermore, the drugs are the same or different and each comprises a therapeutically effective amount of a gefitinib complex.

[0030] Furthermore, the drugs, whether the same or different, can be made into various pharmaceutical dosage forms using conventional methods. These dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, electuary preparations, pills, pills, suspensions, alcohol preparations, tinctures, drops and other oral dosage forms, as well as injections and other non-oral dosage forms, such as injections.

[0031] Furthermore, the drugs, whether the same or different, may also contain one or more pharmaceutically acceptable carriers or excipients.

[0032] Furthermore, the excipients may include diluents, wetting agents, lubricants, fillers, preservatives, etc.

[0033] The present invention also provides a pharmaceutical composition comprising the gefitinib complex or other pharmaceutically acceptable components thereof.

[0034] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0035] The present invention forms a complex by forming a cocrystal with TSBO or NCA and GEF, which effectively improves the solubility and dissolution rate of GEF in the intestine, significantly increases its cellular uptake, and enhances the proliferation inhibition and killing effects on cancer cells, thereby improving its therapeutic effect, especially the effect against non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0037] Figure 1 The infrared spectra of the gefitinib complex of the present invention are shown in Figure 1. (A) is GEF@TSBO; (B) is GEF@NCA.

[0038] Figure 2 The figures are powder X-ray diffraction (PXRD) patterns of the gefitinib complex of the present invention, wherein (A) is GEF@TSBO and (B) is GEF@NCA.

[0039] Figure 3 The figures are scanning electron microscopy (SEM) images of the gefitinib complex of the present invention, wherein (A) is GEF@TSBO and (B) is GEF@NCA.

[0040] Figure 4 The 2D HH NMR NOESY spectrum of the gefitinib complex of the present invention is shown in Figure 1, wherein (A) is GEF@TSBO and (B) is GEF@NCA.

[0041] Figure 5 This is a solubility diagram of the gefitinib complex of the present invention.

[0042] Figure 6 This is a dissolution curve of the gefitinib complex of the present invention.

[0043] Figure 7 Figure 2 is a graph showing the uptake of the gefitinib complex of the present invention by lung cancer cells, wherein (A) is A549 cells and (B) is H1299 cells.

[0044] Figure 8 This is a graph showing the half-maximal inhibitory concentration of the gefitinib complex of the present invention on lung cancer cells, wherein A represents A549 cells and B represents H1299 cells.

[0045] Figure 9 and Figure 10 The figure shows the effect of the gefitinib complex of the present invention on lung cancer cell clones, wherein A represents A549 cells and B represents H1299 cells.

[0046] Figure 11 The figure shows the effect of the gefitinib complex of the present invention on the changes in the volume and weight of A549 cell tumors.

[0047] Figure 12 The figure shows the effect of the gefitinib complex of the present invention on the body weight changes of mice. DETAILED DESCRIPTION

[0048] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0049] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention pertains. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The methods described in the following examples are conventional methods unless otherwise noted, and the materials involved are commercially available unless otherwise noted. The amounts of each component are expressed in parts by mass and volume, mg, and mL.

[0050] In one embodiment, an orally available gefitinib complex with enhanced anti-cancer efficacy is formed by combining at least one of nicotinamide (NCA) and 3-thiosemicarbano-butan-2-oneoxime (TSBO) with gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to nicotinamide in the gefitinib complex may be 1:3 to 3:1. In one embodiment, the molar ratio is 1:3; in another embodiment, the molar ratio is 1:1; and in yet another embodiment, the molar ratio is 3:1.

[0052] In the present invention, gefitinib or a pharmaceutically acceptable salt thereof and nicotinamide can be combined in a molar ratio within the range of 1:3-3:1 to obtain a gefitinib complex. The complex obtained by the combination can significantly and effectively improve the solubility and dissolution rate of gefitinib, thereby exhibiting an enhanced therapeutic effect on cancer. The uptake of gefitinib by cancer cells can be increased, thereby exhibiting a stronger ability to inhibit cancer cell proliferation and having a better anti-cancer effect.

[0053] In one embodiment, the molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to 3-aminothioamino-butan-2-one oxime in the gefitinib complex may be 1:3 to 3:1. In one embodiment, the molar ratio is 1:3; in another embodiment, the molar ratio is 1:1; and in yet another embodiment, the molar ratio is 3:1.

[0054] In the present invention, gefitinib or a pharmaceutically acceptable salt thereof and 3-aminothioamino-butan-2-one oxime can be combined in a molar ratio within the range of 1:3-3:1 to obtain a gefitinib complex. The complex obtained by the combination can significantly and effectively improve the solubility and dissolution rate of gefitinib, thereby exhibiting an enhanced therapeutic effect on cancer; it can also increase the uptake of gefitinib by cancer cells, thereby exhibiting a stronger ability to inhibit cancer cell proliferation and having a better anti-cancer effect.

[0055] In one embodiment, the molecular formula of nicotinamide is C6H6N2O, the molecular weight is 122.1, and its chemical structure is shown below:

[0056]

[0057] In one embodiment, the molecular formula of 3-aminothioamino-butan-2-one oxime is C5H 10 SN4O, molecular weight 174.2, its chemical structure is as follows:

[0058]

[0059] In one embodiment, an orally administrable gefitinib complex (GEF@NCA) with enhanced anti-cancer effects is formed by combining nicotinamide (NCA) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the orally administrable gefitinib complex (GEF@NCA) with enhanced anti-cancer effect is formed by combining nicotinamide (NCA) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof in a molar ratio of 1:1.

[0061] In one embodiment, the orally administrable gefitinib complex (GEF@NCA) with enhanced anti-cancer effect uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed by the 2θ diffraction angle is 6.17±0.2°, 7.10±0.2°, 9.55±0.2°, 12.40±0.2°, 14.2±0.2°, 18.20±0.2°, 18.40±0.2°, 18.80±0.2°, 19.7±0.2°, 21.10±0.2°, 22.30±0.2°, 23.4±0.2°, 24.80±0.2°, and 25.90±0.2°. There are characteristic peaks.

[0062] In one embodiment, an orally available gefitinib complex (GEF@TSBO) with enhanced anti-cancer efficacy is formed by combining 3-thiosemicarbano-butan-2-oneoxime (TSBO) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment, an orally available gefitinib complex (GEF@TSBO) with enhanced anti-cancer efficacy is formed by combining 3-thiosemicarbano-butan-2-oneoxime (TSBO) and gefitinib (GEF) or a pharmaceutically acceptable salt thereof in a molar ratio of 1:1.

[0064] In one embodiment, the orally administrable gefitinib complex (GEF@TSBO) with enhanced anti-cancer effect uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed by 2θ diffraction angles has characteristic peaks at 7.13±0.2°, 9.40±0.2°, 11.30±0.2°, 14.10±0.2°, 15.9±0.2°, 17.80±0.2°, 18.61±0.2°, 19.50±0.2°, 20.70±0.2°, 22.61±0.2°, 24.53±0.2°, and 26.8±0.2°.

[0065] In one embodiment, the gefitinib complex of the present invention can be obtained by a recrystallization method.

[0066] In one embodiment, the gefitinib complex of the present invention can be obtained by recrystallization in an organic solvent-water mixed solvent.

[0067] In one embodiment, the organic solvent may include at least one of methanol, ethanol, hexane, chloroform, acetone, and dimethyl sulfoxide. In one embodiment, the organic solvent is ethanol; in another embodiment, the organic solvent is acetone; and in yet another embodiment, the organic solvent is dimethyl sulfoxide.

[0068] The gefitinib complex of the present invention can be obtained by fully dissolving each component in a mixed solvent and then recrystallizing to form a eutectic complex. The ratio of the organic solvent to the water mixed solvent can be adjusted as needed. In one embodiment, the volume ratio of the organic solvent to water is 9:1; in another embodiment, the volume ratio of the organic solvent to water is 7:3; and in yet another embodiment, the volume ratio of the organic solvent to water is 8:2.

[0069] In one embodiment, the gefitinib complex is used in the preparation of a drug for preventing and / or treating lung cancer, particularly in the preparation of a drug for preventing and / or treating non-small cell lung cancer.

[0070] The orally administrable gefitinib complex of the present invention has significantly improved solubility and dissolution rate, showing enhanced therapeutic effect on cancer; it can improve its uptake by cancer cells, showing stronger ability to inhibit cancer cell proliferation, and has better anti-cancer effect.

[0071] In one embodiment, the drugs are the same or different and each comprises a therapeutically effective amount of a gefitinib complex.

[0072] In one embodiment, the drugs, whether the same or different, can be prepared into various pharmaceutical dosage forms using conventional methods. These dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, granules, pills, pills, suspensions, alcoholic drinks, tinctures, drops and other oral dosage forms, as well as injections and other non-oral dosage forms, such as injections.

[0073] In one embodiment, the drugs, whether the same or different, may further contain one or more pharmaceutically acceptable carriers or excipients.

[0074] In one embodiment, the excipient may include a diluent, a wetting agent, a lubricant, a filler, a preservative, and the like.

[0075] In one embodiment, a pharmaceutical composition comprises the gefitinib complex or other pharmaceutically acceptable components thereof.

[0076] Example 1: Synthesis of Gefitinib Cocrystal Complex by Recrystallization Method

[0077] Dissolve 1 part by mass of GEF and TSBO in 15-25 parts by volume of an ethanol-water mixture (e.g., 9:1 v / v). Reflux the solution at 80-90°C with stirring for 2-5 hours. After the reaction is complete, allow the solution to cool to room temperature for 72 hours. Slow evaporation is then used to obtain a white eutectic GEF@TSBO.

[0078] Similarly, 1 part by mass of GEF and NCA was dissolved in 15-25 parts by volume of an ethanol-water mixture (e.g., 7:3 v / v). The solution was stirred and refluxed at 60-70°C for 1-3 hours. After the reaction was complete, the solution was allowed to cool naturally to room temperature for 48 hours. A white eutectic complex, GEF@NCA, was obtained by slow evaporation.

[0079] In order to further characterize the gefitinib complex of the present invention, performance tests were conducted on GEF@TSBO and GEF@NCA prepared with a molar ratio of GEF to TSBO and a molar ratio of GEF to NCA of 1:1, and the results are as follows.

[0080] Figure 1 The infrared spectrum of the gefitinib complex of the present invention.

[0081] Figure 2 The powder X-ray diffraction (PXRD) pattern of the gefitinib complex of the present invention was obtained using a rotating anode Cu target X-ray source (λ = 1.5406), operating at 40 kV, 250 mA, with a scan range of 3.0 to 90°, a speed of 5° / min, a step size of 0.02°, and a scan time of 0.5-3 seconds.

[0082] Figure 3 The scanning electron micrograph of the gefitinib complex of the present invention was used to test the morphology of the co-crystal. A bulk sample was photographed at an accelerating voltage of 4 kV without any coating.

[0083] Figure 4 The HH 2D NMR NOESY spectrum of the gefitinib complex of the present invention. The GEF@TSBO and GEF@NCA cocrystal complexes were dissolved in DMSO-d6, respectively. The samples were examined at room temperature, and the spectra were analyzed using MestReNova software.

[0084] As can be seen from the figure, the present invention prepares the gefitinib cocrystal complex by the recrystallization method.

[0085] Example 2

[0086] Firstly, the GEF absorption spectrum curve was obtained using an ultraviolet-visible spectrometer, and a standard curve of GEF concentration and absorbance was established through the correspondence between standard solutions of different concentrations and their characteristic absorption peaks.

[0087] (1) Solubility measurement: GEF, GEF@TSBO, and GEF@NCA were prepared as supersaturated solutions in distilled water at pH 7.0 at 37°C and stirred at 150 rpm for 24 h at 37°C. After stopping stirring, the supernatant was filtered through a 0.45 μm filter and diluted in multiples. The UV-visible spectrum was measured and the concentration of the original solution was calculated using a standard curve. The results are shown in Figure 5 As can be seen from the figure, the gefitinib complex of the present invention has significantly improved solubility, which can be more than 4 times that of GEF.

[0088] (2) Dissolution rate measurement: Excess amounts of GEF, GEF@TSBO, and GEF@NCA were added to 200 mL of water, respectively, and stirred at 150 rpm at 37°C for 3 h. At regular intervals, 3 mL of disintegration medium was removed and replaced with a certain volume of fresh medium to maintain a constant volume. The UV-visible spectrum of the extract at each time point was measured and the concentration of the original solution was calculated using the standard curve. The results are shown in Figure 6 As can be seen from the figure, the gefitinib complex of the present invention has a significantly improved dissolution rate, and can quickly achieve the effect of high GEF concentration in the solution.

[0089] (3) Cell uptake experiment: A549 cells (human non-small cell lung cancer cells, purchased from the Chinese Academy of Sciences Cell Bank, product number SCSP-503) and H1299 cells (human non-small cell lung cancer cells, purchased from the Chinese Academy of Sciences Cell Bank, product number SCSP-589) were respectively cultured at 1×10 6 After culturing for 24 hours, 50 μM GEF, GEF@TSBO, and GEF@NCA were added to a 6-well plate. After the incubation period, the cells were washed with PBS, digested with trypsin, and prepared into a cell suspension. The GEF fluorescence intensity was detected by flow cytometry and the obtained data were analyzed. Figure 7 As can be seen from the figure, the gefitinib complex of the present invention has a higher fluorescence intensity of gefitinib in A549 cells and H1299 cells, and the average fluorescence intensity of cells treated with the gefitinib complex is twice that of cells treated with gefitinib alone, indicating that the complex effectively improves the uptake rate of gefitinib.

[0090] Example 3

[0091] (1) Cell half-inhibitory concentration experiment: 5×10 3A549 cells and H1299 cells were seeded at a density of 100 μM / well in 96-well plates and cultured for 24 hours. The cells were then incubated for 24 hours with culture medium containing different concentrations of 0-150 μM GEF, 0-45 μM GEF@TSBO, and 0-45 μM GEF@NCA. 10% CCK8 solution was added to each well and shaken evenly using a microplate shaker. The culture medium was read using a microplate reader and the absorbance at 450 nm was measured to calculate cell viability. Results are shown in Figure 8 As can be seen from the figure, the gefitinib complex of the present invention has a significantly reduced IC 50 value, with a more significant and excellent inhibitory effect.

[0092] (2) In the cell clone inhibition test, A549 cells and H1299 cells were seeded in 6-well plates at a density of 250 cells / well and cultured for 24 hours. Then, 50 μM GEF, GEF@TSBO, and GEF@NCA were used to incubate the cells for 24 hours. The control group was added with an equal volume of neutral PBS solution. The cells were then cultured in normal culture medium. The experiment was terminated when more than 50 cell colonies were formed in the control group. The cells were fixed in 6-well plates by incubation with 4% paraformaldehyde for 10 minutes and stained with crystal violet. The cells were photographed and the cell clones were counted. The results are shown in Figure 9 and Figure 10 As can be seen from the figure, the gefitinib complex of the present invention significantly and effectively inhibits the cloning of lung cancer cells.

[0093] Example 4

[0094] Eight-week-old female Balb / C nude mice were used for the experiment. The specific operation was as follows: sufficient A549 cells were cultured and when they reached the plateau phase after exponential growth, the cells were digested with trypsin and prepared into a concentration of 1×10 8 / mL live cell suspension, 100μL of cell suspension was inoculated subcutaneously in the right leg of each mouse. Tumor growth and body weight of mice were monitored and recorded regularly. Tumor volume was calculated as V = 0.5 × L × W 2 Calculate, where L is the long diameter and W is the short diameter. When the average tumor volume grows to about 100 mm 3The treatment was started at 14:00 pm. The experimental animals were randomly divided into 5 groups: PBS group (intravenous injection of 100 μL neutral PBS solution); GEF group (intravenous injection of 100 μL PBS solution containing 0.5 mg GEF, totaling 1.12 μmoL of GEF); GEF+TSBO group (intravenous injection of 100 μL PBS mixed solution containing 0.5 mg GEF and 0.19 mg TSBO, totaling 1.12 μmoL of GEF); GEF@TSBO group (intravenous injection of 100 μL PBS solution containing 0.69 mg of GEF@TSBO eutectic complex, totaling 1.12 μmoL of GEF@TSBO); GEF@TSBO ig group (oral administration of 100 μL PBS mixed solution containing 0.69 mg of GEF@TSBO eutectic complex, totaling 1.12 μmoL of GEF@TSBO). After the experiment, the mice were killed, and the tumor tissues were collected, weighed, and recorded. The results are shown in Table 1. Figure 11-12 As can be seen from the figure, after administration of the gefitinib complex of the present invention, the volume and weight of the A549 cell tumor were significantly reduced and eventually disappeared, and there was no significant change in the weight of the mice, indicating that the gefitinib complex of the present invention has significantly improved therapeutic effects and significant therapeutic efficacy.

[0095] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. An orally available gefitinib complex for enhancing anticancer effects, characterized in that It is formed by combining at least one of nicotinamide and 3-aminothioamino-butan-2-one oxime with gefitinib or a pharmaceutically acceptable salt thereof; When the complex is formed by combining nicotinamide and gefitinib or a pharmaceutically acceptable salt thereof; using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ diffraction angles has characteristic peaks at 6.17±0.2°, 7.10±0.2°, 9.55±0.2°, 12.40±0.2°, 14.2±0.2°, 18.20±0.2°, 18.40±0.2°, 18.80±0.2°, 19.7±0.2°, 21.10±0.2°, 22.30±0.2°, 23.4±0.2°, 24.80±0.2°, and 25.90±0.2°; When the complex is formed by the combination of 3-aminothioamino-butan-2-one oxime and gefitinib or a pharmaceutically acceptable salt thereof; using Cu-Kα radiation, the X-ray powder diffraction pattern expressed by 2θ diffraction angles has characteristic peaks at 7.13±0.2°, 9.40±0.2°, 11.30±0.2°, 14.10±0.2°, 15.9±0.2°, 17.80±0.2°, 18.61±0.2°, 19.50±0.2°, 20.70±0.2°, 22.61±0.2°, 24.53±0.2°, and 26.8±0.2°.

2. The orally available gefitinib complex for enhancing anticancer effects according to claim 1, characterized in that The molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to nicotinamide is 1:3-3:

1.

3. The orally available gefitinib complex for enhancing anticancer effects according to claim 1, characterized in that The molar ratio of gefitinib or a pharmaceutically acceptable salt thereof to 3-aminothioamino-butan-2-one oxime is 1:3-3:

1.

4. Use of the orally administrable gefitinib complex with enhanced anti-cancer effect according to any one of claims 1 to 3 in the preparation of a drug for preventing and / or treating lung cancer.

5. Use of the orally administrable gefitinib complex with enhanced anti-cancer effect according to any one of claims 1 to 3 in the preparation of a drug for preventing and / or treating non-small cell lung cancer.

6. The use according to claim 4 or 5, characterized in that: The same or different drugs are prepared into various pharmaceutical dosage forms by conventional methods, including oral dosage forms such as tablets, capsules, oral liquids, granules, pills, pills, alcoholic preparations, tinctures and other dosage forms such as injections.

7. The use according to claim 4 or 5, characterized in that: The drugs, which are the same or different, further contain one or more pharmaceutically acceptable excipients.

8. A pharmaceutical composition, characterized in that The invention comprises the gefitinib complex according to any one of claims 1 to 3.

Images