阅读说明：本技术 一种包含舒尼替尼的药物组合物及其制剂和应用 (Pharmaceutical composition containing sunitinib, and preparation and application thereof ) 是由 岳欣 刘然义 刘听雨 于 2020-06-01 设计创作，主要内容包括：本发明提供了一种包含舒尼替尼的药物组合物及其制剂和应用,在原有舒尼替尼的基础上,进一步加入至少一种酪氨酸激酶受体抑制剂,尤其是阿帕替尼和/或阿西替尼,能够与之产生非常显著的协同增效作用,从而明显抑制癌细胞的增殖,对癌细胞具有极为显著的杀伤效率。本发明所提供的药物组合物能够明显改善现有技术中单纯采用舒尼替尼所带来的严重耐药性问题以及在降低舒尼替尼常规使用量时明显减低的治疗效果的问题,大大提高了临床治疗效率,降低患者的治疗毒副作用,对于临床治疗提供了新的方案,具有十分广阔的市场前景以及极其重大的社会意义。(The invention provides a pharmaceutical composition containing sunitinib, a preparation and an application thereof, wherein at least one tyrosine kinase receptor inhibitor, especially apatinib and/or axitinib, is further added on the basis of the original sunitinib, and a very obvious synergistic effect can be generated with the sunitinib, so that the proliferation of cancer cells is obviously inhibited, and the pharmaceutical composition has very obvious killing efficiency on the cancer cells. The pharmaceutical composition provided by the invention can obviously improve the problems of serious drug resistance caused by the simple adoption of sunitinib in the prior art and the treatment effect obviously reduced when the conventional use amount of sunitinib is reduced, greatly improves the clinical treatment efficiency, reduces the toxic and side effects of patients, provides a new scheme for clinical treatment, and has very wide market prospect and extremely important social significance.)

1. A pharmaceutical composition comprising sunitinib, comprising sunitinib or a pharmaceutically acceptable salt thereof and at least one tyrosine kinase receptor inhibitor other than sunitinib or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein the tyrosine kinase receptor inhibitor is selected from one or more of Nilotinib (Nilotinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Afatinib (Afatinib), Dacomitinib (Dacomitinib), Vandetanib (Vandetanib), Neratinib (Neratinib), ositinib (osiritinib), Apatinib (Apatinib), Axitinib (Axitinib), Rociletinib, olutinib, naqutinib, tervatinib, and nazatinib.

3. The pharmaceutical composition of claim 2, wherein the tyrosine kinase inhibitor is selected from one or more of apatinib or axitinib.

4. The pharmaceutical composition of claim 1, wherein the tumor is selected from one or more of renal cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer, cervical cancer, breast cancer, leukemia, malignant lymphoma, nasopharyngeal cancer, and pancreatic cancer.

5. Pharmaceutical composition comprising sunitinib according to claim 4, wherein said tumor is selected from renal cancer.

6. A pharmaceutical formulation comprising sunitinib, comprising a pharmaceutical composition comprising sunitinib according to any one of claims 1-5, and a pharmaceutically acceptable pharmaceutical excipient.

7. The pharmaceutical formulation comprising sunitinib according to claim 6, wherein the formulation is selected from one or more of tablets, capsules, pills, granules, injections, aerosols, sprays, films, suppositories.

8. The pharmaceutical formulation comprising sunitinib according to claim 6, wherein the pharmaceutically acceptable pharmaceutical excipient is selected from one or more of a filler, a disintegrant, a binder, a lubricant, a flavoring agent, a preservative, an antioxidant, a coloring agent.

9. Use of a pharmaceutical composition comprising sunitinib according to any one of claims 1-5 for the preparation of a formulation for the treatment of a tumor.

10. The use according to claim 9, wherein the tumor is selected from one or more of renal cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer, cervical cancer, breast cancer, leukemia, malignant lymphoma, nasopharyngeal cancer, pancreatic cancer.

Technical Field

The invention belongs to the technical field of tumor treatment, and particularly relates to a sunitinib-containing pharmaceutical composition, and a preparation and application thereof.

Background

Sunitinib (Sunitinib) is a potent, multi-target tyrosine kinase Receptor inhibitor, the targets of which include vascular endothelial cell growth factor receptors 1,2,3(VEGF receptors, VEGFR-1,2,3), platelet growth factor receptors α, β (PDGF receptors, PDGFR- α, β), c-KIT, and the like. According to the existing research results, sunitinib exerts an antitumor effect mainly through three pathways: inhibiting tumor angiogenesis, destroying tumor blood vessels, and killing tumor cells directly. Sunitinib is currently approved for the treatment of advanced metastatic renal cell carcinoma and imatinib-resistant Gastrointestinal Stromal tumors (GIST). Corresponding research and clinical trials are also ongoing in other cancer species such as non-small cell lung cancer, intestinal cancer, osteosarcoma. In the field of kidney cancer, sunitinib has been the first line of use for metastatic kidney cancer since FDA approval in the united states in 2006.

Before the advent of targeted drugs, the treatment of advanced kidney cancer was dominated by cytokines. Sunitinib, after its advent, showed anti-tumor effects in both in vitro and in vivo preclinical studies. One phase II clinical trial reported in 2006 incorporated 63 patients who failed first-line cytokine therapy of advanced renal cancer receiving second-line therapy with sunitinib, with 39% objective response rate, 23% -27% of patients with stable disease, a median Time To Tumor Progression (TTP) of 8.7 months, and a median overall survival of 16.4 months. A phase III clinical trial followed by 2007 included 750 untreated patients with advanced renal carcinoma treated randomly with either sunitinib or IFN-a, and showed that sunitinib had a higher ORR (31% vs. 6%, p < 0, 001), PFS (11.0 months vs. 5.0 months, p < 0.001), and OS (26.4 months vs. 21.8 months, p = 0.051) than IFN-a, and subsequently reported that the failure of OS was statistically due to the use of second-line targeted drugs in 33% of the patients who failed therapy, and subgroup analysis of cases who did not receive second-line therapy showed better OS with sunitinib (28.1 months vs. 14.1 months, p = 0.003). Moreover, the clinical efficacy of sunitinib has been demonstrated through observations over a decade.

Although sunitinib slows the progression of metastatic renal cancer and improves patient prognosis, almost all patients eventually develop resistance and eventually progress again. According to the existing research reports, although the evaluation criteria of each research are slightly different, it can be seen that about 70% of patients are sensitive to sunitinib in the first line treatment, and 30% of patients show primary drug resistance to sunitinib. In sensitive patients, the effective period is usually only 6-15 months, after which acquired resistance and disease progression occurs. There are many studies on the mechanism of acquired drug resistance, and the mechanism can be generally classified into the following: activation of pro-angiogenic signals, alterations in the tumor microenvironment, lysosomal retention, action of non-coding RNAs, and activation of other signaling pathways.

Meanwhile, the results of clinical trials (NCT 00083889) with sunitinib in western patients showed that 98.13% of patients developed Adverse effects (overture Event, AE), with a incidence of treatment-related severe Adverse effects (seriousadoverture Event, SAE) of 23.7% and Adverse effects with incidence > 50% of diarrhea (65.6%), fatigue (62.4%) and nausea (57.6%) respectively. The results of clinical trials in chinese patients (NCT 00706706) showed that the occurrence rate of AE was 97.14%, the occurrence rate of SAE was 12.38%, and adverse reactions with an incidence rate > 50% were hand-foot syndrome (63.8%), leukopenia (52.4%), fatigue (51.4%) and thrombocytopenia (51.4%), respectively. From the research results, the sunitinib has more adverse reactions and high incidence, the adverse reactions seriously affect the life quality of patients, and although most of the adverse reactions can be relieved by reducing the drug dosage and changing the administration period, the adverse reactions are accompanied with the reduction of the anti-tumor effect, so that the sunitinib has larger application limitation.

Disclosure of Invention

In view of the above problems and disadvantages, the present invention provides a pharmaceutical composition comprising sunitinib, which solves the problems of severe drug resistance caused by the use of conventional doses of sunitinib and the problem of significantly reduced therapeutic effect after reduction of therapeutic dose in the prior art, thereby obtaining more significant clinical therapeutic effects and reduced drug resistance and toxic side effects of sunitinib.

The invention is realized by the following technical scheme:

the invention provides a pharmaceutical composition containing sunitinib, which comprises sunitinib or a pharmaceutically acceptable salt thereof and at least one tyrosine kinase receptor inhibitor other than sunitinib or a pharmaceutically acceptable salt thereof.

Preferably, the tyrosine kinase receptor inhibitor is selected from one or more of Nilotinib (Nilotinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Afatinib (Afatinib), Dacomitinib (Dacomitinib), Vandetanib (Vandetanib), Neratinib (Neratinib), oxitinib (osiritinib), Apatinib (Apatinib), Axitinib (Axitinib), Rociletinib, Olmutinib, Naquotinib, tervatinib, and nazzatinib.

Preferably, the tyrosine kinase receptor inhibitor is selected from one or more of apatinib and axitinib.

Preferably, the tumor is one or more selected from renal cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer, cervical cancer, breast cancer, leukemia, malignant lymphoma, nasopharyngeal cancer and pancreatic cancer.

Preferably, the tumor is selected from renal cancer.

The second aspect of the invention provides a preparation of a pharmaceutical composition containing sunitinib, which comprises sunitinib or a pharmaceutically acceptable salt thereof, at least one tyrosine kinase receptor inhibitor except sunitinib or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable pharmaceutical excipients.

Preferably, the preparation dosage form is selected from one or more of tablets, capsules, pills, granules, injections, aerosols, sprays, films and suppositories.

Preferably, the pharmaceutically acceptable pharmaceutical excipients are selected from one or more of fillers, disintegrants, binders, lubricants, flavoring agents, preservatives, antioxidants and coloring agents.

Preferably, the tyrosine kinase receptor inhibitor is selected from one or more of Nilotinib (Nilotinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Afatinib (Afatinib), Dacomitinib (Dacomitinib), Vandetanib (Vandetanib), Neratinib (Neratinib), oxitinib (osiritinib), Apatinib (Apatinib), Axitinib (Axitinib), Rociletinib, Olmutinib, Naquotinib, tervatinib, and nazzatinib.

Preferably, the tyrosine kinase inhibitor is selected from one or more of apatinib and axitinib.

Preferably, the tumor is one or more selected from renal cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer, cervical cancer, breast cancer, leukemia, malignant lymphoma, nasopharyngeal cancer and pancreatic cancer.

Preferably, the tumor is selected from renal cancer.

In a third aspect, the invention provides an application of a pharmaceutical composition containing sunitinib in preparing a preparation for treating tumors.

Preferably, the tyrosine kinase receptor inhibitor is selected from one or more of Nilotinib (Nilotinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Afatinib (Afatinib), Dacomitinib (Dacomitinib), Vandetanib (Vandetanib), Neratinib (Neratinib), oxitinib (osiritinib), Apatinib (Apatinib), Axitinib (Axitinib), Rociletinib, Olmutinib, Naquotinib, tervatinib, and nazzatinib.

Preferably, the tyrosine kinase inhibitor is selected from one or more of apatinib and axitinib.

Preferably, the tumor is one or more selected from renal cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer, cervical cancer, breast cancer, leukemia, malignant lymphoma, nasopharyngeal cancer and pancreatic cancer.

Preferably, the tumor is selected from renal cancer.

Although sunitinib is widely used clinically for cancer treatment and can achieve relatively remarkable effect, sunitinib has been used as a first-line drug in the treatment of diseases such as kidney cancer. However, neither improvement in the patient's prognosis nor delay in the progression of the cancer prevents the development of resistance to sunitinib in the patient and ultimately leads to the disease progressing again; and when sunitinib is used in large quantities for a long time, serious toxic and side effects are often generated, so that the life quality of patients is greatly reduced. To date, no better treatment regimen has emerged to improve the severe resistance, reduced therapeutic efficacy, and severe toxic side effects of sunitinib, thereby compromising its clinical use and therapeutic efficacy in patients.

In this regard, the inventors have conducted extensive studies using a compound library from the ceramic company for screening, which includes 1374 FDA-approved drugs on the market, in hopes of obtaining compounds that improve clinical resistance to sunitinib and that can produce additive or even synergistic therapeutic effects therewith. In the screening process, it is found that the combination of at least one tyrosine kinase receptor inhibitor, especially apatinib and/or axitinib, and the sunitinib is further added on the basis of the original sunitinib, and the obvious synergistic effect (CI < 1) can be generated.

Apatinib (Apatinib) is a multi-target Tyrosine Kinase Inhibitor (TKIs) aiming at c-Kit, c-RET, Src and VEGFR, is widely applied clinically, has good effects in clinical curative effect verification of late gastric cancer, adenocarcinoma at the junction of esophagus and stomach, colorectal cancer, lung cancer, liver cancer and soft tissue sarcoma, and has great potential in the adaptation verification stage of more cancers at present. The invention relates to aResearches show that the apatinib can remarkably improve the sensitivity of sunitinib to cancer cells and greatly reduce the IC of sunitinib₅₀The value (reduction of about 92.4%) combined with the two results in a very significant synergistic effect.

The Axitinib is a tyrosine kinase inhibitor for resisting tumor angiogenesis, mainly aims at a target spot of VEGFR1/2/3, is mainly used for treating recurrent and metastatic renal cell carcinoma clinically at present, and belongs to a second-line medicament. Clinical applications in non-small cell lung cancer are under investigation. In a non-clinical model, Axitinib achieves inhibition of primary tumor growth by interfering with tumor angiogenesis and anti-tumor cell survival in colorectal cancer, breast cancer, melanoma, and glioma. According to the invention, research shows that the axitinib can remarkably improve the sensitivity of sunitinib to cancer cells and greatly reduce the IC of sunitinib₅₀The combined use of the two results in a very significant synergistic effect (reduction of about 83.2%).

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention improves the existing clinical cancer treatment scheme, screens a large amount of compounds, and obtains the compound which can be combined with sunitinib to obviously reduce the drug resistance of the sunitinib.

(2) On the basis of the original sunitinib, at least one tyrosine kinase receptor inhibitor, especially apatinib and/or axitinib, is further added, and a very obvious synergistic interaction effect can be generated with the tyrosine kinase receptor inhibitor, so that the apoptosis of cancer cells is promoted in a combined manner, the proliferation of the cancer cells can be obviously inhibited, and the sunitinib has very obvious killing efficiency on the cancer cells.

(3) The pharmaceutical composition provided by the invention can obviously improve the problem of serious drug resistance caused by singly adopting sunitinib in the prior art and the problem of obviously reduced treatment effect when the conventional use amount of sunitinib is reduced; the clinical dosage of the sunitinib is greatly reduced, the high-efficiency treatment effect of the sunitinib can be always kept, and drug resistance caused by long-term use of sunitinib is prevented; meanwhile, the serious adverse reaction caused by long-term large-dose sunitinib use can be avoided, the medication safety and the life quality of patients are improved, the clinical treatment efficiency is obviously improved, a new scheme is provided for clinical treatment of tumor diseases, and the sunitinib composition has very wide market prospect and extremely important social significance.

Drawings

FIG. 1 shows the results of 786-O cell combination index experiments in vitro.

FIG. 2 shows the results of 786-O, A498 and Caki-1 cell combination index experiments in vitro.

FIG. 3 shows the results of in vivo antitumor experiments.

FIG. 4 shows the experimental results of the in vivo tumor weight trend.

Detailed Description

In order to make the objects, technical solutions and effects of the present invention clearer and clearer, the present invention is further described in detail below with reference to examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Cell lines listed in the context of the present invention, including 786-O, A498 and Caki-1, were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured according to ATCC guidelines, unless otherwise specified. All cell lines were identified by short tandem repeat analysis of the chinese typical culture collection (wuhan) and verified for the presence of mycoplasma contamination using a PCR assay kit (shanghai Biothrive Sci) while being cryopreserved in liquid nitrogen and used for subsequent experiments. The reagents used in the present invention are commercially available.

Representative results from selection of biological replicates are presented in the context figures, and data are presented as mean ± SD and mean ± SEM as specified in the figure. All in vitro experiments were repeated at least three times and animal experiments were repeated twice. Data were analyzed using GraphPad Prism 5.0 or SPSS 20.0 software. And comparing the difference of the mean values of two or more groups by using a t test or an analysis of variance. p < 0.05 was considered a significant difference.