阅读说明：本技术 一种治疗肺癌的药物组合物 (Medicine composition for treating lung cancer ) 是由 苗春兴 艾恒玲 董丽 武晓萌 于生龙 薛久巍 于 2020-06-29 设计创作，主要内容包括：本发明提供了一种用于治疗肺癌的药物组合物,所述肺癌优选地为小细胞肺癌。所述药物组合物包含免疫检查点抑制剂和桃叶珊瑚苷。还提供了所述药物组合物的相关制剂及其用途。所述药物组合物显著抑制肺癌裸鼠移植瘤生长并显著改善裸鼠的生存期,效果显著优于同等剂量免疫检查点抑制剂和桃叶珊瑚苷单独用药,这表明药物联用后,具有显著的协同增效作用,临床应用前景良好。(The present invention provides a pharmaceutical composition for the treatment of lung cancer, preferably small cell lung cancer. The pharmaceutical composition comprises an immune checkpoint inhibitor and aucubin. Related formulations of the pharmaceutical compositions and uses thereof are also provided. The pharmaceutical composition can obviously inhibit the growth of the transplanted tumor of the lung cancer nude mouse and obviously improve the survival period of the nude mouse, and the effect is obviously better than that of the independent medication of the same dose of the immune check point inhibitor and aucubin, which shows that the pharmaceutical composition has obvious synergistic effect and good clinical application prospect after the combination.)

1. A pharmaceutical composition for treating lung cancer, which comprises an immune checkpoint inhibitor and aucubin, wherein the weight ratio of the immune checkpoint inhibitor to the aucubin is 1: 0.1-1.

2. The pharmaceutical composition of claim 1, wherein the immune checkpoint inhibitor is selected from one or more of ipilimumab, nivolumab, pembrolizumab, astuzumab, avizumab, and devolizumab.

3. The pharmaceutical composition of claim 1 or 2, wherein the weight ratio of immune checkpoint inhibitor to aucubin is 1: 0.2-0.8.

4. The pharmaceutical composition of any one of claims 1-3, wherein the immune checkpoint inhibitor is selected from the group consisting of astuzumab, and the weight ratio of astuzumab to aucubin is 1: 0.2.

5. the pharmaceutical composition of any one of claims 1-4, further comprising a chemotherapeutic agent, wherein the immune checkpoint inhibitor, aucubin, and the chemotherapeutic agent are present in a weight ratio of 1: 0.1-1:0.1-1.

6. The pharmaceutical composition of any one of claims 1-5, wherein the chemotherapeutic agent is selected from one or more of cisplatin, carboplatin, paclitaxel, docetaxel, etoposide, pemetrexed.

7. The pharmaceutical composition of any one of claims 1-6, wherein the immune checkpoint inhibitor is selected from astuzumab, the chemotherapeutic agent is selected from etoposide, and the weight ratio of astuzumab, aucubin, and etoposide is 1: 0.2: 0.4.

8. a pharmaceutical preparation for treating lung cancer, wherein the pharmaceutical preparation is prepared from the pharmaceutical composition of any one of claims 1-7 and a pharmaceutically acceptable carrier, and preferably the pharmaceutical preparation is an injection.

9. Use of the pharmaceutical composition of any one of claims 1-7 or the pharmaceutical formulation of claim 8 in the manufacture of a medicament for the treatment of lung cancer.

10. The use of claim 9, wherein the lung cancer is small cell lung cancer, preferably the small cell lung cancer is restricted small cell lung cancer or extensive small cell lung cancer, more preferably the extensive small cell lung cancer is extensive small cell lung cancer after chemotherapy.

Technical Field

The invention relates to a pharmaceutical composition for treating lung cancer. In particular to a medicine composition for treating small cell lung cancer.

Background

Lung cancer is a common malignant tumor, and both the prevalence and the mortality rate of lung cancer are among the top of the malignant tumors in the world. According to the histological classification of lung tumors proposed by the World Health Organization (WHO), lung cancer can be classified into two main categories: small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC). The small cell lung cancer accounts for 15% -20% of primary bronchogenic carcinoma and belongs to neuroendocrine tumors. Compared with non-small cell lung cancer, small cell lung cancer has the pathophysiological characteristics of low differentiation degree, high malignancy degree, early occurrence of distal metastasis and the like, the prognosis is poor, and the average five-year survival rate is not more than 10%. Unfortunately, small cell lung cancer research is slow and clinical treatment regimens are extremely limited. For a long time, first-line therapy for small cell lung cancer is generally systemic chemotherapy based on platinum drugs in combination with etoposide. Although small cell lung cancer is sensitive to chemotherapy, the vast majority of patients relapse quickly and die within two years.

In recent years, immune checkpoint inhibitors (immune checkpoint inhibitors) have made a great breakthrough in the treatment of small cell lung cancer, and the overall layout of the treatment methods for small cell lung cancer is being changed. Alemtuzumab (atezolizumab) for first line therapy, nivolumab (nivolumab) and pembrolizumab (pembrolizumab) for third line therapy have received formal approval by the U.S. Food and Drug Administration (FDA). Attrituximab is currently the only approved immunotherapeutic approach for the initial treatment of extensive small cell lung cancer. Is also a major breakthrough in the treatment of small cell lung cancer in recent 20 years. Immune checkpoint inhibitors are becoming a research hotspot in the field of small cell lung cancer which has long been considered as "forbidden regions of research" (see, for example, the book Juanpsis, et al, "Current State of clinical research of immune checkpoint inhibitors in the treatment of small cell lung cancer", J. Clinoperaceae, Vol. 25, 5 th, 2020, 5 th, 788, 793).

However, in clinical studies and clinical applications, it has been found that despite their strong therapeutic effect, immune checkpoint inhibitors suffer from a number of disadvantages, for example, PD-1/PD-L1 mab, which is very expensive, is prone to severe adverse reactions in the skin, endocrine, liver and lung systems, and even in some patients, is resistant. The above-mentioned deficiencies of immune checkpoint inhibitors, such as tumor resistance, production of synergistic effects and reduction of toxic side effects, appear to be overcome by the use of combinations. However, how to select a combination from a large number of drugs that can produce synergistic effects with immune checkpoint inhibitors and reduce their toxicity has become a new challenge for scientists in the field of drug development. The research shows that the natural product has unique advantages in the aspects of regulating the tumor microenvironment, inhibiting tumor metastasis and improving tumor drug resistance. Therefore, the search for natural products capable of enhancing the curative effect of the immune checkpoint inhibitor and reducing the toxic and side effects of the immune checkpoint inhibitor has important clinical significance for improving the treatment outcome and the survival period of patients with lung cancer (especially, small cell lung cancer).

Aucubin (aucubin) belongs to iridoid compounds, and is widely present in plants of Plantaginaceae, Scrophulariaceae, Polulariaceae, Eucommiaceae, etc., wherein the content of herba plantaginis is the highest. The aucubin has effects of protecting liver, removing toxic substance, resisting inflammation, resisting oxidation, and resisting osteoporosis. The oral administration bioavailability of aucubin is low, and the administration modes of the oral administration of aucubin from high bioavailability to low bioavailability are intravenous administration, intraperitoneal administration and oral administration. Studies show that aucubin has obvious cytotoxicity on human myeloid leukemia K562 cells and can induce apoptosis. In addition, studies show that aucubin can increase the amount of p53 and p21 proteins in a549 cell line of human non-small cell lung cancer, and further block cells at the stage of G0/G1, and finally cause apoptosis of A549 cells (see, for example, Hanmanfei et al, "research on chemical structures and pharmacological actions of natural aucubin and derivatives thereof" Chinese herbal medicines, Vol.19, No. 2017, No. 4105-one 4113). However, there is no study on the combination of aucubin and an immune checkpoint inhibitor in the treatment of lung cancer (especially small cell lung cancer).

Disclosure of Invention

The invention aims to provide a pharmaceutical composition with synergistic effect for treating lung cancer (especially small cell lung cancer) patients, and provides a new idea for safely, effectively and economically treating lung cancer (especially small cell lung cancer) clinically.

The technical scheme for realizing the purpose of the invention is as follows:

the first aspect of the invention provides a pharmaceutical composition for treating lung cancer, which comprises an immune checkpoint inhibitor and aucubin, wherein the weight ratio of the immune checkpoint inhibitor to the aucubin is 1: 0.1-1.

In one embodiment, the immune checkpoint inhibitor is selected from one or more of ipilimumab, nivolumab, pembrolizumab, astuzumab, avilimumab, and desvolumab.

In another embodiment, the weight ratio of immune checkpoint inhibitor to aucubin is 1: 0.2-0.8.

In a preferred embodiment, the immune checkpoint inhibitor is selected from altritizumab, and the weight ratio of altritizumab to aucubin is 1: 0.2.

in one embodiment, the pharmaceutical composition further comprises a chemotherapeutic agent, and the immune checkpoint inhibitor, aucubin, and the chemotherapeutic agent are in a weight ratio of 1: 0.1-1:0.1-1.

In another embodiment, the chemotherapeutic agent is selected from one or more of cisplatin, carboplatin, paclitaxel, docetaxel, etoposide, pemetrexed.

In a preferred embodiment, the immune checkpoint inhibitor is selected from alt-rubimab, the chemotherapeutic agent is selected from etoposide, and the weight ratio of alt-rubimab, aucubin, and etoposide is 1: 0.2: 0.4.

the second aspect of the invention provides a pharmaceutical preparation for treating lung cancer, which is prepared from the pharmaceutical composition and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical formulation is an injection.

In another embodiment, the injectable formulation is selected from the group consisting of an injectable solution, a sterile powder for injection, and a concentrated solution for injection.

The route of administration may be parenteral, including but not limited to intravenous, subcutaneous, intramuscular, and the like.

The active ingredients (e.g., alemtuzumab, aucubin, and/or etoposide) in the pharmaceutical composition of the invention may be administered simultaneously or separately in sequential order. The active ingredients of the pharmaceutical compositions of the present invention may be administered in combination in the same pharmaceutical formulation or in separate and distinct formulations.

A third aspect of the invention provides the use of a pharmaceutical composition or pharmaceutical formulation as described above in the manufacture of a medicament for the treatment of lung cancer.

In a preferred embodiment, the lung cancer is small cell lung cancer.

In a more preferred embodiment, the small cell lung cancer is a limited-term small cell lung cancer or a broad-term small cell lung cancer.

In a more preferred embodiment, the extensive small cell lung cancer is post-chemotherapy extensive small cell lung cancer.

By "localized small cell lung cancer" is meant a patient whose tumor is confined to one thoracic cavity, including metastasis to the pre-mediastinal, ipsilateral supraclavicular and anterior oblique horn lymph nodes. By "extensive small cell lung cancer" is meant the development of a tumor that exceeds the range of the limited stage.

The aucubin used in the pharmaceutical composition of the present invention can be extracted and separated from plants of plantago, scrophulariaceae, globulariaceae, eucommia ulmoides, etc. containing the active ingredient by a biological purification method, or can be purchased from commercially available products.

In the above-mentioned medical applications, the administration time, administration frequency, etc. of the composition of the present invention are required depending on the specific diagnosis result of the disease state, which is within the technical scope of those skilled in the art.

The therapeutic regimen for mice is applied to human body, and the effective dose of all drugs to human body can be converted by the effective dose of the drugs to mice, which is also easy to be realized by the ordinary skilled person in the art.

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

(1) the invention combines the advantages of China in the aspect of natural product research, screens out a pharmaceutical composition with synergistic effect in the aspect of treating lung cancer (especially small cell lung cancer), remarkably enhances the effect of the immune checkpoint inhibitor in treating lung cancer (especially small cell lung cancer) by combining aucubin and the immune checkpoint inhibitor, and further makes it possible to increase the effectiveness and safety of the drugs by reducing the dosage of the immune checkpoint inhibitor.

(2) The plant containing aucubin (such as plantain herb, figwort root, eucommia bark and the like) has wide sources in China, and the aucubin has simple preparation method, mature industrial production method and lower cost. Therefore, the curative effect is enhanced by adding aucubin into the expensive immune check point inhibitor, so that the medicine cost of lung cancer (especially small cell lung cancer) patients in China can be greatly reduced, and the economic burden of the patients is really reduced.

Detailed Description

The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.