Pharmaceutical combinations, kits comprising the same and uses thereof

Abstract

The present application provides a kind of drug combination, kit comprising and its purposes in the preparation of drug for treating breast cancer.The drug combination includes first active ingredient and second active ingredient, first active ingredient is the compound with the structure shown in structural formula I, its stereoisomer, its tautomer, its polymorph, its solvate and its pharmaceutically acceptable salt Any one or more of;Second active ingredient is estrogen receptor antagonist or aromatase inhibitor.The above-mentioned first active ingredient and the combination of second active ingredient are jointly applied, and the common therapeutic activity achieved has outstanding improvement effect relative to each active ingredient when being applied alone, and realizes synergistic effect.

Description

Technical Field

[0001] This invention relates to the field of breast cancer drugs, and more specifically, to a drug combination, a kit containing the drug, and its use. Background Technology

[0002] Breast cancer has become the most serious threat to women's health. Currently, there are at least 156 breast cancer drugs under development and on the market, 68% of which are targeted therapies. Numerous studies have found a correlation between tumors and cell cycle abnormalities. Extensive mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferative disorders. Simultaneously, most tumors exhibit genomic instability (GIN) and chromosomal instability (CIN), and these three fundamental cell cycle defects are directly or indirectly caused by the dysregulation of cyclin-dependent kinases (CDKs). Cyclin-dependent kinase (CDK) inhibitors are increasingly becoming popular targets.

[0003] The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins. CDK-mediated catalytic steps involve the transfer of phosphate from ATP to macromolecular enzyme substrates. Several groups of compounds have been found (see, for example, Fischer, PMCurr. Opin. Drug DiscoveryDev. 2001, 4, 623-634) to possess antiproliferative properties due to CDK-specific ATP antagonism.

[0004] Currently, marketed breast cancer drugs include Palbociclib (PD-0332991), Ribociclib (LEE011), and Abemaciclib (LY2835219). However, the availability of monotherapy drugs still falls short of clinical needs. Therefore, this invention provides a CDK inhibitor in combination with other pharmaceutical formulations, aiming to achieve a synergistic effect through this combination therapy. Summary of the Invention

[0005] The main objective of this invention is to provide a drug combination, a kit containing the same, and its use in the preparation of a drug for treating breast cancer, in order to improve the efficacy of monotherapy.

[0006] To achieve the above objectives, according to one aspect of the present invention, a pharmaceutical composition is provided, comprising: a first active ingredient, wherein the first active ingredient is any one or more of a compound having the structure shown in structural formula I, its stereoisomers, its tautomers, its polymorphs, its solvates, and its pharmaceutically acceptable salts.

[0007]

[0008] Wherein, ring A is aryl or heteroaryl; Z is selected from CH2, NH, O or S; R1 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic, heterocyclic-(CH2) m -,Aryl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, NR 12 R 13 NR 12 -C 1-6 Alkylene-NR 12 R 13 Or heterocyclic group -C(O)-, where C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic, heterocyclic-(CH2) m -,Aryl-C 1-6 Alkyl, heteroaryl-C 1-6 The alkyl or heterocyclic group -C(O)- is unsubstituted or is selected from at least one halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, heterocyclic, NR 12 R 13 (CH2) t The -OH group is substituted; R2 and R3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, or heterocyclic; wherein C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, or heterocyclic groups are each unsubstituted or are selected from at least one of halogen, hydroxyl, C 1-8 Alkyl, C 3-8 Substitution of cycloalkyl or heterocyclic groups; R 12 and R 13 Each is independently selected from hydrogen and C. 1-8 Alkyl, aryl, heteroaryl, heterocyclic or C 3-8 cycloalkyl; wherein C 1-8 Alkyl, aryl, heteroaryl, heterocyclic or C 3-8 The cycloalkyl group is unsubstituted or is selected from at least one of halogen, hydroxyl, C 1-8 Alkyl, C 3-8Substituents of cycloalkyl or heterocyclic groups; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4; aryl is a 6- to 10-membered monocyclic or bicyclic aromatic ring group; heteroaryl is a 5- or 6-membered monocyclic aromatic ring system composed of a carbon atom and 1-4 heteroatoms selected from N, O or S; heterocyclic group is a 3- to 8-membered stable saturated monocyclic system composed of a carbon atom and 1-3 heteroatoms selected from N, O or S; second active ingredient, which is an estrogen receptor antagonist or aromatase inhibitor.

[0009] Further, the first active ingredient is any one or more of the following: a compound having any of the structural formulas IA-ID or I-4, I-6; its stereoisomers; its tautomers; its polymorphs; its solvates; and its pharmaceutically acceptable salts.

[0010]

[0011]

[0012] Furthermore, the first active ingredient is any one or more of the following: a compound having any of the structures shown in structural formulas I-1 to I-3, I-5, and I-7; its stereoisomers; its tautomers; its polymorphs; its solvates; and its pharmaceutically acceptable salts.

[0013]

[0014] Furthermore, the aforementioned first active ingredient is any one or more of a compound having the structure shown in structural formula I-1 and its pharmaceutically acceptable salt.

[0015]

[0016] Furthermore, the pharmaceutically acceptable salts mentioned above are tartrate compounds and methanesulfonate compounds of the compound, preferably the first active ingredient is the compound or a tartrate compound of the compound.

[0017] Furthermore, the above-mentioned tartrate compound has crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 23.6±0.2° and 26.9±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°. More preferably, the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°.

[0018] Furthermore, the estrogen receptor antagonist mentioned above is selected from fulvestrant and tamoxifen, and the aromatase inhibitor is selected from letrozole and anastrozole.

[0019] Furthermore, the first and second active ingredients mentioned above may be applied simultaneously, separately, or sequentially.

[0020] Further, the first active ingredient is the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof; preferably, the daily dosage of the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof (based on the compound represented by structural formula I-1) ranges from 50 to 500 mg; more preferably, the daily dosage of the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof (based on the compound represented by structural formula I-1) ranges from 200 to 500 mg; even more preferably, the daily dosage of the compound represented by structural formula I-1 or a pharmaceutically acceptable salt thereof (based on the compound represented by structural formula I-1) ranges from 300 to 400 mg.

[0021] Further, the second active ingredient is fulvestrant; preferably, the dosage of fulvestrant is 1-2000 mg per dose, and the frequency of administration is 1-2 times a day; more preferably, the dosage of fulvestrant is 100-800 mg per dose, and the frequency of administration is 1-2 times a day; even more preferably, the dosage of fulvestrant is 200-600 mg per dose, and the frequency of administration is 1-2 times a day.

[0022] Further, the second active ingredient is letrozole; preferably, the dosage of letrozole is 1-200 mg per dose, and the frequency of administration is 1-2 times a day; more preferably, the dosage of letrozole is 1-20 mg per dose, and the frequency of administration is 1-2 times a day; even more preferably, the dosage of letrozole is 1-5 mg per dose, and the frequency of administration is 1-2 times a day.

[0023] Further, the second active ingredient is anastrozole; preferably, the dosage of anastrozole is 0.1 to 50 mg per dose, and the frequency of administration is 1 to 2 times a day; more preferably, the dosage of anastrozole is 1 to 25 mg per dose, and the frequency of administration is 1 to 2 times a day; even more preferably, the dosage of anastrozole is 1 to 10 mg per dose, and the frequency of administration is 1 to 2 times a day.

[0024] Furthermore, in the preparation of a drug for treating breast cancer using the above-mentioned drug combination, the breast cancer is preferably estrogen receptor-positive (ER+) breast cancer, or / and human epidermal growth factor receptor 2-negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

[0025] According to another aspect of the invention, a kit is provided comprising any of the above-described pharmaceutical combinations packaged in a container device, wherein the first active ingredient and the second active ingredient in the pharmaceutical combination are administered simultaneously, separately, or sequentially.

[0026] According to another aspect of the present invention, the use of any of the above-mentioned pharmaceutical combinations in the preparation of a medicament for treating breast cancer is provided.

[0027] Furthermore, the aforementioned breast cancers are estrogen receptor-positive (ER+) breast cancer, and / or human epidermal growth factor receptor 2-negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

[0028] By applying the technical solution of the present invention, the combined application of the first active ingredient and the second active ingredient in this application achieves a significant improvement in therapeutic activity compared to the individual application of each active ingredient. Therefore, it is demonstrated that the two achieve a synergistic effect. Attached Figure Description

[0029] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0030] Figure 1 The XRD pattern of the first active ingredient according to Example 1 of the present invention is shown;

[0031] Figure 2 This demonstrates the synergistic effect of the first active ingredient of Example 1 of the present invention, in combination with fulvestrant, on the inhibition of T-47D cell proliferation;

[0032] Figure 3The following figures illustrate tumor growth curves in Balb / c nude mice with MCF-7 cell xenograft tumors, as shown in Example 2, after administration of the first active ingredient or in combination with fulvestrant. Data points represent mean volume within groups, and error bars represent standard errors (SEM).

[0033] Figure 4 The changes in body weight of Balb / c nude mice with MCF-7 cell xenograft tumors in Example 2 are shown. The data points represent the mean body weight within the group, and the error bars represent the standard error (SEM). Detailed Implementation

[0034] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0035] Unless otherwise stated, the basic terms used in this application are defined in the following ways:

[0036] Unless otherwise stated, the terms “comprising” and “including” are used in this application as open-ended and non-restrictive concepts.

[0037] Unless otherwise stated in this application or obviously contradicted by the context, the terms “a” and “the”, and similar expressions in describing the invention (especially in the context of the claims), should be understood to cover both singular and plural forms.

[0038] When using the plural form of compounds, salts, etc., this is considered to represent a single compound, salt, etc.

[0039] In the term "drug combination," the first and second active ingredients can be administered independently as separate formulations for synergistic effect, or synergistically through the use of different fixed combinations containing varying amounts of the combination (i.e., simultaneously or at different time points). For ease of administration, they can be presented as "kits," "drug kits," or "combination formulations." For example, in a kit, the components can be administered simultaneously or sequentially (i.e., any part of the kit is administered at the same or different time intervals at different time points). In combination formulations, the ratio of the total amounts of the first and second active ingredients can vary, for example, to suit the needs of a subgroup of patients requiring treatment or the needs of an individual patient, specifically, for example, age or weight-specific requirements.

[0040] The term "pharmaceutical composition" is defined herein as a mixture or solution containing at least one therapeutic agent administered to an individual (e.g., a mammal or a human) for the prevention or treatment of a specific disease or ailment affecting a mammal.

[0041] The term “pharmaceutically acceptable” is defined in this application as compounds, materials, compositions and / or dosage forms that are suitable for contact with an individual (e.g., a mammal or a human) tissues without causing excessive toxicity, irritation, allergic reactions and other complications, and have a reasonable benefit / risk ratio commensurate with such contact.

[0042] As used in this application, the terms “co-administration” or “combined administration” are defined to cover the administration of selected therapeutic agents to a single patient and mean treatment regimens in which the agents are not necessarily administered via the same route or simultaneously.

[0043] The term "treatment" as used herein includes treatments that alleviate, reduce, or decrease at least one symptom in an individual or affect the delay of disease progression. For example, treatment may be the elimination of one or more symptoms of a condition or the complete eradication of a condition (e.g., cancer). In the context of this invention, the term "treatment" also means preventing, delaying the onset (i.e., the time before the clinical manifestations of a disease appear) and / or reducing the risk of disease development or worsening. The term "protection" herein refers to the prevention, delay, or treatment (or, where appropriate, all) of the development, continuation, or exacerbation of an individual's disease.

[0044] The terms "co-therapeutic activity" or "co-therapeutic effect" refer to the administration of therapeutic agents at time intervals, either alone (in an alternating manner, particularly in a specific sequence) and according to the preferences of the warm-blooded animal (especially humans) receiving the treatment, yet still producing (preferably synergistic) interactions (co-therapeutic effects). Whether this is the case can be determined by tracking blood levels that show the presence of both compounds in the blood of the person being treated at least during certain time intervals.

[0045] The term "pharmacologically effective amount," "clinically effective amount," or "therapeuticly effective amount" for a combination of therapeutic agents refers to the amount that, when used in combination, is sufficient to provide an observable improvement in the symptoms and signs observed at the clinical baseline of the disease.

[0046] Unless otherwise stated, "pharmaceutically acceptable salt" in this application includes salts that can contain acidic and basic groups in the compounds of the present invention. The compounds of the present invention are basic APIs that can form various different salts with a variety of inorganic and organic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the present invention are those that form non-toxic acid addition salts (i.e., salts containing pharmaceutically acceptable anions, such as acetates, benzoates, bromides, chlorides, citrates, fumarates, hydrobroms, hydrochlorides, iodates, lactates, maleates, mandelates, nitrates, oxalates, salicylates, succinates, and tartrates). "Pharmaceutically acceptable salt" in this application can also refer to amorphous or crystalline materials in which free base API and acid are ionized, or homogeneous crystalline materials in which the free base API and acid components are bound together by mutual intermolecular interactions, such as hydrogen bonds, or eutectic materials formed by the co-precipitation of free base and acid anions. It should be understood that the salt in this application may also be a mixture of partially ionized material and partially eutectic material.

[0047] As analyzed in the background section of this application, this application aims to enable CDK inhibitors to achieve ideal synergistic effects when used in combination with other pharmaceutical formulations. Based on this, this application provides a pharmaceutical combination, a kit containing the same, and its use in the preparation of a medicament for treating breast cancer.

[0048] It is particularly important to note that although CDK4 / 6 inhibitors encompass compounds of various structural types, the inventors of this application have discovered that not all CDK4 / 6 inhibitors can produce a synergistic effect with the aforementioned second active ingredient—estrogen receptor antagonists or aromatase inhibitors—and some degree of antagonism may even occur. In particular, the inventors have found that CDK4 / 6 inhibitors, which exhibit considerable inhibitory activity against breast cancer when used alone, often show significantly different effects when combined with the aforementioned second active ingredient.

[0049] Based on the above background, this application provides a drug combination comprising a first active ingredient and a second active component, wherein the first active ingredient is any one or more of a compound having the structure shown in structural formula I, its stereoisomers, its tautomers, its polymorphs, its solvates, and its pharmaceutically acceptable salts.

[0050]

[0051] Wherein, ring A is aryl or heteroaryl; Z is selected from CH2, NH, O or S; R1 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8Cycloalkyl, aryl, heteroaryl, heterocyclic, heterocyclic-(CH2) m -,Aryl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, NR 12 R 13 NR 12 -C 1-6 Alkylene-NR 12 R 13 Or heterocyclic group -C(O)-, where C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic, heterocyclic-(CH2) m -,Aryl-C 1-6 Alkyl, heteroaryl-C 1-6 The alkyl or heterocyclic group -C(O)- is unsubstituted or is selected from at least one halogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, heterocyclic, NR 12 R 13 (CH2) t The -OH group is substituted; R2 and R3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, or heterocyclic; wherein C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, aryl, heteroaryl, or heterocyclic groups are each unsubstituted or are selected from at least one of halogen, hydroxyl, C 1-8 Alkyl, C 3-8 Substitution of cycloalkyl or heterocyclic groups; R 12 and R 13 Each is independently selected from hydrogen and C. 1-8 Alkyl, aryl, heteroaryl, heterocyclic or C 3-8 cycloalkyl; wherein C 1-8 Alkyl, aryl, heteroaryl, heterocyclic or C 3-8 The cycloalkyl group is unsubstituted or is selected from at least one of halogen, hydroxyl, C 1-8 Alkyl, C 3-8Substituents of cycloalkyl or heterocyclic groups; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4; aryl is a 6- to 10-membered monocyclic or bicyclic aromatic ring group; heteroaryl is a 5- or 6-membered monocyclic aromatic ring system composed of a carbon atom and 1-4 heteroatoms selected from N, O or S; heterocyclic group is a 3- to 8-membered stable saturated monocyclic system composed of a carbon atom and 1-3 heteroatoms selected from N, O or S; the second active ingredient is an estrogen receptor antagonist or aromatase inhibitor.

[0052] The first active ingredient in this application is a CDK4 / 6 inhibitor. The combined application of the first and second active ingredients demonstrates a significant improvement in therapeutic activity compared to the individual application of each active ingredient, indicating a synergistic effect. Furthermore, experimental results show that the combined use of the first and second active ingredients in this invention results in better drug sensitivity against breast cancer cells and a more effective inhibitory effect at low doses, which also helps avoid the side effects associated with high-dose drug administration.

[0053] When the first active ingredient described above in this application is used in combination with the second active ingredient, their synergistic effects differ. In some embodiments, the first active ingredient is any one or more of the following: a compound having a structure of any one of the structural formulas IA-ID or I-4, I-6, its stereoisomers, its tautomers, its polymorphs, its solvates, and its pharmaceutically acceptable salts, in order to further improve the synergistic effect.

[0054]

[0055] More preferably, the first active ingredient is any one or more of the following: a compound having any one of the structures shown in structural formulas I-1 to I-3, I-5, and I-7; its stereoisomers; its tautomers; its polymorphs; its solvates; and its pharmaceutically acceptable salts:

[0056]

[0057] The above-mentioned drug combination, especially when used in the preparation of a drug for treating breast cancer, has shown in experiments to have a more prominent synergistic effect, such as when the breast cancer is estrogen receptor-positive (ER+) breast cancer, human epidermal growth factor receptor 2 negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

[0058] The overall effect is more stable, especially when the first active ingredient is any one or more of a compound having the structure shown in Formula I-1 and its pharmaceutically acceptable salt.

[0059]

[0060] In some embodiments of this application, the pharmaceutically acceptable salts are preferably tartrate compounds and methanesulfonate compounds of the compound, and the first active ingredient is preferably the compound or a tartrate compound of the compound.

[0061] In some embodiments of this application, the pharmaceutically acceptable salts are preferably tartrate compounds and methanesulfonate compounds of the compound, and the first active ingredient is preferably the compound or a tartrate compound of the compound.

[0062] The structural formula of a tartrate compound of the above-mentioned compound is as follows:

[0063]

[0064] The structural formula of a methanesulfonate compound of the above compound A is as follows:

[0065]

[0066] The first active ingredient used in this application is a compound that already exists in the prior art. For example, you can refer to the PCT patent application documents with publication numbers WO2018 / 113771A1 and WO2019242719A1. More specific preparation methods will not be described here.

[0067] Furthermore, to improve the stability when the first and second active ingredients are applied in combination, the tartrate compound preferably has crystal form A. The X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 23.6±0.2°, and 26.9±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A has diffraction angles 2θ of 4.4±0.2° and 8.7±0.2°. Characteristic peaks were observed at 10.8±0.2°, 18.4±0.2°, 23.6±0.2°, and 26.9±0.2°. Further optimization of the X-ray powder diffraction pattern of crystal form A revealed characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, 18.4±0.2°, 23.6±0.2°, and 26.9±0.2°. Tartrate compounds possessing the aforementioned crystal form A exhibit better solubility and stability, thus demonstrating more pronounced pharmacological efficacy.

[0068] In some embodiments of this application, the estrogen receptor antagonist is selected from fulvestrant and tamoxifen. The aromatase inhibitor is selected from letrozole and anastrozole. These drugs are all active ingredients of commonly used first- or second-line clinical drugs, thus offering higher safety.

[0069] Although the optional components of the second active ingredient are not the same as those in commonly used drugs, the methods and dosages of application vary. In order to better achieve the synergistic effect between the second active ingredient and the first active ingredient, the corresponding clinical application range can be given according to the individual needs of the patient.

[0070] In clinical application, patients can choose to administer the first and second active ingredients simultaneously, separately, or sequentially, depending on the specific form of the drug combination. The specific dosage relationship between the two types of active ingredients can be adjusted. Of course, to better exert a synergistic effect, the first active ingredient is preferably the compound shown in structural formula I-1 or a pharmaceutically acceptable salt thereof. Preferably, the daily dosage (based on the compound shown in structural formula I-1) of the compound shown in structural formula I-1 or a pharmaceutically acceptable salt thereof ranges from 50 to 500 mg, more preferably from 200 to 500 mg, and even more preferably from 300 to 400 mg. In some embodiments, the second active ingredient is fulvestrant. Preferably, the dosage of fulvestrant is 1 to 2000 mg per administration, administered once or twice daily. More preferably, the dosage of fulvestrant is 100 to 800 mg per administration, administered once or twice daily. Even more preferably, the dosage of fulvestrant is 200 to 600 mg per administration, administered once or twice daily. Alternatively, the second active ingredient is letrozole; preferably, the dosage of letrozole is 1-200 mg per dose, administered once or twice daily; more preferably, the dosage of letrozole is 1-20 mg per dose, administered once or twice daily; even more preferably, the dosage of letrozole is 1-5 mg per dose, administered once or twice daily. Alternatively, the second active ingredient is anastrozole; preferably, the dosage of anastrozole is 0.1-50 mg per dose, administered once or twice daily; more preferably, the dosage of anastrozole is 1-25 mg per dose, administered once or twice daily; even more preferably, the dosage of anastrozole is 1-10 mg per dose, administered once or twice daily.

[0071] The aforementioned drug combinations of this application can be formulated into corresponding preparations using currently available active ingredients and pharmaceutically acceptable carriers, and then administered. The aforementioned estrogen receptor antagonists, such as fulvestrant, are administered in the form of injections. Unless otherwise stated, they are prepared in ways known per se, such as through various conventional mixing, pulverizing, direct compression, granulation, sugar coating, dissolving, lyophilizing, melt granulation, or processing techniques well known to those skilled in the art. It should be noted that the unit content of the combined compounds in an individual dose of each dosage form does not necessarily constitute an effective amount, as the desired effective amount can be achieved by administering multiple dose units.

[0072] The term "pharmaceutically acceptable carrier" as used above refers to conventional pharmaceutical carriers suitable for the desired drug formulation, such as: diluents and excipients like water and various organic solvents; fillers like starch and sucrose; binders like cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); humectants like glycerin; disintegrants like agar, calcium carbonate, and sodium bicarbonate; absorption enhancers like quaternary ammonium compounds; surfactants like hexadecyl alcohol; absorption carriers like kaolin and bentonite; and lubricants like talc, calcium stearate, magnesium stearate, and polyethylene glycol. Other pharmaceutically acceptable excipients may also be added, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes. Excipients suitable for the desired dosage form and route of administration are preferred.

[0073] In another typical embodiment of this application, the use of any of the above-mentioned drug combinations in the preparation of a medicament for treating breast cancer is provided.

[0074] The combined application of the first and second active ingredients in this application results in a significant improvement in therapeutic activity compared to the individual application of each active ingredient, thus demonstrating a synergistic effect.

[0075] In some embodiments, the breast cancer described above is estrogen receptor-positive (ER+) breast cancer, human epidermal growth factor receptor 2-negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

[0076] In another typical embodiment of this application, a kit is provided comprising any of the above-described drug combinations packaged in a container, wherein the first and second active ingredients in the drug combination are administered simultaneously, separately, or sequentially. The above-described kit is one convenient method of administering the drug combinations of this application, but it does not imply that the drug combinations of this application can only exist in the form of kits.

[0077] The first and second active ingredients can be administered independently or by using different fixed combinations containing varying amounts of the combination (i.e., simultaneously or at different time points). The components of the kit can then be administered simultaneously or sequentially (i.e., any part of the kit is administered at the same or different time intervals at different time points). When administered as a combination formulation formed by the kit, the ratio of the total amounts of the first and second active ingredients can be varied, for example, to suit the needs of a subgroup of patients requiring treatment or the needs of an individual patient, specifically, for example, age or weight-specific requirements.

[0078] In yet another typical embodiment of this application, a method for treating breast cancer using a combination of drugs is provided. During treatment, appropriate clinical dosage ranges of the first and second active ingredients can be administered according to the individual needs of the patient.

[0079] The beneficial effects of this application will be further illustrated below with reference to embodiments and comparative examples.

[0080] Example 1: Inhibitory effect of the first active ingredient combined with fulvestrant on tumor cell proliferation

[0081] The chemical formula of the first active ingredient is: (Structural Formula II), crystal form is crystal form A, spectrum shown below. Figure 1 The first active ingredient was prepared according to the method described in WO2019242719A1, and fulvestrant is commercially available.

[0082] Methods: This experiment used materials from PerkinElmer... The Cell Proliferation Kit method was used to investigate the synergistic effect of the primary active ingredient (PNI) and fulvestrant on the inhibitory activity of T-47D cell proliferation, supporting clinical combination therapy strategies. This method utilizes the addition of BrdU (5-bromo-2'-deoxyuridine) as a DNA analog to the cells during the proliferation process, followed by an immunoreaction (anti-BrdU antibody) to detect the amount of BrdU incorporated into the DNA, reflecting the level of cell proliferation. The cell culture conditions in this experiment simulated estrogen stimulation under breast cancer pathological conditions, and activated charcoal treatment was used to remove potential hormonal factors from the serum, ensuring system controllability. Therefore, the combination therapy of the PNI and fulvestrant was performed under conditions of activated charcoal-treated serum and β-estradiol in the culture medium to maximize the combined therapeutic effect.

[0083] The specific experimental steps were as follows: T-47D cells were cultured in phenol red-free DMEM medium with 10 μg / mL human insulin, 10% FBS, and 1% penicillin antibiotics. The cells were cultured at 37°C and 5% CO2. After conventional culture until cell saturation reached 80%–90%, and the desired cell count was achieved, the cells were harvested. Cells were resuspended in medium containing activated charcoal-treated serum and β-estradiol, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to 96-well plates at 100 μL per well (3000 cells / well). Cells were cultured overnight. The first active ingredient and fulvestrant were diluted with DMSO and then diluted in medium for later use. 24 hours after cell seeding, 90 μL of medium was added to each well, followed by 10 μL of the prepared compound. The final concentrations of the compounds were: first active ingredient concentration: 60 nM; fulvestrant concentration: 150 nM. Combined drug concentration: 150 nM fulvestrant + 60 nM primary active ingredient. Incubate cell culture plates for 96 hours. Dilute BrdU Labeling Reagent 10-fold with culture medium, then add 2 μL to each well. Incubate cell culture plates overnight. Gently aspirate the culture medium, add 100 μL of fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100 μL of 0.5 μg / mL Anti-BrdU-Eu antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash four times with washing buffer. Add 200 μL of LDELFIA Inducer to each well and incubate at room temperature for 30 minutes. Read the fluorescence signal using Envision.

[0084] Data Analysis: The efficacy of combined drug therapy is evaluated using the drug-in-interaction (CDI) coefficient. CDI is calculated using the formula: CDI = AB / A × B, where AB is the ratio of cell pore readings in the combined drug group to the DMSO control group, and A or B is the ratio of cell pore readings in the individual drug group to the control group. If CDI < 1, the two drugs exhibit synergistic effects; a CDI < 0.7 indicates a highly significant synergistic effect. If CDI = 1, the two drugs exhibit additive effects; if CDI > 1, the two drugs exhibit antagonistic effects.

[0085] Results: The experimental results on the inhibition of T-47D cell proliferation by the combined use of the primary active ingredient and fulvestrant showed that the CDI of the combined use of 60 nM primary active ingredient and 150 nM fulvestrant was 0.59. Based on the judgment criteria for the combination drug index, this indicates that the synergistic effect of the two drugs is very significant. The results are shown in Table 1 and... Figure 2 As shown.

[0086] Conclusion: In T-47D cells, under estrogen stimulation conditions simulating the pathological conditions of breast cancer patients, the combination index (CDI) of 60 nM primary active ingredient and 150 nM fulvestrant was 0.59, indicating a very significant synergistic effect between the two drugs.

[0087] Table 1

[0088] Group Fluorescence readings %Ctrl CDI DMSO 20160±705.9 100.0±3.5 / First active ingredient 10783±425.6 53.5±2.1 / Fulvestrant 11053±248.0 54.8±1.2 / First active ingredient + fulvestrant 3466±130.1 17.2±0.6 0.59

[0089] Note: Readings and %Ctrl are both average ± SEM representations.

[0090] Example 2

[0091] In vivo pharmacodynamic studies of the tartrate salt of the first active ingredient (Formula II) or in combination with fulvestrant in a BALB / c nude mouse model of subcutaneous xenograft tumors of human breast cancer MCF-7 cells.

[0092] Methods: Balb / c nude mice were subcutaneously injected with 17β-estradiol tablets (0.18 mg, 90-day sustained release) 3 days before cell inoculation. MCF-7 cells were subcutaneously inoculated into the back of mice to establish an MCF-7 xenograft tumor animal model. The experiment was divided into four groups: a solvent blank control group, a group with 25 mg / kg of the first active ingredient, a group with 50 mg / kg of the first active ingredient, a group with 200 mg / kg of fulvestrant, a group with 25 mg / kg of the first active ingredient plus 200 mg / kg of fulvestrant, and a group with 50 mg / kg of the first active ingredient plus 200 mg / kg of fulvestrant. Eight animals were in each group. The first active ingredient was administered by gavage once daily for 29 days (QD×29 days) starting from the day of grouping. Fulvestrant was administered subcutaneously once weekly for 5 weeks starting from the day of grouping (QW x 5 times). Safety was evaluated based on changes in animal body weight and mortality, and efficacy was evaluated based on the relative tumor inhibition rate (TGI%).

[0093] The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound was evaluated using TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0094] Relative tumor proliferation rate △T / △C (%): The calculation formula is as follows: △T / △C (%) = (Ti - T0) / (Vi - V0) x 100. Where V0 is the average tumor volume measured in the solvent control group when the drugs are administered in groups (i.e., D0), Vi is the average tumor volume of the solvent control group at a certain measurement, T0 is the average tumor volume measured in the drug administration group when the drugs are administered in groups (i.e., D0), and Ti is the average tumor volume of the drug administration group at a certain measurement.

[0095] result:

[0096] 1. Evaluation of the efficacy of the compound in a tumor model of MCF-7 cell xenograft:

[0097] On day 28 after administration to mice, the first active ingredient (25 mg / kg) group did not show a significant antitumor effect on the mean tumor volume compared to the solvent control group (p = 0.1706), with a relative tumor proliferation rate (ΔT / ΔC%) of 62.02% and a tumor growth inhibition rate (TGI%) of 37.98%. However, the first active ingredient (50 mg / kg) group showed a significant antitumor effect on the mean tumor volume compared to the solvent control group (p = 0.0020), with a relative tumor proliferation rate (ΔT / ΔC%) of 28.97% and a tumor growth inhibition rate (TGI%) of 71.03%. The fulvestrant (200 mg / kg) group also showed a significant antitumor effect on the mean tumor volume compared to the solvent control group (p = 0.0001), with a relative tumor proliferation rate (ΔT / ΔC%) of 11.13% and a tumor growth inhibition rate (TGI%) of 88.87%. Compared with the solvent control group, the first active ingredient (25 mg / kg) + fulvestrant (200 mg / kg) group and the first active ingredient (50 mg / kg) + fulvestrant (200 mg / kg) group also showed significant antitumor effects on average tumor volume, with p values ​​of <0.0001 and <0.0001, respectively; the relative tumor proliferation rate ΔT / ΔC (%) was -12.05% and -12.80%, respectively; and the tumor growth inhibition rate TGI (%) was 112.05% and 112.80%, respectively. The evaluation of the antitumor efficacy is shown in Table 2; the tumor growth curve is shown in... Figure 3 As shown.

[0098] Table 2. Evaluation of the antitumor efficacy of the first active ingredient or fulvestrant in a MCF-7 xenograft model (calculated based on tumor volume on day 28 after administration).

[0099]

[0100]

[0101] Note:

[0102] a. Mean ± SEM, n = 8.

[0103] b. Tumor growth inhibition is determined by ΔT / ΔC and TGI (TGI(%) = [1-(T)] / ΔC). 28 -T0) / (V 28 Calculate using -V0)]×100).

[0104] The cp value was used to compare the tumor volume between the treatment group and the solvent control group.

[0105] 2. Safety evaluation of the compound in a tumor model of MCF-7 cell xenograft.

[0106] In this model, such as Figure 4 As shown, none of the animals experienced significant weight loss during the administration period.

[0107] in conclusion:

[0108] In terms of drug safety, tumor-bearing mice showed good tolerance to the first active ingredient at two doses of 25 mg / kg and 50 mg / kg, or in combination with fulvestrant (200 mg / kg).

[0109] In terms of tumor volume and tumor weight, the first active ingredient also showed significant antitumor effects when used in combination with fulvestrant (200 mg / kg) at two doses of 25 mg / kg and 50 mg / kg.

[0110] Regarding drug sensitivity, the data in the table above shows that the p-values ​​of the first active ingredient at both 25 mg / kg and 50 mg / kg doses are <0.0001, which is significantly lower than the p-values ​​of other CDK4 / 6 inhibitors in the prior art. This sufficiently demonstrates that the combined use of the first and second active ingredients provided by this invention exhibits more significant drug sensitivity against breast cancer cell proliferation, and plays a better role in reducing drug dosage and minimizing toxic side effects.

[0111] Examples 3 to 7, Comparative Example 1

[0112] In Examples 3 to 8, different first active ingredients were combined with fulvestrant in the amounts shown in the table to inhibit the proliferation of T47D tumor cells. The specific experimental procedures are as follows:

[0113] This experiment used the Abcam BrdU ELISA kit to detect the synergistic effect of the primary active ingredient and fulvestrant on the inhibitory activity of T47D cell proliferation, supporting clinical combination therapy strategies. This method involves adding BrdU (5-bromo-2'-deoxyuridine) as a DNA analog to cells during cell proliferation, and then detecting the amount of BrdU incorporated into the DNA using an anti-BrdU antibody to reflect the level of cell proliferation. The cell culture conditions in this experiment simulated estrogen stimulation under postmenopausal breast cancer pathological conditions. Activated charcoal treatment was used to remove any potential hormonal factors in the serum to ensure system controllability. Therefore, the combination therapy of the primary active ingredient and fulvestrant was performed under conditions of activated charcoal-treated serum and estradiol in the culture medium to maximize the combined therapeutic effect.

[0114] The specific experimental steps were as follows: T47D cells were cultured in phenol red-free RPMI-1640 medium with 10 μg / mL human insulin, 10% FBS, and 1% penicillin antibiotics. The cells were cultured at 37°C and 5% CO2. After standard culture until cell saturation reached 80%-90%, and the desired number was achieved, the cells were harvested. The cells were resuspended in estradiol-treated serum medium, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to 96-well plates and incubated overnight. The first active ingredient and fulvesin were diluted with DMSO and then diluted in medium for later use. 24 hours after cell seeding, the prepared compounds were added to the wells. The cell culture plates were incubated for 96 hours. 20 hours before the end of the experiment, 10 μL of 1X BrdU was added to each well, and 10 μL of phenol red-free RPMI-1640 medium containing 10% activated charcoal-adsorbed fetal bovine serum was added to the background wells. Incubation continued. Gently aspirate the culture medium, add fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100 μL of anti-BrdU monoclonal detector antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash four times with washing buffer. Add 100 μL of 1X Peroxidase Goat Anti-Mouse IgG Conjugate to each well and incubate at room temperature for 30 minutes. Add 100 μL of TMB to each well, incubate at room temperature for 30 minutes, and then read the OD450.

[0115] Efficacy evaluation method: The efficacy of combination drug therapy was evaluated using the Bliss independence model. A synergistic score was calculated using both the Bliss independence model and the Loewe additive model. A score above 5 indicates a synergistic effect, while a score below -5 indicates an antagonistic effect.

[0116] The results are shown in Table 3:

[0117] Table 3

[0118]

[0119] Note: Structural formulas I-8 are compounds.

[0120] Examples 9 to 11

[0121] In Examples 9 to 11, different first active ingredients were combined with letrozole in the amounts shown in the table to inhibit the proliferation of MCF-7 tumor cells. The specific experimental procedures are as follows:

[0122] This experiment used the Abcam BrdU ELISA kit to detect the synergistic effect of different primary active ingredients combined with letrozole on the inhibitory activity of MCF-7 cell proliferation, supporting clinical combination therapy strategies. This method utilizes the addition of BrdU (5-bromo-2'-deoxyuridine) as a DNA analog to the cells during cell proliferation, and then detects the amount of BrdU incorporated into the DNA through an immunoreaction (anti-BrdU antibody) to reflect the level of cell proliferation. The cell culture conditions in this experiment simulated estrogen stimulation under postmenopausal breast cancer pathological conditions. Activated charcoal treatment was used to remove potential hormonal factors from the serum to ensure system controllability. Therefore, the combination therapy of different primary active ingredients with letrozole was conducted under conditions of activated charcoal-treated serum and androstenedione in the culture medium to maximize the efficacy of the combination therapy.

[0123] The specific experimental steps were as follows: MCF-7 cells were cultured in phenol red-free RPMI-1640 medium with 10 μg / mL Human Insulin, 10% FBS, and 1% penicillin antibiotics. The cells were cultured at 37℃ and 5% CO2. After conventional culture until cell saturation reached 80%-90%, and the desired number was achieved, the cells were harvested. The cells were resuspended in medium containing activated charcoal-treated serum and androstenedione, counted, and prepared into a cell suspension of appropriate density. The cell suspension was added to a 96-well plate and incubated overnight. The first active ingredient and letrozole were diluted with DMSO and then diluted in medium for later use. 24 hours after cell seeding, the prepared compounds were added to the wells. The cell culture plate was incubated for 96 hours. 20 hours before the end of the experiment, 10 μL of 1X BrdU was added to each well, and 10 μL of phenol red-free RPMI-1640 medium containing 10% activated charcoal-adsorbed fetal bovine serum was added to the background wells. Continue incubation, gently aspirate the culture medium, add fixative to each well, and incubate at room temperature for 30 minutes. Discard the fixative, add 100 μL of anti-BrdU monoclonal detector antibody to each well, and incubate at room temperature for 60 minutes. Discard the antibody solution and wash four times with washing buffer. Add 100 μL of 1X Peroxidase Goat Anti-Mouse IgG Conjugate to each well and incubate at room temperature for 30 minutes. Add 100 μL of TMB to each well, incubate at room temperature for 30 minutes, and then read the OD450.

[0124] Efficacy evaluation method: The efficacy of combination drug therapy was evaluated using the Bliss independence model. A synergistic score was calculated using both the Bliss independence model and the Loewe additive model. A score above 5 indicates a synergistic effect, while a score below -5 indicates an antagonistic effect.

[0125] The results are shown in Table 4:

[0126] Table 4

[0127]

[0128]

[0129] Example 12

[0130] Clinical trials of the first active ingredient tartrate (the compound shown in structural formula II above) or in combination with fulvestrant.

[0131] Inclusion criteria:

[0132] 1. (Dose escalation phase) Monotherapy: For patients with histological or cytologically confirmed advanced breast cancer who do not benefit from existing standard treatment regimens and are not suitable for curative surgical resection or radiation therapy;

[0133] 2. (Expanded Enrollment Phase) Combination Therapy: The following conditions must be met simultaneously.

[0134] Women with locally advanced or recurrent / metastatic breast cancer who are histologically or cytologically confirmed by a research center as HR positive and HER-2 negative (if a biopsy of metastatic lesions has been performed, the results of the metastatic lesions shall prevail) and who are not suitable for surgical resection or radiation therapy for the purpose of cure.

[0135] Postmenopausal women in their natural state; or premenopausal women who have previously undergone bilateral oophorectomy or medical castration to reach a postmenopausal state.

[0136] 3. (Expanded enrollment phase) Combination therapy:

[0137] ① Patients with recurrent or metastatic disease are permitted to receive no more than one line of chemotherapy.

[0138] ② The following criteria must be met simultaneously:

[0139] Patients who have received first-line endocrine therapy during the relapse / metastasis stage must meet the following criteria: progression-free period of ≥6 months after continuous first-line endocrine therapy, and disease progression confirmed by imaging.

[0140] Patients who have received adjuvant endocrine therapy must meet the requirement of having radiographically confirmed disease relapse within 12 months from the start of adjuvant endocrine therapy (continuous medication for at least 2 years) until the completion of adjuvant endocrine therapy.

[0141] Measurable lesions as defined by RECIST V.1.1, tumor lesions that have previously received radiotherapy or other local treatments, are considered measurable lesions only if there is a clear record of disease progression at the treatment site after the completion of treatment;

[0142] Dosage regimen:

[0143] (Dose Escalation Phase) Monotherapy: This phase is designed with 6 doses: drug A (tartrate capsules of the compound shown in structural formula I-1) at 50 mg / day, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, and 500 mg / day. Oral administration is initiated with a single dose of drug A capsules, followed by a 7-day washout period before continuous once-daily dosing.

[0144] (Expanded Enrollment Phase) Combination Therapy: Drug A (tartrate capsules of the compound shown in structural formula I-1) 300 mg / day combined with fulvestrant 500 mg / 28 days, or Drug A 400 mg / day combined with fulvestrant 500 mg / 28 days. The first active ingredient capsules are administered orally once daily for continuous use. Fulvestraant 500 mg: Administered once each on days 1 and 15 of the first cycle, and once on day 1 of each cycle thereafter, via slow, continuous intramuscular injection into the buttock (1-2 min / 5 mL), one injection per buttock. Each cycle lasts 28 days.

[0145] in conclusion:

[0146] As of February 25, 2022, in the dose escalation phase, among the 13 evaluable patients in the monotherapy groups (300 mg / day, 400 mg / day, and 500 mg / day), one patient achieved partial remission (PR), resulting in an objective response rate (ORR) of 7.7%. In the expanded enrollment phase, among the 30 evaluable patients in the combination therapy group (300 mg / day and 400 mg / day of the first active ingredient capsules combined with fulvestrant), 17 patients achieved partial remission (PR), resulting in an ORR of 56.7%. In the drug A capsule 400 mg / day combined with fulvestrant group, among the 21 evaluable patients, 14 patients achieved partial remission (PR), resulting in an ORR as high as 66.7%.

[0147] The efficacy of drug A combined with fulvestrant (≥300mg / d) was superior to that of drug A alone; at the same time, compared with historical data of fulvestrant in the treatment of advanced breast cancer that had relapsed or progressed after previous endocrine therapy (ORR: 9-21.3%), the combination therapy also showed superior efficacy.

[0148] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A pharmaceutical combination product for treating breast cancer, characterized in that, include: The first active ingredient is a tartrate compound having the structure shown in Structure II. Structural Form II The second active ingredient is fulvestrant.

2. The pharmaceutical combination product according to claim 1, characterized in that, The tartrate compound has crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°.

3. The pharmaceutical combination product according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic peaks with diffraction angles 2θ of 4.4±0.2°, 8.7±0.2°, 10.8±0.2°, 15.9±0.2°, 18.4±0.2°, 23.6±0.2° and 26.9±0.2°.

4. The pharmaceutical combination product according to any one of claims 1 to 3, characterized in that, The first active ingredient and the second active ingredient may be applied simultaneously, separately, or sequentially.

5. The pharmaceutical combination product according to claim 4, characterized in that, Based on the compound represented by structural formula I-1, the daily dosage range of the tartrate compound with the structure shown in formula II is 50~500 mg. Structural formula I-1 is: Structural formula I-1.

6. The pharmaceutical combination product according to claim 5, characterized in that, The daily dosage range of the tartrate compound with the structure shown in Formula II is 200~500 mg.

7. The pharmaceutical combination product according to claim 6, characterized in that, The daily dosage range of the tartrate compound with the structure shown in Formula II is 300~400 mg.

8. The pharmaceutical combination product according to claim 4, characterized in that, The dosage of fulvestrant is 1-2000 mg per administration, and the frequency of administration is 1-2 times per day.

9. The pharmaceutical combination product according to claim 8, characterized in that, The dosage of fulvestrant is 100-800 mg per dose, administered once or twice daily.

10. The pharmaceutical combination product according to claim 9, characterized in that, The dosage of fulvestrant is 200-600 mg per administration, and the frequency of administration is 1-2 times per day.

11. A reagent kit, characterized in that, The kit comprises a pharmaceutical combination product according to any one of claims 1 to 10 packaged in a container device, wherein the first active ingredient and the second active ingredient in the pharmaceutical combination product are administered simultaneously, separately, or sequentially.

12. Use of a pharmaceutical combination product according to any one of claims 1 to 10 in the preparation of a medicament for treating breast cancer.

13. The use according to claim 12, characterized in that, The breast cancer referred to is estrogen receptor-positive (ER+) breast cancer, and / or human epidermal growth factor receptor 2-negative (HER2-) breast cancer, or locally advanced or metastatic breast cancer.

Images