Pharmaceutical composition for synergistic treatment of non-small cell lung cancer

Abstract

The application provides a pharmaceutical composition for synergistically treating non-small cell lung cancer, and belongs to the technical field of biological medicine. The application provides a synergistic pharmaceutical composition containing Capivasertib and doxorubicin for specifically treating non-small cell lung cancer. Compared with other similar pharmaceutical combinations, the composition can achieve a synergistic effect. The composition does not present a synergistic killing effect in the tested control tumor cell lines, indicating that the synergistic effect is disease selective. The application provides a pharmaceutical composition with better effect for the clinical treatment of non-small cell lung cancer, and has clear clinical application value and good commercialization prospect.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to pharmaceutical compositions for the synergistic treatment of non-small cell lung cancer. Background Technology

[0002] Non-small cell lung cancer (NSCLC) is the most prevalent histological subtype of lung cancer, accounting for 80%–85% of all lung cancer cases. Its pathological types mainly include lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Despite continuous advancements in early screening technologies and diagnostic methods for NSCLC, its insidious onset means that most patients are already in locally advanced stages or have distant metastases at the time of diagnosis, thus losing the opportunity for radical surgical resection. Consequently, the overall five-year survival rate has remained low for a long time.

[0003] In the clinical treatment of non-small cell lung cancer (NSCLC), platinum-based combination chemotherapy remains the cornerstone of traditional treatment for patients with negative driver genes. However, its efficacy has reached a bottleneck, and it suffers from significant toxic side effects and poor patient tolerance. For patients carrying specific molecular targets such as epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusion genes, targeted therapy can bring significant short-term objective responses, but secondary drug resistance is almost inevitable, making it difficult to further improve progression-free survival. Meanwhile, immunotherapies such as programmed death receptor 1 (PD-1) and its ligand (PD-L1) inhibitors have shown some activity in later-line treatment of NSCLC, but the overall single-agent efficacy is low, and clinical benefits are only observed in subgroups of patients who have undergone strict biomarker screening. Summary of the Invention

[0004] The purpose of this invention is to provide a pharmaceutical composition for the synergistic treatment of non-small cell lung cancer, thereby solving the technical problem of the lack of synergistic pharmaceutical compositions that can effectively treat non-small cell lung cancer in the prior art.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides the use of a pharmaceutical composition in the preparation of a medicament for the synergistic treatment of non-small cell lung cancer, the pharmaceutical composition comprising capivasertib and doxorubicin.

[0006] Preferably, the concentration of capivasertib is 0.8 μM to 3.2 μM, and the concentration of doxorubicin is 100 nM to 400 nM.

[0007] Preferably, the concentration of capivasertib is 3.2 μM and the concentration of doxorubicin is 400 nM.

[0008] Preferably, the non-small cell lung cancer cell line is selected from at least one of NCI-H1299 and A-549.

[0009] Preferably, the capivasertib and / or doxorubicin are in the form of their pharmaceutically acceptable salts, hydrates, or solvates.

[0010] Preferably, the dosage form of the pharmaceutical composition is an injection or an oral preparation.

[0011] Preferably, the injection is a lyophilized powder injection or a liposome injection.

[0012] Preferably, the drug further comprises a pharmaceutically acceptable excipient selected from at least one of excipients, disintegrants, lubricants, and binders.

[0013] Preferably, when the drug is an injection, the content of doxorubicin is 10mg to 100mg per unit dose.

[0014] Preferably, when the drug is an oral preparation, the content of Capivasertib is 100mg to 400mg per unit dose.

[0015] The beneficial effects of this invention are: This invention provides a synergistic pharmaceutical composition comprising capivasertib and doxorubicin for the specific treatment of non-small cell lung cancer. Compared with other similar drug combinations, the composition of this invention achieves a synergistic effect; furthermore, this composition did not exhibit synergistic killing activity in the tested control tumor cell lines, indicating that its synergistic effect is disease-selective. This invention provides a more effective pharmaceutical composition for the clinical treatment of non-small cell lung cancer, with clear clinical application value and good commercial prospects. Attached Figure Description

[0016] Figure 1 The diagram shows the chessboard method and Chou-Talalay synergistic effect evaluation of the pharmaceutical composition of the present invention in NCI-H1299 and A-549 cells. Figure 2 This is a statistical validation graph showing the multi-drug screening and synergistic effects of various compositions in non-small cell lung cancer cell lines (NCI-H1299, A-549); Figure 3 This is a graph showing the efficacy evaluation and statistical analysis of the drug composition of the present invention in HCT116 colon cancer cells after combined drug administration. Figure 4 This is a graph showing the efficacy evaluation and statistical analysis of the drug composition of the present invention in glioblastoma U87MG cells after combined drug administration. Figure 5This is a graph showing the efficacy evaluation and statistical analysis of the combined drug combination of the present invention in melanoma SK-SML-28 cells; Figure 6 This is a graph showing the efficacy evaluation and statistical analysis of the drug composition of the present invention in combined use in Ishikawa and An3CA endometrial cancer cells. Detailed Implementation

[0017] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for the synergistic treatment of non-small cell lung cancer, the pharmaceutical composition comprising capivasertib and doxorubicin.

[0018] Non-small cell lung cancer (NSCLC) is the most prevalent histological subtype of lung cancer, accounting for 80%–85% of all lung cancer cases. Its pathological types mainly include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Despite continuous advancements in early screening and diagnostic methods for NSCLC, its insidious onset means that most patients are diagnosed at a locally advanced stage or with distant metastases, thus losing the opportunity for radical surgical resection. Overall, the five-year survival rate remains low. In clinical treatment of NSCLC, platinum-based combination chemotherapy remains the cornerstone of traditional treatment for patients with negative driver genes, but its efficacy has reached a bottleneck, with significant toxic side effects and poor patient tolerance. For patients carrying specific molecular targets such as EGFR mutations or ALK fusion genes, targeted therapy can bring significant short-term objective responses, but secondary drug resistance is almost inevitable, making it difficult to further improve progression-free survival. Meanwhile, although immunotherapies such as PD-1 / PD-L1 inhibitors have shown some activity in the later-line treatment of non-small cell lung cancer, the overall single-agent efficacy rate is low, and clinical benefits can only be seen in subgroups of people who have undergone strict biomarker screening.

[0019] Preferably, the concentration of capivasertib is 0.8 μM to 3.2 μM, and the concentration of doxorubicin is 100 nM to 400 nM.

[0020] In this invention, the concentration of capivasertib refers to the effective concentration of capivasertib in the pharmaceutical composition. The concentration range of 0.8 μM to 3.2 μM covers multiple effective concentration points where capivasertib exhibits synergistic activity in in vitro cell experiments. More preferably, the concentration of capivasertib can be 1.0 μM to 3.0 μM; more preferably, the concentration of capivasertib can be 2.0 μM to 3.2 μM. The concentration of doxorubicin refers to the effective concentration of doxorubicin in the pharmaceutical composition. The concentration range of 100 nM to 400 nM covers multiple effective concentration points where doxorubicin exhibits synergistic activity in in vitro cell experiments. More preferably, the concentration of doxorubicin can be 150 nM to 350 nM; more preferably, the concentration of doxorubicin can be 200 nM to 400 nM.

[0021] Preferably, the concentration of capivasertib is 3.2 μM and the concentration of doxorubicin is 400 nM.

[0022] In this invention, the concentration of capivasertib is further preferably 3.2 μM, and the concentration of doxorubicin is further preferably 400 nM. Under these preferred concentration conditions, the combination of capivasertib and doxorubicin can produce a more significant synergistic anticancer effect.

[0023] Preferably, the non-small cell lung cancer cell line is selected from at least one of NCI-H1299 and A-549.

[0024] In this invention, the non-small cell lung cancer (NSCLC) cell line is a cell model used to validate the antitumor activity of the drug composition in vitro. The NCI-H1299 cell line is derived from lymph node metastases in NSCLC patients. This cell line contains a deletion mutation in the p53 gene and is commonly used to study the metastatic mechanisms and drug sensitivity of NSCLC. The A-549 cell line is one of the most classic NSCLC cell lines, derived from a 58-year-old male patient with lung adenocarcinoma. This cell line exhibits characteristics of type II alveolar epithelial cells, synthesizes lecithin, and expresses various pulmonary surfactant-related proteins, making it widely used in lung cancer research and drug screening. All of the above cell lines possess well-defined biological characteristics and genetic backgrounds, making them ideal models for evaluating the activity of anti-NSCLC drugs in vitro. The drug composition of this invention exhibits synergistic inhibitory effects against at least one of the above cell lines.

[0025] Preferably, the capivasertib and / or doxorubicin are in the form of their pharmaceutically acceptable salts, hydrates, or solvates.

[0026] In this invention, "pharmaceutically acceptable salt" refers to the derivative form obtained by modifying the compound (Capivasertib or doxorubicin) by preparing its acid addition salt or base addition salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amino groups), and alkali metal or organic salts of acidic residues (such as carboxylic acids). It is estimated that approximately 50% of marketed pharmaceutical products are administered in salt form. Salt formation can improve properties such as drug solubility, dissolution rate, bioavailability, or physicochemical stability. "Hydrate" refers to a solvate with water as the solvent, i.e., a complex formed by intermolecular interactions between compound molecules and water molecules. "Solvent" refers to a molecular complex formed by intermolecular interactions or complexation between a compound and one or more pharmaceutically acceptable solvent molecules. Pharmaceutically acceptable solvates include solvates with isotopically substituted solvents. From a scientific point of view, solvates and hydrates can be considered a subgroup of cocrystals, whose co-formation is either solvent or water. The capivasertib and / or doxorubicin described in this invention may be present and used in pharmaceutically acceptable salt, hydrate or solvate form, all of which are within the scope of protection of this invention.

[0027] Preferably, the dosage form of the pharmaceutical composition is an injection or an oral preparation.

[0028] In this invention, the pharmaceutical composition can be formulated into a suitable dosage form according to clinical needs and route of administration. Injectable and oral formulations are the two most common dosage forms in the field of pharmaceutical preparations. Injectables are characterized by rapid onset of action and high bioavailability, making them suitable for situations requiring rapid onset of action or where patients cannot take oral medication. Oral formulations offer advantages such as convenient administration and good patient compliance, making them suitable for chronic diseases or maintenance therapy scenarios requiring long-term administration. The pharmaceutical composition of this invention can be selected in either injectable or oral form according to actual treatment needs.

[0029] Preferably, the injection is a lyophilized powder injection or a liposome injection.

[0030] In this invention, the lyophilized powder injection refers to a sterile powder preparation obtained by freeze-drying a drug solution under sterile conditions, which is then reconstituted with an appropriate solvent before injection. The advantage of lyophilized powder injections is that they can improve the stability of drugs during storage and extend the shelf life of the preparation, especially suitable for drugs that are unstable to heat or moisture. The preparation of lyophilized powder injections usually involves the use of lyophilization protectants to protect the drug from denaturation or degradation during freezing and drying. Commonly used lyophilization protectants include, but are not limited to, mannitol, sucrose, trehalose, glucose, lactose, sorbitol, glycine, and polyethylene glycol. The preparation process of lyophilized powder injections typically includes steps such as formulation, sterile filtration, filling, freezing, primary drying (sublimation drying), secondary drying (desorption drying), stoppering, and capping. The liposome injection refers to an injectable dosage form in which the drug is encapsulated in liposomes (microvesicles composed of a phospholipid bilayer). The advantages of liposome injections lie in their ability to achieve targeted drug release, enhance passive or active drug accumulation in tumor tissues, and reduce drug exposure in normal tissues, thereby minimizing systemic toxicity. Furthermore, liposomes possess excellent biocompatibility and biodegradability, making them an ideal drug carrier. Liposome injection formulations typically include components such as active pharmaceutical ingredients, phospholipids, cholesterol, stabilizers, emulsifiers, lyophilization protectants, and pH adjusters.

[0031] Preferably, the drug further comprises a pharmaceutically acceptable excipient selected from at least one of excipients, disintegrants, lubricants, and binders.

[0032] In this invention, pharmaceutically acceptable excipients refer to materials added to pharmaceutical preparations, other than the active pharmaceutical ingredient, to meet purposes such as formulation shaping, stabilization, excipient formation, or improvement of user experience. Excipients, also known as diluents or fillers, are inert substances used in formulations to increase the volume or weight of the contents of tablets or capsules, enabling the formulation to achieve a suitable size and shape for ease of production and administration. Commonly used excipients include, but are not limited to: starch, pregelatinized starch, dextrin, sucrose, lactose, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, and calcium carbonate. Excipients should have good flowability and compressibility and should not interact with the active pharmaceutical ingredient. Disintegrants are excipients that promote the rapid disintegration of tablets or capsules into fine particles in the gastrointestinal tract. Their function is to increase the contact area between the formulation and digestive juices, thereby promoting the dissolution and absorption of the active pharmaceutical ingredient. Commonly used disintegrants include, but are not limited to: sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, and effervescent disintegrants (such as a combination of citric acid and sodium bicarbonate). The dosage and type of disintegrant need to be optimized according to the formulation composition and disintegration time requirements. Lubricants are excipients added during tableting or filling to reduce friction between particles and between particles and the mold wall. Their function is to improve material flowability, prevent sticking, smooth the tablet surface, and facilitate tablet ejection. Commonly used lubricants include, but are not limited to: magnesium stearate, stearic acid, sodium stearate fumarate, talc, micronized silica gel, polyethylene glycol, and sodium lauryl sulfate. The amount of lubricant used is usually small; excessive use may affect tablet hardness and disintegration performance. Binders are excipients added during wet granulation or direct tableting to increase the adhesion between material particles. Their function is to aggregate powdered materials into particles with a certain strength and hardness to ensure the mechanical strength of the formulation. Commonly used binders include, but are not limited to: hydroxypropyl methylcellulose, povidone (polyvinylpyrrolidone), sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, starch paste, gelatin, sodium alginate, syrup, gum arabic, etc. The selection and dosage of binders must be determined based on the properties of the materials and the granulation process. Those skilled in the art can rationally select one or more of the above excipients according to specific dosage form requirements and formulation processes to achieve optimal formulation performance.

[0033] Preferably, when the drug is an injection, the content of doxorubicin is 10mg to 100mg per unit dose.

[0034] In this invention, when the pharmaceutical composition is prepared as an injection, the content of doxorubicin per unit dose is 10 mg to 100 mg. This content range covers the commonly used dosage range of doxorubicin in clinical injection administration and can be flexibly adjusted according to the patient's specific condition, weight, body surface area, and combination therapy regimen. For example, when doxorubicin is used as a monotherapy in clinical practice, the commonly used dose calculated based on body surface area is 60–75 mg / m² every three weeks; the commonly used dose calculated based on weight is 1.2–2.4 mg / kg every three weeks. The above-mentioned content range of 10 mg to 100 mg per unit dose can meet the clinical administration needs of patients with different weights and body surface areas. More preferably, the content of doxorubicin in the injection is 20 mg to 80 mg per unit dose; more preferably, the content of doxorubicin in the injection is 30 mg to 60 mg per unit dose. In addition, depending on the different injectable subtypes (such as conventional injections, liposome injections, or lyophilized powder injections), the unit dose of doxorubicin can be appropriately adjusted within the above range.

[0035] Preferably, when the drug is an oral preparation, the content of Capivasertib is 100mg to 400mg per unit dose.

[0036] In this invention, when the pharmaceutical composition is prepared as an oral formulation, the content of capivasertib per unit dose is 100 mg to 400 mg. Capivasertib, as an orally effective pan-AKT inhibitor, is typically administered orally in clinical practice. In clinical studies, the dosage range of capivasertib is relatively wide; for example, in some studies, the dosage of capivasertib has been explored and adjusted within the range of 80 mg to 800 mg. The content range of 100 mg to 400 mg per unit dose covers the effective dosage range for oral administration of capivasertib and can be individually adjusted according to the patient's specific condition, tolerability, and combination therapy regimen. More preferably, the content of capivasertib in the oral formulation is 150 mg to 350 mg per unit dose; more preferably, the content of capivasertib in the oral formulation is 200 mg to 300 mg per unit dose. The oral formulation can be made into various forms such as tablets, capsules, and granules. Each unit dose refers to the amount of capivasertib contained in each tablet, capsule, or unit package granule. Within the above content range, the dosage specifications can be further refined according to clinical needs, such as 100mg, 200mg, 400mg, etc., to facilitate flexible adjustment of clinical administration.

[0037] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0038] Example 1 This embodiment provides a pharmaceutical composition for specifically killing non-small cell lung cancer, comprising active ingredient A: Capivasertib (Capi) and active ingredient B: Doxorubicin (Dox).

[0039] The concentration of capivasertib was 0.8 μM, and the concentration of doxorubicin was 400 nM.

[0040] Example 2 This embodiment provides a pharmaceutical composition for specifically killing non-small cell lung cancer, comprising active ingredient A: Capivasertib (Capi) and active ingredient B: Doxorubicin (Dox).

[0041] The concentration of capivasertib was 1.6 μM, and the concentration of doxorubicin was 400 nM.

[0042] Example 3 This embodiment provides a pharmaceutical composition for specifically killing non-small cell lung cancer, comprising active ingredient A: Capivasertib (Capi) and active ingredient B: Doxorubicin (Dox).

[0043] The concentration of capivasertib was 2.4 μM, and the concentration of doxorubicin was 400 nM.

[0044] Example 4 This embodiment provides a pharmaceutical composition for specifically killing non-small cell lung cancer, comprising active ingredient A: Capivasertib (Capi) and active ingredient B: Doxorubicin (Dox).

[0045] The concentration of capivasertib was 3.2 μM, and the concentration of doxorubicin was 400 nM.

[0046] Example 5 This embodiment verifies the in vitro efficacy and evaluates the synergistic specificity of the drug compositions described in Examples 1-4.

[0047] 1. Experimental Materials and Methods Cell lines: human non-small cell lung cancer cell lines (NCI-H1299, A-549), and other tumor cell lines used for comparative specificity validation (glioblastoma U87MG, melanoma SK-SML-28, colon cancer HCT116, endometrial cancer Ishikawa and An3CA).

[0048] Drugs: Capivasertib (Capi, 3.2 μM), Doxorubicin (Dox, 400 nM), Cisplatin (Cis, 4 μM), 4-hydroperoxycyclophosphamide (4-HC, 2 μM).

[0049] Group setup: To comprehensively evaluate the effects of different single-drug and combination therapies, the experiment set up 8 treatment groups, namely: control group, capi monotherapy group, dox monotherapy group, cis monotherapy group, 4-HC monotherapy group, dox+capi combination group, cis+capi combination group, and 4-HC+capi combination group.

[0050] Processing and detection: Using the CCK-8 assay, cells were seeded at 5000-8000 cells / well in 96-well plates. After 24 hours of adhesion, the cells were treated with drugs for 48 hours. The absorbance was measured at 450 nm and the viability was calculated. The synergy index (CI) was assessed using the checkerboard assay and the Chou-Talalay algorithm.

[0051] 2. Summary of Core Data The original absorbance (OD value) data mentioned above are stored in the laboratory records. The cell viability percentage presented in this example is calculated by the formula [(OD value of experimental wells - OD value of blank wells) / (OD value of control wells - OD value of blank wells)] × 100%. The data in the table below are obtained by averaging the viability of multiple replicates in the same group. The statistical p-value is calculated by unpaired t-test.

[0052] As shown in Table 1 and as shown in the table below Figure 2 As shown, this experiment tested different single-drug and combination drug regimens in two types of non-small cell lung cancer cells, NCI-H1299 and A-549. The results showed that among the experimental groups, the Dox+Capi combination group had the best proliferation inhibition effect, and the Dox+Capi combination group had a significant statistical difference compared with the Dox single-drug group (P values ​​were 0.000717 and 0.000757, respectively, both P<0.01) (n = 3).

[0053] Table 1: Comparison and significance analysis of cell viability (%) among different treatment groups Control 100±0 100±0 Capi monotherapy 78.5±3.22 96.44±3.14 Dox monotherapy 67.27±1.65 76.2±2.15 Cis monotherapy 95.78±4.38 97.88±3.71 4-HC monotherapy 91.06±2.87 98.16±3.36 Dox+Capi 56.58±1.08 56.04±3.1 Cis+Capi 83.83±4.7 80.76±4.57 4-HC+Capi 80.84±0.77 84.37±2.29 P-value (Dox vs Dox+Capi) P = 0.000717 P = 0.000757 Furthermore, such as Figure 1 As shown in Table 2, this experiment used a checkerboard method to combine different concentrations of Capi and Dox in NCI-H1299 and A-549 cell lines, and calculated the combination index (CI) based on the Chou-Talalay method. As shown in Table 2, within the effective concentration range tested, the CI values ​​for each concentration combination were significantly less than 1, indicating a significant synergistic effect between the two drugs in non-small cell lung cancer cells (Note: In the Chou-Talalay method, a combination index CI < 1 indicates a synergistic effect) (n = 3).

[0054] Table 2: Joint Index Analysis Using the Chessboard Method (Chou-Talalay Method) 0.8 400 39.25±2.03 58.08±3.24 CI < 1 (synergistic) 1.6 400 38.43±1.33 53.73±4.62 CI < 1 (synergistic) 2.4 400 36.43±2.44 52±1.44 CI < 1 (synergistic) 3.2 400 35.57±1.5 58.39±3.59 CI < 1 (synergistic) like Figure 3 , Figure 4 , Figure 5 and Figure 6 As shown in Table 3, to verify the tumor specificity of this drug composition, it was applied to four other solid tumor cell lines under the same treatment protocol. The statistical results show that in these control tumor cells, the cell survival rate of the Dox+Capi combination group was not statistically significantly different from that of the Dox monotherapy group (P > 0.05), demonstrating that this synergistic effect did not occur in colon cancer, glioblastoma, melanoma, and endometrial cancer (n = 3).

[0055] Table 3: Survival rate (%) and statistical analysis of other tumor cell lines specifically validated. cell lines HCT116 U87MG SK-SML-28 Ishikawa / An3CA Control 100±0 100±0 100±0 100±0 / 100±0 Capi monotherapy 78.79±2.81 87.02±4.89 94.34±1.37 53.01±3.45 / 94.46±0.9 Dox monotherapy 24.36±0.62 50.17±11.99 73.82±1.59 15.01±4.45 / 86.19±5.51 Dox+Capi 25.53±1.03 50.25±8.2 74±1.64 18.27±3.01 / 81.18±2.77 P-value (comparing the Dox group and the combined group) P = 0.165817 P = 0.993085 P = 0.901592 P = 0.352094 / 0.231812 3. Experimental Conclusions In summary, the pharmaceutical composition Capivasertib and doxorubicin provided by this invention exhibit significant synergistic killing effects in non-small cell lung cancer cells. Figure 1 , Figure 2 Furthermore, this synergistic effect is tumor-specific, and it has not produced a synergistic killing effect in colon cancer, glioblastoma, melanoma, and endometrial cancer. Figures 3 to 6 ).

[0056] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The use of a pharmaceutical composition in the preparation of a medicament for the synergistic treatment of non-small cell lung cancer, characterized in that, The pharmaceutical composition comprises capivasertib and doxorubicin.

2. The application according to claim 1, characterized in that, The concentration of capivasertib is 0.8 μM to 3.2 μM, and the concentration of doxorubicin is 100 nM to 400 nM.

3. The application according to claim 2, characterized in that, The concentration of capivasertib was 3.2 μM, and the concentration of doxorubicin was 400 nM.

4. The application according to claim 1, characterized in that, The non-small cell lung cancer cell line is selected from at least one of NCI-H1299 and A-549.

5. The application according to claim 1, characterized in that, The capivasertib and / or doxorubicin are in their pharmaceutically acceptable salt, hydrate, or solvate forms.

6. The application according to claim 1, characterized in that, The dosage form of the pharmaceutical composition is an injection or an oral preparation.

7. The application according to claim 6, characterized in that, The injection is a lyophilized powder injection or a liposome injection.

8. The application according to claim 6, characterized in that, The drug also includes pharmaceutically acceptable excipients selected from at least one of excipients, disintegrants, lubricants, and binders.

9. The application according to claim 6, characterized in that, When the drug is an injectable preparation, the content of doxorubicin is 10mg to 100mg per unit dose.

10. The application according to claim 6, characterized in that, When the drug is an oral preparation, the content of Capivasertib is 100mg to 400mg per unit dose.

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