Formulation comprising n,n-dimethylbiguanide, pharmaceutical combination comprising n,n-dimethylbiguanide and drug, composition, kit, use thereof, and method for preparing same

Abstract

Provided are a formulation comprising N,N-dimethylbiguanide and use thereof in preparing a lesion interventional drug. Also provided are a pharmaceutical combination comprising N,N-dimethylbiguanide and a drug with a synergistic effect, a pharmaceutical composition, formulation and kit comprising the pharmaceutical combination, a method for preparing same, and use thereof.

Description

Preparation containing N,N-dimethylbiguanide, and pharmaceutical combination, composition, kit containing N,N-dimethylbiguanide and drugs, and use and preparation method thereof Technical Field

[0001] The present application discloses novel uses of metformin-like compounds, as well as their combination with different components (Z) based on the advantages of these novel uses (such as reduced dosage and increased efficacy, reduced biological barrier function, and improved heterogeneous adaptability), and their uses. Z includes or is selected from at least one of the following groups: a cell-reactive anti-tumor drug (abbreviated as B), an (injectable) weakly alkaline sodium salt (abbreviated as C), a methylene blue dye (abbreviated as D), and an immunomodulator (abbreviated as E), such as an injectable immunomodulator. Background Art

[0002] Many substances have shown anti-tumor activity in cell-based assays. However, even those with strong activity are often less likely to demonstrate the expected efficacy in animal studies, and those with better efficacy are also less likely to demonstrate the expected efficacy in clinical trials. Only a very small number of the best are approved for indications and used to treat the most targeted tumors. However, after careful selection, clinical practice has found that even within the approved indications, efficacy varies from patient to patient, and many cases are unsatisfactory. The key limitations are as follows:

[0003] Biological barrier issues. These cell-reactive drugs or their active forms can only produce anti-tumor reactions when they come into contact with tumor cells. Cell suspensions are already too simple compared to the tumor tissue of model animals, while the tumor tissue of animal patients is more complex, and the degree of biological barriers (tissue barriers, cell membrane barriers, etc.) is also greatly increased, becoming a key control step in their cellular response.

[0004] Heterogeneity. Heterogeneity includes tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. Different tumors of the same type, or different regions of the same tumor, can differ significantly in tissue barrier function, morphological distribution, or safety impact. If the results of drug cell or animal trials are simply based on the results without fully considering these heterogeneity issues, anti-cancer drugs, even those administered to tumors, will be difficult to administer according to their characteristics and will not produce the expected efficacy.

[0005] Dose-effect problem. The efficacy of cell-responsive drugs is highly dependent on their anti-tumor reaction concentration, and their dosage is usually limited by their side effects. Many drugs partially reduce safety at the expense of causing patients to suffer from side effects during treatment. The efficacy (timeliness, effectiveness, long-term effect, heterogeneous adaptability) provided by them at larger doses still needs to be improved. For example, due to the superposition of the above-mentioned biological barriers and heterogeneity, the amount of drug delivered to different areas and the time for maintaining this amount can be very different. If the dose-effect of the drug is not strong, the anti-tumor effect in some areas may not be sufficient to effectively inhibit tumor cells, and these areas may become the source of tumor resistance and recurrence. The weak dose-effect of the drug thus includes a large dose but still low heterogeneous adaptability.

[0006] In the prior art, metformin (typically C₄H₁₁₁₁₁₁₁₁₁₁₁₁) is indicated for lowering blood sugar levels in type 2 diabetes. Research into new uses for metformin is ongoing, and all reported anti-tumor effects of metformin (hereinafter referred to as conventional metformin anti-tumor effects) are directed against tumor cells, for example, by influencing tumor cell proliferation through activation of the AMP-activated protein kinase pathway (Morales DR, Morris AD. Metformin in Cancer Treatment and Prevention [J]. Annual Review of Medicine, 2015). In cell-based assays, the half-maximal effective concentration (EC₅₀) for selected sensitive cells is in the millimolar range, more than 100 times higher than the micromolar range for conventional anti-tumor drugs such as 5-FU, indicating that metformin's anti-tumor effects, if any at all, are very weak at the cellular level.

[0007] Compared to approved drugs for solid tumor indications, metformin faces even more significant limitations in the three key areas mentioned above (biological barriers, heterogeneity, and dose-response). In summary, conventional metformin drugs or formulations exhibit a fundamental characteristic of low efficacy with high doses (weak dose-response), manifested in the need for long-term (e.g., continuous administration for more than 30 days in mouse studies) high doses (e.g., 1000-2000 mg per day) to produce still very low efficacy. For example, among five metformin clinical studies using Ki-67 as a tumor proliferation marker, only two studies showed a significant decrease in Ki-67, while two studies showed no significant change in Ki-67, and one study found elevated Ki-67 levels (Vancura A, Bu P, Bhagwat M, et al. Metformin as an Anticancer Agent [J]. Trends Pharmacol. Sci., 2018, Vol. 39, No. 10, pp. 867-878).

[0008] The combined use of conventional metformin with other drugs (for example, cell-responsive anti-tumor drugs) essentially exploits their interactions at the cellular level (Kan Guanting, Yu Jiandong, Xiong Yang, "Research Progress of Metformin Combined with Chemotherapy for Anti-tumor Effects," Chinese Journal of Modern Applied Pharmacy, Vol. 37, No. 16, August 2020, p2025-2030). This combination does not alter the anti-tumor pharmacology of the active ingredients, and the aforementioned weak dose-response effect of conventional metformin persists. The challenges to be addressed do not involve the aforementioned biological barriers and heterogeneity.

[0009] This application involves local lesions and conducts research using tumors as an example, with the goal of solving the above-mentioned problems of conventional metformin drugs and their use in combination with other drugs (taking cell-responsive anti-tumor drugs as an example) (Problem 1: the dose-response is too weak, especially under biological barrier and heterogeneity conditions; Problem 2: when used in combination with other drugs, it can only provide the cytotoxic effect limited by Problem 1, which does not help to solve the latter's biological barrier and heterogeneity problems). The application aims to give metformin and its use in combination with anti-tumor drugs new therapeutic values ​​(such as new indications) that are not available in existing technologies but are urgently needed in clinical practice, so as to meet various clinical needs that cannot be met by existing technologies. Summary of the Invention

[0010] The inventors of the present invention unexpectedly discovered that an aqueous solution of metformin hydrochloride and an aqueous solution of N,N-dimethylbiguanide, which are generally regarded as pharmaceutical equivalents, respectively, showed differences in intratumoral cell morphology one hour after being introduced into tumors containing drug-resistant tumor cells, and differences in tumor inhibition rates were observed at the experimental endpoint. These results clearly contradict the existing structure-activity concept of "same basic chemical structure, basically the same pharmacological efficacy" (which is also the basis for the common reference of metformin salts to metformin in the prior art), and exceed the expectations of the conventional anti-tumor effects of metformin.

[0011] Therefore, according to the first aspect of the present invention, a product specifically for lesion intervention is provided, specifically a preparation comprising N,N-dimethylbiguanide (abbreviated as R) and optionally a medium, such as a solvent, and the preparation does not contain an acid capable of converting the R into a salt thereof, such as an acidic pH regulator required to meet the safety requirements of cell culture or routine injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its administration concentration, wherein the administration concentration (w / w) is 0.5% ≦ C R ≦51%, preferably, 1%-50%, more preferably 3%-50% or 5%-30%.

[0012] More specifically, the formulations of the present invention are preferably used to treat a lesion such as a tumor or nodule in a subject, preferably, the treatment is localized.

[0013] In some embodiments, the tumor comprises a solid tumor.

[0014] In some embodiments, the above-mentioned preparation comprises a medium such as a solvent. Preferably, the solvent comprises water, more preferably water for injection.

[0015] In some embodiments, the above formulation does not include a salt of N,N-dimethylbiguanide (referred to as metformin salt, abbreviated as R').

[0016] In some embodiments, the concentration (w / w) of the salt of N,N-dimethylbiguanide in the above-mentioned preparation is ≦30%, preferably ≦25%, preferably ≦10%, more preferably ≦5%, ≦4%, or ≦3%, still more preferably ≦2%, particularly preferably ≦1%, such as 1% or 0.5%, and most preferably 0%, that is, the preparation does not contain a salt of N,N-dimethylbiguanide.

[0017] In some embodiments, the amount of N,N-dimethylbiguanide administered in the above formulation is: Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and: Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the injection point, wherein the v R(ii) ≦3 times the target volume of application point ii (abbreviated as v 靶(ii) ), and C R The concentration of R is 0.5-51%, wherein 0.5% is the common concentration threshold of R and 51% is the upper limit of the solubility threshold of R.

[0018] In some embodiments, the formulation is a fast-acting formulation used only to rapidly reduce lesion volume.

[0019] In some embodiments, the formulation is a low-frequency-effective formulation for only infrequent administration.

[0020] In some embodiments, the formulation is provided as a liquid, wherein the liquid is a microvolume liquid, and the microvolume is 2-1000 μl, 5-500 μl, 5-100 μl, 5-50 μl, or 5-20 μl.

[0021] In some embodiments, the salt of N,N-dimethylbiguanide includes hydrochloride, sulfate, acetate, phosphate, citrate, lactate, nitrate, carbonate, etc. of N,N-dimethylbiguanide.

[0022] In some embodiments, the acidic pH adjuster includes or is selected from strong acids such as hydrochloric acid and sulfuric acid; or weak acids such as acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0023] In some embodiments, N,N-dimethylbiguanide is a compound of formula C4H 11 N5 organic compound (a), which has the following formula 1:

[0024] In some embodiments, the metformin drug used as a conventional drug is generally a complex of N,N-dimethylbiguanide and an acid (referred to as metformin salt, abbreviated as R'), and its chemical formula is C4H 11 N5·acid (a+b), the most commonly used metformin drug is metformin hydrochloride (C4H 11 N5·HCl), i.e., metformin hydrochloride, which has the following formula 2:

[0025] In some embodiments, the formulation consists of N,N-dimethylbiguanide and water. In one embodiment, in the formulation, the concentration of N,N-dimethylbiguanide administered (C R， w / w) can be 0.75%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50%, or any range therebetween, such as 0.75% to 20%, 1% to 20%, 2% to 20%, 3% to 20%, 5% to 20%, 5% to 40%, etc. In another embodiment, in the formulation, the administered concentration of N,N-dimethylbiguanide (C R， w / w) is 20%, 30%, 35%, or 40% to a maximum solubility such as 51%, or, alternatively, can be in the range of 0.5%-51%, 0.5-50%, 1%-50%, 5%-50%, 15%-50%, 25%-50%, 35%-50%.

[0026] In some embodiments, the formulation does not contain an acid that can significantly convert N,N-dimethylbiguanide in the aqueous solution into a metformin salt. Specifically, the acid is an acidic pH regulator required for cell culture or routine injection safety, including or selected from, for example, hydrochloric acid, sulfuric acid, lactic acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0027] In some embodiments, the formulation is specifically for lesion intervention, preferably it is used to treat a lesion such as a tumor or nodule in a subject.

[0028] According to a second aspect of the present invention, a preparation specifically for lesion intervention is provided, which comprises N,N-dimethylbiguanide (abbreviated as R) and optionally a solvent, wherein the preparation does not contain an acid that can convert the R into its salt, such as an acidic pH regulator required to meet the safety of cell culture or routine injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its intervention concentration, wherein the intervention concentration (w / w) is 0.5% ≦ C ≦ 51%, preferably, 1%-50%, more preferably 3%-40% or 5%-35%, preferably used for interventional treatment of lesions such as tumors or nodules in a subject.

[0029] In some embodiments, the preparation may comprise a solvent. Preferably, the solvent comprises water, more preferably water for injection.

[0030] In some embodiments, the above formulation may not include metformin salt.

[0031] In some embodiments, the N,N-dimethylbiguanide in the above-mentioned preparation has the structure (Formula 1) described in the first aspect above, and its concentration (w / w) can be ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, or ≦10%, ≦5%, ≦2%, such as 1%, 0.75% or 0.5%.

[0032] In some embodiments, the concentration (w / w) of the N,N-dimethylbiguanide (R) in the formulation can be 0.5%-51%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 15%-50%, 25%-50%, 35%-50%, 5%-20%, 0.5%-10%, or 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0033] In some embodiments, the acidic pH adjuster may include or be selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0034] In some embodiments, the formulation consists of N,N-dimethylbiguanide (R) and water.

[0035] In some embodiments, the formulation does not include an acid that can significantly convert N,N-dimethylbiguanide (R) in the aqueous solution into a metformin salt.

[0036] According to a third aspect of the present invention, a pharmaceutical combination is provided, comprising N,N-dimethylbiguanide (R) and a component (Z), wherein the N,N-dimethylbiguanide is administered at a concentration of 0.1% to 51%, preferably 0.2% to 50%, on a weight / weight (w / w) basis, and the component (Z) comprises or is selected from at least one of the following: a cell-reactive anti-tumor drug (abbreviated as B), a near-neutral or weakly alkaline sodium salt (abbreviated as C), a methylene blue dye (abbreviated as D), and an immunomodulator (abbreviated as E). In some embodiments, in the pharmaceutical combination, N,N-dimethylbiguanide (R) has the structure described in the first aspect (Formula 1).

[0037] In some embodiments, a pharmaceutical combination is provided that is useful for treating a lesion, such as a tumor or nodule, in a subject.

[0038] In some embodiments, in the above-mentioned drug combination, the N,N-dimethylbiguanide is used to provide an active form different from the conventional metformin drug (whose active ingredient is R') by the following definition:

[0039] 4). Not mixed with an acid that significantly converts the R to R';

[0040] 5). Application to local lesions;

[0041] 6) The dosage for one course of treatment is:

[0042] Where Q R <50% or 25% of the equivalent usage of R', n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0043] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the needle insertion point, wherein the c R(ii) The concentration threshold of (W / W) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ,

[0044] The active form of R' is in the form of complete complex with acid in solution; while the active form of R is in the form of less complex with acid in solution, and mainly exists in the form of very little or partial complex, thereby providing activity (abbreviated as activity A) that is difficult for R' to provide through the transient local action of this different active form, including at least one of the following: the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), or / and the effect of effectively releasing diseased immune substances or / and inflammatory signals in the lesion (abbreviated as activity A3).

[0045] In some embodiments, in a drug combination, which is a drug combination for treating solid tumors, comprising said R and B, wherein:

[0046] - The activity A of said R at least includes effectively reducing the biological barrier function (activity A1);

[0047] - The cell-reactive anti-tumor drug (B) provides the cell response (abbreviated as activity B) by the following definition, one of the key control steps of the response is to pass through the above-mentioned biological barrier:

[0048] 1). Tumor administration and / or systemic administration;

[0049] 2) The dosage for one course of treatment is:

[0050] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B ,q B(j) are the number of systemic administrations of B in a course of treatment and the jth (j=1,...n B ) Application rate, n B＇ 、c B(j＇) , and v B(j＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application.

[0051] In some embodiments, in the above-mentioned drug combination, the drug combination comprises said R, C, or / and D, wherein:

[0052] - The activity A of the R at least includes the effect of effectively damaging diseased tissue (activity A2);

[0053] - The C is used to improve the local efficacy-toxicity ratio of the R (abbreviated as active C) through the following definition:

[0054] 1). Mixed with the R and applied;

[0055] 2) The mixing ratio of C to R (QC / QR) is 0.5 to 4.0;

[0056] - The D provides a pharmacological effect that enhances the pharmacological effect of the R by:

[0057] 1). Pathological administration, including mixed administration with the R or separate administration;

[0058] 2) The dosage QE for one course of treatment is ≤ the effective dosage for transient local effect.

[0059] In some embodiments, the above-mentioned pharmaceutical combination comprises R and E, wherein:

[0060] - The activity A of the R at least includes the effect of effectively reducing the biological barrier function (activity A1) and / or effectively releasing lesion immune substances and / or inflammatory signals in the lesion (activity A3);

[0061] - The E is defined as follows: providing an immunomodulatory effect benefiting from the effect of the active A1, or / and optimizing the local or / and systemic immune response by utilizing the effect of the active A3 (abbreviated as active E):

[0062] 1) Pathological administration and / or systemic administration;

[0063] 2) The dosage for one course of treatment is:

[0064] Where Q E =≦the conventional dosage of E in the anti-lesional application, n E ,q E(k) are the number of systemic administrations of E in a course of treatment and the kth administration (j=1, ...n k ) Application rate, n E＇ 、c E(k＇) , and v E(k＇) are the number of times E is administered to the tumor in one course of treatment, and the k'th time (k'=1, ...n k＇ ) concentration and volume at the time of application.

[0065] In some embodiments, in the above-mentioned drug combination, the tumor is a solid tumor suitable for tumor administration. In some embodiments, in the above-mentioned drug combination, component (Z) includes a cell-reactive anti-tumor drug (B), and the R provides an activity (abbreviated as activity A) that conventional metformin (active ingredient is metformin salt, abbreviated as R') cannot provide, including effectively reducing biological barrier function (abbreviated as activity A1) through the following definitions:

[0066] 1). Administration to tumor;

[0067] 2). Application amount:

[0068] Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0069] Where n Ri is the number of needle points at the time of R administration for the i-th time, c R(ii) , and v R(ii) are the concentration and volume of R applied at the iith injection point, respectively, where c R(ii) The concentration threshold of (W / W) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ;

[0070] - The B provides a specific anti-tumor effect (abbreviated as active B) in which one of the key control steps is to cross the tumor tissue barrier through the following definition:

[0071] 1). Tumor administration and / or systemic administration;

[0072] 2). Application amount:

[0073] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B ,q B(j) are the number of systemic administrations of B in a course of treatment and the jth (j=1,...n B ) Application amount, n B＇ 、c B(j＇) , and v B(j＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application;

[0074] - The type of combination is a synergistic combination in which the pharmacological effects of activity A of R and activity B of B enhance each other.

[0075] In some embodiments, in the above-mentioned drug combination, component (Z) includes a nearly neutral or weakly alkaline sodium salt (C); R is limited to lesion administration, and C improves the efficacy-toxicity ratio of R lesion administration by mixing with the R; and the mixing amount ratio of C to R (Q C / Q R ) is 0.5 to 4.0.

[0076] In some embodiments, in the above-mentioned pharmaceutical combination, component (Z) includes the methylene blue dye (D); the R and D are administered only to the lesion, and D improves the efficacy of R by mixing with R or administering it independently.

[0077] In some embodiments, in the above-mentioned pharmaceutical combination, component (Z) includes an immunomodulator (E), wherein:

[0078] -R is used to provide activities (abbreviated as activity A) that conventional metformin (active ingredient is metformin salt, abbreviated as R') cannot provide through the following definitions, including effectively reducing biological barrier function (abbreviated as activity A1), and / or effectively releasing pathological immune substances and / or inflammatory signals in lesions (abbreviated as activity A3):

[0079] 1). Application to lesions;

[0080] 2) The dosage for one course of treatment is:

[0081] Where n R is the number of times R is applied to the lesions in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0082] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the needle insertion point, wherein the c R(ii) The concentration threshold of (W / V) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ;

[0083] - The E is defined as follows to provide an immunomodulatory effect that benefits from reducing the biological barrier function, and / or optimizes the local and / or systemic immune response by utilizing the lesion immune substances and / or inflammatory signals effectively released within the lesion (abbreviated as active E):

[0084] 1) Pathological administration and / or systemic administration;

[0085] 2) The dosage for one course of treatment is:

[0086] Where Q E=≦the conventional dosage of E in the anti-lesional application, n E ,q E(k) are the number of systemic administrations of E in a course of treatment and the kth administration (j=1, ...n k ) Application rate, n E＇ 、c E(k＇) , and v E(k＇) are the number of times E is administered to the tumor in one course of treatment, and the k'th time (k'=1, ...n k＇ ) concentration and volume at the time of application.

[0087] In some embodiments, c R(ii) The concentration threshold of (W / W) can be 0.1% (synergistic threshold) or 0.2% (effective threshold), and the upper limit of the concentration threshold is 51%; the v R(ii) The volume threshold can be 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) .

[0088] In some embodiments, in the above-mentioned pharmaceutical combination, N,N-dimethylbiguanide (R) comprises <30% (w / w), preferably ≤5% metformin salt (R'), or more preferably does not comprise metformin salt (R'). Preferably, N,N-dimethylbiguanide (R) is in the form of a powder injection.

[0089] In some embodiments, the above-mentioned drug combination is suitable for local lesions such as tumors. Preferably, the drug combination contains B and / or E and is used for refractory malignant tumors. Preferably, the refractory malignant tumors include or are selected from at least one of the following groups: chemotherapy drug-resistant tumors, tumors with unfavorable microenvironment, anti-tumor drug-discontinued tumors, tumors for which there are no effective chemotherapy drugs, and tumors carried by patients who are contraindicated or not suitable for conventional chemotherapy drugs.

[0090] In some embodiments, the above-mentioned drug combination is applicable to heterogeneous tumors, wherein the heterogeneity includes at least one of tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. The heterogeneous tumor is a tumor that is beneficial for treatment by establishing different tumor bodies of the same type or different areas of the same tumor body as different target areas based on the heterogeneity for differentiated administration.

[0091] In some embodiments, in the above-mentioned drug combination, component (Z) comprises an anti-tumor drug, and the anti-tumor drug comprises or is selected from a cell-reactive drug (B) whose key control step is to pass through the tumor tissue barrier.

[0092] In some embodiments, in the above drug combination, the cell-responsive drug includes a cytotoxic drug and a targeted anti-tumor drug.

[0093] In some embodiments, in the above drug combination, the cytotoxic drug includes a DNA damaging agent, an antimetabolite, a microtubule inhibitor, and a topoisomerase inhibitor.

[0094] In some embodiments, in the above-mentioned drug combination, representative compounds of the DNA damaging agent include cisplatin, carboplatin, oxaliplatin, ifosfamide, and doxorubicin.

[0095] In some embodiments, in the above-mentioned drug combination, representative compounds of the antimetabolite drugs include fluorouracil, gemcitabine, and methotrexate.

[0096] In some embodiments, in the above-mentioned drug combination, representative compounds of the microtubule inhibitor include paclitaxel and vincristine.

[0097] In some embodiments, in the above-mentioned drug combination, the targeted anti-tumor drug includes gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and derivatives thereof.

[0098] In some embodiments, in the above-mentioned drug combination, drug B includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and its derivatives.

[0099] In some embodiments, in the above-mentioned drug combination, the nearly neutral or weakly alkaline sodium salt (C) includes or is selected from one or more of the following: sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium lactate, sodium acetate, etc. Preferably, the weakly alkaline sodium salt (C) includes an injectable weakly alkaline sodium salt, such as sodium bicarbonate.

[0100] In some embodiments, in the above-mentioned pharmaceutical combination, the methylene blue dye (D) includes or is selected from one or more of the following: methylene blue, patent blue, isosulfan blue and new methylene blue.

[0101] In some embodiments, in the above-mentioned drug combination, the immunomodulator (E) includes an immunomodulator and / or an immunosuppressant. Specifically, the immunomodulator can include or be selected from the following: one or more biomacromolecule immunomodulators (abbreviated as E1), immune cell immunomodulators (abbreviated as E2), and vaccine immunomodulators (abbreviated as E3).

[0102] In some embodiments, biomacromolecule immunomodulators can include, for example, immune checkpoint inhibitors, cytokines, and TLR agonists. In one embodiment, immune checkpoint inhibitors can include Anti-PD-1 (CD279), cytokines include interleukin-15, and TLR agonists include CpG ODN 1826 (abbreviated as CpG).

[0103] In some embodiments, immune cell immunomodulators include, for example, CAR-T cell therapy, DC cell therapy, TIL cell therapy, etc.

[0104] In some embodiments, the vaccine-based immunomodulator comprises Bacillus Calmette-Guérin (BCG).

[0105] In some embodiments, in the pharmaceutical combination, the administered concentration (w / w) of dimethylbiguanide (R) can be 0.5%-51%, 0.5-50%, 0.5-45%, 1%-45%, 5%-45%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, 15%-50%, 25%-50%, 35%-50%, 5%-20%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0106] In some embodiments, the above-mentioned drug combination includes dimethylbiguanide (R) and doxorubicin (doxorubicin, DOX), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the doxorubicin (DOX) can be administered at a concentration of 0.025%-1%. Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.5%-50%, and the doxorubicin (DOX) is administered at a concentration of 0.1%-1%. Optionally, dimethylbiguanide (R) and doxorubicin (DOX) are both administered intratumorally.

[0107] In some embodiments, the drug combination comprises dimethylbiguanide (R) and ifosfamide (IFO), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the ifosfamide (IFO) can be administered at a concentration of 0.1%-15%, preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45%, and the ifosfamide (IFO) is administered at a concentration of 0.1%-10%, more preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45%, and the ifosfamide (IFO) is administered at a concentration of 0.5%-10%.

[0108] In some embodiments, the drug combination comprises dimethylbiguanide (R) and cisplatin (DDP), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the cisplatin (DDP) can be administered at a concentration of 0.01%-0.4%. Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.5%-50%, and the cisplatin (DDP) is administered at a concentration of 0.01%-0.04%.

[0109] In some embodiments, the drug combination includes dimethylbiguanide (R) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the 5-fluorouracil (5-FU) can be administered at a concentration of 0.05%-9%. Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45%, and the 5-fluorouracil (5-FU) is administered at a concentration of 0.5%-9%. More preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45%, and the 5-fluorouracil (5-FU) is administered at a concentration of 0.9%-9%.

[0110] In some embodiments, the drug combination comprises dimethylbiguanide (R), cisplatin (DDP) and gemcitabine (GEM), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, the cisplatin (DDP) can be administered at a concentration of 0.05%-1%, and the gemcitabine (GEM) can be administered at a concentration of 0.5-2%, preferably at a concentration of 1%.

[0111] In some embodiments, the drug combination includes dimethylbiguanide (R), paclitaxel (PTX) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, the 5-fluorouracil (5-FU) can be administered at a concentration of 0.1%-10%, and the paclitaxel can be administered at a concentration of 0.02-1%, preferably, at a concentration of 0.03%.

[0112] In some embodiments, the drug combination comprises dimethylbiguanide (R) and osimertinib, wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the osimertinib can be administered at a concentration of 0.05%-2%. Preferably, the dimethylbiguanide (R) is administered at a concentration of 5%, and the osimertinib is administered at a concentration of 0.15%.

[0113] In some embodiments, the drug combination comprises dimethylbiguanide (R) and gefitinib (GEF), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the gefitinib (GR) can be administered at a concentration of 0.1%-2%. Preferably, the dimethylbiguanide (R) is administered at a concentration of 1%-50%, and the gefitinib (GR) is administered at a concentration of 0.5%.

[0114] In some embodiments, the drug combination comprises dimethylbiguanide (R), cisplatin (DDP), and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5%, the gefitinib (GR) is administered at a concentration of 0.5%, and the cisplatin (DDP) is administered at a concentration of 0.15.

[0115] In some embodiments, the drug combination comprises dimethylbiguanide (R), ifosfamide (IFO), and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5%, the ifosfamide (IFO) is administered at a concentration of 1%, and the gefitinib (GR) is administered at a concentration of 0.5%.

[0116] In some embodiments, the drug combination comprises dimethylbiguanide (R), doxorubicin (DOX), and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5%, the doxorubicin (DOX) is administered at a concentration of 0.05%, and the gefitinib (GR) is administered at a concentration of 0.5%.

[0117] In some embodiments, the drug combination comprises dimethylbiguanide (R) and sodium bicarbonate (SB), wherein dimethylbiguanide (R) can be administered at a concentration of 0.5%-4%, and sodium bicarbonate (SB) can be administered at a concentration of 0.5%-15%, preferably 0.5%-10%, more preferably 1.5%-9%; preferably dimethylbiguanide (R) is administered at a concentration of 1%-3%, and sodium bicarbonate (SB) is administered at a concentration of 1%-9%; more preferably, dimethylbiguanide (R) is administered at a concentration of 3%, and sodium bicarbonate (SB) is administered at a concentration of 3%-9%. Optionally, the drug combination further comprises ifosfamide (IFO) at a concentration of 0.5%, 5-fluorouracil (5-FU) at a concentration of 0.4%, or osimertinib at a concentration of 0.3%.

[0118] In some embodiments, the drug combination includes dimethylbiguanide (R) and a methylene blue dye (D) such as methylene blue (MB). In one embodiment, the drug combination includes dimethylbiguanide (R) and methylene blue (MB), wherein the dimethylbiguanide (R) can be administered at a concentration of 1%-50%, and the MB can be administered at a concentration of 0.3%-5%, preferably 0.5%-5%; more preferably, dimethylbiguanide (R) is administered at a concentration of 5%-50%, and MB is administered at a concentration of 0.5%-5%; preferably, dimethylbiguanide (R) is administered at a concentration of 5%-50%, and MB is administered at a concentration of 0.5%-1%. Optionally, the drug combination further includes one or more of ifosfamide (IFO) at a concentration of 0.5%-1%, 5-fluorouracil (5-FU) at a concentration of 0.4%-1%, and osimertinib at a concentration of 0.3%. Preferably, the drug combination comprising dimethylbiguanide (R) and methylene blue (MB) can be administered intratumorally and / or systemically. In some embodiments, the drug combination comprises dimethylbiguanide (R), MB and any one of the following: IFO, 5-FU and osimertinib, wherein dimethylbiguanide (R) is administered at a concentration of 5%, MB is administered at a concentration of 1%, IFO is administered at a concentration of 0.5%, 5-FU is administered at a concentration of 0.4%, and osimertinib is administered at a concentration of 0.3%. In some embodiments, the drug combination comprises dimethylbiguanide (R), SB, MB and any one of the following: IFO, 5-FU and osimertinib, wherein dimethylbiguanide (R) is administered at a concentration of 5%, SB is administered at a concentration of 5%-10%, MB is administered at a concentration of 0.5%, IFO is administered at a concentration of 0.5%, 5-FU is administered at a concentration of 0.4%, and osimertinib is administered at a concentration of 0.3%.

[0119] In some embodiments, the drug combination includes dimethylbiguanide (R) and an immunomodulator (E), and the immunomodulator includes or is selected from a biomacromolecule immunomodulator (abbreviated as E1), an immune cell immunomodulator (abbreviated as E2), and a vaccine immunomodulator (abbreviated as E3). In some embodiments, the biomacromolecule immunomodulator can be, for example, an immune checkpoint inhibitor, a cytokine, and a TLR agonist. In one embodiment, the immune checkpoint inhibitor can be Anti-PD-1 (CD279), the cytokine includes interleukin-15, and the TLR agonist includes CpG ODN 1826 (abbreviated as CpG), and the vaccine immunomodulator can be BCG.

[0120] In some embodiments, the drug combination includes dimethylbiguanide (R) and CpG ODN 1826 (CpG), wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, and CpG can be administered at a concentration of 0.1%; preferably, dimethylbiguanide (R) is administered at a concentration of 2.5%-50%, and CpG is administered at a concentration of 0.1%. Preferably, the drug combination also includes MB at a concentration of 1%, IFO at a concentration of 0.5%, and / or SB at a concentration of 10%. In some embodiments, the drug combination comprises dimethylbiguanide (R) and CpG and any one or two of the following: IFO, MB, and SB, wherein dimethylbiguanide (R) is administered at a concentration of 2.5%-50%, IFO at a concentration of 0.5%, CpG at a concentration of 0.1%, MB at a concentration of 1%, and SB at a concentration of 10%.

[0121] In some embodiments, the drug combination includes dimethylbiguanide (R) and an immune checkpoint inhibitor Anti-PD-1 (CD279), such as RMP1-14, wherein dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and RMP1-14 can be administered at a concentration of 0.1%; preferably, dimethylbiguanide (R) is administered at a concentration of 1%-50%, and RMP1-14 is administered at a concentration of 0.1%.

[0122] In some embodiments, the drug combination comprises dimethylbiguanide (R) and BCG, wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, preferably 2.5%-50%, more preferably 5%-50%, and BCG can be administered at a concentration of 1×10 6 CFU; preferably, dimethylbiguanide (R) is administered at a concentration of 50%, and BCG is administered at a concentration of 1×10 6 CFU. Optionally, the drug combination further comprises ifosfamide (IFO) at a concentration of 0.5% and SB at a concentration of 10%. In some embodiments, the drug combination comprises dimethylbiguanide (R) and BCG and any one of the following: IFO and SB, wherein dimethylbiguanide (R) is administered at a concentration of 5%-50%, and BCG is administered at a concentration of 1×10 6 The amount of CFU was used, IFO was used at a concentration of 0.5%, and SB was used at a concentration of 10%.

[0123] In some embodiments, dimethylbiguanide (R) and component (Z) in the pharmaceutical combination can be administered simultaneously, sequentially, or intermittently.

[0124] In some embodiments, the dimethylbiguanide (R) and component (Z) in the drug combination are both administered to the tumor (combination relationship I); the R and Z are administered to the tumor and systemically, respectively (combination relationship II); or the R and part of Z are administered to the tumor, and the other part of Z is administered systemically (combination relationship III).

[0125] In some embodiments, the drug combination can be used to treat a lesion, such as a tumor or nodule, in a subject.

[0126] According to a fourth aspect of the present invention, there is provided a pharmaceutical combination comprising formulation I and formulation II, wherein formulation I comprises N,N-dimethylbiguanide (R) or R and a partial component (Z), and formulation II comprises Z but does not contain R, wherein:

[0127] 1) In the preparation I, the N,N-dimethylbiguanide (R) includes ≤5% or does not include a salt of N,N-dimethylbiguanide;

[0128] 2) The method of using the preparations I and II together is:

[0129] Formulation I is only for intratumoral administration and cannot be used for systemic administration.

[0130] Formulation II can be used for intratumoral administration or / and systemic administration;

[0131] 3) The shared amount of the preparation I and the preparation II is defined by the shared amount of Z and R:

[0132] (1) R application rate:

[0133] Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0134] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the injection point, wherein the v R(ii) ≦3 times the target volume of application point ii (abbreviated as v 靶(ii) ), and cR is 0.2-51%, where 0.2% is the common concentration threshold of R and 51% is the upper solubility threshold of R;

[0135] (2) The application rate of Z is:

[0136] Where QZ The conventional dosage is ≤ Z, n Z ,q Z(j) are the number of systemic administrations of Z in a course of treatment and the jth (j=1,...n B ) Application rate, n Z＇ 、c Z(j＇) , and v Z(j＇) Z is the number of times Z is administered to the tumor in one course of treatment, and the j'th time (j'=1,...n Z＇ ) concentration and volume at the time of application.

[0137] In some embodiments, in the above-mentioned drug combination, the component Z includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin and mitoxantrone.

[0138] In some embodiments, in the above-mentioned drug combination, the mixing contraindications of R are any one of the following groups:

[0139] 1) Salts of N,N-dimethylbiguanide (R');

[0140] 2) an acidulant that significantly converts the R into R', wherein the acidulant comprises an acidic pH adjuster and other acidic substances;

[0141] 3) conventional metformin pharmaceutical adjuvants having a dosage ratio to R (Q adjuvant / QR) of >3.0 or >4.0, including conventional sustained-release dosage form carriers thereof, such as gel carriers and nanocarriers;

[0142] 4) adjuvants that are unstable in strong alkaline aqueous solutions, including, for example, reducing sugars, cellulose, liposomes, carbomer, and polyethylene glycol-modified nanocarriers,

[0143] The mixing taboos mentioned herein refer to the need to avoid mixing with the substance during the entire process of formulation, preparation, product and use.

[0144] In some embodiments, in the above-mentioned drug combination, the sharing method includes:

[0145] 1) R and Z are mixed for intralesional or intratumoral administration,

[0146] 2) R and Z are used for intralesional or intratumoral administration, respectively,

[0147] 3) R and Z are used for intralesional or intratumoral administration and systemic administration, respectively,

[0148] 4) R and part of Z are mixed or used separately for intralesional or intratumoral administration, while the other Z is used for systemic administration.

[0149] In some embodiments, in the above-mentioned drug combination, the common threshold is 0.5%, 1%, 3.3%, 5%, or 10%.

[0150] According to a fifth aspect of the present invention, a pharmaceutical composition is provided, comprising N,N-dimethylbiguanide (R) or any of the above-mentioned pharmaceutical combinations of the present invention.

[0151] According to a sixth aspect of the present invention, there is provided a preparation comprising any of the above-mentioned pharmaceutical combinations or compositions according to the invention.

[0152] According to a seventh aspect of the present invention, there is provided use of N,N-dimethylbiguanide (R) and an anti-tumor drug in the preparation of a drug, drug combination or kit for treating tumors.

[0153] According to an eighth aspect of the present invention, there is provided use of the above-mentioned preparation, drug combination or composition of the present invention in the preparation of a drug, drug combination or kit for treating a lesion such as a tumor or nodule in a subject.

[0154] In particular, the above-mentioned formulations, pharmaceutical combinations or compositions of the present invention can be used to treat lesions such as tumors or nodules in a subject.

[0155] R in the above-mentioned preparation, pharmaceutical combination or composition of the present invention is used to provide transient activity, wherein the transient activity refers to the local activity provided within a transient time before the active form of R is converted into the active form of R'.

[0156] In some embodiments, in the above-mentioned use, the administration concentration (w / w) of dimethylbiguanide is ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, ≦10%, ≦5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0157] In some embodiments, in the above-mentioned use, the administration concentration (w / w) of the N,N-dimethylbiguanide (R) is 0.2%-51%, 0.5-51%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0158] In some embodiments, in the above-mentioned use, the concentration (w / w) of the salt of N,N-dimethylbiguanide contained in the preparation, pharmaceutical combination or composition is ≦30%, preferably ≦20%, preferably ≦10%, more preferably ≦5%, ≦4%, or ≦3%, more preferably ≦2%, particularly preferably ≦1%, such as 1% or 0.5%, and most preferably 0%, that is, the preparation, pharmaceutical combination or composition does not contain a salt of N,N-dimethylbiguanide.

[0159] In some embodiments, the preparation of the present invention comprises N,N-dimethylbiguanide and optionally a solvent, and the preparation does not contain additives required to meet the safety requirements of cell culture or routine injection, and the concentration of N,N-dimethylbiguanide contained in the preparation is ≧ its intervention concentration, wherein the administration or intervention concentration (w / w) is 0.5% ≦ C ≦ 51%, preferably, 1-51%, 2-50%, 3-50%, 4-50 %, 5-50%, 6-50%, 7-50%, 8-50%, 9-50%, 10-50%, 15-50%, 20-50%, 25-50%, 30-50%, 35-50%, 40-50%, 1-40%, 5-50%, 10-40%, 15-40%, 20-40%, 25-40%, 30-40%, 35-40%, or 1-35%, 5%-30 %, etc., or any value and range therebetween, for example, 1.5%, 2%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7.7.5%, 8.8.5%, 9.9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5% , 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 45%, 50%.

[0160] In some embodiments, the formulation comprises a vehicle, such as a pharmaceutically acceptable carrier, preferably water, more preferably (sterile) water for injection.

[0161] In some embodiments, the formulation does not include a salt of N,N-dimethylbiguanide.

[0162] In some embodiments, the concentration (w / w) of the salt of N,N-dimethylbiguanide contained in the preparation is ≦30%, ≦25%, preferably ≦10%, preferably ≦5%, more preferably ≦4%, more preferably ≦3%, still more preferably ≦2%, particularly preferably ≦1%, and most preferably 0%, that is, the preparation does not contain a salt of N,N-dimethylbiguanide.

[0163] In one embodiment, the additional agent includes an acidic pH adjuster.

[0164] In one embodiment, the acidity pH regulator includes or is selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, carbonic acid, and the like.

[0165] In some embodiments, the drug combination or composition for the above-mentioned use includes an anti-tumor drug or agent, and the anti-tumor drug or agent includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin and mitoxantrone.

[0166] In some embodiments, in the above-mentioned use, the anti-tumor drug is doxorubicin (DOX), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the doxorubicin (DOX) can be administered at a concentration of 0.025%-1% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-50% (w / w), and the doxorubicin (DOX) is administered at a concentration of 0.1%-1% (w / w).

[0167] In some embodiments, in the above-mentioned use, the anti-tumor drug is ifosfamide (IFO), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the ifosfamide (IFO) can be administered at a concentration of 0.1%-10% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.1%-10% (w / w). More preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.5%-10% (w / w).

[0168] In some embodiments, in the above-mentioned use, the anti-tumor drug is cisplatin (DDP), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the cisplatin (DDP) can be administered at a concentration of 0.01%-0.4% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.5%-50% (w / w), and the cisplatin (DDP) is administered at a concentration of 0.01%-0.04% (w / w).

[0169] In some embodiments, in the above-mentioned use, the anti-tumor drug is 5-fluorouracil (5-Fu), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and the 5-fluorouracil (5-FU) can be administered at a concentration of 0.05%-9% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the 5-fluorouracil (5-Fu) is administered at a concentration of 0.5%-9% (w / w). More preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the 5-fluorouracil (5-Fu) is administered at a concentration of 0.9%-9% (w / w).

[0170] In some embodiments, in the above-mentioned use, the anti-tumor drug includes cisplatin (DDP) and gemcitabine (GEM), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), the cisplatin (DDP) can be administered at a concentration of 0.05%-1% (w / w), and the gemcitabine (GEM) can be administered at a concentration of 0.5-2% (w / w), preferably at a concentration of 1% (w / w).

[0171] In some embodiments, in the above use, the anti-tumor drug includes paclitaxel (PTX) and 5-fluorouracil (5-Fu), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), the 5-fluorouracil (5-Fu) can be administered at a concentration of 0.1%-10% (w / w), and the paclitaxel can be administered at a concentration of 0.02-1% (w / w), preferably, at a concentration of 0.03% (w / w).

[0172] In some embodiments, in the above-mentioned use, the anti-tumor drug is osimertinib, wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the osimertinib can be administered at a concentration of 0.05%-2% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), and the osimertinib is administered at a concentration of 0.15% (w / w).

[0173] In some embodiments, in the above-mentioned use, the anti-tumor drug is gefitinib (GR), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the gefitinib (GR) can be administered at a concentration of 0.1%-2% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 1%-50% (w / w), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w).

[0174] In some embodiments, in the above use, the anti-tumor drug comprises cisplatin (DDP) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), the gefitinib (GR) is administered at a concentration of 0.5% (w / w), and the cisplatin (DDP) is administered at a concentration of 0.15% (w / w).

[0175] In some embodiments, in the above use, the anti-tumor drug comprises ifosfamide (IFO) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), the ifosfamide (IFO) is administered at a concentration of 1% (w / w), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w).

[0176] In some embodiments, in the above use, the anti-tumor drug comprises doxorubicin (DOX) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), the doxorubicin (DOX) is administered at a concentration of 0.05% (w / w), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w).

[0177] In some embodiments, in the above use, dimethylbiguanide and the anti-tumor drug can be administered simultaneously, sequentially or intermittently.

[0178] In some embodiments, in the above-mentioned uses, dimethylbiguanide and the anti-tumor drug are both administered intralesionally or in the tumor (combination relationship I); R and B are administered intralesionally or in the tumor and systemically (combination relationship II); or R and part of B are administered intralesionally or in the tumor, and the other part of B is administered systemically (combination relationship III).

[0179] In some embodiments, in the above-mentioned use, the N,N-dimethylbiguanide is used to provide a morphological manifestation different from that of conventional metformin drugs (whose active ingredient is R'), wherein the active form of R' is in the form of complete complex with acid in solution; and the active form of R is less complex with acid in solution, and mainly exists in the form of very little or partial complex, thereby providing the activity (abbreviated as activity A) that is difficult for R' to provide through the transient local action of the distinguished active form, including the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), or / and the effect of effectively releasing diseased immune substances or / and inflammatory signals in the lesion (abbreviated as activity A3).

[0180] In some embodiments, N,N-dimethylbiguanide is used to provide an effect that can maximize the effect of the anti-tumor drug, including an effect that effectively reduces the barrier function of tumor tissue (abbreviated as activity A).

[0181] In some embodiments, the anti-tumor drug is used to provide an anti-tumor effect that maximizes the transient effect of the N,N-dimethylbiguanide, including an anti-tumor effect induced at the tumor cell level (abbreviated as activity B).

[0182] In some embodiments, the N,N-dimethylbiguanide (R) must not be mixed with a sufficient amount of R' or an acidulant that can convert R into a sufficient amount of R', wherein the sufficient amount refers to an amount such that the ratio of R' to R (R' / R) is ≥ 1 / 3.

[0183] In some embodiments, in the above use, synergy is produced between N,N-dimethylbiguanide and the anti-tumor drug. The synergy is a dose-reduction and synergistic effect (response) compared to the conventional combined combination (R' / B combination), which is manifested as providing the following better effects when the metformin dosage is at least halved (QR≦1 / 2QR') and the B dosage is reduced by at least 20%:

[0184] 1) Significantly improved drug performance, including adaptability to tumor heterogeneity, as demonstrated by at least a 100% increase in at least one of the drug adjustability indicators, where drug adjustability refers to the ability of a drug to provide differentiated administration parameters to different target areas while maintaining efficacy; or / and

[0185] 2) The drug efficacy is significantly enhanced, as shown by at least 25% increase in at least one of the drug efficacy indicators.

[0186] In some embodiments, in the above-mentioned use, the synergy is further a further enhancement relative to the strongest single-drug regimen of R and B, which is manifested as at least one of the drug adjustability indicators being increased by at least 10%, or / and at least one of the drug efficacy indicators being enhanced by at least 10%.

[0187] In some embodiments, the drug regulatability indicator comprises at least one of the following tumor administration regulatability coefficients:

[0188] 1). The concentration of R can be adjusted by the coefficient c R The ratio of the highest value to the threshold value (c R ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to> 10, 50, 100 or 150, which allows the R to provide highly variable concentrations to different regions while still maintaining its activity stable, including, for example, heterogeneous tumor drug delivery;

[0189] 2). The target volume adjustment coefficient of R is the target volume (v 靶 ) to the threshold value (v 靶 The maximum value / threshold of the adjustable index is the increase of the coefficient, preferably the coefficient is increased to >2, 10, 50, or 100, which allows the R to select different v 靶 Administer drugs based on the characteristics of different treatment situations, including, for example, heterogeneous tumors;

[0190] 3). R dosage volume ratio adjustable coefficient, which is the dosage volume (v R ) and its target volume (v 靶 ) to the threshold value (v R / v 靶 ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to >5, 10, or 100, which allows the R to provide highly variable volume ratios to different regions while still maintaining its activity stable, including, for example, heterogeneous tumor-specific drug delivery;

[0191] 4). The single dosage of R can be adjusted by the coefficient, which is the single dosage (c Ri ×v Ri ) to the threshold value (c Ri ×v Ri ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to >2, 6, or 10, which allows R to select different single doses for different treatment situations, including, for example, heterogeneous tumors; and

[0192] 5). The adjustable coefficient of the dosing point density of R is the density of the dosing point (n ii / v 靶 ) to the threshold value (n ii / v 靶 ), and the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to >3, 10, 50, or 100, which allows the R to provide highly variable densities to different regions while still maintaining its activity stable, including, for example, the administration of drugs to heterogeneous tumors.

[0193] In some embodiments, the drug efficacy indicator includes at least one of the following:

[0194] 1) Timeliness, as measured by the time to significant effect (the day when the tumor proliferation rate is <42%) in mouse studies, is at least 25% shorter than that of the R' regimen, the R' / B combination regimen, and the B monotherapy regimen. This makes the combination a fast-acting or even faster-acting combination, particularly suitable for tumors requiring rapid reduction in tumor size.

[0195] 2) An efficacy indicator, represented by a tumor inhibition rate or objective response rate in a mouse study, wherein the tumor inhibition rate or objective response rate is at least 25% higher than that of the control regimen (the R' regimen, the R' combined with B, D, or / and E regimen, and the B, D, or / and E monotherapy regimen), making the combination a highly effective or further highly effective combination, particularly suitable for tumors requiring maximum suppression of tumor size;

[0196] 3) Long-term efficacy, as measured by progression-free time or survival rate in mouse studies, where the progression-free time or survival rate is at least 25% higher than that of the control regimen (the R' regimen, the R' combined with B, D, or / and E regimen, or the B, D, or / and E single-agent regimen). This makes the combination a long-acting or further long-acting combination, particularly suitable for tumors requiring prolonged progression-free time as much as possible.

[0197] According to the ninth aspect of the present invention, a method for treating cells of a lesion such as a tumor is provided, comprising administering or intervening the above-mentioned preparation, drug combination, or composition of the present invention into the lesion, penetrating into the lesion tissue, and contacting with cells in the tissue.

[0198] According to the tenth aspect of the present invention, a method for treating tumors is provided, comprising: administering the above-mentioned preparation, drug combination and composition of the present invention to the tumor, preferably, the administration includes administering the preparation of the present invention to the tumor body, and / or administering the metformin to the tumor body and administering the drug into the tumor body or systemically.

[0199] According to an eleventh aspect of the present invention, there is provided a method for treating a tumor in a subject, comprising administering the above-mentioned preparation or pharmaceutical combination of the present invention to the subject.

[0200] In the above method, the preparation comprises dimethylbiguanide and optionally a solvent, wherein the preparation does not contain an acidic pH regulator required to meet the safety requirements for cell culture or routine injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its intervention concentration, wherein the intervention concentration (w / w) is 0.5% ≦ C ≦ 51%, preferably, 1%-50%, more preferably 3%-40% or 5%-35%.

[0201] In some embodiments, the preparation may comprise a solvent. Preferably, the solvent is water, more preferably water for injection.

[0202] In some embodiments, the formulation may not include a metformin salt.

[0203] In some embodiments, the concentration (w / w) of dimethylbiguanide in the formulation can be ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, ≦10%, ≦5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0204] In some embodiments, the concentration (w / w) of the N,N-dimethylbiguanide (R) in the formulation can be 0.2%-51%, 0.2%-50%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 1-10%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0205] In some embodiments, the acidic pH adjuster may include or be selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0206] In some embodiments, in the above method, the R is contained in a powder.

[0207] In some embodiments, in the above method, the powder consists of a dry powder comprising R and a solvent.

[0208] In some embodiments, in the above method, the dry powder is R dry powder, and the solvent is water for injection.

[0209] In some embodiments, in the above methods, the formulation does not contain an acid that can significantly convert N,N-dimethylbiguanide (R) in the aqueous solution into a metformin salt.

[0210] In the above method, the administered drug combination or composition comprises N,N-dimethylbiguanide (R) and component (Z), wherein the administered concentration of N,N-dimethylbiguanide is 0.1%-51%, preferably 0.2%-50%, on a weight / weight (w / w) basis, and the drug includes a cell-reactive anti-tumor drug (abbreviated as B).

[0211] In some embodiments, in the above method, R in the drug combination is defined as follows to provide an activity (abbreviated as activity A) that is difficult to provide with conventional metformin (the active ingredient is a metformin salt, abbreviated as R'), including the effect of effectively damaging diseased tissue (abbreviated as activity A2):

[0212] 1). Application to lesions;

[0213] 2) The dosage for one course of treatment is:

[0214] Where n R is the number of times R is applied to the lesions in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0215] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the needle insertion point, wherein the c R(ii) The concentration threshold of (W / V) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ;

[0216] - The B provides the cellular response (abbreviated as active B) through the following definition, one of the key control steps of the response is to pass through the above-mentioned biological barrier:

[0217] 1). Tumor administration and / or systemic administration;

[0218] 2) The dosage for one course of treatment is:

[0219] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B ,q B(j) are the number of systemic administrations of B in a course of treatment and the jth (j=1,...nB ) Application rate, n B＇ 、c B(j＇) , and v B(j＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application;

[0220] - The type of combination is a synergistic combination in which the pharmacological effects of activity A of R and activity B of B enhance each other.

[0221] In some embodiments, the N,N-dimethylbiguanide (R) comprises <30%, preferably ≦5%, or does not comprise metformin salt (R'). Preferably, the N,N-dimethylbiguanide (R) is in the form of powder injection.

[0222] In some embodiments, in the above methods, component (Z) in the drug combination or composition comprises an anti-tumor drug selected from cell-reactive drugs whose key control step is to cross the tumor tissue barrier.

[0223] In some embodiments, the cell-reactive drugs include cytotoxic drugs and targeted anti-tumor drugs.

[0224] In some embodiments, the cytotoxic drugs include DNA damaging agents, antimetabolites, microtubule inhibitors, and topoisomerase inhibitors.

[0225] In some embodiments, representative compounds of the DNA damaging agent include cisplatin, carboplatin, oxaliplatin, ifosfamide, and doxorubicin.

[0226] In some embodiments, representative compounds of the antimetabolite drugs include fluorouracil, gemcitabine, and methotrexate.

[0227] In some embodiments, representative compounds of the microtubule inhibitors include paclitaxel and vincristine.

[0228] In some embodiments, in the above method, the targeted anti-tumor drug comprises a kinase inhibitor.

[0229] In some embodiments, in the above method, the kinase inhibitor comprises gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab, and derivatives thereof.

[0230] In some embodiments, in the above method, B includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and derivatives thereof.

[0231] In some embodiments, in the above methods, the administration concentration (w / w) of the N,N-dimethylbiguanide (R) can be 0.2%-51%, 0.2%-50%, 0.5-50%, 0.5-45%, 1%-45%, 5%-45%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0232] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and doxorubicin (doxorubicin, DOX), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the doxorubicin (DOX) can be administered at a concentration of 0.025%-1% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-50% (w / w), and the doxorubicin (DOX) is administered at a concentration of 0.1%-1%, optionally, dimethylbiguanide (R) and doxorubicin (DOX) are both administered intratumorally.

[0233] In one embodiment, the dimethylbiguanide (R) is administered intratumorally at a concentration of 0.2%-50% (w / w), the doxorubicin (DOX) is administered intratumorally at a concentration of 0.025%-1% (w / w), and the doxorubicin (DOX) is administered systemically, such as intraperitoneally, at a concentration of 0.05%-0.06% (w / w).

[0234] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and ifosfamide (IFO), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the ifosfamide (IFO) can be administered at a concentration of 0.1%-10% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.1%-10% (w / w), more preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.5%-10% (w / w), optionally, dimethylbiguanide (R) and ifosfamide (IFO) are both administered intratumorally.

[0235] In one embodiment, the dimethylbiguanide (R) is administered intratumorally at a concentration of 5%-50% (w / w), the ifosfamide (IFO) is administered intratumorally at a concentration of 0.5%-10% (w / w), and the ifosfamide (IFO) is administered systemically, such as intraperitoneally, at a concentration of 0.5% (w / w).

[0236] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and cisplatin (DDP), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the cisplatin (DDP) can be administered at a concentration of 0.01%-0.4% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.5%-50% (w / w), and the cisplatin (DDP) is administered at a concentration of 0.01%-0.04% (w / w), optionally, dimethylbiguanide (R) and cisplatin (DDP) are both administered intratumorally.

[0237] In one embodiment, the dimethylbiguanide (R) is administered to the tumor at a concentration of 0.5%-50% (w / w), and the cisplatin (DDP) is administered to the tumor at a concentration of 0.013%-0.4% (w / w). Preferably, the cisplatin (DDP) is systemically administered to the tumor at a concentration of 0.015% (w / w), such as intraperitoneally.

[0238] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the 5-fluorouracil (5-FU) can be administered at a concentration of 0.05%-9% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the 5-fluorouracil (5-FU) is administered at a concentration of 0.5%-9% (w / w), more preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the 5-fluorouracil (5-FU) is administered at a concentration of 0.9%-9% (w / w), optionally, dimethylbiguanide (R) and 5-fluorouracil (5-FU) are both administered intratumorally.

[0239] In one embodiment, the dimethylbiguanide (R) is administered intratumorally at a concentration of 5%-45% (w / w), the 5-fluorouracil (5-FU) is administered intratumorally at a concentration of 0.9%-9% (w / w), and the 5-fluorouracil (5-FU) is systemically administered, such as intraperitoneally, at a concentration of 0.5% (w / w).

[0240] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R), cisplatin (DDP) and gemcitabine (GEM), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), the cisplatin (DDP) can be administered at a concentration of 0.05%-1% (w / w), and the gemcitabine (GEM) can be administered at a concentration of 0.5-2% (w / w), preferably at a concentration of 1% (w / w), optionally, or dimethylbiguanide (R) and cisplatin (DDP) are administered intratumorally and gemcitabine (GEM) is administered systemically, such as intraperitoneally.

[0241] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R), paclitaxel (PTX) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), the 5-fluorouracil (5-FU) can be administered at a concentration of 0.1%-10% (w / w), and the paclitaxel can be administered at a concentration of 0.02-1% (w / w), preferably, at a concentration of 0.03% (w / w). Optionally, dimethylbiguanide (R) and 5-fluorouracil (5-FU) are administered intratumorally and paclitaxel (PTX) is administered systemically, such as intraperitoneally.

[0242] In some embodiments, in the above method, the drug combination or composition comprises dimethylbiguanide (R) and osimertinib, wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the osimertinib can be administered at a concentration of 0.05%-2% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), and the osimertinib is administered at a concentration of 0.15% (w / w), optionally, the dimethylbiguanide (R) is administered intraemetically, and the osimertinib is administered systemically, such as intraperitoneally.

[0243] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and gefitinib (GR), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the gefitinib (GR) can be administered at a concentration of 0.1%-2% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 1%-50% (w / w), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w). Optionally, the dimethylbiguanide (R) is administered intratumorally, and the gefitinib (GR) is administered systemically, such as intraperitoneally.

[0244] In some embodiments, in the above method, the drug combination comprises dimethylbiguanide (R), cisplatin (DDP) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally), and the cisplatin (DDP) is administered at a concentration of 0.15 (w / w) (e.g., tumor).

[0245] In some embodiments, in the above method, the drug combination or composition comprises dimethylguanidine (R), ifosfamide (IFO) and gefitinib (GR), wherein the dimethylguanidine (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the ifosfamide (IFO) is administered at a concentration of 1% (w / w) (e.g., tumor), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally).

[0246] In some embodiments, in the above method, the drug combination or composition comprises dimethylbiguanide (R), doxorubicin (DOX) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the doxorubicin (DOX) is administered at a concentration of 0.05% (w / w) (e.g., tumor), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally).

[0247] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and sodium bicarbonate (SB), wherein dimethylbiguanide (R) can be administered at a concentration of 0.5%-4%, and sodium bicarbonate (SB) can be administered at a concentration of 0.5%-15%, preferably 0.5%-10%, more preferably 1.5%-9%; preferably dimethylbiguanide (R) is administered at a concentration of 1%-3%, and sodium bicarbonate (SB) is administered at a concentration of 1%-9%; more preferably, dimethylbiguanide (R) is administered at a concentration of 3%, and sodium bicarbonate (SB) is administered at a concentration of 3%-9%. Optionally, the drug combination further includes ifosfamide (IFO) at a concentration of 0.5%, 5-fluorouracil (5-FU) at a concentration of 0.4%, or osimertinib at a concentration of 0.3%. Preferably, the above-mentioned drug combination comprising dimethylbiguanide (R) and sodium bicarbonate (SB) is administered to the tumor.

[0248] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and a methylene blue dye (D) such as methylene blue (MB). In one embodiment, the drug combination includes dimethylbiguanide (R) and methylene blue (MB), wherein the dimethylbiguanide (R) can be administered at a concentration of 1%-50%, and the MB can be administered at a concentration of 0.3%-5%, preferably 0.5%-5%; more preferably, dimethylbiguanide (R) is administered at a concentration of 5%-50%, and MB is administered at a concentration of 0.5%-5%; preferably, dimethylbiguanide (R) is administered at a concentration of 5%-50%, and MB is administered at a concentration of 0.5%-1%. Optionally, the drug combination further includes one or more of ifosfamide (IFO) at a concentration of 0.5%-1%, 5-fluorouracil (5-FU) at a concentration of 0.4%-1%, and osimertinib at a concentration of 0.3%. Preferably, the drug combination comprising dimethylbiguanide (R) and methylene blue (MB) can be administered intratumorally and / or systemically. In some embodiments, the drug combination comprises dimethylbiguanide (R), MB and any one of the following: IFO, 5-FU and osimertinib, wherein dimethylbiguanide (R) is administered at a concentration of 5%, MB is administered at a concentration of 1%, IFO is administered at a concentration of 0.5%, 5-FU is administered at a concentration of 0.4%, and osimertinib is administered at a concentration of 0.3%. In some embodiments, in the above method, the drug combination comprises dimethylbiguanide (R), SB, MB and any one of the following: IFO, 5-FU and osimertinib, wherein dimethylbiguanide (R) is administered at a concentration of 5%, SB is administered at a concentration of 5%-10%, MB is administered at a concentration of 0.5%, IFO is administered at a concentration of 0.5%, 5-FU is administered at a concentration of 0.4%, and osimertinib is administered at a concentration of 0.3%.

[0249] In some embodiments, in the above method, the drug combination includes dimethylbiguanide (R) and an immunomodulator (E), and the immunomodulator includes or is selected from a biomacromolecule immunomodulator (abbreviated as E1), an immune cell immunomodulator (abbreviated as E2), and a vaccine immunomodulator (abbreviated as E3). In some embodiments, the biomacromolecule immunomodulator can be, for example, an immune checkpoint inhibitor, a cytokine, and a TLR agonist. In one embodiment, the immune checkpoint inhibitor can be Anti-PD-1 (CD279), the cytokine includes interleukin-15, and the TLR agonist includes CpG ODN 1826 (abbreviated as CpG), and the vaccine immunomodulator can be BCG.

[0250] In some embodiments, in the above method, the drug combination includes dimethylbiguanide (R) and CpG ODN 1826 (CpG), wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, and CpG can be administered at a concentration of 0.1%; preferably, dimethylbiguanide (R) is administered at a concentration of 2.5%-50%, and CpG is administered at a concentration of 0.1%. Preferably, the drug combination or composition further includes MB at a concentration of 1%, IFO at a concentration of 0.5%, and / or SB at a concentration of 10%. In some embodiments, the drug combination or composition comprises dimethylbiguanide (R) and CpG and any one or two of the following: IFO, MB, and SB, wherein dimethylbiguanide (R) is administered at a concentration of 2.5%-50%, IFO at a concentration of 0.5%, CpG at a concentration of 0.1%, MB at a concentration of 1%, and SB at a concentration of 10%.

[0251] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and an immune checkpoint inhibitor Anti-PD-1 (CD279), such as RMP1-14, wherein dimethylbiguanide (R) can be administered at a concentration of 0.2%-50%, and RMP1-14 can be administered at a concentration of 0.1%; preferably, dimethylbiguanide (R) is administered at a concentration of 1%-50%, and RMP1-14 is administered at a concentration of 0.1%.

[0252] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and BCG, wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, preferably 2.5%-50%, more preferably 5%-50%, and BCG can be administered at a concentration of 1×10 6 CFU; preferably, dimethylbiguanide (R) is administered at a concentration of 50%, and BCG is administered at a concentration of 1×10 6CFU. Optionally, the pharmaceutical combination or composition further comprises any one of ifosfamide (IFO) at a concentration of 0.5% and SB at a concentration of 10%. In some embodiments, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and BCG and any one of the following: IFO and SB, wherein dimethylbiguanide (R) is administered at a concentration of 5%-50%, and BCG is administered at a concentration of 1×10 6 The amount of CFU was used, IFO was used at a concentration of 0.5%, and SB was used at a concentration of 10%.

[0253] In some embodiments, in the above method, the drug combination or composition includes dimethylbiguanide (R) and an immunomodulator (E), wherein the immunomodulator includes or is selected from BCG, CpG ODN 1826 (CpG), and immune checkpoint inhibitors such as anti-PD-1.

[0254] In some embodiments, in the above method, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and BCG, wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, preferably 2.5%-50%, more preferably 5%-50%, and BCG can be administered at a concentration of 1×10 6 CFU; preferably, dimethylbiguanide (R) is administered at a concentration of 50%, and BCG is administered at a concentration of 1×10 6 CFU. Optionally, the pharmaceutical combination or composition further comprises any one of ifosfamide (IFO) at a concentration of 0.5%, MB at a concentration of 1%, and SB at a concentration of 10%. In some embodiments, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and BCG and any one of the following: IFO, MB, and SB, wherein dimethylbiguanide (R) is administered at a concentration of 50%, BCG is administered at a concentration of 1×10 6 MB was administered at a concentration of 1%, IFO was administered at a concentration of 0.5%, and SB was administered at a concentration of 10%.

[0255] In some embodiments, in the above methods, the pharmaceutical combination or composition includes dimethylbiguanide (R) and CpG ODN 1826 (CpG), wherein dimethylbiguanide (R) can be administered at a concentration of 1%-50%, preferably 2.5%-50%, and CpG can be administered at a concentration of 0.1%; preferably, dimethylbiguanide (R) is administered at a concentration of 2.5%-50%, and CpG is administered at a concentration of 0.1%. Preferably, the pharmaceutical combination or composition further includes MB at a concentration of 1% or SB at a concentration of 10%. In some embodiments, the pharmaceutical combination or composition comprises dimethylbiguanide (R) and CpG and any one of the following: MB and SB, wherein dimethylbiguanide (R) is administered at a concentration of 50%, CpG is administered at a concentration of 0.1%, MB is administered at a concentration of 1%, and SB is administered at a concentration of 10%.

[0256] Preferably, in the above method, the drug combination or composition comprising dimethylbiguanide (R) and an immunomodulator such as BCG, anti-PD-1 or CpG ODN 1826 (CpG) is administered intralesionally or in a tumor, or is administered intralesionally or in a tumor and systemically, such as by intraperitoneal injection or intravenous injection or intralesional or tumor administration.

[0257] In some preferred embodiments, in the above methods, the contact or administration or intervention may include micro-multi-point contact or administration or intervention, preferably, micro-multi-point injection, wherein the micro-volume may be a drug administration volume of ≦5% or 10% of the target volume, for example, an amount of 5 μL-1000 μL, such as 5 μL-500 μL, 5 μL-250 μL, 5 μL-200 μL, 5 μL-100 μL, 5 μL-75 μL, 5 μL-50 μL. The dosage form may be 50 μL, 20 μL, 30 μL, 10 μL, 25 μL, 5 μL, 20 μL, 100 μL, 10 μL, 75 μL, 20 μL, 200 μL, 20 μL, 100 μL, 20 μL, 75 μL, 30 μL, 200 μL, 30 μL, 100 μL, 40 μL, 200 μL, 40 μL, 100 μL, 50 μL, 200 μL, 50 μL, 100 μL, or 50 μL, etc. Preferably, micro-multiple (position) point contact or administration is performed, more preferably, micro-multiple (position) point injection is performed.

[0258] In some embodiments, the above-mentioned treatment, intervention or therapy can be continued for at least one course of treatment. The duration of the course of treatment can be about 7-40 days, such as about 9 to about 37 days, such as about 15, 20, 25, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0259] In one embodiment, in one course of treatment, contact or administration of the formulation of the present invention can be low frequency, such as administration about 1-6 times / course, preferably 1-5 times / course, 1-4 times / course, 1-3 times / course, or 1-2 times / course.

[0260] In some embodiments, in the above methods, dimethylbiguanide (R) and component (Z) in the pharmaceutical combination can be administered simultaneously, sequentially, or intermittently.

[0261] In some embodiments, in the above methods, the pharmaceutical combination, formulation or composition may be administered topically.

[0262] In some embodiments, in the above method, the dimethylbiguanide (R) and component (Z) in the drug combination are both administered intralesionally or to the tumor (combination relationship I); the R and Z are administered intralesionally or to the tumor and systemically, respectively (combination relationship II); or the R and part of Z are administered intralesionally or to the tumor, and the other part of Z is administered systemically (combination relationship III).

[0263] In some embodiments, in the above methods, the tumor is a solid tumor suitable for intratumoral administration, preferably local administration.

[0264] In some embodiments, in the above method, the tumor is selected from tumors whose tissue barrier function is not conducive to the cellular action of Z, preferably selected from refractory tumors of Z, including chemotherapy drug-resistant tumors, tumors containing unfavorable microenvironment, anti-tumor drug discontinuation tumors, tumors for which there are no effective chemotherapy drugs, and tumors carried by patients with contraindications or inappropriate indications for conventional chemotherapy drugs.

[0265] In some embodiments, in the above method, the tumor is selected from heterogeneous tumors, wherein the heterogeneity includes at least one of tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. The heterogeneous tumor is a tumor that is beneficial for treatment by establishing different tumor bodies of the same type or different areas of the same tumor body as different target areas for differentiated administration based on the heterogeneity.

[0266] In some embodiments, in the above methods, the contacting or administering comprises multi-point contacting or administering, preferably, micro-multi-point contacting or administering, more preferably, micro-multi-point injection.

[0267] In some embodiments, the microamount comprises a microvolume.

[0268] In some embodiments, in the above methods, the formulation or drug combination is suitable for use in microvolume administration or intervention to reduce (Y) the lesion volume (X), and the ratio of the administered volume to the target volume (Vadministered / Vtarget) is approximately 0.02-0.056, 0.02-0.10 or 0.02-0.34.

[0269] In some embodiments, in the above methods, when the lesion is ≥ about 3.5 cm 3 , or when the maximum size is ≧ about 2 cm, the multiple points are ≧ 5 points, for example 10, 15, 20, 25, 30, 35 or 50 points.

[0270] In some embodiments, in the above methods, the contacting or administering is low frequency, preferably, the low frequency is 1-6 times / treatment course, more preferably, 1-5 times / treatment course, 1-4 times / treatment course, 1-3 times / treatment course, or 1-2 times / treatment course.

[0271] In some embodiments, in the above method, preferably, the maximum value of the applied concentration cR of R is ≧5%, ≧10%, ≧20%, or ≦30%; the number of application points is >3, 10, 15, 20, 25, 30, 35 or 100 points.

[0272] In some embodiments, in the above method, the metformin R and component Z may be provided by one or more formulations, and wherein:

[0273] The R and Z are administered in the lesion or tumor;

[0274] R and Z are respectively administration into the lesion or tumor and systemic administration; or

[0275] The R and part Z are administered intralesionally or intratumorally, and another part Z is administered systemically.

[0276] In some embodiments, in the above method, said R and said Z act synergistically, and wherein

[0277] - The synergy is that compared with the conventional co-administered combination (R' / Z combination), when the metformin dosage is at least halved (QR≦1 / 2QR') and the Z dosage is reduced by at least 20%, the following effects can still be provided:

[0278] 1) Improved drug performance, including adaptability to tumor heterogeneity, as demonstrated by at least a 100% increase in at least one of the drug adjustability indicators, where drug adjustability refers to the ability of a drug to provide differentiated administration parameters to different target areas while maintaining efficacy; and / or

[0279] 2) Enhanced drug efficacy, as shown by at least one drug efficacy indicator being enhanced by at least 40%.

[0280] In some embodiments, in the above method, the synergy further comprises: relative to R and B, at least one of the drug adjustability indicators is increased by at least 10%, and / or at least one of the drug efficacy indicators is enhanced by at least 10%.

[0281] In some embodiments, in the above uses and methods, the N,N-dimethylbiguanide (R) is used to provide an active form that is different from conventional metformin drugs (whose active ingredient is R') by the following definition:

[0282] 1). Not mixed with an acid that significantly converts the R into R';

[0283] 2). Application to local lesions;

[0284] 3). The dosage for one course of treatment is:

[0285] Where Q R <50% or 25% of the equivalent usage of R', n R R is the number of times it is applied to the lesion or tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0286] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the needle insertion point, wherein the c R(ii) The concentration threshold of (W / V) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%; the v R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ,

[0287] The active form of R' is in the form of complete complex with acid in solution; while the active form of R is in the form of less complex with acid in solution, and mainly exists in the form of very little or partial complex, thereby providing activity (abbreviated as activity A) that is difficult for R' to provide through the transient local action of this different active form, including at least one of the following: the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), or / and the effect of effectively releasing diseased immune substances or / and inflammatory signals in the lesion (abbreviated as activity A3).

[0288] In some embodiments, in the above uses and methods, the R and drug (Z) are used together, wherein the administration concentration (w / w) of the R is 0.1%-51%, preferably 0.2%-50%, and the drug (Z) comprises at least one selected from the following group: a cell-reactive anti-tumor drug (abbreviated as B), a near-neutral or weakly alkaline sodium salt (abbreviated as C), methylene blue (abbreviated as D), an immunomodulator (abbreviated as E), wherein:

[0289] - The cell-reactive anti-tumor drug (B) provides the cell response (abbreviated as activity B) by the following definition, one of the key control steps of the response is to pass through the above-mentioned biological barrier:

[0290] 1) Pathological administration and / or systemic administration;

[0291] 2) The dosage for one course of treatment is:

[0292] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B ,q B(j) are the number of systemic administrations of B in a course of treatment and the jth administration (j=1, ...n B ) Application rate, n B＇ 、c B(i＇) , and v B(i＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application;

[0293] - The C is used to improve the local efficacy-toxicity ratio of the R (abbreviated as active C) through the following definition:

[0294] 1). Mixed with the R and applied;

[0295] 2) The mixing ratio of C and R (Q C / Q R ) is 0.5 to 4.0;

[0296] - The D provides a pharmacological effect that enhances the pharmacological effect of the R by:

[0297] 1). Pathological administration, including mixed administration with the R or separate administration;

[0298] 2). Dosage for one course of treatment Q E The C is defined as follows: ≦ a transient local effective dose to provide an effect of improving the local efficacy-toxicity ratio of the R (abbreviated as active C):

[0299] 1). Mixed with the R and applied;

[0300] 2) The mixing ratio of C and R (Q C / Q R ) is 0.5 to 4.0;

[0301] - The D provides a pharmacological effect that enhances the pharmacological effect of the R by:

[0302] 1). Pathological administration, including mixed administration with the R or separate administration;

[0303] 2). Dosage for one course of treatment Q E The effective dose is ≤ 1 transient local effect.

[0304] - The E is defined as follows: providing an immunomodulatory effect benefiting from the effect of the active A1, or / and optimizing the local or / and systemic immune response by utilizing the effect of the active A3 (abbreviated as active E):

[0305] 1) Pathological administration and / or systemic administration;

[0306] 2) The dosage for one course of treatment is:

[0307] Where Q E =≦the conventional dosage of E in the anti-lesional application, n E ,q E(k) are the number of systemic administrations of E in a course of treatment and the kth administration (j=1, ...n k ) Application rate, n E＇ 、c E(k＇) , and v E(k＇) are the number of times E is administered to the tumor in one course of treatment, and the k'th time (k'=1,...n k＇ ) concentration and volume at the time of application.

[0308] In some embodiments, in the above uses and methods, the R is used in conjunction with a cell-reactive anti-tumor drug (abbreviated as B) and an immunomodulator (abbreviated as E), wherein:

[0309] - The cell-reactive anti-tumor drug (B) provides the cell response (abbreviated as activity B) by the following definition, one of the key control steps of the response is to pass through the above-mentioned biological barrier:

[0310] 1) Pathological administration and / or systemic administration;

[0311] 2) The dosage for one course of treatment is:

[0312] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B,q B(j) are the number of systemic administrations of B in a course of treatment and the jth administration (j=1, ...n B ) Application rate, n B＇ 、c B(i＇) , and v B(i＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application,

[0313] - The immunomodulator (E) is defined as follows: providing an immunomodulatory effect benefiting from the effect of the active A1, or / and utilizing the effect of the active A3 to optimize the local or / and systemic immune response (abbreviated as active E):

[0314] 1) Pathological administration and / or systemic administration;

[0315] 2) The dosage for one course of treatment is:

[0316] Where Q E =≦the conventional dosage of E in the anti-lesional application, n E ,q E(k) are the number of systemic administrations of E in a course of treatment and the kth administration (j=1, ...n k ) Application rate, n E＇ 、c E(k＇) , and v E(k＇) are the number of times E is administered to the tumor in one course of treatment, and the k'th time (k'=1,...n k＇ ) concentration and volume at the time of application.

[0317] In some embodiments, in the above method, the drug regulatability indicator comprises at least one of the following tumor administration regulatability coefficients:

[0318] 1) Concentration coefficient = ratio of the highest value to the lowest value of cR(ii), and the coefficient is >50, 100 or 150, which allows the combination to provide highly variable administered concentrations of R to different tumors of the same tumor or / and different areas of the same tumor while maintaining its activity A stable;

[0319] 2). Volume ratio coefficient = the ratio of the highest value to the lowest value of the volume ratio of vR(ii) to vtarget(ii), and the coefficient is >5, 10 or 100, which allows the combination to provide highly variable administration volume ratios of R to different tumors of the same tumor or / and different areas of the same tumor while maintaining its activity A stable; and

[0320] 3). Administration point density coefficient = the ratio of the highest to the lowest nRi value within the v target (ii), and the coefficient is >5, 10 or 100, which allows the combination to provide highly variable injection point density R to different tumors of the same type or / and different areas of the same tumor while still maintaining its activity A stable.

[0321] In some embodiments, in the above method, the drug efficacy indicator includes at least one of the following:

[0322] 1) Timeliness, as measured by the time to significant effect (the day when the tumor proliferation rate is <42%) in mouse studies, is at least 25% shorter than that of the R' regimen, the R' / Z combination regimen, and the Z monotherapy regimen. This makes the combination a fast-acting or even faster-acting combination, particularly suitable for tumors requiring rapid reduction in tumor size.

[0323] 2) An efficacy indicator, represented by a tumor inhibition rate or objective response rate in a mouse study, wherein the tumor inhibition rate or objective response rate is at least 25% higher than that of the R' regimen, the R' / Z combination regimen, and the Z monotherapy regimen, making the combination a highly effective or further highly effective combination, particularly suitable for tumors requiring maximum suppression of tumor size;

[0324] 3) Long-term efficacy, as measured by progression-free time in mouse studies, is at least 25% longer than that of the R' regimen, R' / Z combined regimen, and Z monotherapy regimen, making the combination a long-acting or further long-acting combination, particularly suitable for tumors requiring prolonged progression-free time as much as possible.

[0325] According to a twelfth aspect of the present invention, a kit is provided, which comprises the above-mentioned preparation, pharmaceutical combination or composition of the present invention, and instructions for implementing the above-mentioned method of the present invention.

[0326] In some embodiments, the kit further comprises a microvolume interventional device.

[0327] In some embodiments, in the above kit, the microvolume interventional device is suitable for micro-multi-point contact or administration, and preferably comprises a microinjection device.

[0328] According to a thirteenth aspect of the present invention, a method for preparing a preparation is provided, comprising: selecting N,N-dimethylbiguanide having a metformin salt content of less than 30%, ≤25%, preferably ≤10%, and more preferably ≤5% as a raw material, excluding from the formula and avoiding during the preparation contact with an acidic pH regulator added to enable the N,N-dimethylbiguanide to meet the requirements of cell culture or the safety requirements of conventional injections; using a strong alkali-resistant preparation system; and dispersing the N,N-dimethylbiguanide in a solvent.

[0329] In some embodiments, the solvent is water.

[0330] In some embodiments, the N,N-dimethylbiguanide is dissolved in water.

[0331] According to the fourteenth aspect of the present invention, there is provided the use of N,N-dimethylbiguanide as a transient active ingredient in the preparation of a preparation, a drug, a drug combination or a kit for treating tumors or nodules, wherein the N,N-dimethylbiguanide is used to provide a transient effect on diseased tissue and the cells contained therein.

[0332] In this application, the term "transient activity" or "transient effect" activity refers to the activity or effect provided by the active form of R within a transient period of time before it is converted into the active form of R' in vivo.

[0333] In one embodiment, N,N-dimethylbiguanide is a compound of formula C4H 11 The organic compound of N5 has the formula 1 as described above in the first aspect.

[0334] According to the fifteenth aspect of the present invention, a method for treating cells within a lesion in a subject is provided, comprising administering the above-mentioned N,N-dimethylbiguanide of the present invention or the preparation of the present invention to intervene in the lesion, penetrate into the lesion, and contact the cells within the lesion tissue, wherein the N,N-dimethylbiguanide is used as a transient active ingredient to provide a transient effect on the lesion tissue and the cells contained therein, such as a transient tissue penetration effect.

[0335] According to a sixteenth aspect of the present invention, there is provided a method for treating a lesion in a subject, comprising: administering the N,N-dimethylbiguanide or the formulation of the present invention to the lesion, allowing the N,N-dimethylbiguanide or the formulation of the present invention to penetrate into the lesion tissue, and contact the lesion tissue with a constituent of the lesion tissue, or administering the formulation of the present invention to the lesion tissue. Preferably, the administration or contacting may be systemic or local, such as by injection into a tumor or tumor microenvironment.

[0336] According to the seventeenth aspect of the present invention, there is provided a method for treating a lesion, such as a tumor or nodule, in a subject, comprising intervening in or administering to the subject the drug combination, composition or preparation of the present invention as described above.

[0337] In some embodiments, the intervention or administration may be systemic or local, preferably, the administration or intervention may include intratumoral administration or intervention, preferably local intratumoral intervention administration, preferably such as local injection administration or intervention into a tumor or tumor microenvironment.

[0338] In some embodiments, administration by injection may include infusion, liquid particle injection, or implantation.

[0339] In some preferred embodiments, the formulation of the present invention is suitable for micro-volume administration or interventional administration, and the ratio of the administration volume to the target volume (V 施用 / V 靶 ) is approximately 0.02-0.05, 0.02-0.10 or 0.02-0.34.

[0340] In some embodiments, the above-mentioned contact, intervention or administration comprises multi-point contact, intervention or administration, preferably, local multi-point contact or intervention.

[0341] The above-mentioned contact or administration may include multi-point contact or administration or intervention, and the multi-point refers to that the number of micro-volume intervention points at which the total target area efficacy evaluation is observed to be effective is significantly higher than that of the conventional metformin drug. Specifically, the multi-points are, for example, multiple sites at the target area, such as ≧5, ≧10, ≧20, ≧30, ≧ or 50 sites, such as at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or more sites, such as 10 to 20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50, 25-50, 30-50 or more sites. Preferably, the contact points or administration sites or intervention points are evenly distributed, especially distributed to places where conventional intervention cannot diffuse.

[0342] In some preferred embodiments, wherein the lesion is ≥ about 3.5 cm 3 , or when the maximum size is ≧ about 2 cm, the multiple points are ≧ 5 sites, for example 10, 15, 20, 25, 30, 35 or 50 sites.

[0343] In some preferred embodiments, the above-mentioned contact or administration or intervention may include micro-multi-point contact or administration or intervention, preferably, micro-multi-point injection, wherein the micro-volume is a drug administration volume of ≦5% or 10% of the target volume, for example, an amount of 5 μL-1000 μL, for example, 5 μL-500 μL, 5 μL-250 μL, 5 μL-200 μL, 5 μL-100 μL, 5 μL-75 μL, 5 μL-50 μL, 5 μL -25 μL, 5 μL-20 μL, 10 μL-200 μL, 10 μL-100 μL, 10 μL-75 μL, 20 μL-200 μL, 20 μL-100 μL, 20 μL-75 μL, 30 μL-200 μL, 30 μL-100 μL, 40 μL-200 μL, 40 μL-100 μL, 50 μL-200 μL, 50 μL-100 μL, or 50 μL-75 μL, etc. Preferably, micro-multiple (position) point contact or administration, more preferably, micro-multiple (position) point injection.

[0344] In some embodiments, the above treatment can be continued for at least one course of treatment. The duration of the course of treatment can be about 7-40 days, such as about 9 to about 37 days, such as about 15, 20, 25, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0345] In one embodiment, in one course of treatment, contact or administration of the formulation of the present invention can be low frequency, such as administration about 1-6 times / course, preferably 1-5 times / course, 1-4 times / course, 1-3 times / course, or 1-2 times / course.

[0346] According to an eighteenth aspect of the present invention, a kit is provided, comprising the preparation, pharmaceutical combination or composition of the present invention as described above, and instructions for implementing the treatment or therapeutic method of the present invention as described above.

[0347] In one embodiment, the kit of the present invention further comprises a micro-volume intervention device, preferably, the device is suitable for micro-multi-point contact or administration, preferably comprising a micro-injection device such as a syringe.

[0348] In one embodiment, the volume intervention device may include, for example, a puncture needle, an injection needle, a catheter, or other devices with the same function.

[0349] In one embodiment, in the above-mentioned use, method and kit of the present invention, the dosage of R in the preparation of the present invention for one course of treatment (Q R ) is ≤ 20% or 50% of the regular metformin drug (R') dosage for one course of treatment (Q R＇), wherein R is a transient active ingredient that exceeds the expectation of "R and R' are pharmaceutical equivalents", which is manifested by a significant reduction in the dosage but a significant increase in the drug effect, including at least one drug adjustability index being increased by at least 100%, and at least one drug efficacy index being enhanced by at least 40%.

[0350] In this application, the term "transient activity" or "transient effect" refers to the local activity or local effect provided by the active form of R within a transient period of time before it is converted into the active form of R' in vivo.

[0351] In one embodiment, in the above-mentioned use, the above-mentioned method, and the above-mentioned kit of the present invention, the transient dose (Q R and Q Z ) is significantly less than the dosage of the combination of conventional metformin drugs (R') and Z (abbreviated as R' / Z) (Q R＇ and Q Z＇ ):Q R ≦25% or 50% Q R＇ and Q Z No greater than Q Z＇ , the R / Z is a synergistic combination that exceeds the expectation of "R / Z and R' / Z are pharmaceutically equivalent combinations", which is manifested in that the dosage is significantly reduced but the drug effect is significantly increased, including at least one drug adjustability index being increased by at least 100%, and at least one drug efficacy index being enhanced by at least 25%, wherein the drug adjustability refers to the performance of the drug in providing differentiated dosing parameters to different target areas while still maintaining efficacy.

[0352] In one embodiment, in the above-mentioned use, the above-mentioned method, and the above-mentioned kit of the present invention, the amount (Q) of the combination of R and Z (abbreviated as R / Z) in the preparation of the present invention is R and Q B ) is lower than the dosage of R and Z alone (Q R0 and Q Z0 ):Q R No greater than Q R0 and Q Z ≦80%Q B0 , the R / Z is a synergistic combination that exceeds the expectations of the HSA method or Bliss method based on the effects of R and Z alone, as manifested by a reduction in dosage but an increase in drug effect, including an increase of at least 10% in at least one drug adjustability index and an enhancement of at least 10% in at least one drug efficacy index.

[0353] In one embodiment, in the above-mentioned uses, methods, and kits of the present invention, the intervention or application concentration (C, w / w) of N,N-dimethylbiguanide in the preparation of the present invention is 1.0% ≦ C ≦ 30%, for example, 1.0% ≦ C ≦ 20%, preferably 3.0% ≦ C ≦ 30%, preferably 3.0% ≦ C ≦ 20%, more preferably 5.0% ≦ C ≦ 30%, more preferably 5.0% ≦ C ≦ 20%, and particularly preferably, 6.0% ≦ C ≦ 20%.

[0354] In one embodiment, in the above-mentioned uses, methods, and kits of the present invention, the intervention or application concentration (C, w / w) of N,N-dimethylbiguanide in the preparation of the present invention is 20% ≦ C ≦ 50%, preferably 25% ≦ C ≦ 50%, preferably 30% ≦ C ≦ 50%, more preferably 40% ≦ C ≦ 50%, and particularly preferably, 45% ≦ C ≦ 50%.

[0355] In the present invention, the indication (Y, X) is suitable for use in treating (Y) lesion disease or lesion symptom (X), wherein X is the volume of the lesion, and Y is effective or rapid reduction, wherein the lesion includes malignant lesions and non-malignant lesions.

[0356] In the present invention, X is the volume of the lesion, and Y is an effective or rapid reduction. In the present invention, the lesion is a lesion that is ineffective or has failed to respond to conventional treatment, including at least one selected from the following groups: a tumor that is ineffective or has failed to respond to conventional treatment; a malignant tumor or non-malignant nodule that is refractory to conventional chemotherapy drugs. Preferably, the lesion is a malignant tumor that is refractory to conventional chemotherapy drugs.

[0357] In the present invention, the refractory malignant tumor includes or is selected from at least one of the following groups: tumors resistant to chemotherapy drugs, tumors containing unfavorable microenvironment, tumors with discontinued drugs, tumors for which there are no effective chemotherapy drugs, and tumors carried by patients with contraindications or inappropriate indications for conventional chemotherapy drugs.

[0358] The non-malignant nodule is a nodule including but not limited to at least one of the following non-malignant cells: connective tissue cells, secretory gland cells, epithelial cells. In one embodiment, the nodule includes or is selected from, for example: organ nodules rich in organ cells (such as breast nodules, thyroid nodules, lung gland nodules), non-malignant tumors rich in connective tissue cells (lipomas, fibroids, etc.), connective tissue lesions rich in connective tissue cells (rheumatoid arthritis, systemic lupus erythematosus, polymyositis) and other nodules, preferably, mammary hyperplasia nodules.

[0359] In the present invention, the lesions include tumors of non-drug-resistant malignant tumor cells.

[0360] In the present invention, the malignant tumor cells are non-metformin cytotoxic specific tumor cells.

[0361] In the present invention, the chemotherapy drug-resistant tumor includes a tumor that is resistant to conventional chemotherapy drugs, including but not limited to paclitaxel, 5-fluorouracil, cyclophosphamide, doxorubicin, and / or cisplatin, or a tumor that is resistant to targeted anti-tumor drugs such as gefitinib, osimertinib and / or trastuzumab, for example, including liver cancer tumors, breast cancer tumors, sarcoma tumors, pancreatic cancer, lung cancer, gastric cancer, and colon cancer tumors containing an unfavorable microenvironment. In one embodiment, the refractory malignant tumor includes or is selected from liver cancer tumors, breast cancer tumors, sarcoma tumors, pancreatic cancer, lung cancer, gastric cancer, and colon cancer tumors that are resistant to chemotherapy drugs. Preferably, the chemotherapy drug-resistant tumor is 5-fluorouracil-resistant liver cancer.

[0362] In the above-mentioned uses and methods of the present invention, the lesions include tumors due to any pathology (malignant and / or non-malignant) and at any stage, including, for example, the following groups classified according to tumor cell types: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, embryonic cell tumors; and tumors named according to the organs or tissues where the tumor cells are concentrated, including, for example, tumors named according to the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, bladder muscle, large intestine, small intestine, spleen, stomach, prostate, testicle, ovary or uterus.

[0363] Specifically, the malignant tumors include, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, sarcoma, etc.

[0364] Furthermore, the above-mentioned malignant tumors include refractory tumors, such as tumors that progress after chemotherapy. The tumors that progress after chemotherapy include those that progress after treatment with chemotherapeutic drugs such as paclitaxel, 5-fluorouracil, cyclophosphamide, doxorubicin, and cisplatin, or those that progress after treatment with targeted anti-tumor drugs such as gefitinib, osimertinib, tranelizumab, and their derivatives.

[0365] The non-malignant tumors include, for example, breast tumors, pancreatic tumors, thyroid tumors, prostate tumors, liver tumors, lung tumors, intestinal tumors, oral tumors, esophageal tumors, gastric tumors, nasopharyngeal tumors, laryngeal tumors, testicular tumors, vaginal tumors, uterine tumors, fallopian tube tumors, ovarian tumors, etc.

[0366] In the above uses and methods of the present invention, according to one embodiment, the malignant cells include or are selected from conventional malignant cells for which conventional metformin preparations alone are ineffective, such as cancer cells other than liver cancer cells and sarcoma cells.

[0367] In the above uses and methods of the present invention, according to one embodiment, the non-malignant cells include or are selected from at least one of connective tissue cells and organ tissue cells.

[0368] In the above uses and methods of the present invention, according to one embodiment, the connective tissue cells include fibroblasts.

[0369] In the above uses and methods of the present invention, according to one embodiment, the organ tissue cells include or are selected from at least one of the following: liver cells, breast cells, thyroid cells, and skin cells.

[0370] In the above uses and methods of the present invention, the non-malignant lesions include or are selected from at least one of the following groups: benign tumors and nodules.

[0371] In the above uses and methods of the present invention, the non-malignant nodules include benign lesions other than benign tumors, including, for example, hyperplasia (e.g., hyperplasia of the breast, thyroid, parathyroid, prostate, etc.), cysts, abnormal venous masses (e.g., hemorrhoids, etc.), local inflammatory swelling, swelling caused by microbial infection, etc. The hemorrhoids include internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids.

[0372] In one embodiment, the benign lesions include local inflammation, especially refractory inflammation. The refractory inflammation includes, but is not limited to, for example, alterative inflammation, exudative inflammation and hyperplastic inflammation, which can be any suitable ones known to those skilled in the art, for example, one or more of the following: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, oophoritis, etc.

[0373] In one embodiment, the benign lesions include skin diseases, especially refractory skin diseases. The refractory skin diseases include, but are not limited to, one or more of the following: skin cancer, non-malignant skin tumors, viral skin diseases (such as herpes, warts, rubella, hand, foot and mouth disease), bacterial skin diseases (such as impetigo, furuncle, leprosy), fungal skin diseases (such as various ringworms), sexually transmitted diseases (such as syphilis, gonorrhea and genital warts), allergic and autoimmune skin diseases (such as contact dermatitis, eczema, urticaria), physical skin diseases (such as solar dermatitis, frostbite, corns, chapped hands and feet, pressure sores), connective tissue diseases (such as lupus erythematosus), pigmentary disorders (such as freckles, moles, various spots), skin appendage diseases (such as acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis and bromhidrosis), cortical hyperplasia, such as spontaneous cortical hyperplasia.

[0374] In the above-mentioned uses and methods of the present invention, the subject includes a mammal. Preferably, the subject includes a human. Still more preferably, the subject includes a non-human mammal, such as a non-human primate, livestock, and pets. The livestock include, but are not limited to, camels, pigs, cattle, sheep, horses, donkeys, goats, and sheep; and the pets include various mammalian pets such as dogs, cats, rabbits, monkeys, and gorillas.

[0375] In some embodiments, in the above-mentioned preparations, pharmaceutical combinations, compositions, uses, methods, or kits, the intervention or administration concentration of N,N-dimethylbiguanide (C or C R , w / w) is 1.0%≦C≦20%, preferably 3.0%≦C≦20%, more preferably 5.0%≦C≦20%, and particularly preferably 6.0%≦C≦20%.

[0376] In some embodiments, in the above-mentioned preparations, pharmaceutical combinations, compositions, uses, methods, or kits, the intervention or administration concentration of N,N-dimethylbiguanide (C or C R , w / w) is 20%≦C≦50%, preferably 30%≦C≦50%, more preferably 40%≦C≦50%, and particularly preferably, 45%≦C≦50%.

[0377] In some embodiments, in the above-mentioned preparations, drug combinations, compositions, uses, methods, or kits, the tumor is a malignant tumor that is refractory to conventional chemotherapy drugs. Preferably, the refractory malignant tumor includes or is selected from at least one of the following groups: a tumor that is resistant to chemotherapy drugs, a tumor containing an unfavorable microenvironment, a tumor that has stopped taking drugs, a tumor for which there is no effective chemotherapy drug, and a tumor carried by a patient who has contraindications or is not suitable for conventional chemotherapy drugs.

[0378] In some embodiments, in the above-mentioned preparation, pharmaceutical combination, composition, use, method, or kit, the nodule is a nodule comprising at least one of the following non-malignant cells: a non-malignant nodule of connective tissue cells, secretory gland cells, and epithelial cells.

[0379] In some embodiments, in the above-mentioned formulation, pharmaceutical combination, composition, use, method, or kit, the lesion comprises a tumor containing non-resistant malignant tumor cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0380] Figures 1-C: HE staining and histological analysis of tumor specimens from nude mouse tumor models containing human hepatocellular carcinoma cells (Bel-7409 / 5-Fu) treated with metformin hydrochloride, N,N-dimethylbiguanide, and 5-Fu, respectively, 1 hour after administration (X, Y, Z) in Example 1.1. X: 1.3% metformin hydrochloride; Y: 0.5% N,N-dimethylbiguanide; Z: 0.25% 5-Fu (w / w).

[0381] Figure 2 AC: Enlarged images (400×) of the HE-stained images in Figure 1A-C.

[0382] Figure 3: Tumor samples in the nude mouse tumor model containing human liver cancer 5-Fu-resistant cells (Bel-7409 / 5-Fu) after administration of metformin hydrochloride, N,N-dimethylbiguanide and 5-Fu in Example 1.1 for 1 hour (AG)

[0383] Figure 4: Treatment effect on beagle dogs with spontaneous cortical hyperplasia in Example 4.2 (A: lesions before treatment, B: lesions after treatment)

[0384] Figure 5: Treatment effect on rats with spontaneous fibroids in Example 4.2 (A: lesions before treatment, B: lesions after treatment) DETAILED DESCRIPTION

[0385] definition

[0386] In this application, the term "activity" refers to the ability of a compound to exert a specific biological or pharmacological effect. The term "active form" refers to the specific form of a compound that provides a specific activity, such as the specific form that binds to a specific target and triggers a biological effect. The term "active ingredient" refers to the chemical entity in a drug or formulation that directly provides a specific active form. A compound may not be directly active in its original state. For example, salicylic acid, produced by hydrolysis of aspirin, is its active form, and sulfonamides must dissociate into their free form to exert their antibacterial effect.

[0387] In this application, the term "conventional metformin" (codenamed R' in this application) refers to the metformin used in the prior art. The metformin is defined according to its main characteristics (can be systemically administered and can provide the required pharmacology through systemic administration), so it can only be a metformin salt. For example, in the catalog of a major supplier such as Sigma, the only compound under the metformin item is methylformin hydrochloride. Any metformin sourced from Sigma, or any metformin that can be used for cell experiments, or can be systemically administered (including intraperitoneal administration), or locally administered with the same drug mechanism as systemic administration, can only be a metformin salt. In this application, the most commonly used "metformin", i.e., methylformin hydrochloride, is used as a representative of conventional metformin drugs. In the prior art, metformin salts and metformin are often used interchangeably.

[0388] In this application, the term "N-dimethylbiguanide" (designated R in this application and used interchangeably with metformin compounds) is a distinguishing compound from conventional metformin (metformin salts). According to the International Union of Pure and Applied Chemistry (IUPAC), the metformin compound known as N,N-dimethylbiguanide has a chemical formula of C4H11N5, a simplified structural formula of H3CNCNH3CNCH3, and a molecular weight of 129.2 (see Formula 1 below for specific results). Metformin salts are salts of N,N-dimethylbiguanide formed with different acids. Their chemical formula is C4H11N5 (acid) and their simplified structural formula is H3CNCNH3CNCH3 (acid). The specific IUPAC nomenclature depends on the acid contained therein. For example, the salt formed by N,N-dimethylbiguanide and hydrochloric acid has a chemical formula of C4H11N5 hydrochloric acid, a simplified structural formula of H3CNCNH3CNCH3·HCl, an IUPAC name of N,N-dimethylbiguanide hydrochloride, and a molecular weight of 165.6 (see Formula 2 below).

[0389] Different IUPAC standard nomenclatures correspond to distinct chemical structures. The "N,N-dimethyl" in N,N-dimethylbiguanide indicates two methyl groups (CH3-) attached to two nitrogen atoms in the molecule. "Biguanide" refers to a derivative of biguanidine in which the guanidine group is free. In N,N-dimethylbiguanide hydrochloride, the guanidine group adsorbs a chloride ion, forming an ion pair of the positively charged metformin ion and the corresponding chloride ion. This is also true for other metformin salts. This structural difference is also reflected in their different preparation methods. N,N-dimethylbiguanide hydrochloride is cheaper to prepare, and N,N-dimethylbiguanide is typically prepared using N,N-dimethylbiguanide hydrochloride as the starting material.

[0390] In fact, when N,N-dimethylbiguanide enters body fluids such as blood, it can form metformin salts with acid groups therein. For example, the guanidine group in N,N-dimethylbiguanide combines with a chloride ion (Cl-) to form an ion pair, forming N,N-dimethylbiguanide hydrochloride. Prior art anticipates that these structural differences in vitro do not result in significant differences in biological activity, and R and R' are considered pharmaceutical equivalents.

[0391] However, the results in the examples of the present application unexpectedly show that their structural differences produce different biological activities under specific conditions, i.e., different structure-activity relationships. According to these results, it is possible to more completely evaluate whether N,N-dimethylbiguanide and metformin salts are different active ingredients. Assuming that they all enter the body through systemic administration, have the same form after being dispersed in the blood, and then play the same role, they are pharmaceutical equivalents and are considered to be the same active ingredient. However, if they enter the body through local administration, have different active forms in a specific solution (such as an aqueous solution), and different forms can provide different core activities and play different roles, then they are not pharmaceutical equivalents, and active ingredients need to be defined separately according to different active forms.

[0392] In fact, N,N-dimethylbiguanide (R) has a morphological manifestation different from that of conventional metformin drugs (whose active ingredient is R') under the conditions of the present application, wherein the active form of R' is in the form of complete complex with acid in solution (as shown in Example 5, which can be used for systemic administration); on the contrary, the active form of R is less complexed with acid in solution and mainly exists in the form of very little or partial complex (as shown in Example 5, which cannot be used for systemic administration and can only be used for local administration), thereby providing activity (activity A) that R' cannot provide, and activity A includes a transient local effect.

[0393] In this application, the term "cell-responsive drug" (codenamed B in this application) refers to a class of anti-tumor drugs that act on tumor cells, primarily by modulating tumor cell growth, division, or death signaling pathways and intervening in key metabolic and biological processes, thereby achieving anti-tumor effects. This class of drugs includes cytotoxic drugs and targeted anti-tumor drugs. The term "cytotoxic drug" (codenamed B1 in this application) refers to a class of anti-tumor drugs that kill tumor cells through non-specific mechanisms (directly damaging DNA, inhibiting RNA synthesis, or interfering with protein polymerization). The term "targeted anti-tumor drug" (codenamed B2 in this application) refers to a class of drugs that selectively inhibit tumor cell growth or induce tumor cell death by binding to tumor cell-specific targets (such as products of specific gene mutations or abnormally expressed receptor proteins) to modulate cell signaling pathways. Cytotoxic drugs and targeted anti-tumor drugs are often considered to be very different drugs, but they share the following characteristics: they inhibit tumor progression by intervening in key tumor cell signaling pathways (such as proliferation, metabolism, apoptosis, or DNA repair), and thus face common problems:

[0394] As used herein, the term "nearly neutral or weakly alkaline sodium salt" (abbreviated as C) refers to a sodium salt compound that is injectable and whose aqueous solution exhibits a near-neutral pH (pH 5.0-8.5) within a certain concentration range. Such sodium salts include, but are not limited to, the following: sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium lactate, sodium acetate, and the like.

[0395] In this application, the term "immunomodulator" refers to a substance that can optimize local or / and systemic immune responses by utilizing lesion immune substances or / and inflammatory signals released within the lesion, including but not limited to the following three categories: biomacromolecule immunomodulators, immune cell immunomodulators, and vaccine immunomodulators. The term "biomacromolecule immunomodulator" (abbreviated as E1) refers to an immunomodulator based on protein or nucleic acid, wherein the representative drugs based on protein are immune checkpoint inhibitors and cytokines, and the representative drugs based on nucleic acid are TLR agonists. The term "immune cell immunomodulator" (abbreviated as E2) refers to cell products in therapeutic methods that directly or indirectly enhance immune responses by transplantation or injection of immune cells, such as DC vaccines, NK cells, and CAR-T cells. The term "vaccine immunomodulator" (abbreviated as E3) refers to preparations that promote immune responses by inducing specific immunity or nonspecific immune enhancement, such as lesion immune substance vaccines, oncolytic virus vaccines, and BCG vaccines.

[0396] In this application, the term "formulation" refers to a pharmaceutical product that is prepared from a pharmaceutical raw material through a specific process and can be used directly. It can be, for example, a tablet, capsule, injection, cream, suspension, etc. The term "optimized formulation" refers to a pharmaceutical formulation that, through systematic research and preference evaluation, selects the most suitable pharmaceutical raw materials, excipients, and preparation process, so that the product achieves the best performance (most preferably oral administration, followed by other systemic administration), efficacy, stability, safety, etc. After decades of selection, topical formulations are far from the preferred formulation for conventional metformin drugs.

[0397] In this application, the term "regimen" refers to a specific drug combination, pharmaceutical composition, formulation, method, kit, or use. The term "this application's regimen" refers to the R-based drug combination, pharmaceutical composition, formulation, method, kit, or use of this application. The term "control regimen" refers to the drug combination, pharmaceutical composition, formulation, method, kit, or use used as a control for this application's regimen. The term "conventional metformin regimen" refers to the R'-based regimen (commonly used as a control regimen). Indications are the core effect of the regimen and its core value.

[0398] In this application, the term "indication" is distinguished from "disease or disease symptom". The latter refers to an abnormal life activity process, while the former refers to "a disease or condition suitable for a certain treatment measure" (Cihai (1989 edition)), or "the scope of a drug applicable to a certain disease symptom" (National Science and Technology Terminology Committee, Pharmaceutical Terminology (Second Edition)). In short, the indication of a regimen refers to the scope of its application to a specific disease or disease symptom, based on its effect characteristics (Y) to solve the clinical needs of a specific disease (X) or its core pathological conditions, recorded as (X, Y). Those skilled in the art know that the effect characteristics (Y) are the core conditions for limiting the scope of applicable diseases or symptoms (X), and must be specific, strict, clear and without error. Authoritative organizations in various countries in this field have regulations on this. For example, the China Food and Drug Administration (CFDA) stipulates in the "Detailed Specifications for Instructions for Chemical Drugs and Therapeutic Biological Products (2006 Edition)" that "[Indications] should be accurately expressed based on the intended use of the drug, clearly indicating its use for the prevention, treatment, diagnosis, relief, or adjunctive treatment of a certain disease (condition) or syndrome." The efficacy characteristics (Y) of the drug or method determine its use, for example, Y = prevention, treatment, diagnosis, relief, or adjunctive treatment. Within the field of "treatment," Y can be further subdivided based on meeting more refined efficacy characteristics standards. For example, based on the satisfaction of specific effects, it can be distinguished as: effective treatment, rapid-acting treatment, high-efficacy treatment, long-acting treatment, and heterogeneous equivalence (regimens).

[0399] In this application, the term "structure-activity relationship" refers to the relationship between an indication (X, Y) and a set of drug components, such as (α, β, γ). An indication is the most essential and valuable characteristic "effect" of a pharmaceutical regimen, while the set of essential components is clearly its characteristic "structure." The pharmacological conditions that allow the "structure" to manifest the "effect" define the relationship between them, i.e., f: (α, β, γ) → (X, Y). Here, Y represents the efficacy characteristics, including synergism, dose-response, efficacy (timeliness, effectiveness, long-lasting effect), and heterogeneous adaptability; X represents the range of pathological conditions for which efficacy characteristic Y is applicable; α represents the pharmacological characteristics or set of characteristics required to satisfy efficacy characteristic Y for indication X, such as a shared chemical structure subset (A, B); β represents the conditions for the active ingredients in the drug to achieve activity, such as the dosage of A and the functional combination or synergistic conditions of (A, B), including, for example, the shared concentration threshold of A and B and the synergistic concentration ratio range between them; γ represents the formulation compatibility (such as the exclusivity of A), ensuring drug stability and efficacy under specific conditions. The relationship f maps the "structure" set (α, β, γ) to the "effect" set (X, Y), f: (α, β, γ) → (X, Y). f includes, for example, the administration method for the active form of the structure required for efficacy.

[0400] As described in the "Technical Background" section above, the EC50 of conventional metformin in sensitive tumor cell experiments is in the millimolar range, over a hundred times higher than that of conventional anti-tumor drugs (e.g., 5-FU). Besides safety, it lacks any significant activity advantage or efficacy characteristics (Y) advantage. For example, the indications for conventional metformin are limited to (X' = sensitive tumors, Y' = effective but not rapid-acting, highly effective, or long-lasting treatment), rather than the commonly expanded claim of (X = tumor, Y = treatment). Extending its indications (X', Y') to (X, Y) could lead to serious clinical consequences, such as delayed treatment due to misuse of the regimen, and scientifically, would be misleading to those skilled in the art.

[0401] The scientific combination of α, β, and γ (α, β, γ) is the key to achieving the desired effect (efficacy) of the drug, which is reflected in the precise matching of the specific indication (X, Y). For example, the differences in (α, β, γ) between R and R' include: different molecular structures (α) that provide the active form (N,N-dimethylbiguanide vs. N,N-dimethylbiguanide hydrochloride), different concentration thresholds or dosage solubility (β) (Q R / Q R＇ <50% or more), and the stability (γ) of the drug formulation is different (with vs. without mixing contraindications).

[0402] The present application scheme produces new therapeutic effect characteristics or (Y) and its suitable for treating diseases or conditions (X) by providing a new set of drug components (α, β, γ) and new pharmacology (f), that is, f: (α, β, γ) → (X, Y).

[0403] The comparison system, evaluation method and standard, and related definitions of effect characteristics (Y) are as follows.

[0404] 1. Comparison system

[0405] In this application, the term "conventional comparison" refers to the comparison between the research scheme and the currently existing solutions or solutions within the technical forecast period (conventional solutions), to evaluate whether the research scheme exceeds the expectations of the conventional solutions in terms of technical effects; the term "further comparison" refers to an in-depth evaluation of multiple research schemes on the basis of conventional comparison, and through refined and expanded comparisons, further evaluation of whether a combination scheme exceeds the expectations based on the component schemes in terms of technical effects.

[0406] Conventional comparisons of single drugs primarily study the metformin drug (R) versus a conventional metformin drug (R'). According to prior art, there are no structural differences between metformin drugs; R and R' are considered to have the same active ingredient and are expected to have the same efficacy. Comparing the actual efficacy of R in the study protocol with the results of R' indicates that the efficacy is the same as expected; significantly stronger efficacy exceeds expectations, making it an unconventional drug that conflicts with the aforementioned teachings.

[0407] Conventional comparisons of combinations primarily involve comparing the R / Z combination with the conventional R' / Z combination. As previously mentioned, based on the teachings of the prior art, it is expected that R / Z and R' / Z would have the same efficacy. Comparing the actual efficacy of R / Z in the study protocol with the R' / Z results would meet expectations if the efficacy were the same; significantly stronger efficacy would exceed expectations, making it an unconventional combination that conflicts with the aforementioned teachings.

[0408] Under the condition that R becomes an extraordinary metformin drug, the comparison of the study combination R / Z with either drug alone, especially R, clearly exceeds the expected range of conventional comparisons and is no longer applicable. Further comparisons can only be conducted between different study regimens. Further comparisons will be conducted based on the HSA or Bliss methods described below for the individual drug results to predict the combination results. The actual efficacy of R / Z in the study regimen will be compared with the expected efficacy. Equal efficacy is considered in line with expectations; greater efficacy exceeds expectations, making it a further extraordinary combination.

[0409] 2. Compatibility

[0410] The expected interactions (antagonism, additivity, synergy) between the active components (e.g., R and Z) in a combined approach are highly uncertain, a phenomenon known as compatibility. The probability of synergy occurring is far lower than that of non-synergy, centered on exceeding compatibility expectations of existing technology solutions. This is often a key goal of combined approach research, a major technical challenge, and an essential characteristic. It also provides important evidence for the unique innovation of the combination mechanism.

[0411] In this application, taking the mouse test in the examples as an example, the compatibility evaluation is as follows:

[0412] In this application, taking the mouse experiment in the examples as an example, the dose-effect evaluation is as follows.

[0413] (1) Calculation of compatibility index

[0414] The compatibility index is the ratio of the actual shared effect (q1) widely used in the industry to the expected shared effect (q2) calculated based on the prediction model: q = q1 / q2.

[0415] (2) General evaluation

[0416] When q>1, it is synergistic, otherwise it is non-synergistic (it may be an independent effect or an antagonistic effect).

[0417] (3) Relative evaluation

[0418] (A) Conventional comparison

[0419] In conventional comparisons, q2 is the expected R / Z synergy effect based on prior art (R / Z and R' / Z have the same effect). The evaluation criteria are: when the actual effect of R / Z (q1) is greater than R' / Z, then q = q1 / q2 > 1.0, it is synergistic; otherwise, it is non-synergistic.

[0420] This synergy reflects the unexpected synergy produced by the combination of R instead of R' (metformin in the prior art) and Z, manifesting as unexpected synergy. For example, the combination of a conventional metformin drug (R') and a cell-reactive drug (B) is expected to result in an interaction between cellular effects; however, the combination of N,N-dimethylbiguanide (R) and B in this application provides an interaction between R's local biological barrier function weakening effect and B's cell-reactive anti-tumor effect, the latter exceeding the expectations of the former. This is the above-mentioned unconventional pharmacological mechanism of synergy.

[0421] (B) Further comparison

[0422] When the R / Z combination is synergistic in conventional comparison, further comparison is performed, and q2 is the expected shared effect based on the efficacy of single drugs R and Z, where R is the active ingredient expected to exceed the existing metformin technical solution. The calculation of q2 is a comparison between the combination solution and the single drug solution, which can be used for both conventional comparison and further comparison. The following two methods are used for anti-tumor animal experiments. In this application, the actual single-use effects of drugs R and Z are respectively recorded as E R and E Z .

[0423] (a) Highest single-drug effect (HSA) method

[0424] The HSA (Highest Single Agent) method is one of the most widely used methods in anti-tumor animal experiments. Its core idea is to compare the actual effect of combined drug therapy (q1) with the predicted value of the best effect of a single drug (q2), that is, q2 = max (E R , E Z ), the same effect is in line with expectations, and a stronger effect is beyond expectations. The evaluation standard is: when the actual efficacy (q1) of the combination is greater than max (E R , E Z ) is further collaboration, otherwise it is not further collaboration.

[0425] (B) Bliss method

[0426] The Bliss independence model (Bliss, CI (1939). The toxicity of poisons applied jointly. Annals of Applied Biology, 26 (3), 585-615.) is another most widely used method in anti-tumor animal experiments. Its core assumption is that the effects of two drugs are independent of each other and obey the probability superposition principle: q2 = E R +E Z -E R ×E Z , the same effect is in line with expectations, and a stronger effect is beyond expectations. The evaluation criteria are: when the actual effect of the combination (q1) is greater than q2, it is further synergistic; otherwise, it is not further synergistic.

[0427] In this application, the terms "further synergy" (scheme), "synergy" (scheme), and "non-synergy" (scheme) refer to (schemes) that meet the above evaluation criteria of further synergy, synergy, and non-synergy, respectively.

[0428] In one embodiment, the present application provides a drug combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a synergistic combination that exceeds the expected effect of the combination of conventional metformin drug (R') and Z (R' / Z combination), and is expressed as a course of treatment dose of R (Q R ) is ≤25% or 50% of the dosage for a course of treatment (Q R＇ ) and Z are not increased during the course of treatment, the drug effect is significantly increased, including at least one of the drug adjustability indicators being increased by at least 100%, and at least one of the drug efficacy indicators being enhanced by at least 25%, or the local effect-to-toxicity ratio being increased by at least 25%.

[0429] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further synergistic combination that exceeds the expected effect of the HSA method or Bliss method based on R alone and Z alone, and is expressed as a course of treatment dose of R (Q R ) does not increase the dosage of Z for one course of treatment (Q B ) is reduced by at least 20%, while the drug effect is increased, including at least one of the drug adjustability indicators increasing by at least 10%, and at least one of the drug efficacy indicators increasing by at least 10%, or the local effect-to-toxicity ratio increasing by at least 10%.

[0430] In one embodiment, the synergistic regimen or further synergistic regimen of the present application is preferably applicable to tumors that require the interaction between the intratumor barrier function weakening effect of R and the intratumor cell reactive anti-tumor effect of B to produce higher therapeutic effects, including, for example, highly invasive tumors, advanced tumors, rapidly deteriorating tumors, and refractory tumors.

[0431] 3. Dose-effect

[0432] In this application, the term "dose-response" refers to the strength of the drug's unit dose effect. The expected dose-response of the regimen can range from strong to weak to ineffective, and is highly uncertain. The difference between normal cells and tumor cells is not large, and the difference between the effective dose and the safety limit of anti-tumor drugs is usually not large. The expected strength is usually not high, which is manifested in serious side effects when the patient does not benefit much. Improving dose-response is an important purpose of regimen research, and it is also a major technical difficulty and essential feature. If the new regimen exceeds the expected dose-response of the old regimen, it not only exceeds the expected efficacy, but also provides important evidence of unique innovation in treatment mechanism or drug design.

[0433] In this application, taking the mouse experiment in the examples as an example, the dose-effect evaluation is as follows.

[0434] (1) Dose-effect index

[0435] In this application, the term "dose-response index" refers to the numerical expression of a specific drug effect (such as a therapeutic effect) produced in the body per unit of drug (such as per mmol or per milligram of drug), which is used to measure the minimum dose of drug efficacy or the relationship between its therapeutic effect (X) and the minimum dose or the minimum frequency of administration related thereto, usually the number of a course of treatment.

[0436] (2) Relative evaluation

[0437] (A) Conventional comparison

[0438] Single drug comparison: Evaluation criteria: the dosage of R is halved (Q R =1 / 2Q R＇ ) when at least one of its drug effects is improved by at least 30%; or at least one of the actual dose-effect indicators of R alone is improved by at least 50% or 70% compared with R' alone, then its dose-effect exceeds the expectations of the prior art (R and R' are regarded as pharmaceutical equivalents) and is considered to be potent.

[0439] Combination comparison: The evaluation criteria are: when the dosage of at least one of R / Z is halved, at least one of the drug effects of the combination is improved by at least 30%; or the actual dose-effect index of at least one of R / Z is improved by at least 50% or 70% compared with the corresponding component in R' / B, then the dose-effect of the combination exceeds the expectations of the prior art (R and R' are pharmaceutical equivalents) and is considered potent.

[0440] (B) Further comparison

[0441] In further comparisons, R / Z had the lowest shared dose-response index based on the expected dose-response (HSA) of the single agents R and Z. The evaluation criteria are: when R / Z is potent, and when the dosage of at least one of R and Z is reduced by 10%, the actual dose-response index of the combination is at least 10% or 20% higher than the highest single-agent dose, then its dose-response further exceeds expectations and is considered further potent.

[0442] In this application, the terms "further potent" (regimen), "potent" (regimen), and "non-potent" (regimen) refer to (regimens) that meet the above further potent, potent, and non-potent evaluation criteria, respectively.

[0443] In one embodiment, the differentiated structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differentiated indications (X, Y) are the range (X) to which the potent or further potent (Y) of the R or R / Z is applicable, while the non-potent R' or R' / Z is not applicable: patients with localized lesions who need to benefit from low (dosage) doses or low (frequency) high efficiency; the differentiated pharmacology (f) mainly includes the potent or further potent transient local effect of the R that is different from R'; the differentiated component set (α, β, γ) is the selection of potent or further potent components and their range defined by the (X, Y) and f.

[0444] In one embodiment, the present application provides a preparation, method, kit, or use for treating local lesions, wherein R is a potent active ingredient that exceeds the expected effect of conventional metformin drugs (R'), expressed as R-course dosage (Q R ) is ≤25% or 50% of the R' course of treatment dosage (Q R＇ ), the drug effect is significantly increased, including at least one of the drug adjustability indicators increased by at least 100%, and at least one of the drug efficacy indicators enhanced by at least 25%, or the local effect-toxicity ratio increased by at least 25%.

[0445] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a potent combination that exceeds the expected effect of the combination of conventional metformin drug (R') and Z (R' / Z combination), as shown by a course of treatment dose of R (Q R ) is ≤25% or 50% of the R' course of treatment dosage (Q R＇ ) and Z are not increased during the course of treatment, the drug effect is significantly increased, including at least one of the drug adjustability indicators being increased by at least 100%, and at least one of the drug efficacy indicators being enhanced by at least 25%, or the local effect-to-toxicity ratio being increased by at least 25%.

[0446] In one embodiment, the present application provides a further synergistic combination, pharmaceutical composition, preparation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further synergistic combination that exceeds the expected effect of the HSA method or Bliss method based on R monotherapy and Z monotherapy, and is expressed as a course of treatment dose of R (Q R ) does not increase the dosage of Z for one course of treatment (Q Z ) is reduced by at least 20%, while the drug effect is increased, including at least one of the drug adjustability indicators being increased by at least 10%, and at least one of the drug efficacy indicators being enhanced by at least 10%.

[0447] In one embodiment, the potent or further potent regimen of the present application is preferably suitable for tumors that require a regimen with the strongest possible dose-response, including, for example, highly aggressive tumors, advanced tumors, rapidly deteriorating tumors, and refractory tumors. If the present application regimen is not selected and the above-mentioned comparative regimen is selected, clinically, there may be many risks of increasing the drug dosage but not improving the efficacy due to misuse of the regimen (selecting a non-potent regimen when a potent regimen should be preferred), thereby losing the opportunity for treatment.

[0448] 4. Efficacy

[0449] In this application, the term "efficacy" refers to the ability to produce a significant therapeutic effect on the target disease or symptom, including, for example, timeliness, effectiveness, long-term effect, etc. The level of efficacy is affected by many factors and is highly uncertain (high efficacy, low efficacy, no efficacy, etc.). The probability of high efficacy is the lowest, which is the main technical difficulty in drug development and an important basic indicator for innovation of a solution. When the efficacy of the old solution is not expected to be high (for example, it is not fast-acting, not effective, or not lasting), if the new solution exceeds the expectation of being fast-acting, effective, or lasting, this is not only an unexpected synergy, but also provides important evidence of unique innovation in treatment mechanism or drug design.

[0450] 1) Timeliness

[0451] In this application, the term "timeliness" refers to the ability to make the target disease or symptoms show an effect (marked effect) under the action of the treatment regimen. This is an important indicator to measure the speed of the treatment effect. The timeliness expectations of the regimen include rapid effect, non-rapid effect, etc., which are highly uncertain. Tumors usually progress very quickly, and the timeliness expectations (such as anti-tumor drugs) are usually not high. The probability of rapid effect is much lower than that of non-rapid effect. This is an important purpose of regimen research, as well as a major technical difficulty and essential feature. If the new regimen exceeds the old regimen and is not expected to be rapid, this not only exceeds the expected effect, but also provides important evidence of the unique innovation in the combination mechanism.

[0452] In this application, taking the mouse test in the examples as an example, the timeliness evaluation is as follows.

[0453] (1) Timeliness index

[0454] In this application, the term "timeliness index" refers to the time to significant effect, wherein the significant effect refers to the relative tumor proliferation rate (T / C%) ≤ 42% (according to relevant NCI guidelines), and the time to significant effect is the day when significant effect is observed.

[0455] (2) Relative evaluation

[0456] (A) Conventional comparison

[0457] Comparison of single drugs: The evaluation criteria are: when the actual effective time of R single drug is at least 25% or 40% shorter than that of R' single drug, its timeliness exceeds the expectations of the prior art (R and R' are pharmaceutical equivalents) and is considered fast-acting.

[0458] Combination comparison: The evaluation criteria are: when the actual effective time of R / Z is shorter than that of R' / Z, or at least 25% or 40% shorter, its timeliness exceeds the expectations of the prior art (R / Z and R' / Z are pharmaceutical equivalents) and is considered fast-acting.

[0459] (B) Further comparison

[0460] In further comparisons, R / Z showed the fastest combined timeliness based on the expected timeliness of the individual drugs R and Z (HSA method). The evaluation criteria were: if the actual time to onset of action of R / Z was shorter than the fastest of the individual drugs R and Z, or at least 10% or 20% shorter, its timeliness further exceeded expectations and was considered to be more rapid-acting.

[0461] In this application, the terms "further rapid-acting" (regimen), "rapid-acting" (regimen), and "non-rapid-acting" (regimen) refer to (regimens) that meet the above-mentioned further rapid-acting, rapid-acting, and non-rapid-acting evaluation criteria, respectively. Drugs with strong time-effectiveness can be better combined with other treatment modalities to enhance the potential of combinations.

[0462] In one embodiment, the differentiated structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differentiated indications (X, Y) are the range (X) to which the fast-acting or further fast-acting (Y) of the R or R / Z is applicable, while the non-fast-acting of the R' or R' / Z is not applicable: patients with local lesions who need rapid effects during disease progression; the differentiated pharmacology (f) mainly includes the fast-acting or further fast-acting transient local effects of the R that distinguishes it from R'; the differentiated component set (α, β, γ) is the selection and range of the fast-acting or further fast-acting components defined by the (X, Y) and f.

[0463] In one embodiment, the present application provides a preparation, method, kit, or use for treating local lesions, wherein R is a fast-acting active ingredient that exceeds the expected effect of conventional metformin drugs (R'), expressed as R-course dosage (Q R ) is ≤25% or 50% of the R' course of treatment dosage (Q R＇ ), the drug effect is significantly increased, including a significant improvement in drug time-efficiency indicators, as shown by the time to significant effect in mouse experiments (the day when the tumor proliferation rate is less than 42%) being at least 25% lower than that of the R'.

[0464] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a fast-acting combination that exceeds the expected effect of the combination of conventional metformin drugs (R') and Z (R' / Z combination), and is expressed as a dose of R for one course of treatment (Q R ) is ≤25% or 50% of the R' course of treatment dosage (Q R＇ ) and Z did not increase the course of treatment, the drug effect was significantly increased, including a significant improvement in the drug time-effect index, which was manifested in that the time to significant effect in mouse experiments (the day when the tumor proliferation rate was <42%) was at least 25% lower than that of the R' / Z.

[0465] In one embodiment, the present application provides a further reduced-dose and synergistic combination, pharmaceutical composition, preparation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further reduced-dose and fast-acting combination that exceeds the expected effect of the HSA method or Bliss method based on R monotherapy and Z monotherapy, and is expressed as R-treatment dose (Q R ) does not increase the dosage of Z for one course of treatment (Q Z ) was reduced by at least 20%, the drug effect was significantly increased, including a significant improvement in the drug time-effect index, which was manifested in that the effective time in the mouse test (the day when the tumor proliferation rate was <42%) was reduced by at least 25% compared with the R'.

[0466] In one embodiment, the reduced-dose, fast-acting regimen of this application is preferably suitable for treating tumors that require the strongest possible dose-response and fastest possible rapidity, including, for example, highly aggressive tumors, advanced tumors, rapidly deteriorating tumors, refractory tumors, and tumors with urgent symptoms requiring rapid unloading. Choosing a conventional metformin regimen instead of the potent, fast-acting regimen of this application can lead to numerous clinical risks, such as increased drug dosage with lower efficacy and prolonged onset of effect, resulting in lost therapeutic opportunities due to misuse of the regimen.

[0467] 2) Effectiveness

[0468] In this application, the term "effectiveness" refers to the ability to suppress the target disease or symptoms. The expected effectiveness of a regimen can range from highly effective, to slightly effective (effective but not yet highly effective), to ineffective (ineffective but with some efficacy), and to uneffective (ineffective with no reasonable efficacy), thus exhibiting a high degree of uncertainty. Effectiveness expectations are generally low. For example, among anti-cancer drugs, first-line treatments are generally expected to be highly effective, while second-line treatments are often expected to be slightly effective. Furthermore, drugs that are still useful beyond first- and second-line treatments are rarely effective (e.g., adjuvant therapy), and most drugs are actually uneffective. Therefore, the probability of highly effective is far less than that of ineffective, which in turn is far less than that of ineffective. Improving effectiveness is a key objective of regimen research, as well as a major technical difficulty and essential characteristic. If a new regimen exceeds the expected effectiveness of an old one, this not only demonstrates unexpected efficacy but also provides important evidence of unique innovation in therapeutic mechanism or drug design.

[0469] In this application, taking the mouse test in the embodiment as an example, the effectiveness evaluation is as follows.

[0470] (1) Calculation of effectiveness index

[0471] In this application, the term "effectiveness index" refers to the tumor inhibition rate or objective response rate. When there is a negative control group, the effectiveness index is the tumor inhibition rate and tumor weight; when there is no negative control group, the effectiveness index is the objective response rate (ORR). The latter divides the efficacy of the study group into the following 4 levels (RECIST guidelines) for observation: the disappearance of the target lesion is a complete response (CR); a 30% reduction in the target lesion volume is a partial response (PR); an increase of 20% or more in the target lesion volume is progressive disease (PD); and a change in the target lesion volume between PR and PD is stable disease (SE). ORR is the sum of CR and PR within a predetermined minimum time (e.g., N days after discontinuation of the drug).

[0472] (2) General evaluation

[0473] When a negative control group is present, the efficacy evaluation criteria for the study group (as per the CFDA's "Guidelines for the Pharmacodynamics of Antitumor Drugs") are: Effectiveness is determined when the tumor inhibition rate is ≥40% and the difference in tumor weight compared to the negative control group is statistically analyzed with a P < 0.05; otherwise, it is considered ineffective. When a negative control group is not present, the commonly used efficacy evaluation criteria are: Effectiveness is determined when the ORR is ≥60%; otherwise, it is considered ineffective.

[0474] For the ineffective study group, the evaluation criteria are: when the tumor inhibition rate is greater than 25% or the objective response rate is greater than 40%, it is considered ineffective; otherwise, it is considered to have no (effectiveness) expectations.

[0475] (3) Relative evaluation

[0476] (A) Conventional comparison

[0477] Comparison of single drugs: The evaluation criteria are: when the actual tumor inhibition rate or objective response rate of R single drug is at least 25% or 50% higher than that of R' single drug, its effectiveness exceeds the expectations of the existing technology (R and R' are pharmaceutical equivalents) and is considered highly effective.

[0478] Combination comparison: The evaluation criteria are: when the actual tumor inhibition rate or objective response rate of R / Z is at least 10%, 20%, or 40% higher than that of R' / Z, its effectiveness exceeds the expectations of the prior art (R / Z and R' / Z are pharmaceutical equivalents) and is considered highly effective.

[0479] (B) Further comparison

[0480] In further comparisons, R / Z achieved the highest shared efficacy based on the expected efficacy of R and Z alone (HSA method). The evaluation criteria are: when R / Z is highly effective and its actual tumor inhibition rate or objective response rate is at least 10% or 20% higher than the highest of R and Z alone, its efficacy exceeding expectations is considered further highly effective.

[0481] In this application, the terms "further efficient" (scheme), "efficient" (scheme), "ineffective" (scheme), "ineffective and useful" (scheme), and "no hope" (scheme) respectively refer to (schemes) that meet the above further efficient, efficient, ineffective, ineffective and useful, and no hope evaluation criteria.

[0482] In this application, the term "refractory tumor" refers to a tumor that is not effectively treated by a certain regimen, such as a cell-responsive drug or conventional metformin, including tumors in patients with contraindications or inappropriate for the regimen and tumors that are not effectively treated.

[0483] In this application, the term "off-indication tumor" refers to a tumor that is not within the scope of a certain regimen, such as cell-responsive drugs or conventional metformin drugs, for example, a tumor that is not included in the first-line or second-line treatment drugs published by an authoritative agency, including ineffective and useful tumors and hopeless tumors. Ineffective and useful tumors include, for example, tumors with unfavorable microenvironments, and hopeless tumors include, for example, drug-resistant tumors and drug-stopping tumors.

[0484] In this application, the term "drug-resistant tumor" refers to a tumor containing drug-resistant cells or tissues (e.g., tumor tissues derived from patients resistant to clinical anti-tumor drugs or targeted drugs) that are resistant to specific anti-tumor drugs. Drug-resistant tumors are usually also insensitive to a variety of other anti-tumor drugs and thus become ineffective, thus becoming refractory tumors.

[0485] In this application, the term "microenvironmentally unfavorable tumor" refers to a tumor containing a microenvironment that is unfavorable for the action of anti-tumor drugs, such as a tumor formed by a mixture of tumor cells and fibroblasts in animal experiments, or a tumor derived from clinical tissue with a high stromal ratio (such as pancreatic cancer tissue). It is well known that this type of microenvironment significantly reduces the sensitivity of tumor cells therein to conventional anti-tumor drugs, thereby becoming a refractory tumor.

[0486] In this application, the term "drug-discontinued tumor" refers to a tumor that has stopped taking an anti-tumor drug for any reason. There are many reasons for discontinuing tumor medication, including the patient's physical condition is no longer suitable and the drug treatment fails, and failure includes drug desensitization for any reason. There are many mechanisms of this desensitization, which have not been fully revealed by existing research. It involves the cellular level (such as cell drug resistance) and the tissue level (such as it becomes more difficult to penetrate into the tissue), thus becoming a refractory tumor.

[0487] In one embodiment, the differentiated structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differentiated indications (X, Y) are the range (X) to which the highly effective or further highly effective (Y) of the R or R / Z is applicable, while the ineffective, ineffective and useful, or undesirable inapplicability of the R' or R' / Z is inapplicable: patients with localized lesions requiring highly effective or further highly effective treatment; the differentiated pharmacology (f) mainly includes the highly effective or further highly effective transient local effect of the R that is different from R'; the differentiated component set (α, β, γ) is the selection of highly effective or further highly effective components and their ranges defined by the (X, Y) and f, wherein X includes cell-responsive drugs or conventional metformin-refractory tumors.

[0488] In one embodiment, the present application provides a preparation, method, kit, or use for treating local lesions, wherein R is a reduced-dose, high-efficiency active ingredient that exceeds the expected effect of conventional metformin drugs (R'), expressed as a R-course dosage (Q R ) is ≤25%-50% of the R' course of treatment dosage (Q R＇ ), the drug effect is significantly increased, including a significant improvement in drug effectiveness indicators, as shown by a tumor inhibition rate or objective response rate in mouse experiments that is at least 25%-50% higher than the R'.

[0489] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a reduced-dose, high-efficiency combination that exceeds the expected effect of the combination of conventional metformin drugs (R') and Z (R' / Z combination), as shown by the R-course dosage (Q R ) is ≤25%-50% of the R' course of treatment dosage (Q R＇) and Z do not increase in the course of treatment, the drug effect is significantly increased, including a significant improvement in drug effectiveness indicators, as manifested in a tumor inhibition rate or objective response rate in mouse experiments that is at least 10%, 20%, 30% or 40% higher than that of the R' / Z.

[0490] In one embodiment, the present application provides a further reduced-dose and synergistic combination, pharmaceutical composition, preparation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further reduced-dose and fast-acting combination that exceeds the expected effect of the HSA method or Bliss method based on R monotherapy and Z monotherapy, and is expressed as R-treatment dose (Q R ) does not increase the dosage of Z for one course of treatment (Q Z ) is reduced by at least 20%, the drug effect is significantly increased, including the improvement of drug effectiveness indicators, which is manifested in that the tumor inhibition rate or objective response rate in mouse experiments is at least 10%-20% higher than the highest of the single drugs.

[0491] In one embodiment, the reduced-dose, high-efficiency regimen described herein is preferably suitable for treating tumors that require the strongest possible dose-response and highest possible efficacy, including, for example, highly aggressive tumors, advanced tumors, rapidly deteriorating tumors, drug-resistant tumors, tumors with unfavorable microenvironments, and tumors that have stopped taking medication. Choosing a conventional metformin regimen instead of the reduced-dose, high-efficiency regimen described herein can lead to clinical risks of increasing the drug dosage but achieving lower efficacy due to misuse of the regimen, thereby losing therapeutic opportunities.

[0492] 3). Long-term effect

[0493] In this application, the term "long-term effect" refers to the ability to achieve lasting suppression of the target disease or symptoms or to obtain lasting benefits to the patient. The expected long-term effect of the regimen can be long-term, non-long-term, etc., which is highly uncertain. Tumor growth is usually difficult to control, and the duration of drug efficacy (such as anti-tumor drugs) is mostly not long. The probability of long-term effect is much lower than that of non-long-term effect. This is an important purpose of regimen research, as well as a major technical difficulty and essential feature. If the new regimen exceeds the old regimen and is not expected to be long-term, this is not only an unexpected synergistic effect, but also provides important evidence of unique innovation in treatment mechanism or drug design.

[0494] In this application, taking the mouse test in the examples as an example, the long-term effect evaluation is as follows.

[0495] (1) Calculation of long-term effectiveness indicators

[0496] In this application, the term "long-term effect index" refers to the progression-free time or long-term survival rate (abbreviated as survival rate), where the progression-free time is the number of days from the first day of administration to the day when progression is observed, wherein the progression is evaluated by the relative tumor volume (RTV), and when RTV>150% and then increases continuously until the end point, it is considered as progression; the survival rate is the ratio of the number of survivors observed in the study group at the time when most of the deaths in the negative control group (e.g., day 30) to the number of enrolled patients, wherein according to this convention, the tumor volume>2000mm 3 Those who died were counted as deaths.

[0497] (2) Relative evaluation

[0498] Single-agent comparison: In the prior art, R and R' are considered pharmaceutically equivalent and are expected to have the same long-term efficacy. The evaluation criteria are: if the actual progression-free time or survival rate of R alone is at least 20%-40% higher than that of R' alone, its long-term efficacy exceeds the prior art expectation.

[0499] Combination comparison: As mentioned above, the long-term efficacy of R / Z, as predicted by existing technologies, is consistent with that of R' / Z. The evaluation criteria are: if the actual progression-free time or survival rate of R / Z is at least 20%-40% higher than that of R' / Z, its long-term efficacy is considered to exceed existing technology expectations.

[0500] (B) Further comparison

[0501] In further comparisons, R / Z demonstrated the highest combined longevity, based on the expected longevity of single-agent R and Z (HSA method). The evaluation criteria were: if the actual progression-free time or survival rate of R / Z exceeded the highest of the single-agent R and Z by at least 10%-20%, its longevity exceeded expectations and was considered further long-lasting.

[0502] In this application, the terms "further long-term" (regimen), "long-term" (regimen), and "non-long-term" (regimen) refer to (regimens) that meet the above further long-term, long-term, and non-long-term evaluation criteria, respectively.

[0503] In one embodiment, the differentiated structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differentiated indications (X, Y) are the range (X) to which the long-acting or further long-acting (Y) of the R or R / Z is applicable, and the non-long-acting of the R' or R' / Z is not applicable: patients with local lesions who need to prolong the therapeutic effect; the differentiated pharmacology (f) mainly includes the long-acting or further long-acting transient local effect of the R that is different from R'; the differentiated component set (α, β, γ) is the selection and range of the long-acting or further long-acting component defined by the (X, Y) and f.

[0504] In one embodiment, the present application provides a preparation, method, kit, or use for treating local lesions, wherein R is a long-acting active ingredient with a reduced dosage that exceeds the expected effect of conventional metformin drugs (R'), which is expressed as a dose of R for a course of treatment (Q R ) is ≤R' for one course of treatment (Q R＇ ) is 25%-50%, the drug effect is significantly increased, including a significant improvement in the long-term efficacy of the drug, which is manifested in that the progression-free time or survival rate in mouse experiments is at least 20%-40% higher than that of the R'.

[0505] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a reduced-dose, high-efficiency combination that exceeds the expected effect of the combination of conventional metformin drugs (R') and Z (R' / Z combination), as shown by the R-course dosage (Q R ) is ≤25%-50% of the R' course of treatment dosage (Q R＇ ) and Z do not increase the course of treatment, the drug effect is significantly increased, including a significant improvement in the long-term efficacy of the drug, as shown by a progression-free time or survival rate in mouse experiments that is at least 20%-40% higher than that of the R' / Z.

[0506] In one embodiment, the present application provides a further reduced-dose and synergistic combination, pharmaceutical composition, preparation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further reduced-dose and fast-acting combination that exceeds the expected effect of the HSA method or Bliss method based on R monotherapy and Z monotherapy, and is expressed as R-treatment dose (Q R ) does not increase the dosage of Z for one course of treatment (Q Z ) is reduced by at least 20%, the drug effect is significantly increased, including the improvement of the long-term effect of the drug, which is manifested in that the progression-free time or survival rate in mouse experiments is increased by at least 10%-20% compared with the highest of the single drugs.

[0507] In one embodiment, the reduced-dose, long-acting regimen of the present application is preferably suitable for treating tumors that require a regimen that is as strong and effective as possible and as long-lasting as possible, including, for example, highly aggressive tumors, advanced tumors, rapidly deteriorating tumors, drug-resistant tumors, tumors with unfavorable microenvironments, and tumors that have stopped taking medication. Choosing a conventional metformin regimen instead of the potent, long-acting regimen of the present application can lead to clinical risks such as increased drug dosage without improved efficacy, a shorter progression-free time, and a loss of treatment opportunities due to misuse of the regimen.

[0508] 4). Local efficacy-toxicity ratio

[0509] In this application, the term "local efficacy-toxicity ratio" (abbreviated as efficacy-toxicity ratio) refers to the balance between the therapeutic effect (local efficacy) and the toxicity (local toxicity) of a drug when it is administered topically. It is generally believed that the desired local efficacy produced by classical chemical ablative agents (such as anhydrous ethanol) is consistent with its local toxicity. Improving the efficacy-toxicity ratio to break this consistent expectation is an important purpose of the research scheme, as well as a major technical difficulty and essential feature. If the new scheme exceeds the efficacy-toxicity ratio expectation of the old scheme, it is not only an unexpected synergistic effect, but also provides important evidence of unique innovation in therapeutic mechanism or drug design.

[0510] In this application, taking the mouse test in the embodiment as an example, the study of the efficacy-toxicity ratio was mainly carried out under the condition of Z=C, and the evaluation was as follows.

[0511] (1) Efficacy-toxicity ratio

[0512] In this application, the term "efficacy-to-toxicity ratio" refers to the ratio (X / Y) of the desired therapeutic effect (X, selected from efficacy, e.g., >40% tumor inhibition rate) to the local tissue irritation response (Y, local irritation score) after topical application of equal amounts of a drug. When local administration of a drug produces neither a significant therapeutic effect (e.g., tumor inhibition rate <20%) nor significant local irritation (e.g., score <1.0), the efficacy-to-toxicity ratio is considered to be close to zero in this application.

[0513] (2) Relative evaluation

[0514] (A) Conventional comparison

[0515] The evaluation criteria are: when the dosage of at least one component in R / C is reduced by 50% compared with the corresponding dosage of R' / C, and its efficacy-toxicity ratio index (such as X / Y) is increased by at least 0.5 times, it is considered that the efficacy-toxicity ratio of R / C exceeds the expectations of the existing technology (R / C and R' / C are pharmaceutical equivalents) and is a "high efficacy-toxicity ratio".

[0516] (B) Further comparison

[0517] In a further comparison, the expected value of the efficacy-toxicity ratio (q2) was calculated based on the HSA method for single drugs R and C. The evaluation standard is: when the ratio of the actual efficacy-toxicity index (q1) of R / C to the expected index (q2) (q = q1 / q2) is greater than 1, it is considered to be a further high efficacy-toxicity ratio that exceeds expectations.

[0518] In one embodiment, the differential structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differential indications (X, Y) are the range (X) to which the high efficiency-toxicity ratio or further high efficiency-toxicity ratio (Y) of the R or R / C is applicable, while the R' or R' / C is not applicable due to ineffectiveness: patients with local lesions who are intolerant to local irritation; the differential pharmacology (f) mainly includes the high efficiency-toxicity ratio or further high efficiency-toxicity ratio transient local effect of the R that is different from R'; the differential component element set (α, β, γ) is the selection and range of the high efficiency-toxicity ratio or further high efficiency-toxicity ratio component defined by the (X, Y) and f.

[0519] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating local lesions, wherein the combination of R and C is a high-efficiency-toxicity combination that exceeds the expected effect of the combination of R' and C, as shown by the actual efficacy-toxicity index (q1) of R / C exceeding the expected index (q2) based on the equivalence of R and R'.

[0520] In one embodiment, the present application provides a further dose-reducing and synergistic combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and C is a further synergistic combination that exceeds the expectations based on the HSA method of R alone and C alone, as manifested by the actual efficacy-toxicity ratio index (q1) of the combination exceeding the expected index (q2) based on single drugs R and C.

[0521] In one embodiment, the high-efficiency-toxicity ratio scheme or further high-efficiency-toxicity ratio scheme of the present application is preferably applicable to patients or tumors or tumor sites that require a scheme with a high efficacy-toxicity ratio as much as possible for treatment, including, for example, highly invasive tumors, late-stage tumors, rapidly deteriorating tumors, refractory tumors, or sites where the tumor is prone to leaking liquid. If the present application scheme is not selected and the above-mentioned comparative scheme is selected, clinically, there may be many risks of normal tissue damage due to misuse of the scheme (the opposite of the high efficacy-toxicity ratio that should be preferred is selected).

[0522] 4. Heterogeneous adaptability

[0523] In this application, the term "heterogeneous adaptability" refers to the ability of a regimen to exhibit convergent therapeutic effects (such as rapid-acting, long-lasting, and highly effective) in heterogeneous areas (such as different tissues or lesions) of a target disease or symptom. The term "adjustability" refers to the ability of a regimen to adjust its therapeutic effects or administration parameters based on dynamic changes in the disease state (including the heterogeneity) or changes in external conditions. The heterogeneous adaptability or adjustability of a regimen is expected to be highly adaptable / highly adjustable, generally adaptable / adjustable, unadaptable / unadjustable, etc., and is highly uncertain.

[0524] One of the basic characteristics of malignant tumors is high heterogeneity, and conventional anti-tumor regimens, including conventional metformin regimens, usually have problems with heterogeneous adaptability. For tumor administration regimens (such as anhydrous ethanol regimens), there are also usually problems with heterogeneous adaptability, and it is difficult to administer drugs according to their quality. Heterogeneity includes tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. In short, improving heterogeneous adaptability or adjustability is an important goal of research on anti-tumor drug technical solutions, as well as a major technical difficulty and an essential feature. If the new regimen exceeds the adjustability expectations of the old regimen, this will not only exceed expectations in terms of efficacy, but can also be adjusted and optimized under different conditions to adapt to the flexibility and diversity required for clinical individualized treatment, and also provide important evidence of unique innovation in treatment mechanism or drug design.

[0525] In this application, taking the mouse experiment in the embodiment as an example, the heterogeneous adaptability / adjustability is evaluated as follows.

[0526] 1) Calculate heterogeneous adaptability / adjustability indicators

[0527] In this application, the term "heterogeneous adaptability index" or "adjustability index" refers to the difference in the therapeutic effect of the regimen in different tissues or lesions (different tumors, different lesions, etc.), or the adjustable coefficient of the local administration parameter to achieve the same target therapeutic effect in the same tissue or lesion. These coefficients are the ratio of the highest value in the adjustable range to its threshold value, including the local administration concentration adjustable coefficient (abbreviated as concentration adjustable coefficient, for example, c R The highest value / threshold of the target volume), the local application target volume adjustment coefficient (abbreviated as target volume adjustment coefficient, v 靶 The maximum value / threshold of the local application volume ratio adjustable coefficient (abbreviated as volume ratio adjustable coefficient, for example, v R / v 靶 The maximum value / threshold of the local application single dosage adjustable coefficient (referred to as the single dosage adjustable coefficient, for example, c R ×v R The maximum value / threshold of the local application point density adjustment coefficient (referred to as the application point density adjustment coefficient, for example, n i / v 靶 maximum value / threshold of ), etc.

[0528] 2) Relative evaluation

[0529] (1) Conventional comparison

[0530] Single-drug comparison: The evaluation criteria are: when R' is effective as a single agent across different tissues or lesions, or when the actual value of any of the aforementioned adjustable coefficients for R' is at least 100% or 300% higher than that for R' alone, its heterogeneous adaptability or adjustability exceeds prior art expectations (R and R' are pharmaceutically equivalent), and is considered highly adjustable. According to prior art teachings, the therapeutic efficacy of R' alone across different tissues or lesions (different tumors, different lesions, etc.) varies widely (only in rare tumors). Even for those rare tumors where it is effective, R''s efficacy is dose-dependent rather than dependent on local administration parameters, and its local adjustable coefficient is low.

[0531] Combination comparison: The evaluation criteria are: when R / Z is effective for different tissues or lesions, or the actual value of any of the above adjustable coefficients of R / Z is at least 100% or 300% higher than that of R' / Z, its heterogeneous adaptability or adjustability exceeds the expectations of the prior art (R / Z and R' / Z are pharmaceutical equivalents) and is highly adjustable; otherwise, it is not highly adjustable.

[0532] (2) Further comparison

[0533] In further comparison, the shared adjustability of R / Z, based on the expected adjustability of the individual drugs R and Z (HSA method), was the highest. The evaluation criteria are: when the actual value of any of the above adjustability coefficients of R / Z is at least 20% higher than the highest of the individual drugs R and Z, its adjustability further exceeds expectations and is further highly adjustable.

[0534] In this application, the terms "further highly adjustable" (regimen), "highly adjustable" (regimen), and "non-highly adjustable" (regimen) respectively refer to (regimens) that meet the above further highly adjustable, highly adjustable, and non-highly adjustable evaluation criteria, which respectively provide further highly heterogeneous equivalence, highly heterogeneous equivalence, and non-highly heterogeneous equivalence drug effects.

[0535] In one embodiment, the differentiated structure-activity relationship of the present application scheme can be simply expressed as f: (α, β, γ) → (X, Y), wherein the differentiated indications (X, Y) are the range (X) to which the highly adjustable or further highly adjustable (Y) of R or R / Z is applicable, while the non-highly adjustable of R' or R' / Z is not applicable: patients with localized lesions who require heterogeneous adaptability and adjustability of drugs to optimize treatment regimens; the differentiated pharmacology (f) mainly includes the highly adjustable or further highly adjustable transient local effects of R that are different from R'; the differentiated component set (α, β, γ) is the selection of highly adjustable or further highly adjustable components and their ranges defined by (X, Y) and f.

[0536] In one embodiment, the present application provides a preparation, method, kit, or use for treating local lesions, wherein R is an active ingredient that exceeds the expected effect of conventional metformin drugs (R'), which is expressed as R-course dosage (Q R ) is ≤R' for one course of treatment (Q R＇ ) is 25%-50%, the drug effect is significantly increased, including at least one drug adjustability index is significantly improved, which is manifested in that at least one of the following adjustable coefficients is increased by more than 100% in mouse experiments: concentration adjustable coefficient, target volume adjustable coefficient, volume ratio adjustable coefficient, sub-dose adjustable coefficient, and application point density adjustable coefficient.

[0537] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a dose-reducing and synergistic combination that exceeds the expected effect of the combination of conventional metformin drugs (R') and Z (R' / Z combination), and is expressed as a dose of R for one course of treatment (Q R ) is ≤25%-50% of the R' course of treatment dosage (Q R＇ ) and Z did not increase the course dosage, the drug effect was significantly increased, including at least one drug adjustability index was significantly improved, which was manifested in that at least one of the following adjustable coefficients was increased by more than 100% in the mouse experiment: concentration adjustable coefficient, target volume adjustable coefficient, volume ratio adjustable coefficient, sub-dose adjustable coefficient, and application point density adjustable coefficient.

[0538] In one embodiment, the present application provides a further dose-reducing and synergistic combination, pharmaceutical composition, preparation, method, kit, or use for treating solid tumors, wherein the combination of R and Z (R / Z combination) is a further dose-reducing and synergistic combination that exceeds the expected effect of the HSA method or Bliss method based on R monotherapy and Z monotherapy, and is expressed as R one course of treatment (Q R ) does not increase the dosage of Z for one course of treatment (Q Z ) is reduced by at least 20%, the drug effect is significantly increased, including a significant improvement in at least one drug adjustability index, which is manifested in that in mouse experiments, at least one of the following adjustable coefficients is increased by at least 10%-20% compared with the highest of the single drug: concentration adjustable coefficient, target volume adjustable coefficient, volume ratio adjustable coefficient, sub-dose adjustable coefficient, and application point density adjustable coefficient.

[0539] In one embodiment, the local application concentration of R is adjustable by a coefficient (c RThe highest value / threshold of R is >10, 50, 100, or 150, which allows the R to provide highly variable concentrations to different regions while still maintaining its activity stable, including, for example, genomic administration of heterogeneous tumors.

[0540] In one embodiment, the local administration target volume of R is adjustable by a factor (v 靶 The highest value / threshold of is>2, 10, 50, or 100, which allows the R to select different v 靶 The drug can be administered based on the specific treatment situation, including, for example, heterogeneous tumors.

[0541] In one embodiment, the local application volume ratio of R is adjustable coefficient (v R / v 靶 The highest value / threshold of R is >5, 10, or 100, which allows the R to provide highly variable volume ratios to different regions while still keeping its activity stable, including, for example, genomic administration of heterogeneous tumors.

[0542] In one embodiment, the local application single dose of R can be adjusted by a coefficient (c Ri ×v Ri The highest value / threshold of R is >2, 6, or 10, which allows the selection of different single doses of R to be used for different treatment situations, including, for example, heterogeneous tumors; and

[0543] In one embodiment, the local application point density of R is adjustable by a factor (n ii / v 靶 The highest value / threshold of R is >3, 10, 50, or 100, which allows the R to provide highly variable densities to different regions while still keeping its activity stable, including, for example, phenotypic drug delivery to heterogeneous tumors.

[0544] In this application, the term "microvolume" or "microamount" (protocol) refers to a topical administration volume ratio in which the volume ratio is highly adjustable (protocol). 施用 / v 靶 The term "high density" (scheme) refers to a scheme in which the density of the local application point is highly adjustable (scheme). ii / V 靶 per cm 3 ≧1 or 2 points of the solution, otherwise it is "constant density" (solution).

[0545] In one embodiment, the present application provides a formulation, method, kit, or use for treating solid tumors, which is a highly adjustable volume regimen for local administration, including v 施用 / v靶 The microvolume is 0.02-0.056, or 0.02-0.10. It is suitable for intratumoral differential administration or administration based on quality, including administration based on shape (shape heterogeneity), administration based on tissue (tissue heterogeneity), or administration based on safety risk (safety risk heterogeneity).

[0546] In one embodiment, the present application provides a combination, pharmaceutical composition, formulation, method, kit, or use for treating solid tumors, which is a highly adjustable local administration point density regimen, including n ii / V 靶 per cm 3 High-density administration of ≥1 point. It is suitable for differentiated administration within the tumor or administration based on quality, including administration based on shape (shape heterogeneity), administration based on tissue (tissue heterogeneity), or administration based on safety risk (safety risk heterogeneity).

[0547] In one embodiment, for lesions of larger size (e.g., long diameter > 2 cm), especially large size (e.g., long diameter > 3 cm), the height adjustment includes multi-point administration due to tissue heterogeneity, multi-point administration due to morphological heterogeneity, or / and multi-point administration due to safety risk heterogeneity, wherein the multi-point refers to the number of administration points being >3, >5, or 10-200, and at least one of the points is a micro-volume administration.

[0548] In one embodiment, the highly adjustable level includes low concentration (R administration concentration≦3%) or / and micro volume (R administration volume≦250 μl) administration close to the edge of the lesion.

[0549] In one embodiment, the highly adjustable level includes high concentration (R administration concentration ≧ 10%) or / and large volume (R administration volume ≧ 1000 μl) administration close to the center of the lesion.

[0550] In one embodiment, the dosage-reducing, efficacy-enhancing regimen of this application is preferably suitable for treating heterogeneous tumors that require the strongest possible dosage-response and the highest possible adjustability, including, for example, highly aggressive tumors, advanced tumors, rapidly deteriorating tumors, drug-resistant tumors, tumors with unfavorable microenvironments, and tumors that have stopped taking medication. Choosing a conventional metformin regimen instead of the potent, long-acting regimen of this application can lead to clinical risks, such as increased drug dosage without improved efficacy due to misuse of the regimen, and low adjustability due to medication quality, thus losing therapeutic opportunities.

[0551] Other terms used herein are intended to be defined by their commonly understood meanings in the art.

[0552] 5) In this application, the term "lesion" refers to a local abnormality in the structure or function of the body, usually comprising diseased tissue, which in turn comprises cells. A lesion is a local manifestation of a disease.

[0553] In this application, the term "intervention" is distinguished from conventional injection and refers to the administration (dosage) method of delivering therapeutic substances to the local lesion through a specific administration device (such as a puncture needle, injection needle, catheter, or others) or other media (such as natural body orifices, minimally invasive incisions), including vascular intervention (such as transvascular perfusion) and non-vascular intervention (such as percutaneous injection).

[0554] The term "conventional injection" refers to an administration method that does not exclude, is even mainly, or preferably absorption injection; the term "absorption injection" refers to an injection method that allows the drug to be absorbed by the blood after entering the body, including, for example, intravenous injection, intramuscular injection, intraperitoneal injection, etc.

[0555] The term "routine injection safety" refers to one of the quality standards of routine injection, that is, no local side effects (such as local irritation, local tissue damage, etc.) are produced during routine injection. Therefore, it must have, for example, isotonicity, isotonicity, and isoacidity (pH 4.5-9.0).

[0556] In the present application, the term "exclusive" means that it cannot be used, or is even strictly prohibited from being used, outside of the designated purpose. For example, interventional-only means that it is limited to intervention and is excluded from use for absorption injection.

[0557] In the present application, the term "drug solution" refers to an aqueous solution of a drug that can be injected into the human body and produce therapeutic effects, comprising an active ingredient and an aqueous solvent.

[0558] The term "composition" (or structure, abbreviated as "structure") refers to the components that are necessary to provide a specific function ("effect") but cannot be selected according to common knowledge, including, for example, active ingredients, their adjuvants, and their intervention concentrations that must be limited.

[0559] The term "concentration" refers to the concentration of a specified component in a solution in terms of weight percent (Wcomponent / Wsolution, %) or molar concentration by weight (Wcomponent / Mcomponent / 1 liter).

[0560] The term "intervention concentration" refers to the concentration of a specified component in the drug solution at the time of intervention (eg, at the orifice of an injection needle or the outlet of an infusion tube).

[0561] In this application, the term "prior art" (or "conventional" (e.g., drug, injection, injection, dosage form, method, use, or reaction) refers to the prior art (e.g., drug, injection, injection, dosage form, method, use, or reaction) according to the existing predicted scope.

[0562] In the present application, the term "transient active ingredient" is distinguished from "persistent active ingredient". The former and the latter refer to active ingredients that provide transient effects and sustained effects, respectively. The former is exemplified by chemical ablative agents, and the latter is exemplified by conventional anti-tumor drugs (including anti-tumor drugs); the term "transient effect" is distinguished from "sustained effect". The former and the latter refer to the effects provided by the active ingredient maintaining a specific concentration briefly once and continuously for a longer period of time, respectively. The required duration of action is shorter and longer, respectively. They are respectively unrelated to and closely related to drug metabolic dynamics (such as half-life), and they are respectively faster-appearing and later-appearing drug effects. The former is exemplified by chemical ablation, and the latter is exemplified by conventional effects (including cytotoxic effects).

[0563] Within the scope of the present invention, the term "tumor" refers to a pathological disease with a tumor as a pathological symptom, which can be due to any pathology (malignant and non-malignant) and at any stage, including, for example, the following groups classified according to tumor cell type: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, embryonic cell tumors; and tumors named according to the organs or tissues where the tumor cells are concentrated, including, for example, tumors named according to the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testicle, ovary or uterus.

[0564] Specifically, the malignant tumors include, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, sarcoma, etc.

[0565] The non-malignant tumors include, for example, breast tumors, pancreatic tumors, thyroid tumors, prostate tumors, liver tumors, lung tumors, intestinal tumors, oral tumors, esophageal tumors, gastric tumors, nasopharyngeal tumors, laryngeal tumors, testicular tumors, vaginal tumors, uterine tumors, fallopian tube tumors, ovarian tumors, etc.

[0566] The drug of the present application is a therapeutic drug. When it is used as the main therapeutic drug for the treatment of solid tumor diseases, it can also be used in combination with other interventional therapies, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or a combination of such therapies to further improve the efficacy.

[0567] According to one aspect of the present invention, the present invention provides a metformin (R) monotherapy product (R monotherapy regimen 1), specifically a formulation (referred to herein as "the R monotherapy formulation of the present application"), comprising N,N-dimethylbiguanide and optionally a solvent, the formulation not comprising an acidic pH regulator required to meet the safety requirements for cell culture or conventional injection, the formulation containing N,N-dimethylbiguanide at a concentration ≧ its intervention or administration concentration, the intervention or administration concentration (w / w) being 0.5% ≦ C ≦ 51%, preferably 1%-50%, more preferably 3%-50%, 5%-50%, or 5%-30%.

[0568] The R single-drug product (R single-drug solution 2) provided by the present invention is specifically used for lesion intervention, including a metformin solution (referred to as "the R single-drug solution of the present application" in this application), which can be an aqueous solution of N,N-dimethylbiguanide, wherein the aqueous solution does not contain an acidic pH regulator required to meet the safety of cell culture or conventional injection, and the concentration of the N,N-dimethylbiguanide solution {[W metformin / (W metformin + W solvent)] %} is ≧ its intervention concentration, wherein the intervention concentration is 0.5% ≦ C ≦ the maximum solubility concentration (or saturation concentration) of N,N-dimethylbiguanide.

[0569] The present invention provides a metformin monotherapy drug (R monotherapy regimen 3) specifically for lesion intervention (referred to herein as "R monotherapy drug of the present application"), which is an aqueous solution of N,N-dimethylbiguanide, wherein the aqueous solution does not contain an acidic pH regulator required to meet the safety requirements of cell culture or conventional injection, and the N,N-dimethylbiguanide monotherapy solution concentration {[W metformin / (W metformin + W solvent)] %} is ≧ its intervention concentration, wherein the intervention concentration is 0.5% ≦ C ≦ the maximum solubility concentration of N,N-dimethylbiguanide. In fact, the R monotherapy drug of the present application is a drug whose intervention form is the R monotherapy solution of the present application.

[0570] The present invention provides a metformin R mono-drug dosage form (R mono-drug regimen 4) specifically for lesion intervention (referred to herein as the "R mono-drug dosage form of the present application"), which is an aqueous solution of N,N-dimethylbiguanide, wherein the aqueous solution does not contain an acidic pH regulator required to meet the safety requirements of cell culture or conventional injection, and the R mono-drug liquid concentration of the N,N-dimethylbiguanide {[W metformin / (W metformin + W solvent)] %} is ≥ its intervention concentration, wherein the intervention concentration is 0.5% ≤ C ≤ N,N-dimethylbiguanide maximum solubility concentration (saturation concentration). In fact, the R mono-drug dosage form of the present application is a dosage form that facilitates the intervention of the R drug of the present application with the drug solution of the present application into lesions.

[0571] In the preparations, solutions, drugs, and / or drug dosage forms described above, the intervention concentration (w / w) is 0.5% ≤ C ≤ 51%, preferably, 1%-50%, more preferably 3%-50%, 3%-40%, 5%-50%, 5%-35% or 5%-30%.

[0572] The formulations, solutions, drugs, and dosage forms described above are used for interventional treatment of lesions, such as tumors or nodules, in a subject.

[0573] In the preparation as described above, the preparation comprises a solvent. Preferably, the solvent is water, more preferably water for injection.

[0574] In the above-mentioned preparation, pharmaceutical solution, medicine, or pharmaceutical dosage form, it does not include a salt of N,N-dimethylbiguanide.

[0575] In the preparations, solutions, drugs, and / or drug dosage forms described above, the administration or intervention concentration (w / w) of metformin is ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, ≦10%, ≦5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0576] In the preparations, solutions, drugs, and / or dosage forms described above, metformin (R) is administered or administered at a concentration (w / w) of 0.2%-51%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0577] In the above-mentioned preparations, pharmaceutical solutions, drugs, and / or pharmaceutical dosage forms, the acidic pH adjuster includes or is selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0578] In this application, the preparation, liquid, drug, or dosage form of this application is referred to as the "R single-drug drug of this application" (R single-drug regimen).

[0579] The R single-drug drug in this application is a special interventional product, not a general injection, and is even strictly prohibited from being used for routine injection (for example, it must be stated in the instructions for use).

[0580] According to one embodiment, the R single-drug solution in the R single-drug drug of the present application is a solution for providing a transient effect of metformin.

[0581] According to one embodiment, the R single-drug dosage form of the present application is a low-frequency, fast-acting intervention-specific dosage form. The existing dosage form of metformin is a regular-frequency, long-acting dosage form mainly used for regular-frequency administration and long-term treatment, and the existing anti-lesion, such as anti-cancer response of metformin cannot provide low-frequency, fast-acting, and can only provide high-frequency, long-term effect at most. On the contrary, the low-frequency, fast-acting intervention-specific dosage form of the present application is strictly prohibited from being used for high-frequency injection (for example, it must be stated in the instructions for use), and is not a regular-acting injection dosage form. The former must provide the low-frequency administration, fast-acting properties that the latter has not anticipated. The difference between the two is further expanded on the basis of the above-mentioned structure-activity characteristics: the latter must provide high-frequency, long-term effects, including the benefits and safety of high-frequency administration and the appearance of therapeutic effects after a long time, which must be implemented by a structural solution that further meets the safety requirements of high-frequency, long-period conventional injections (for example, minimizing local irritation); the former must provide low-frequency, fast-acting properties, which can only be achieved by a structural solution that deviates further from the safety requirements of conventional injections (1.5% ≦ C A <10%) to implement.

[0582] According to one embodiment, the low-frequency, fast-acting interventional special dosage form of the present application is further suitable for patients who are not suitable for high-frequency intervention and are not suitable for conventional treatment on the basis of the indications of the above-mentioned R single-drug dosage form of the present application, such as patients whose intervention compliance is not particularly good and who are in urgent need of therapeutic effect (not suitable for patients who still have no obvious therapeutic effect after a long time, such as those whose disease progresses rapidly or who undergo palliative treatment).

[0583] According to one embodiment, the R single-drug dosage form of the present application is a powder injection for interventional use, comprising a sterile powder and a solvent required for preparing the drug solution of the present application, wherein the sterile powder comprises N,N-dimethylbiguanide and is contained in a container filled with an inert gas; the solvent comprises a pharmaceutically acceptable carrier such as a solvent or a medium, wherein the solvent is a reagent for dissolving N,N-dimethylbiguanide, such as water for injection, and has a volume capable of dissolving the N,N-dimethylbiguanide to the concentration described in the R single-drug drug solution of the present application. The metformin powder injection of the present invention is strictly prohibited from being used as a conventional powder injection.

[0584] According to another aspect of the present invention, the present invention provides uses of N,N-dimethylbiguanide and its single-drug solution (R single-drug solution 2), specifically:

[0585] The present invention provides the use of the medicinal solution of the present application as a transient agent in the preparation of the medicine of the present application or the dosage form of the present application (referred to as "the use of the R single-drug medicinal solution of the present application" in the present application), wherein the medicinal solution is used to provide the transient effect of the N,N-dimethylbiguanide on diseased tissues and the cells contained therein.

[0586] The present invention provides a use of N,N-dimethylbiguanide as a transient active ingredient in the preparation of a special liquid, special medicine, or special dosage form for lesion intervention (referred to in this application as "the single-drug use of metformin in this application"), wherein the N,N-dimethylbiguanide is used to provide a transient effect on diseased tissue and the cells contained therein.

[0587] The present invention provides a method for treating cells in lesions (referred to herein as the "R single-drug cell treatment method of the present invention"), comprising the following steps: introducing a special N,N-dimethylbiguanide intervention solution into the lesion or allowing the lesion to contact with the N,N-dimethylbiguanide of the present invention, wherein the N,N-dimethylbiguanide is used as a transient active ingredient to provide a transient effect on the lesion tissue and the cells contained therein.

[0588] The present invention provides a method for treating lesions (referred to herein as the "R single-drug lesion treatment method of the present invention"), comprising the following steps: introducing a specialized N,N-dimethylbiguanide solution into the lesion, contacting the lesion with the N,N-dimethylbiguanide of the present invention, or administering N,N-dimethylbiguanide to the lesion, wherein the N,N-dimethylbiguanide serves as a transient active ingredient for providing a transient effect on the lesion tissue and the cells contained therein. In practice, the lesion treatment method of the present invention encompasses the cell treatment method of the present invention.

[0589] The present invention provides a method for treating a lesion (referred to herein as "R Single-Drug Disease Treatment Method 1 of the Present Application"), comprising the following steps: introducing a specialized N,N-dimethylbiguanide solution into the lesion, contacting the lesion with the N,N-dimethylbiguanide of the present invention, or applying N,N-dimethylbiguanide to the lesion, wherein the N,N-dimethylbiguanide serves as a transient active ingredient for providing a transient effect on the lesion tissue and the cells contained therein. In practice, the R Single-Drug Disease Treatment Method of the Present Application includes the R Single-Drug Lesion Treatment Method of the Present Application.

[0590] The present invention provides a method for treating lesions such as tumors or nodules in a subject (referred to herein as "the present application R single-drug disease treatment method 2"), comprising intervening in or administering the present application R single-drug drug or preparation as described above to the subject.

[0591] In some embodiments, the intervention or administration may be systemic or local, preferably, the administration or intervention may include intratumoral administration or intervention, preferably local intratumoral intervention administration, preferably such as local injection administration or intervention into a tumor or tumor microenvironment.

[0592] In some embodiments, administration by injection may include infusion, liquid particle injection, or implantation.

[0593] In some preferred embodiments, the formulations of the present invention are suitable for micro-volume administration or micro-volume administration for interventional reduction of (Y) lesions (X), and the ratio of the administered volume to the target volume (V 施用 / V 靶 ) is approximately 0.02-0.056, 0.02-0.10 or 0.02-0.34.

[0594] In some embodiments, the above-mentioned contact, intervention or administration comprises multi-point contact, intervention or administration, preferably, local multi-point contact or intervention.

[0595] The above-mentioned contact or administration may include multi-point contact or administration or intervention, and the multi-point refers to that the number of micro-volume intervention points at which the total target area efficacy evaluation is observed to be effective is significantly higher than that of the conventional metformin drug. Specifically, the multi-points are, for example, multiple sites at the target area, such as ≧5, ≧10, ≧20, ≧30, ≧ or 50 sites, such as at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or more sites, such as 10 to 20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50, 25-50, 30-50 or more sites. Preferably, the contact points or administration sites or intervention points are evenly distributed, especially distributed to places where conventional intervention cannot diffuse.

[0596] In some preferred embodiments, wherein the lesion is ≥ about 3.5 cm 3 , or when the maximum size is ≧ about 2 cm, the multiple points are ≧ 5 sites, for example 10, 15, 20, 25, 30, 35 or 50 sites.

[0597] In some preferred embodiments, the above-mentioned contact or administration or intervention may include micro-multi-point contact or administration or intervention, preferably, micro-multi-point injection, wherein the micro-volume includes an amount of 5 μL-1000 μL for lesions larger than 3 cm in size, such as 5 μL-500 μL, 5 μL-250 μL, 5 μL-200 μL, 5 μL-100 μL, 5 μL-75 μL, 5 μL-50 μL, 5 μL-25 μL. The amount of the solution may be in the range of 1: 1: 1: 1: 1: 1: 2: 1: 2: 3: 5: 6: 7: 8: 9: 10: 11: 12: 13: 14: 15: 16: 17: 18: 19: 20: 21: 22: 23: 24: 25: 26: 27: 28: 29: 30: 31: 32: 33: 34: 35: 36: 37: 38: 39: 40: 51: 52: 53: 54: 55: 60: 71: 72: 73: 74: 85: 96: 101: 111: 112: 123: 133: 134: 135: 146: 157: 167: 178: 189: 200: 214: 225: 236: 189: 240: 258: 269: 271: 272: 289: 300: 301: 302: 303: 304: 305: 306: 307: 308: 309: 309: 301: 302: 303: 309: 301: 303: 305: 309: 301: 303: 305: 309: 301: 303: 303: 309: 309: 301: 301: 301: 301: 301: 30

[0598] In some embodiments, the above treatment can be continued for at least one course of treatment. The duration of the course of treatment can be about 7-40 days, such as about 9 to about 37 days, such as about 15, 20, 25, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0599] In one embodiment, in one course of treatment, contact or administration of the formulation of the present invention can be low frequency, such as administration about 1-6 times / course, preferably 1-5 times / course, 1-4 times / course, 1-3 times / course, or 1-2 times / course.

[0600] In this application, the use of the R single-drug liquid of this application or the use of metformin alone of this application is referred to as the R single-drug use of this application; the R single-drug cell treatment method of this application, the R single-drug lesion treatment method of this application, or the R single-drug disease treatment method of this application is referred to as the R single-drug treatment method of this application; the R single-drug use of this application or the R single-drug treatment method of this application is referred to as the R single-drug use (or method) of this application; the transient effect of the N,N-dimethylbiguanide on the diseased tissue and the cells contained therein is referred to as the R single-drug effect of this application.

[0601] In the above-mentioned R single-drug use of the present application or the R single-drug cell treatment method of the present application, the R single-drug lesion treatment method of the present application, or the R single-drug disease treatment method of the present application, referred to as the R single-drug treatment method of the present application, the lesions include malignant cells and / or non-malignant cells.

[0602] In the above-mentioned uses and methods of the present invention, the lesions are lesions for which conventional treatments are ineffective or failed, including at least one of the following groups: tumors for which conventional treatments are ineffective or failed; non-malignant nodules.

[0603] In the above-mentioned uses and methods of the present invention, the tumor that is ineffective or has failed to respond to conventional treatment includes at least one selected from the following groups: chemotherapy drug-resistant tumors, tumors with a high stromal ratio, tumors that are ineffective or have failed to respond to conventional chemotherapy drugs, and patients with unfavorable chemotherapy.

[0604] In the above uses and methods of the present invention, the non-malignant nodules are nodules comprising at least one of the following non-malignant cells: connective tissue cells, secretory gland cells, and epithelial cells.

[0605] In the above uses and methods of the present invention, the lesion comprises a tumor of non-drug-resistant malignant tumor cells.

[0606] In the above uses and methods of the present invention, the malignant tumor cells are non-metformin cytotoxic specific tumor cells.

[0607] According to one embodiment, the drug solution described in the R single-drug use (or method) of the present application is the R single-drug drug solution of the present application.

[0608] According to one embodiment, the R single-drug solution of the present application is the R single-drug solution described in the R single-drug use (or method) of the present application.

[0609] According to one embodiment, the transient effect in the R single-drug use (or method) of the present application includes a transient tissue permeation effect and a transient cell deformation effect.

[0610] According to one embodiment, the cell deformation comprises effective cell deformation.

[0611] In this application, the term "cell deformation" refers to observable changes in cell morphology (such as volume), which includes reversible and irreversible deformation, wherein irreversible deformation can develop into necrosis; the term "effective cell deformation" refers to cell deformation that can cause effective necrosis of the tissue composed of the cells.

[0612] According to one embodiment, in the above method of the present application, the selection scheme for the dosage of the R single drug solution is: the volume of the drug solution based on the lesion volume × the transient effective intervention concentration.

[0613] According to one embodiment, in the above method of the present application, the concentration selection scheme of the R single drug solution is: ≧ transient effective intervention concentration.

[0614] According to one embodiment, in the above method of the present application, the frequency selection scheme for using the R single-drug solution is: the number of times required for transient treatment of the lesion.

[0615] The R single-drug solution usage scheme in the present application method breaks through and even deviates from the existing R' method. The former and the latter drug solution usage methods are closed (interventional) and open (any injection method that can form drug-carrying blood, preferably absorption injection), respectively. The drug solution dosage selection schemes are (drug solution volume based on lesion volume × transient effective intervention concentration) and (patient blood volume or body weight or surface area × sustained blood drug effective concentration), respectively. The drug solution concentration selection schemes are ≧ transient effective intervention concentration and (safety requirements) preferably lower concentration, respectively. The drug solution usage frequency selection schemes are (several times required for transient treatment that does not reach the lesion) and (tens to hundreds of times required for metformin half-life and sustained blood drug effective concentration).

[0616] The above technical solutions in the method of the present application produce technical effects that exceed the expectations of the existing methods, such as rapid effect, single-drug effectiveness, single or low-frequency effectiveness, effectiveness for lesions that are ineffective or intolerant to existing metformin drugs, etc.

[0617] According to one embodiment, in the liquid medicine or preparation of the present application or the use (or method) of the present application, the concentration of N,N-dimethylbiguanide (C R ) is 1.0% ≤ C R ≦N,N-dimethylbiguanide maximum solubility concentration (or saturation concentration).

[0618] According to one embodiment, in the liquid of the R single-drug drug or R single-drug preparation or the R single-drug use (or method) of the present application, the concentration of N,N-dimethylbiguanide (C R ) is 3.0% ≤ C R ≦N,N-dimethylbiguanide maximum solubility concentration (or saturation concentration).

[0619] According to one embodiment, in the liquid of the R single-drug drug or the R single-drug use (or method) of the present application, the concentration of N,N-dimethylbiguanide (C R ) is 5.0% ≤ C R ≦N,N-dimethylbiguanide maximum solubility concentration (or saturation concentration).

[0620] According to one embodiment, the R single-drug drug or the R single-drug use (or method) of the present application is the fast-acting liquid, drug, dosage form, use, or method of the N,N-dimethylbiguanide.

[0621] According to one embodiment, the R single-drug drug or the R single-drug use (or method) of the present application is a low-frequency administration solution, drug, dosage form, use, or method of the N,N-dimethylbiguanide. The drug or use (or method) of the present application

[0622] According to one embodiment, the indication of the R monotherapy drug or the R monotherapy use (or method) of the present application [(Y, X), referred to as the indication of the present application in the present application] is suitable for use in the treatment of (Y) pathological disease or pathological symptoms (X), wherein the lesion contains malignant cells and / or non-malignant cells.

[0623] According to one embodiment, in the indications of the present application, X is the volume of the lesion, and Y is an effective or rapid reduction.

[0624] According to one embodiment, in the indications of the present application, the lesion is a lesion for which the conventional action of metformin is either effective or not fast-acting, is effective at low frequency, or / and is effective with micro-volume intervention.

[0625] According to one embodiment, in the indications of the present application, the lesion is a lesion for which metformin can be used as an adjuvant treatment, but is ineffective when used alone.

[0626] According to one embodiment, in the indications of the present application, the lesion is a lesion on which the conventional effects of metformin are ineffective.

[0627] According to one embodiment, in the indications of the present application, the lesion is a lesion to which conventional effects are ineffective or failed.

[0628] According to one embodiment, in the indications of this application, the lesions are refractory to conventional chemotherapy or are ineffective, and include or are selected from at least one of the following groups: tumors refractory to conventional chemotherapy drugs and non-malignant nodules. According to one embodiment, in the indications of this application, the lesions are refractory to conventional chemotherapy drugs and include or are selected from at least one of the following groups: drug-resistant tumors, tumors with unfavorable microenvironments, and drug-discontinued tumors.

[0629] According to one embodiment, in the indications of the present application, the drug-resistant tumor is a tumor containing drug-resistant malignant tumor cells.

[0630] According to one embodiment, in the indications of the present application, the drug-resistant tumor is a tumor containing primary drug-resistant cells.

[0631] According to one embodiment, in the indications of the present application, the drug-resistant tumor is a tumor containing a drug-resistant microenvironment.

[0632] According to one embodiment, in the indications of the present application, the tumor containing a drug-resistant microenvironment is a tumor containing an unfavorable microenvironment.

[0633] According to one embodiment, in the indications of the present application, the tumor containing an unfavorable microenvironment is a tumor in which the ratio of non-malignant cells to malignant cells is ≥43%.

[0634] According to one embodiment, in the indications of the present application, the tumor that is ineffective or failed after chemotherapy is a tumor that is ineffective or failed after treatment with recognized first-line or second-line chemotherapy drugs.

[0635] According to one embodiment, in the indications of the present application, the non-malignant nodules include or are selected from at least one of the following non-malignant cell groups: connective tissue cells, secretory gland cells, and epithelial cells.

[0636] According to one embodiment, in the indications of the present application, the connective tissue cells include or are selected from at least one of the following: fibroblasts, adipocytes, and macrophages.

[0637] According to one embodiment, in the indications of the present application, the secretory gland cells include or are selected from at least one of the following: breast cells, thyroid cells, and prostate cells.

[0638] According to one embodiment, in the indications of the present application, the epithelial cells include or are selected from keratinocytes.

[0639] According to one embodiment, in the indications of the present application, the lesion includes or is selected from a tumor containing sensitive tumor cells.

[0640] According to one embodiment, in the indications of the present application, the malignant tumor cells include or are selected from non-metformin cytotoxic-specific tumor cells.

[0641] According to one embodiment, in the indications of this application, the tumor containing sensitive tumor cells is one that is ineffectively treated with conventional metformin, particularly one that is rapidly effective. The drug or use (or method) of this application can provide technical effects that conventional metformin drugs or uses (or methods) cannot, including the type of action (transient vs. sustained action), speed of action (rapid vs. long-lasting), and method of administration required for action (low-frequency vs. regular frequency), thereby meeting treatment needs that its existing uses cannot meet (e.g., high efficacy, or even rapid effect).

[0642] According to one embodiment, in the indications of the present application, the conventional tumor is a tumor that cannot or can no longer be effectively treated by conventional chemotherapy drugs.

[0643] According to one embodiment, in the indications of the present application, X is the pathological disease or pathological symptom that is not applicable or no longer applicable to conventional treatment.

[0644] According to one embodiment, in the indications of the present application, X is the disease or symptom requiring rapid treatment (not suitable for treatment without significant therapeutic effect after a long period of time, such as rapid disease progression or palliative treatment).

[0645] According to one embodiment, in the indications of the present application, Y is the treatment, especially the rapid-acting treatment, produced by the transient effect of the N,N-dimethylbiguanide solution on the diseased tissue and the cells contained therein.

[0646] Within the scope of the present invention, the term "tumor" refers to a pathological disease with a tumor as a pathological symptom, which can be due to any pathology (malignant and non-malignant) and at any stage, including, for example, the following groups classified according to tumor cell type: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, embryonic cell tumors; and tumors named according to the organs or tissues where the tumor cells are concentrated, including, for example, tumors named according to the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testicle, ovary or uterus.

[0647] Specifically, the malignant tumors include, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, sarcoma, etc.

[0648] The non-malignant tumors include, for example, breast tumors, pancreatic tumors, thyroid tumors, prostate tumors, liver tumors, lung tumors, intestinal tumors, oral tumors, esophageal tumors, gastric tumors, nasopharyngeal tumors, laryngeal tumors, testicular tumors, vaginal tumors, uterine tumors, fallopian tube tumors, ovarian tumors, etc.

[0649] According to one embodiment, the malignant cells include or are selected from conventional malignant cells for which conventional metformin solution alone is ineffective, such as cancer cells other than liver cancer cells and sarcoma cells.

[0650] According to one embodiment, the non-malignant cells include or are selected from at least one of connective tissue cells and organ tissue cells.

[0651] According to one embodiment, the connective tissue cells include fibroblasts.

[0652] According to one embodiment, the organ tissue cells include or are selected from at least one of the following: liver cells, breast cells, thyroid cells, and skin cells.

[0653] According to one embodiment, the non-malignant lesions in the indications of the present application include or are selected from at least one of the following groups: benign tumors and nodules.

[0654] In this application, the term "nodule" refers to benign lesions other than benign tumors, including, for example, hyperplasia (e.g., hyperplasia of the breast, thyroid, parathyroid, prostate, etc.), cysts, abnormal venous masses (e.g., hemorrhoids, etc.), local inflammatory swelling, swelling caused by microbial infection, etc. Hemorrhoids include internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids.

[0655] In one embodiment, the benign lesions include local inflammation, especially refractory inflammation. Within the scope of the present invention, the term "local inflammation" refers to non-neoplastic inflammation of a local site, including, for example, alterative inflammation, exudative inflammation, and hyperplastic inflammation, which can be any suitable one known to those skilled in the art, for example, one or more of the following: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, oophoritis, etc.

[0656] In one embodiment, the benign lesions include skin diseases, especially refractory skin diseases. Within the scope of the present invention, the term "skin disease" refers to a lesion that is primary or secondary to the skin or skin appendages, which can be any suitable one known to those skilled in the art, for example, it can include one or more of the following: skin cancer, non-malignant skin tumors, viral skin diseases (such as herpes, warts, rubella, hand, foot and mouth disease), bacterial skin diseases (such as impetigo, furuncle, leprosy), fungal skin diseases (such as various ringworms), sexually transmitted diseases (such as syphilis, gonorrhea and condyloma acuminata), allergic and autoimmune skin diseases (such as contact dermatitis, eczema, urticaria), physical skin diseases (such as solar dermatitis, frostbite, corns, chapped hands and feet, pressure sores), connective tissue diseases (such as lupus erythematosus), pigmentary disorders (such as freckles, moles, various spots), skin appendage diseases (such as acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis and bromhidrosis).

[0657] The present invention provides a pharmaceutical combination comprising metformin (R) and a component (Z), wherein the administration concentration (w / w) of metformin is 0.2%-51%, preferably 0.5%-50%, and the component includes a cell-reactive anti-tumor drug (abbreviated as B).

[0658] In some embodiments, the drug combination can be used to treat a lesion, such as a tumor or nodule, in a subject.

[0659] In some embodiments, in the pharmaceutical combination, the tumor is a solid tumor suitable for intratumoral administration.

[0660] In some embodiments, in the above-mentioned drug combination, the R provides specific activities that are difficult for conventional metformin (the active ingredient is metformin salt, abbreviated as R') to provide, including a specific effect of effectively reducing biological barrier function (abbreviated as activity A) through the following definitions:

[0661] 1). Administration to tumor;

[0662] 2). Application amount:

[0663] Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0664] Where n Ri is the number of needle points at the time of R administration for the i-th time, c R(ii) , and v R(ii)are the concentration and volume of R applied at the iith needle point, respectively, where c R(ii) The concentration threshold of (W / W) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ;

[0665] - The Z provides a specific anti-tumor effect (abbreviated as activity B) in which one of the key control steps is to cross the tumor tissue barrier through the following definition:

[0666] 1). Tumor administration and / or systemic administration;

[0667] 2). Application amount:

[0668] Where n Z ,q B(j) are the number of systemic administrations of Z in a course of treatment and the jth (j=1,...n B ) Application amount, n Z＇ 、c Z(j＇) , and v Z(j＇) Z is the number of times Z is administered to the tumor in one course of treatment, and the j'th time (j'=1,...n Z＇ ) concentration and volume at the time of application;

[0669] - The type of combination is a synergistic combination in which the pharmaceutical effects of activity A of R and activity B of B enhance each other.

[0670] In some embodiments, in the above-mentioned drug combination, the N,N-dimethylbiguanide (R) includes <30%, preferably ≦5% of metformin salt (R'), or does not include metformin salt (R'). Preferably, N,N-dimethylbiguanide (R) is in the form of powder injection.

[0671] In some embodiments, in the above-mentioned drug combination, the tumor is selected from the tumor whose tissue barrier function is not conducive to the inhibitory effect of Z on tumor cells, preferably selected from the refractory tumor of Z, including chemotherapy drug-resistant tumors, tumors containing unfavorable microenvironment, anti-tumor drug discontinuation tumors, tumors for which there are no effective chemotherapy drugs, and tumors carried by patients with contraindications or inappropriate indications for conventional chemotherapy drugs.

[0672] In some embodiments, in the above-mentioned drug combination, the tumor is selected from a heterogeneous tumor, wherein the heterogeneity includes at least one of tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. The heterogeneous tumor is a tumor that is beneficial for treatment by establishing different tumor bodies of the same type of tumor or different areas of the same tumor body as different target areas for differentiated administration based on the heterogeneity.

[0673] In some embodiments, in the above-mentioned drug combination, component (Z) comprises an anti-tumor drug selected from cell-reactive drugs, one of whose key control steps is to cross the tumor tissue barrier.

[0674] In some embodiments, in the above drug combination, the cell-responsive drug includes a cytotoxic drug and a targeted anti-tumor drug.

[0675] In some embodiments, in the above drug combination, the cytotoxic drug includes a DNA damaging agent, an antimetabolite, a microtubule inhibitor, and a topoisomerase inhibitor.

[0676] In some embodiments, in the above-mentioned drug combination, representative compounds of the DNA damaging agent include cisplatin, carboplatin, oxaliplatin, ifosfamide, and doxorubicin.

[0677] In some embodiments, in the above-mentioned drug combination, representative compounds of the antimetabolite drugs include fluorouracil, gemcitabine, and methotrexate.

[0678] In some embodiments, in the above-mentioned drug combination, representative compounds of the microtubule inhibitor include paclitaxel and vincristine.

[0679] In some embodiments, in the above-mentioned drug combination, the agent includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and its derivatives.

[0680] In some embodiments, in the pharmaceutical combination, the administered concentration (w / w) of dimethylbiguanide (R) can be 0.2%-51%, 0.2%-50%, 0.5-50%, 0.5-45%, 1%-45%, 5%-45%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0681] In some embodiments, in the above pharmaceutical combination, the dimethylbiguanide (R) and component (Z) can be administered simultaneously or sequentially, preferably with a certain time interval.

[0682] In some embodiments, in the above-mentioned drug combination, the dimethylbiguanide (R) and component (Z) can be administered intratumorally, or dimethylbiguanide (R) can be administered intratumorally and a portion of component (Z) can be administered intratumorally, and the other portion of component (Z) can be administered systemically, for example, intraperitoneally, or dimethylbiguanide (R) can be administered intratumorally and component (Z) can be administered systemically, for example, intraperitoneally.

[0683] In some embodiments, in the above-mentioned drug combination, the dimethylbiguanide (R) and component (Z) can be administered to the tumor simultaneously or sequentially, or dimethylbiguanide (R) and a part of the component (Z) can be administered to the tumor simultaneously or sequentially, and the other part of the component (Z) can be administered systemically, for example, intraperitoneally, simultaneously or sequentially, or dimethylbiguanide (R) can be administered to the tumor simultaneously or sequentially with component (Z) being administered systemically, for example, intraperitoneally or enterally.

[0684] In some embodiments, in the above-mentioned drug combination, the dimethylbiguanide (R) and component (Z) can be sequentially administered intratumorally, or dimethylbiguanide (R) and a portion of component (Z) can be sequentially administered intratumorally, and the other portion of component (Z) can be sequentially administered systemically, for example, intraperitoneally, or component (Z) can be systemically administered, for example, intraperitoneally, before or after the intratumoral administration of dimethylbiguanide (R).

[0685] In some embodiments, the dimethylbiguanide (R) and component (Z) in the drug combination are both administered to the tumor (combination relationship I); the R and Z are administered to the tumor and systemically, respectively (combination relationship II); or the R and part BZ are administered to the tumor, and the other part Z is administered systemically (combination relationship III).

[0686] The present invention also provides a pharmaceutical combination comprising preparation I and preparation II, wherein preparation I comprises N,N-dimethylbiguanide (R) or N,N-dimethylbiguanide (R) and component (Z), and preparation II contains Z but does not contain R, wherein:

[0687] 1) In the preparation I, the N,N-dimethylbiguanide (R) includes ≤5% or does not include a salt of N,N-dimethylbiguanide;

[0688] 2) The method of using the preparations I and II together is:

[0689] Formulation I is only for intratumoral administration and cannot be used for systemic administration.

[0690] Formulation II can be used for intratumoral administration or / and systemic administration;

[0691] 3) The shared amount of the preparation I and the preparation II is defined by the shared amount of Z and R:

[0692] (1) R application rate:

[0693] Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0694] Where n Ri is the number of application points, such as the number of needle insertion points, at the time of R administration for the i-th time. R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the injection point, wherein the v R(ii) ≦3 times the target volume of application point ii (abbreviated as v 靶(ii) );

[0695] (2) The application rate of Z is:

[0696] Where n Z ,q Z(j) are the number of systemic administrations of Z in a course of treatment and the jth (j=1,...n B ) Application rate, n Z＇ 、c Z(j＇) , and v Z(j＇) Z is the number of times Z is administered to the tumor in one course of treatment, and the j'th time (j'=1,...n Z＇ ) concentration and volume at the time of application.

[0697] In some embodiments, in the above-mentioned drug combination, the component Z includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and derivatives thereof.

[0698] In some embodiments, in the above-mentioned drug combination, the drug C includes or is selected from at least one of the following: sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium lactate, and sodium acetate.

[0699] In some embodiments, in the above-mentioned drug combination, the drug E includes or is selected from at least one of the following: biomacromolecule immunomodulators such as immune checkpoint inhibitors, cytokines, and TLR agonists; immune cell immunomodulators; and vaccine immunomodulators such as BCG.

[0700] In some embodiments, in the above-mentioned drug combination, the mixing contraindications of R are any one of the following groups:

[0701] 1) Salts of N,N-dimethylbiguanide (R');

[0702] 2) an acidulant that significantly converts the R into R', wherein the acidulant comprises an acidic pH adjuster and other acidic substances;

[0703] 3) conventional metformin pharmaceutical adjuvants having a dosage ratio to R (Q adjuvant / QR) of >3.0 or >4.0, including conventional sustained-release dosage form carriers thereof, such as gel carriers and nanocarriers;

[0704] 4) adjuvants that are unstable in strong alkaline aqueous solutions, including, for example, reducing sugars, cellulose, liposomes, carbomer, and polyethylene glycol-modified nanocarriers,

[0705] The mixing taboos mentioned herein refer to the need to avoid mixing with the substance during the entire process of formulation, preparation, product and use.

[0706] In some embodiments, in the above-mentioned drug combination, the sharing method includes:

[0707] 1) R and Z are mixed for intratumoral administration,

[0708] 2) R and Z are used for intratumoral administration,

[0709] 3) R and Z are used for intratumoral administration and systemic administration, respectively,

[0710] 4) R and part of Z are mixed or used separately for intratumoral administration, while the other Z is used for systemic administration.

[0711] In some embodiments, in the above-mentioned drug combination, the common threshold is 0.5%, 1%, 3.3%, 5%, or 10%.

[0712] According to the present invention, provided are pharmaceutical compositions comprising any of the above-mentioned drug combinations of the present invention (compositions of the present invention) and preparations comprising any of the above-mentioned drug combinations or compositions according to the invention (referred to as R combination preparations of the present invention).

[0713] According to the present invention, provided are N,N-dimethylbiguanide (R) and component (Z), and their use in a drug, drug combination or kit for treating tumors or nodules (referred to as R combination therapeutic use 1 of the present invention).

[0714] According to the present invention, the use of the above-mentioned drug combination or composition of the present invention in preparing a drug, a pharmaceutical combination or a kit for treating lesions such as tumors or nodules in a subject is provided (referred to as R combination therapeutic use 2 of the present invention).

[0715] In some embodiments, in the above-mentioned R combination therapy use of the present invention, the administration concentration (w / w) of dimethylbiguanide is ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, preferably ≦10%, preferably ≦5%, more preferably ≦2% such as 1%, 0.75% or 0.5%.

[0716] In some embodiments, the administration concentration (w / w) of metformin (R) in the above-mentioned R combination therapy of the present invention is 0.2%-51%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, preferably 0.5%-10%, preferably 1%-5%, more preferably ≦2% such as 1%, 0.75% or 0.5%.

[0717] In some embodiments, the concentration (w / w) of the salt of N,N-dimethylbiguanide in the R combination therapeutic use of the present invention is ≦30%, preferably ≦20%, preferably ≦10%, more preferably ≦5%, ≦4%, or ≦3%, more preferably ≦2%, particularly preferably ≦1%, such as 1% or 0.5%, and most preferably 0%, that is, the R of the drug combination does not contain a salt of N,N-dimethylbiguanide.

[0718] In some embodiments, the R composition of the present invention comprises N,N-dimethylbiguanide and optionally a solvent, the composition does not contain an additive required to meet the safety requirements of cell culture or routine injection, the concentration of N,N-dimethylbiguanide contained in the composition is ≧ its intervention concentration, wherein the administration or intervention concentration (w / w) is 0.5% ≦ C A≦51%, preferably, 1-51%, 2-50%, 3-50%, 4-50%, 5-50%, 6-50%, 7-50%, 8-50%, 9-50%, 10-50%, 15-50%, 20-50%, 25-50%, 30-50%, 35-50%, 40-50%, 1-40%, 5-50%, 10-40%, 15-40%, 20-40%, 25-40%, 30-40%, 35-40%, or 1-35%, 5%-30%, etc., or any value and range therebetween, for example, 1.5%, 2%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7.7.5%, 8.8.5%, 9.9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 45%, 50%.

[0719] In some embodiments, the composition comprises a solvent, such as a pharmaceutically acceptable carrier, preferably water.

[0720] In some embodiments, the composition does not include a salt of N,N-dimethylbiguanide.

[0721] In some embodiments, the concentration (w / w) of the salt of N,N-dimethylbiguanide contained in the composition is ≦25%, preferably ≦10%, preferably ≦5%, preferably ≦4%, more preferably ≦3%, more preferably ≦2%, particularly preferably ≦1%, and most preferably 0%, that is, the composition does not contain a salt of N,N-dimethylbiguanide.

[0722] In one embodiment, the additional agent includes an acidic pH adjuster.

[0723] In one embodiment, the acidity pH regulator includes or is selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, carbonic acid, and the like.

[0724] In some embodiments, the pharmaceutical combination or composition for the above use includes component Z, wherein Z includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and derivatives thereof.

[0725] In some embodiments, the drug combination or composition in the above use includes drug C, and the drug C includes or is selected from at least one of the following: sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium lactate, and sodium acetate.

[0726] In some embodiments, the drug combination or composition in the above-mentioned use includes drug E, which includes or is selected from at least one of the following: biomacromolecule immunomodulators such as immune checkpoint inhibitors, cytokines, and TLR agonists; immune cell immunomodulators; and vaccine immunomodulators such as BCG.

[0727] According to the present invention, a method for treating cells of lesions such as tumors or nodules (referred to as the R combination treatment method of the present invention) is provided, comprising administering or intervening the above-mentioned drug combination or composition of the present invention into the lesion, penetrating into the lesion tissue, and contacting with cells in the tissue.

[0728] According to the present invention, a method for treating tumors or nodules (referred to as the R combination treatment method 1 of the present invention) is also provided, comprising: administering the above-mentioned drug combination and composition of the present invention to the tumor or nodule, preferably, the administration includes administering the preparation of the present invention to the tumor body or nodule, and / or administering the metformin to the tumor body or nodule and administering the drug inside the tumor or systemically.

[0729] According to the present invention, a method for treating a tumor in a subject is provided (referred to as R combination treatment method 2 of the present invention), comprising administering the above-mentioned pharmaceutical combination or composition of the present invention to the subject.

[0730] In the above-mentioned R combination treatment method, the drug combination or composition includes dimethylbiguanide and optionally a solvent, wherein the preparation does not contain an acidic pH regulator required to meet the safety of cell culture or routine injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its intervention concentration, wherein the intervention concentration (w / w) is 0.5% ≦ C ≦ 51%, preferably, 1%-50%, more preferably 3%-40% or 5%-35%.

[0731] In some embodiments, the pharmaceutical combination or composition may comprise a solvent. Preferably, the solvent is water, more preferably water for injection.

[0732] In some embodiments, the pharmaceutical combination or composition may not include a metformin salt.

[0733] In some embodiments, the concentration (w / w) of dimethylbiguanide in the pharmaceutical combination or composition can be ≦51%, ≦50%, ≦40%, ≦30%, ≦25%, ≦20%, preferably ≦10%, preferably ≦5%, more preferably ≦2% such as 1%, 0.75% or 0.5%.

[0734] In some embodiments, the concentration (w / w) of metformin (R) in the pharmaceutical combination or composition can be 0.2%-51%, 0.2%-50%, 0.5-50%, 1%-40%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, preferably 0.5%-10%, preferably 1%-5%, or preferably ≦2% such as 1%, 0.75% or 0.5%.

[0735] In some embodiments, the acidic pH adjuster may include or be selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, and carbonic acid.

[0736] In some embodiments, in the above method, the R is contained in a powder.

[0737] In some embodiments, in the above method, the powder consists of a dry powder comprising R and a solvent.

[0738] In some embodiments, in the above method, the dry powder is R dry powder, and the solvent is water for injection.

[0739] In some embodiments, the pharmaceutical combination or composition does not contain an acid that can significantly convert N,N-dimethylbiguanide (R) in the aqueous solution into a metformin salt.

[0740] In the above-mentioned R combination treatment method or R combination treatment method, the administered drug combination or composition comprises metformin (R) and component (Z), wherein the administration concentration of metformin is 0.2%-51%, preferably 0.5%-50% on a weight / weight (w / w) basis, and the component includes a cell-reactive anti-tumor drug (abbreviated as B).

[0741] In some embodiments, in the above-mentioned R combination treatment method or R combination treatment method, the drug combination:

[0742] - The R provides an activity (abbreviated as activity A) that conventional metformin (the active ingredient is metformin salt, abbreviated as R') cannot provide, including effectively reducing the biological barrier function (abbreviated as activity A1) through the following definitions:

[0743] 1). Administration to tumor;

[0744] 2) The dosage for one course of treatment is:

[0745] Where n R is the number of times R is applied to the tumor in one course of treatment, q R(i) is the number of times R is in the ith time (i=1,...n R ) in the amount used in the application, and:

[0746] Where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are respectively the concentration and volume of R applied at the iith administration point, such as the needle insertion point, wherein the c R(ii) The concentration threshold of (w / w) is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%. R(ii) The volume threshold is 1 / 800 or 1 / 300 target volume (abbreviated as v 靶(ii) ), the upper limit of the volume threshold is 3 times v 靶(ii) ;

[0747] - The cell-reactive anti-tumor drug (B) provides the cell response (abbreviated as activity B) by the following definition, one of the key control steps of the response is to pass through the above-mentioned biological barrier:

[0748] 1). Tumor administration and / or systemic administration;

[0749] 2) The dosage for one course of treatment is:

[0750] Where Q B is ≦ the conventional dosage in sensitive tumors of B, n B ,q B(j) are the number of systemic administrations of B in a course of treatment and the jth administration (j=1, ...n B ) Application rate, n B＇ 、c B(j＇) , and v B(j＇) are the number of times B is administered to the tumor in a course of treatment, and the j'th time (j'=1,...n B＇ ) concentration and volume at the time of application;

[0751] - The type of combination is a synergistic combination in which the pharmaceutical effects of activity A of R and activity B of B enhance each other.

[0752] In some embodiments, the N,N-dimethylbiguanide (R) comprises <30% (w / w), preferably ≦5% metformin salt (R'), or does not comprise metformin salt (R'). Preferably, the N,N-dimethylbiguanide (R) is in the form of powder injection.

[0753] In some embodiments, component (Z) of the drug combination comprises an anti-tumor drug selected from a cell-reactive drug (B) whose key control step is to cross the tumor tissue barrier.

[0754] In some embodiments, the cell-reactive drug (B) includes a cytotoxic drug and a targeted anti-tumor drug.

[0755] In some embodiments, the cytotoxic drugs include DNA damaging agents, antimetabolites, microtubule inhibitors, and topoisomerase inhibitors.

[0756] In some embodiments, representative compounds of the DNA damaging agent include cisplatin, carboplatin, oxaliplatin, ifosfamide, and doxorubicin.

[0757] In some embodiments, representative compounds of the antimetabolite drugs include fluorouracil, gemcitabine, and methotrexate.

[0758] In some embodiments, representative compounds of the microtubule inhibitors include paclitaxel and vincristine.

[0759] In some embodiments, the targeted anti-tumor drug comprises a small molecule targeted anti-tumor drug, preferably a kinase inhibitor.

[0760] In some embodiments, the kinase inhibitor comprises gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab, and derivatives thereof.

[0761] In some embodiments, in the above-mentioned R combination treatment method, the component Z includes or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and its derivatives.

[0762] In some embodiments, in the above-mentioned R combination treatment method, the drug C includes or is selected from at least one of the following: sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, sodium lactate, and sodium acetate.

[0763] In some embodiments, in the above-mentioned R combination therapy method, the drug E includes or is selected from at least one of the following: biological macromolecule immunomodulators such as immune checkpoint inhibitors, cytokines, and TLR agonists; immune cell immunomodulators; and vaccine immunomodulators such as BCG.

[0764] In some embodiments, in the above-mentioned R combination treatment methods, the administration concentration (w / w) of dimethylbiguanide (R) can be 0.2%-51%, 0.2%-50%, 0.5-51%, 0.5-50%, 0.5-45%, 1%-45%, 5%-45%, 5%-40%, 5%-30%, 5%-25%, 5%-20%, 1%-30%, 1%-25%, 1%-20%, 0.5%-10%, 1%-5%, or ≦2%, such as 1%, 0.75% or 0.5%.

[0765] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and doxorubicin (DOX), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the doxorubicin (DOX) can be administered at a concentration of 0.025%-1% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-50% (w / w), and the doxorubicin (DOX) is administered at a concentration of 0.1%-1%, optionally, dimethylbiguanide (R) and doxorubicin (DOX) are both administered intratumorally.

[0766] In one embodiment, metformin (R) is administered intratumorally at a concentration of 0.2%-50% (w / w), doxorubicin (DOX) is administered intratumorally at a concentration of 0.025%-1% (w / w), and doxorubicin (DOX) is administered systemically, such as intraperitoneally, at a concentration of 0.05%-0.06% (w / w).

[0767] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and ifosfamide (IFO), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the ifosfamide (IFO) can be administered at a concentration of 0.1%-10% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.1%-10% (w / w), more preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the ifosfamide (IFO) is administered at a concentration of 0.5%-10% (w / w), optionally, dimethylbiguanide (R) and ifosfamide (IFO) are both administered intratumorally.

[0768] In one embodiment, the dimethylbiguanide (R) is administered intratumorally at a concentration of 5%-50% (w / w), the ifosfamide (IFO) is administered intratumorally at a concentration of 0.5%-10% (w / w), and the ifosfamide (IFO) is administered systemically at a concentration of 0.5% (w / w), such as intraperitoneally or parenterally.

[0769] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and cisplatin (DDP), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the cisplatin (DDP) can be administered at a concentration of 0.01%-0.4% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.5%-50% (w / w), and the cisplatin (DDP) is administered at a concentration of 0.01%-0.04% (w / w), optionally, dimethylbiguanide (R) and cisplatin (DDP) are both administered intratumorally.

[0770] In one embodiment, the dimethylbiguanide (R) is administered to the tumor at a concentration of 0.5%-50% (w / w), the cisplatin (DDP) is administered to the tumor at a concentration of 0.013%-0.4% (w / w), and the cisplatin (DDP) is systemically administered to the tumor at a concentration of 0.015% (w / w), such as intraperitoneally.

[0771] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), and the 5-fluorouracil (5-FU) can be administered at a concentration of 0.05%-9% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 0.2%-45% (w / w), and the 5-fluorouracil (5-FU) is administered at a concentration of 0.5%-9% (w / w), more preferably, the dimethylbiguanide (R) is administered at a concentration of 5%-45% (w / w), and the 5-fluorouracil (5-FU) is administered at a concentration of 0.9%-9% (w / w), optionally, dimethylbiguanide (R) and 5-fluorouracil (5-FU) are both administered intratumorally.

[0772] In one embodiment, the dimethylbiguanide (R) is administered intratumorally at a concentration of 5%-45% (w / w), the 5-fluorouracil (5-FU) is administered intratumorally at a concentration of 0.9%-9% (w / w), and the 5-fluorouracil (5-FU) is systemically administered, such as intraperitoneally, at a concentration of 0.5% (w / w).

[0773] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R), cisplatin (DDP) and gemcitabine (GEM), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2%-50% (w / w), the cisplatin (DDP) can be administered at a concentration of 0.05%-1% (w / w), and the gemcitabine (GEM) can be administered at a concentration of 0.5-2% (w / w), preferably at a concentration of 1% (w / w), optionally, or dimethylbiguanide (R) and cisplatin (DDP) are administered intratumorally and gemcitabine (GEM) is administered systemically, such as intraperitoneally.

[0774] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R), paclitaxel (PTX) and 5-fluorouracil (5-FU), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2% 0-50% (w / w), the 5-fluorouracil (5-FU) can be administered at a concentration of 0.1%-10% (w / w), and the paclitaxel can be administered at a concentration of 0.02-1% (w / w), preferably, at a concentration of 0.03% (w / w). Optionally, dimethylbiguanide (R) and 5-fluorouracil (5-FU) are administered intratumorally and paclitaxel (PTX) is administered systemically, such as intraperitoneally.

[0775] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and osimertinib, wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2% 0-50% (w / w), and the osimertinib can be administered at a concentration of 0.05%-2% (w / w), preferably, the dimethylbiguanide (R) is administered at a concentration of 5% (w / w), and the osimertinib is administered at a concentration of 0.15% (w / w), optionally, the dimethylbiguanide (R) is administered intraemetically, and the osimertinib is administered systemically, such as intraperitoneally.

[0776] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R) and gefitinib (GR), wherein the dimethylbiguanide (R) can be administered at a concentration of 0.2% 0-50% (w / w), and the gefitinib (GR) can be administered at a concentration of 0.1%-2% (w / w). Preferably, the dimethylbiguanide (R) is administered at a concentration of 1%-50% (w / w), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w). Optionally, the dimethylbiguanide (R) is administered intratumorally, and the gefitinib (GR) is administered systemically, such as intraperitoneally.

[0777] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R), cisplatin (DDP) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally), and the cisplatin (DDP) is administered at a concentration of 0.15 (w / w) (e.g., tumor).

[0778] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R), ifosfamide (IFO) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the ifosfamide (IFO) is administered at a concentration of 1% (w / w) (e.g., tumor), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally).

[0779] In some embodiments, in the above-mentioned R combination treatment method, the drug combination includes dimethylbiguanide (R), doxorubicin (DOX) and gefitinib (GR), wherein the dimethylbiguanide (R) is administered at a concentration of 5% (w / w) (e.g., tumor), the doxorubicin (DOX) is administered at a concentration of 0.05% (w / w) (e.g., tumor), and the gefitinib (GR) is administered at a concentration of 0.5% (w / w) (systemically, e.g., intraperitoneally).

[0780] In some preferred embodiments, in the above-mentioned R combination treatment method, the contact or administration or intervention may include micro-multi-point contact or administration or intervention, preferably, micro-multi-point injection, and the micro-volume includes an amount of 5 μL-1000 μL for lesions larger than 3 cm in size, such as 5 μL-500 μL, 5 μL-250 μL, 5 μL-200 μL, 5 μL-100 μL, 5 μL-75 μL, 5 μL-50 μL, 5 μL-50 μL, 5 μL-100 μL, 5 μL-250 μL, 5 μL-200 μL, 5 μL-100 μL, 5 μL-75 μL, 5 μL-50 μL, 5 μL-10 ... μL-25 μL, 5 μL-20 μL, 10 μL-200 μL, 10 μL-100 μL, 10 μL-75 μL, 20 μL-200 μL, 20 μL-100 μL, 20 μL-75 μL, 30 μL-200 μL, 30 μL-100 μL, 40 μL-200 μL, 40 μL-100 μL, 50 μL-200 μL, 50 μL-100 μL, or 50 μL-75 μL, etc. Preferably, micro-multiple (position) point contact or administration, more preferably, micro-multiple (position) point injection.

[0781] In some embodiments, the above treatment can be continued for at least one course of treatment. The duration of the course of treatment can be about 7-40 days, such as about 9 to about 37 days, such as about 15, 20, 25, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0782] In one embodiment, in one course of treatment, contact or administration of the formulation of the present invention can be low frequency, such as administration about 1-6 times / course, preferably 1-5 times / course, 1-4 times / course, 1-3 times / course, or 1-2 times / course.

[0783] In some embodiments, in the above-mentioned R combination treatment methods, dimethylbiguanide (R) and component (Z) in the drug combination can be administered simultaneously, sequentially or intermittently.

[0784] In some embodiments, in the above-mentioned R combination treatment method, the dimethylbiguanide (R) and component (Z) in the drug combination are both administered to the tumor (combination relationship I); the R and Z are administered to the tumor and systemically, respectively (combination relationship II); or the R and part of Z are administered to the tumor, and the other part of Z is administered systemically (combination relationship III).

[0785] In some embodiments, in the above methods, the tumor is a solid tumor suitable for tumor administration.

[0786] In some embodiments, in the above-mentioned R combination treatment method, the tumor is selected from tumors whose tissue barrier function is not conducive to the inhibitory effect of Z on tumor cells, preferably refractory tumors selected from Z, including non-indication tumors, drug-resistant tumors, tumors with unfavorable microenvironment, and drug-stopping tumors.

[0787] In some embodiments, in the above-mentioned R combination treatment method, the tumor is selected from a heterogeneous tumor, wherein the heterogeneity includes at least one of tissue heterogeneity, spatial heterogeneity, and safety heterogeneity. The heterogeneous tumor is a tumor that is beneficial for treatment by establishing different tumor bodies of the same type or different areas of the same tumor body as different target areas for differentiated administration based on the heterogeneity.

[0788] In some embodiments, in the above-mentioned R combination treatment method, the contacting or administering comprises multi-point contacting or administering, preferably, micro-multi-point contacting or administering, more preferably, micro-multi-point injection.

[0789] In some embodiments, in the above-mentioned R combination treatment methods, the formulation or drug combination is suitable for application in microvolume administration or intervention to reduce (Y) the lesion volume (X), and the ratio of the administered volume to the target volume (Vadministered / Vtarget) is approximately 0.02-0.056, 0.02-0.10 or 0.02-0.34.

[0790] In some embodiments, in the above-mentioned R combination treatment method, when the lesion is ≥ about 3.5 cm 3 , or when the maximum size is ≧ about 2 cm, the multiple points are ≧ 5 points, for example 10, 15, 20, 25, 30, 35 or 50 points.

[0791] In some embodiments, in the above-mentioned R combination treatment method, the contact or administration is low frequency, preferably, the low frequency is 1-6 times / treatment course, more preferably, 1-5 times / treatment course, 1-4 times / treatment course, 1-3 times / treatment course, or 1-2 times / treatment course.

[0792] In some embodiments, in the above-mentioned R combination treatment method, preferably, the maximum value of the R application concentration cR is ≧5%, ≧10%, ≧20%, or ≦30%; the number of application points is >3, 10, 15, 20, 25, 30, 35 or 100 points.

[0793] In some embodiments, in the above R combination treatment method, the metformin R and component Z can be provided by one or more formulations, and wherein:

[0794] The R and Z are administered intratumorally;

[0795] R and Z are intratumoral administration and systemic administration, respectively; or

[0796] The R and part Z are administered intratumorally, and another part Z is administered systemically.

[0797] In some embodiments, in the above-mentioned R / Z combination treatment method, the combination of R and Z (R / Z combination) is a synergistic combination that exceeds the expected effect of the combination of conventional metformin drugs (R') and Z (R' / Z combination), which is expressed as a course of treatment dose of R (Q R ) is ≤ 25% or 50% of the R' course of treatment dosage (Q R＇ ) and Z are not increased during the course of treatment, the drug effect is significantly increased, including at least one of the drug adjustability indicators being increased by at least 100%, and at least one of the drug efficacy indicators being enhanced by at least 25%, wherein the drug adjustability refers to the ability of the drug to provide differentiated administration parameters to different target areas while still maintaining efficacy.

[0798] In some embodiments, in the above-mentioned R / Z combination treatment method, the R / Z combination is also a synergistic combination that exceeds the expected effect of the HSA method or Bliss method based on R single drug and Z single drug, and is expressed as a course of treatment dose of R (Q R ) does not increase the dosage of Z for one course of treatment (Q B ) is reduced by at least 20%, while the drug effect is increased, including at least one of the drug adjustability indicators being increased by at least 10%, and at least one of the drug efficacy indicators being enhanced by at least 10%.

[0799] In some embodiments, in the above-mentioned R or R / Z combination treatment methods, the drug adjustability index includes at least one of the following local administration parameter adjustable coefficients (the ratio of the highest value in the adjustable range to its threshold value):

[0800] 1). The concentration of R can be adjusted by the coefficient c R The ratio of the highest value to the threshold value (c R ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to> 10, 50, 100 or 150, which allows the R to provide highly variable concentrations to different regions while still maintaining its activity stable, including, for example, heterogeneous tumor-specific administration;

[0801] 2). The target volume adjustment coefficient of R is the target volume (v 靶 ) to the threshold value (v 靶 The maximum value / threshold of the value of the adjustable index is the maximum value / threshold of the value of the adjustable index, and the increase of the adjustable index is preferably the increase of the coefficient to >2, 10, 50, or 100, which makes the R select different values ​​of v 靶 Administer drugs based on the characteristics of different treatment situations, including, for example, heterogeneous tumors;

[0802] 3). R dosage volume ratio adjustable coefficient, which is the dosage volume (v R ) and its target volume (v靶 ) to the threshold value (v R / v 靶 ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to >5, 10, or 100, which allows the R to provide highly variable volume ratios to different regions while still maintaining its activity stable, including, for example, heterogeneous tumor-specific drug delivery;

[0803] 4). The single dosage of R can be adjusted by the coefficient, which is the single dosage (c Ri ×v Ri ) to the threshold value (c Ri ×v Ri ), and wherein the increase in the adjustable index is the increase in the coefficient, preferably the coefficient is increased to >2, 6, or 10, which allows R to select different single doses for different treatment situations, including, for example, heterogeneous tumors; and

[0804] 5). The adjustable coefficient of the dosing point density of R is the density of the dosing point (n ii / v 靶 ) to the threshold value (n ii / v 靶 The maximum value / threshold of the R value is set as R, and the increase in the adjustable index is the increase in the coefficient. Preferably, the coefficient is increased to >3, 10, 50, or 100. This allows R to provide highly variable densities to different regions while maintaining stable activity, including, for example, tailored drug delivery to heterogeneous tumors.

[0805] In some embodiments, in the above-mentioned R or R / Z combination treatment methods, the drug efficacy indicator includes at least one of the following:

[0806] 1) Time-effectiveness, as measured by the time to significant effect (the day when the tumor proliferation rate is <42%) in mouse studies, where the magnitude of the enhancement in efficacy is the magnitude of the shortening in time to significant effect, making the regimen a fast-acting regimen, particularly suitable for tumors requiring rapid reduction in tumor size;

[0807] 2) An efficacy indicator, represented by a tumor inhibition rate or objective response rate in a mouse study, wherein the magnitude of the enhancement in the efficacy indicator is the magnitude of the increase in the tumor inhibition rate or objective response rate, making the regimen a highly effective regimen, particularly suitable for tumors requiring minimal tumor size reduction;

[0808] 3) Long-term efficacy, represented by the progression-free time in mouse studies, wherein the magnitude of the enhancement of the efficacy indicator is the magnitude of the extension of the progression-free time, making the regimen a long-term regimen, particularly suitable for tumors that require the progression-free time to be extended as much as possible.

[0809] According to the present invention, a kit is provided, which comprises the formulation of the present invention as described above, and instructions for practicing the above method of the present invention.

[0810] According to the present invention, a kit is provided, comprising the pharmaceutical combination or composition of the present invention as described above, and instructions for carrying out the treatment or therapeutic method of the present invention as described above.

[0811] In one embodiment, the above kit further comprises a micro-volume intervention device, preferably, the device is suitable for micro-multi-point contact or administration, preferably comprising a micro-injection device such as a syringe.

[0812] In one embodiment, the volume intervention device may include, for example, a puncture needle, an injection needle, a catheter, or other devices with the same function.

[0813] According to the present invention, the drug of the present application is a therapeutic drug. When it is used to treat pathological diseases as the main therapeutic drug, it can also be used in combination with other interventional therapies, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or a combination of such therapies to further improve the therapeutic effect.

[0814] Beneficial effects of the present invention

[0815] First, it should be noted that since R can only be administered locally and not systemically like R', this application scheme is limited to patients with tumors who require administration to the tumor itself. Treatment issues for this type of patient still need to be addressed, although tumor administration currently accounts for less than 1% of clinical cases. This scheme provides the following beneficial effects for this type of patient:

[0816] 1. Comparison between the present invention and the prior art of metformin: The active ingredient in the preparation of the present invention is N,N-dimethylbiguanide (R), while the active ingredient in the prior art is metformin salt (R'). After topical application, R has a different active form from the latter within a short period before converting to R', showing a reduction in dosage and an increase in efficacy that exceeds the expectations of the prior art (R and R' are pharmaceutical equivalents). When the R dosage for a course of treatment (Q R ) is less than R' dosage (Q R＇) is 25%-50% of the original dose, the drug effect is significantly increased, including at least one drug adjustability index increased by at least 100%, and at least one drug efficacy index increased by at least 40%. The efficacy indexes include time to significant effect, tumor inhibition rate or objective response rate, and progression-free time. The improved efficacy enables R to solve the following problems that R' cannot solve: rapid effect, high efficiency, and / or long-term effect. The adjustability indexes include: c R The highest value / threshold value, v 靶 The highest value / threshold value, v R / v 靶 The highest value / threshold of c Ri ×v Ri The highest value / threshold value, n ii / v 靶 The maximum value / threshold of , the increased adjustability allows the R to solve the following problems that R' cannot solve: providing highly variable administration parameters to different tumor areas while still maintaining stable therapeutic efficacy, including, for example, the administration of drugs according to the quality of heterogeneous tumors.

[0817] 2. Comparison between the present invention and the prior art of transient local-acting drugs (e.g., anhydrous ethanol): 1). The soluble concentration (e.g., 51%) / threshold concentration (e.g., 0.2% or 0.5%) of R in the present invention is dozens of times higher, solving the long-awaited problem of low adjustability index for this type of drug. 2). The transient local action of R in the present invention is more complementary to the mechanism of local action of other drugs (e.g., methylene blue), providing better synergistic effects. 3). The efficacy-toxicity ratio of R in the present invention is higher, and the efficacy-toxicity ratio of the combination comprising R and C (e.g., SB) is further greatly improved, thus providing a more preferred technical solution for patients sensitive to local irritation.

[0818] 3. Comparison of the present invention with the prior art combining metformin (R') and B (R' / B): The transient activity of R in the combination of R and B in this scheme can provide a barrier-lowering effect that R' cannot provide, even in tumor tissues where it cannot completely necrotize. This facilitates Z's breakthrough of this critical control step, which in turn promotes the development of R's efficacy in this region. The combination of R and B thus provides a mutually reinforcing synergistic effect that exceeds prior art expectations (R / B and R' / B are pharmaceutically equivalent). This is demonstrated by the beneficial effects of R (the dose-reducing, synergistic effect) described in 1 above being realized, and at least one efficacy indicator, such as tumor inhibition rate and progression-free time, being further improved by combining R with B. Even when compared with R alone and a cell-responsive anti-tumor drug (B), the present invention demonstrates even greater synergy than the strongest single agent, at least in B-refractory tumors, as demonstrated by an increase of at least 10% in at least one of the aforementioned drug-regulatable indicators and / or at least 10% in at least one of the drug efficacy indicators.

[0819] 4. Comparison of the present invention with the prior art combining metformin (R') and E (R' / E): The transient activity of R in the R and E combination of this regimen effectively releases diseased immune substances and inflammatory signals, even in tumor tissues where it cannot completely necrotize. Combined with the aforementioned effective reduction of biological barrier function, this facilitates immune cell infiltration. These effects provide an important foundation and synergistic mechanism for the action of E. The combination of R and an immunomodulator (E) provides a mutually reinforcing synergistic effect that exceeds prior art expectations (R / E and R' / E are pharmaceutically equivalent), manifested by a greater than 50% improvement in the beneficial effects of R / E (e.g., long-term survival rate) compared to R' / E. Even when compared to R or E alone, this regimen further enhances the synergy of the most potent single agents, demonstrating at least a 25% increase in long-term survival rate.

[0820] Based on the research described in more detail below, although the specific mechanism needs further study, R in the drug of the present application shows a transient effect, especially a transient penetration effect on the diseased tissue structure, which enables the drug solution to reach the cells in the tissue and cause them to produce effective morphological changes, ultimately leading to the effective destruction of the diseased tissue or a reduction in its volume, and also causing direct damage to tumor cells.

[0821] Other objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. In addition, each of the various embodiments and aspects of the present invention as described above and claimed in the claims section will find experimental support in the following examples.

[0822] Example

[0823] The present invention is further described by the following specific examples, but is not intended to be limiting thereof. The present invention is further described by the following specific examples, but is not intended to be limiting thereof. In the following examples, all experimental animals were used in accordance with relevant laws and regulations and industry self-regulation.

[0824] Unless otherwise specified, the cells, materials, reagents, etc. used in the following specific examples can be obtained from commercial channels.

[0825] In the following examples, unless otherwise stated, all cells used were purchased from West China Hospital of Sichuan University and its wholly-owned subsidiary (Sichuan Kangcheng Biotechnology Co., Ltd.), and the drug resistance index of the drug-resistant cells was above 4; the tumor tissues of the patient-derived xenograft models (abbreviated as PDX in this application) and their drug resistance verification were provided by West China Hospital of Sichuan University, and related experiments were conducted in collaboration with West China Hospital.

[0826] In the following examples, the tissue barrier function-lowering agent investigated was N,N-dimethylbiguanide (abbreviated as R, CAS 657-24-9), and its comparative agent was metformin hydrochloride (abbreviated as R', CAS 1115-70-4). Both raw materials were purchased from Shanghai MacLean Biochemical Technology Co., Ltd. The supplier explained that the dry powder of N,N-dimethylbiguanide used was prepared by removing hydrochloric acid from metformin hydrochloride. Its purity standard was ≥95% (quality inspection result was 95.02%), and it was tested to be sterile. The highest concentration of 51% (w / w) was achieved after dissolving under rapid stirring at room temperature (25°C) and allowing to stand for 2 hours without precipitation. Therefore, 51% (w / w) is used in this application to represent the maximum solubility concentration of N,N-dimethylbiguanide in aqueous solution.

[0827] In the following examples, a sufficient number of representative cell-reactive drugs (abbreviated as B) are selected to demonstrate that the following results can be reasonably extended to this class of drugs: tumor tissue barrier function is reduced by the same compound (R), which facilitates the pharmacological effect of any representative drug on the anti-tumor response at the tumor cell level. Representative drugs for B are selected from cytotoxic drugs (B1) and targeted anti-tumor drugs (B2), and their raw materials were purchased from Shanghai MacLean Biochemical Technology Co., Ltd. and Shanghai Weihuan Biotechnology Co., Ltd.

[0828] In the following examples, representative cytotoxic drugs are selected from DNA damaging agents, antimetabolites, and microtubule inhibitors. Among them, representative compounds of DNA damaging agents ...

Claims

1. A preparation comprising N,N-dimethylbiguanide (abbreviated as R) and optionally a solvent, wherein the preparation does not contain an acidic pH regulator required to meet the safety requirements for cell culture or conventional injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its administration concentration, and wherein the administration concentration (w / w) is 0.5% ≦ C R ≦ 51%, preferably 1% - 50%, more preferably 3% - 50% or 5% - 30%.

2. A preparation specifically for lesion intervention, which contains N,N-dimethylbiguanide (abbreviated as R) and optionally a solvent, wherein the preparation does not contain an acidic pH regulator required to meet the safety requirements of cell culture or conventional injection, wherein the concentration of the N,N-dimethylbiguanide is ≧ its intervention concentration, and the intervention concentration (w / w) is 0.5% ≦ C ≦ 51%, preferably 1% - 50%, more preferably 3% - 40% or 5% - 35%, and preferably it is used for intervening in lesions such as tumors or nodules in a subject for treatment.

3. The preparation according to any one of claims 1 - 2, wherein the preparation contains a solvent, preferably the solvent is water, and more preferably water for injection.

4. The preparation according to any one of claims 1 - 3, wherein the preparation does not include biguanide salts and an acid that causes the obvious conversion of the R into R'.

5. The preparation according to any one of claims 1 - 3, wherein the concentration (w / w) of the N,N-dimethylbiguanide in the preparation is ≦ 51%, ≦ 50%, ≦ 40%, ≦ 30%, ≦ 25%, ≦ 20%, preferably ≦ 10%, and preferably ≦ 5%.

6. The preparation according to any one of claims 1 - 3, wherein the concentration (w / w) of the N,N-dimethylbiguanide (R) in the preparation is 0.5 - 50%, 1% - 40%, 5% - 50%, 5% - 40%, 15% - 50%, 25% - 50%, 35% - 50%.

7. The preparation according to any one of claims 1 - 7, wherein the acidic pH regulator or acid includes or is selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, phosphoric acid, malic acid, tartaric acid, lactic acid, carbonic acid.

8. The preparation according to any one of claims 1 - 7, wherein the preparation consists of N,N-dimethylbiguanide (R) and water.

9. [Corrected according to Rule 26 on 19.02.2025] The preparation according to any one of claims 1 - 8, wherein the preparation is used to provide an active form of the R that is different from the conventional biguanide preparation (whose active ingredient is R'), and the active form of the R' is in the form of being completely complexed with an acid in solution; while the active form of the R is in the form of being less complexed with an acid in solution and mainly exists in a very little or partially complexed form.

10. [Corrected according to Rule 26 on 19.02.2025] The preparation according to any one of claims 1 - 9, which is a pharmaceutical ingredient for a drug combination, wherein the drug combination further contains a component (Z), and the Z is selected from at least one of the following groups: a cell-reactive anti-tumor drug (abbreviated as B), a near-neutral or weakly basic sodium salt (abbreviated as C), a methylene blue dye (abbreviated as D), an immunomodulator (abbreviated as E).

11. A pharmaceutical combination for treating local lesion diseases, comprising N,N-dimethylbiguanide (abbreviated as R) and component (Z), wherein the application concentration (w / w) of the N,N-dimethylbiguanide is 0.1%-51%, preferably 0.2%-50%, and the component (Z) includes at least one selected from the following groups: cell-reactive anti-tumor drugs (abbreviated as B), near-neutral or weakly basic sodium salts (abbreviated as C), methylene blue dyes (abbreviated as D), and immunomodulators (abbreviated as E).

12. The pharmaceutical combination according to claim 11, wherein the N,N-dimethylbiguanide is used to provide an active form different from the conventional metformin drug (whose active ingredient is R') through the following definitions: 1). It is not mixed with an acid that causes the obvious conversion of R into R'; 2). It is applied locally to the lesion; 3). The dosage for one treatment course is as follows: Wherein, Q R <equivalent usage amount of 50% or 25% of said R', n R is the number of times of tumor administration of R in one treatment course, q R(i) is the dosage of R in the i-th (i = 1,... n R ) administration, and: where n Ri is the number of application points of R at the i-th application, e.g., the number of injection points, c R(ii) , and v R(ii) are the concentration and volume of R applied at the ii-th application point, e.g., the injection point, respectively, where the concentration threshold of the c R(ii) (W / W) is 0.1% or 0.2%, the upper limit of the concentration threshold is 51%, and the volume threshold of the v R(ii) is 1 / 800 or 1 / 300 of the target volume (abbreviated as v 靶(ii) ), and the upper limit of the volume threshold is 3 times v 靶(ii) . wherein the active form of R' is manifested as a form completely complexed with an acid in solution; while the active form of R is manifested as a form that is less complexed with an acid in solution and mainly exists in a form of extremely little or partial complexation, so as to provide an activity (abbreviated as activity A) that is difficult to provide by R' through the transient local action of this different active form, including at least one of the following: the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the lesion tissue (abbreviated as activity A2), and / or the effect of effectively releasing lesion immune substances and / or inflammatory signals in the lesion (abbreviated as activity A3).

13. The pharmaceutical combination according to claim 11 or 12, which is a pharmaceutical combination for treating solid tumors, comprising the R and B, wherein: - The activity A of the R includes at least effectively reducing the biological barrier function (activity A1); - The cell-reactive anti-tumor drug (B) provides the cell reaction (abbreviated as activity B) through the following definitions, and one of the key control steps of this reaction is to cross the above biological barrier: 1). It is applied to the tumor mass or / and systemically administered; 2). The dosage for one treatment course is: Wherein, Q B is ≤ the conventional dosage in the sensitive tumor of said B, n B , q B(j) are respectively the number of systemic administrations of B in a treatment course and the dosage at the j-th (j = 1,... n B ) administration, n B＇ , c B(j＇) , and v B(j＇) are respectively the number of tumor administrations of B in a treatment course, and the concentration and volume at the j'-th (j' = 1,... n B＇ ) administration.

14. The pharmaceutical combination according to any one of claims 11-13, comprising the R, C, and / or D, wherein: - The activity A of the R includes at least the effect of effectively damaging the lesion tissue (activity A2); - The C is used to provide the effect of improving the local efficacy-to-toxicity ratio of the R (abbreviated as activity C) through the following definitions: 1). It is administered in mixture with the R; 2). The mixing ratio (Q C / Q R ) of C to R is from 0.5 to 4.0; - The D provides the drug effect of improving the drug effect of the R through the following definitions: 1). It is applied to the lesion, including being administered in mixture with the R or separately administered; 2). Dosage Q for one treatment course E is ≤ the effective dosage for transient local action.

15. The pharmaceutical combination according to any one of claims 11-14, comprising the R and E, wherein: - The activity A of the R includes at least the effect of effectively reducing the biological barrier function (activity A1) and / or the effect of effectively releasing lesion immune substances and / or inflammatory signals in the lesion (activity A3); - The E is used to provide an immunomodulatory effect that benefits from the effect of the activity A1 and / or the effect of optimizing local and / or systemic immune responses by utilizing the effect of the activity A3 (abbreviated as activity E) through the following definitions: 1). It is applied to the lesion or / and systemically administered; 2). The dosage for one course of treatment is: Wherein, Q E is ≤ the conventional dosage in the anti-pathogenic application of the said E, n E , q E(k) are respectively the number of systemic administrations of E in a treatment course and the dosage at the kth time (j = 1,..., n k ), n E＇ , c E(k＇) , and v E(k＇) are respectively the number of tumor administrations of E in a treatment course, and the concentration and volume at the k'th time (k' = 1,..., n k＇ ).

16. The preparation according to any one of claims 1-10 or the pharmaceutical combination according to any one of claims 11-15, wherein the N,N-dimethylsubbiguanide (R) comprises < 30% (w / w), preferably ≦ 5% (w / w) of the biguanide salt (R'), or more preferably does not comprise the biguanide salt (R'). Optionally, the N,N-dimethylsubbiguanide (R) is in the form of a powder for injection.

17. The pharmaceutical combination according to any one of claims 11-16, wherein the cell-reactive anti-tumor drug comprises or is selected from at least one of the following: cisplatin, cyclophosphamide, carboplatin, doxorubicin, ifosfamide, nitrogen mustard, fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, fludarabine salt, paclitaxel, docetaxel, vincristine, vinblastine, vindesine, etoposide, irinotecan, topotecan, daunorubicin, mitoxantrone, gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and its derivatives.

18. A composition comprising the preparation according to any one of claims 1-10 or the pharmaceutical combination according to any one of claims 11-17.

19. A preparation comprising the pharmaceutical combination according to any one of claims 11-17 or the composition according to claim 18.

20. Use of N,N-dimethylsubbiguanide (abbreviated as R) as a transient active ingredient in the preparation of a preparation, a drug, a pharmaceutical combination or a kit for treating tumors or nodules.

21. Use of the preparation according to any one of claims 1-10, the pharmaceutical combination according to any one of claims 11-17, the composition according to claim 18 or the preparation according to claim 19 in the preparation of a drug, a pharmaceutical combination or a kit for treating a lesion such as a tumor or a nodule in a subject.

22. The use according to claim 20 or 21, wherein the N,N-dimethylsubbiguanide is used to provide a morphological manifestation different from that of a conventional biguanide drug (the active ingredient thereof is R'), wherein the active morphological manifestation of R' is in the form of being completely complexed with an acid in solution; while the active morphological manifestation of R is less complexed with an acid in solution and mainly exists in the form of being rarely or partially complexed, so as to provide an activity (abbreviated as activity A) that is difficult to provide by R' through the transient local action of this different active form, including the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), or / and the effect of effectively releasing diseased immune substances or / and inflammatory signals in the lesion (abbreviated as activity A3).

23. A method of treating cells within a lesion, such as cells of a tumor or nodule, comprising administering or intervening the N,N-dimethylbiguanide (R) in the preparation according to any one of claims 1-10, the drug combination according to any one of claims 11-17, the composition according to claim 18, or the preparation according to claim 19 into the lesion, permeating into the lesion tissue, and contacting and killing the cells within the tissue.

24. A method for treating a lesion, comprising: Administering or intervening the N,N-dimethylbiguanide (R) in the preparation according to any one of claims 1-10, the drug combination according to any one of claims 11-17, the composition according to claim 18, or the preparation according to claim 19 into the lesion, permeating into the lesion tissue, and contacting and killing the cells within the tissue.

25. A method of treating a tumor in a subject, comprising: Intervening or administering the preparation according to any one of claims 1-10 into the tumor in the subject, or, Intervening or administering the N,N-dimethylbiguanide (R) in the preparation according to any one of claims 1-10, the drug combination according to any one of claims 11-17, the composition according to claim 18, or the preparation according to claim 19 into the tumor in the subject, and systemically administering to the subject and / or intervening or administering one or more of B, D, and E to the tumor mass.

26. The method according to any one of claims 23-25, wherein the intervening or administering comprises multi-point intervening or administering, preferably, comprises micro multi-point intervening or administering, and more preferably, comprises micro multi-point injection.

27. The method according to any one of claims 23-26, wherein the formulation is suitable for administration or intervention in a microvolume to reduce the lesion volume, and the ratio of the administration volume to the target volume (V 施用 / V 靶 ) is about 0.02-0.056, 0.02-0.10 or 0.02-0.

34.

28. The method according to any one of claims 23-27, wherein when the lesion is ≧ about 3.5 cm 3 or the maximum dimension is ≧ about 2 cm, the plurality of points is ≧ 5 points, such as 10, 15, 20, 25, 30, 35, 50, or 100 points.

29. The method according to any one of claims 20-28, wherein the intervening or administering is low-frequency, preferably, the low frequency is 1-6 times per course of treatment, and more preferably, is 1-5 times per course of treatment, is 1-4 times per course of treatment, is 1-3 times per course of treatment, or is 1-2 times per course of treatment.

30. The method according to any one of claims 23-29, wherein the R and B can be provided by one or more preparations, and wherein: The R and B are administered within the lesion or tumor mass; The R and B are respectively administered within the lesion or tumor mass and systemically; or The R and a part of B are administered within the lesion or tumor mass, and another part of B is systemically administered.

31. The method according to any one of claims 23-29, wherein the R and C can be provided by one or more preparations, and wherein both the R and C are administered within the lesion or tumor mass.

32. The method according to any one of claims 23-29, wherein the R and D can be provided by one or more preparations, and wherein both the R and D are administered within the lesion or tumor mass.

33. The method according to any one of claims 23-29, wherein the R and E can be provided by one or more preparations, and wherein: Both the R and E are administered within the lesion or tumor mass; The R and E are respectively administered within the lesion or tumor mass and systemically; or The R and a part of E are administered within the lesion or tumor mass, and another part of E is systemically administered.

34. The preparation according to any one of claims 1-10, the pharmaceutical combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, or the use according to any one of claims 20-22 or the method according to any one of claims 23-33, wherein the R is not mixed with a sufficient amount of R' or an acidifying agent capable of converting the R into a sufficient amount of R', and the sufficient amount means an amount such that the amount ratio of R' to R (R' / R) is ≧1 / 3.

35. The use according to any one of claims 20-22 or the method according to any one of claims 23-34, wherein the N,N-dimethylbiguanide (R) is used to provide an active form different from the conventional metformin drug (whose active ingredient is R') as defined below: 1). It is not mixed with an acid that significantly converts the R into R'; 2). It is administered locally to the lesion; 3). The dosage for one treatment course is as follows: Wherein, Q R <50% or 25% of the equivalent usage amount of said R', n R is the number of times of administration of R to the lesion or tumor mass in one treatment course, q R(i) is the dosage of R in the i-th (i = 1,... n R ) administration, and: where n Ri is the number of application points of R at the i-th application, such as the number of needle insertion points, c R(ii) , and v R(ii) are the concentration and volume of R applied at the ii-th application point, such as the needle insertion point, where the c R(ii) (W / V) concentration threshold is 0.1% or 0.2%, and the upper limit of the concentration threshold is 51%; the v R(ii) volume threshold is 1 / 800 or 1 / 300 of the target volume (abbreviated as v 靶(ii) ), and the upper limit of the volume threshold is 3 times v 靶(ii) . wherein the active form of the R' is in the form of being completely complexed with an acid in solution; while the active form of the R is in the form of being less complexed with an acid in solution and mainly existing in a very little or partially complexed form, so as to provide an activity (abbreviated as activity A) that is difficult for the R' to provide through the transient local action of the different active forms, including at least one of the following: the effect of effectively reducing the biological barrier function (abbreviated as activity A1), the effect of effectively damaging the diseased tissue (abbreviated as activity A2), and / or the effect of effectively releasing the diseased immune substances and / or inflammatory signals within the lesion (abbreviated as activity A3).

36. The use or method according to claim 35, wherein the R and the drug (Z) are used in combination, and the application concentration (w / w) of the R is 0.1%-51%, preferably 0.2%-50%, and the drug (Z) includes at least one selected from the following groups: cell-reactive anti-tumor drugs (abbreviated as B), near-neutral or weakly basic sodium salts (abbreviated as C), methylene blue (abbreviated as D), and immunomodulators (abbreviated as E), wherein: - The cell-reactive anti-tumor drug (B) provides the cell reaction (abbreviated as activity B) as defined below, and one of the key control steps of this reaction is to cross the above biological barrier: 1). It is administered to the lesion or / and systemically; 2). The dosage for one treatment course is as follows: Wherein, Q B is the conventional dosage in the sensitive tumor of B, n B , q B(j) are respectively the number of systemic administrations of B in a treatment course and the dosage at the j-th time (j = 1,..., n B ), n B＇ , c B(i＇) , and v B(i＇) are respectively the number of tumor administrations of B in a treatment course, and the concentration and volume at the j'-th time (j' = 1,..., n B＇ ) of administration; - The C is used to provide the effect of improving the local efficacy-to-toxicity ratio of the R (abbreviated as activity C) as defined below: 1). It is administered in combination with the R; 2). The mixing ratio (Q C / Q R ) of C to R is 0.5 to 4.0; - The D provides the pharmacodynamic effect of improving the drug effect of the R as defined below: 1). It is administered to the lesion, including being administered in combination with the R or separately; 2). Dosage Q for one course of treatment E The C for ≤ the effective dosage of transient local action is defined as follows to provide an effect of improving the local efficacy-to-toxicity ratio of the R (abbreviated as active C): 1). It is administered in combination with the R; 2). The mixing ratio (Q C / Q R ) of C to R is 0.5 to 4.0; - The D provides the pharmacodynamic effect of improving the drug effect of the R as defined below: 1). It is administered to the lesion, including being administered in combination with the R or separately; 2). Dosage Q for one treatment course E is ≤ the effective dosage for transient local action, - The E is used to provide an immunomodulatory effect benefiting from the effect of the activity A1 and / or an effect of optimizing the local or / and systemic immune response by utilizing the effect of the activity A3 (abbreviated as activity E): 1). It is administered to the lesion or / and systemically; 2). The dosage for one treatment course is: Wherein, Q E is ≤ the conventional dosage in the anti-pathogenic application of the said E, n E , q E(k) are respectively the number of times of systemic administration of E in a treatment course and the dosage at the k-th time (j = 1,... n k ), n E＇ , c E(k＇) , and v E(k＇) are respectively the number of times of tumor administration of E in a treatment course, and the concentration and volume at the k'-th time (k' = 1,... n k＇ ).

37. The use or method according to claim 35 or 36, wherein the R is used in combination with a cell-reactive anti-tumor drug (abbreviated as B) and an immunomodulator (abbreviated as E), wherein: - The cell-reactive anti-tumor drug (B) provides the cell reaction (abbreviated as activity B) through the following definition, and one of the key control steps of this reaction is to cross the above biological barrier: 1). Lesion administration or / and systemic administration; 2). The dosage for one treatment course is as follows: Wherein, Q B is the conventional dosage in the sensitive tumor of B, n B , q B(j) are the number of times of systemic administration of B in a course of treatment and the dosage at the j-th time (j = 1,... n B ), respectively, n B＇ , c B(i＇) , and v B(i＇) are the number of times of tumor body administration of B in a course of treatment, and the concentration and volume at the j'-th time (j' = 1,... n B＇ ), respectively, - The immunomodulator (E) is used to provide an immunomodulatory effect that benefits from the effect of the activity A1, or / and to optimize the local or / and systemic immune response by utilizing the effect of the activity A3 (abbreviated as activity E) through the following definition: 1). Lesion administration or / and systemic administration; 2). The dosage for one treatment course is as follows: Wherein, Q E is the conventional dosage in the anti-pathological application of the said E, n E , q E(k) are respectively the number of times of systemic administration of E in a treatment course and the dosage at the k-th time (j = 1,... n k ), n E＇ , c E(k＇) , and v E(k＇) are respectively the number of times of tumor administration of E in a treatment course, and the concentration and volume at the k'-th time (k' = 1,... n k＇ ).

38. The preparation according to any one of claims 1-10, the drug combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20-22 or the method according to any one of claims 23-37, wherein the R is contained in a powder.

39. The preparation according to claim 10, the drug combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20-22 or the method according to any one of claims 23-37, wherein the cell-reactive anti-tumor drug (B) includes cytotoxic drugs and targeted anti-tumor drugs.

40. The drug combination, composition, preparation, use or method according to claim 39, wherein the cytotoxic drugs include DNA-damaging agents, antimetabolites or antimicrotubule agents, and the DNA-damaging agents include cisplatin, carboplatin, oxaliplatin, ifosfamide, doxorubicin; the antimetabolites include fluorouracil, gemcitabine, methotrexate; the antimicrotubule agents include paclitaxel, vincristine.

41. The drug combination, composition, preparation, use or method according to claim 39, wherein the targeted anti-tumor drugs include kinase inhibitors.

42. The drug combination, composition, preparation, use or method according to claim 41, wherein the kinase inhibitors include gefitinib, osimertinib, larotrectinib, pazopanib, trastuzumab and its derivatives.

43. The preparation according to claim 10, the pharmaceutical combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20-22 or the method according to any one of claims 23-37, wherein the near-neutral or weakly basic sodium salt (C) comprises: Sodium chloride, sodium bicarbonate (abbreviated as SB), sodium dihydrogen phosphate (MSP), sodium lactate (abbreviated as Nal), sodium acetate (abbreviated as SA).

44. The preparation according to claim 10, the drug combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20-22 or the method according to any one of claims 23-37, wherein the near-neutral or weakly alkaline sodium salt (C) is sodium bicarbonate (SB).

45. The preparation according to claim 10, the pharmaceutical combination according to any one of claims 11 - 17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20 - 22, or the method according to any one of claims 23 - 37, wherein the methylene blue dye (D) comprises methylene blue, patent blue, isothiocyanine blue, and new methylene blue.

46. The preparation according to claim 10, the pharmaceutical combination according to any one of claims 11 - 17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20 - 22, or the method according to any one of claims 23 - 37, wherein the methylene blue dye (D) is methylene blue.

47. The preparation according to claim 10, the pharmaceutical combination according to any one of claims 11 - 17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20 - 22, or the method according to any one of claims 23 - 37, wherein the immunomodulator (E) comprises biological macromolecule immunomodulators (abbreviated as E1), immune cell immunomodulators (abbreviated as E2), and vaccine immunomodulators (abbreviated as E3).

48. A kit, which comprises the preparation according to any one of claims 1 - 10 or the pharmaceutical combination according to any one of claims 11 - 20, and instructions for implementing the method according to any one of claims 23 - 37.

49. The kit according to claim 48, which further comprises a micro - volume intervention device.

50. The kit according to claim 49, wherein the micro - volume intervention device is suitable for micro - volume multi - point contact or administration, preferably comprising a micro - injection device, wherein the micro - volume is a drug administration volume of ≤ 5% or 10% of the target volume.

51. The preparation according to any one of claims 2 - 10, the pharmaceutical combination according to any one of claims 11 - 17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20 - 22, the method according to any one of claims 23 - 37, or the kit according to any one of claims 48 - 50, wherein the local lesion or tumor is a malignant tumor refractory to conventional chemotherapeutic drugs. Preferably, the refractory malignant tumor comprises or is selected from at least one of the following groups: chemotherapy - drug - resistant tumors, tumors with an adverse microenvironment, tumors with discontinued use of anti - tumor drugs, tumors for which there are no effective chemotherapeutic drugs, and tumors carried by patients with contraindications or ineligibilities for conventional chemotherapeutic drugs.

52. The preparation according to any one of claims 2 - 10, the pharmaceutical combination according to any one of claims 11 - 17, the composition according to claim 18, the preparation according to claim 19, the use according to any one of claims 20 - 22, the method according to any one of claims 23 - 37, wherein the nodule is a nodule containing at least one of the following non - malignant cells: connective tissue cells, secretory gland cells, non - malignant nodules of epithelial cells. The preparation according to any one of claims 2-10, the pharmaceutical combination according to any one of claims 11-17, the composition according to claim 18, the preparation according to claim 19, or the use according to any one of claims 20-22, the method according to any one of claims 23-37, wherein the lesion comprises a solid tumor.

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