Composition and drug-device combination product for local tumor administration, and use

Abstract

A composition and drug-device combination product for local tumor injection, and the use thereof in the preparation of a drug for local tumor injection administration. The composition comprises an anti-tumor pharmaceutical ingredient, an immune adjuvant and a pharmaceutical carrier. By means of a specially designed jet microneedle delivery device, an anti-tumor drug can be locally administered to a tumor, thus avoiding the problem that traditional intravenous administration limits the maximum dose and therapeutic effect of the drug due to systemic toxicity. High-concentration local administration of the composition not only improves the local therapeutic effect on the tumor, but also can effectively produce a tumor antigen. In the subsequent course of treatment after the initial treatment, only a composition of an immune adjuvant and a tumor-specific polypeptide, or the immune adjuvant alone, can be administered to maintain and enhance the established tumor-specific immune response, avoiding the cumulative toxicity caused by repeated use of chemotherapeutic drugs.

Description

Compositions, drug-device combinations and uses for local tumor administration

[0001] This application claims priority to Chinese Patent Application No. 202411585426.8, filed on November 7, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedical technology, specifically to a composition, drug-device combination product, and its use for local tumor administration. Background Technology

[0003] Malignant tumors are among the major diseases threatening human health and life. Currently, the main clinical treatments for malignant tumors include surgery, radiotherapy, chemotherapy, and targeted therapy. Among these, tumor treatment drugs, such as chemotherapy drugs, are usually administered intravenously. However, due to systemic toxicity, the dosage and therapeutic effect are limited, and drug resistance is easily developed. This method of administration results in insufficient drug concentration at the tumor site and can cause some damage to normal tissues throughout the body. While targeted therapy has a certain degree of selectivity, target selection is difficult and lacks universality, it is also prone to drug resistance, and is costly.

[0004] Tumor vaccines work by activating the body's immune system to recognize and attack tumor cells. To enhance the immunogenicity of vaccines, adjuvants are usually added as auxiliary components. However, in practical applications, the effectiveness of tumor vaccines in the rapid treatment of solid tumors needs further improvement, and the efficacy of single-treatment methods still requires enhancement.

[0005] Therefore, despite the availability of various treatment options, their effectiveness remains limited for patients with advanced cancer. Combined therapy using multiple techniques is currently the preferred approach. However, current clinical applications of combined therapy involve the sequential use of multiple treatment modalities. There is currently no single treatment regimen that incorporates multiple therapeutic techniques. Therefore, new single-treatment strategies that integrate multiple therapeutic techniques are urgently needed.

[0006] The background description is provided for the purpose of understanding the relevant technologies in this field and is not intended as an admission of prior art. Summary of the Invention

[0007] The purpose of this invention is to provide a composition, a drug-device combination product, a preparation method, and uses for local tumor administration.

[0008] In a first aspect, the present invention provides a composition for local injection into a tumor, comprising:

[0009] (a) An antitumor drug component, wherein the content of the antitumor drug component is preferably from 0.05% to 5% by weight, and the concentration of the antitumor drug component is preferably 0.1-20 mg / mL, wherein the antitumor drug component is preferably a cytotoxic antitumor drug, and more preferably, selected from at least one of the following categories:

[0010] (i) A drug that interferes with nucleic acid metabolism, preferably selected from at least one of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, and hydroxyurea.

[0011] (ii) Drugs that affect DNA function, preferably selected from at least one of alkylating agents, platinum compounds, antibiotics, and topoisomerases.

[0012] (iii) A drug that interferes with the transcription process, preferably selected from at least one of doxorubicin, daunorubicin, and actinomycin.

[0013] (iv) A drug that inhibits protein synthesis, preferably selected from at least one of L-asparaginase, vinca alkaloids, and paclitaxel.

[0014] (v) A drug for regulating the body's hormonal balance, preferably selected from at least one of estrogen, androgen, medroxyprogesterone acetate, tamoxifen, glucocorticoids, and omeprazole.

[0015] (vi) Radiopharmaceuticals,

[0016] (vii) Targeted drugs,

[0017] (viii) Immune checkpoint inhibitors;

[0018] Preferably, the antitumor drug component is selected from at least one of paclitaxel derivatives, albumin-bound paclitaxel derivatives, PDL-1 derivatives, dual-target PDL-1 derivatives, multi-target PDL-1 derivatives, radiopharmaceuticals, and cisplatin derivatives;

[0019] (b) An immune adjuvant, preferably in an amount of 0.05% to 5% by weight, preferably at a concentration of 10-1,000 μg / mL, and preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably selected from one or more of the following:

[0020] - Saponin adjuvants, preferably QS-21 and GPI-0100;

[0021] - Mycoglycolipid adjuvants, preferably MPL and RC-529;

[0022] - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives;

[0023] - Polymer I:C and its derivatives;

[0024] -MDP derivatives, preferably MDP and Nor-MDP;

[0025] - Cytokines, preferably GM-CSF, IL-2, and IL-12;

[0026] -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein AS01B is a complex adjuvant composed of MPL and saponin QS-21;

[0027] (c) The drug carrier may be one or more of physiological saline, polymer materials, emulsions and liposomes.

[0028] In some embodiments of the present invention, the drug carrier comprises:

[0029] The erodeable sustained-release agent is preferably composed of 45% to 85% by weight, more preferably 55% to 75% by weight, and is composed of polyorthoester polymers.

[0030] The viscosity reducer is preferably present in a content of 15% to 55% by weight, more preferably 25% to 45% by weight, and preferably composed of a glycerol ester compound, more preferably composed of glycerol triacetate.

[0031] In some embodiments of the invention, the viscosity of the composition, measured at 25°C, is from 100 mPa·s to 5000 mPa·s, preferably from 500 mPa·s to 4000 mPa·s, and more preferably from 800 mPa·s to 3000 mPa·s.

[0032] In some embodiments of the present invention, the number average molecular weight of the polyorthoester is 1,000 to 20,000 Daltons, preferably 2,000 to 10,000 Daltons, and most preferably 4,000 to 7,000 Daltons.

[0033] In some embodiments of the present invention, a thermally sensitive sustained-release agent is used, wherein the content of the thermally sensitive sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 75% to 99.5% by weight, and preferably the curing temperature of the thermally sensitive sustained-release agent is from 30°C to 45°C at a low-temperature curing temperature (from liquid to solid), preferably from 35°C to 39°C, more preferably from 36°C to 38°C, wherein the thermally sensitive sustained-release agent comprises at least one of the following:

[0034] Polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (poloxamer 407),

[0035] Lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA).

[0036] Preferably, the temperature-sensitive sustained-release agent consists of PEO-PPO-PEO or PLGA-PEG-PLGA.

[0037] In some embodiments of the present application, the drug carrier comprises:

[0038] a non-sustained-release agent, preferably in an amount of 45% to 99.95% by weight, more preferably 55% to 99.95% by weight, consisting of liposomes, physiological saline or glucose water.

[0039] In a second aspect, the present application provides a fluid delivery device for delivering a composition to a tumor site, comprising:

[0040] (i) a tube for containing the composition,

[0041] (ii) an injection head fixedly connected to the storage chamber of the tube or an injection head detachably connected to the storage chamber of the tube, the injection head comprising one or more needle pieces, preferably with a pore size of 0.05-2mm and a length of 1-30mm,

[0042] (iii) a motorized power mechanism for controlling the delivery of the composition;

[0043] Preferably, the fluid delivery device further comprises (iv) an interventional soft needle, one end of which is connected to the tube and the other end of which is connected to the injection head or integrated with the injection head;

[0044] Optionally, the tumor site comprises at least one of the following sites: intratumoral, peritumoral, local lymph node.

[0045] In a third aspect, the present application provides a pharmaceutical kit, which can comprise:

[0046] (a) the composition described above;

[0047] (b) a fluid delivery device, comprising:

[0048] (i) a tube for containing the composition,

[0049] (ii) an injection head fixedly connected to the storage chamber of the tube or detachably connected to the storage chamber of the tube, the injection head comprising one or more needle members, preferably the needle members have a bore diameter of 0.05-2 mm and a length of 1-30 mm,

[0050] (iii) a motorized power mechanism for controlling the delivery of the composition;

[0051] Preferably, the fluid delivery device further comprises (iv) an interventional soft needle, one end of the interventional soft needle being connected to the tube and the other end being connected to the injection head or integrated with the injection head.

[0052] In a fourth aspect, the present application provides use of the above-mentioned composition or pharmaceutical product in the preparation of a medicament for treating a tumor by local administration.

[0053] Preferably, the tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, brain glioma or bladder cancer.

[0054] Preferably, the local administration is selected from at least one of the following modes: intratumoral injection, peritumoral injection, local lymph node injection.

[0055] In a fifth aspect, the present application provides use of a composition containing an antitumor drug component and an immunoadjuvant in the preparation of a medicament for local injection administration to a tumor, the composition being injected locally to the tumor, thereby preferably causing the antitumor drug component to induce the production of a tumor antigen (preferably, the tumor antigen is selected from a tumor-associated antigen or a tumor-specific antigen; further, the tumor-specific antigen includes a tumor neoantigen), while the immunoadjuvant enhances the activity of tumor-specific immune cells activated in vivo against the produced tumor antigen;

[0056] Preferably, the antitumor drug is a cytotoxic antitumor drug, more preferably selected from at least one of the following categories:

[0057] (i) a nucleic acid metabolism interfering drug, preferably selected from at least one of the following: methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, hydroxyurea,

[0058] (ii) a DNA function affecting drug, preferably selected from at least one of the following: alkylating agents, platinum compounds, antibiotics, topoisomerase drugs,

[0059] (iii) a transcription process interfering drug, preferably selected from at least one of the following: doxorubicin, daunorubicin, actinomycin,

[0060] (iv) a drug that inhibits protein synthesis, preferably at least one selected from the group consisting of L-Asparaginase, Vinca alkaloids, Taxol,

[0061] (v) a drug that modulates the hormonal balance in the body, preferably at least one selected from the group consisting of estrogens, androgens, medroxyprogesterone esters, tamoxifen, glucocorticoids, anastrozole,

[0062] (vi) a radiopharmaceutical,

[0063] (vii) a targeted drug,

[0064] (viii) an immune checkpoint inhibitor drug;

[0065] Preferably, the antitumor drug component is selected from at least one of the group consisting of taxols, albumin taxols, PDL-1s, dual-target PDL-1s, multi-target PDL-1s, radiopharmaceuticals, cisplatin drugs;

[0066] Preferably, the immunoadjuvant is preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably selected from one or more of the following:

[0067] - saponin adjuvants, preferably QS-21, GPI-0100;

[0068] - mycosphingolipid adjuvants, preferably MPL, RC-529;

[0069] - guanylate cyclase adjuvants, preferably guanylic acid (CDG) and its derivatives;

[0070] - poly I:C and its derivatives;

[0071] - MDP derivatives, preferably MDP, Nor-MDP;

[0072] - cytokines, preferably GM-CSF, IL-2, IL-12;

[0073] - more preferably at least one selected from the group consisting of AS01B and GM-CSF, wherein AS01B is a complex adjuvant consisting of MPL and saponin QS-21.

[0074] Preferably, the tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, brain glioma or bladder cancer.

[0075] Preferably, the local administration mode is selected from at least one of the following modes: intratumoral injection, peritumoral injection, local lymph node injection.

[0076] In a sixth aspect, the present application provides the use of an immunoadjuvant or a combination of an immunoadjuvant and a tumor-specific polypeptide for the manufacture of a medicament for local injection into a tumor, preferably said medicament comprising said immunoadjuvant is injected into said tumor locally in a subsequent course of treatment after a composition comprising an anti-tumor drug component has been injected into said tumor locally, thereby preferably maintaining or enhancing the activity of tumor-specific immune cells activated by tumor antigens induced by said anti-tumor drug component in vivo;

[0077] Preferably, said medicament comprising an immunoadjuvant does not comprise an anti-tumor drug component or a tumor vaccine component.

[0078] Preferably, said immunoadjuvant is preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably selected from one or several of:

[0079] - saponin-based adjuvants, preferably QS-21, GPI-0100;

[0080] - mycolic acid-based adjuvants, preferably MPL, RC-529;

[0081] - guanylate-based adjuvants, preferably guanylic acid (CDG) and derivatives thereof;

[0082] - poly I:C and derivatives thereof;

[0083] - MDP derivatives, preferably MDP, Nor-MDP;

[0084] - cytokines, preferably GM-CSF, IL-2, IL-12;

[0085] - more preferably at least one selected from AS01 B and GM-CSF, wherein AS01 B is a complex adjuvant consisting of MPL and saponin QS-21.

[0086] Preferably, said tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma or bladder cancer.

[0087] Preferably, said local administration is selected from at least one of the following modes: intratumoral injection, peritumoral injection, local lymph node injection.

[0088] In a seventh aspect, the present application provides a combination product comprising:

[0089] (a) a composition according to the above or a pharmaceutical device combination according to the above; and

[0090] (b) a personalized tumor vaccine, wherein said personalized tumor vaccine comprises a personalized antigen series matching the tumor patient.

[0091] In an eighth aspect, the present application provides use of the above-mentioned combination product in the manufacture of a combination product for treating a malignant tumor.

[0092] In a ninth aspect, the present application provides use of the above-mentioned composition or pharmaceutical combination product in the manufacture of a combination product for treating a malignant tumor in combination with a personalized tumor vaccine.

[0093] In a ninth aspect, the present application provides a method for treating a tumor using the above-mentioned pharmaceutical combination product, comprising the following steps:

[0094] (a) obtaining a multi-modal medical image of a patient;

[0095] (b) performing image fusion and path planning by using an image processing system;

[0096] (c) guiding an injection head or an interventional soft needle of the fluid delivery device to a tumor site according to the path planning, the tumor site preferably including an intratumoral site, a peritumoral site, a lymph node site;

[0097] (d) applying a delivery force by the power mechanism to control the composition to implement drug diffusive delivery at the tumor site;

[0098] Preferably, it further comprises: (e) performing efficacy evaluation 1-8 weeks after administration, and deciding whether to repeat steps (a)-(d) according to the evaluation result.

[0099] In some embodiments of the present application, the obtaining a multi-modal medical image of a patient comprises: obtaining a first modality medical image and a second modality medical image of a patient; preferably, the first modality medical image is selected from one of CT image, MRI image, PET image, SPECT image, and ultrasound image, and the second modality medical image is selected from another one of CT image, MRI image, PET image, SPECT image, and ultrasound image.

[0100] In some embodiments of the present application, the performing image fusion and path planning by using an image processing system comprises: performing three-dimensional reconstruction on the obtained first modality medical image; fusing the reconstructed first modality medical image and the second modality medical image to obtain a fused three-dimensional modeling model; performing path planning in the three-dimensional modeling model; preferably, the three-dimensional reconstruction algorithm is selected from at least one of filtered back projection, maximum likelihood expectation maximization, ordered subset expectation maximization, deep learning reconstruction, time-of-flight (TOF) reconstruction, and Fourier transform reconstruction.

[0101] In some embodiments of the present application, the guiding step is accomplished by a guiding system, which comprises a steerable catheter, a first step steering mechanism for coarsely steering the catheter, and a second step steering mechanism for finely steering the catheter, wherein the interventional soft needle extends within the catheter.

[0102] In some embodiments of the present application, the guiding step is accomplished by a navigation system, preferably one or more of the following:

[0103] i) an electromagnetic navigation system;

[0104] ii) an optical navigation system;

[0105] iii) an image-guided navigation system.

[0106] In some embodiments of the present application, the guiding step is accomplished by an endoscopic system.

[0107] In some embodiments of the present application, the endoscopic system is one or more of the following:

[0108] i) an optical endoscopic system;

[0109] ii) an ultrasonic endoscopic system;

[0110] iii) a confocal microscopic endoscopic system.

[0111] In some embodiments of the present application, the guiding step is accomplished by a guiding system comprising a navigation system and an endoscopic system, preferably the guiding step comprises:

[0112] using the navigation system to guide the interventional soft needle of the fluid delivery device to the vicinity of the target region;

[0113] using the endoscopic system to finely position the interventional soft needle of the fluid delivery device to the tumor site.

[0114] In some embodiments of the present application, the method further comprises the following steps:

[0115] acquiring tissue information of the tumor site in real time using data of the guiding system;

[0116] superimposing the acquired tissue information onto the three-dimensional modeling model;

[0117] adjusting the delivery parameters of the drug delivery in real time based on the three-dimensional modeling model superimposed with the tissue information. The present application has the following beneficial effects:

[0118] The present application adopts local injection of tumor to administer the drug, and the anti-tumor drug and the immune adjuvant can be directly delivered in the tumor tissue through a specially designed fluid delivery device. This administration method avoids the systemic toxicity caused by the drug entering the blood system, thereby breaking through the dosage limit of traditional intravenous administration, achieving better effect on tumor cells and allowing higher local administration dosage.

[0119] Further, the high concentration of anti-tumor drugs plays a dual role in the local part: on the one hand, it can kill tumor cells more effectively, significantly improving the local treatment effect; on the other hand, through the strong cell killing effect, a large number of tumor antigens, especially tumor neoantigens with high specificity, are induced. The tumor antigens generated in situ can synergize with the immune adjuvant under the premise that the patient's immune system is not damaged by drug systemic toxicity, significantly improve the immune response to these tumor antigens by enhancing the antigen presentation function of dendritic cells and activating and enhancing the function of T cells and NK cells, thereby forming a strong local and systemic anti-tumor immune effect.

[0120] The present inventors have also found that after the initial combination therapy establishes an immune response, only the combination of immune adjuvants and tumor-specific polypeptides or the immune adjuvant alone can be administered for local injection of the tumor to maintain and enhance the established systemic immunotherapy of tumor-specific immune response. This step-by-step treatment strategy not only avoids the cumulative toxicity of repeated use of chemotherapy drugs, but also maintains the activity of tumor-specific immune cells through continuous immune stimulation, producing a long-term anti-tumor effect.

[0121] In summary, the innovative administration method of the present application not only reduces systemic toxicity, but also kills tumor cells and induces tumor antigens through high-concentration local administration, and enhances immune response with immune adjuvants, achieving the synergistic effect of drugs and immunity. In particular, the strategy of using immune adjuvants alone or in combination with tumor-specific polypeptides in subsequent treatment maintains and enhances the established tumor-specific immune effect, and as a whole forms an efficient and sustainable treatment plan, providing a new treatment option for patients with advanced tumors.

[0122] Some of the other optional features and technical effects of the embodiments of the present application are described below, and some can be understood by reading this document. BRIEF DESCRIPTION OF DRAWINGS

[0123] In the following, embodiments of the present application will be described in detail with reference to the accompanying drawings, wherein the shown elements are not limited by the proportions shown in the drawings, and wherein the same or similar reference signs refer to the same or similar elements, and wherein:

[0124] Fig. 1 shows a schematic structural diagram of a fluid delivery device according to an embodiment of the present application;

[0125] FIG. 2 shows a non-limiting schematic diagram of the mechanism of tumor treatment by local diffuse injection of the present application and by several comparative modes of tumor injection;

[0126] FIG. 3 shows a non-limiting schematic diagram of the comparison of drug concentration over time in different modes of administration for intravenous injection and intratumoral injection, wherein: (a) is a schematic diagram of the distribution of the drug in blood vessels and tumor tissue for intravenous injection, (b) is a schematic drug concentration-time curve in blood and in the tumor local (intratumoral) for intravenous injection, (c) is a schematic diagram of the distribution of the drug in blood vessels and tumor tissue for intratumoral injection, and (d) is a schematic drug concentration-time curve in blood and in the tumor local (intratumoral) for intratumoral injection;

[0127] FIG. 4 shows a comparison of the size of tumor tissues isolated after treatment of late-stage tumors in mice, wherein: (a) is a saline needle injection group, (b) is a paclitaxel intraperitoneal needle injection group, (c) is a paclitaxel intratumoral needle injection group, (d) is a paclitaxel + immune adjuvant intratumoral needle injection group, and (e) is a composition of the present application for intratumoral diffuse needle injection group;

[0128] FIG. 5 shows a comparison of the size of tumor tissues isolated after treatment of early-stage tumors in mice, wherein: (a) is a saline needle injection group, (b) is a paclitaxel intraperitoneal needle injection group, and (c) is a composition of the present application for intratumoral diffuse needle injection group with erodible sustained-release agent;

[0129] FIG. 6 shows a graph of the change in tumor volume over time for each of the treatment groups of FIG. 5, which shows the treatment effect of each group within 14 days (8 times of administration every 2 days). DETAILED DESCRIPTION

[0130] In order to make the objectives, technical solutions, and advantages of the present application clearer, further detailed description of the present application is provided below in conjunction with specific embodiments and drawings. In this regard, the schematic embodiments of the present application and their descriptions are used to explain the present application, but are not intended to limit the present application.

[0131] In this regard, various experimental or measurement means or parameters obtained by experimental or measurement means are performed under conventional conditions or manufacturer's recommended conditions, unless otherwise specified. The reagents or instruments used are conventional products that can be obtained by commercial purchase, unless otherwise specified.

[0132] The term "comprising" and its variations as used herein signify open inclusion, i.e., "including but not limited to". Unless otherwise stated, the term "or" means "and / or". The term "based on" means "at least partially based on". The terms "one example embodiment" and "one embodiment" mean "at least one example embodiment". The term "another embodiment" means "at least one additional embodiment". The terms "first", "second", etc., may refer to different or the same objects. Other explicit and implicit definitions may also be included below.

[0133] Where numerical ranges are provided herein, it is meant that every intermediate value between the upper and lower limits of that range, and any other specified or intermediate value within that range, is included in the disclosure. For example, if a range of 10 to 20 weight percentages (wt%), such as 11, 12, 13, 14, 15, 16, 17, 18, and 19 wt%, is indicated, as are value ranges greater than or equal to 10 wt% up to about 20 wt% and value ranges less than or equal to 20 wt% down to about 10 wt%, these are also explicitly disclosed.

[0134] The term “basically” means to a great extent or close to complete with respect to a feature or entity, that is, 85% or more.

[0135] The term “about,” especially when modifying a quantity, means including a deviation of plus or minus 5%, 10%, 15%, or 20%.

[0136] The terms “preferred,” “preferred,” “optional,” or “optionally” mean that the situation described below may or may not occur, such that the description includes both the occurrence and non-occurrence of such situation.

[0137] definition

[0138] In this context, the “molecular weight” of a polymer refers to its nominal average molecular weight, typically determined by size exclusion chromatography, light scattering, or sedimentation rate methods. Molecular weight can be expressed as number-average molecular weight or weight-average molecular weight. Unless otherwise stated, all molecular weights mentioned herein are exponential-average molecular weights. Both number-average and weight-average molecular weights can be determined using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​can also be used to determine the number-average molecular weight, such as colligative measurements (e.g., freezing point depression, boiling point elevation, or osmotic pressure), or to determine the weight-average molecular weight using light scattering, ultracentrifugation, or viscometry.

[0139] In this document, "pharmaceutical ingredient" or "active ingredient" refers to any compound or mixture of compounds that produces beneficial or useful results. Generally, "active pharmaceutical agent" or "pharmaceutical" refers to any organic or inorganic compound or substance that is biologically active and suitable for or intended for therapeutic purposes. As used herein, reference to a pharmaceutical agent, and to other chemical compounds mentioned herein, is intended to include any pharmaceutically acceptable salt form of the compound, including isomers of applicable compounds of this invention such as diastereomers and enantiomers, salts, solvates, polymorphs, specific crystalline forms, and racemic mixtures and pure isomers. An active pharmaceutical agent is distinct from components such as carriers, diluents, lubricants, binders, and other formulation aids, encapsulation agents, or other protective ingredients. An example of an active pharmaceutical agent is a pharmaceutical product. Suitable pharmaceutical agents include locally or systemically acting active pharmaceutical agents that can be administered to the subject by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection, either locally or intralesionally (including, for example, application to abrasions, lacerations, puncture wounds, etc., and entry into surgical wounds or incisions). Prodrugs and pharmaceutically acceptable salts of the active pharmaceutical agent are also included within the scope of this application.

[0140] In this article, "pharmaceutically acceptable salt" means a salt form of a drug having at least one suitable salt-forming group that does not cause significant adverse toxicological effects on patients.

[0141] In this paper, "biodegradable" refers to the degradation, decomposition, or digestion of polymers through biological environmental processes, including those of living organisms, particularly at physiological pH and temperature. As an example, the primary mechanism of polyorthoester biodegradation is the hydrolysis of bonds between and within polyorthoester units.

[0142] In this article, “treatment” for a disease or condition includes preventing the disease or condition from occurring in a person or animal who may be predisposed to having the disease or condition but has not yet experienced or shown symptoms of the disease or condition (preventive treatment), suppressing the disease or condition (slowing down or stopping its development), providing relief from the symptoms or side effects of the disease or condition, and alleviating the disease or condition.

[0143] In this article, "therapeutic effective amount" means the amount that is sufficient to effectively treat a disease or condition when administered to a human or animal. In this article, "standard dose" means the dose specified in the package insert of a marketed drug when administered to a human or animal to treat a disease; if the package insert specifies multiple doses or a range, then it is the maximum dose.

[0144] Currently, antitumor drugs can only be administered intravenously due to systemic toxicity limitations, resulting in insufficient local drug concentrations on the tumor. Although there have been attempts to utilize tumor antigens through intratumoral injection of adjuvants, this passive approach to utilizing existing antigens has limited effectiveness.

[0145] The inventors have discovered that by combining antitumor drugs with immune adjuvants in the same formulation for local tumor administration, a unique synergistic mechanism can be formed: high concentrations of antitumor drugs can not only effectively kill tumor cells, but more importantly, they can actively induce the production of a large number of tumor antigens, while the simultaneously present immune adjuvants can immediately enhance the immune response to these newly generated antigens.

[0146] This combination not only overcomes the limitation that anti-tumor drugs can only be administered intraperitoneally, but also achieves spatiotemporal synergy between drug therapy and immune response.

[0147] Furthermore, the present invention also found that, after initial combination therapy, local administration of immune adjuvants alone can maintain and enhance the established antitumor immune effect.

[0148] Accordingly, embodiments of the present invention provide a composition for local injection into a tumor, the composition comprising an antitumor drug component, an immune adjuvant, and a drug carrier. Embodiments of the present invention also provide a fluid delivery device for delivering the composition to a tumor site, and a pharmaceutical device combination product comprising the composition and the fluid delivery device. Embodiments of the present invention further provide the use of the above-described composition or a composition comprising an antitumor drug component and an immune adjuvant in the preparation of a medicament for local injection into a tumor, wherein the antitumor drug component and the immune adjuvant are used in an initial combination. Embodiments of the present invention further provide the use in subsequent treatment courses of a medicament for maintaining or enhancing the activity of tumor-specific in vivo immune cells activated by tumor antigens induced by the antitumor drug component, using an immune adjuvant alone or a composition of an immune adjuvant and a tumor-specific peptide.

[0149] Composition

[0150] In one embodiment, the composition for local tumor administration provided by the present invention may include an antitumor drug component, an immune adjuvant (component), and a drug carrier.

[0151] In one embodiment, the composition for local tumor administration provided by the present invention can be in the form of a solution, suspension, or emulsion, whereby the components of the composition can be injected (e.g., diffusely injected) onto the tumor site. The composition includes an antitumor drug component, an immune adjuvant, and a drug carrier. In one embodiment, the antitumor drug component is a non-tumor vaccine component. Preferably, the antitumor drug component is a cytotoxic antitumor drug. By way of explanation and not limitation, although immune adjuvants are generally used in combination with tumor vaccines, the antitumor drug component in this composition is a non-tumor vaccine component, preferably a cytotoxic antitumor drug, whose innovative combination with the immune adjuvant kills tumor cells and induces the production of tumor antigens through cytotoxic drugs, while simultaneously enhancing the immune response to these antigens using the immune adjuvant, forming a unique synergistic effect. The antitumor drug component can be dissolved in the carrier to form a solution or dispersed in the carrier to form a suspension, while the immune adjuvant can form a homogeneous mixture with the carrier. When liposomes are used as the carrier, an emulsion system can be formed. Antitumor drug components can be dissolved in a carrier to form a solution or dispersed in a carrier to form a suspension, while immune adjuvants can form a homogeneous mixture with the carrier. When liposomes are used as a carrier, an emulsion system can be formed. This invention does not limit these possibilities.

[0152] In one embodiment, the antitumor drug ingredient is selected from at least one of the following categories:

[0153] (i) Drugs that interfere with nucleic acid metabolism, preferably methotrexate (CAS No.: 59-05-2, molecular formula: C 20 H 22 N8O5), Pemetrexed (molecular formula: C 20 H 21 N5O6), mercaptopurine (molecular formula: C5H4N4S), fluorouracil (CAS No.: 51-21-8, molecular formula: C4H3FN2O2), capecitabine (molecular formula: C5H4N4S), N5O6), mercaptopurine (molecular formula: C5H4N4S), fluorouracil (CAS No.: 51-21-8, molecular formula: C4H3FN2O 15 H 22 At least one of FN3O6 and hydroxyurea (molecular formula: CH4N2O2),

[0154] (ii) Drugs that affect DNA function, preferably selected from at least one of alkylating agents, platinum compounds, antibiotics, and topoisomerases.

[0155] (iii) Drugs that interfere with transcription, preferably selected from doxorubicin (molecular formula: C 27 H 29 NO 11 CAS No.: 23214-92-8), daunorubicin (molecular formula: C 27 H 29 NO 10Actinomycin (molecular formula: C) 62 H 86 N 12 O 16 At least one of the following,

[0156] (iv) A drug that inhibits protein synthesis, preferably selected from at least one of L-asparaginase, vinca alkaloids, and paclitaxel.

[0157] (v) Drugs that regulate the body's hormonal balance, preferably selected from estrogens, androgens, and medroxyprogesterone acetate (molecular formula: C 24 H 34 O4), Tamoxifen (molecular formula: C 26 H 29 NO), glucocorticoids, and Anluminate (molecular formula: C) 14 H 13 At least one of NO2S,

[0158] (vi) Radiopharmaceuticals,

[0159] (vii) Targeted drugs,

[0160] (viii) Immune checkpoint inhibitor drugs.

[0161] Preferably, the antitumor drug component is selected from at least one of paclitaxel, albumin-bound paclitaxel, PDL-1 class, dual-target PDL-1 class, multi-target PDL-1 class, radiopharmaceutical, and cisplatin class drugs.

[0162] In some implementations, alkylating agents in drugs that affect DNA function exert their effects by forming covalent bonds with DNA. Platinum compounds such as cisplatin (molecular formula: Cl2H6N2Pt, CAS number: 15663-27-1) inhibit DNA replication by cross-linking. Antibiotics and topoisomerases affect DNA function by interfering with DNA structure.

[0163] Paclitaxel is a natural product isolated from yew trees, with the molecular formula C64. 47 H 51 NO 14 It has a molecular weight of 853.9 g / mol. Paclitaxel exerts its antitumor effect by stabilizing microtubules and inhibiting cell mitosis.

[0164] Albumin-bound paclitaxel (CAS No.: 503605-66-1, molecular formula: C) 47 H 51 NO 14(Conjugated with human serum albumin) is a nanoparticle formulation that forms nanoparticles of approximately 130 nm by combining paclitaxel with human serum albumin (HSA) at a mass ratio of approximately 1:9. This formulation eliminates the need for the solubilizer Cremophor EL, improving the water solubility and bioavailability of paclitaxel while significantly reducing the occurrence of allergic reactions.

[0165] PD-L1 inhibitors are a class of monoclonal antibodies targeting programmed death-ligand 1 (PD-L1). They block the PD-1 / PD-L1 pathway, thereby activating T cell-mediated anti-tumor immune responses. Commonly used PD-L1 inhibitors include atezolizumab, durvalumab, and avelumab.

[0166] Radiopharmaceuticals kill tumor cells by producing radiation through the decay of radioactive isotopes.

[0167] Cisplatin is a platinum-containing inorganic complex with the chemical formula cis-[PtCl2(NH3)2]. Cisplatin exerts its antitumor effect by inhibiting DNA replication and transcription through cross-linking with DNA.

[0168] In embodiments of the present invention, the content of the antitumor drug component is from 0.05% to 5% by weight, preferably from 0.1% to 3% by weight. Specifically, the content of the antitumor drug component can be any one of the following values, or a range between any two adjacent values: 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, and 5.0% by weight.

[0169] In some embodiments, the concentration of the antitumor drug component is 0.1-20 mg / mL, preferably 0.5-15 mg / mL, and more preferably 1-10 mg / mL. Specifically, the concentration of the antitumor drug component can be any value from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0 mg / mL, or a range between any two adjacent values.

[0170] In some implementations, the specific concentration ranges for different types of antitumor drugs are as follows:

[0171] The concentration of paclitaxel is 0.5-10 mg / mL, preferably 1-6 mg / mL. Specifically, it can be any value from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 mg / mL, or a range between any two adjacent values.

[0172] The concentration of albumin-bound paclitaxel is 1-15 mg / mL, preferably 2-10 mg / mL. Specifically, it can be any value from 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0 mg / mL, or a range between any two adjacent values.

[0173] The concentration of PDL-1 class drugs is 0.5-8 mg / mL, preferably 1-5 mg / mL. Specifically, it can be any value from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 mg / mL, or a range between any two adjacent values.

[0174] The concentration of dual-target PDL-1 class drugs is 0.3-6 mg / mL, preferably 0.5-4 mg / mL. Specifically, it can be any value from 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0 mg / mL, or a range between any two adjacent values.

[0175] The concentration of multi-target PDL-1 class drugs is 0.2-5 mg / mL, preferably 0.5-3 mg / mL. Specifically, it can be any value from 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg / mL, or a range between any two adjacent values.

[0176] The concentration of cisplatin-based drugs is 0.2-5 mg / mL, preferably 0.5-3 mg / mL. Specifically, it can be any value from 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg / mL, or a range between any two adjacent values.

[0177] The concentration of the radiopharmaceutical is 0.1-4 mg / mL, preferably 0.3-2 mg / mL. Specifically, it can be any value from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0 mg / mL, or a range between any two adjacent values.

[0178] The specific concentration of the antitumor drug component can be adjusted according to factors such as the type of drug, the administration site, and the therapeutic purpose, as long as the effective concentration required for treatment is achieved. For those skilled in the art, selecting a suitable specific concentration within the concentration range provided by this invention is obvious.

[0179] Furthermore, the present invention can also combine different types of anti-tumor drugs according to the above concentration range, based on specific treatment needs.

[0180] In one embodiment, the immune adjuvant is preferably an adjuvant capable of stimulating T cells, NK cells, and / or dendritic cells, and is preferably selected from one or more of the following:

[0181] - Saponin adjuvants, preferably QS-21 and GPI-0100;

[0182] - Mycoglycolipid adjuvants, preferably MPL and RC-529;

[0183] - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives;

[0184] - Polymer I:C and its derivatives;

[0185] -MDP derivatives, preferably MDP and Nor-MDP;

[0186] - Cytokines, preferably GM-CSF, IL-2, and IL-12;

[0187] More preferably, the immune adjuvant is selected from at least one of AS01B and GM-CSF.

[0188] QS-21 (Molecular formula: C) 92 H 148 O 46 (CAS No.: 141256-04-4) is derived from South American soap bark. GPI-0100 is a semi-synthetic derivative of QS-21, containing: 3-deacylated-QS-21 and 3-deacylated glycoside-QS-21.

[0189] MPL (monophospholipid A) is a product of Salmonella lipopolysaccharide detoxification, and RC-529 is a synthetic analogue of MPL (molecular formula: C). 96 H 184 N3O 21 P).

[0190] Cyclic guanosine monophosphate (CDG, CAS No.: 987-78-0, Molecular formula: C 20 H 24 N 10 O 14 P2 and its derivatives are bacterial second messenger molecules.

[0191] Poly(I:C) (Polyinosinic-polycytidylic acid) is a synthetic double-stranded RNA (dsRNA), CAS number: 42524-50-0.

[0192] MDP (xylosyl-N-acetylmuracil dipeptide, molecular formula: C0) 32 H 49 N5O 17 Nor-MDP and its derivative are derived from bacterial cell wall components.

[0193] GM-CSF (recombinant human granulocyte-macrophage colony-stimulating factor) is a recombinant protein produced by an Escherichia coli expression system.

[0194] IL-2 (recombinant human interleukin-2) is a glycoprotein with a molecular weight of approximately 15.4 kDa.

[0195] IL-12 (recombinant human interleukin-12) is a heterodimer composed of two subunits, P35 and P40.

[0196] Specifically, AS01B is a compound adjuvant composed of MPL and QS-21.

[0197] The content of the immune adjuvant is from 0.05% to 5% by weight, preferably from 0.1% to 3% by weight. Specifically, the content of the immune adjuvant can be any one of the following values, or a range between any two adjacent values: 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, and 5.0% by weight.

[0198] The concentration of the immune adjuvant is 10-1,000 μg / mL, preferably 20-500 μg / mL, and more preferably 50-300 μg / mL. Specifically, the concentration of the immune adjuvant can be any value from 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1000 μg / mL, or a range between any two adjacent values.

[0199] Specifically, the concentration of the preferred adjuvant AS01B compound adjuvant (comprising MPL and QS-21) is 50-500 μg / mL, preferably 100-300 μg / mL. Specifically, it can be any value from 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, and 500 μg / mL, or a range between any two adjacent values. The mass ratio of MPL to QS-21 can be 3:1-1:3, preferably 2:1-1:2, and more preferably 1:1.

[0200] The concentration of GM-CSF is 10-300 μg / mL, preferably 30-200 μg / mL. Specifically, it can be any value from 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 μg / mL, or a range between any two adjacent values.

[0201] The specific concentration of the immune adjuvant can be adjusted according to factors such as the type of adjuvant, the administration site, and the therapeutic purpose, as long as it can enhance the immune response. For those skilled in the art, selecting a suitable specific concentration within the concentration range provided by this invention is obvious.

[0202] Furthermore, the present invention can also combine different types of immune adjuvants within the above concentration range according to specific treatment needs.

[0203] In one embodiment, the drug carrier is preferably in excess and may be one or more of physiological saline, polymer materials, emulsions, and liposomes.

[0204] In one embodiment, the drug carrier comprises an erosive sustained-release agent and a viscosity reducer. The erosive sustained-release agent is preferably composed of a polyorthoester polymer, more preferably a polyorthoester. As an example, the polyorthoester may include polylactic acid (PLA, CAS No.: 26100-51-6), polyglycolic acid (PGA, CAS No.: 26247-02-5), or copolymers thereof, such as polylactic acid-glycolic acid copolymer (PLGA, CAS No.: 26780-50-7). These materials exhibit good biocompatibility and biodegradability, and their molecular weight and degradation rate can be adjusted according to specific application requirements.

[0205] Polyorthoesters used in the compositions provided by the present invention are typically composed of alternating residues derived from the reaction of diene acetals and diols, wherein the adjacent diol residues of each diene acetal-derived residue are separated from the reacted diol residues. Polyorthoesters include subunits containing α-hydroxy acids, i.e., subunits derived from α-hydroxy acids or their cyclic diesters, such as subunits containing glycolide, lactide, or combinations thereof (i.e., poly(glycol-co-lactide)), comprising all lactide and glycolide in ratios such as 75:25, 65:35, 50:50, etc. Such subunits are also referred to as latent acid subunits; due to their terminal hydroxyl groups, these latent acid subunits also fall into the more general class of "diols" used in the present invention. Polyorthoesters can be prepared as described, for example, in U.S. Patent Nos. 4,549,010 and 5,968,543. Polyorthoesters suitable for use in the compositions provided by the present invention are described in U.S. Patent No. 8,252,304.

[0206] Contains α-hydroxy acid subunit (R 1 The molar percentage of ) typically ranges from approximately 0 to 20 mol% of the total diol component (R). 1 and R 3(As provided below). In one or more embodiments, the polyorthoester formulation contains at least about 0.01 molar percentage of α-hydroxy acid subunits. Exemplary percentages of α-hydroxy acid subunits in the polymer range from about 0 to about 50 molar percentages, or from about 0 to about 25 molar percentages, or from about 0.05 to about 30 molar percentages, or from about 0.1 to about 25 molar percentages. For example, in one embodiment, the polymer contains about 0 to about 50 molar percentages of α-hydroxy acid subunits. In another embodiment, the polymer contains about 0 to about 25 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.05 to about 30 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.1 to about 25 molar percentages of α-hydroxy acid subunits. As an example, the percentage containing the α-hydroxy acid subunit can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 26, 27, 28, 29, or 30 molar percentages, including any and all ranges formed by combining any lower molar percentage figure with any higher molar percentage figure.

[0207] More specifically, the polyorthoester used in the compositions provided by the present invention is described by the following formula:

[0208] Where R* is C 1-4 Alkyl (e.g., C1, C2, C3, or C4 alkyl), n is an integer ranging from 5 to 400, and A in each subunit is R. 1 Or R 3 That is, any monomer unit of the polymer of formula I. In this context, A can be R. 1 Or R 3 .

[0209] In a particular embodiment, R* is an ethyl (i.e., C2 alkyl) subunit according to Formula I, wherein R* is an ethyl, corresponding to the subunit obtained by reacting the diol provided in this invention with 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU), having the following structure.

[0210] For equation I, as mentioned above, A can correspond to R. 1 R 1 for

[0211] Where p and q are each independently an integer ranging from approximately 1 to 20 (e.g., each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20), and each R 5 Independently hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); and R 6 for:

[0212] Where s is an integer from 0 to 10 (e.g., selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); t is an integer from 2 to 30; and R 7 It is hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); in one or more specific embodiments, R 7 It is hydrogen. R 1 The subunit is a subunit containing an α-hydroxy acid, that is, a subunit derived from an α-hydroxy acid and its cyclic diester.

[0213] For equation I, A can also correspond to R. 3 , where R 3 for

[0214] x is an integer from 1 to 100, and in certain specific cases, selected from 1, 2, 3, 4, and 5. y is an integer from 2 to 30; and R 8 It is hydrogen or C 1-4 Alkyl (C1, C2, C3, or C4 alkyl).

[0215] In a particular implementation, R 8 It is hydrogen.

[0216] In some embodiments, the polyorthoester is wherein A is R 1 Or R 3 , of polyorthoester, where R 1 for

[0217] Where p and q are each independently an integer ranging from about 1 to 20, where R is present in the polyorthoester polymer. 1 The mean of p or the mean of the sum of p and q (p+q) is approximately between 1 and 7 (e.g., 1, 2, 3, 4, 5, 6, 7); x and s are each independently an integer from 0 to 10; and t and y are each independently an integer from 2 to 30. In one or more specific implementations, R 5 It is hydrogen.

[0218] Another specific polyorthoester is in which A is R 1 Or R 3 'of those, among which R 1 for

[0219] Where p and q are each independently an integer varying from about 1 to 20, or from about 1 to 15, or from about 1 to 10, where R is present in the polyorthoester polymer. 1 The average of p, or the average of the sum of p and q (i.e., p+q), is approximately between 1 and 7. Additionally, specific ranges for x and s (for the specific embodiments described above or for any polyorthoester provided according to the invention) are those where each is an integer ranging from 0 to 7 or from 1 to 5 independently. Similarly, specific ranges for t and y are those where each varies independently from 2 to 10.

[0220] The specific polyorthoester is R 5 Those that are hydrogen or methyl.

[0221] In some specific embodiments, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In some specific embodiments, s is 2. In some other specific embodiments, x is 2.

[0222] Exemplary polyorthoesters contain alternating residues of 3,9-diethyl-3,9-2,4,8,10-tetraoxohelic[5.5]undecane-3,9-diyl and A.

[0223] A is as described above.

[0224] Polyorthoesters, such as those described in this invention, can be produced by adding a demonstrative diene acetal, 3,9-di(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU).

[0225] With one or more of the diols described above, such as HO-R 1 -OH or HO-R 3Prepared via a -OH reaction. Exhibitory diols include oligoethylene glycols, such as triethylene glycol (TEG), oligoethylene glycols modified with one or more α-hydroxy acids at one or more ends, such as oligoethylene glycol glycolide or oligoethylene glycol lactide, and organic diols having a hydrocarbon core of 2 to 30 carbon atoms, such as 1,6-hexanediol, 1,10-decanediol, cis / trans-1,4-cyclohexanediol, p-menthane-3,8-diol, 1,4-butanediol, 1,5-pentanediol, 1,7-heptanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, and their cyclic equivalents, wherein the hydroxyl group can be in any two positions on a cycloalkyl or alkylene ring. Organic diols can have 2 to 20 carbon atoms. Organic diols can be linear, branched, or cyclic, and can be saturated or unsaturated. Typically, unsaturated diols will have 1-3 unsaturated elements. A particular polyorthoester may contain from about 10 to 50 total molar percentages of subunits derived from one or more organic diols with a hydrocarbon core.

[0226] Diols are prepared as described in U.S. Patent Nos. 5,968,543 and Heller et al., J. Polymer Sci., Polymer Letters Ed. 18:293-297 (1980), such as HO-R. 1 -OH. For example, this can be achieved by changing the formula HO-R 3 The -OH diol reacts with 0.5 to 10 molar equivalents of α-hydroxy acid cyclic diesters, such as lactide and glycolide, and the reaction is allowed to proceed at 100-200°C for approximately 12 to 48 hours to prepare HO-R compounds containing polyester groups. 1 -OH diols. Suitable solvents for the reaction include organic solvents such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methyl butyl ether. Although diol products in this invention generally refer to isolated and simplified entities, such as TEG glycolide (and diol reaction products such as TEG glycolide), those skilled in the art will understand that due to the reactivity of the reactants, such as the ring-opening of glycolide, diols are actually derived from complex mixtures of reactants, which makes the term TEG glycolide (or any other term for similar products) generally refer to the average or overall properties of the products.

[0227] Specific polyorthoesters are prepared by reacting 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU) with one or more reactive diols. Polyorthoesters are typically prepared by reacting DETOSU with two or more reactive diols under anhydrous conditions. Specific polyorthoesters are also prepared, as described in U.S. Patent No. 8,252,305, by reacting DETOSU with polyethylene glycol and polyethylene glycol glycolide. Specific polyorthoesters prepared from DETOSU-polyethylene glycol-polyethylene glycol glycolide have the following molar ratio: 90:80:20, although the component ratios can be appropriately modified as described above.

[0228] Polyorthoesters formed by the reaction of DETOSU with TEG and TEG glycolide can generally be described as having the following subunits, where R 1 This corresponds to the glycol ester portion derived from polyethylene glycol glycolide (formed by the reaction of glycolide and TEG), while R 3 Corresponding to the glycol ester portion derived from polyethylene glycol:

[0229] Where A is R 1 , and R 1 for Where R 5 For hydrogen and R 6 for

[0230] The polyorthoester composition obtained is as follows:

[0231] The sum of p and q averages 2, while s is 2; and when A is R 3 At that time, R 3 for Where x is 2, the resulting polyorthoester subunit or component is:

[0232] The structures of corresponding polyorthoesters prepared from the various α-hydroxy acid subunits and other diols described in this invention can be readily envisioned.

[0233] In one embodiment, the polyorthoester described in this section is a semi-solid at room temperature and above room temperature. In one embodiment, it contains 80 to 100 mol% R 3 , where R 3 for Polyorthoesters with x = 2 are semi-solid at room temperature and above. Semi-solid polymers exist in a glassy or viscous liquid state. Semi-solid polymers typically exhibit a glass transition temperature (Tg) below room temperature. Below Tg, the semi-solid polymer can be considered to exist in a glassy state, while above Tg, the polyorthoester can be considered to exist in a liquid state. Semi-solid polyorthoester polymers are not thermoplastic polymers.

[0234] Generally, polyorthoesters according to any of the following formulas, Formula I, Formula II, Formula III, or Formula IV, are suitable for the compositions and / or delivery carriers provided by the present invention:

[0235] For equations I-IV,

[0236] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2) c -; where a is an integer from 1 to 12 (e.g., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), while b and c are independently integers from 1 to 5 (e.g., selected from 1, 2, 3, 4, and 5);

[0237] R* is C 1-4 alkyl;

[0238] R o R” and R”' are independently H or C 1-4 alkyl;

[0239] n is an integer of at least 5; and

[0240] A is a diol.

[0241] For example, the compositions and delivery systems of the present invention may be composed of polyorthoesters of formula I, II, III, or IV, wherein

[0242] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2) c -; where a is an integer from 1 to 12, while b and c are independently integers from 1 to 5;

[0243] R* is C 1-4 alkyl;

[0244] R o R” and R”' are independently H or C 1-4 alkyl;

[0245] n is an integer of at least 5; and

[0246] A is R1 R 2 R 3 , or R 4 ,in

[0247] R 1 It is a subunit containing an α-hydroxy acid, as described in the preceding paragraphs;

[0248] R 5 For H or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl); and R 6 Selected from the following groups:

[0249] in:

[0250] s is an integer from 0 to 10;

[0251] t is an integer from 2 to 30; and

[0252] R 7 For H or C 1-4 alkyl;

[0253] R 2 for:

[0254] R 3 for:

[0255] in:

[0256] x is an integer ranging from 0 to 200;

[0257] y is an integer in the range from 2 to 30;

[0258] R 8 For H or C 1-4 alkyl;

[0259] R 9 and R 10 Independently for C 1-12 Alkylene;

[0260] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene; and

[0261] R 4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and carbmate groups.

[0262] In some cases, the polyorthoester is a polyorthoester according to any one of formulas I-IV, where A is R 1 R 3 , or R 4 , where R 3 Selected from

[0263] in

[0264] x is an integer from 0 to 100;

[0265] y is an integer from 2 to 30;

[0266] R 8 For H or C 1-4 alkyl;

[0267] R 9 and R 10 Independently for C 1-12 Alkylene;

[0268] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene;

[0269] R 4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and polyurethane groups; and R 5 For H or C 1-4 alkyl.

[0270] In a specific embodiment of a polyorthoester, formula R 1 The fraction of Unit A is between 0 and 20 mole percentages.

[0271] An exemplary polyorthoester is described by formula I, II, III or IV, wherein

[0272] No unit has an equivalent to R 2 A;

[0273] R 3 for:

[0274] in

[0275] x is an integer from 1 to 100;

[0276] y is an integer from 2 to 30; and

[0277] R6 for:

[0278] in:

[0279] s is an integer from 1 to 10;

[0280] t is an integer from 2 to 30; and

[0281] R 5 R 7 , and R 8 It can be hydrogen or methyl on its own.

[0282] Another representative polyorthoester of formula I, II, III or IV is R. 3 and R 6 Both are -(CH2-CH2-O)2-(CH2-CH2)-; R 5 is methyl; and wherein each of p and q is independently selected from polyorthoesters of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0283] In another polyorthoester embodiment of formula I, II, III or IV, R 3 and R 6 Both are -(CH2-CH2-O)9-(CH2-CH2)-; R 5 It is methyl; and the sum of p or p and q is 2.

[0284] In another variant, the polyorthoester is of formula I, II, III, or IV, and R is -(CH2). b -O-(CH2) c -; where b and c are both 2; R* is a C2 alkyl group.

[0285] Other representative polyorthoesters of formulas I, II, III, or IV, wherein R 5 It is hydrogen or methyl; R 6 for Where s is an integer from 1 to 10, or in some embodiments s is selected from 1, 2, 3, or 4; t is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 7 It is hydrogen or methyl; while R 3 for Where x is an integer from 1 to 10, or in some embodiments selected from 1, 2, 3, or 4; y is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 8 It is hydrogen or methyl; R 4Selected from aliphatic diol residues having 2-20 carbon atoms (e.g., selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms), while in some embodiments R 4 It has 2-10 carbon atoms, broken by one or two amide, imide, urea, or polyurethane groups. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from approximately 0.01 to 50 molar percentages. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from about 0 to 30 mole percentages, or from about 0.1 to 25 mole percentages. Demonstrative mole percentages include 10, 15, 20, and 25 mole percentages of polyorthoesters in which A is R. 1 The subunit. In one embodiment, the molar percentage is 20. Alternatively, in one or more embodiments, where A is R 2 The proportion of subunits is less than approximately 20%, less than approximately 10%, or less than approximately 5%, and A is R. 4 The proportion of subunits is less than about 20 percent, less than about 10 percent, or less than about 5 percent.

[0286] The erosive sustained-release agent is used to control the release rate of antitumor drugs and immune adjuvants, and its content is preferably from 45% to 85% by weight, more preferably from 55% to 75% by weight. Specifically, it can be any one of 45, 50, 55, 60, 65, 70, 75, 80, 85% by weight, or a range between any two adjacent values.

[0287] To adjust the rheological properties of the composition and make it suitable for injection, the drug carrier further includes a viscosity reducer. The content of the viscosity reducer is preferably from 15% to 55% by weight, more preferably from 25% to 45% by weight. Specifically, it can be any value from 15, 20, 25, 30, 35, 40, 45, 50, 55% by weight, or a range between any two adjacent values. Preferably, the viscosity reducer is composed of a glyceryl ester compound, more preferably triacetin (CAS No.: 102-76-1, molecular formula: C9H). 14 O6). Glyceryl triacetate can significantly reduce the viscosity of the composition, thereby improving injection flowability and workability.

[0288] The viscosity of the composition at 25°C ranges from 100 mPa·s to 5000 mPa·s, preferably from 500 mPa·s to 4000 mPa·s, and more preferably from 800 mPa·s to 3000 mPa·s. Specifically, it can be any value from 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and 5000 mPa·s, or a range between any two adjacent values.

[0289] The solubility at 37°C can be greater than 5 mg / mL, preferably greater than 10 mg / mL.

[0290] In some embodiments of the present invention, the mass ratio of the antitumor active ingredient to the erosive sustained-release agent can be 1:90-1:170, preferably 1:100-1:150. The mass ratio of the antitumor active ingredient to the viscosity reducer can be 1:30-1:1100, preferably 1:50-1:900.

[0291] In one specific embodiment, the drug carrier of the present invention includes a thermosensitive sustained-release agent, wherein the content of the thermosensitive sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 55% to 99.5% by weight. Specifically, the content of the thermosensitive sustained-release agent can be any one of 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, and 99.5% by weight, or a range between any two adjacent values.

[0292] The thermosensitive sustained-release agent exhibits reversible sol-gel transition behavior with temperature changes. It is liquid at low temperatures (e.g., 0-8°C), suitable for injection administration; as the temperature rises, it undergoes a solidification (including semi-solidification or gelation) transition. Specifically, the solidification (including semi-solidification or gelation) temperature (the transition temperature from liquid to solid (including semi-solid or gel)) of the thermosensitive sustained-release agent is 30°C to 45°C, preferably 35°C to 39°C, more preferably 36°C to 38°C, and even more preferably 36°C-37°C. Specifically, the solidification temperature can be any value from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45°C, or a range between any two adjacent values.

[0293] The thermosensitive sustained-release agent may be a polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO, poloxamer 407) or a lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA). Preferably, the thermosensitive sustained-release agent is composed of poloxamer 407 or PLGA-PEG-PLGA.

[0294] The chemical structure of the PLGA-PEG-PLGA thermosensitive hydrogel is shown in the figure:

[0295] Poloxamer 407 is a chemically stable triblock copolymer whose chemical stability gives it high stability in oxidizing, reducing, and acid / alkali environments.

[0296] In a preferred embodiment of the present invention, the thermosensitive sustained-release agent poloxamer 407 can be used as an in-situ gel for local injection. Its gel is transparent and highly hydrophilic, forming a three-dimensional mesh structure that firmly binds the drug within, thereby prolonging the drug's residence time at the affected area and improving bioavailability. Poloxamer 407 gel exhibits good tissue compatibility and significantly reduces the irritation of surrounding tissues caused by the drug dosage. Poloxamer 407 can have any of the aforementioned curing temperatures.

[0297] In another specific embodiment, the thermosensitive sustained-release agent PLGA-PEG-PLGA remains in a liquid state (sol state) below the phase transition temperature; when the temperature reaches the phase transition temperature, it rapidly gels to form a solid structure. PLGA-PEG-PLGA hydrogels are particularly suitable for local chemotherapy applications, enabling precise drug delivery to the target site and prolonging drug release time through gel formation, thereby reducing systemic side effects. By adjusting the molecular weight and copolymerization ratio of PLGA-PEG-PLGA, precise control of the drug release rate can be achieved. The thermosensitive sustained-release agent PLGA-PEG-PLGA can have any of the aforementioned curing temperatures.

[0298] Specifically, the composition of the PLGA-PEG-PLGA hydrogel can be further optimized to meet the delivery requirements of different drugs. For the PLGA-PEG-PLGA thermosensitive hydrogel, it is preferred that its purity is above 95%, its storage conditions are -20°C, and it exhibits phase transition behavior at a specific temperature.

[0299] To meet diverse drug and therapeutic needs, the thermosensitive sustained-release formulation of this invention can be combined with other types of drug carriers, such as saline, emulsions, and liposomes. The composition is designed to achieve precise release and sustained retention of the drug at the tumor site, ensuring therapeutic efficacy and reducing side effects.

[0300] In one specific embodiment, the drug carrier of the present invention comprises a non-sustained-release agent. The content of the non-sustained-release agent is preferably from 45% to 99.5% by weight, more preferably from 55% to 99.5% by weight. Specifically, the content of the non-sustained-release agent can be any one of 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, and 99.5% by weight, or a range between any two adjacent values. The non-sustained-release agent comprises liposomes, physiological saline, or glucose solution, preferably liposomes.

[0301] In specific embodiments of liposomes, liposomes can be further classified into cationic liposomes and neutral liposomes. The cationic liposomes may include any one or more of DOTAP (1,2-dioleoyl-3-trimethylammonium chloride propaneuryl chloride), DOTMA (1,2-dioleoyl-3-trimethylammonium chloride methacrylate), and DC-Chol (a cholesterol derivative, DC-Cholesterol). Cationic liposomes are commonly used to enhance the cellular uptake efficiency and targeting of drugs.

[0302] Neutral liposomes can include any one or more of DOPC (1,2-dioleoyl-sn-glycerol-3-phosphorylcholine), DSPC (1,2-distearatel-sn-glycerol-3-phosphorylcholine), and DPPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine). Neutral liposomes are widely used in drug delivery systems due to their stability and good biocompatibility.

[0303] In a preferred embodiment, the mass ratio of cationic liposomes to neutral liposomes is preferably from 1:8 to 1:12. Specifically, it can be any one of 1:8, 1:9, 1:10, 1:11, and 1:12, or a range between any two. This mass ratio improves the distribution and retention time of the drug in vivo by optimizing the charge characteristics and equilibrium stability of the liposome carrier.

[0304] In some embodiments, the particle size of the cationic liposomes is preferably between 100 nm and 300 nm, specifically any value from 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, and 300 nm, or a range between any two. Choosing the appropriate particle size helps optimize the drug's distribution characteristics and improve its stability and targeting.

[0305] To further improve the stability and processing performance of the antitumor composition of the present invention, one or more pharmaceutical excipients may be added to the composition, including but not limited to dissolving agents, osmotic pressure regulators, pH regulators, or maintenance agents. The specific dosage of these excipients can be adjusted according to actual needs.

[0306] Preparation method

[0307] The compositions of the present invention can be prepared in any suitable manner, such as by simple mixing.

[0308] In a further embodiment, when the composition contains an erosive slow-release agent and a viscosity reducer, the composition can also be prepared using the following steps:

[0309] (a) Dissolving or dispersing the antitumor active ingredient in an organic solvent; (b) dissolving the erosive sustained-release agent in an organic solvent; (c) mixing the solutions from steps (a) and (b), and optionally adding a viscosity reducer, and stirring at 60-80°C, preferably 70°C, for 0.5-6 hours; (d) cooling the mixture obtained in step (c) to room temperature, and slowly adding a pharmaceutically acceptable carrier, and stirring until homogeneous; (e) evaporating the mixture obtained in step (d) under reduced pressure to remove the organic solvent, thereby obtaining the composition.

[0310] In step (a), the organic solvents that can be used include, but are not limited to, dichloromethane, ethanol, acetone, etc. In some embodiments, solubilizers such as dimethyl sulfoxide (DMSO) or methanol may also be used to improve the solubility of the antitumor active ingredient.

[0311] Delivery device

[0312] In several embodiments of the present invention, as shown in FIG1, a fluid delivery device is provided, particularly a fluid delivery device for drugs and vaccines, which may include a tube 100 for containing fluid, the tube 100 having a storage cavity for storing fluid, and the tube 100 having a first end 110 and a second end 120. As shown in FIG1, the second end 120 may be provided with a hole 121 for dispensing fluid within the tube.

[0313] In some embodiments of the present invention, the fluid delivery device further includes an interventional soft needle, one end of which is connected to the tube and the other end to or integrated with the injection head. The interventional soft needle can improve the accuracy and flexibility of drug delivery, and is particularly suitable for local drug delivery to deep tumors. The interventional soft needle can be flexible, capable of reaching the target location along a curved path.

[0314] The fluid delivery device may also include an injection head 200 detachably connected to the tube 100, the injection head 200 including one or more needle elements 210. The one or more needle elements 210 are configured to removably engage with a self-closing resilient portion 122 in the second end 120 or an aperture 121 for dispensing fluid 130 within the tube 100. In some embodiments, the injection head may be fixedly connected to the tube.

[0315] The fluid delivery device may further include a power mechanism 300. The power mechanism is a motorized power mechanism, meaning that, in the context of this disclosure, the power mechanism does not include manually operated components. The power mechanism 300 includes a piston 310 disposed in the first end 110 of the tube 100, capable of pushing the fluid 130, or operatively connected to the piston 310 to apply delivery pressure to the piston 310 pushing the fluid 130.

[0316] In some embodiments of the present invention, as shown in FIG1, the piston 310 may be provided as a separate component, and the power mechanism 300 is configured to operate connected to the piston 310 to apply delivery pressure to the piston 310. Similarly, it is conceivable that in other embodiments of the present invention, the power mechanism 300 may be integrally integrated with the piston 310.

[0317] In some embodiments of the present invention, the driving method of the power mechanism 300 may include any one of compressed gas driving, spring driving, electromagnetic driving, or a combination of the above driving methods. For example, in some embodiments, the power mechanism 300 may be driven by compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, or by compressed mechanical spring, or by piezoelectric actuator, without limitation.

[0318] In some embodiments of the present invention, compared to manual needle injection (where the piston inside the needle travels at a speed of approximately 0.01 m / s), the piston speed of the fluid delivery device of the present invention when the piston 310 pushes the fluid 130 in the tube 100 is greater than or equal to 10 times the piston speed of manual needle injection. The piston speed of the piston 310 when pushing the fluid 130 is 0.05 m / s to 0.50 m / s, preferably 0.09 m / s to 0.25 m / s, and even more preferably 0.14 to 0.20 m / s.

[0319] In some embodiments of the present invention, compared to manual needle injection (where the outlet jet velocity of the fluid ejected from the needle is approximately 2 m / s), the outlet jet velocity of the fluid 130 of the fluid delivery device of the present invention when it is pushed away by the piston 310 from the plurality of holes 121 in the second end 120 or one or more needle parts 210 of the injection head 200 is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, more preferably greater than or equal to 100 m / s, and more preferably greater than or equal to 150 m / s.

[0320] In some embodiments of the present invention, at least one of the one or more needle elements 210 is substantially inserted into a human or animal body.

[0321] In some embodiments of the present invention, at least one of the one or more needle components is substantially inserted into a human or animal body;

[0322] In some embodiments of the present invention, at least one of the one or more needle components has an aperture in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.11 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm.

[0323] In some embodiments of the present invention, at least one of the self-sealing elastic part or the hole for distributing fluid in the pipe has a diameter in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.11 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm.

[0324] In some embodiments of the present invention, the total fluid delivery area of ​​the plurality of needle elements or the plurality of orifices for dispensing fluid within the tube is 0.009 mm. 2 The above is preferably 0.020 mm. 2 The above, more preferably, is 0.053mm. 2 The above, more preferably 0.28mm 2 The area of ​​a single hole in the aforementioned needle or hole is 0.0028–0.035 mm². 2 Preferably, the diameter is 0.0028–0.020 mm. 2 More preferably, it is 0.0028–0.009 mm. 2 The single-hole area of ​​the needle tip refers to the single-hole area calculated from the inner diameter of the needle tip.

[0325] In some embodiments of the present invention, the fluid delivery device is configured such that the diffusion volume of the fluid 130 within the body is greater than the undelivered volume. Preferably, the diffusion volume of the fluid within the body is at least 1.50 times the undelivered volume, more preferably at least 1.80 times, even more preferably at least 2.40 times, more preferably at least 3.00 times, and even more preferably at least 3.60 times. Specifically, the diffusion volume ratio can be from 3.00 times to 10.00 times, from 4.00 times to 10.00 times, more preferably from 4.40 times to 8.00 times, and even more preferably from 5.0 times to 6.50 times. The specific values ​​listed include, but are not limited to: 4.00 times, 4.40 times, 4.60 times, 4.80 times, 5.00 times, 5.10 times, 5.20 times, 5.30 times, 5.40 times, 5.50 times, 5.60 times, 5.80 times, 5.90 times, 6.00 times, 6.50 times, 7.00 times, 8.00 times, 9.00 times, and 10.00 times, or any range between these values.

[0326] In some embodiments of the present invention, the dispersion volume ratio refers to the ratio of the volume of the dispersion region of the fluid delivered by the fluid delivery device in the body to the original volume of the undelivered fluid, that is:

[0327] In other embodiments of the present invention, the diffusion volume ratio may also refer to the ratio of the diffusion volume of fluid delivered by the fluid delivery device of the present invention in the body to the diffusion volume of fluid delivered by manual needle injection in the body, that is:

[0328] The diffusion volume of the delivery fluid can be calculated in various ways, without limitation. For example, in some embodiments of the present invention, a fluorescent marker can be added to the drug or vaccine in advance, and then the volume of the diffusion region can be calculated by scanning with medical imaging technology and using image analysis software, such as calculating the envelope map of the diffusion region to estimate the volume of the diffusion region.

[0329] It is understandable that when a delivery fluid enters the body through a fluid delivery device, its three-dimensional spatial distribution area increases due to the diffusion effect of the fluid within the body. This diffusion process increases the surface area of ​​the fluid, especially drugs or vaccines, in contact with tissues in the body, thereby improving the bioavailability and efficacy of the drug.

[0330] In some embodiments of the present invention, the outlet jet velocity v of the one or more needle elements can be configured such that the fluid jet passing through the one or more needle elements has a variety of different bulk dispersions, i.e., different dispersion volume ratios, dispersion depths, or dispersion extents; thus, in some embodiments of the present invention, the outlet jet velocities v of the one or more needle elements can be equal and have a first outlet jet velocity v1, the magnitude of which is configured such that the fluid jet passing through the one or more needle elements has different dispersions.

[0331] In several embodiments of the present invention, the fluid delivery device may include an interventional soft needle. One end of the interventional soft needle is connected to the tube, and the other end is connected to or integrated with the injection head. The interventional soft needle is primarily used for drug delivery to specific tumor sites, particularly when the tumor is located deep or inaccessible. Its flexible structure allows it to reach the target location along a curved path, thereby improving the flexibility and adaptability of drug administration and ensuring better drug distribution within the tumor area. The interventional soft needle is an optional component in the present invention, depending primarily on the specific location of the tumor and treatment needs. When the tumor is located on the body surface or in other easily accessible areas, drug delivery can be achieved directly using the injection head without the need for an interventional soft needle. This flexibility allows the multimodal fluid delivery device to be adapted to different clinical scenarios, thereby simplifying the device structure and reducing operational complexity and cost.

[0332] In specific applications, interventional soft needles can be made of flexible biocompatible materials, such as medical-grade polyurethane, polyethylene, or silicone. These materials provide sufficient flexibility while ensuring safety and stability during use. Furthermore, the outer diameter of the interventional soft needle is preferably between 0.50 mm and 1.50 mm, and the length is preferably between 10 mm and 50 mm, more preferably between 15 mm and 30 mm, to allow for adjustment based on the depth and location of the tumor.

[0333] This design offers flexibility for different tumor locations, enabling the fluid delivery device to adapt to a variety of treatment needs, providing effective drug delivery solutions for both superficial and deep tumors.

[0334] Drug-device combination products

[0335] The present invention also provides a drug-device combination product suitable for local drug delivery to tumors. This combination product comprises the above-described composition and the above-described matching fluid delivery device, specifically designed for efficient and precise delivery of drugs to the target tumor site.

[0336] The pharmaceutical composition comprises an antitumor drug component and an immune adjuvant, which work synergistically to enhance the antitumor effect. The antitumor drug component may include cytotoxic drugs, radiopharmaceuticals, or targeted drugs, the specific components and concentration ranges of which have been described in detail above. The immune adjuvant is used to modulate and enhance the immune response, further improving the efficacy of the drug.

[0337] The fluid delivery device consists of several components, including a tube for containing the composition, an injection head, and a motorized power mechanism. The tube stores the drug composition and is connected to the injection head. The injection head is designed to be fixedly or detachably connected to the storage cavity of the tube and is equipped with one or more needle elements. The motorized power mechanism controls the drug delivery pressure. To address different clinical needs, particularly for deep or difficult-to-access tumor sites, the fluid delivery device can be equipped with an interventional soft needle. Details are omitted here.

[0338] use

[0339] This invention also relates to the use of pharmaceutical compositions or pharmaceutical-device combinations in the preparation of medicaments for local injection into tumors. This design allows for direct delivery of the medicament to the tumor site, achieving more effective therapeutic results and reducing systemic side effects.

[0340] In some embodiments, the pharmaceutical composition comprises an antitumor drug component and an immune adjuvant. The specific composition and concentration range of the antitumor drug component and the immune adjuvant can be found in the detailed description above. In some embodiments, the pharmaceutical composition is the composition described above. In the use of this invention, the antitumor drug component can induce tumor cells to release tumor antigens, stimulating an immune response in vivo, while the immune adjuvant further enhances this immune response and activates the activity of tumor-specific immune cells; details of this will not be elaborated here.

[0341] In one embodiment, the above-described composition, or a composition containing an antitumor drug component and an immune adjuvant, is used in the preparation of a medicament for local injection into a tumor. The drug composition can be delivered to the tumor site via multiple injections to achieve a sustained antitumor effect. For example, the composition can be repeatedly injected at different time points to ensure that the drug concentration at the tumor site remains at a highly effective therapeutic level, thereby maximizing the drug's efficacy.

[0342] In one embodiment, the aforementioned immune adjuvant or a composition of immune adjuvant and tumor-specific peptides is used in the preparation of a medicament for local injection into a tumor. The use of the immune adjuvant can also be designed as part of a subsequent treatment regimen, particularly after the initial injection of the antitumor drug composition. In this case, the immune adjuvant can be injected alone or in combination with the composition of tumor-specific peptides to maintain or further enhance the immune response induced by the antitumor drug. Through this subsequent administration strategy, the immune adjuvant can maintain the activity of tumor-specific in vivo immune cells, prolong the therapeutic effect, and reduce the risk of tumor recurrence.

[0343] In another embodiment, a combination of the two embodiments is proposed, namely, combining the above-mentioned multiple administrations with subsequent immune adjuvant injections to form a comprehensive treatment plan.

[0344] Additional embodiments include adjusting the diffusion volume ratio during drug delivery to optimize drug distribution and action in vivo. The diffusion volume of the fluid delivered via the multi-mode fluid delivery device is preferably greater than the undelivered volume in vivo. Preferably, the diffusion volume of the fluid in vivo is at least 1.50 times the undelivered volume, more preferably at least 1.80 times, even more preferably at least 2.40 times, more preferably at least 3.00 times, and even more preferably at least 3.60 times. Specifically, the diffusion volume ratio can be from 3.00 to 10.00 times, from 4.00 to 10.00 times, more preferably from 4.40 to 8.00 times, and even more preferably from 5.0 to 6.50 times. The specific values ​​listed include, but are not limited to: 4.00 times, 4.40 times, 4.60 times, 4.80 times, 5.00 times, 5.10 times, 5.20 times, 5.30 times, 5.40 times, 5.50 times, 5.60 times, 5.80 times, 5.90 times, 6.00 times, 6.50 times, 7.00 times, 8.00 times, 9.00 times, and 10.00 times, or any range between these values.

[0345] The antitumor compositions or drug-device combinations of the present invention can be used to prepare medicaments for treating tumors by topical administration. Applicable tumor types include, but are not limited to, melanoma, breast cancer, kidney cancer, lung cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, and glioma.

[0346] Local administration methods can include intratumoral injection, peritumoral injection, and local lymph node injection.

[0347] Treatment

[0348] The present invention also provides a method for treating tumors using the above-mentioned drug-device combination product, comprising the following steps:

[0349] (a) Acquire multimodal medical images of the patient; (b) Perform image fusion and path planning using an image processing system; (c) Guide the injection head or interventional soft needle of the fluid delivery device to a target location, including intratumoral, peritumoral, and lymph node locations, according to the path planning; (d) Apply delivery force through the power mechanism to control the diffusion delivery of the composition to the target location; (e) Efficacy assessment is performed 1-8 weeks after administration, and steps (a)-(d) are repeated based on the assessment results.

[0350] Acquiring multimodal medical images may include acquiring a first modality of medical images and a second modality of medical images. The first modality of medical images and the second modality of medical images may be selected from two different types of CT images, MRI images, PET images, SPECT images, and ultrasound images, respectively.

[0351] In image fusion and path planning, the acquired first modality medical image can be reconstructed in 3D. Then, the reconstructed first modality medical image and the second modality medical image are fused to obtain a fused 3D modeling model. Finally, path planning is performed on this 3D modeling model. The 3D reconstruction algorithm can be selected from at least one of the following: filtered back projection, maximum likelihood expectation maximization, ordered subset expectation maximization, deep learning reconstruction, time-of-flight (TOF) reconstruction, and Fourier transform reconstruction.

[0352] When guiding the drug delivery device to the target location, various guidance systems can be used.

[0353] In some embodiments of the invention, the guiding system includes a manipulable catheter, a first-step manipulator for coarse adjustment of the catheter, and a second-step manipulator for fine adjustment of the catheter. An interventional soft needle extends within the catheter. This design allows the operator to precisely control the catheter's position, thereby achieving more accurate drug delivery. The first-step manipulator is used for a wide range of catheter movement, while the second-step manipulator is used for fine-tuning the catheter position to achieve the optimal drug delivery location.

[0354] In some embodiments of the present invention, the guidance system includes a navigation system or an endoscope system (including an optical endoscope system, an ultrasonic endoscope system, a confocal microendoscopy system, etc.), or a combination of a navigation system and an endoscope system. The navigation system is first used to guide the interventional soft needle of the drug delivery device to the vicinity of the target area, and then the endoscope system is used for precise positioning to the target location. In some embodiments of the present invention, the navigation system may include an electromagnetic navigation system, an optical navigation system, or an image-guided navigation system. Electromagnetic navigation systems utilize electromagnetic fields to locate the catheter; optical navigation systems use optical markers and cameras to track the catheter; and image-guided navigation systems combine real-time medical images for navigation. In some embodiments of the present invention, the endoscope system may include an optical endoscope system, an ultrasonic endoscope system, or a confocal microendoscopy system. These systems can provide real-time tissue images, helping physicians to accurately locate the target area and monitor the drug delivery process. In some embodiments of the present invention, a navigation system and an endoscope system may be used in combination. For example, the navigation system is first used to guide the interventional soft needle of the drug delivery device to the vicinity of the target area, and then the endoscope system is used for precise positioning to ensure accurate arrival at the target location.

[0355] In addition, during drug administration, the data from the guidance system can be used to obtain tissue information at the target location in real time. The obtained tissue information can be superimposed on the three-dimensional model, and the drug delivery parameters can be adjusted in real time based on the three-dimensional model with superimposed tissue information.

[0356] The method of this invention may further include acquiring tissue information at the target location in real time using data from the guidance system. This information may include tissue density, vascular distribution, tumor boundaries, etc. The acquired tissue information can be overlaid onto a pre-constructed three-dimensional modeling model to form a dynamically updated comprehensive model. Based on this three-dimensional modeling model overlaid with real-time tissue information, physicians can adjust drug delivery parameters in real time. These parameters may include delivery speed, pressure, dose distribution, etc. This real-time adjustment capability makes drug delivery more precise, optimizes treatment effects according to actual conditions, and minimizes the impact on surrounding healthy tissues.

[0357] Combination drug products

[0358] This invention also provides a combination therapy product, comprising the above-mentioned antitumor composition or drug-device combination product and a personalized tumor vaccine. This combination therapy strategy can fully leverage the synergistic effect of the two treatment modalities, thereby improving treatment efficacy.

[0359] Personalized cancer vaccines include a personalized antigen series matched to the cancer patient, which can be in the form of peptides, proteins, mRNA, DNA, or plasmids. Specifically, the personalized antigen series can be:

[0360] 5-50 (preferably 10-30) tumor-specific mutant peptides, each peptide containing 8-100 (preferably 10-50, more preferably 15-30) amino acid residues;

[0361] Proteins carrying 1-20 (preferably 1-10) tumor-specific mutation epitopes;

[0362] mRNA encoding 5-50 (preferably 10-30) tumor-specific mutant antigens;

[0363] DNA encoding 5-50 (preferably 10-30) tumor-specific mutant antigens;

[0364] Plasmids encoding 5-50 (preferably 10-30) tumor-specific mutation antigens.

[0365] Personalized cancer vaccines may also optionally include immune adjuvants and drug carriers. Immune adjuvants can be selected from those that stimulate T cells, NK cells, and dendritic cells, such as AS01B or GM-CSF. Drug carriers can be saline, polymer materials, emulsions, or liposomes.

[0366] Methods of using combination drugs

[0367] The combination drug product of this invention can be used to treat a variety of malignant tumors, including but not limited to melanoma, non-small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma, or bladder cancer. The combination drug can be administered simultaneously, sequentially, or alternately.

[0368] The specific dosing regimen can be adjusted according to the patient's individual condition and tumor type. For example, an antitumor composition can be administered topically first, followed by a personalized tumor vaccine 1-4 weeks later. Alternatively, two formulations can be administered simultaneously: the antitumor composition topically, and the personalized tumor vaccine subcutaneously or intramuscularly.

[0369] The dosage and frequency of administration of the antitumor composition can be set according to the description in the claims, for example, the administration period can be greater than or equal to 7 days, preferably greater than or equal to 14 days and less than or equal to 90 days. The dosage and frequency of administration of personalized tumor vaccines can be adjusted according to the specific antigen type and patient condition, and can usually be administered once every 1-4 weeks for several months.

[0370] By combining the antitumor composition of this invention with a personalized tumor vaccine, local chemotherapy and systemic immunotherapy can be integrated, potentially improving treatment efficacy and prolonging patient survival. This combined medication strategy may produce a synergistic effect, enhancing the antitumor immune response while reducing systemic toxicity through local administration.

[0371] In some embodiments, the combination therapy regimen can be dynamically adjusted based on the patient's treatment response and tumor progression to achieve individualized precision treatment.

[0372] The mechanism of local tumor injection according to an embodiment of the present invention will be explained below with reference to Figures 2 and 3.

[0373] Figure 2 shows a non-limiting mechanism diagram of different administration methods of the present invention, to illustrate the potential differences between local diffusion injection of the tumor using the embodiments of the present invention and conventional administration methods for treating tumors, and the innovative effects of the present invention.

[0374] Part (a) of Figure 2 illustrates the diffusion injection of antitumor drugs into the tumor site (intratumoral region) using a jet microneedle-type fluid delivery device. With the fluid delivery device of this embodiment, the antitumor drug is uniformly diffused into the tumor tissue, forming a wide drug distribution area. This diffusion method significantly increases the contact area between the drug and tumor cells, providing a more efficient cell-killing effect. However, when the antitumor drug component induces the production of tumor antigens, no immune adjuvant is obtained to enhance the activity of tumor-specific in vivo immune cells activated by the tumor antigens, and systemic immunotherapy cannot be achieved.

[0375] Figure 2(b) illustrates the traditional method of intratumoral (needle-based) injection of antitumor drugs. Compared to diffusion injection, needle-based injection typically results in drug concentration near the injection site, with limited diffusion, potentially leading to uneven drug distribution within the tumor tissue and reduced therapeutic efficacy. Furthermore, even in the early stages, tumors (malignant tumors) may exhibit localized micro-invasion and distant metastasis, making it difficult for intratumoral (needle-based) injection to sustainably kill metastatic cancer cells. In this paper, needle-based injection (NI) involves manual injection.

[0376] Figure 2(c) illustrates one preferred embodiment of the invention, namely, the diffuse injection of a combination of an antitumor drug and an immune adjuvant (and subsequent injection of the immune adjuvant alone or other compositions containing the immune adjuvant but without the antitumor drug) into the tumor site (intratumoral region) via a jet microneedle-type fluid delivery device. This administration method not only effectively kills tumor cells with high concentrations of antitumor drugs and induces the release of large amounts of tumor antigens, but also enhances the function of dendritic cells, NK cells, and T cells through the immune adjuvant, improving the strength and persistence of the immune response, thus achieving local and systemic immunotherapy for the tumor. Furthermore, the compositions of the present invention and the subsequently used immune adjuvants or compositions containing immune adjuvants can be combined with a sustained-release system to further improve the distribution and retention characteristics of the drug in the tumor site, as further explained below in conjunction with Figure 3. In particular, this administration strategy also includes a flexible stepwise treatment strategy: initial injection of a combination of an antitumor drug and an immune adjuvant, followed by subsequent injection of the immune adjuvant alone or other compositions containing the immune adjuvant but without the antitumor drug to maintain and enhance the immune response, thereby achieving long-term antitumor immune effects while reducing the cumulative toxicity of chemotherapy drugs.

[0377] Part (d) of Figure 2 illustrates the traditional needle-based intravenous injection method. Because the drug enters the bloodstream, it can cause high systemic toxicity and makes it difficult to achieve highly effective drug concentrations at the tumor site. Therefore, this method has certain limitations in terms of drug dosage and efficacy.

[0378] As shown in sections (a) and (b) of Figure 3, existing intravenous injection methods result in rapid drug distribution within the bloodstream, achieving high blood drug concentrations. However, the drug concentration at the tumor site is often insufficient, making it difficult to provide adequate antitumor effects. Furthermore, antitumor drug components are often toxic, and high blood drug concentrations have adverse effects. In addition, while intratumoral needle injection (as shown in section (b) of Figure 2) can increase the drug concentration at the tumor site, needle injection cannot achieve uniform drug distribution within the tumor, and the drug can still easily diffuse into the vascular system.

[0379] As shown in sections (c) and (d) of Figure 3, the embodiments of the present invention achieve uniform drug distribution at the tumor site (intratumoral) by diffusing an antitumor drug and an immune adjuvant, resulting in a highly efficient diffusion effect. This not only optimizes the antitumor effect but also effectively kills tumor cells through high-concentration antitumor drugs, inducing the release of large amounts of tumor antigens. Furthermore, the combination with the immune adjuvant enhances the function of dendritic cells, NK cells, and T cells, improving the strength and persistence of the immune response. In a further embodiment, by incorporating a sustained-release system (such as an erosive or thermosensitive sustained-release agent) into the composition (or subsequent immune adjuvant or a composition containing an immune adjuvant), the local drug concentration at the tumor site is maintained for a long time, resulting in a long-term highly efficient diffusion effect. At the same time, the diffusion of the drug into the blood vessels is significantly reduced, thereby reducing systemic toxicity and achieving a "diffuse but not diffuse" drug distribution effect.

[0380] As can be seen from the mechanism diagrams in Figures 2 and 3 above, the innovative solution of the present invention overcomes several difficulties of the prior art.

[0381] As an illustrative explanation of the present invention, the application of local tumor injection has not yet achieved ideal clinical results. It is speculated that the following reasons may exist: First, it is impossible to achieve effective distribution of the drug in the local tumor area (including inside the tumor), making it impossible to clear tumor cells over a large area; second, local tumor injection cannot be injected into micrometastatic lesions and cannot prevent subsequent tumor metastasis; third, it is difficult to achieve long-term retention of the drug in the local tumor area (including inside the tumor), thus making it difficult to continuously clear tumor cells. Furthermore, needle injection cannot effectively deliver high-viscosity drug formulations with sustained-release systems, so practitioners in the field do not currently consider combining sustained-release agents with drugs.

[0382] To address the aforementioned problems, this invention provides innovative solutions: First, it achieves effective diffusion distribution of drugs at the tumor site through a jet microneedle-like fluid delivery device. Second, it innovatively combines antitumor drugs with immune adjuvants (or uses an antitumor drug and immune adjuvant combination initially, followed by the use of an immune adjuvant or a combination containing an immune adjuvant), utilizing the high local concentration of antitumor drugs to generate a large amount of in situ tumor-specific antigens, and forming a sustained immune response through the synergistic effect of the immune adjuvant, thereby effectively controlling metastatic lesions and the risk of subsequent metastasis. Third, addressing the problem of drugs failing to remain at the tumor site for extended periods, this invention provides two different innovative solutions: On the one hand, the inventors overcome the limitation of conventional needle injection in delivering high-viscosity drugs by using a jet microneedle-like fluid delivery device, enabling direct diffusion injection of high-viscosity formulations with sustained-release effects; on the other hand, the inventors have also innovatively designed a thermosensitive sustained-release system, cleverly avoiding the problem of high-viscosity delivery. Specifically, the thermosensitive sustained-release system exhibits a low-viscosity state at low temperatures for easy injection, and subsequently forms a gel at body temperature to achieve long-term retention.

[0383] It will be understood that the schematic diagrams shown in Figures 2 and 3, as well as the related mechanistic descriptions, are illustrative and not intended to limit the invention.

[0384] Example 1: Evaluation of the diffusion effect of a fluid delivery device

[0385] This embodiment uses a thermosensitive gel (density 1.05 g / cm³). 3 A nanosponge filled with a porosity of 90+% was used as a tissue-mimicking medium (simulating a tumor). This thermosensitive gel is liquid at 0-8°C and forms a gel at temperatures above 25°C. A methylene blue solution was used as the tracer.

[0386] The fluid delivery device of the present invention has a narrowed section at the second end that gradually narrows from the tube axis toward the distal end, and three holes are provided on the end face of the narrowed section. Specifically, the end face is constructed as a circle with a diameter of 2.5 mm, and the three holes are arranged in a ring at equal intervals around the center of the end face, with the lines connecting adjacent holes to the center of the end face forming a 120° angle. The diameter of the three holes is uniformly set to 150 μm (single-point injection) or 105 μm (three-point injection), and their distance from the center of the end face is uniformly set to 875 μm.

[0387] The experimental groups are as follows:

[0388] Comparative Example 1-1: Injection with a standard syringe, using a 23G medical injection needle (inner diameter 232μm).

[0389] Comparative Examples 1-2: Needleless injector injection, nozzle inner diameter 150 μm, injection pressure 14 MPa

[0390] Example 1-1: The device of the present invention performs single-point injection with an orifice diameter of 150 μm and an injection pressure of 14 MPa.

[0391] Examples 1-2: The device of the present invention uses three-point injection, with each orifice having a diameter of 105 μm and an injection pressure of 14 MPa.

[0392] Experimental conditions:

[0393] Injection volume: 0.2 mL

[0394] - Viscosity of the fluid to be delivered: 1cp

[0395] - Medium temperature: 37℃

[0396] - Obtain cross-sectional images using 2mm equidistant slices.

[0397] - Analyze stained regions using the Otsu thresholding algorithm

[0398] Table 1. Diffusion effect data of different injection methods (n=3, Mean±SD)

[0399] Results analysis:

[0400] 1. The fluid delivery device of the present invention has a significantly higher diffusion volume ratio (4.41±0.24) than that of a conventional syringe (2.93±0.20) and comparable to that of a needle-free syringe (4.42±0.35) when injecting at a single point.

[0401] 2. When using a three-point injection design, the dispersion volume ratio is further increased to 5.74±0.28, and the dispersion depth and width are also correspondingly improved;

[0402] 3. Three-point injection not only increases the overall diffusion volume, but also improves the uniformity of drug distribution through multi-point administration.

[0403] This embodiment validates the excellent diffusion performance of the fluid delivery device of the present invention using an in vitro model. In particular, the three-point injection design significantly improves the drug diffusion volume ratio, laying the foundation for subsequent clinical applications.

[0404] Example 2: Local diffusion injection into the tumor

[0405] This embodiment aims to evaluate the therapeutic effect of the composition of the present invention and the local (intratumoral) diffusion injection administration method on advanced tumors.

[0406] Materials and Methods

[0407] 1. Laboratory animals

[0408] Fifty healthy male C57BL / 6 mice, aged 6-8 weeks and weighing 18-22g, were selected and randomly divided into 5 groups (n=10 per group) using a random number table.

[0409] 2. Experimental materials used in the examples

[0410] The composition comprises an antitumor drug component: paclitaxel injection (concentration 1 mg / mL); an immunoadjuvant: AS01B (containing MPL 50 μg / mL and QS-21 50 μg / mL); and a drug carrier: the remainder being physiological saline.

[0411] 3. Dosing grouping

[0412] (a) Control Example 2-1: Intratumoral injection of saline solution (negative control), using the needle injector of Control Example 1-1;

[0413] (b) Control Example 2-2: Paclitaxel (concentration 1 mg / mL, the remainder being physiological saline) was administered via intraperitoneal needle injection (conventional administration method) using the needle injector of Control Example 1-1 (in the embodiments of the present invention, since the experimental subjects were mice, the conventional intravenous administration method could not be used, and the relevant control examples used the intraperitoneal administration method to evaluate the therapeutic effect of the drug on the tumor site).

[0414] (c) Control Examples 2-3: Paclitaxel (concentration 1 mg / mL, the remainder being physiological saline) was injected intratumorally with a needle, using the needle injector of Control Example 1-1;

[0415] (d) Example 2-2: Intratumoral needle injection of the paclitaxel + AS01B composition described in item 2, using the needle injector of Control Example 1-1;

[0416] (e) Examples 2-3: Intratumoral diffusion injection of the composition containing paclitaxel + AS01B described in item 2 using a fluid delivery device (three-point injection of Examples 1-2, with the same injection parameters).

[0417] 4. Experimental Methods

[0418] 4.1 Establishing a model of advanced tumors

[0419] Lewis lung cancer cells (5 × 10⁸ cells / mouse) were subcutaneously inoculated into the right axilla of mice. The primary tumor volume was increased to approximately 500 mm². 3 Administer the medication at approximately 14 days after vaccination.

[0420] 4.2 Dosing regimen

[0421] Dosage frequency: Once every 2 days starting from day 0.

[0422] Dosage frequency: 7 times in total (on days 0, 2, 4, 6, 8, 10, and 12).

[0423] Dosage:

[0424] Paclitaxel (if applicable): 0.1 mg / vial / dose, other components determined accordingly.

[0425] Dosage volume: 100 μL / animal / dose

[0426] 4.3 Observation Indicators

[0427] Tumor volume measurement: Measured every two days using calipers starting from day 1, and calculated using the formula V = length × width² × 0.5.

[0428] Safety assessment: Monitoring weight changes and adverse reactions

[0429] Results and Analysis:

[0430] Tumor volume changes

[0431] Figure 4(ae) shows the tumor tissue in each group during the experiment. Changes in tumor tissue and volume are evident.

[0432] Control Example 2-1 (Figure 4a): The tumor remained essentially unchanged.

[0433] Control Example 2-2 (Figure 4b): It showed a certain inhibitory effect compared to Control Example 2-1, but the inhibition rate was less than 50%.

[0434] Control Example 2-3 (Figure 4c): It showed a certain inhibitory effect compared to Control Example 2-1, but the inhibition rate was less than 50%.

[0435] Example 2-1 (Figure 4d): The inhibitory effect was slightly better than that of the control group 2-3 with paclitaxel alone.

[0436] Example 2-2 (Figure 4e): Showed the best tumor-suppressing effect, with significant inhibition of tumor volume growth, and an inhibition rate of over 70% on day 11.

[0437] Safety assessment

[0438] Throughout the experiment, mice in the control group that received intraperitoneal administration experienced weight loss. In Example 2-2, the weight changes in the mice remained within the normal range, and no significant adverse reactions were observed at the injection site, indicating that the local administration method of the present invention has good safety.

[0439] This embodiment demonstrates that using the fluid delivery device of this invention for local (intratumoral) diffusion injection of the compositions of this invention significantly improves the delivery of antitumor drugs and immune adjuvants; compared to conventional administration methods, this invention can more effectively control the growth of advanced tumors. The administration method of this invention has better safety, with no significant systemic toxicity observed. The treatment strategy of this invention can significantly inhibit tumor metastasis.

[0440] Example 3: Local diffusion injection of a composition with a sustained-release system into a tumor

[0441] This embodiment aims to evaluate the therapeutic effects of the composition containing an erosive sustained-release agent (and an immune adjuvant containing an erosive sustained-release agent) and the local (intratumoral) diffusion injection administration method of the present invention on early-stage tumors.

[0442] Materials and Methods

[0443] 1. Laboratory animals

[0444] Forty healthy male C57BL / 6 mice, aged 6-8 weeks and weighing 18-22g, were selected and randomly divided into four groups (n=10 per group) using a random number table.

[0445] 2. Experimental materials used in the examples

[0446] Composition for first injection: The composition comprises the antitumor drug: paclitaxel (concentration 4 mg / mL); the immunoadjuvant: AS01B (containing MPL 200 μg / mL and QS-21 200 μg / mL); the erosive sustained-release agent: polyorthoester (Mn = 5000 Da): 65 wt%; the viscosity reducer: triglyceride: 35 wt%; the balance being physiological saline.

[0447] Subsequent injectable drugs: Immunoadjuvant: AS01B (containing MPL 200 μg / mL and QS-21 200 μg / mL); Erosive sustained-release agent: Polyorthoester (Mn = 5000 Da): 65% by weight; Viscosity reducer: Triglyceride: 35% by weight; Balance: physiological saline.

[0448] Final composition viscosity: 2000 mPa·s (measured at 25°C)

[0449] 3. Dosing grouping

[0450] (a) Control Example 3-1: Intratumoral injection of saline solution (negative control), using the needle injector of Control Example 1-1;

[0451] (b) Control Example 3-2: Paclitaxel (concentration 1 mg / mL, the remainder being physiological saline) was administered via intraperitoneal needle injection (conventional administration method) using the needle injector of Control Example 1-1;

[0452] (c) Control Example 3-3: Paclitaxel (concentration 1 mg / mL, the remainder being physiological saline) was administered percutaneously without needles using the needleless injector of Control Example 1-2;

[0453] (d) Example 3-1: The material described in item 2 was diffusely injected into the tumor using a fluid delivery device (three-point diffusion injection of Example 1-2, with the same injection parameters), that is, the sustained-release composition was given first, and then only AS01B with the sustained-release system was given thereafter.

[0454] 4. Establishing a tumor model

[0455] Lewis lung cancer cells (4 × 10⁸ cells / mouse) were subcutaneously injected into the right axilla of mice. Drug administration began approximately day 0 post-inoculation.

[0456] 4.2 Dosing regimen

[0457] Example 3-1 Dosage frequency: Once every 7 days starting from day 0.

[0458] Example 3-1 Dosage frequency: 2 times in total

[0459] Dosing frequency for the remaining groups: once every 2 days starting from day 0.

[0460] Other doses: 7 in total

[0461] Dosage:

[0462] Example 3-1 Paclitaxel: 0.4 mg / animal / dose, other components were determined based on this.

[0463] Paclitaxel for other groups (if applicable): 0.1 mg / animal / dose

[0464] Dosage volume: 100 μL / animal / dose

[0465] 4.3 Observation Indicators

[0466] Tumor volume measurement: Measured every two days using calipers starting from day 1, and calculated using the formula V = length × width² × 0.5.

[0467] Results and Analysis:

[0468] (1) Changes in tumor volume

[0469] As shown in Figures 5(ac) and 6, the tumor tissues of each group were examined during the experiment. Changes in tumor tissue and volume are evident.

[0470] Control Example 3-1 (Fig. 5a, Fig. 6): Tumor size grows rapidly.

[0471] Control Example 3-2 (Figure 5b, Figure 6): Compared with Control Example 3-1, it has a certain inhibitory effect on tumor size growth, but the tumor size grows more rapidly.

[0472] Control Example 3-3 (Figure 6): Compared with Control Example 3-1, it has a certain inhibitory effect on tumor size growth, but the tumor size grows faster. On the 13th, the tumor tissue size was similar to that of Control Example 3-2.

[0473] Example 3-1 (Figure 5c, Figure 6): showed the best tumor suppression effect, with significant inhibition of tumor volume growth. The inhibition rate was 100% on day 7 (i.e., the tumor disappeared) and there was no recurrence.

[0474] (2) Sustained-release effect: It can achieve fewer dosing times and higher single-dose concentration.

[0475] This embodiment demonstrates that, based on the effects of Examples 2-2, Example 3-1, using a composition with a sustained-release system and subsequent treatment with an immunoadjuvant containing a sustained-release system for intratumoral diffusion injection, not only inhibits early tumor growth (and prevents recurrence), but also achieves fewer dosing sessions and higher single-dose concentrations. Furthermore, the fluid delivery device of this invention (as in Examples 1-2) can effectively deliver high-viscosity drugs with sustained-release systems using appropriate delivery parameters.

[0476] (3) Safety evaluation

[0477] The control group mice experienced a slight decrease in body weight during the experiment. The mice in the Example 3-1 group maintained stable body weight, showed good tolerance at the injection site, and no obvious local or systemic adverse reactions were observed, demonstrating that the sustained-release composition of the present invention has good safety.

[0478] Example 4: Local diffusion injection of a composition containing a thermosensitive sustained-release agent into a tumor

[0479] This embodiment aims to evaluate the therapeutic effect of the composition containing a thermosensitive sustained-release agent and the local (intratumoral) diffusion injection administration method of the present invention on early-stage tumors.

[0480] Materials and Methods

[0481] 1. Laboratory animals

[0482] Thirty healthy male C57BL / 6 mice, aged 6-8 weeks and weighing 18-22g, were selected and randomly divided into 3 groups (n=10 per group) using a random number table.

[0483] 2. Experimental materials used in the examples

[0484] The composition comprises an antitumor drug: paclitaxel (concentration 4 mg / mL); an immunoadjuvant: AS01B (containing MPL 200 μg / mL and QS-21 200 μg / mL); a thermosensitive sustained-release agent: poloxamer 407 (PEO-PPO-PEO): 95% by weight; and the balance being physiological saline.

[0485] Gel transition temperature: 36℃.

[0486] The composition is pre-filled in a fluid delivery device and stored in a refrigerator at 4°C before use. After removing the pre-filled fluid delivery device from the refrigerator, the injection operation is performed immediately.

[0487] 3. Dosing grouping

[0488] (a) Control Example 4-1: Intratumoral injection of saline solution (negative control), using the needle injector of Control Example 1-1;

[0489] (b) Control Example 4-2: Paclitaxel (concentration 1 mg / mL, the remainder being physiological saline) was administered via intraperitoneal needle injection (conventional administration method) using the needle injector of Control Example 1-1;

[0490] (c) Example 4-1: Intratumoral diffusion injection of the material described in item 2 using a fluid delivery device (single-point diffusion injection of Example 1-1, with the same injection parameters).

[0491] 4. Establishing a tumor model

[0492] Lewis lung cancer cells (4 × 10⁸ cells / mouse) were subcutaneously injected into the right axilla of mice. Drug administration began approximately day 0 post-inoculation.

[0493] 4.2 Dosing regimen

[0494] Example 4-1 Dosage frequency: Once every 7 days starting from day 0.

[0495] Example 4-1 Dosage frequency: 2 times in total

[0496] Dosing frequency for the remaining groups: once every 2 days starting from day 0.

[0497] Other doses: 7 in total

[0498] Dosage:

[0499] Example 4-1 Paclitaxel: 0.4 mg / animal / dose, other components were determined based on this.

[0500] Paclitaxel for other groups (if applicable): 0.1 mg / animal / dose

[0501] Dosage volume: 100 μL / animal / dose

[0502] 4.3 Observation Indicators

[0503] Tumor volume measurement: Measured every two days using calipers starting from day 1, and calculated using the formula V = length × width² × 0.5.

[0504] Safety assessment: Monitoring weight changes and adverse reactions

[0505] Results and Analysis:

[0506] (1) Changes in tumor volume

[0507] Control Example 4-1: Tumor size increased rapidly.

[0508] Control Example 4-2: Compared with Control Example 3-1, it has a certain inhibitory effect on tumor size growth, but the tumor size still grows relatively rapidly.

[0509] Example 4-1: It showed the best tumor suppression effect, with significant inhibition of tumor volume growth. The inhibition rate was 100% on day 9 (i.e., the tumor disappeared) and there was no recurrence.

[0510] (2) Sustained-release effect: When injected at a low temperature of 4°C, the composition is in a liquid state, which facilitates precise injection control and achieves better diffusion injection. After injection into the body, it rapidly forms a solid gel at body temperature, which not only allows for fewer administrations and higher single-dose concentrations, but also effectively controls the drug's residence time at the injection site (within the tumor) and significantly reduces the tendency of the drug to diffuse into the vascular system.

[0511] (3) Safety evaluation

[0512] The control group mice experienced a slight decrease in body weight during the experiment. The mice in the Example 4-1 group maintained stable body weight, showed good tolerance at the injection site, and no obvious local or systemic adverse reactions were observed, demonstrating that the sustained-release composition of the present invention has good safety.

[0513] This embodiment demonstrates that, based on the effects of Examples 2-2, Example 4-1 uses a composition with a thermosensitive sustained-release gel for intratumoral diffusion injection. Good diffusion is achieved through liquid injection at low temperatures, followed by gel formation at body temperature, effectively controlling drug retention within the tumor and inhibiting diffusion into the vascular system. This thermosensitive characteristic allows the present invention to achieve fewer administrations and higher single-dose concentrations, inhibiting early tumor growth and preventing recurrence, resulting in significant therapeutic effects. Furthermore, the fluid delivery device of the embodiments of the present invention (such as Examples 1-1) can effectively deliver high-viscosity drugs with sustained-release systems using appropriate delivery parameters.

[0514] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A composition for local injection into a tumor, characterized in that, include: (a) An antitumor drug component, wherein the content of the antitumor drug component is preferably from 0.05% to 5% by weight, and the concentration of the antitumor drug component is preferably 0.1-20 mg / mL, wherein the antitumor drug component is preferably a cytotoxic antitumor drug, and more preferably, selected from at least one of the following categories: (i) A drug that interferes with nucleic acid metabolism, preferably selected from at least one of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, and hydroxyurea. (ii) Drugs that affect DNA function, preferably selected from at least one of alkylating agents, platinum compounds, antibiotics, and topoisomerases. (iii) A drug that interferes with the transcription process, preferably selected from at least one of doxorubicin, daunorubicin, and actinomycin. (iv) A drug that inhibits protein synthesis, preferably selected from at least one of L-asparaginase, vinca alkaloids, and paclitaxel. (v) A drug for regulating the body's hormonal balance, preferably selected from at least one of estrogen, androgen, medroxyprogesterone acetate, tamoxifen, glucocorticoids, and omeprazole. (vi) Radiopharmaceuticals, (vii) Targeted drugs, (viii) Immune checkpoint inhibitors; Preferably, the antitumor drug component is selected from at least one of paclitaxel derivatives, albumin-bound paclitaxel derivatives, PDL-1 derivatives, dual-target PDL-1 derivatives, multi-target PDL-1 derivatives, radiopharmaceuticals, and cisplatin derivatives; (b) An immune adjuvant, preferably in an amount of 0.05% to 5% by weight, preferably at a concentration of 10-1,000 μg / mL, and preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably selected from one or more of the following: - Saponin adjuvants, preferably QS-21 and GPI-0100; - Mycoglycolipid adjuvants, preferably MPL and RC-529; - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives; - Polymer I:C and its derivatives; -MDP derivatives, preferably MDP and Nor-MDP; - Cytokines, preferably GM-CSF, IL-2, and IL-12; -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein AS01B is a complex adjuvant composed of MPL and saponin QS-21; (c) The drug carrier may be one or more of physiological saline, polymer materials, emulsions and liposomes.

2. The composition according to claim 1, characterized in that, The drug carrier includes: An erodeable slow-release agent, wherein the content of the slow-release agent is preferably from 45% to 85% by weight, more preferably from 55% to 75% by weight, and the slow-release agent is composed of a polyorthoester polymer material, preferably the slow-release agent is composed of a polyorthoester. The viscosity reducer is preferably composed of 15% to 55% by weight, more preferably 25% to 45% by weight, and preferably composed of glyceryl ester compounds, preferably triacetic acid esters. Preferably, the viscosity of the composition, measured at 25°C, is from 100 mPa·s to 5000 mPa·s, more preferably from 500 mPa·s to 4000 mPa·s, and even more preferably from 800 mPa·s to 3000 mPa·s. Preferably, the number average molecular weight of the polyorthoester is 1,000 to 20,000 Daltons, more preferably 2,000 to 10,000 Daltons, and most preferably 4,000 to 7,000 Daltons.

3. The composition according to claim 1, characterized in that, The drug carrier includes: A thermosensitive sustained-release agent, wherein the content of the thermosensitive sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 75% to 99.5% by weight; preferably, the curing temperature of the thermosensitive sustained-release agent is from 30°C to 45°C, more preferably from 35°C to 39°C, more preferably from 36°C to 38°C, wherein the thermosensitive sustained-release agent comprises at least one of the following: Polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (Poloxamer 407) Lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA); Preferably, the thermosensitive sustained-release agent is composed of PEO-PPO-PEO or PLGA-PEG-PLGA.

4. The composition according to claim 1, characterized in that, The drug carrier includes: The non-sustained-release agent is preferably present in an amount of 45% to 99.95% by weight, more preferably in an amount of 55% to 99.5% by weight, and is composed of liposomes, physiological saline or glucose solution.

5. A fluid delivery device for delivering a composition to a tumor site, characterized in that, include: (i) A tube for containing the composition, (ii) An injection head fixedly connected to the storage cavity of the tube or detachably connected to the storage cavity of the tube, the injection head comprising one or more needle components, preferably having an orifice diameter of 0.05-2 mm and a length of 1-30 mm. (iii) A motorized power mechanism for controlling the delivery of the composition; Preferably, the fluid delivery device further includes (iv) an interventional soft needle, one end of which is connected to the tube and the other end of which is connected to the injection head or integrated with the injection head; Optionally, the tumor site includes at least one of the following locations: within the tumor, around the tumor, and local lymph nodes.

6. A combination drug and medical device product, characterized in that, include: (a) The composition according to any one of claims 1 to 4; (b) A fluid delivery device, comprising: (i) A tube for containing the composition, (ii) An injection head fixedly connected to the storage cavity of the tube or detachably connected to the storage cavity of the tube, the injection head comprising one or more needle components, preferably having an orifice diameter of 0.05-2 mm and a length of 1-30 mm. (iii) A motorized power mechanism for controlling the delivery of the composition; Preferably, the fluid delivery device further includes (iv) an interventional soft needle, one end of which is connected to the tube and the other end of which is connected to the injection head or integrated with the injection head.

7. Use of the composition of any one of claims 1 to 4 or the pharmaceutical-device combination product of claim 6 in the preparation of a medicament for administration by local injection into a tumor.

8. Use of a composition containing an antitumor drug component and an immune adjuvant in the preparation of a medicament for local injection into a tumor, wherein the composition is injected into the tumor site, thereby preferably causing the antitumor drug component to induce the production of tumor antigens, while the immune adjuvant enhances the activity of tumor-specific in vivo immune cells activated by the produced tumor antigens. Preferably, the antitumor drug is a cytotoxic antitumor drug; more preferably, it is selected from at least one of the following categories: (i) A drug that interferes with nucleic acid metabolism, preferably selected from at least one of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, and hydroxyurea. (ii) Drugs that affect DNA function, preferably selected from at least one of alkylating agents, platinum compounds, antibiotics, and topoisomerases. (iii) A drug that interferes with the transcription process, preferably selected from at least one of doxorubicin, daunorubicin, and actinomycin. (iv) A drug that inhibits protein synthesis, preferably selected from at least one of L-asparaginase, vinca alkaloids, and paclitaxel. (v) A drug for regulating the body's hormonal balance, preferably selected from at least one of estrogen, androgen, medroxyprogesterone acetate, tamoxifen, glucocorticoids, and omeprazole. (vi) Radiopharmaceuticals, (vii) Targeted drugs, (viii) Immune checkpoint inhibitors; Preferably, the antitumor drug component is selected from at least one of paclitaxel derivatives, albumin-bound paclitaxel derivatives, PDL-1 derivatives, dual-target PDL-1 derivatives, multi-target PDL-1 derivatives, radiopharmaceuticals, and cisplatin derivatives; Preferably, the immune adjuvant is an adjuvant capable of stimulating T cells, NK cells, and / or dendritic cells, and is preferably selected from one or more of the following: - Saponin adjuvants, preferably QS-21 and GPI-0100; - Mycoglycolipid adjuvants, preferably MPL and RC-529; - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives; - Polymer I:C and its derivatives; -MDP derivatives, preferably MDP and Nor-MDP; - Cytokines, preferably GM-CSF, IL-2, and IL-12; -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein, AS01B is a compound adjuvant composed of MPL and saponin QS-21.

9. Use of an immune adjuvant or a composition of an immune adjuvant and a tumor-specific polypeptide in the preparation of a medicament for local injection into a tumor, preferably wherein the medicament containing the immune adjuvant is injected into the tumor site in a subsequent course of treatment after the composition containing the antitumor drug component is injected into the tumor site, thereby preferably maintaining or enhancing the activity of tumor-specific in vivo immune cells activated by tumor antigens induced by the antitumor drug component. Preferably, the drug containing the immune adjuvant does not contain any antitumor drug components or tumor vaccine components; Preferably, the immune adjuvant is an adjuvant capable of stimulating T cells, NK cells, and dendritic cells, and is preferably selected from one or more of the following: - Saponin adjuvants, preferably QS-21 and GPI-0100; - Mycoglycolipid adjuvants, preferably MPL and RC-529; - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives; - Polymer I:C and its derivatives; -MDP derivatives, preferably MDP and Nor-MDP; - Cytokines, preferably GM-CSF, IL-2, and IL-12; -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein, AS01B is a compound adjuvant composed of MPL and saponin QS-21.

10. The use according to any one of claims 7 to 9, characterized in that, The tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma, or bladder cancer.

11. A combination drug product, characterized in that, include: (a) the composition according to any one of claims 1 to 4 or the pharmaceutical-device combination product according to claim 6; and (b) Personalized cancer vaccines, wherein the personalized cancer vaccines include a personalized antigen series matched to cancer patients.

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