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CN-121987551-A - Composition for local administration of tumor, pharmaceutical combination product and application

CN121987551ACN 121987551 ACN121987551 ACN 121987551ACN-121987551-A

Abstract

The invention relates to a composition for local injection of tumor, a pharmaceutical and mechanical combination product and application thereof in preparing medicines for local injection administration of tumor. The composition comprises an anti-tumor drug component, an immunoadjuvant and a drug carrier. Through the jet microneedle delivery device with special design, the anti-tumor drug can realize local tumor drug delivery, and the problem that the traditional intravenous drug delivery limits the highest dosage and the treatment effect of the drug due to systemic toxicity is avoided. The high-concentration local administration of the composition not only improves the local treatment effect of tumors, but also can effectively generate tumor antigens. The tumor antigen generated in situ can be matched with an immune adjuvant in the composition to generate tumor specific immune cells on the premise that the immune system of a patient is not destroyed due to the toxicity of a drug system, so that the immune response of the patient to tumors locally and systemically is improved. In addition, in the subsequent course of treatment following the initial treatment, only the combination of an immunoadjuvant and a tumor-specific polypeptide or the immunoadjuvant can be administered to maintain and enhance the established tumor-specific immune response, avoiding the cumulative toxicity caused by repeated use of the chemotherapeutic drug.

Inventors

  • MAO SHANHONG
  • Mao Jieqian
  • Mao Meixiu

Assignees

  • 诺曼德美国有限责任公司
  • 北京诺曼德工场药物递送创新科技有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (11)

  1. 1. A composition for local injection of a tumor, comprising: (a) An antitumor drug ingredient, preferably in an amount of 0.05 to 5% by weight, preferably in a concentration of 0.1-20mg/mL, said antitumor drug ingredient preferably being a cytotoxic antitumor drug, more preferably selected from at least one of the following classes: (i) A drug interfering with nucleic acid metabolism, preferably at least one selected from the group consisting of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, hydroxyurea, (Ii) Drugs affecting the function of DNA, preferably at least one selected from alkylating agents, platinum compounds, antibiotics, topoisomerase drugs, (Iii) A drug interfering with the transcription process, preferably at least one selected from doxorubicin, daunorubicin, actinomycin, (Iv) A drug for inhibiting protein synthesis, preferably at least one selected from L-asparaginase, vinblastine, and taxol, (V) A drug for regulating the homeostasis of the body, preferably at least one selected from the group consisting of estrogens, androgens, medroxyprogesterone, tamoxifen, glucocorticoids, and aminoglutethimide, (Vi) The radioactive nuclide is used as a drug, (Vii) The drug is targeted to the target and the drug, (Viii) Immune checkpoint inhibitor drugs; Preferably, the antitumor drug component is at least one selected from paclitaxel, albumin paclitaxel, PDL-1, double-target PDL-1, multi-target PDL-1, radionuclide and cisplatin; (b) An immunoadjuvant, preferably in an amount of 0.05 to 5 wt%, at a concentration of preferably 10-1,000 μg/mL, preferably an adjuvant capable of stimulating T cells, NK cells and/or dendritic cells, preferably selected from one or several of the following: -saponine adjuvants, preferably QS-21, GPI-0100; -a mycelial glycolipid adjuvant, preferably MPL, RC-529; -cyclic guanosine-group adjuvants, preferably cyclic guanosine-group (CDG) and derivatives thereof; -poly I: C and derivatives thereof; -MDP derivatives, preferably MDP, nor-MDP; -cytokines, preferably GM-CSF, IL-2, IL-12; More preferably at least one selected from AS01B and GM-CSF, wherein AS01B is a complex adjuvant consisting of MPL and saponin QS-21; (c) A pharmaceutical carrier, optionally one or more of physiological saline, polymeric material, emulsion and liposome.
  2. 2. The composition of claim 1, wherein the pharmaceutical carrier comprises: An erodable (erodeable) sustained-release agent, the content of which is preferably 45 to 85 wt%, more preferably 55 to 75 wt%, the sustained-release agent being composed of polyorthoester polymer material, preferably the sustained-release agent being composed of polyorthoester; A viscosity reducing agent, preferably in an amount of 15 to 55 wt%, more preferably 25 to 45 wt%, preferably consisting of a glycerate compound, preferably of triacetin; Preferably, the viscosity of the composition, measured at 25 ℃, is from 100 to 5000 mPa-s, preferably from 500 to 4000 mPa-s, more preferably from 800 to 3000 mPa-s; Preferably, the polyorthoester has a number average molecular weight of 1000 daltons to 20000 daltons, preferably 2000-10000 daltons, most preferably 4000-7000 daltons.
  3. 3. The composition of claim 1, wherein the pharmaceutical carrier comprises: A temperature-sensitive (THERMAL SENSITIVE) sustained-release agent, the content of the temperature-sensitive (THERMAL SENSITIVE) sustained-release agent is preferably 45 to 99.95 wt%, more preferably 75 to 99.5 wt%, preferably, the curing temperature of the temperature-sensitive (THERMAL SENSITIVE) sustained-release agent is 30 to 45 ℃, preferably 35 to 39 ℃, more preferably 36 to 38 ℃, and 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 temperature-sensitive slow release agent consists of PEO-PPO-PEO or PLGA-PEG-PLGA.
  4. 4. The composition of claim 1, wherein the pharmaceutical carrier comprises: A non-sustained release agent, preferably 45 to 99.95% by weight of the agent, more preferably 55 to 99.5% by weight, which consists of a liposome, physiological saline or glucose water.
  5. 5. A fluid delivery device for delivering a composition to a tumor site, comprising: (i) A tube for containing the composition, (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 members, preferably having an aperture of 0.05-2mm and a length of 1-30mm, (Iii) A motorized power mechanism for controlling delivery of the composition; preferably, the fluid delivery device further comprises (iv) an interventional soft needle having one end connected to the tube and the other end connected to the injection head or integrated with the injection head; Optionally, the tumor locally includes at least one of intratumoral, peritumoral, regional lymph nodes.
  6. 6. A combination of pharmaceutical and mechanical products, comprising: (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 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 members, preferably having an aperture of 0.05-2mm and a length of 1-30mm, (Iii) A motorized power mechanism for controlling delivery of the composition; preferably, the fluid delivery device further comprises (iv) an interventional soft needle having one end connected to the tube and the other end connected to the injection head or integrated with the injection head.
  7. 7. Use of a composition according to any one of claims 1 to 4 or a pharmaceutical combination according to claim 6 for the preparation of a medicament for local injection administration in a tumor.
  8. 8. Use of a composition comprising an anti-tumour pharmaceutical ingredient and an immunoadjuvant in the manufacture of a medicament for local administration by injection in a tumour, said composition being administered by injection to a tumour, whereby preferably the anti-tumour pharmaceutical ingredient induces the production of tumour antigen, while the immunoadjuvant enhances the activity of tumour-specific in vivo immune cells activated by the produced tumour antigen; preferably, the antineoplastic agent is a cytotoxic antineoplastic agent, more preferably at least one selected from the following classes: (i) A drug interfering with nucleic acid metabolism, preferably at least one selected from the group consisting of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, hydroxyurea, (Ii) Drugs affecting the function of DNA, preferably at least one selected from alkylating agents, platinum compounds, antibiotics, topoisomerase drugs, (Iii) A drug interfering with the transcription process, preferably at least one selected from doxorubicin, daunorubicin, actinomycin, (Iv) A drug for inhibiting protein synthesis, preferably at least one selected from L-asparaginase, vinblastine, and taxol, (V) A drug for regulating the homeostasis of the body, preferably at least one selected from the group consisting of estrogens, androgens, medroxyprogesterone, tamoxifen, glucocorticoids, and aminoglutethimide, (Vi) The radioactive nuclide is used as a drug, (Vii) The drug is targeted to the target and the drug, (Viii) Immune checkpoint inhibitor drugs; Preferably, the antitumor drug component is at least one selected from paclitaxel, albumin paclitaxel, PDL-1, double-target PDL-1, multi-target PDL-1, radionuclide and cisplatin; preferably, the immunoadjuvant is preferably an adjuvant capable of stimulating T cells, NK cells and/or dendritic cells, preferably selected from one or several of the following: -saponine adjuvants, preferably QS-21, GPI-0100; -a mycelial glycolipid adjuvant, preferably MPL, RC-529; -cyclic guanosine-group adjuvants, preferably cyclic guanosine-group (CDG) and derivatives thereof; -poly I: C and derivatives thereof; -MDP derivatives, preferably MDP, nor-MDP; -cytokines, preferably GM-CSF, IL-2, IL-12; more preferably at least one selected from AS01B and GM-CSF, wherein AS01B is a complex adjuvant consisting of MPL and saponin QS-21.
  9. 9. Use of an immunoadjuvant or a combination of an immunoadjuvant and a tumor specific polypeptide for the manufacture of a medicament for administration by local injection in a tumor, preferably the medicament containing the immunoadjuvant is injected into the tumor in a subsequent course of treatment after the composition containing an anti-tumor drug component is injected into the tumor, thereby preferably maintaining or enhancing the activity of tumor specific in vivo immune cells activated by a tumor antigen induced by the anti-tumor drug component; Preferably, the immunoadjuvant-containing medicament does not contain an anti-tumor pharmaceutical ingredient or a tumor vaccine ingredient; preferably, the immunoadjuvant is preferably an adjuvant capable of stimulating T cells, NK cells and dendritic cells, preferably selected from one or several of the following: -saponine adjuvants, preferably QS-21, GPI-0100; -a mycelial glycolipid adjuvant, preferably MPL, RC-529; -cyclic guanosine-group adjuvants, preferably cyclic guanosine-group (CDG) and derivatives thereof; -poly I: C and derivatives thereof; -MDP derivatives, preferably MDP, nor-MDP; -cytokines, preferably GM-CSF, IL-2, IL-12; more preferably at least one selected from AS01B and GM-CSF, wherein AS01B is a complex adjuvant consisting of MPL and saponin QS-21.
  10. 10. The use according to any one of claims 7 to 9, wherein the tumour is selected from at least one of melanoma, non-small cell lung cancer, breast cancer, renal cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, brain glioma or bladder cancer.
  11. 11. A product for combined use in the treatment of cancer, characterized by comprising the following steps: (a) The composition according to any one of claims 1 to 4 or the pharmaceutical combination according to claim 6, and (B) A personalized tumor vaccine, wherein the personalized tumor vaccine comprises a personalized antigen series that matches a tumor patient.

Description

Composition for local administration of tumor, pharmaceutical combination product and application Technical Field The invention relates to the technical field of biological medicines, in particular to a composition for local administration of tumors, a pharmaceutical and mechanical combination product and application thereof. Background Malignant tumors are one of the major diseases threatening human health and life. The main means for clinically treating malignant tumors at present comprise operations, radiotherapy, chemotherapy, targeted therapies and the like. Among them, tumor therapeutic drugs such as chemotherapeutic drugs are usually administered intravenously, but since they cause systemic toxicity, the dosage and therapeutic effect are limited and resistance is easily developed. This mode of administration results in insufficient local drug concentration in the tumor and may cause some damage to normal tissues throughout the body. Although the targeting treatment has certain selectivity, the target is difficult to find and has no universality, drug resistance is easy to generate, and the cost is high. Tumor vaccines recognize and attack tumor cells by activating the immune system of the body. In order to enhance the immunogenicity of a vaccine, it is often necessary to add adjuvants to the vaccine as adjunct ingredients. However, in practical application, the effect of the tumor vaccine on the rapid treatment of solid tumors needs to be enhanced, and the effect of a single treatment means needs to be improved. Thus, despite the various treatments currently available, the efficacy is still limited for patients with advanced tumors. Combination therapy of multiple technologies is currently preferred. However, the combination therapy in clinical application is used for multiple times of treatment means. There is currently no therapeutic means for disposable treatment that involves multiple therapeutic techniques. Thus, new disposable therapeutic strategies comprising a variety of therapeutic techniques are urgently to be developed. The description of the background art is only for the purpose of facilitating an understanding of the relevant art and is not to be taken as an admission of prior art. Disclosure of Invention The invention aims to provide a composition for local administration of tumors, a pharmaceutical and mechanical combination product, a preparation method and application. In a first aspect, the present invention provides a composition for local injection of a tumor comprising: (a) An antitumor drug ingredient, preferably in an amount of 0.05 to 5% by weight, preferably in a concentration of 0.1-20mg/mL, said antitumor drug ingredient preferably being a cytotoxic antitumor drug, more preferably selected from at least one of the following classes: (i) A drug interfering with nucleic acid metabolism, preferably at least one selected from the group consisting of methotrexate, pemetrexed, mercaptopurine, fluorouracil, capecitabine, hydroxyurea, (Ii) Drugs affecting the function of DNA, preferably at least one selected from alkylating agents, platinum compounds, antibiotics, topoisomerase drugs, (Iii) A drug interfering with the transcription process, preferably at least one selected from doxorubicin, daunorubicin, actinomycin, (Iv) A drug for inhibiting protein synthesis, preferably at least one selected from L-asparaginase, vinblastine, and taxol, (V) A drug for regulating the homeostasis of the body, preferably at least one selected from the group consisting of estrogens, androgens, medroxyprogesterone, tamoxifen, glucocorticoids, and aminoglutethimide, (Vi) The radioactive nuclide is used as a drug, (Vii) The drug is targeted to the target and the drug, (Viii) Immune checkpoint inhibitor drugs; Preferably, the antitumor drug component is at least one selected from paclitaxel, albumin paclitaxel, PDL-1, double-target PDL-1, multi-target PDL-1, radionuclide and cisplatin; (b) An immunoadjuvant, preferably in an amount of 0.05 to 5 wt%, at a concentration of preferably 10-1,000 μg/mL, preferably an adjuvant capable of stimulating T cells, NK cells and/or dendritic cells, preferably selected from one or several of the following: -saponine adjuvants, preferably QS-21, GPI-0100; -a mycelial glycolipid adjuvant, preferably MPL, RC-529; -cyclic guanosine-group adjuvants, preferably cyclic guanosine-group (CDG) and derivatives thereof; -poly I: C and derivatives thereof; -MDP derivatives, preferably MDP, nor-MDP; -cytokines, preferably GM-CSF, IL-2, IL-12; More preferably at least one selected from AS01B and GM-CSF, wherein AS01B is a complex adjuvant consisting of MPL and saponin QS-21; (c) A pharmaceutical carrier, optionally one or more of physiological saline, polymeric material, emulsion and liposome. In some embodiments of the invention, the pharmaceutical carrier comprises: An erodable (erodeable) sustained-release agent, the content of the erodable sustained-release agent is preferably 45