WO2023050297A1 - Composition pharmaceutique topique, application et kit - Google Patents

Composition pharmaceutique topique, application et kit Download PDF

Info

Publication number
WO2023050297A1
WO2023050297A1 PCT/CN2021/122134 CN2021122134W WO2023050297A1 WO 2023050297 A1 WO2023050297 A1 WO 2023050297A1 CN 2021122134 W CN2021122134 W CN 2021122134W WO 2023050297 A1 WO2023050297 A1 WO 2023050297A1
Authority
WO
WIPO (PCT)
Prior art keywords
synergistic
drug
local
drugs
tumor
Prior art date
Application number
PCT/CN2021/122134
Other languages
English (en)
Chinese (zh)
Inventor
邹方霖
邹礼常
王建霞
Original Assignee
成都夸常奥普医疗科技有限公司
夸常股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都夸常奥普医疗科技有限公司, 夸常股份有限公司 filed Critical 成都夸常奥普医疗科技有限公司
Priority to PCT/CN2021/122134 priority Critical patent/WO2023050297A1/fr
Priority to PCT/CN2022/122537 priority patent/WO2023051682A1/fr
Publication of WO2023050297A1 publication Critical patent/WO2023050297A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a local pharmaceutical composition, application and kit.
  • solid tumors are a representative model of locally diseased disease, which is typically a tumor body containing tumor cells and lymph nodes contaminated by tumor cells.
  • tumor cells In addition to tumor cells, there are often fibroblasts, intercellular matrix, pipelines and other components in tumor tissues, which are sometimes called the microenvironment of tumor cells.
  • pancreatic cancer tumors pancreatic cancer cells only account for about 30% of the tumor tissue. These microenvironments complicate the reaction kinetics between cytotoxic drugs and tumor cells, which may greatly reduce the drug efficacy.
  • the present invention aims to propose a new pharmacology (a special local synergistic activity) based on a high-molecular blood volume expander (hereinafter referred to as an expander)-that is, a drug that does not cause a local synergistic effect when shared with it alone.
  • the topical pharmaceutical composition prepared by converting it into a synergistic shared product can achieve high efficiency and low toxicity, especially in the medium and long term, so as to provide various options for clinical use.
  • ethanol is widely used as a fungicide in the preparation of medicines; in the 1980s, scientists discovered that high-concentration ethanol can be shown to target tumor tissues through intratumoral administration. In the following 20 years, high-concentration ethanol was widely used in the chemical ablation therapy of local lesions such as tumors.
  • polyvinylpyrrolidone which is usually used as a blood volume expander
  • a variety of non-synergistic drugs have synergistic effects with it, and other expanders whose composition and structure are very different from it also show this new pharmacology.
  • the "synergistic effect” is one of the common pharmacological effects, which means that the common use of multiple specific active ingredients produces an actual joint effect (q 1 ) that exceeds their respective actual single-use effects under specific conditions (such as concentration).
  • Additive and expected (q 2 ) pharmacological effects It is generally believed that the pharmacological basis of the additive effect is that the same type of effects (such as local effects) of different active ingredients can be displayed without interference (such as local additive effects) when they are used together, and the pharmacological basis of the synergistic effect is then considered to be different when they are used together.
  • Mutual enhancement such as local synergistic effect between similar effects (such as local effects) of active ingredients.
  • short-term synergistic effect refers to the synergistic effect based on the drug effects (q 1 , q 2 ) in the short term (such as within 5 days after the last administration); After the 14th day of administration) the synergistic effect of drug effects (q 1 , q 2 ).
  • non-synergistic drug refers to a single drug that does not show the aforementioned synergistic effect when co-administered with a specific active ingredient, such as dextran, under specific conditions (eg, dextran is not the pharmacological concentration that maximizes the local effect).
  • local administration refers to the administration method in which the drug is directly delivered to the target area (such as the tumor body), which is different from the conventional administration methods such as oral administration, intravenous injection, and intraperitoneal injection.
  • topical pharmaceutical composition refers to a pharmaceutical composition of multiple topically administrable active ingredients that can be intimately mixed into a target area in the desired concentration or concentration ratio, preferably, said "topical pharmaceutical composition” does not Sodium chloride-containing isotonic agents are often used as additives to nontopical medications.
  • the "local pharmaceutical composition” has the following differences from conventional drugs: 1) The pharmacology of the target area (such as a tumor body) is different: the short-term drug effect of the former is mainly a local effect; the latter is a local manifestation of a systemic effect; 2) Medication requirements are different: the former requires precise concentration ratio and high purity in the target area, while the latter prefers routine administration with better compliance; 3) Drug composition and dosage form are different: the former’s drug composition and dosage form must be strictly equivalent The composition of the target area required to achieve its target pharmacology, the latter requires as little local side effects as possible.
  • the invention provides a local pharmaceutical composition, comprising a blood volume expander, a non-synergistic drug, and an appropriate amount of vehicle, the pharmacological concentration of the expander is ⁇ 30%, preferably 2-30%, more preferably 2-5% % or 5-20%; the pharmacological concentration of the non-synergistic drug is 0.36-40%.
  • the vehicle is water for injection.
  • the blood volume expander includes at least one of a dextran blood volume expander, a starch-derived blood volume expander, a gelatin-derived blood volume expander, and a synthetic blood volume expander.
  • the dextran blood volume expander is selected from at least one of dextran 10, dextran 40, dextran 70, and polymer condensed glucose;
  • the starch-derived blood volume expander is selected from carboxyethyl starch 20, carboxyethyl starch At least one of ethyl starch 40, carboxyethyl starch 130/0.38-0.45, and carboxyethyl starch 200/0.5.
  • the gelatin-derived blood volume expander may be oxidized polygelatin and/or succinylated gelatin; the synthetic blood volume expander may be fluorocarbon artificial blood and/or polyvinylpyrrolidone.
  • the non-synergistic drugs include non-synergistic drugs A and B, and wherein no short-term synergistic effect occurs when the blood volume expander is shared with the non-synergistic drugs A or B, and the blood volume expander and the non-synergistic There is a synergistic effect when drug A and non-synergistic drug B are used together.
  • the non-synergistic drugs include non-synergistic drugs A, B, and C, and wherein the blood volume expander does not have a short-term synergistic effect when shared with the non-synergistic drugs A, B, or C, and the blood volume expander There is a synergistic effect when the drug is used with non-synergistic drugs A, B and C.
  • the non-synergistic drugs include non-synergistic drugs A, B, C and D, and wherein no short-term synergistic effect occurs when the blood volume expander is shared with the non-synergistic drugs A, B, C or D, so There is a synergistic effect when the above blood volume expanders are used together with non-synergistic drugs A, B, C and D.
  • synergistic effect including synergistic drug effect and/or safety synergy, such as short-term safety synergistic effect and/or mid- to long-term drug effect synergistic effect.
  • the synergy that exists when the blood volume expander is used together with the non-synergistic drug A, B or A, B, C or A, B, C, D includes drug efficacy synergy and/or safety synergy, for example Short-term synergy and/or mid- to long-term pharmacodynamic synergy.
  • the non-synergistic drug A is selected from the group consisting of alkali metal hydroxides, basic organic compounds, and basic inorganic salts.
  • the non-synergistic drugs A, B or A, B, C or A, B, C, D are respectively selected from the following different groups: alkali metal hydroxides, basic organic compounds, basic inorganic salts, polyhydric Alcohols, cytotoxic drugs, methylene blue and its analogues, immunomodulators, weak acids, non-basic amino acids and their acid salts.
  • the concentration of the alkali metal hydroxide can be 0.5-7%, the concentration of the basic inorganic salt can be 1.0-10% or 1.0-15%, and the concentration of the basic organic compound can be 2.5-25% , the concentration of the methylene blue and its analogs can be 0.35-5%, the concentration of the polyol can be 5-25%; the concentration of the cytotoxic drug can be 0.10-10%, the immune regulation
  • the concentration of the agent can be 0.10-25%, the concentration of the weak acid can be 1-25%, and the concentration of the non-basic amino acid and its acid salt can be 1-25%.
  • the non-synergistic drug A is selected from alkali metal hydroxides
  • B is selected from the following group: basic organic compounds, basic inorganic salts, polyhydric alcohols, cytotoxic drugs, methylene blue and analogs thereof, Immunomodulators, for example, the drug combination formed by the non-synergistic drugs A and B is alkali metal hydroxide/basic inorganic salt, the concentration ratio is (1-5%)/(3-15%) or alkali metal hydroxide substance/cytotoxic drug, the concentration ratio is (1-5%)/(0.1-15%) or alkali metal hydroxide/basic organic compound, the concentration ratio is (1-5%)/(5-25%) .
  • the non-synergistic drug A is selected from basic organic compounds
  • the non-synergistic drug B is selected from the following group: alkali metal hydroxides, basic inorganic salts, polyhydric alcohols, cytotoxic drugs, methylene blue And analogs thereof, immunomodulators, weak acids, non-basic amino acids and acid salts thereof
  • the drug combinations formed by the non-synergistic drugs A and B are basic organic compounds/basic inorganic salts, and the concentration ratio is (5 -25%)/(3-15%) or basic organic compound/immunomodulator, concentration ratio is (5-25%)/(1-15%) or basic organic compound/methylene blue and its analogs , the concentration ratio is (5-25%)/(0.35-3.5%) or basic organic compound/cytotoxic drug, the concentration ratio is (5-25%)/(0.1-10%) or basic organic compound/acidification agent, the concentration ratio is (5-25%)/(2-15%) or basic organic compound/non-basic amino acid and its acid salt, the concentration ratio is
  • the non-synergistic drug A is selected from cytotoxic drugs
  • B is selected from the following groups: alkali metal hydroxides, basic organic compounds, basic inorganic salts, polyhydric alcohols, methylene blue and analogs thereof, Immunomodulators, weak acids, non-basic amino acids and their acid salts.
  • the non-synergistic drug A is selected from alkali metal hydroxides
  • the non-synergistic drug B is selected from basic inorganic salts
  • the non-synergistic drug C or/and D is selected from the following group: basic organic compounds , polyols, cytotoxic drugs, methylene blue and its analogs, immunomodulators, such as the following combinations: alkali metal hydroxides/basic inorganic salts/basic organic compounds, alkali metal hydroxides/basic inorganic salts /Methylene blue and its analogs, alkali metal hydroxides/basic inorganic salts/immunomodulators, alkali metal hydroxides/basic inorganic salts/cytotoxic drugs.
  • the methylene blue and its analogues include at least one of methylene blue, patent blue, isosulfur blue and new methylene blue, the concentration of which is 0.25-5%, preferably 0.35-2.5%.
  • the cytotoxic drugs refer to active ingredients that mainly target diseased cells or intracellular structures to achieve their drug effects, such as substances that have shown anti-cancer cell proliferation in cell experiments or in tumor-bearing animals, such as chemotherapy drugs.
  • the chemotherapeutic drugs include: 1) drugs that destroy DNA structure and function, such as alkylating agents-cyclophosphamide, carmustine, etc., metal platinum complexes-cisplatin, carboplatin, etc., DNA topoisomerase inhibitors Drugs-doxorubicin, topotecan, irinotecan, etc.; 2) Drugs embedded in DNA that interfere with the transcription of RNA, such as anti-tumor antibiotics-actinomycins, daunorubicin, doxorubicin, etc.; 3) Drugs that interfere with DNA synthesis, such as pyrimidine antagonists-uracil derivatives, such as 5-fluorouracil, furofluorouracil, bisfururouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc.
  • drugs that destroy DNA structure and function such as alkylating agents-cyclophosphamide, carmustine, etc., metal platinum
  • Purine antagonists - such as carcine, thioguanine, etc., folic acid antagonists - such as methotrexate, etc.
  • Drugs that affect protein synthesis such as colchicines, vinblastines, taxanes - such as Paclitaxel, Docetaxel, etc.
  • the chemotherapeutic drugs are selected from uracil derivatives, cyclophosphamides, gemcitabines, epirubicins, antitumor antibiotics, teniposide, metal platinum complexes, taxanes
  • uracil derivatives preferably, including at least one of 5-fluorouracil, cyclophosphamide, gemcitabine, epirubicin, antitumor antibiotics, teniposide, metal platinum complexes, and paclitaxel.
  • the concentration of the chemotherapeutic drug in the local pharmaceutical composition is (w/v) 0.03-6%, for example, the concentration of alkylating agents such as cyclophosphamide and carmustine is (w/v) 0.5- 6%, preferably 0.75-1.5%; the concentration (w/v) of metal platinum complexes such as cisplatin and carboplatin is 0.03-0.15%, preferably 0.05-0.15%; doxorubicin, topotecan
  • concentration (w/v) of DNA topoisomerase inhibitors such as , irinotecan is 0.05-0.20%, is preferably 0.075-0.15%; /v) is 1-4%, preferably 1-2%; uracil derivatives such as 5-fluorouracil, furofluorouracil, and bisfurofluorouracil, and cytosines such as cytarabine, cyclocytidine, and 5-azacytidine
  • concentration (w/v) of the derivative is
  • the immunomodulator includes at least one of BCG and components thereof, probiotics and components thereof, and at least one of immunomodulatory antibodies; the BCG and components thereof include BCG, inactivated BCG, BCG polysaccharide nucleic acid, etc., and the probiotics Bacteria and its components include inactivated probiotics, probiotic cell wall polysaccharides and their derivatives, probiotic ribonucleic acid, etc., and the immunomodulatory antibodies include plasma immunoglobulins, polyclonal immunoglobulins, and monoclonal immunoglobulins.
  • the monoclonal immunoglobulin includes antibody blockers against inhibitory receptors, such as blocking antibodies against CTLA-4 molecules and PD-1 molecules; antibody blockers against ligands of inhibitory receptors Antibodies, activating antibodies against stimulating molecules on the surface of immune response cells, such as anti-OX40 antibody, anti-CD137 antibody, anti-4-1BB antibody; neutralizing antibodies against immunosuppressive molecules in the local disease microenvironment, such as anti-TGF-p1 Antibody.
  • inhibitory receptors such as blocking antibodies against CTLA-4 molecules and PD-1 molecules
  • Antibodies antibody blockers against ligands of inhibitory receptors Antibodies, activating antibodies against stimulating molecules on the surface of immune response cells, such as anti-OX40 antibody, anti-CD137 antibody, anti-4-1BB antibody
  • neutralizing antibodies against immunosuppressive molecules in the local disease microenvironment such as anti-TGF-p1 Antibody.
  • BCG (or probiotic) component refers to a preparation derived from natural BCG (or probiotic) or its engineered bacteria (such as cell wall polysaccharide) or an engineering analog of the preparation (such as similar to cell wall Synthetic polysaccharides of polysaccharides or polysaccharides from other sources).
  • the drug combination formed by the non-synergistic drugs A and B is alkali metal hydroxide/basic inorganic salt
  • the concentration ratio is (1-5%)/(3-15%) or basic organic compound/base
  • Non-toxic inorganic salt the concentration ratio is (5-25%)/(3-15%) or alkali metal hydroxide/basic organic compound, the concentration ratio is (1-5%)/(5-25%).
  • the alkali metal hydroxide/basic inorganic salt the concentration ratio is (0.5-5%)/(3.0-10%) or the basic organic compound/basic inorganic salt, the concentration ratio is (1.0- 10%)/(2.5-25%).
  • the drug combination formed by the non-synergistic drugs A and B can also be basic organic compound/cytotoxic drug, the concentration ratio is (2.5-25%)/(0.03-6%), basic organic compound/immune regulator, The concentration ratio is (2.5-25%)/(0.01-20%), immunomodulator/methylene blue and its analogues, the concentration ratio is (0.01-20%)/(0.3-2.5), methylene blue and its Analogue/cytotoxic drug, concentration ratio (0.3-2.5%)/(0.03-6%), cytotoxic drug/acidifier, concentration ratio (0.03-6%)/(1-25%), non-alkali Sexual amino acid and its acid salt/weak acid, the concentration ratio is (5-25%)/(2-15%).
  • the topical pharmaceutical composition may be 20% dextran 40/10% arginine/1% methylene blue in water, 20% dextran 40/10% arginine/1% methylene blue/2% sodium bicarbonate in water, 20% Dextran 40/20% Mannitol/1% Methylene Blue/1% 5-Fluorouracil in water, 20% Dextran 40/10% Arginine/1% Methylene blue/1% 5-Fluorouracil in water, 20% Hydroxy Ethyl starch/10% arginine/1% methylene blue/1% 5-fluorouracil in water.
  • the drug combination formed by the non-synergistic drugs A and B is basic organic compound/immunomodulator
  • the concentration ratio is (5-25%)/(1-15%) or basic organic compound/methylene blue And its analogs
  • the concentration ratio is (5-25%)/(0.35-3.5%) or basic organic compound/cytotoxic drug
  • the concentration ratio is (5-25%)/(0.1-10%) or basic Organic compound/acidulant
  • the concentration ratio is (5-25%)/(2-15%).
  • the acidulant is at least one selected from weak acids, non-basic amino acids and acid salts thereof.
  • the concentration of the immunomodulator can be 0.10-25%, the concentration of the cytotoxic drug can be 0.1-5%, the concentration of the acidulant can be 2.5-25%, such as the concentration of weak acid is 2-15% , the concentration of non-basic amino acids and their acid salts is 5-25%.
  • the weak acids include oxalic acid, maleic acid, tartaric acid, acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1 , 2,3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid);
  • the non-basic amino acids include glycine, cysteine, alanine, serine, aspartic acid, glutamic acid .
  • a non-synergistic drug C is also included, and the combination of the non-synergistic drugs A, B, and C includes: alkali metal hydroxide/basic inorganic salt/cytotoxic drug, alkali metal hydroxide/basic inorganic salt /Methylene blue and its analogs, basic inorganic salts/basic organic compounds/cytotoxic drugs, basic inorganic salts/basic organic compounds/methylene blue and its analogs, basic inorganic salts/basic organic compounds /Cytotoxic Drugs/Methylene Blue and Its Analogs, Basic Organic Compounds/Methylene Blue and Its Analogs/Cytotoxic Drugs, Basic Organic Compounds/Cytotoxic Drugs/Immunomodulators, Polyols/Cytotoxic Drugs/ Methylene blue and its analogs, immunomodulators/cytotoxic drugs/methylene blue and its analogs, methylene blue and its analogs/cytotoxic drugs/acidifiers, methylene blue and its analogs/
  • the combination of the non-synergistic drugs A, B, and C is: 15% polyvinylpyrrolidone/1% NaOH/2% NaHCO 3 aqueous solution, 15% dextran 40/20% arginine/7% sodium bicarbonate Aqueous solution, 15% dextran 40/20% arginine/1% 5-fluorouracil in water, 15% dextran 40/20% arginine/1% methylene blue in water, 15% dextran 40/5% mouse immunoglobulin /1% methylene blue aqueous solution, 15% hydroxyethyl starch/20% arginine/4% sodium bicarbonate aqueous solution, 15% hydroxyethyl starch/20% arginine/1% 5-fluorouracil aqueous solution, 15% Hetastarch/20% arginine/1% methylene blue aqueous solution, 15% hydroxyethyl starch/20% arginine/5% mouse immunoglobulin aqueous solution.
  • the alkali metal hydroxide includes sodium hydroxide, potassium hydroxide, calcium hydroxide;
  • polybasic weak acid basic inorganic salt includes for example sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium hydrosulfate, sodium dihydrogen phosphate, Disodium hydrogen phosphate;
  • the weak acid strong base salt includes sodium phosphate, sodium carbonate, potassium carbonate, borax, sodium acetate;
  • the basic organic compound includes 2-aminoethanol, tromethamine, triethanolamine, trimethylol Aminomethane, 2-aminoethanol, tromethamine, triethanolamine, meglumine, ethylglumine, choline, arginine, acid-resistant acid.
  • the basic inorganic salt is sodium bicarbonate at a concentration of 1-10%.
  • the basic organic compound is arginine or/and arginine.
  • the basic organic compound is arginine or/and oleic acid, and its concentration is 5-30%, preferably 5-25%.
  • the pH of the pharmaceutical composition is 10.0 ⁇ 1.5 or 4.0 ⁇ 1.5.
  • the topical pharmaceutical composition is 20% dextran 20/20% arginine/5% sodium bicarbonate aqueous solution, pH 10.0, 20% dextran 20/5% immunoglobulin/2% methylene blue/10 % glycine/5% acetic acid in water, pH 4.1.
  • the present invention also provides a method of treating locally diseased diseases, comprising the step of: locally administering a therapeutically effective amount of the above topical pharmaceutical composition to the diseased area of an individual in need thereof.
  • the therapeutic effects include short-term local treatment with local effects (or local synergistic effects) or/and mid- to long-term treatments involving immune effects.
  • the local effect includes local chemical effect (or local chemical synergistic effect) and optionally other effects, which are independent of the pathogenic (cellular, viral or bacterial) toxic effect of the local lesion.
  • Said immunization includes secondary immunization of local action (or local synergy) and optionally other immunization in the lesion area,
  • local treatment is different from “systemic treatment”, the latter refers to the treatment of the whole body of the patient (such as the tumor body, the area connected with the tumor body, and tumor cells contained in other parts of the body), while the former refers to the treatment of the patient's local lesion.
  • the treatment of the local area (such as administration of local lesions and other diseased areas connected with it).
  • the role of blood volume expanders is based on the therapeutic auxiliary effect they can provide as a heterogeneous antigen, such as immune enhancement, rather than therapeutic effect, let alone local therapeutic effect.
  • the term "local effect” is different from the conventional effect, which refers to the pharmacological effect of the drug in the local area (such as tumor cell microenvironment) where the lesion tissue space penetrates after local administration, while the conventional effect refers to the pharmacological effect of the drug after conventional administration.
  • topical chemical action refers to local action including chemical action.
  • local synergy refers to local effects including synergy.
  • the term “local chemical synergy” refers to local chemistry including synergy.
  • Local chemical action pharmacologically includes common local chemical action, chemical ablation and chemical-like ablation.
  • common local chemical effect refers to a local chemical effect in which the drug effect does not exceed the maximum expected (eg, within 200%) of the kinetic difference of conventional chemical effects of the same drug, such as chemotherapeutic effects resulting from conventional administration of cytotoxic drugs.
  • chemical ablation refers to a localized chemical effect in which the effect of the drug exceeds the maximum expected (e.g., greater than 200%, preferably greater than 400) kinetic difference of conventional chemical effects of the same drug (e.g., the chemotherapeutic effect produced by conventional administration of high-concentration ethanol) , which traditionally refers to the local chemical action exhibited by classical chemical ablative agents (eg, high concentrations of ethanol, high concentrations of acids, high concentrations of bases).
  • classical chemical ablative agents eg, high concentrations of ethanol, high concentrations of acids, high concentrations of bases.
  • chemical-like ablation refers to local effects including chemical ablation. Although chemical-like ablation is not caused by classical chemical ablative agents, it is obviously different from ordinary local chemical effects in pharmacology.
  • immunotherapy is different from the term “immunoenhancement”.
  • the former refers to the immune effect (such as the immune effect of therapeutic vaccines, specific antibodies, etc.) Function, but still have auxiliary immune function (such as immune enhancer has the effect of improving the immune function of the body).
  • Said therapeutic effect includes immunotherapy involving said local action (or local synergy) and immunotherapy includes secondary immune action and optionally Other immune effects present.
  • Applicable patients for the treatment include one or more of the following groups: patients who can be administered into local lesions and the local lesion tissue can be ablated by chemicals or/and can produce secondary immune effects in the local lesions, patients who can be administered outside the lesion Patients who can produce secondary immune effects in the drug area.
  • the composition is an in situ or/and ex situ immunotherapy drug.
  • Said therapeutic effect is comprised of said local treatment or/and immunotherapy involving said local action (or local synergy), and wherein said local treatment comprises chemical-like ablation of one or more local lesions and optionally the presence of said immunotherapy includes said local acting (or local synergistic) secondary immune effects and optionally other immune effects within said lesion.
  • the applicable patients for the treatment are selected from one or more of the following groups: immunosuppressed patients, patients who can be administered into local lesions, patients whose local lesions can be chemically ablated, patients whose local lesions can be administered Patients with secondary immunity.
  • the composition is a chemoablation-in situ immunotherapy-like drug.
  • Said therapeutic effect is meant to include local treatment involving local action (or local synergy), and wherein said local treatment comprises chemo-like ablation of one or more local lesions and optionally other chemotherapy.
  • the applicable patients for the treatment are selected from one or more of the following groups: immunosuppressed patients, patients who can be administered into local lesions, and patients whose local diseased tissues can be ablated by chemicals.
  • the composition is a chemoablative drug-like.
  • Said therapeutic effects include immunotherapy involving local effects (or local synergies), and wherein said immunotherapy includes secondary immune effects of said local effects (or local synergies) within said lesion and optionally Other immune effects.
  • the suitable patients for the treatment are selected from patients who can be administered in local lesions, and the local lesions can produce secondary immune effects.
  • the composition is an in situ immunotherapeutic drug, eg, an immunotherapeutic drug that provides in situ vaccine activation and optionally other immune effects at the target region within the lesion.
  • Said therapeutic effects include immunotherapy involving local effects (or local synergies), and wherein said immunotherapy includes secondary immune effects of said local effects (or local synergies) outside said lesion and optionally Other immune effects.
  • the applicable patients for the treatment are selected from patients who can produce secondary immune effects in the area of administration outside the lesion.
  • the composition is an immunotherapeutic drug that provides extralesional secondary immunity and optionally other immunity.
  • said extralesional secondary immunity comprises said locally acting (or locally synergistic) secondary immunity of abnormal structures such as nodules.
  • the immunotherapeutic drug includes, for example, a vaccine-like drug.
  • the topical dosage forms include injections, paints or ointments.
  • the "injection” refers to a sterile preparation containing the active ingredient and its solvent and available for in vivo administration, divided into local injections, intravenous injections, etc. according to the mode of administration, and local injections are injections in the form of local pharmaceutical compositions; Divided into liquid injections, semi-fluid injections, powder injections for injection, etc.
  • the powder for injection comprises sterile dry powder and solvent, wherein the sterile dry powder contains part or all of the active ingredients, and the solvent contains all liquid carriers.
  • the concentration of the active ingredient in the injection is the concentration of the active ingredient in its mixture with all the liquid carriers, usually the end point of the local drug delivery device (syringe, puncture, injection catheter, etc.) ) of the active ingredient concentration in the liquid medicine.
  • the concentration of the active ingredient is the concentration of the active ingredient in the mixture of sterile dry powder and vehicle (such as reconstitution solution or the pharmaceutically acceptable liquid carrier).
  • the present invention also provides the application of the above local pharmaceutical composition in the preparation of pharmaceutical preparations for treating local disease.
  • the local pathological diseases include tumors, non-neoplastic masses such as hyperplasia, cysts, nodules, etc., local inflammations such as cervical erosion, abnormal function of secretory glands and skin diseases.
  • the secretory glands include thyroid gland, mammary gland, liver, lung, intestine, etc. Described skin disease comprises chronic mucocutaneous candidiasis, various tinea etc.
  • the "tumor” refers to a mass formed due to abnormal proliferation of cells or mutated cells, such as a solid tumor.
  • the “solid tumor” refers to a tumor with a tumor body, which can be due to any pathology (malignant and non-malignant) and tumors at any stage, according to tumor cell types, including epithelial cell tumors, sarcoma, lymphoma, germ cell tumors , blastoma; according to the organ or tissue where the tumor cells are concentrated, including brain tumors, skin tumors, bone tumors, muscle tumors, breast tumors, kidney tumors, liver tumors, lung tumors, gallbladder tumors, pancreatic tumors, and esophageal tumors , tumors of the bladder muscle, large intestine, small intestine, spleen, stomach, prostate, ovaries, or uterus.
  • the tumors include malignant tumors and non-malignant tumors
  • the malignant tumors include breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, Testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, malignant lymphoma, malignant brain tumor, etc.
  • the non-malignant tumors include breast tumors, pancreatic tumors, thyroid tumors, prostate tumors, liver tumors, lung tumors, intestinal tumors, oral tumors , Esophageal tumors, gastric tumors, nasopharyngeal tumors, laryngeal tumors, testicular tumors, vaginal tumors, uterine tumors, fallopian tube tumors, ovarian tumors, lymphomas, brain tumors, etc.
  • the present invention also provides a pharmaceutical kit, which is characterized by comprising a container comprising the following independently packaged formulations: comprising the above topical pharmaceutical composition; and a formulation comprising a solvent.
  • a container comprising the following independently packaged formulations: comprising the above topical pharmaceutical composition; and a formulation comprising a solvent.
  • Such containers may include ampoules, vials, and the like.
  • the pharmaceutical kit further includes instructions or labels.
  • the ratio of the administration amount of the local pharmaceutical composition to the volume of the target area in the local lesion is >0.1, 0.15-1.5, preferably 0.23-1.5 or 0.5-1.5.
  • the dosage of the local pharmaceutical composition is ⁇ 1ml, or the dosage inside the local lesion is 10-150ml or/and the dosage outside the local lesion is 1.5-50ml.
  • the topical pharmaceutical composition of the present invention has the following advantages:
  • the local pharmaceutical composition has good medium and long-term curative effect and has almost non-toxic systemic drug safety; compared with molecular targeted drugs, it does not require harsh indication screening, and is suitable for rapid Growing tumors, large tumors and hypovascular tumors show great potential; compared with chemical ablative agents or chemical ablative agents, local irritation is less, specificity is strong and duration is long; (2) the present application
  • the local pharmaceutical composition does not have the problem of drug resistance, the preparation method is simple, the cost is low, and it benefits a wide range of groups.
  • mice (BALB/c) and nude mice (BALB/c) c Nude) are healthy females aged 6-8 weeks, weighing 17.5-20.5g.
  • Animal modeling of local lesions (such as tumors) generated by subcutaneous transplantation of cells is an existing technology. When the tumors grow to the required volume (such as 50-500mm 3 for mice bearing tumors), the modeling is successful. After modeling, the animal Divided into several groups, 6 rats in each group, regular observation and determination of general state, body weight, food intake, graft-versus-host disease, tumor volume, tumor weight, survival time, etc.
  • the local lesion is a tumor.
  • Tumor volume (V), tumor proliferation rate (R), tumor inhibition rate (r'), and tumor inhibition rate (r) were calculated according to the following formulas:
  • Tumor volume V 0.5 ⁇ a ⁇ b 2 , where a and b represent the length and width of the tumor respectively;
  • Tumor proliferation rate R TV/CV ⁇ 100, where TV and CV are the tumor volumes of the study group and the negative control group, respectively;
  • Tumor inhibition rate (r) 100% - R, where R is the tumor growth rate.
  • the efficacy of drug i is recorded as Ei, which can be represented by Ri or ri.
  • Ei which can be represented by Ri or ri.
  • the type of action of a drug that is, pharmacology, can be studied through its efficacy, especially the efficacy of the same drug in different regimens.
  • Positive controls for chemotherapy include classic cytotoxic drugs (such as 0.5-1% 5-fluorouracil, whose short-term tumor inhibition rate is ⁇ 30% under the conditions of the following examples) and classic chemical ablative agents (such as 75-99% ethanol, Its short-term tumor inhibition rate under the conditions of the following examples is ⁇ 15%).
  • classic cytotoxic drugs such as 0.5-1% 5-fluorouracil, whose short-term tumor inhibition rate is ⁇ 30% under the conditions of the following examples
  • classic chemical ablative agents such as 75-99% ethanol, Its short-term tumor inhibition rate under the conditions of the following examples is ⁇ 15%).
  • the joint pharmacodynamic effect of the combined administration of drugs A and B is judged as follows: when the drug effect of the combination of drugs A and B is meaningless (r ⁇ 15%) , the composition does not show a co-action, or is considered to be negligible co-action.
  • the shared safety of the drug A/B composition is judged by the following method: if the actual safety of the A/B composition is consistent with the theoretically simple additive expected safety (the worst safety in A or B), then the composition The shared safety of A/B is the additive effect of safety; if the actual safety of the A/B composition obviously exceeds the theoretically simple additive expected safety (the worst safety in A or B), then the shared safety of the composition If the actual safety of the A/B composition is obviously less than the theoretically simple additive expected safety (the worst safety in A or B), then the common safety of the composition is obvious antagonism effect.
  • W A /W B (or W A /W B /W C ) represents the concentration ratio between non-synergistic drugs
  • the above liquid preparation can be freeze-dried to obtain a freeze-dried powder for injection.
  • the freeze-drying adopts the following process: keep the pre-freezing temperature -45°C for 4 hours, the temperature increase rate is 0.1°C/min and rise to -15°C for at least 10 hours for sublimation; Keep for 6 hours for desorption and drying, subpackage (such as 7.5ml/bottle), and cap.
  • the aseptic medium is pumped into the bottle, mixed evenly and can be used as an injection medicine, such as 1.5% broken components of Saccharomyces cerevisiae/20% amino acid.
  • Tumor-bearing nude mice are widely used in drug research of chemotherapy rather than immunotherapy for patients with solid tumors.
  • Nude mice were used as experimental objects, and 2.5 ⁇ 10 5 mouse liver tumor Hepa1-6 cells/only were injected into the right axil
  • the transplanted tumor was modeled subcutaneously, and the average volume of the tumor in the successfully modeled nude mice was 75.7mm 3 .
  • the model animals were randomly divided into 12 groups, and the components of each group were injected into the tumor according to Table 2, and each group received the drug twice. , the medication interval is 2 days, and the volume of each injection is 50 ⁇ l/only.
  • the local lesion volume (V) was measured, and the tumor inhibition rate (r) was calculated according to the negative control group.
  • the order of the short-term efficacy of the following single drugs is: alkali metal hydroxide (1% NaOH aqueous solution), local drug control (75% ethanol aqueous solution), basic inorganic salt (2% NaHCO Aqueous solution) , these short-term effects were in line with their pharmacological expectations for local action.
  • the 15% polyvinylpyrrolidone aqueous solution as a blood volume expander unexpectedly shows similar to 75% ethanol aqueous solution, even higher than 2% NaHCO
  • Combination groups 2 and 3 both showed very weak locally acting potency, and similar non-synergistic results were observed and seemed to be expected for typical co-actions; the minimization of the local effects of a particular active ingredient was not its local action with the co-administration Optimum conditions for mutual enhancement (local synergy).
  • the actual/ The expected ratio q should be less than 1.00. Unexpectedly, its q value>1.00, what is still valuable is the further synergistic effect on the basis of B/C synergistic effect.
  • the preparations of group 12 (A 2 /B/C) and group 9 (A 1 /B/C) are not only completely opposite in the above-mentioned shared efficacy (synergy vs non-synergistic effect), but also in shared safety. Big difference (significant vs no significant improvement compared to least secure). Compared with group 1, the local irritation observed in group 2 during administration was very obvious (all animals struggled with high intensity).
  • group 12 did not observe the higher-intensity struggle that occurred in group 6 (administration B/C) when administered A 2 /B/C, which was closer to the negative control of group 1.
  • Group 12 (A 2 /B/C) had more than 50% fewer animals showing significant local leakage when administered compared to Group 9 (A 1 /B/C). 14 days after the last dose, all peritumoral tissue necrosis caused by leakage of local administration had completely returned to normal.
  • cohort 12 ( A2 /B/C) showed a safety synergy that significantly improved the local safety of B/C.
  • Example 3 Short-term synergistic activity of dilators and screening of common components
  • Nude mice were used as the experimental object, and human pancreatic cancer cells (PANC-1) were used as the model cells ((1 ⁇ 10 5 PANC-1 cells/only), the modeling method of this embodiment was the same as that of Example 2, in I won’t go into details here.
  • the average tumor volume of nude mice successfully modeled is 81.3 mm 3 .
  • the model animals were randomly divided into 38 groups, and the components of each group in Table 3 were injected into the tumor. Each group was given medicine twice. The interval was 3 days, and the volume of each injection was 50 ⁇ l/mouse. On the 3rd day after the second administration, the local lesion volume (V) was measured, and the tumor inhibition rate (r) was calculated according to the negative control group.
  • V local lesion volume
  • r tumor inhibition rate
  • glucose was used as the glyconutrient and dextran 40 and hydroxyethyl starch were used as the blood volume expander.
  • Other glyconutrients and blood volume expanders have similar results, and will not be repeated here. It can be seen from Table 3 that the short-term drug effects of dextran 40 and hydroxyethyl starch are similar to the results of another blood volume expander in Example 2, indicating that both of them can show local effects similar to 75% ethanol solution.
  • the drug with local effect maximization refers to the drug under the condition of local effect maximization (for example, local administration concentration maximization)
  • the drug with local effect minimization refers to the drug under the condition of local effect minimization (for example, deviate from Drugs under conditions of effective potency that is close to, or even less than, meaningful potency (low potency) (eg, local administration concentration deviates from the lower administration concentration that maximizes local effect).
  • Groups 1-3 showed very weak local effects.
  • a 15% glyconutrient can be considered here as a glyconutrient with minimal local effect, compared to a 30%-50% glyconutrient that provides a greater local effect.
  • the actual/expected ratio q ⁇ 1.00 of co-efficacy for groups 10-12 showed no local synergy.
  • a 15% volume expander can also be considered as a volume expander with minimal local effect (r ⁇ 15% no pharmacodynamic significance)
  • groups 13-18 volume expander/common ingredient
  • the co-drug is a non-synergistic drug that is both a glyconutrient and a blood volume expander.
  • Groups 19-24 belong to the combination of non-synergistic drugs; among them, the components in groups 19 and 20 are the same, but the amount ratio between the components is different, and the corresponding actual/expected ratio q of the shared drug effect is respectively ⁇ 1.00 and >1.00, where group 20 showed partial synergy.
  • Groups 25-28 (combinations of glyconutrients/non-synergistic drugs) had an actual/expected ratio q of co-efficacy less than 1.00, showing no partial synergistic effect, so the above-mentioned combination of non-synergistic drugs is still a non-synergistic combination of glyconutrients Combinations, or glyconutrients, did not appear to provide activity reversing the combination effect.
  • the structures of the blood volume expanders in this example are highly similar to glucose, and they probably have the same sharing effect under the same conditions.
  • group 29 (15% dextran 40/8% arginine/4% sodium bicarbonate aqueous solution) actual/expectation ratio q ⁇ 1.00 of shared efficacy, do not show local synergy;
  • group 30 -37 volume expander/non-synergistic drug combination
  • the actual/expected ratio q of co-efficacy is both greater than 1.00, showing local synergy, so these non-synergistic drugs are reversed by combination to synergistic co-coordination of blood volume expander Drugs, or blood volume expanders, have been shown to provide reversal of the synergistic effect in the above regimens.
  • composition formed by the combination of blood volume expander and gluconutrients and non-synergistic drugs is not only completely opposite in the above-mentioned shared drug effects (synergy vs non-synergistic effect), but also in terms of shared safety. Significantly different (significant vs no improvement in local irritation of non-synergistic drug combinations).
  • Groups 30-37 had more than 50% fewer animals with significant local leakage upon dosing compared to Groups 25-28.
  • 14 days after the last administration the peritumoral tissue necrosis caused by the leakage of local administration completely returned to normal.
  • the combination of blood volume expanders and non-synergistic drugs can provide pharmacodynamic synergy and/or safety synergy.
  • Example 4 Comparative study on short-acting pharmacology of dilating agents in different shared ways
  • Nude mice were used as the experimental objects, and malignant sarcoma cells (S180 cells) were used as the modeling cells (1 ⁇ 10 5 cells/mouse).
  • the modeling method of this embodiment was the same as that of Embodiment 2, and will not be repeated here.
  • the average volume of the tumor in the successfully modeled nude mice was 74.9mm 3 , and the model animals were randomly divided into 21 groups, and each group except the 16-18 groups was treated with A, conventional administration (tail vein injection); B, tumor Intra-injection was administered in two ways, and each single group was administered twice, with an interval of 3 days, and the volume of each injection was 50 ⁇ l per mouse.
  • the local lesion volume (V) was measured, and the tumor inhibition rate (r A , r B ) was calculated according to the negative control group of series A and B. The results are shown in Table 5.
  • the pharmaceutical compositions used in each group were prepared according to the conventional aqueous solution preparation method or the preparation method in Example 1.
  • the administration method of group 16-17 in series A is: conventional administration of blood volume expansion agent + intratumoral injection of common ingredient composition
  • the administration method in series B is intratumoral injection of blood volume expander + common ingredient composition Compositions are administered conventionally.
  • the administration method of group 18 in series A is intratumoral sequential injection of blood volume expansion agent and common component composition
  • the administration mode of series B is intratumoral sequential injection of common component composition and blood volume expansion agent.
  • Table 5 The tumor inhibition rate data of different drug combinations and administration methods
  • the efficacy of conventional administration reflects the systemic pharmacological effects caused by the blood containing the drug (such as nutritional enhancement or overall imbalance, tumor cytotoxicity, immune enhancement, blood Sustained release, etc.), while the efficacy of local lesion administration (such as intratumoral injection) reflects the local pharmacological effects (such as local chemical damage, etc.) caused by the drug directly entering the local lesion.
  • the short-term efficacy of drugs is mainly chemotherapy efficacy.
  • Groups 5-7 (dilator/co-ingredient) had efficacy r A ⁇ 15% after routine administration, while r A > 15% and r B /r A > 200% after local lesion administration, the latter showing Different from the former systemic pharmacology, the local pharmacology is the local chemical effect. And the actual/expected ratio q ⁇ 1.00 of its local shared efficacy shows that its local action is not a local synergistic effect, so these shared ingredients (20% arginine aqueous solution, 20% arginine hydrochloride aqueous solution, 5% bicarbonate Sodium aqueous solution) are unsynergistic drugs that are dilators. The above results also indicate that the conventional sharing of the above-mentioned common ingredients and blood volume expanders will not produce synergistic effect of short-term drug effects.
  • Groups 8-11 are combinations between non-synergistic drugs as blood volume expanders (non-synergistic drugs/non-synergistic drugs). Similar to groups 1-2, the efficacy of conventional administration in groups 8-11 r A ⁇ 15%, while the efficacy of local lesion administration r B > 15%, and r B /r A > 200%, Significant local pharmacological, ie local chemical, effects are exhibited.
  • the local effects of groups 8 and 11 showed that the effective drug effect r B > 40%, and the actual/expected ratio of local shared drug effects q > 1.00, indicating that their local pharmacology is mainly local synergistic effect; while groups 9 and 10
  • the local effect of the drug is shown as ineffective drug effect r B ⁇ 40%, and the actual/expected ratio of local shared drug effect q ⁇ 1.00, indicating that its local pharmacology is mainly a non-synergistic effect of local chemical effects.
  • composition of the compositions in groups 14 and 15 is similar, but the pH is different, and the actual/expected ratio q is greater than and less than 1.00 respectively, indicating that non-basic amino acids and their derivatives can only be used as acidifying agents for blood volume Dilators produce synergistic effects in combinations of non-synergistic drugs.
  • blood volume expanders only produce synergistic effects with non-synergistic drug combinations containing amino acids and their derivatives that are weak acids or bases (such as pH 4.0 ⁇ 1.0 or pH 10.0 ⁇ 1.0).
  • compositions in Groups 16, 18 and Group 12, Group 17 and Group 15 have the same components and component volume ratios, the only difference is that the dosage forms are different (non-topical dosage forms in which the active components can be administered separately topical dosage forms that have to be administered in admixture with the active ingredient); unexpectedly, the different dosage forms exhibited quite different co-pharmacology.
  • groups 16 and 17 almost only showed the efficacy of intratumoral injection of the active ingredient in the non-local dosage form, and did not observe the effect of intratumoral injection of all active ingredients in the local administration dosage form in groups 12 and 15.
  • Local synergistic effect the same local synergistic effect of intratumoral injection in group 12 was not observed in group 18.
  • the presence or absence of local synergistic effects of compositions with the same component and component ratio but different dosage forms is ultimately reflected in the level of short-term drug efficacy.
  • necrotic areas were of different sizes, mostly in the form of sheets or bands, and distributed in the edge and central area of the tumor tissue.
  • the number of necrotic tumor cells in the necrosis area is large, the nuclei of a large number of tumor cells are condensed and deeply stained, and a large number of nuclei are fragmented, which further confirms that the compositions of groups 12 and 15 show a local synergistic effect after intratumoral injection.
  • the local pharmaceutical composition containing blood volume expansion agent of the present invention (referred to as the present composition of the present invention) surpasses the blood Anticipation of non-topical pharmaceutical compositions of volume expanders (referred to as prior art compositions, such as expander/sodium chloride, expander/amino acid, etc.):
  • the blood volume expander as a local synergistic active component in the composition of the present invention is based on its new function of targeting local diseased tissues-making a variety of non-synergistic drugs work together synergistically the discovery of an activity that was not implicated in the blood volume expanders in the prior art pharmaceutical compositions;
  • the above-mentioned local synergistic pharmacology of the blood volume expander in the composition of the present invention strictly limits all the active ingredients in the composition to enter the target area reactor and must be strictly limited to local administration, while the prior art
  • the pharmacology of the systemic action of the pharmaceutical composition does not require local administration, preferably intravenous infusion. This also allows the formulation of the composition and the process of its preparation to vary significantly;
  • the pharmacological composition exceeds expectations, for example: completely different pharmacologically active ingredient optimization principles, completely different pharmacological content (pharmacological concentration, or/and pharmacological volume), different pharmacological environments (such as salt osmotic pressure regulators) Rejection), etc.; firstly, the local synergistic activity of blood volume expanders can be independent of their systemic activity, so there can be different or even opposite blood volume expander types (such as preferred dextrans) and pharmacokinetic preferences , for example, the pharmacological concentration of its local synergistic activity far exceeds the pharmacological concentration of the systemic action, the concentration dependence of its local synergistic activity is completely different from the dose dependence of the systemic action, and the lesion tissue volume dependence of its local synergistic activity (pharmacological Volume) is completely different from systemic effects Therapy is often more related to systemic conditions such as the patient's body weight, immunocompetence, genotype, etc.
  • the therapeutic effect on local lesions exceeded expectations.
  • the drug effect r composition of the present invention /r prior art composition > 200%, preferably r present composition
  • the drug effect can be compared with recognized effective drugs, greatly exceeding the short-term expected drug effect of the prior art composition Invention composition /r prior art composition >400%).
  • This pharmacodynamic feature also leads to an unexpected range of indications.
  • the above-mentioned animal models can represent immunodeficiency patients, elderly patients, and patients with weakened immunity after various treatments. These also further show that the difference between the two compositions is not a kinetic difference but a pharmacological difference (eg local vs conventional action).
  • Example 5 Comparative study on short-acting pharmacology of topical use of dilators
  • Nude mice were used as the experimental object, and breast cancer cells (4T1 cells) were used as the modeling cells (1 ⁇ 10 5 cells/mouse).
  • the modeling method of this embodiment was the same as that of Embodiment 2, and will not be repeated here.
  • the average volume of the tumor in the successfully modeled nude mice was 84.1 mm 3 .
  • the model animals were randomly divided into 24 groups, and the components of each group were injected into the tumor according to Table 6. Each group was administered twice with an interval of 3 days. The injection volume is 50 ⁇ l/only. On the 3rd day after the second administration, the local lesion volume (V) was measured, and the tumor inhibition rate (r) was calculated according to the negative control group.
  • V local lesion volume
  • r tumor inhibition rate
  • the local action intensity (drug efficacy) of groups 1-3 increased with the increase of the administration concentration
  • groups 11-13 glyconutrients/alkaline organic compounds
  • the actual/expected ratio q>1.00 of group 11 and the actual/expected ratio q ⁇ 1.00 of groups 12 and 13
  • different concentrations of glyconutrients showed different sharing effects. Maximization of the local action of the glyconutrients (concentrations towards 30% or higher) appears to favor synergy, as would normally be expected for synergy.
  • Groups 4-6 did not observe the increase of the local effect with the increase of the administration concentration, in fact, almost no local effect was observed, and the concentration of 2-30% was the pharmacological concentration to minimize the local effect of the dilator.
  • the co-efficacy of groups 14-16 did not increase significantly with the increase of the concentration of the stimulant, and their actual/expected ratio q ⁇ 1.00.
  • the basic organic compound is only a non-synergistic drug for glyconutrients in the concentration range ⁇ 25%, while it is a non-synergistic drug for dilators in the concentration range ⁇ 30%.
  • the actual/expected ratio q>1.00 of groups 17, 18 indicates that the two drugs and their concentration ratio can produce local synergy.
  • the actual/expected ratio q of the shared efficacy of groups 20 and 21 was less than 1.00, indicating that the synergistic combination of the glyconutrients and the non-synergistic drugs did not show local synergy. Therefore, the combination of non-synergistic drugs is still a non-synergistic co-product of the above-mentioned glyconutrients, or the glyconutrients do not show the activity of providing reversal of the synergistic effect.
  • group 25 (dilator/combination of 3 non-synergistic drugs) had an actual/expected ratio q greater than 1.00 for co-efficacy, also showing local synergy.
  • the shared effect of at least 2 non-synergistic drugs is a partial synergistic effect.
  • the blood volume expander can produce a local synergistic effect with an appropriate combination of its non-synergistic drug under the condition that its local effect is minimized, or even has no local effect.
  • pharmacological expectations defined by local synergy reciprocal enhancement of local effects during co-administration.
  • blood volume expanders can provide a previously undiscovered but useful pharmacological function in related technical solutions-that is, local synergistic effects do not originally occur.
  • Multiple components non-synergistic drugs
  • provide short-term synergistic activity including local pharmacodynamic synergy and local safety synergy.
  • composition of the above-mentioned composition comprising blood volume expander and its non-synergistic drug has the following requirements: 1), blood volume expander with minimal local effect, its pharmacological concentration is ⁇ 30% (or 2-30%), Preferably ⁇ 25% (or 2-25%, 2-5%, 5-25%); 2) multiple (2 or more) non-synergistic drugs with a specific combination relationship, the combination contains at least Two non-synergistic drugs selected from different classes (groups) that can produce local synergistic effects when shared at an appropriate concentration ratio.
  • dextran 70 When using dextran 10, dextran 70, polymer condensed glucose and other dextran blood volume expanders under the conditions that meet the above requirements, and other starch-derived blood volume expanders, gelatin-derived blood volume expanders, and synthetic blood volume expanders have similar The experimental results will not be repeated here.
  • the alkali metal hydroxide also includes potassium hydroxide, calcium hydroxide
  • the multi-component weak acid basic inorganic salt can also include potassium bicarbonate, calcium bicarbonate, sodium hydrosulfate, disodium hydrogen phosphate
  • the weak acid strong Alkali salt can also include sodium phosphate, sodium carbonate, potassium carbonate, borax, sodium acetate
  • the methylene blue and its analogues also include patent blue, isosulfur blue, and new methylene blue.
  • the cytotoxic drugs can also include drugs that destroy the structure and function of DNA, such as cyclophosphamide, carmustine, metal platinum complexes, doxorubicin drugs, topotecan, irinotecan; embedded in DNA Drugs that interfere with the transcription of RNA, such as antitumor antibiotics; drugs that interfere with DNA synthesis, such as 5-fluorouracil (5-Fu), furofluorouracil, bisfurofluorouracil, cytarabine, cyclocytidine, and 5-azacytidine ; Drugs that affect protein synthesis, such as colchicine drugs, vinblastine drugs, taxane drugs.
  • drugs that destroy the structure and function of DNA such as cyclophosphamide, carmustine, metal platinum complexes, doxorubicin drugs, topotecan, irinotecan; embedded in DNA Drugs that interfere with the transcription of RNA, such as antitumor antibiotics; drugs that interfere with DNA synthesis, such as
  • the weak acids may also include oxalic acid, maleic acid, tartaric acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1 , 2,3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid);
  • the non-basic amino acid can also include cysteine, alanine, serine, aspartic acid, glutamic acid .
  • the combination of non-synergistic drugs that meet the above requirements 2) in local synergy can be selected from the combination comprising the following 2 non-synergistic drug groups and concentration ratios:
  • the concentration ratio (W alkali metal hydroxide /W basic organic compound ) is (1-5%)/5-25 % alkali metal hydroxide/basic organic compound combination
  • concentration ratio (W alkali metal hydroxide /W basic inorganic salt ) is the alkali metal hydroxide of (1-5%)/(3-15%) compound/basic inorganic salt combination
  • concentration ratio (W basic organic compound /W basic inorganic salt ) is the basic organic compound combination of (5-25%)/(3-15%);
  • concentration ratio (W basic organic compound /W immunomodulator ) is (5-25%)/(1-15%) basic organic compound/immunomodulator Regulator combination
  • concentration ratio (W basic organic compound /W methylene blue and its analog ) is (5-25%)/(0.35-3.5%) basic organic compound/methylene blue and its analog combination
  • concentration ratio (W basic organic compound/W cytotoxic drug ) is (5-25%)/(0.1-10%) basic organic compound/cytotoxic drug combination
  • concentration ratio (W basic organic compound /W Non-basic amino acid and its acid salt ) is (5-25%)/(10-25%) basic organic compound/non-basic amino acid and its acid salt;
  • the combination that comprises polyhydric alcohol for example following combination: concentration ratio (W polyhydric alcohol /W basic organic compound ) is (5-25%)/(10-25%) polyhydric alcohol/basic organic compound, concentration The ratio (W polyol /W methylene blue and its analogs ) is (5-25%)/(0.35-3.5%) polyol/methylene blue and its analog combinations, concentration ratio (W polyol /W Cytotoxic drug ) is (5-25%)/(0.1-10%) polyol/cytotoxic drug combination;
  • the concentration ratio (W methylene blue and its analogs /W immunomodulator ) is (0.35-5%)/(1-15%) Basic organic compound/immunomodulator combination, concentration ratio (W methylene blue and its analog /W cytotoxic drug ) is (0.35-5%)/(0.1-10%) methylene blue and its analog/ Cytotoxic drug combination, concentration ratio (W methylene blue and its analogs /W non-basic amino acid and its acid salt) is (0.35-5%)/(10-25%) methylene blue and its analogs / Non-basic amino acids and their acid salts;
  • the combination that comprises non-basic amino acid and acid salt thereof such as the following combination: the concentration ratio (W weak acid /W non-basic amino acid and acid salt thereof ) is (5-25%)/(10-25%) ) weak acid/non-basic amino acid and acid salt thereof, concentration ratio (W weak acid /W cytotoxic drug ) is (5-25%)/(0.1-10%) weak acid/cytotoxic drug combination, concentration ratio ( A weak acid / methylene blue and its analog combination of (5-25%)/(0.35-5%) W weak acid/W methylene blue and its analog.
  • the local pharmaceutical composition containing blood volume expansion agent according to the present invention surpasses the local effect in the prior art in the following respects:
  • Expectations of topical pharmaceutical compositions (abbreviated prior art compositions) of drugs e.g. ethanol, conventional glyconutrients, etc.:
  • the synergistic activity of the blood volume expander in the composition of the present invention may be independent of its local action strength, and even dextran with weaker local action is preferred instead of stronger polyvinylpyrrolidone.
  • the pharmacological concentration of the blood volume expander for this synergistic activity need not provide the maximization of the local effect, but rather the pharmacological concentration which minimizes the local effect (towards lower concentrations such as 2% vs.
  • the shared substances in the composition of the present invention are not selected from synergistic drugs but non-synergistic drugs, and are not selected from unlimited types of shared substances but are selected from not less than two kinds of different shared substances, and are not The selection is not limited to a plurality of joints that interact with themselves but is selected from a variety of joints in which synergistic effects can independently occur between not less than two joints. This also leads to the requirement that the co-products have different preferred species (e.g. alkalizers, polyols, immunopotentiators, etc.), necessary number of species (at least two vs not necessarily two), or/and concentration ratios between species (at least two are synergistic concentration ratios);
  • preferred species e.g. alkalizers, polyols, immunopotentiators, etc.
  • the blood volume expander in the composition of the present invention and a variety of non-synergistic drugs produce a synergistic effect under the condition that the composition of the prior art does not produce a synergistic effect, and the synergistic effect makes the treatment of local lesions effective. Beyond the curative effect and indication of prior art composition.
  • the blood volume expander and a variety of non-synergistic drugs produce a synergistic effect under the condition that the prior art composition does not produce a safety synergistic effect, and the synergistic effect makes local lesion treatment effective. Indications beyond prior art compositions.
  • the scope of its indications is, for example: refractory patients who are limited by the insufficient local drug effect of the prior art composition (for example, patients who still have no obvious curative effect after multiple treatments, patients whose disease still progresses after treatment, patients who have undergone treatment, etc.) patients with rebound disease), frail patients and elderly patients limited by local irritation of prior art compositions, larger size (eg mean diameter > 3.0 cm) limited by systemic toxic doses of prior art compositions , 4.0cm, or 5.0cm) local lesions, and the composition of the present invention can also obtain better curative effect in such patients as described above.
  • mice were used as the experimental objects, and mouse breast cancer cells (4T1 cells) were used as the modeling cells (0.5 ⁇ 10 5 cells/mouse).
  • the modeling method of this embodiment was the same as that of Embodiment 2, and will not be repeated here.
  • the average tumor volume of the successfully modeled mice was 107.3mm 3 , and the model animals were randomly divided into 19 groups, and each group except the 16-18 group was treated with A, conventional administration (tail vein injection); B, intratumoral Injection is given in two ways, and each single group is administered twice, with an interval of 3 days, and the volume of each injection is 100 ⁇ l per mouse.
  • the local lesion volume (V) was measured on the 3rd and 21st day after the second administration, and the drug efficacy-tumor inhibition rate (r 3d , r 21d ) was calculated according to the negative control group. The results are shown in Table 7.
  • compositions used in Groups 9-12 respectively form Compositions 1-4 for sharing, and each composition is prepared according to the conventional aqueous solution preparation method or the preparation method in Example 1. Calculate the actual/expected ratio q 3d of the short-term drug effect and the actual/expected ratio q 21d of the medium and long-term drug effect according to the drug effects (r 3d , r 21d ) at different times (3 days, 21 days),
  • the short-acting actual/expected ratio q 3d and the medium and long-acting actual/expected ratio q 21d of groups 9-13 are both less than 1.00, indicating that the basic organic compounds in group 4, methylene blue and its analogs in group 5 , the cytotoxic drugs of group 6, the basic inorganic salts of group 7, and the polyols of group 8 are all short-acting and medium- and long-acting non-synergistic drugs of the above dextran. It is also known from other experiments that they are also non-synergistic drugs of the above starch derivatives and glyconutrients.
  • Groups 14-16 show the activity of Compositions 1-4 for sharing, respectively.
  • the q 3d >1.00 of group 14 indicates that there is a local synergistic effect; while its q 21d ⁇ 1.00 indicates that there is no medium- and long-term synergistic effect.
  • groups 15, 16 three-component compositions containing basic organic compounds/methylene blue and its analogs
  • group 17 three-component compositions containing partially synergistic polyols/methylene blue
  • Both q 3d and q 21d are less than 1.00, so there is neither local synergy nor mid- and long-term synergy.
  • composition 1 basic organic compound/methylene blue and its analogs/basic inorganic salts
  • composition 2 basic organic compound/methylene blue and its analogs /cytotoxic drug
  • composition 3 polyol/methylene blue and its analogs/cytotoxic drug
  • the tumor samples of animals treated in groups 18-20 had more immune cells, neutrophils and lymphocytes than normal in the area near the tumor; Many focal necrotic areas were seen, and the necrotic areas were of different sizes and mostly distributed in the edge and central area of the tumor tissue in the form of sheets or bands; the number of necrotic tumor cells in the necrotic area (such as Figure 2) was relatively large, and a large number of Condensed and deeply stained nuclei and fragmented nuclei can also be observed with traces of blood vessels and red blood cells that are difficult to see in conventional necrosis. Therefore, it is speculated that the medium and long-term curative effect may be related to the effect of immunotherapy, which needs to be confirmed by follow-up studies.
  • the composition formed by combining the blood volume expander and the glyconutrient with the same non-synergistic drug is not only completely opposite in the above-mentioned shared drug effect (synergy vs non-synergistic effect), but also in terms of shared safety. Significantly different (significant vs no improvement in local irritation of non-synergistic drug combinations). Similarly, during administration, it was observed that the experimental animals of the negative control group did not struggle with higher intensity, and the phenomenon of local stimulation was the weakest; more than 25% of the experimental animals in groups 15-17 (combination of non-synergistic drugs) showed higher intensity.
  • the blood volume expander r 21d ⁇ 15%
  • the composition of the medium and long-term synergistic pharmaceutical composition comprising blood volume expander has the following requirements: 1), blood volume expander with minimal local effect, its pharmacological concentration is ⁇ 30% (or 3-30% ), preferably ⁇ 25% (or 2-25%, 2-5%, 5-20%); 2), multiple (preferably 3 or more) non-synergistic drugs with a specific combination relationship, so The multiple non-synergistic drugs in the above combination may not necessarily produce local synergistic effects or medium- and long-term synergistic effects, but at least two non-synergistic drugs selected from different types and shared at an appropriate concentration ratio can produce local synergistic effects.
  • the polyol may also include xylitol, sorbitol, glycerin, and the like.
  • the non-synergistic pharmaceutical combination preferably comprises at least 3 or more of the above-mentioned different groups, and although two of them are used together, the Non-synergistic drugs that do not necessarily produce local synergy when shared between 3 or more groups.
  • the combination of non-synergistic drugs can also be a combination comprising one or more of alkali metal hydroxides, basic inorganic salts, and selected from the following groups: methylene blue and its analogs, immunomodulatory Agents, cytotoxic drugs, such as the following combination: the concentration ratio (W alkali metal hydroxide /W basic inorganic salt /W methylene blue and its analogs ) is (1-5%)/(3-15%)/ (0.35-5%) alkali metal hydroxide/basic inorganic salt/methylene blue and its analog combination, concentration ratio (W alkali metal hydroxide /W basic inorganic salt /W immunomodulator ) is ( 1-5%)/(3-15%)/(1-15%) alkali metal hydroxide/basic inorganic salt/immunomodulator combination, concentration ratio (W alkali metal hydroxide /W basic inorganic Salt / cytotoxic drug ) is (1-5%)/(3-15%)/(0.1-10%) alkali metal hydrox
  • non-synergistic drug combination can also be selected from a combination comprising basic organic compounds, basic inorganic salts, and one or more of the following groups: methylene blue and its analogs, immunomodulators, cell Toxic drugs, such as the following combinations: the concentration ratio (W basic organic compound /W basic inorganic salt / methylene blue and its analogs ) is (5-25%)/(3-15%)/(0.35-5%) ) of basic organic compound/basic inorganic salt/methylene blue and its analog combination, the concentration ratio (W basic organic compound /W basic inorganic salt / immune regulator ) is (5-25%)/(3 -15%)/(1-15%) basic organic compound/basic inorganic salt/immunomodulator combination, concentration ratio (W basic organic compound /W basic inorganic salt / cytotoxic drug ) is (5- 25%)/(3-15%)/(0.1-10%) combination of basic organic compound/basic inorganic salt/cytotoxic drug.
  • non-synergistic drug combination can also be selected from a combination comprising basic organic compounds, methylene blue and its analogs, and one or more of the following groups: immunomodulators, cytotoxic drugs, non-alkali Sexual amino acids and acid salts thereof, such as the following combinations: the concentration ratio (W basic organic compound /W methylene blue and its analogs / immunomodulator ) is (5-25%)/(0.35-3.5%)/( 1-15%) basic organic compound/methylene blue and its analog/immunomodulator combination, concentration ratio (W basic organic compound /W methylene blue and its analog / cytotoxic drug ) is (5- 25%)/(0.35-3.5%)/(0.1-10%) basic organic compound/methylene blue and its analogs/cytotoxic drug combination, concentration ratio (W basic organic compound /W methylene blue and Its analogs / non-basic amino acids and their acid salts ) are (5-25%)/(0.35-3.5%)/(10-25%) basic organic compounds/methylene blue and its analogs/(10
  • the non-synergistic drug combination can also be selected from the combination comprising cytotoxic drugs and at least two selected from the following groups: basic organic compounds, immunomodulators, polyhydric alcohols, methylene blue and analogs thereof, such as the following Combination: concentration ratio (W cytotoxic drug /W basic organic compound /W immunomodulator ) is the cytotoxic drug/basic organic compound of (0.1-10%)/(5-25%) / (1-15%) Compound/immunomodulator combination, concentration ratio (W cytotoxic drug /W polyol /W methylene blue and its analogs ) is (0.1-10%)/(5-25%)/(0.35-3.5%) Cytotoxic drug/polyol/methylene blue and its analog combination, concentration ratio (W cytotoxic drug /W methylene blue and its analog /W immunomodulator ) is (0.1-10%)/(0.35-5 %)/(1-15%) of cytotoxic drugs/methylene blue and its analogs/immunomodulator combination, cytotoxic drugs
  • the local pharmaceutical composition comprising a blood volume expander described in the present invention (abbreviated as the present invention) Compositions) further exceed the expectations of topical pharmaceutical compositions (referred to as prior art compositions) comprising locally acting drugs (such as alcohol, conventional glyconutrients, etc.) in the prior art in the following respects:
  • the co-pharmacology of blood volume expanders includes the combination with various short-term non-synergistic and medium-term drugs under the conditions of no obvious mid- and long-term drug effects (such as the conditions of small or even minimal local effects).
  • the long-term synergistic effect between co-products with no obvious long-term drug effect (even under the condition of no short-term synergistic effect or even short-term antagonism independent of them) produces medium and long-term synergistic effects, which may include Immunity.
  • the common pharmacology of local active components in the prior art is to produce short-term (local) synergistic effects with synergistic drugs under conditions where their local effects are relatively large, or even maximized.
  • the composition of the present invention exceeds, and the composition of the prior art meets the expectations of the existing synergistic effect definition (synergistic effect is that the similar effects of multiple specific active ingredients are mutually enhanced by sharing);
  • the technical effect is beyond expectations: such as the medium and long-term synergistic effect produced under the condition that the prior art composition does not produce a medium-term and long-term synergistic effect (for example, there is no short-term synergistic drug effect, or even a short-term antagonistic drug effect).
  • the range of indications for the immunological effects likely to be included in this medium and long-term synergistic effect will greatly exceed the range of indications for the local synergistic effect of the prior art compositions.
  • compositions of the present invention prepared by the method of Example 1 can also obtain similar results in the similar experiments of the above-mentioned examples, which will not be repeated here.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique topique, comprenant un dilatateur de volume sanguin, un médicament non synergique et une quantité appropriée de solvant. La concentration pharmacologique du dilatateur est inférieure ou égale à 30 %, de préférence de 2 à 30 %, et idéalement de 2 à 25 % ou de 2 à 20 % ; et la concentration pharmacologique du médicament non synergique est de 0,36 à 40 %. Un kit comprend la composition pharmaceutique topique. La composition pharmaceutique topique est utilisée dans la préparation d'une préparation pharmaceutique pour le traitement de tumeurs.
PCT/CN2021/122134 2021-09-29 2021-09-30 Composition pharmaceutique topique, application et kit WO2023050297A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2021/122134 WO2023050297A1 (fr) 2021-09-30 2021-09-30 Composition pharmaceutique topique, application et kit
PCT/CN2022/122537 WO2023051682A1 (fr) 2021-09-29 2022-09-29 Composition pharmaceutique topique, et utilisation et trousse correspondantes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/122134 WO2023050297A1 (fr) 2021-09-30 2021-09-30 Composition pharmaceutique topique, application et kit

Publications (1)

Publication Number Publication Date
WO2023050297A1 true WO2023050297A1 (fr) 2023-04-06

Family

ID=85780373

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/122134 WO2023050297A1 (fr) 2021-09-29 2021-09-30 Composition pharmaceutique topique, application et kit

Country Status (1)

Country Link
WO (1) WO2023050297A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1583006A (en) * 1978-05-24 1981-01-21 Fisons Ltd Treatment of animals with a blood volume expander
CN110870869A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含糖类营养素和常规无效化合物的药物组合物及其应用
CN110870868A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含亚甲蓝类染料、营养素或/和抗肿瘤化合物的药物组合物及其应用
CN112438942A (zh) * 2019-08-30 2021-03-05 成都夸常奥普医疗科技有限公司 包含碱化剂及其协同物的药物组合物及其应用
WO2021163897A1 (fr) * 2020-02-18 2021-08-26 成都夸常奥普医疗科技有限公司 Composition pharmaceutique contenant un colorant bleu de méthylène, un élément nutritif et/ou un médicament antitumoral classique, et son application
WO2021164706A1 (fr) * 2020-02-18 2021-08-26 成都夸常奥普医疗科技有限公司 Composition pharmaceutique contenant un colorant bleu de méthylène et son utilisation
WO2022068918A1 (fr) * 2020-09-30 2022-04-07 成都夸常奥普医疗科技有限公司 Composition pharmaceutique comprenant une combinaison de neutralisation acide-base et son application
WO2022068924A1 (fr) * 2020-09-30 2022-04-07 成都夸常奥普医疗科技有限公司 Utilisation d'un constituant probiotique et composition pharmaceutique contenant un constituant probiotique

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1583006A (en) * 1978-05-24 1981-01-21 Fisons Ltd Treatment of animals with a blood volume expander
CN110870869A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含糖类营养素和常规无效化合物的药物组合物及其应用
CN110870868A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含亚甲蓝类染料、营养素或/和抗肿瘤化合物的药物组合物及其应用
CN112438942A (zh) * 2019-08-30 2021-03-05 成都夸常奥普医疗科技有限公司 包含碱化剂及其协同物的药物组合物及其应用
WO2021163897A1 (fr) * 2020-02-18 2021-08-26 成都夸常奥普医疗科技有限公司 Composition pharmaceutique contenant un colorant bleu de méthylène, un élément nutritif et/ou un médicament antitumoral classique, et son application
WO2021164706A1 (fr) * 2020-02-18 2021-08-26 成都夸常奥普医疗科技有限公司 Composition pharmaceutique contenant un colorant bleu de méthylène et son utilisation
WO2022068918A1 (fr) * 2020-09-30 2022-04-07 成都夸常奥普医疗科技有限公司 Composition pharmaceutique comprenant une combinaison de neutralisation acide-base et son application
WO2022068924A1 (fr) * 2020-09-30 2022-04-07 成都夸常奥普医疗科技有限公司 Utilisation d'un constituant probiotique et composition pharmaceutique contenant un constituant probiotique

Similar Documents

Publication Publication Date Title
US11833147B2 (en) Procaspase 3 activation by combination therapy
US7091226B2 (en) Cancer treatment with epothilones
JP7568185B2 (ja) アミノ酸ベースの栄養素の使用及びそれを含む医薬組成物
JP2023544310A (ja) プロバイオティクス成分の使用及びプロバイオティクス成分を含む医薬組成物
WO2021164706A1 (fr) Composition pharmaceutique contenant un colorant bleu de méthylène et son utilisation
WO2023272831A1 (fr) Application de stachyose dans la préparation d'un médicament pour le traitement du cancer de la prostate résistant à la castration
WO2022068918A1 (fr) Composition pharmaceutique comprenant une combinaison de neutralisation acide-base et son application
WO2023051682A1 (fr) Composition pharmaceutique topique, et utilisation et trousse correspondantes
WO2023050297A1 (fr) Composition pharmaceutique topique, application et kit
KR20050106119A (ko) 항종양 효과 증강제 및 항종양제
JPH07501534A (ja) ガンの治療のためのクレアチンホスフェート又はホスホエノールピルビン酸の使用
JP2557303B2 (ja) 抗腫瘍効果増強剤及び抗腫瘍剤
CN113329734A (zh) 新颖的药物制剂
JP6498610B2 (ja) カバジタキセル組成物
CN109528731B (zh) 具有协同作用治疗多发性骨髓瘤的药物组合物及其应用
CN101181230A (zh) 一种治疗实体肿瘤的雌二醇氮芥缓释植入剂
CN101185629A (zh) 一种治疗实体肿瘤的地西他滨缓释剂
CN102526714B (zh) 治疗肿瘤的药物组合物及其制备方法
CN101181232B (zh) 一种治疗实体肿瘤的马赛替尼缓释植入剂
CN101185627A (zh) 一种治疗实体肿瘤的尼罗替尼缓释植入剂
JP2016521760A (ja) がんの処置のための、ｒｏ５５０３７８１、カペシタビン及びオキサリプラチンの組み合わせ
WO2022174812A1 (fr) Composition pharmaceutique comprenant de l'immunoglobuline et son utilisation
JP2009046450A (ja) 抗がん剤へのヒアルロン酸添加
WO2022068925A1 (fr) Application d'un composant associé à une cellule non pathogène animale et composition pharmaceutique comprenant le composant
CN117357534A (zh) 包含维甲酸的药物组合物在制备治疗肝细胞癌伴腹腔转移的药物中的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21958871

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE