WO2021163897A1 - Composition pharmaceutique contenant un colorant bleu de méthylène, un élément nutritif et/ou un médicament antitumoral classique, et son application - Google Patents

Composition pharmaceutique contenant un colorant bleu de méthylène, un élément nutritif et/ou un médicament antitumoral classique, et son application Download PDF

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WO2021163897A1
WO2021163897A1 PCT/CN2020/075765 CN2020075765W WO2021163897A1 WO 2021163897 A1 WO2021163897 A1 WO 2021163897A1 CN 2020075765 W CN2020075765 W CN 2020075765W WO 2021163897 A1 WO2021163897 A1 WO 2021163897A1
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Prior art keywords
methylene blue
concentration
pharmaceutical composition
tumor
cancer
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PCT/CN2020/075765
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English (en)
Chinese (zh)
Inventor
邹方霖
邹礼常
王建霞
王艺羲
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成都夸常奥普医疗科技有限公司
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Priority to PCT/CN2020/075765 priority Critical patent/WO2021163897A1/fr
Priority to PCT/CN2021/076749 priority patent/WO2021164706A1/fr
Publication of WO2021163897A1 publication Critical patent/WO2021163897A1/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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

Definitions

  • the disclosure of this application relates to the application of methylene blue dye as a combination of local active ingredients and nutrients or/and conventional anti-tumor drugs in the preparation of topical pharmaceutical compositions for the treatment of malignant solid tumors, comprising the methylene blue dye and nutrients or/ A local pharmaceutical composition for treating malignant solid tumors with conventional antitumor drugs, and a method for treating malignant solid tumors including administering the pharmaceutical composition.
  • anti-solid tumor drugs One of the main problems facing the development of anti-solid tumor drugs is specificity. Since conventional anti-tumor drugs cannot sufficiently distinguish between target cells and normal cells, and the difference between the effective dose and the safety limit is not large enough, they will produce systemic effects (tumor cell inhibitory effects inside and outside the tumor) at the same time. Greater risk of systemic toxicity. In addition, the drug molecule needs to penetrate effectively in the tumor tissue to have an effect on the tumor cells in between. For some tumors with poor blood supply (such as pancreatic cancer), the chance of benefiting the patient is even smaller.
  • Intratumoral administration has the advantage of physically targeting drugs.
  • intratumoral administration of conventional anti-tumor drugs increased the concentration of the target area, it did not show a significant improvement in efficacy.
  • conventional anti-tumor drugs are almost still administered systemically in clinical practice.
  • Conventional chemical ablation agents high-purity ethanol, high-concentration acids and bases
  • the target tissue cannot be sufficiently distinguished from other tissues, the actual intervention volume (for example, the amount of acid and alkali does not exceed 0.2 ml/kg) and the intervention site are very limited. Therefore, chemical ablation agents have gradually faded out of malignant solid tumors in the past ten years. In fact, there are almost no local special drugs with high local safety and high local curative effect in clinical practice.
  • the purpose of the present invention is to provide a topical drug that physically targets tumors, but has higher efficacy, higher compliance, or/and higher specificity than existing drugs, and includes administration of the drug composition A method for treating malignant solid tumors.
  • a topical pharmaceutical composition for the treatment of malignant solid tumors which comprises a methylene blue dye, a local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable Liquid carrier, wherein the synergistic drug is selected from nutrients or/and conventional anti-tumor drugs, and in the topical pharmaceutical composition, the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35- 2%, 0.5-2%, 0.5-1.5% or 0.5-1%, the concentration of the nutrient (w/v) ⁇ 2%, preferably 3-40%, and the concentration of the conventional anti-tumor drug is greater than that
  • the saturated concentration is 20% or 30%, preferably 30%-100% of its saturated concentration, wherein the saturated concentration refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • methylene blue dye as a topical active ingredient and a local synergistic drug of the methylene blue dye in the preparation of a topical pharmaceutical composition for the treatment of malignant solid tumors ,
  • the synergistic drug is selected from nutrients or/and conventional anti-tumor drugs.
  • the topical pharmaceutical composition comprises the methylene blue dye, the local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable liquid carrier, wherein the topical drug In the composition, the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35-2%, 0.5-2%, 0.5-1.5% or 0.5-1%, and the concentration of the nutrient (w/v) w/v) ⁇ 2%, preferably 3%-40%, and the concentration of the conventional anti-tumor drug is greater than 20% or 30% of its saturated concentration, preferably 30%-100% of its saturated concentration, wherein The saturated concentration refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • it provides a method for treating malignant solid tumors, which comprises intratumorally administering the pharmaceutical composition disclosed in the present application to an individual in need thereof.
  • composition containing the methylene blue dye and the local synergistic drug disclosed according to the present application has the following advantages compared with a single drug containing the corresponding components: it provides a synergistic effect against malignant solid tumors to improve effectiveness, and at the same time has the advantages of It may provide antagonism against non-specific tissue destruction to improve safety.
  • the embodiment according to the present invention has the following advantages: Compared with the existing cytotoxic drugs and related treatment methods, it shows almost non-toxic systemic safety and significantly higher local treatment Efficacy; Compared with the existing molecular targeted drugs and related treatment methods, it shows less stringent indication screening, and has great potential for reducing the load of fast-growing tumors, large tumors and poor blood donor tumors; Compared with chemical ablation agents and related methods, they show higher compliance (such as irritation, corrosivity) or specificity, so that they can have a larger range of intervention and a higher application volume.
  • the method and composition of the present invention are also not troubled by the drug resistance problems encountered by existing cytotoxic drugs and existing molecular targeted drugs. In addition, the method and composition are convenient in application and low in cost, and are particularly helpful for the general population who cannot afford high expenses to enjoy safe and effective treatment.
  • the inventor of the present invention unexpectedly discovered in a tumor-bearing animal experiment that although the addition of DHA generally cannot, it can form a highly synergistic effect with methylene blue under certain specific conditions, which also makes the use of methylene blue
  • the dose can be reduced exponentially to reduce the risk of side effects.
  • substances selected from other nutrients or/and conventional anti-tumor drugs can also form an unexpected synergistic effect with lower concentrations (for example, ⁇ 1%) of methylene blue under these specific conditions.
  • These specific conditions are not the conditions of methylene blue dyes, nutrients or/and conventional anti-tumor drugs in the existing anti-malignant solid tumor technology (for example, intratumoral administration concentration), but are as defined below.
  • composition in the scope of the present invention, the term “topical drug (composition)” is distinguished from conventional drugs (compositions), which refer to conventional administration (or systemic administration, such as oral administration, intravenous injection, intraperitoneal injection, pleural injection, etc.) ) So that its active ingredients are transported to the tumor through the blood and diffuse and penetrate through the blood vessels (compositions), while the former refers to intratumoral administration and mainly diffuse and penetrate through the spaces of extravascular structures, and mainly Therapeutic drugs (compositions) that produce medicinal effects through local action.
  • local action or “local activity” refers to a pharmacological action or pharmacological activity that preferentially targets tumor tissues rather than tumor cells.
  • the term "locally active ingredient” is distinguished from chemical ablation agents, which refers to chemical substances (such as 50% acetic acid, absolute ethanol, 5% methylene blue) under effective ablation conditions of the tumor (usually exceeding the ablation concentration threshold) , While the former refers to not through its conventional effects (not any administration other than intratumoral administration), nor its chemical ablation effect (used under conditions lower than its chemical ablation concentration), but mainly through providing local synergy Active ingredient (for example 0.5 to 1.5% methylene blue).
  • chemical ablation agents refers to chemical substances (such as 50% acetic acid, absolute ethanol, 5% methylene blue) under effective ablation conditions of the tumor (usually exceeding the ablation concentration threshold) , While the former refers to not through its conventional effects (not any administration other than intratumoral administration), nor its chemical ablation effect (used under conditions lower than its chemical ablation concentration), but mainly through providing local synergy Active ingredient (for example 0.5 to 1.5% methylene blue).
  • local synergistic drug or local synergist refers to the methylene blue that can be combined with the local active ingredient (for example, topical administration and administration concentration ⁇ 2%, preferably ⁇ 1%) Dyestuffs) produce local synergistic effects, which are selected from nutrients or/and conventional anti-tumor drugs.
  • local synergistic effect refers to a synergistic effect that is mainly shown as a local effect.
  • concentration a synergistic effect
  • the term “synergistic effect” refers to the combination of active ingredients exhibiting a higher desired medicinal effect than any component used alone, and/or the combination of any component exhibiting no single use. Need drug effect (for example, the tissue necrosis effect produced by the sharing of two cytotoxic drugs).
  • Need drug effect for example, the tissue necrosis effect produced by the sharing of two cytotoxic drugs.
  • the term “synergistic safety” means that when effective pharmacological effects are obtained, the active components collectively show a higher required safety than any component used alone.
  • a topical pharmaceutical composition for the treatment of malignant solid tumors which comprises a methylene blue dye, a local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable
  • the liquid carrier wherein the synergistic drug is selected from nutrients or/and conventional anti-tumor drugs
  • the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35 -2%, 0.5-2%, 0.5-1.5% or 0.5-1%, the concentration of the nutrient (w/v) ⁇ 2%, preferably 3%-40%, and the concentration of the conventional anti-tumor drug It is greater than 20% or 30% of its saturated concentration, preferably 30%-100% of its saturated concentration, wherein the saturated concentration refers to the saturated concentration of the conventional antitumor drug in the liquid carrier.
  • methylene blue dye as a topical active ingredient and a local synergistic drug of the methylene blue dye in the preparation of a topical pharmaceutical composition for the treatment of malignant solid tumors ,
  • the synergistic drug is selected from nutrients or/and conventional anti-tumor drugs.
  • the topical pharmaceutical composition comprises the methylene blue dye, the local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable liquid carrier, wherein the topical drug In the composition, the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35-2%, 0.5-2%, 0.5-1.5% or 0.5-1%, and the concentration of the nutrient (w/v) w/v) ⁇ 2%, preferably 3%-40%, and the concentration of the conventional anti-tumor drug is greater than 20% or 30% of its saturated concentration, preferably 30%-100% of its saturated concentration, wherein The saturated concentration refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • it provides a method for treating malignant solid tumors, which comprises intratumorally administering a therapeutically effective amount of the methylene blue dye disclosed in the present application to an individual in need thereof.
  • a pharmaceutical composition of a topical active ingredient and the synergistic drug is provided.
  • intramoral administration refers to the injection of drugs (such as injections) into the tumor through devices, such as transcatheter arterial infusion, transcatheter intratumor infusion, intratumoral injection, and the like.
  • therapeutically effective amount refers to the amount of a drug used to treat a disease (such as a tumor) and obtain an effective effect (such as reducing or/and alleviating the symptoms of the disease).
  • concentration refers to the weight/volume percentage concentration% (w/v) of the specified component in the topical pharmaceutical composition.
  • intramoral administration concentration refers to the concentration of the specified component when the drug is administered intratumorally, which may be the concentration of the specified component where the drug contacts the target area (for example, the injection needle hole or the outlet of the perfusion tube).
  • methylene blue dyes at the above concentrations have many applications, such as antidote, analgesic, vital dyes, and so on.
  • high-concentration (for example, 5%) methylene blue dyes can also be used as chemical ablation agents. It is generally believed that the greater the concentration of the chemical ablation agent, the more effective it is.
  • the inventors of the present invention unexpectedly discovered that methylene blue dyes can be very different from conventional pharmacological conditions under non-chemical ablative conditions (for example, 1% methylene blue administration concentration).
  • These unexpected synergistic effects may be the key point of pharmacology, which significantly improves the specificity of methylene blue dyes, nutrients or/and conventional anti-tumor drug compositions against intratumoral tissue destruction.
  • the drug should specify the intratumoral administration concentration of methylene blue chromosome in its instructions to ensure that it is applied as a local active ingredient rather than as a chemical ablation agent to avoid risks.
  • the methylene blue dye is preferably selected from the following compounds and their derivatives: methylene blue, patent blue, isosulfur blue, and neomethylene blue.
  • the methylene blue dye is more preferably selected from methylene blue and its derivatives.
  • the low-concentration methylene blue dye as a local synergistic drug in the treatment of malignant solid tumors may be one or more selected from nutrients and/or conventional anti-tumor drugs.
  • the term "nutrient” refers to organic compounds with nutritional and health effects, which are usually used in the preparation of nutritional health products, traditional diets and functional diets (such as health diets), which mainly include amino acid nutrients , Carbohydrate nutrients and lipid nutrients.
  • the concentration of the nutrient in the composition is 2.5-50%, preferably 4-40%.
  • the local synergistic medicine includes amino acid nutrients, and the concentration (w/v) of the amino acid nutrients in the pharmaceutical composition is ⁇ 2%, ⁇ 2.5, ⁇ 5% , Preferably ⁇ 7.5%, 10-25% or 18-25%, more preferably 15%-25% or 20%-25%.
  • amino acid nutrients refers to amino acid compounds with nutritional and health effects, preferably selected from amino acids, amino acid polymers and amino acid derivatives with nutritional and health effects, more preferably selected from China , Amino acid nutritional drugs and amino acid excipients with nutritional and health effects contained in the official pharmacopoeias or guidelines of the United States or Europe.
  • amino acid-based nutrients amino acids and amino acid derivatives is preferably a polymer selected from the group of amino acids, or an amino acid of the group of oligopeptide and polypeptide, or the group The amino acid salt in the amino acid: protein amino acid and non-protein amino acid.
  • the protein amino acids include amino acids selected from the following group: non-polar amino acids (such as alanine, valine, leucine, isoleucine, phenylalanine , Proline), polar neutral amino acids (such as tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine), basic amino acids (such as lysine) Acid, arginine, histidine), acidic amino acids (e.g. aspartic acid, glutamic acid). All the above except glycine are L-type ⁇ -amino acids.
  • non-polar amino acids such as alanine, valine, leucine, isoleucine, phenylalanine , Proline
  • polar neutral amino acids such as tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine
  • basic amino acids such as lysine
  • Acid arg
  • the non-protein amino acids may include the following amino acids: ⁇ -alanine, taurine, ⁇ -aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyridine) Alkanoic acid), glutamine, citrulline, ornithine, etc.
  • oligopeptide refers to a polymer of amino acids comprises 2 to 10 identical or different amino acids linked by peptide bonds employed; the term “polypeptide” refers to a same or different 11-100 amino acid polymer linked by peptide bonds.
  • the amino acids constituting the oligopeptide or polypeptide may all be one or more of the above-mentioned amino acids, or may additionally include other amino acids.
  • the oligopeptide may be one or more selected from the group consisting of: glycyl-L-tyrosine, glycylalanine, glycylglycine, lysine-glycine two Peptides, glutathione, carnosine ( ⁇ -alanine histidine copolymer), glutathione, collagen oligopeptides, casein hydrolyzed peptides, soybean oligopeptides, oligoarginine, oligoglycine, oligo-lysine Acid.
  • the polypeptide may be one or more selected from the group consisting of polyaspartic acid, polyglutamic acid, and polylysine.
  • amino acid salt refers to the salt formed by the above-mentioned amino acid and acid or base, such as lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride , Cysteine hydrochloride, arginine hydrochloride, glycine sulfate, iron glycine sulfate, lysine hydrochloride, aspartic acid hydrochloride, etc.
  • the amino acid nutrient may be one or more of amino acids, amino acid salts, oligopeptides, and polypeptides, for example, 2, 3, 4, or 5 or more. .
  • amino acids, amino acid salts, oligopeptides and polypeptides as the amino acid nutrients are preferably amino acids or their salts selected from the following group, or oligopeptides and polypeptides comprising or consisting of the following amino acids: alanine , Valine, leucine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, serine, cysteine, methionine, threonine, lysine, arginine Acid, histidine, aspartic acid, glutamic acid, ⁇ -alanine, taurine, ⁇ -aminobutyric acid (GABA), theanine, citrulline, ornithine; more preferably selected from Amino acids in the following groups or their salts or oligopeptides and polypeptides comprising or consisting of the following amino acids: arginine, lysine, glycine, cysteine, alanine, serine
  • the amino acid nutrient includes arginine.
  • the amino acid nutrient is selected from compound amino acids including arginine, for example: arginine/tolerant, arginine/serine, arginine/glycine, arginine/cysteine Hydrochloride and so on.
  • the amino acid nutrient includes lysine.
  • the amino acid nutrient includes glycine.
  • the amino acid nutrient includes glutamic acid.
  • the amino acid nutrient is selected from amino acids or amino acid salts with nutritional and health effects, and the concentration (w/v) of the amino acid or amino acid salt in the topical pharmaceutical composition is ⁇ 2%, ⁇ 2.5, ⁇ 5%, ⁇ 7.5%, 10-25% or 18-25%, preferably 15%-25% or 20%-25%.
  • the amino acid nutrients are selected from oligopeptides and polypeptides with nutritional and health effects, and the concentration (w/v) of the oligopeptides and polypeptides in the topical pharmaceutical composition is greater than ⁇ 5%, Preferably it is 7.5-25%, more preferably 10%-25%.
  • the amino acid nutrient is a combination of the amino acid and/or amino acid salt and the oligopeptide and/or polypeptide, and the concentration (w/v) of the combination in the topical pharmaceutical composition is More than ⁇ 5%, preferably 7.5%-25%, more preferably 10-25%.
  • the local synergistic medicine includes carbohydrate nutrients, and the concentration (w/v) of the carbohydrate nutrients in the pharmaceutical composition is greater than 5%, preferably ⁇ 10%, 10% -50%, 15-50% or 25-50%.
  • carbohydrate nutrient refers to carbohydrate compounds with nutritional and health effects, preferably selected from monosaccharides, sugar polymers and sugar derivatives with nutritional and health effects, more preferably selected from Carbohydrate nutritional medicines and carbohydrate excipients with nutritional and health effects contained in the official pharmacopoeias or guidelines of China, the United States or Europe.
  • the monosaccharides, sugar polymers, and sugar derivatives as the carbohydrate nutrients are preferably monosaccharides selected from the following groups, sugar polymers containing monosaccharides in the following groups, or their derivatives Substances: glucose, ribose, deoxyribose, xylose, fructose, galactose, fucose.
  • the sugar polymer may be selected from disaccharides, oligosaccharides and polysaccharides containing monosaccharides as described above.
  • disaccharide used refers to a polymer containing two monosaccharides connected by glycosidic bonds
  • oligosaccharide used refers to a polymer containing 3-10 monosaccharides connected by glycosidic bonds.
  • Sugar polymer and the term “polysaccharide” as used refers to a polymer containing more than 10 monosaccharides connected by glycosidic bonds.
  • the monosaccharides constituting the disaccharides, oligosaccharides or polysaccharides may all be one or more of the above-mentioned monosaccharides, or may additionally contain other monosaccharides.
  • the disaccharide may be one or more selected from the group consisting of lactulose, maltose, sucrose, lactose, and trehalose.
  • the oligosaccharide may be one or more selected from the group consisting of chitooligosaccharides, xylo-oligosaccharides, fructooligosaccharides, mannose oligosaccharides, malto-oligosaccharides, and isomalto-oligosaccharides.
  • the polysaccharide may be one or more selected from the group consisting of starch, cellulose, dextran, and glycosaminoglycan.
  • the sugar derivative may be, for example, the following sugar derivatives selected from the above-mentioned monosaccharides or sugar polymers: sugar acid, sugar acid salt, sugar alcohol.
  • sugar acid used refers to acid derivatives of monosaccharides or sugar polymers
  • sugar acid salt refers to salt derivatives of monosaccharides or sugar polymers
  • sugar alcohol refers to monosaccharides or alcohol derivatives of sugar polymers.
  • the sugar acid may be one or more selected from the group consisting of gluconic acid, mannonic acid, and arabinonic acid.
  • the sugar acid salt may be one or more selected from the group consisting of sodium gluconate, sodium mannate, and sodium arabinate.
  • the sugar alcohol may be one or more selected from the group consisting of mannitol, maltitol, lactitol, and xylitol.
  • the carbohydrate nutrient may be one or more of monosaccharides, oligosaccharides, polysaccharides, sugar acids, saccharates, and sugar alcohols, such as 2, 3, 4 Species or 5 species or more.
  • the carbohydrate nutrient is selected from glucose, glucose-containing sugar polymers, or glucose derivatives.
  • the carbohydrate nutrient is selected from ribose, ribose-containing sugar polymers, or ribose derivatives.
  • the carbohydrate nutrient is selected from xylose, xylose-containing sugar polymers, or xylose derivatives.
  • the carbohydrate nutrient is preferably one or more selected from the following: glucose, fructose, chitooligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose , Sucrose, lactose, trehalose, xylo-oligosaccharides, fructooligosaccharides, mannose oligosaccharides, xylitol, more preferably one or more selected from the following: glucose, sodium gluconate, chitooligosaccharides, glucosamine, Lactulose, ribose, mannose oligosaccharides, xylitol.
  • the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is greater than 5%, preferably ⁇ 10%, 10-40%, 15-50% or 25-50%.
  • the topical synergistic drug includes lipid nutrients, and the concentration (w/v) of the lipid nutrients in the pharmaceutical composition is ⁇ 4%, preferably 4-25% .
  • the lipid nutrient includes any pharmaceutically acceptable lipid nutrient, preferably selected from the group of lipids with nutritional and health effects contained in the official pharmacopoeias or guidelines of China, the United States or Europe.
  • the compound is more preferably one or more selected from the group consisting of fats, fatty acids, fat emulsions and lipids.
  • the lipid nutrient is one or more selected from the group consisting of vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat emulsion, Medium chain fat milk, phospholipids.
  • the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is ⁇ 4%, preferably 4-25%.
  • conventional antineoplastic drug refers to a drug that can effectively inhibit solid tumors by absorption at a safe dose, which is selected from any pharmaceutically acceptable conventional antineoplastic drugs, preferably selected from the present invention.
  • Conventional anti-tumor drugs known in the art are more preferably selected from China, the United States or Europe, which has been approved or will be approved by the official competent administrative department of China, the United States or Europe (such as the FDA or China Food and Drug Administration), or has been included in the official pharmacopoeia of China, the United States or Europe. The anti-tumor drugs to be loaded.
  • absorption refers to the pharmacological effect of the drug being absorbed by the blood to form the drug-carrying blood into the target area.
  • Some conventional anti-tumor drugs have been expected to improve their efficacy through intratumoral administration, but the increase in drug efficacy with the increase in concentration (chemical kinetics) is far lower than its theoretical correlation.
  • different drugs were shared locally in a large number of studies, there was not much local synergy, let alone unexpected synergy, indicating that the synergy of these drugs under special conditions in the tumor (such as the microenvironment of cancer cells) has a high degree of inefficiency. Certainty. .
  • the conventional anti-tumor drugs may be one or more selected from the group consisting of: drugs that disrupt the structure and function of DNA, drugs that intercalate in DNA and interfere with transcription of RNA, drugs that interfere with DNA synthesis, and proteins that affect the structure and function of DNA. Synthetic drugs.
  • the drugs that disrupt DNA structure and function include, for example, alkylating agents (e.g., cyclophosphamide, carmustine, etc.), metal platinum complexes (e.g., cisplatin, carboplatin, etc.), DNA topoisomerase inhibitors ( For example, doxorubicin, topotecan, irinotecan, etc.).
  • the drugs that intercalate DNA to interfere with transcription of RNA include, for example, anti-tumor antibiotics, such as actinomycins, daunorubicin, doxorubicin, and the like.
  • the drugs that interfere with DNA synthesis include, for example, pyrimidine antagonists (such as uracil derivatives 5-fluorouracil, furfurouracil, difurfurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc.) , Purine antagonists (e.g. oncolytic, thioguanine, etc.), folic acid antagonists (e.g., methotrexate, etc.).
  • the drugs that affect protein synthesis include, for example, colchicines, vinblastines, taxanes (such as paclitaxel, docetaxel, etc.) and the like.
  • the pharmaceutically acceptable liquid carrier includes water and/or ethanol.
  • the pharmacologically acceptable liquid carrier is mainly selected according to the properties of conventional anti-tumor drugs, so that the drug can reach a corresponding concentration.
  • the conventional anti-tumor drug is selected from the group consisting of water-soluble conventional anti-tumor drugs and alcohol-soluble conventional anti-tumor drugs.
  • the term "alcohol-soluble conventional anti-tumor drugs” refers to conventional anti-tumor drugs whose solubility in ethanol or ethanol aqueous solution at room temperature is greater than or equal to the concentration required for effective local action, which includes, for example, yew Alkanes, vinblastines, etc.
  • water-soluble conventional antitumor drug refers to a conventional antitumor drug whose solubility in aqueous solution at room temperature is greater than or equal to the concentration required for its effective local action, which includes, for example, one or more water-soluble drugs selected from the following groups Sexual compounds: uracil derivatives, cyclophosphamide, gemcitabine (such as gemcitabine hydrochloride), epirubicin (such as epirubicin hydrochloride), antitumor antibiotics (such as doxorubicin, actinomycetes) Vinblastine, etc.), vinblastines (for example, vinblastine sulfate), teniposide, metal platinum complexes, etc.
  • sexual compounds uracil derivatives, cyclophosphamide, gemcitabine (such as gemcitabine hydrochloride), epirubicin (such as epirubicin hydrochloride), antitumor antibiotics (such as doxorubicin, actinomycetes) Vinblastine, etc
  • the conventional anti-tumor drugs may be one or more selected from the following groups: uracil derivatives, cyclophosphamides, gemcitabine, epirubicin, Anti-tumor antibiotics, teniposide, metal platinum complexes, taxanes; preferably one or more selected from the following drugs and their analogous derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, epirubin Bicin, antitumor antibiotic, teniposide, metal platinum complex, paclitaxel.
  • the concentration of the conventional anti-tumor drug is greater than 30% of its saturated concentration, preferably 50-100%, 60-100%, 70-100%, 80% of its saturated concentration. -100%, or 90-100%, wherein the saturated concentration refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • the concentration (w/v) of a conventional anti-tumor drug (such as cyclophosphamide, carmustine, etc.) selected from the alkylating agent in the topical pharmaceutical composition is 0.5-6 %, preferably 0.75-1.5%.
  • the concentration (w/v) of a conventional anti-tumor drug (such as cisplatin, carboplatin, etc.) selected from the metal platinum complex in the topical pharmaceutical composition is 0.03-0.08% , Preferably 0.03-0.06%.
  • the concentration of a conventional anti-tumor drug (such as doxorubicin, topotecan, irinotecan, etc.) selected from the DNA topoisomerase inhibitor in the topical pharmaceutical composition is 0.05-0.20%, preferably 0.75-0.15%.
  • the concentration (w/v) of conventional anti-tumor drugs selected from the anti-tumor antibiotics (such as actinomycins, daunorubicin, etc.) in the topical pharmaceutical composition is 1 -4%, preferably 1-2%.
  • a conventional antitumor drug selected from the pyrimidine antagonist for example, uracil derivative 5-fluorouracil, furfurouracil, difurfurouracil, cytosine derivative cytarabine, cyclocytidine, 5
  • concentration (w/v) of azacytidine, etc.) in the topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.
  • the concentration (w/v) of a conventional anti-tumor drug selected from the taxanes (such as paclitaxel, docetaxel, etc.) in the topical pharmaceutical composition is 0.5-2% , Preferably 0.75-1.5%.
  • composition disclosed according to the present application it also optionally includes one or more selected from the group consisting of analgesics, sustained-release carriers, pH adjusters, and excipients.
  • the pharmaceutical composition disclosed according to the present application may further optionally include an analgesic.
  • the analgesic is used to alleviate the pain of the patient, and it may be any suitable one known to those skilled in the art, such as benzyl alcohol, procaine hydrochloride, chlorobutanol, lidocaine hydrochloride and the like.
  • the concentration of the analgesic in the pharmaceutical composition may be, for example, 0.1-4% by weight.
  • the concentration of benzyl alcohol in the pharmaceutical composition may be 1-4% by weight
  • the concentration of procaine hydrochloride, chlorobutanol, and lidoca hydrochloride in the pharmaceutical composition may be 1- 3% by weight.
  • the pharmaceutical composition disclosed according to the present application may further optionally include a sustained-release carrier.
  • the sustained-release carrier may be any suitable one known to those skilled in the art, including, for example, a gel matrix, a particulate carrier, a micellar matrix, and the like.
  • the concentration (w/v) of the sustained-release carrier in the pharmaceutical composition can be, for example, 0.5-13%, preferably 1-12% or 1-15%.
  • the pharmaceutical composition disclosed according to the present application may further optionally include excipients.
  • the excipient may be any suitable one known to those skilled in the art, which may include, for example, one or more of the following: dispersion medium, preservative, stabilizer, wetting agent and/or emulsifier, solubilizer, Tackifiers, etc.
  • the viscosity increasing agent is, for example, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone or gelatin.
  • the preservatives are, for example, antioxidants (such as ascorbic acid).
  • the pharmaceutical composition disclosed according to the present application may include active ingredients (the methylene blue dye, nutrients and/or conventional anti-tumor drugs, and optionally other active ingredients as described above) and a liquid carrier (e.g. Water, ethanol, or water/ethanol mixture) any dosage form suitable for intratumoral administration, preferably the following dosage forms: injections (preferably local injections), external liquids, nebulizers, and the like.
  • active ingredients the methylene blue dye, nutrients and/or conventional anti-tumor drugs, and optionally other active ingredients as described above
  • a liquid carrier e.g. Water, ethanol, or water/ethanol mixture
  • any dosage form suitable for intratumoral administration preferably the following dosage forms: injections (preferably local injections), external liquids, nebulizers, and the like.
  • injection refers to a sterile preparation containing an active ingredient and a liquid carrier for in vivo administration.
  • the injections are divided into local injections, intravenous injections, etc. according to the mode of administration, and intravenous injections can be used as local injections only after a given intratumoral administration concentration.
  • Injections are classified into liquid injections, powder injections for injection, etc. according to their commercial form.
  • the injection powder contains sterile dry powder and a solvent, the sterile dry powder contains part or all of the active ingredients, and the solvent contains all the liquid carriers.
  • the concentration of the active ingredient in the injection is the concentration of the active ingredient in the mixture with all the liquid carriers, which is usually the end point of the intratumoral drug delivery device (syringe, puncture, injection catheter, etc.) (such as needle hole, catheter outlet, etc.) Etc.)
  • the concentration of the active ingredient in the liquid medicine is usually the end point of the intratumoral drug delivery device (syringe, puncture, injection catheter, etc.) (such as needle hole, catheter outlet, etc.) Etc.)
  • the concentration of the active ingredient in the liquid medicine is usually the end point of the intratumoral drug delivery device (syringe, puncture, injection catheter, etc.) (such as needle hole, catheter outlet, etc.) Etc.)
  • the concentration of the active ingredient in the liquid medicine is usually the end point of the intratumoral drug delivery device (syringe, puncture, injection catheter, etc.) (such as needle hole, catheter outlet, etc.) Etc.)
  • the concentration of the active ingredient in the liquid medicine is usually the end
  • a topical pharmaceutical composition for the treatment of malignant solid tumors in a freeze-dried or semi-lyophilized form which is lyophilized or semi-lyophilized according to the disclosed Methylene blue dyes, nutrients and/or conventional anti-tumor drugs and a pharmaceutically acceptable carrier are partly or wholly obtained.
  • composition of the present invention should be made into a dosage form that can be administered into the target area intratumorally, preferably a topical pharmaceutical dosage form.
  • the preparation of the pharmaceutical composition of the present invention includes the following steps: preparing a liquid medicine containing the methylene blue dye, nutrients and/or conventional anti-tumor, liquid medium and optionally other substances.
  • the liquid medicine may be a solution (for example, a solution in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion containing a topical active ingredient.
  • the dispersion medium therein can be any suitable one known to those skilled in the art, such as micro-materials or nano-materials.
  • the dispersion medium therein can be any suitable one known to those skilled in the art, such as vegetable oil, synthetic oil or semi-synthetic oil that can be used for injection.
  • the vegetable oil may be, for example, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and peanut oil.
  • the pharmaceutical composition liquid injection of the present invention can be prepared by a method comprising the following steps: 1) The necessary components (such as the methylene blue Dyes, nutrients and/or conventional anti-tumor drugs) and optional other components are added to the solvent to prepare a liquid; 2) other necessary components (such as other nutrients) and Optionally, add the liquid prepared in 1) and mix uniformly to obtain a liquid medicine; 3) sterilize the liquid medicine prepared in 2) and prepare a liquid injection.
  • the sterilizing liquid medicine in the liquid injection can be used directly or diluted as a liquid medicine for intratumoral administration.
  • the pharmaceutical composition liquid injection of the present invention can be prepared by a method including the following steps: 1) The amount of methylene blue dye, nutrients and/or conventional The anti-tumor drug and optional other components are added to the solvent (or pharmaceutically acceptable liquid carrier), mixed uniformly and sterilized, and then prepared as a sterile liquid I; 2) The amount required is based on the intratumor administration concentration The optional other components (such as acidulant) are added to the solvent (or pharmaceutically acceptable liquid carrier), mixed uniformly, and sterilized to prepare the sterilizing liquid II.
  • the sterilizing liquid I and the sterilizing liquid II form a mixed liquid before or after entering the intratumoral administration device, which can be used directly or diluted as a liquid drug for intratumoral administration.
  • the injection powder of the pharmaceutical composition of the present invention can be prepared by a method including the following steps: And/or sterile dry powder of conventional antitumor drugs; and preparing a sterile vehicle containing the required amount of the other components (such as amino acid nutrients, analgesics, etc.) according to the intratumor administration concentration.
  • the sterile dry powder is preferably a sterile freeze-dried dry powder, and its preparation method includes: 1) preparing a solution containing methylene blue dyes, nutrients and/or conventional anti-tumor drugs and optional other components; 2) removing Bacteria filtration and packaging; 3) freeze-drying; 4) plugging and capping.
  • the process conditions of the freeze-drying include, for example, the pre-freezing condition is kept at the pre-freezing temperature -45°C for 4 hours; the sublimation drying condition is that the temperature rise rate is 0.1°C/min and the temperature is raised to -15°C and kept for at least 10 hours; The adsorption drying conditions are 30°C for 6 hours.
  • the sterile dry powder of the injection powder is re-dissolved in a sterile solvent to form a re-solution drug, which can be used directly or diluted as a liquid drug for intratumoral administration.
  • the changes in the composition of the present invention include: containing different types and concentrations of the methylene blue dye, containing different types and concentrations of synergistic drugs (such as nutrients and/or conventional anti-tumor drugs), containing different types and concentrations Concentration of other additives (such as analgesics, acidulants, etc.).
  • the pharmaceutical composition is mainly used to treat malignant solid tumors, especially refractory malignant solid tumors (such as pancreatic cancer) by intratumoral administration.
  • Intratumoral administration requires that the composition of the drug (local active ingredients, composition ratio and component concentration) can be administered into the tumor by interventional means, and produce the desired therapeutic effect in it.
  • the composition of the drug local active ingredients, composition ratio and component concentration
  • tumor refers to a mass formed due to abnormal proliferation of cells or mutated cells, which includes solid tumors.
  • malignant solid tumor refers to malignant tumors with tumor bodies, including, for example, the following groups classified according to tumor cell types: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, and blastoma; Tumors named after the organ or tissue where the area is located include, for example, tumors named after the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder muscle, large intestine, Small intestine, spleen, stomach, prostate, testes, ovaries or uterus.
  • the malignant solid tumors include, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, bowel cancer, oral cancer, esophageal cancer, stomach cancer, laryngeal cancer, testicular cancer, and vaginal cancer. , Uterine cancer, ovarian cancer, etc.
  • the local drug in the present invention is a therapeutic drug.
  • it can also be combined with other interventional therapies, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or Combinations of such therapies are administered in combination to further improve the efficacy.
  • the pharmaceutical composition is mainly used for the treatment of malignant solid tumors by intratumoral administration.
  • the acidifying agent and the ineffective absorption compound are administered intratumorally at their concentration or amount in the local pharmaceutical composition. This concentration or amount can provide a synergistic effect of local response compared to intratumoral administration.
  • composition of the present invention has been shown to be effective in promoting the relevant structures of the tissue where the local disease is located (such as diseased tissue, diseased cells, and any structure involved in the formation of them) It destroys and minimizes damage to the patient's normal tissues at the same time, so as to achieve a safe and effective pharmaceutical effect for the treatment of malignant solid tumors.
  • L-amino acids are abbreviated as amino acids (for example, L-arginine is abbreviated as arginine), reduced glutathione is abbreviated as glutathione, and alanyl-glutamine dipeptide is abbreviated as For glutathione.
  • the animal tests of subcutaneous transplantation tumors are carried out in accordance with the test guidelines issued by the drug administration authority.
  • the test animals are Balb/c nude mice or mice aged 6-8 weeks and weighing 17.5-20.5 g.
  • the subcutaneous transplantation is carried out according to the conventional method of subcutaneous inoculation of tumor cells.
  • the PEMS 3.2 software compiled by West China School of Public Health, Sichuan University
  • the items to be observed, measured and analyzed in the experiment include general status, body weight, food intake, tumor volume, tumor weight, thymus weight, spleen weight, etc.
  • the tumor volume calculation formula is as follows:
  • Tumor volume (V) 1/2 ⁇ a ⁇ b 2 , where a represents the length of the tumor and b represents the width of the tumor.
  • tumor growth inhibition rate (abbreviated as tumor inhibition rate in the present invention) is as follows:
  • Tumor inhibition rate Y(%) (TW-CW)/CW ⁇ 100%, where TW is the average tumor weight of the study group; CW is the average tumor weight of the negative control group.
  • B/A the combination of A drug and B drug is denoted as B/A.
  • drug A and drug B are methylene blue dyes and other active components, respectively.
  • the single-use efficacy of A and B (denoted as E A and E B , respectively) and the actual combined efficacy of A/B (denoted as E A+B ) are both tumor inhibition rates.
  • One method for judging the effect of combined medication in animal experiments is the Burgi method (Burgi Y. Pharmacology; Drug actions and reactions. Cancer res. 1978, 38(2), 284-285). Jin Zhengjun improved the Burgi method (Jin Zhengjun, Addition in combined medication, Chinese Journal of Pharmacology 1980; 1(2), 70-76), and the formula for q is:
  • compositions of the present invention can be formulated.
  • the compositions of some of the compositions of the present invention prepared in this example are listed in Table 3.
  • methylene blue dye e.g. 1g of methylene blue
  • conventional anti-tumor drugs or/and conventional ineffective compounds e.g. 10g of glutathione
  • optionally other compounds according to the required concentration (as described in Table 2)
  • the components and the liquid carrier such as water for injection
  • the preparation for example, 1% methylene blue/10% glutathione in water
  • Solution I and solution II are mixed evenly according to the required concentration of each component (for example, 8.5ml of solution I and 1.5ml of solution II are mixed) into a mixed solution (for example, 1% methylene blue/30% glucose/5% acetic acid aqueous solution) )
  • a mixed solution for example, 1% methylene blue/30% glucose/5% acetic acid aqueous solution
  • methylene blue dye e.g. 1g methylene blue
  • conventional anti-tumor drugs or/and conventional ineffective compounds e.g. 20g arginine, 30g glucose
  • a liquid carrier such as water for injection
  • a liquid carrier such as water for injection
  • Freeze-drying, stoppering and capping prepare as sterile dry powder for later use.
  • % Methylene blue/20% arginine/30% glucose/5% acetic acid aqueous solution can be used as a liquid drug for intratumoral administration.
  • the experimental animals S180-bearing mice with an average tumor volume of 121mm 3
  • the negative control was normal saline, and the 11 study drugs were as shown in the table below. They were injected intraperitoneally and intratumorally, respectively.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1. The medicine is administered once every 3 days, a total of 3 times, and the injection volume is less than or equal to 120 ⁇ l/mouse.
  • Ten days after the end of the medication the animals were euthanized, and the tumor weight was measured after anatomy, and the tumor inhibition rate was calculated from the negative control group of each medication mode. The results are shown in Table 4.
  • the intraperitoneal injection group and intratumor injection group of the positive control substance showed almost the same tumor inhibition rate, although some people believe that the drug in the tumor can increase its local drug concentration and thus significantly increase its tumor inhibition rate.
  • Medicinal effect shows that the drug did not substantially change its targeting (tumor cells) and pharmacology (inhibition of tumor cells) when injected intratumorally. Therefore, unless placed in a sustained-release system, conventional anti-tumor drugs are still mainly administered by absorption rather than intratumoral administration. 2.50 (respectively
  • the tumor inhibition rates of the methylene blue intraperitoneal injection group and the intratumor injection group were both at a negligibly low level, indicating that it did not show any ablation effect when used alone at this concentration.
  • the tumor weight of the methylene blue/nutrient composition group and its component single-drug group (group 6 and groups 5 and 2, group 7 and groups 5 and 3, and group 8 and groups 5 and 4)
  • the difference was not statistically significant in each group of intraperitoneal injection (all p>0.05), and no synergistic efficacy was shown, while there were statistically significant in each group of intratumoral injection (all p ⁇ 0.05), and
  • the q value of the composition calculated based on the tumor inhibition rate of the latter is far greater than 1.00, and even extremely rarely greater than 2.50 (2.81, 3.32, and 4.00, respectively).
  • the intratumor injection group of the same composition showed a tumor inhibition rate of more than 10 times than that of the intraperitoneal injection group, thus showing significantly different targeting and pharmacology.
  • the difference in tumor weight between the methylene blue/conventional antineoplastic drug group and its component single agent group was not statistically significant between the intraperitoneal injection group 9 and group 1 (p>0.05), no synergistic drugs were shown
  • the group 9 injected intratumorally was statistically significant between groups 1 and 5 (all p ⁇ 0.05), and the q value of the composition calculated based on the tumor inhibition rate of the latter was much higher than 1.00 (1.30).
  • the tumor inhibition rate of the intratumor injection group of the same composition was 159% of that of the intraperitoneal injection group, which showed significantly different targeting and pharmacology.
  • the difference in tumor weight between the methylene blue/conventional antitumor drug/nutrient group and its component single agent group was not statistically significant between the intraperitoneal injection group 11 and group 10 (p>0.05).
  • Synergistic drug effect, and the intratumoral injection group 11 was statistically significant between groups 10 and 5 (both p ⁇ 0.05), and the q value of the composition calculated based on the tumor inhibition rate was much higher than 1.00 (1.24).
  • the tumor inhibition rate of the intratumor injection group of the same composition was 175% of that of the intraperitoneal injection group, which showed significantly different targeting and pharmacology.
  • the preferred synergistic pharmacology of the composition of the present invention is not conventional synergistic effects, but local synergistic effects.
  • the experimental animals PANC-1-bearing nude mice with an average tumor volume of 218 mm 3
  • the negative control is physiological saline
  • the 9 study drugs are shown in the table below.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1.
  • the drugs are injected intratumorally.
  • the two drugs containing 50% acetic acid are administered once, and the injection volume is 1000ul/only.
  • Other drugs are administered once every 3 days for a total of 3 times, with an injection volume of 100 ⁇ l/only.
  • Tumor inhibition rate 0 Normal saline 2.83 ⁇ 0.22g (0) 1 3% gemcitabine 1.47 ⁇ 0.18 48% 2 30% xylitol 2.32 ⁇ 0.13 18% 3 90% ethanol 0.91 ⁇ 0.21 68% 4 50% acetic acid 0.62 ⁇ 0.19 78% 5 0.7% methylene blue 2.52 ⁇ 0.17 11% 6 3% gemcitabine/0.7% methylene blue 0.42 ⁇ 0.11 85% 7 30% xylitol/0.7% methylene blue 0.34 ⁇ 0.09 88% 8 90% ethanol/0.7% methylene blue 0.82 ⁇ 0.12 71% 9 50% acetic acid/0.7% methylene blue 0.57 ⁇ 0.15 80%
  • composition of the present invention shows certain specificity, and its local synergistic effect shows very different specificity from the usual synergistic effect (same pharmacological synergistic effect).
  • the local synergist of the methylene blue dye in the composition of the present invention is not selected from chemical ablative agents with strong local action, preferably selected from drugs with relatively mild local action, more preferably selected from nutrients or/and conventional anti-inflammatory agents. Oncology medicine.
  • the experimental animals (mice bearing S180 cells with an average tumor volume of 112mm 3 ) that were successfully modeled were randomly divided into a negative control group and 40 study groups.
  • the negative control is physiological saline
  • the study drugs include: 4 kinds of methylene blue single drugs with varying concentrations (X%, X is methylene blue), 16 kinds of varying types and concentrations of other component single drugs (Y%, Y is other Components), 20 compositions (X%/Y%) composed of varying concentrations of methylene blue and varying types and concentrations of other components (nutrients, conventional anti-tumor drugs), and their compositions are shown in the following table.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1.
  • All groups were injected intratumorally, once every 3 days for a total of 3 times.
  • the dose of each administration was: methylene blue ⁇ 100mg/kg, lysine ⁇ 1000mg/kg, DHA ⁇ 375mg/kg, glucose ⁇ 2250mg/kg , 5-Fluorouracil ⁇ 50mg/kg, injection volume ⁇ 150 ⁇ l.
  • the animals were euthanized on the 10th day after the treatment, the tumor weight was measured after anatomy, and the tumor inhibition rate was calculated from the negative control group.
  • the tumor inhibition rate of each study drug group is shown in Table 6.
  • the data in the brackets is the average tumor inhibition rate of the X% methylene blue group, for example, the average tumor inhibition rate of the 0.15% methylene blue group is 3%
  • the data in the column bracket is the average tumor inhibition rate of Y% other component groups, for example, the average tumor inhibition rate of 1% lysine group is 5%
  • the data without brackets is the average tumor inhibition rate of X% methylene blue/Y% other component groups, for example, the average tumor inhibition rate of 3% methylene blue/1% lysine group is 45%
  • mice modeled with 1 ⁇ 10 6 breast tumor 4T1 cells per mouse mice modeled with 2 ⁇ 10 6 liver cancer H22 cells per mouse, and 1 ⁇ 10 6 liver cancer H22 cells per mouse.
  • mice modeled with 2 ⁇ 10 6 liver cancer H22 cells per mouse mice modeled with 2 ⁇ 10 6 liver cancer H22 cells per mouse
  • mice modeled with 1 ⁇ 10 6 liver cancer H22 cells per mouse mice modeled with 1 ⁇ 10 6 liver cancer H22 cells per mouse.
  • 106 CT26 mouse colon cancer cells modeling to 2 ⁇ 10 6 mouse B16-f10 th melanoma cells modeling each a similar effect can be observed.
  • the successfully modeled test animals (breast tumor-bearing 4T1 cell mice with an average tumor volume of 119mm 3 ) were randomly divided into a negative control group and 9 study groups.
  • the negative control is physiological saline, and the 9 study drugs are shown in the table below.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1.
  • the drugs are injected intratumorally.
  • the two drugs containing 50% acetic acid are administered once, and the injection volume is 1000ul/only.
  • Other drugs are administered once every 3 days for a total of 3 times, with an injection volume of 100 ⁇ l/only.
  • Table 7 The results are shown in Table 7.
  • Tumor inhibition rate 0 Normal saline 1.81 ⁇ 0.22g (0) 1 1% 5-fluorouracil 0.98 ⁇ 0.17 46% 2 30% xylitol 1.57 ⁇ 0.19 13% 3 0.5% methylene blue 1.67 ⁇ 0.20 8% 4 1% 5-fluorouracil/0.5% methylene blue 0.45 ⁇ 0.13 75% 5 30% xylitol/0.5% methylene blue 0.58 ⁇ 0.12 68% 6 0.5% 5-fluorouracil 1.18 ⁇ 0.18 35% 7 15% xylitol 1.61 ⁇ 0.16 11%
  • the difference in tumor weight between methylene blue/conventional anti-tumor drug group 4 and single-agent group 1 and 3 is statistically significant (both p ⁇ 0.05), and is calculated based on the tumor inhibition rate
  • the composition q value of 1.50 is far greater than the theoretical expected value of 1.00, showing a significant synergistic effect.
  • the difference in tumor weight between the methylene blue/nutrient group 5 and the single-agent group 2 and 3 was statistically significant (both p ⁇ 0.05), and the q value of the composition calculated based on the tumor inhibition rate was 3.40 It is much larger than the theoretical expected value of 1.00, showing a clear synergistic effect.
  • the difference in tumor weight between the composition group 9 and the single-agent group 6, and the composition groups 10 and 7) was not statistically significant (p>0.05) and did not show a synergistic drug effect.
  • the synergistic technical solution of the methylene blue dye, nutrient or/and conventional anti-tumor drug composition of the present invention is intratumoral administration, and its synergistic composition is not conventional during intratumoral administration.
  • the amount ratio in the synergistic composition but the concentration relationship as defined below:
  • the intratumoral administration concentration (w/V) of the methylene blue dye is ⁇ 2%, preferably 0.3%-1.8%;
  • intratumoral administration concentration of the conventional antitumor drug is greater than 20% of its saturated concentration, preferably 30%-100% of its saturated concentration; or/and
  • the intratumoral administration concentration of the nutrient is greater than 1%, preferably 2%-40%, wherein:
  • the intratumoral administration concentration of the amino acid nutrients is greater than 2%, preferably 2%-35%;
  • the intratumoral administration concentration of the lipid nutrient is greater than 2%, preferably 3%-25%; or/and
  • the intratumoral administration concentration of the carbohydrate nutrient is greater than 10%, preferably 20%-40%.
  • the composition of the present invention can not only produce a synergistic effect, but the synergistic effect can be further optimized under specific conditions to obtain a super effective synergistic effect. These specific conditions are not the conditions in the prior art for methylene blue dyes and nutrients or/and conventional anti-tumor drugs. The following test example investigated this.
  • Example 5 Further optimization of the intratumoral administration concentration of methylene blue dyestuff in the synergistic composition
  • the successfully modeled test animals (S180 cell-bearing mice with an average tumor volume of 132mm 3 ) were randomly divided into a negative control group, a positive control group and 7 study groups.
  • the negative control is physiological saline
  • the positive control is 1% 5-fluorouracil
  • the study drug contains 20% lysine and methylene blue (20% lysine/X%) with varying concentrations (X%) as shown in the table below. Methylene blue).
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1. Each group was injected intratumorally, once every 3 days for a total of 3 times.
  • the dose of each administration was: methylene blue ⁇ 75 mg/kg, 5-fluorouracil 50 mg/kg, and injection volume ⁇ 150 ⁇ l.
  • the animals were dissected and the tumor weight was determined, and the tumor inhibition rate was calculated from the negative control group. The results are shown in Table 8.
  • composition of the present invention is: its composition is such that the intratumoral administration concentration of the methylene blue dye provided by the composition is ⁇ 0.35%, preferably 0.35 -1.5%, more preferably 0.5-1.5% or 0.5-1%.
  • the same substance can show completely different pharmacology according to its administration mode, so it can be used as different drugs.
  • systemically administered methylene blue is usually used as an antidote, but cannot be used as the local active ingredient in the composition of the present invention; systematically administered nutrients or/and conventional antitumor drugs are usually used as nutrients and antitumor drugs, but cannot As a local synergist of methylene blue dyes in the composition of the present invention.
  • the same substance can also show completely different pharmacology according to its local administration conditions and be used as different drugs.
  • ultra-high concentration (for example, ⁇ 3%) methylene blue can be used as a chemical ablation agent but not suitable for use in the present invention
  • the local active ingredient in the composition, while low concentration (for example, ⁇ 1%) methylene blue is usually used as a staining agent, but this local active ingredient can produce local synergistic effects with nutrients or/and conventional anti-tumor drugs.
  • Methylene blue dyes show unusual synergistic conditions. For example, it can be used as a chemical ablation agent at a high concentration but does not show local synergy with conventional chemical ablation agents at a low concentration. This is contrary to The prior art shares enhanced teaching about the same pharmacology; it actually produces a high synergy (q ⁇ 2.0) with nutrients that have little damage to tissues (such as lipid nutrients), which is contrary to the prior art’s similar pharmacology.
  • the teaching of sharing enhancement can produce almost uniform synergy (the q value is close), which is contrary to the prior art teaching about sharing enhancement of the same target.
  • the decisive synergy condition is not only the quantity ratio (concentration ratio) but also the concentration value itself.
  • concentration ratio concentration ratio
  • the intratumoral administration concentration of methylene blue dyestuffs below a certain threshold will not produce the local synergistic effect, which is contrary to the prior art teaching that the synergistic effect of conventional cytotoxic drugs is usually determined by the dosage ratio. .
  • composition of the present invention show higher specificity for tumor tissues.
  • composition of the present invention is compared with a conventional chemical ablation agent (50% acetic acid).
  • Example 6 Optimal intratumoral administration concentration of nutrients in the synergistic composition
  • the successfully modeled test animals (S180 cell-bearing mice with an average tumor volume of 128mm 3 ) were randomly divided into a negative control group (0), a positive control group (7) and 6 study groups (1-6 ).
  • the negative control is physiological saline, and the positive control is 1% 5-fluorouracil.
  • the composition of the study drug is shown in the table below, which contains varying concentrations (X%) of arginine and a fixed concentration (1%) of methylene blue ( X% arginine/1% methylene blue).
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1. Each group was injected intratumorally, once every 3 days for a total of 3 times.
  • the dose of each administration was: arginine ⁇ 1500 mg/kg, 5-fluorouracil 50 mg/kg, and injection volume ⁇ 150 ⁇ l.
  • the animals were euthanized 5 days after the treatment, and the tumor weight was measured after anatomy, and the tumor inhibition rate was calculated from the negative control group. The results are shown in Table 9.
  • a super-effective and synergistic technical solution of the composition of the present invention is: its composition is such that the intratumoral administration concentration of the nutrient provided by the composition is ⁇ 3%, preferably When the nutrient is selected from carbohydrate nutrients, the intratumoral administration concentration of the nutrient is ⁇ 20%, preferably 20-40%; when the nutrient is selected from lipid nutrients, the lipid The intratumoral administration concentration of the nutrient is ⁇ 4%, preferably 4-25%; when the nutrient is selected from amino acid nutrients, the intratumoral administration concentration of the amino acid nutrient is ⁇ 3%, preferably 3-25%, and more Preferably it is 5-25% or 15-25%.
  • the successfully modeled test animals (S180 cell-bearing mice with an average tumor volume of 151mm 3 ) were randomly divided into a negative control group, a positive control group and 15 study groups.
  • the negative control is physiological saline
  • the positive control is 1% 5-fluorouracil
  • the research drug is 1% methylene blue/10% amino acid nutrient composition.
  • the amino acid nutrients in the compositions used in the study groups 1-13 are: arginine, glycine, cysteine hydrochloride, valine, threonine, proline, histidine hydrochloride, benzene Alanine, lysine, leucine, alanine, glutathione, serine, alanyl-glutamine dipeptide, the study group 15 medication was 1% methylene blue/5% arginine/ 5% glycine.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1.
  • Each group was injected intratumorally, once every 3 days for a total of 3 times, and the volume of each injection was ⁇ 150 ⁇ l.
  • the animals were euthanized on the 10th day after the treatment, the tumor weight was measured after anatomy, and the tumor inhibition rate was calculated from the negative control group.
  • the tumor inhibition rate of the positive control group was 51%, and the results of the study group are shown in Table 10.
  • the amino acid nutrient is preferably selected from the following amino acids and contains one of the following amino acids
  • One or more amino acid derivatives arginine, glycine, cysteine, threonine, proline, lysine, leucine, alanine, serine, glutamic acid, more preferably selected From the following amino acids and amino acid derivatives containing one or more of the following amino acids: arginine, glycine, cysteine, lysine, alanine, serine, glutamic acid.
  • the successfully modeled nude mice bearing human cancer cells were randomly divided into a negative control group and 5 study groups (groups A, B, C, D, and E).
  • the corresponding negative control is physiological saline
  • the 5 study drugs are: 1% methylene blue/5% DHA/5% acetic acid, 1% methylene blue/20% arginine, 1% methylene blue/10 % Glycine/10% lysine, 1% methylene blue/30% glucose, 1% methylene blue/1% 5-fluorouracil.
  • the medicines are all aqueous solutions, which are prepared according to the preparation method of Example 1.
  • Each group was injected intratumorally, once every 3 days, a total of 3 times, each time 100-150 ⁇ l/mouse.
  • the animals were euthanized, the tumor weight was measured after anatomy, and the tumor inhibition rate was calculated from the respective negative control group.
  • the successfully modeled nude mice bearing human head and neck cancer cells (F ⁇ da) (the average tumor volume is 169mm 3 ) were randomly divided into a negative control group and 5 study groups (groups A, B, C, D, and E) ).
  • the tumor inhibition rates of groups A, B, C, D, and E were 76%, 82%, 74%, 88%, 70%, respectively, which all met the generally considered effective anti-tumor standards (tumor inhibition rate ⁇ 40%).
  • CNE1 human nasopharyngeal carcinoma cells
  • compositions of the present invention prepared in Example 1 for example, the composition in Table 2
  • similar results can be obtained in the application of the above-mentioned tumor treatments.
  • a topical pharmaceutical composition for the treatment of malignant solid tumors comprising a methylene blue dye, a local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable liquid carrier, wherein the synergistic drug It is selected from nutrients or/and conventional anti-tumor drugs, and in the topical pharmaceutical composition, the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35-2%, 0.5-2%, 0.5-1.5% or 0.5-1%, the concentration of the nutrient is greater than 2%, preferably 3%-40%, and the concentration of the conventional antitumor drug is greater than 20% or 30% of its saturated concentration, preferably The saturated concentration is 30%-100%, wherein the saturated concentration refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • the topical pharmaceutical composition comprises the methylene blue dye, the local synergistic drug of the methylene blue dye, and a pharmaceutically acceptable liquid carrier, wherein the topical drug
  • the concentration (w/v) of the methylene blue dye is ⁇ 2%, preferably 0.35-2%, 0.5-2%, 0.5-1.5% or 0.5-1%
  • the concentration of the nutrient is Greater than 2%, preferably 3%-40%
  • the concentration of the conventional anti-tumor drug is greater than 20% or 30% of its saturated concentration, preferably 30%-100% of its saturated concentration, wherein the saturated concentration is Refers to the saturated concentration of the conventional anti-tumor drug in the liquid carrier.
  • methylene blue dye is selected from methylene blue and its living dye analogs, preferably selected from the following compounds and their derivatives: methylene blue , Patent blue, isosulfur blue, neomethylene blue, more preferably selected from methylene blue and its derivatives.
  • composition or application according to any one of items 1-3, wherein the nutrient is one or more selected from the group consisting of amino acid nutrients, carbohydrate nutrients, lipid nutrients, and they are in the combination
  • concentration in the product is 2.5-50%, preferably 4-40%.
  • amino acid nutrient includes one or more of the following amino acid compounds with nutritional and health effects: amino acids, amino acid salts, oligopeptides and polypeptides; preferably selected from the following Group of amino acids or their salts or oligopeptides and polypeptides containing or consisting of the following amino acids: alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, Tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, ⁇ -alanine Acid, taurine, gamma aminobutyric acid (GABA), tea polyphenols (theanine), pumpkin seed amino acids (3-amino-3-carboxypyranoic acid), glutamine, citrulline, ornithine ; More preferably selected from the group of amino acids, amino acid salts, oligopeptides
  • amino acid nutrient is selected from amino acids or amino acid salts with nutritional and health effects, and the concentration of the amino acid or amino acid salt in the topical pharmaceutical composition (w/v ) Is ⁇ 2%, ⁇ 2.5, ⁇ 5%, ⁇ 7.5%, 10-25% or 18-25%, preferably 15%-25% or 20%-25%.
  • composition or application according to item 6 wherein the amino acid nutrient is selected from oligopeptides and polypeptides with nutritional and health effects, and the concentration of the oligopeptides and polypeptides in the topical pharmaceutical composition (w/v ) Is greater than ⁇ 5%, preferably 7.5-25%, more preferably 10%-25%.
  • concentration (w/v) is greater than ⁇ 5%, preferably 7.5%-25%, more preferably 10-25%.
  • oligopeptide is one or more selected from the group consisting of glycyl-L-tyrosine, glycylalanine, and glycylglycin , Lysine-glycine dipeptide, glutathione, carnosine ( ⁇ -alanine histidine copolymer), glutathione, collagen oligopeptide, casein hydrolyzed peptide, soybean oligopeptide, oligoarginine, Oligoglycine, oligolysine; the polypeptide is one or more selected from the following group: polyaspartic acid, polyglutamic acid, polylysine.
  • carbohydrate nutrient is selected from a carbohydrate compound containing one or more of the following sugar units: glucose, ribose, xylose, fructose, galactose, fucoid
  • the sugar is preferably one or more selected from the following: glucose, fructose, chitooligosaccharides, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, wood Oligosaccharides, fructooligosaccharides, mannose oligosaccharides, gluconic acid, sodium gluconate, xylitol, mannitol, maltitol, lactitol, more preferably one or more selected from the following: glucose, sodium gluconate, Chitooligosaccharides, glucosamine, lactulose, ribos
  • the lipid nutrient is one or more selected from the group consisting of fatty acids, fat milk and lipids, preferably one or more selected from the group consisting of vegetable oils , Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat emulsion, medium-chain fat emulsion, phospholipid, and its concentration in the pharmaceutical composition is ⁇ 4%, preferably 4%-25%.
  • the conventional anti-tumor drugs are one or more selected from the group consisting of uracil derivatives, cyclophosphamides, gemcitabine, epirubicin , Anti-tumor antibiotics, teniposide, metal platinum complexes, taxanes, preferably one or more selected from the following drugs and similar derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, table Rubicin, antitumor antibiotic, teniposide, metal platinum complex, paclitaxel.
  • the conventional anti-tumor drugs are one or more selected from the group consisting of uracil derivatives, cyclophosphamides, gemcitabine, epirubicin , Anti-tumor antibiotics, teniposide, metal platinum complexes, taxanes, preferably one or more selected from the following drugs and similar derivatives: 5-fluorouracil, cyclophosphamide, gemcitabine, table Rubicin, antitumor antibiotic, teniposide,
  • composition or application according to items 1-4 which optionally further comprises one or more of the following groups: analgesics, sustained-release carriers, and C1 optionally substituted by 1-3 hydroxyl groups as an acidulant -10 Aliphatic carboxylic acid.
  • analgesic is one or more selected from the group consisting of benzyl alcohol, procaine hydrochloride, chlorobutanol, and lidocaine hydrochloride, and the analgesic
  • concentration of the agent in the pharmaceutical composition is 0.1-4% by weight.
  • composition or application according to item 15 wherein the acidulant is one or more selected from the group consisting of acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid, lemon Acid, malic acid, tartaric acid, more preferably acetic acid.
  • the acidulant is one or more selected from the group consisting of acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, glycolic acid, lactic acid, lemon Acid, malic acid, tartaric acid, more preferably acetic acid.
  • the injection powder for injection includes a sterile dry powder and a solvent, and part or all of the amino acid nutrients and the ineffective absorption compound are contained in the sterile dry powder, and The liquid carrier is contained in the solvent, and the concentrations of the amino acid nutrients and the ineffective absorption compound are their concentrations in the sterile dry powder and the solvent mixture, respectively.
  • a topical pharmaceutical composition for the treatment of malignant solid tumors which comprises a dry powder obtained by lyophilizing or semi-lyophilizing part or all of the pharmaceutical composition according to one of items 1 and 4-18.
  • a method for preventing and treating malignant solid tumors which comprises administering the pharmaceutical composition according to one of items 1 and 4-21 to an individual in need thereof.
  • malignant solid tumors include breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, colon cancer, oral cancer , Esophageal cancer, stomach cancer, laryngeal cancer, testicular cancer, vagina cancer, uterine cancer, ovarian cancer.

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

Abstract

L'invention concerne une application d'une association d'un colorant bleu de méthylène en tant qu'ingrédient actif local et d'un médicament synergique local du colorant bleu de méthylène dans la préparation d'une composition pharmaceutique locale pour le traitement de tumeurs solides malignes, et la composition pharmaceutique locale ayant le colorant bleu de méthylène en tant qu'ingrédient actif local et le médicament synergique local du colorant bleu de méthylène pour traiter les tumeurs solides malignes.
PCT/CN2020/075765 2020-02-18 2020-02-18 Composition pharmaceutique contenant un colorant bleu de méthylène, un élément nutritif et/ou un médicament antitumoral classique, et son application WO2021163897A1 (fr)

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PCT/CN2021/076749 WO2021164706A1 (fr) 2020-02-18 2021-02-18 Composition pharmaceutique contenant un colorant bleu de méthylène et son utilisation

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