WO2016086776A1 - Formulation de composé antifongique contenant de l'acide chlorogénique et son application - Google Patents

Formulation de composé antifongique contenant de l'acide chlorogénique et son application Download PDF

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Publication number
WO2016086776A1
WO2016086776A1 PCT/CN2015/095246 CN2015095246W WO2016086776A1 WO 2016086776 A1 WO2016086776 A1 WO 2016086776A1 CN 2015095246 W CN2015095246 W CN 2015095246W WO 2016086776 A1 WO2016086776 A1 WO 2016086776A1
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WO
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Prior art keywords
chlorogenic acid
preparation
antifungal
injection
group
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PCT/CN2015/095246
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English (en)
Chinese (zh)
Inventor
张洁
黄望
朱丽娜
张亮
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四川九章生物科技有限公司
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Publication of WO2016086776A1 publication Critical patent/WO2016086776A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the invention relates to an antifungal compound preparation comprising chlorogenic acid and application thereof, and relates to the application of the combined use of chlorogenic acid and antifungal medicine, and belongs to the field of pharmaceutical preparations.
  • Chlorogenic acid a depsipeptide produced from caffeic acid and quinic acid, is a phenylpropanoid compound produced by the plant in the aerobic respiration process by the shikimic acid pathway.
  • Chlorogenic acid has a wide range of biological activities, and modern scientific research on the biological activity of chlorogenic acid has penetrated into many fields such as food, health care, medicine and daily chemical industry. Chlorogenic acid is an important biologically active substance with antibacterial, antiviral, white blood cells, liver and gallbladder, anti-tumor, blood pressure lowering, blood lipid lowering, free radical scavenging and excitatory central nervous system.
  • antifungal infection drugs have relatively large toxic side effects, which greatly limits clinical use.
  • the clinical application of antifungal drugs often has a larger dose in the clinical treatment, longer treatment period, more adverse reactions, more toxicity, urinary system, digestive system, nervous system, endocrine and reproductive system, blood system, circulation
  • the system, skin and others have varying degrees of toxic side effects.
  • amphotericin B is the adverse reactions of the urinary system, which is characterized by red blood cells, white blood cells, proteins and casts in the urine, elevated blood urea nitrogen and creatinine, and reduced creatinine clearance; Acidosis, renal calcinosis, massive discharge of potassium ions, hypokalemia, nephrogenic diabetes insipidus; nausea, vomiting, diarrhea and gastrointestinal bleeding, hepatocyte necrosis and acute liver failure; In the process or after intravenous drip, chills, high fever, headache, nausea, vomiting, blood pressure drop, dizziness, etc. may occur. If the intravenous drip rate is too fast, arrhythmia and blood pressure may rise or fall sharply, and thrombosis may occur. Thrombophlebitis, even caused by ventricular fibrillation or cardiac arrest, heart rhythm disorders.
  • antifungal drugs have the above-mentioned multi-system adverse reactions, on the one hand, the development and development of new antifungal drugs are promoted; on the other hand, it is necessary to make rational use of existing drugs, such as combination drugs, and the combination drugs can reduce antifungal drugs. The dose of a single drug, thereby reducing its toxic side effects.
  • an object of the present invention is to provide a novel compound preparation of an antifungal drug comprising chlorogenic acid, which can improve the antifungal treatment effect of an antifungal drug single component in antifungal treatment, and is remarkable Reduce the toxic side effects of the single component of the antifungal drug; and the combined use of chlorogenic acid and antifungal drugs, when combined, can improve the efficacy of the antifungal drug alone, and reduce its side effects.
  • an antifungal compound preparation comprising chlorogenic acid, comprising:
  • ratio of the chlorogenic acid to the antifungal drug is 1-100:1-50.
  • chlorogenic acid refers to a drug which is obtained by natural extraction or obtained by chemical synthesis and which can be used for clinical research, and the mass fraction of chlorogenic acid in the drug is 10-100%;
  • the excipient is prepared into an oral preparation or an injection, wherein the oral preparation is administered at a dose of 10 to 100 mg/kg, and the injection is administered at a dose of 2 to 15 mg/kg.
  • the antifungal drug refers to a drug capable of inhibiting or killing fungi, and may be a polyene antibiotic or a synthetic drug.
  • the polyene antibiotics may be polyene macrocyclic antibiotics, chain polyenes, nucleosides or other non-olefins; specifically, amphotericin B, erythromycin and methicillin Prime.
  • the synthetic drug includes, but is not limited to, any one of ketoconazole, fluconazole, itraconazole, flucytosine, caspofungin, micafungin sodium, and voriconazole.
  • the ratio of the chlorogenic acid to the antifungal drug is preferably 1:10-50 or 1-10:1.
  • the ratio of the chlorogenic acid to the antifungal drug may be 5:1, 5:2, 2:1, 1:1, 1:2, 1:15, 3:10, 3 :20 and so on.
  • the combination preparation may be an oral preparation or an injection; specifically, the dosage form includes, but is not limited to, a tablet, a granule, a pill, a granule, a capsule, an injection or a powder injection.
  • the compound preparation consisting of chlorogenic acid and ketoconazole has a mass ratio of 10:1 to 1:10 in the oral preparation and a mass ratio of 10:1 to 1:10 in the injection.
  • the ratio of chlorogenic acid to ketoconazole is 1:1 or 1:2.
  • the compound preparation consisting of chlorogenic acid and fluconazole has an oral preparation mass ratio of 1:1 to 1:10 and an injection mass ratio of 1:5 to 1:50.
  • the ratio of chlorogenic acid to fluconazole is 1:1, 1:2 or 3:20.
  • the compound preparation consisting of chlorogenic acid and itraconazole has an oral preparation mass ratio of 10:1 to 1:10 and an injection mass ratio of 1:5 to 1:10. In one embodiment of the invention, the ratio of chlorogenic acid to itraconazole is 3:10 or 5:1.
  • the compound preparation consisting of chlorogenic acid and flucytosine has an oral preparation mass ratio of 5:1 to 1:20 and an injection mass ratio of 5:1 to 1:50.
  • chlorogenic acid and fluorocytosine The ratio is 2:1 or 1:15.
  • the present invention is a combination preparation of chlorogenic acid and caspofungin having an oral preparation mass ratio of 10:1 to 1:10 and an injection mass ratio of 5:1 to 1:5.
  • the ratio of chlorogenic acid to caspofungin is 1:2.
  • the compound preparation consisting of chlorogenic acid and micafungin sodium has an oral preparation mass ratio of 1:1 to 1:10 and an injection mass ratio of 1:1 to 1:10. In one embodiment of the invention, the ratio of chlorogenic acid to micafungin sodium is 1:2.
  • the compound preparation consisting of chlorogenic acid and voriconazole has an oral preparation mass ratio of 5:1 to 1:10 and an injection mass ratio of 1:1 to 1:10. In one embodiment of the invention, the ratio of chlorogenic acid to voriconazole is 5:2 or 3:20.
  • a pharmaceutically acceptable excipient is formulated in the compound preparation, including a filler, a binder, a lubricant for preparing an oral preparation, a diluent for preparing an injection, a stent, and an antioxidant.
  • the filler comprises lactose, starch, mannitol, hydroxypropylcellulose, dextrin;
  • the binder comprises povidone, pre-treated starch, hypromellose;
  • the lubricant comprises stearin Magnesium silicate, talc powder, micro-powder silica gel, polyethylene glycol;
  • the diluent comprises water for injection, physiological saline, glucose injection, glycerin, Tween, vegetable oil;
  • the scaffold comprises mannitol, lactose, glycine;
  • Antioxidants include vitamin C, L-cysteine hydrochloride, sodium metabisulfite, sodium bisulfite.
  • the oral preparation of the compound preparation is prepared to contain 10 mg to 500 mg of chlorogenic acid per unit preparation; and the injection preparation of the compound preparation is prepared to contain 10 mg to 50 mg of chlorogenic acid per unit preparation.
  • Another object of the present invention is to provide a use of the above-mentioned combination preparation for the preparation of a medicament for treating a fungal infection.
  • fungal infections include fungal infections caused by Candida, Aspergillus, and biphasic fungi.
  • the invention also provides a combination of chlorogenic acid and an antifungal drug, which can significantly reduce the side effects caused by the single-dose or long-term continuous administration of the antifungal drugs, in particular, significantly reduce the anti-fungal drugs to the internal organs. Damage.
  • the invention has the beneficial effects of combining the chlorogenic acid and the antifungal drug, improving the curative effect of the antifungal drug single drug and reducing the toxic and side effects thereof; secondly, the antifungal new pharmaceutical preparation containing chlorogenic acid,
  • the antifungal treatment can improve the antifungal treatment effect of the single component of the antifungal drug, and significantly reduce the side effects of the single component of the antifungal drug.
  • the clinical application range is wider and the curative effect is better. Therefore, the antifungal compound preparation containing chlorogenic acid and the combination of chlorogenic acid and antifungal medicine have high medical application value.
  • Example 8 prescription eight
  • Example 10 prescription ten
  • Example 12 prescription twelve
  • Administration test Take healthy SD rats, male and female. They were randomly divided into groups according to body weight, which were compound preparation group, single component positive control group and negative group control group, with 10 rats in each group. The drug was administered orally or intravenously, and was observed continuously for 14 days after administration to observe the toxicity symptoms and death of the animal. The animals were weighed on days 7 and 14.
  • the signs of the single-component positive control group showed obvious abnormalities. After two days, the symptoms were slowed down, but not completely eliminated. Some abnormal signs continued to the end of the test, and there was death during the test. The compound preparation group had a small part. There was a slight abnormality in the signs of the rats. After the second day, the symptoms were completely eliminated, but the diet recovered slowly. There were no deaths during the test. There were no obvious symptoms and deaths in the negative control group.
  • the strain Aspergillus fumigatus is formulated into a suspension solution of Aspergillus fumigatus spores of 1 ⁇ 10 7 cfu/ml with physiological saline.
  • the ear vein was administered intravenously or orally at 24 hours after inoculation, once a day for 5 days.
  • penicillin (150,000 U/kg) and gentamicin (56,000/day) were intramuscularly injected daily to prevent bacterial infection until the end of the trial.
  • the animals were sacrificed 72 h after the end of treatment, and some liver, spleen, kidney and lung tissues were aseptically removed, weighed, and 1 ml was added. Sterile PBS solution, homogenate homogenate, diluted with homogenate, plated on sandcastle chloramphenicol agarose plate medium, and cultured at 26 ° C for 4 days to count colonies. The CFU/g per organ was converted according to the number of colonies counted.
  • each test group had obvious antibacterial effects, especially in the combination preparation group, which was significantly different.
  • the specific test data are shown in Table 3 - Table 8.
  • the strain Aspergillus fumigatus is formulated into a suspension solution of Aspergillus fumigatus spores of 1 ⁇ 10 7 cfu/ml with physiological saline.
  • the ear vein was administered intravenously or orally, once a day for 5 days, and the combined group was given amphotericin B at a dose of 2 mg/kg.
  • the rim acid was instilled into the ear vein or chlorogenic acid was administered by gavage.
  • penicillin (150,000 U/kg) and gentamicin (56,000/day) were intramuscularly injected daily to prevent bacterial infection until the end of the trial.
  • the animals were sacrificed 72 h after the end of treatment, and some liver, spleen, kidney and lung tissues were aseptically removed, weighed, 1 ml of sterile PBS solution was added, and the homogenate was homogenized. The homogenate was diluted and spread on the sandcastle. The agarose plate medium was cultured at 26 ° C for 4 days to count colonies. The CFU/g per organ was converted according to the number of colonies counted.
  • Test method Rabbits were randomly divided into groups according to their body weight. Each group consisted of chlorogenic acid and amphotericin B combined with amphotericin B control group. The combined drug group first gave amphotericin from the ear vein. B, the dose is 4mg/kg, and the chlorogenic acid is infused into the ear vein at a dose of 2mg/kg (in terms of chlorogenic acid) within 24 hours after the end of the administration; The drug group was administered by amphotericin B administration; once a day, continuous administration for 7 days. During the test, blood was collected from the femoral vein of the rabbit before administration, before the second administration, and after 24 hours after the first administration, and ALT, AST, T-BiL, and BUN and Cr were detected.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une formulation de composé antifongique comprenant de l'acide chlorogénique et des médicaments antifongiques suivant un rapport de 1-100:1-50. La formulation de composé antifongique améliore l'efficacité des médicaments antifongiques et réduit l'effet secondaire toxique de ceux-ci.
PCT/CN2015/095246 2014-12-03 2015-11-23 Formulation de composé antifongique contenant de l'acide chlorogénique et son application WO2016086776A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410723025.4 2014-12-03
CN201410723025.4A CN104523693A (zh) 2014-12-03 2014-12-03 一种包含绿原酸的抗真菌复方制剂及其应用

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WO2016086776A1 true WO2016086776A1 (fr) 2016-06-09

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104523693A (zh) * 2014-12-03 2015-04-22 四川九章生物科技有限公司 一种包含绿原酸的抗真菌复方制剂及其应用
CN106692990A (zh) * 2017-01-13 2017-05-24 广东省实验动物监测所 一种抗真菌增效药物体内筛选方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048119A2 (fr) * 2010-10-06 2012-04-12 The Board Of Trustees Of The University Of Arkansas Compositions anti-biofilm et procédés d'utilisation
CN103690543A (zh) * 2013-12-24 2014-04-02 广西医科大学 杀死烟曲霉菌的组合物及方法
CN104523693A (zh) * 2014-12-03 2015-04-22 四川九章生物科技有限公司 一种包含绿原酸的抗真菌复方制剂及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048119A2 (fr) * 2010-10-06 2012-04-12 The Board Of Trustees Of The University Of Arkansas Compositions anti-biofilm et procédés d'utilisation
CN103690543A (zh) * 2013-12-24 2014-04-02 广西医科大学 杀死烟曲霉菌的组合物及方法
CN104523693A (zh) * 2014-12-03 2015-04-22 四川九章生物科技有限公司 一种包含绿原酸的抗真菌复方制剂及其应用

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