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WO2016086776A1 - Antifungal compound formulation containing chlorogenic acid and application thereof - Google Patents

Antifungal compound formulation containing chlorogenic acid and application thereof 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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Prior art keywords
chlorogenic acid
preparation
antifungal
injection
group
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PCT/CN2015/095246
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French (fr)
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/en

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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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Abstract

Disclosed is an antifungal compound formulation comprising chlorogenic acid and antifungal drugs with a ratio of 1-100:1-50. The antifungal compound formulation improves the efficacy of the antifungal drugs and reduces the toxic side effect thereof.

Description

一种包含绿原酸的抗真菌复方制剂及其应用Antifungal compound preparation containing chlorogenic acid and application thereof 技术领域Technical field
本发明涉及一种包含绿原酸的抗真菌复方制剂及其应用，同时涉及绿原酸和抗真菌药物的联合使用的应用，属于药物制剂领域。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.
背景技术Background technique
绿原酸，是由咖啡酸与奎尼酸生成的缩酚酸，是植物体在有氧呼吸过程中经莽草酸途径产生的一种苯丙素类化合物。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.
绿原酸具有广泛的生物活性，现代科学对绿原酸生物活性的研究已深入到食品、保健、医药和日用化工等多个领域。绿原酸是一种重要的生物活性物质，具有抗菌、抗病毒、增高白血球、保肝利胆、抗肿瘤、降血压、降血脂、清除自由基和兴奋中枢神经系统等作用。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.
目前市售的抗真菌感染的药物毒副作用比较大，这大大限制了临床的使用。临床应用的抗真菌药物在临床治疗用药时往往剂量较大，疗程较长，产生的不良反应较多，毒性较大，对泌尿系统、消化系统、神经系统、内分泌及生殖系统、血液系统、循环系统、皮肤及其他都有不同程度的毒副作用。例如两性霉素B最常见的不良反应为泌尿系统的不良反应，表现为尿中有红细胞、白细胞、蛋白和管型，血尿素氮和肌酐值升高，肌酐清除率降低；也可引起肾小管性酸中毒、肾钙质沉着、大量排出钾离子而致低血钾、肾原形尿崩症；并可出现恶心、呕吐、腹泻及胃肠道出血，肝细胞坏死及急性肝功能衰竭；静滴过程中或静滴后，可发生寒战、高热、头疼、恶心、呕吐、血压下降、眩晕等，如果静滴速度过快，还可出现心律失常及血压急剧上升或下降，并可出现血栓，形成血栓性静脉炎，甚至引起心室颤动或心脏骤停、心律紊乱等。Currently, commercially available anti-fungal 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. For example, the most common adverse reaction of 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.
正因为抗真菌药有上述多系统的不良反应，一方面促进了新抗真菌药的研制和开发；另一方面需要合理利用现有的药物，如联合用药，联合用药可降低了抗真菌类药物单药的剂量，从而降低其毒副作用。Because 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.
发明内容Summary of the invention
针对上述技术问题，本发明的目的在于提供一种包含绿原酸的抗真菌类药物的新复方制剂，该制剂在抗真菌治疗中能够提高抗真菌类药物单一组分抗真菌治疗效果，以及显著降低抗真菌类药物单一组分的毒副作用；以及绿原酸和抗真菌药物的联合使用，联合使用后，可以提高抗真菌类药物单药的疗效，并可降低其毒副作用。 In view of the above technical problems, 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.
本发明的上述目的是通过如下技术方案实现的：一种包含绿原酸的抗真菌复方制剂，包括：The above object of the present invention is achieved by the following technical solution: an antifungal compound preparation comprising chlorogenic acid, comprising:
a)绿原酸；a) chlorogenic acid;
b)抗真菌类药物；b) antifungal drugs;
其中所述绿原酸和抗真菌类药物的比例为1-100:1-50。Wherein the ratio of the chlorogenic acid to the antifungal drug is 1-100:1-50.
本发明的联合用药中，绿原酸是指天然提取获得或经化学合成获得的可允许用于临床研究的药物，其绿原酸在药物中的质量分数为10-100％；通过赋予药学可用的辅料制备成口服制剂或注射剂，其中口服制剂给药剂量为10-100mg/kg，注射剂给药剂量为2-15mg/kg。In the combination of the present invention, 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.
在本发明中，所述抗真菌类药物是指能抑制或杀灭真菌的药物，可以是多烯类抗生素类药物，也可以是合成类药物。其中多烯类抗生素类药物可以是多烯大环类抗生素、链状多烯类、核苷类或其他非烯类；具体而言，可以是两性霉素B、球红霉素及甲帕霉素。所述合成类药物具体而言，包括但不限于酮康唑、氟康唑、伊曲康唑、氟胞嘧啶、卡泊芬净、米卡芬净钠、伏立康唑药物当中的任意一种。In the present invention, 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. Specifically, the synthetic drug includes, but is not limited to, any one of ketoconazole, fluconazole, itraconazole, flucytosine, caspofungin, micafungin sodium, and voriconazole.
在本发明中，所述绿原酸和抗真菌类药物的比例优选1:10-50或者是1-10:1。在一个具体的实例中，所述绿原酸与抗真菌类药物的比例可以是5:1、5:2、2:1、1:1、1:2、1:15、3:10、3:20等。In the present invention, the ratio of the chlorogenic acid to the antifungal drug is preferably 1:10-50 or 1-10:1. In a specific example, 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.
在本发明中，所述复方制剂可以是口服剂，也可以是注射剂；具体而言，其剂型包括但不限于片剂、颗粒剂、丸剂、冲剂、胶囊剂、注射液或粉针剂。In the present invention, 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.
在本发明中，由绿原酸与酮康唑组成的复方制剂，口服制剂中其质量比为10:1至1:10，注射剂中其质量比为10:1至1:10。在本发明的一个具体实例中，绿原酸与酮康唑的比例为1:1或1:2。In the present invention, 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. In one embodiment of the invention, the ratio of chlorogenic acid to ketoconazole is 1:1 or 1:2.
在本发明中，由绿原酸与氟康唑组成的复方制剂，其口服制剂质量比为1:1至1:10，其注射剂质量比为1:5至1:50。在本发明的一个具体实例中，绿原酸与氟康唑的比例为1:1、1:2或3:20。In the present invention, 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. In a specific embodiment of the invention, the ratio of chlorogenic acid to fluconazole is 1:1, 1:2 or 3:20.
在本发明中，由绿原酸与伊曲康唑组成的复方制剂，其口服制剂质量比为10:1至1:10，其注射剂质量比为1:5至1:10。在本发明的一个具体实例中，绿原酸与伊曲康唑的比例为3:10或5:1。In the present invention, 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.
在本发明中，由绿原酸与氟胞嘧啶组成的复方制剂，其口服制剂质量比为5:1至1:20，其注射剂质量比为5：1至1:50。在本发明的一个具体实例中，绿原酸与氟胞嘧啶的 比例为2:1或1:15。In the present invention, 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. In a specific embodiment of the invention, chlorogenic acid and fluorocytosine The ratio is 2:1 or 1:15.
在本发明中，它由绿原酸与卡泊芬净组成的复方制剂，其口服制剂质量比为10:1至1:10，其注射剂质量比为5:1至1:5。在本发明的一个具体实例中，绿原酸与卡泊芬净的比例为1:2。In the present invention, it 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. In one embodiment of the invention, the ratio of chlorogenic acid to caspofungin is 1:2.
在本发明中，由绿原酸与米卡芬净钠组成的复方制剂，其口服制剂质量比为1:1至1:10，其注射剂质量比为1:1至1:10。在本发明的一个具体实例中，绿原酸与米卡芬净钠的比例为1:2。In the present invention, 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.
在本发明中，由绿原酸与伏立康唑组成的复方制剂，其口服制剂质量比为5:1至1:10，其注射剂质量比为1:1至1:10。在本发明的一个具体实例中，绿原酸与伏立康唑的比例为5:2或3:20。In the present invention, 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.
在本发明中，作为优选，复方制剂中配予药学可用的辅料，包括制备口服制剂的填充剂、黏合剂、润滑剂，包括制备注射剂的稀释剂、支架剂、抗氧化剂。In the present invention, preferably, 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.
进一步的，所述填充剂包括乳糖、淀粉、甘露醇、羟丙纤维素、糊精；所述黏合剂包括聚维酮、预交化淀粉、羟丙甲纤维素；所述润滑剂包括硬脂酸镁、滑石粉、微粉硅胶、聚乙二醇；所述稀释剂包括注射用水、生理盐水、葡萄糖注射液、甘油、吐温、植物油；所述支架剂包括甘露醇、乳糖、甘氨酸；所述抗氧化剂包括维生素C、L-半胱氨酸盐酸盐、焦亚硫酸钠、亚硫酸氢钠。Further, 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.
在本发明中，所述复方制剂的口服制剂，制备成每单位制剂含量含绿原酸10mg-500mg；复方制剂的注射剂，制备成每单位制剂含量含绿原酸10mg-50mg。In the present invention, 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.
本发明的另一目的是提供一种上述复方制剂在制备治疗真菌感染的药物中的应用。其中真菌感染包括念珠菌属、曲霉菌、双相真菌引起的真菌感染。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. Among them, fungal infections include fungal infections caused by Candida, Aspergillus, and biphasic fungi.
本发明还提供了绿原酸与抗真菌类药物的联合使用，能够显著降低抗真菌类药物一次性给药或长期持续给药所引起的毒副作用，特别地显著降低抗真菌类药物对内脏器官的损伤。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.
本发明的有益效果在于绿原酸和抗真菌类药物的联合用药，提高抗真菌类药物单药的疗效，并降低了其毒副作用；其次包含有绿原酸的抗真菌新的药物制剂，在抗真菌治疗中能够提高抗真菌类药物单一组分抗真菌治疗效果，以及显著降低抗真菌类药物单一组分的毒副作用。使其临床应用范围更广，疗效更好，故在临床上包含有绿原酸的抗真菌复方制剂及绿原酸和抗真菌类药物联合使用具有较高的医学应用价值。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.
具体实施例 Specific embodiment
实施例1处方一Example 1 prescription one
Figure PCTCN2015095246-appb-000001
Figure PCTCN2015095246-appb-000001
将绿原酸及酮康唑加入适量的填充剂后及黏合剂后，过筛混合，制粒，整粒，加入适量的润滑剂，压片。After adding chlorogenic acid and ketoconazole to an appropriate amount of filler and after the binder, sieving and mixing, granulating, granulating, adding an appropriate amount of lubricant, and pressing.
实施例2处方二Example 2 prescription 2
Figure PCTCN2015095246-appb-000002
Figure PCTCN2015095246-appb-000002
将绿原酸及酮康唑加入适量的填充剂后及黏合剂后，过筛混合，填装胶囊。After adding chlorogenic acid and ketoconazole to an appropriate amount of filler and after the binder, the mixture is sieved and filled, and the capsule is filled.
实施例3处方三Example 3 prescription three
Figure PCTCN2015095246-appb-000003
Figure PCTCN2015095246-appb-000003
将绿原酸及氟康唑加入适量的抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装。After adding chlorogenic acid and fluconazole to an appropriate amount of antioxidant, it is dissolved in an appropriate amount of diluent, filtered through an ultrafiltration membrane, and aseptically filled.
实施例4处方四Example 4 prescription four
Figure PCTCN2015095246-appb-000004
Figure PCTCN2015095246-appb-000004
Figure PCTCN2015095246-appb-000005
Figure PCTCN2015095246-appb-000005
将绿原酸及氟康唑加入适量的填充剂后及黏合剂后，过筛混合，制粒，整粒，加入适量的润滑剂，压片。After adding chlorogenic acid and fluconazole to an appropriate amount of filler and after the binder, sieving and mixing, granulating, granulating, adding an appropriate amount of lubricant, and pressing.
实施例5处方五Example 5 prescription five
Figure PCTCN2015095246-appb-000006
Figure PCTCN2015095246-appb-000006
将绿原酸及伊曲康唑加入适量的抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装。After adding chlorogenic acid and itraconazole to an appropriate amount of antioxidant, it is dissolved in an appropriate amount of diluent, filtered through an ultrafiltration membrane, and aseptically filled.
实施例6处方六Example 6 prescription six
Figure PCTCN2015095246-appb-000007
Figure PCTCN2015095246-appb-000007
将绿原酸及伊曲康唑加入适量的填充剂后及黏合剂后，过筛混合，填装胶囊。After adding chlorogenic acid and itraconazole to an appropriate amount of filler and the binder, the mixture is sieved and filled, and the capsule is filled.
实施例7处方四Example 7 prescription four
Figure PCTCN2015095246-appb-000008
Figure PCTCN2015095246-appb-000008
将绿原酸及氟胞嘧啶加入适量的填充剂后，混合，填装胶囊。After adding chlorogenic acid and flucytosine to an appropriate amount of filler, mix and fill the capsules.
实施例8处方八Example 8 prescription eight
Figure PCTCN2015095246-appb-000009
Figure PCTCN2015095246-appb-000009
Figure PCTCN2015095246-appb-000010
Figure PCTCN2015095246-appb-000010
将绿原酸及氟胞嘧啶加入适量的支架剂及抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装，冷冻干燥，轧盖。After adding chlorogenic acid and fluorocytosine to an appropriate amount of scaffold and antioxidant, it is dissolved in an appropriate amount of diluent, ultrafiltration membrane filtration, aseptic filling, freeze drying, and capping.
实施例9处方九Example 9 prescription nine
将绿原酸及卡泊芬净加入适量的抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装。After adding chlorogenic acid and caspofungin to an appropriate amount of antioxidant, it is dissolved in an appropriate amount of diluent, filtered through an ultrafiltration membrane, and aseptically filled.
实施例10处方十Example 10 prescription ten
Figure PCTCN2015095246-appb-000012
Figure PCTCN2015095246-appb-000012
将绿原酸及米卡芬净钠加入适量的抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装。After adding chlorogenic acid and micafungin sodium to an appropriate amount of antioxidant, it is dissolved in an appropriate amount of diluent, filtered through an ultrafiltration membrane, and aseptically filled.
实施例11处方11Example 11 prescription 11
Figure PCTCN2015095246-appb-000013
Figure PCTCN2015095246-appb-000013
将绿原酸及伏立康唑加入适量的支架剂及抗氧化剂后，溶解于适量稀释剂，超滤膜过滤，无菌灌装，冷冻干燥，轧盖。After adding chlorogenic acid and voriconazole to an appropriate amount of scaffold and antioxidant, it is dissolved in an appropriate amount of diluent, ultrafiltration membrane filtration, aseptic filling, freeze drying, and capping.
实施例12处方十二 Example 12 prescription twelve
Figure PCTCN2015095246-appb-000014
Figure PCTCN2015095246-appb-000014
将绿原酸及伏立康唑加入适量的填充剂后及黏合剂后，过筛混合，制粒，整粒，加入适量的润滑剂，压片。After adding chlorogenic acid and voriconazole to an appropriate amount of filler and after the binder, sieving and mixing, granulating, granulating, adding an appropriate amount of lubricant, and tableting.
实施例13毒性对比试验Example 13 toxicity comparison test
1、动物SD大鼠，雌雄各半，体重120～140g。1. Animal SD rats, male and female, weighing 120-140g.
2、给药试验取健康SD大鼠，雌雄各半。按体重随机分组，分别为复方制剂组、单一组分阳性对照组、阴性组对照组，每组10只。一次性口服或静脉注射给药，给药后连续观察14天，观察动物毒性症状和死亡情况。第7、14天称存活动物体重。2. 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.
、结果,result
给药当天，单一组分阳性对照组大鼠体征出现明显的异常，两天后症状有所减缓，但没有完全消除，部分异常体征症状持续到试验结束，试验过程有死亡现象；复方制剂组少部分大鼠体征出现轻微的异常，第二天后症状基本完全消除，但饮食状况恢复缓慢，试验过程无死亡案例；阴性组对照组无明显症状和死亡案例。On the day of administration, 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.
至试验结束时，单一组分阳性对照组大鼠，体重增加不明显；复方制剂组，体重有所增加，但不及于阴性对照组。具体试验数据见表1和表2。By the end of the experiment, the weight of the single-component positive control group was not significantly increased. In the compound preparation group, the body weight increased, but it was not as good as the negative control group. Specific test data are shown in Tables 1 and 2.
实施例14药效对比试验Example 14 comparison test of efficacy
1、动物日本大耳兔，雌性，体重200-240g。1. Animal Japanese big eared rabbit, female, weighing 200-240g.
2、菌种烟曲霉菌，用生理盐水配制成1×107cfu/ml的烟曲霉孢子混悬液。2. The strain Aspergillus fumigatus is formulated into a suspension solution of Aspergillus fumigatus spores of 1×10 7 cfu/ml with physiological saline.
3、给药试验将日本大耳兔按体重随机分组，每组10只，分别为复合制剂组、单一组分阳性对照组、阴性对照组；每只肌注地塞米松0.375mg/kg，连续给3天；第4天耳缘静脉注射1×107cfu/ml的烟曲霉孢子混悬液1ml，在给予孢子后隔天给同量地塞米松。3. Administration test Japanese rabbits were randomly divided into groups according to their body weight. Each group consisted of 10 groups, which were compound preparation group, single component positive control group and negative control group. Each intramuscular injection of dexamethasone 0.375 mg/kg was continuous. For 3 days; on day 4, 1 ml of a 1×10 7 cfu/ml Aspergillus fumigatus spore suspension was injected intravenously, and the same amount of dexamethasone was given the next day after spore administration.
在接种后24h开始耳缘静脉给药或口服给药，每天给药一次，连续给药5天。在试验期间，每天肌注青霉素(15万U/kg)和庆霉素(5.6万/只)以预防细菌感染，直到试验结束。The ear vein was administered intravenously or orally at 24 hours after inoculation, once a day for 5 days. During the trial, penicillin (150,000 U/kg) and gentamicin (56,000/day) were intramuscularly injected daily to prevent bacterial infection until the end of the trial.
在治疗结束后72h处死动物，无菌摘取部分肝、脾、肾、肺组织，称重，加入1ml 无菌PBS溶液，组织匀浆器匀浆，匀浆液稀释后平铺于沙堡氯霉素琼脂糖平板培养基，26℃培养4天计数菌落。根据所计菌落数换算得每器官的CFU/g。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.
4、试验结果4. Test results
通过给药5天后，各试验组均有明显的抗菌效果，尤其复方制剂组，具有显著差异性。具体试验数据见表3-表8。After 5 days of administration, 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.
实施例15联合用药药效试验Example 15 Combination drug efficacy test
1、动物日本大耳兔，雌性，体重200-240g。1. Animal Japanese big eared rabbit, female, weighing 200-240g.
2、菌种烟曲霉菌，用生理盐水配制成1×107cfu/ml的烟曲霉孢子混悬液。2. The strain Aspergillus fumigatus is formulated into a suspension solution of Aspergillus fumigatus spores of 1×10 7 cfu/ml with physiological saline.
3、材料绿原酸，市购，纯度分别为42.38％及99.86％两个样品；两性霉素B，市购，生产厂家华北制药集团新药研究开发有限公司。3, the material chlorogenic acid, commercially available, purity of 42.38% and 99.86% respectively; amphotericin B, commercially available, manufacturer Huabei Pharmaceutical Group New Drug Research and Development Co., Ltd.
4、给药试验将日本大耳兔按体重随机分组，每组10只，分别为联合用药组、阳性对照组、阴性对照组；每只肌注地塞米松0.375mg/kg，连续给3天；第4天耳缘静脉注射1×107cfu/ml的烟曲霉孢子混悬液1ml，在给予孢子后隔天给同量地塞米松。4. Administration test Japanese rabbits were randomly divided into groups according to their body weight, 10 rats in each group, which were combined drug group, positive control group and negative control group; each intramuscular injection of dexamethasone 0.375 mg/kg for 3 consecutive days. On day 4, 1 ml of 1×10 7 cfu/ml of Aspergillus fumigatus spore suspension was injected intravenously, and the same amount of dexamethasone was given the next day after spore administration.
在接种后24h开始耳缘静脉给药或口服给药，每天给药一次，连续给药5天；联合用药组先耳缘静脉给两性霉素B，给药剂量为2mg/kg，给药结束后24h内再耳缘静脉滴注绿原酸或灌胃给绿原酸。在试验期间，每天肌注青霉素(15万U/kg)和庆霉素(5.6万/只)以预防细菌感染，直到试验结束。At the end of 24 hours after inoculation, 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. Within the first 24 hours, the rim acid was instilled into the ear vein or chlorogenic acid was administered by gavage. During the trial, penicillin (150,000 U/kg) and gentamicin (56,000/day) were intramuscularly injected daily to prevent bacterial infection until the end of the trial.
在治疗结束后72h处死动物，无菌摘取部分肝、脾、肾、肺组织，称重，加入1ml无菌PBS溶液，组织匀浆器匀浆，匀浆液稀释后平铺于沙堡氯霉素琼脂糖平板培养基，26℃培养4天计数菌落。根据所计菌落数换算得每器官的CFU/g。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.
5、试验结果5, test results
试验结果表明，绿原酸与抗真菌类药物联合使用能够显著地提高抗真菌类药物单药的疗效，说明了绿原酸在联合用药中具有协同的作用；具体数据见表十一。The results showed that the combination of chlorogenic acid and antifungal drugs can significantly improve the efficacy of antifungal drugs alone, indicating that chlorogenic acid has a synergistic effect in combination therapy; the specific data are shown in Table 11.
实施例16联合用药毒性对比试验Example 16 Contrast test of combined drug toxicity
1、动物家兔，雄性，体重2.0±0.2kg；1. Animal rabbit, male, weighing 2.0±0.2kg;
2、材料绿原酸，市购，纯度99.86％；两性霉素B，市购，生产厂家华北制药集团新药研究开发有限公司。2, material chlorogenic acid, commercially available, purity 99.86%; amphotericin B, commercially available, manufacturer Huabei Pharmaceutical Group New Drug Research and Development Co., Ltd.
3、试验方法将家兔按体重随机分组，每组5只，分别为绿原酸与两性霉素B联合用药组、两性霉素B对照组；联合用药组先由耳缘静脉给两性霉素B，给药剂量为4mg/kg，给药结束后24h内再以2mg/kg(以绿原酸计)剂量耳缘静脉滴注绿原酸；对照组同联合用 药组的两性霉素B给药方式给药；每天一次，连续给药7天。在试验期间，分别于给药前、第一次给药后第二次给药前及最后一次给药24h后从家兔股静脉采血，检测ALT、AST、T-BiL及BUN、Cr。3. 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.
试验结果test results
试验结果表明，抗真菌类药物阳性组对机体内脏器官有明显的损伤，联合用药组对机体内脏器官无明显的损伤；联合用药组与抗真菌类药物阳性对照组相比具有显著差异性，说明绿原酸与抗真菌类药物联合使用可显著缓解抗真菌类药物对机体内脏器官的损伤；具体数据见表十二。 The results showed that the antifungal drug positive group had obvious damage to the internal organs of the body, and the combined drug group had no obvious damage to the internal organs of the body; the combination group had significant difference compared with the antifungal drug positive control group, indicating The combination of chlorogenic acid and antifungal drugs can significantly alleviate the damage of antifungal drugs to the internal organs of the body; the specific data are shown in Table 12.
Figure PCTCN2015095246-appb-000015
Figure PCTCN2015095246-appb-000015
Figure PCTCN2015095246-appb-000016
Figure PCTCN2015095246-appb-000016
Figure PCTCN2015095246-appb-000017
Figure PCTCN2015095246-appb-000017
Figure PCTCN2015095246-appb-000018
Figure PCTCN2015095246-appb-000018
Figure PCTCN2015095246-appb-000019
Figure PCTCN2015095246-appb-000019
Figure PCTCN2015095246-appb-000020
Figure PCTCN2015095246-appb-000020
表十一联合用药药效试验结果(lgcfu±s)Table 11 results of the combined drug efficacy test (lgcfu ± s)
Figure PCTCN2015095246-appb-000021
Figure PCTCN2015095246-appb-000021
各药物组与阴性组比较*p＜0.05，**p＜0.01。Each drug group was compared with the negative group *p<0.05, **p<0.01.
表十二联合用药药毒性对比试验结果Table 12 Comparison of toxicity test results of combined drug use
Figure PCTCN2015095246-appb-000022
Figure PCTCN2015095246-appb-000022
给药后与给药前比较*：p＜0.05；**：p＜0.01；联合用药组与对照组比较△：p＜0.05；△△：p＜0.01。 After administration, it was compared with before administration*: p<0.05; **: p<0.01; the combination group was compared with the control group △: p<0.05; △△: p<0.01.

Claims (10)

  1. 一种包含绿原酸的抗真菌复方制剂，包括：An antifungal combination comprising chlorogenic acid, comprising:
    a)绿原酸；a) chlorogenic acid;
    b)抗真菌类药物；b) antifungal drugs;
    其中所述绿原酸和抗真菌类药物的比例为1-100:1-50。Wherein the ratio of the chlorogenic acid to the antifungal drug is 1-100:1-50.
  2. 如权利要求1所述的复方制剂，其中所述绿原酸在制剂中的质量分数为10-100％；所述绿原酸在口服制剂中给药剂量为10-100mg/kg，在注射剂中给药剂量为2-15mg/kg。The combination preparation according to claim 1, wherein the chlorogenic acid has a mass fraction of 10 to 100% in the preparation; and the chlorogenic acid is administered in an oral preparation at a dose of 10 to 100 mg/kg in an injection. The dose is 2-15 mg/kg.
  3. 如权利要求1或2所述的复方制剂，所述抗真菌类药物为多烯类抗生素类药物或合成类药物。The compound preparation according to claim 1 or 2, wherein the antifungal drug is a polyene antibiotic or a synthetic drug.
  4. 如权利要求3所述的复方制剂，所述多烯类抗生素类药物选自两性霉素B、球红霉素及甲帕霉素中的一种或几种；所述合成类药物选自酮康唑、氟康唑、伊曲康唑、氟胞嘧啶、卡泊芬净、米卡芬净钠、伏立康唑药物中的一种或几种。The compound preparation according to claim 3, wherein the polyene antibiotic is selected from one or more of amphotericin B, erythromycin, and mazamic acid; and the synthetic drug is selected from the group consisting of ketones One or more of conazole, fluconazole, itraconazole, flucytosine, caspofungin, micafungin sodium, voriconazole drugs.
  5. 如权利要求1-4任一项所述的复方制剂，所述绿原酸和抗真菌类药物的比例为1:10-50或1-10:1；优选为5:1、5:2、2:1、1:1、1:2、1:15、3:10或3:20。The compound preparation according to any one of claims 1 to 4, wherein the ratio of the chlorogenic acid to the antifungal drug is 1:10-50 or 1-10:1; preferably 5:1, 5:2 2:1, 1:1, 1:2, 1:15, 3:10 or 3:20.
  6. 如权利要求1-5任一项所述的复方制剂，所述复方制剂为口服剂或注射剂；优选为片剂、颗粒剂、丸剂、冲剂、胶囊剂、注射液或粉针剂。The compound preparation according to any one of claims 1 to 5, which is an oral preparation or an injection; preferably a tablet, granule, pill, granule, capsule, injection or powder injection.
  7. 如权利要求1-6任一项所述的复方制剂，所述复方制剂还包括填充剂、黏合剂、润滑剂、稀释剂、支架剂、抗氧化剂；优选所述填充剂选自乳糖、淀粉、甘露醇、羟丙纤维素、糊精中的一种或几种；所述黏合剂选自聚维酮、预交化淀粉、羟丙甲纤维素中的一种或几种；所述润滑剂选自硬脂酸镁、滑石粉、微粉硅胶、聚乙二醇中的一种或几种；所述稀释剂选自注射用水、生理盐水、葡萄糖注射液、甘油、吐温、植物油中的一种或几种；所述支架剂选自甘露醇、乳糖、甘氨酸中的一种或几种；所述抗氧化剂选自维生素C、L-半胱氨酸盐酸盐、焦亚硫酸钠、亚硫酸氢钠中的一种或几种。The compound preparation according to any one of claims 1 to 6, which further comprises a filler, a binder, a lubricant, a diluent, a stent, an antioxidant; preferably the filler is selected from the group consisting of lactose, starch, One or more of mannitol, hydroxypropyl cellulose, dextrin; the binder is selected from one or more of povidone, pre-treated starch, hypromellose; the lubricant One or more selected from the group consisting of magnesium stearate, talc, micro-silica gel, and polyethylene glycol; the diluent is selected from the group consisting of water for injection, physiological saline, glucose injection, glycerin, Tween, and vegetable oil. Or one or more; the scaffolding agent is selected from one or more of mannitol, lactose, glycine; the antioxidant is selected from the group consisting of vitamin C, L-cysteine hydrochloride, sodium metabisulfite, hydrogen sulfite One or several of sodium.
  8. 如权利要求1-7任一项所述的复方制剂，所述复方制剂的口服制剂中每单位制剂含绿原酸10mg-500mg；复方制剂的注射剂中每单位制剂含绿原酸10mg-50mg。The compound preparation according to any one of claims 1 to 7, wherein the oral preparation of the combination preparation contains 10 mg to 500 mg of chlorogenic acid per unit preparation; and the injection of the compound preparation contains 10 mg to 50 mg of chlorogenic acid per unit preparation.
  9. 如权利要求1-8任一项所述复方制剂在制备治疗真菌感染的药物中的应用；优选所述真菌感染包括念珠菌属、曲霉菌、双相真菌引起的真菌感染。Use of a combination according to any one of claims 1-8 for the preparation of a medicament for the treatment of fungal infections; preferably the fungal infection comprises a fungal infection caused by Candida, Aspergillus, and biphasic fungi.
  10. 如权利要求1-9任一项所述复方制剂在制备降低抗真菌类药物一次性给药或长期持续给药所引起的毒副作用的药物中的应用；优选为在制备降低抗真菌类药物对内脏器官的损伤的药物中的应用。 The use of the compound preparation according to any one of claims 1 to 9 for the preparation of a medicament for reducing toxic side effects caused by one-time administration or long-term continuous administration of an antifungal drug; preferably in the preparation of a reduced antifungal drug pair Application of drugs for damage to internal organs.
PCT/CN2015/095246 2014-12-03 2015-11-23 Antifungal compound formulation containing chlorogenic acid and application thereof WO2016086776A1 (en)

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WO2012048119A2 (en) * 2010-10-06 2012-04-12 The Board Of Trustees Of The University Of Arkansas Anti-biofilm compositions and methods for using
CN103690543A (en) * 2013-12-24 2014-04-02 广西医科大学 Composition and method for killing aspergillus fumigatus
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