WO2022199050A1 - Utilisation d'ulinastatine dans la préparation d'un médicament pour la prévention et le traitement de la covid-19 aiguë - Google Patents
Utilisation d'ulinastatine dans la préparation d'un médicament pour la prévention et le traitement de la covid-19 aiguë Download PDFInfo
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- WO2022199050A1 WO2022199050A1 PCT/CN2021/130409 CN2021130409W WO2022199050A1 WO 2022199050 A1 WO2022199050 A1 WO 2022199050A1 CN 2021130409 W CN2021130409 W CN 2021130409W WO 2022199050 A1 WO2022199050 A1 WO 2022199050A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ulinastatin
- polysaccharide
- injection
- preparation
- medicine
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 43
- 229950008558 ulinastatin Drugs 0.000 title claims abstract description 37
- 108010088854 urinastatin Proteins 0.000 title claims abstract description 37
- ODVKSTFPQDVPJZ-UHFFFAOYSA-N urinastatin Chemical compound C1C=CCCC11COC(C=2OC=CC=2)OC1 ODVKSTFPQDVPJZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229940079593 drug Drugs 0.000 title abstract description 17
- 208000025721 COVID-19 Diseases 0.000 title abstract 2
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 37
- 239000005017 polysaccharide Substances 0.000 claims abstract description 37
- -1 carboxymethyl schizophyllan Chemical compound 0.000 claims abstract description 29
- 229920002305 Schizophyllan Polymers 0.000 claims abstract description 15
- 241000711573 Coronaviridae Species 0.000 claims description 29
- 206010035664 Pneumonia Diseases 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 241001678559 COVID-19 virus Species 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
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- 150000004676 glycans Chemical class 0.000 abstract description 9
- 241000037831 Polygonatum sibiricum Species 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 10
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
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- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
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- 229940044627 gamma-interferon Drugs 0.000 description 1
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- 229940076144 interleukin-10 Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the invention belongs to the technical field of medicine, and in particular relates to the use of ulinastatin in the preparation of a medicine for preventing and treating severe novel coronavirus pneumonia.
- Coronaviruses are a large class of viruses that exist widely in nature. Before 2019, a total of 6 coronaviruses that can infect humans were found, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS. -CoV, and the coronavirus that caused the outbreak was named the new coronavirus (SARS-CoV-2) after isolation and confirmation. According to existing studies, the common symptoms of patients with novel coronavirus infection are fever, cough and myalgia or fatigue; all patients suffered from pneumonia and abnormal chest CT examination findings; complications include acute respiratory distress syndrome , acute cardiac injury and secondary infection.
- the inflammatory factor storm of the new coronavirus will cause damage to multiple organs, mainly the lungs, and sepsis is a systemic inflammatory response syndrome caused by infection, which is one of the most prevalent critical illnesses in the world.
- Leukocyte and platelet recruitment, intravascular coagulation, endothelial injury, surfactant loss, and oxidative stress are all mechanisms of severe lung injury in sepsis. It is aimed at the injury caused by sepsis-like injury in the critical period of patients in the late stage of new coronavirus infection.
- the invention aims to provide the use of ulinastatin in the preparation of medicines for preventing and treating severe novel coronavirus pneumonia.
- Tests have shown that ulinastatin can play a therapeutic effect on the new coronavirus pneumonia, and the present invention further explores whether ulinastatin can play a therapeutic role on the complication sepsis caused by the new coronavirus pneumonia.
- Listatin can have a certain therapeutic effect on the complications of sepsis caused by the new coronavirus pneumonia, and when it is combined with Polygonatum polysaccharide, the therapeutic effect achieved is better than that of a single drug, and it has a significant effect. progress.
- ulinastatin in preparing a medicine for preventing and treating severe novel coronavirus pneumonia, the single administration dosage of ulinastatin is 300,000 to 10,000,000 units.
- the single dosage of ulinastatin is 1 to 9 million units.
- novel coronavirus pneumonia is a disease caused by the novel coronavirus SARS-CoV-2.
- the medicine includes ulinastatin and polysaccharide polysaccharide.
- the medicine includes ulinastatin, polysaccharide polysaccharide and carboxymethyl schizophyllan.
- the medicine is freeze-dried powder injection, injection, spray preparation or atomized preparation.
- the inventors In order to quickly apply the combination of ulinastatin and polysaccharide in medicine, the inventors further made ulinastatin and polysaccharide polysaccharide into an aerosol formulation, and found that the drug was easily unstable in the accelerated test. It may be caused by the inevitable need to adjust the pH in the preparation method and the inevitable exposure to the light environment. For this reason, the inventor found after a large number of experiments that adding carboxymethyl schizophyllan to the drug at the same time can significantly improve the stability of the drug. It is speculated that carboxymethyl schizophyllan has a protective effect on ulinastatin and polysaccharide polysaccharide. .
- each 1000ml of the medicine includes the following components:
- the isotonicity adjusting agent includes one of sodium chloride and glucose.
- the pH adjusting agent includes one or more of hydrochloric acid, citric acid-sodium citrate, and citric acid-disodium hydrogen phosphate.
- preparation method of the medicine comprises the following steps:
- step S2 adding water for injection to dilute the mixed solution of step S1 to 1000ml, sterilizing by filtration with a 0.22 ⁇ m filter membrane, sub-packaging, filling, and packaging, and that’s it.
- the present invention has the following beneficial effects:
- the present invention finds that ulinastatin can play a therapeutic effect on novel coronavirus, and the therapeutic effect of treatment group B is better than that of treatment group A, indicating that ulinastatin and polysaccharide polysaccharide combined can be used for the treatment of severe Complications of sepsis caused by novel coronavirus pneumonia and severe novel coronavirus pneumonia have important social significance.
- the present invention adjusts the composition and preparation method of the medicine.
- Experiment 1 shows that the medicine shows good stability in the 6-month accelerated test, reduces the risk of clinical medication, and is suitable for industrial production.
- Embodiment 1 a kind of medicine for preventing and treating severe novel coronavirus pneumonia
- Embodiment 2 a kind of medicine for preventing and treating severe novel coronavirus pneumonia
- Embodiment 3 a kind of medicine for preventing and treating severe novel coronavirus pneumonia
- the preparation type of the medicine in this example is an atomized preparation, and each 1000ml of the medicine includes the following components:
- Isotonicity regulator sodium chloride 6g
- pH adjuster citric acid-sodium citrate 0.01 ⁇ 15g
- the preparation method of the medicine comprises the following steps:
- step S2 adding water for injection to dilute the mixed solution of step S1 to 1000ml, sterilizing by filtration with a 0.22 ⁇ m filter membrane, sub-packaging, filling, and packaging, and that’s it.
- Embodiment 4 A kind of medicine for preventing and treating severe novel coronavirus pneumonia
- the preparation type of the medicine in this example is an atomized preparation, and each 1000ml of the medicine includes the following components:
- Isotonicity regulator sodium chloride 6g
- pH adjuster (citric acid-disodium hydrogen phosphate) 0.01 ⁇ 15g;
- the preparation method of the medicine comprises the following steps:
- step S2 adding water for injection to dilute the mixed solution of step S1 to 1000ml, sterilizing by filtration with a 0.22 ⁇ m filter membrane, sub-packaging, filling, and packaging, and that’s it.
- Comparative Example 1 A drug for the prevention and treatment of severe novel coronavirus pneumonia
- Example 1 The difference from Example 1 is that no carboxymethyl schizophyllan was added.
- Example 1 The difference from Example 1 is that Polygonatum polysaccharide is not added.
- Treatment methods 75 patients diagnosed with severe novel coronavirus pneumonia were randomly divided into treatment group A, treatment group B, and control group with 25 cases in each.
- the patient was treated with oxygen inhalation or non-invasive ventilator.
- the patients in the control group were treated with the standard treatment plan (conventional antiviral, anti-inflammatory, immune enhancer and supportive treatment); the treatment group A was combined with the example on the basis of the control group (conventional antiviral, anti-inflammatory, immune enhancer and supportive treatment).
- Nebulized preparation for treatment treatment group B was treated with the aerosolized preparation of Example 3 on the basis of the control group (conventional antiviral, anti-inflammatory, immune enhancer and supportive treatment); once every 8 hours, the treatment continued for 5 days.
- Indicators include:
- Cytokines gamma-interferon, alpha-tumor necrosis factor, interleukin-10, interleukin-6, interleukin-4, interleukin-2 and interleukin-17A;
- Cardiac three myoglobin, troponin and creatine kinase isoenzymes
- ROS oxidative stress levels
- treatment group A and treatment group B showed that CDC throat swabs were negative for new coronavirus nucleic acid, chest CT showed that the inflammation was absorbed earlier, and blood indicators returned to healthy reference values.
- the effective number of treatment group A after treatment was lower than that of treatment group B. The specific reason was that the blood treatment of treatment group A did not return to the healthy reference value, so it was ineffective.
- mice 60 C57 mice of 240g ⁇ 260g, half male and half male, were adaptively fed with standard diet for 3 days.
- a mouse model of septic lung injury was established by injecting 5 mg/kg LPS into the tail vein.
- the mice were randomly divided into 4 groups, including the model group, the treatment group, the treatment group 2, and the treatment group 3.
- the control group was injected with the same amount of normal saline and fed normally. .
- One group of treatment was injected with 0.4ml (20,000 units) of ulinastatin + 0.4ml of normal saline, the second group of treatment was injected with 0.4ml (0.2mg) of Polygonatum polysaccharide + 0.4ml of normal saline, and the third group of treatment was injected with 0.4ml (20,000 units) of Ulinastatin + 0.4ml (0.2mg) Polygonatum polysaccharide, model group and control group were injected with 0.8ml normal saline. Once every 24h, blood was collected after 72h, TNF- ⁇ , IL-1 ⁇ and IL-6 were measured, and compared with the control group at 0h; the mortality after 72h was also measured.
- ulinastatin can inhibit TNF ⁇ , IL-1 ⁇ and IL-6-induced inflammatory cytokines, play an active anti-inflammatory effect, and can reduce the mortality of mice with septic lung injury.
- the effect of treatment group 3 is better than that of treatment group 1 and treatment group 2, indicating that the combination of ulinastatin and polysaccharide polysaccharide can play a more positive protective effect.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne en outre l'utilisation d'ulinastatine dans la préparation d'un médicament pour la prévention et le traitement de la COVID-19 aiguë. Le médicament selon l'invention contient de l'ulinastatine, un polysaccharide de polygonatum sibiricum et du carboxyméthyl-schizophyllane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010231469.1A CN111329998A (zh) | 2020-03-27 | 2020-03-27 | 乌司他丁在制备防治重症新型冠状病毒肺炎药物中的用途 |
| CN202110326332.9 | 2021-03-26 | ||
| CN202110326332.9A CN113144179B (zh) | 2020-03-27 | 2021-03-26 | 乌司他丁在制备防治重症新型冠状病毒肺炎药物中的用途 |
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| Publication Number | Publication Date |
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| WO2022199050A1 true WO2022199050A1 (fr) | 2022-09-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/130409 WO2022199050A1 (fr) | 2020-03-27 | 2021-11-12 | Utilisation d'ulinastatine dans la préparation d'un médicament pour la prévention et le traitement de la covid-19 aiguë |
Country Status (2)
| Country | Link |
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| CN (2) | CN111329998A (fr) |
| WO (1) | WO2022199050A1 (fr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111329998A (zh) * | 2020-03-27 | 2020-06-26 | 广东天普生化医药股份有限公司 | 乌司他丁在制备防治重症新型冠状病毒肺炎药物中的用途 |
| CN114668754B (zh) * | 2021-04-28 | 2022-09-13 | 清华大学 | 1,5-脱水山梨醇在制备治疗和预防SARS-CoV-2病毒所致疾病药物中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111803608A (zh) * | 2020-06-01 | 2020-10-23 | 北京中医药大学 | 一种具有抗病毒作用的中药组合物 |
| CN113144179A (zh) * | 2020-03-27 | 2021-07-23 | 广东天普生化医药股份有限公司 | 乌司他丁在制备防治重症新型冠状病毒肺炎药物中的用途 |
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| CN1160123C (zh) * | 2003-05-26 | 2004-08-04 | 广东天普生化医药股份有限公司 | 乌司他丁用于治疗严重急性呼吸综合征的用途及其药物组合物 |
| CN111357984A (zh) * | 2020-03-23 | 2020-07-03 | 李永红 | 一种润肺滋肾的营养组合物 |
| CN112263649A (zh) * | 2020-04-26 | 2021-01-26 | 武汉上治健康生物科技有限公司 | 一种益气健脾代用茶组合物、颗粒剂及其制备方法 |
| CN111991543A (zh) * | 2020-07-17 | 2020-11-27 | 深圳市老年医学研究所 | 用于新冠肺炎重症辅助治疗的中药组合物及其制备方法 |
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2020
- 2020-03-27 CN CN202010231469.1A patent/CN111329998A/zh active Pending
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2021
- 2021-03-26 CN CN202110326332.9A patent/CN113144179B/zh active Active
- 2021-11-12 WO PCT/CN2021/130409 patent/WO2022199050A1/fr active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| Publication number | Publication date |
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| CN113144179B (zh) | 2022-04-01 |
| CN111329998A (zh) | 2020-06-26 |
| CN113144179A (zh) | 2021-07-23 |
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