Pharmaceutical composition for improving respiratory system damage

Abstract

A pharmaceutical composition for improving respiratory system damage, comprising an adsorbent drug and a water-containing carrier, wherein the adsorbent drug comprises a carbon material, a molecular sieve, and a positively and negatively charged compound. The pharmaceutical composition is for use in the manufacture of a pharmaceutical composition for improving respiratory system damage.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for improving respiratory system injuries, and particularly to a pharmaceutical composition for improving respiratory system injuries containing an adsorbent drug. to an object It relates to.

Background Art

[0002] When the lungs are invaded by pathogens, bacteria, toxic substances, fire smoke or foreign substances, an inflammatory reaction occurs, activating immune cells such as white blood cells, macrophages, and natural killer cells. An appropriate inflammatory reaction is beneficial for the removal of pathogens by the body's immune cells, but there are also substances that tend to exacerbate the inflammatory reaction. For example, viruses (e.g., COVID-19, SARS-CoV-2, MERS-CoV, influenza virus (the influenza virus includes types A, B, C, and D, and type A influenza, for example, H1N1, H5N1, H7N9, etc., and the above influenza virus can also be transmitted to species such as poultry, dogs, pigs, cattle, etc. across species in addition to infecting humans), AIDS virus, avian influenza virus, Ebola virus, hantavirus, anthrax virus, Lassa virus, West Nile virus, Zika virus, respiratory syncytial virus (RSV), dengue virus, etc. or other viruses causing viral hemorrhagic fever, bacteria (common ones are, for example, Streptococcus pneumoniae, Haemophilus pluis, and Mycobacterium tuberculosis, etc.), molds (common ones are, for example, Aspergillus niger and Aspergillus albicans, and generally occur frequently in diabetic patients, transplant recipients, patients with malignant tumors in the blood, and patients receiving chronic steroid treatment), toxic substances such as phosgene and chlorine gas. For example, exposure to high concentrations of phosgene causes lung swelling, brings respiratory difficulties to humans, and exposure to higher concentrations of phosgene causes severe lung injury and can be a cause of death. Radiological examinations such as chest X-ray examinations may be the earliest method to confirm whether the lungs have been damaged by drugs.

[0003] When invaded by the above substances, the lungs are prone to excessive inflammatory reactions, and also induce the secretion of a large amount of hormones by cells. Here, pro-inflammatory hormones and chemotactic hormones are the main causes of cytokine storm. Furthermore, they promote the aggregation of more immune cells to the infected lung epithelial cells, and continuously produce a larger amount of pro-inflammatory hormones and chemokines, which may cause pulmonary edema, injury, infiltration, fibrosis, and insufficiency, and ultimately lead to shock and a high fatality rate.

[0004] Current treatment methods mainly involve the use of drugs such as antibiotics, antivirals, and steroids during the pathogen replication period that does not cause cytokine storm. For example, antiviral drugs are used to suppress virus replication. However, when entering the cytokine storm period, currently, there are no specific drugs for cytokine storm in terms of treatment, and only supportive therapy can be used to get through the critical period. For example, the treatment of cytokine storm caused by SARS has conventionally reduced the inflammatory reaction by suppressing the immune reaction using steroids. However, suppressing the body's immune reaction often leads to a rapid deterioration of the disease condition and it becomes uncontrollable, and the mortality rate rather increases. In addition, the clinical guidance for some novel viruses (such as COVID-19) does not suggest steroid treatment. It not only reduces the body immunity of patients but also masks the fever reaction of the autoimmune system, which is highly likely to miss the opportunity for treatment. At the same time, it may also infect more people and cause infectious diseases. During the cytokine storm period in the current treatment of COVID-19, only supportive therapy is mainly used. By providing sufficient oxygen to the patients, assisting in the discharge of sputum, monitoring blood pressure, etc., the patients are allowed to go through the two-week acute phase. In addition, the patients can only produce antibodies through the autoimmune mechanism and recover their health.

[0005] However, neither the above drug therapy nor the supportive therapy can control, relieve, or treat the pulmonary inflammatory site. Generally, in order to remove harmful substances in the lungs at the above stage, a technique is known in which the lungs are observed with a bronchoscope or a nasogastric endoscope, and the lungs are washed with physiological saline to wash away and remove these harmful substances, thereby restoring the normal gas exchange ability of the lungs. However, for toxic substances (e.g., endotoxin), bacteria, viruses, inflammation-promoting hormones, chemotactic hormones, or cytokines that adhere to the lungs, etc., they cannot be easily washed away with physiological saline, so it is difficult to reduce or restore the white blood cell count, inflammatory response, bleeding volume, or white blood cell index to normal values.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention provides a pharmaceutical composition for improving respiratory system injuries to solve the above problems.

Means for Solving the Problems

[0007] According to one object of the present invention, the present invention provides a pharmaceutical composition for improving respiratory system injuries that is injected or inhaled into the cavity of a patient's respiratory system. The active ingredient of this pharmaceutical composition contains an adsorbent drug used for adsorbing inflammatory substances or harmful substances. Here, this adsorbent drug contains a carbon material, the nasal cavity, pharynx, larynx, trachea, bronchus or lung belonging to and the specific surface area (BET) of this carbon material is 300 - 3000 m This carbon material is selected from activated carbon, activated carbon fiber, activated carbon sphere, columnar activated carbon or activated carbon powder. / g. 2

[0008] The pharmaceutical composition according to the present invention has a certain effect on pneumonia in any pathological condition and can achieve the effect of improving respiratory system injuries.

Brief Description of the Drawings

[0009]

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Mode for Carrying Out the Invention

[0010] For those with ordinary knowledge in the technical field to which the present invention pertains to better understand the present invention, the following description shows preferable embodiments of the present invention, and details the content of the present invention and the effects to be achieved in combination with the drawings.

[0011] The present invention provides a pharmaceutical composition for improving the respiratory system. The active ingredient of this pharmaceutical composition contains an adsorbent drug. In one embodiment of the present invention, the pharmaceutical composition may further contain a water-containing carrier, an adjuvant, an excipient or a propellant. The respiratory system of the present invention refers to the respiratory organs (including the nasal cavity, pharynx, larynx, trachea, bronchi) and the lungs. The pharmaceutical composition according to the present invention can be used for injuries caused by common respiratory diseases. The principle is that by containing an adsorbent drug, it adsorbs inflammatory promoting hormones, chemokines, cytokines, bacteria, viruses, molds or toxic substances such as those from fires, nuclear, biological, chemical, etc. in the respiratory system, and is used for the treatment or alleviation of upper respiratory tract inflammation or infections, such as inflammation of the middle pharynx, etc., inflammation or infections related to the lungs and otolaryngology system, and for the treatment or alleviation of lower respiratory tract inflammation or infections, such as pneumonia, airway infections, infections or inflammations caused by assisted lung expansion devices, ventilator associated pneumonia (VAP) , qi Inflammation of the bronchi, inflammation of the pleura , lung Water tumor, Lung injury , acute Acute Respiratory Distress Syndrome (ARDS) ) of It is used for treatment or alleviation, improvement of symptoms of dyspnea, pulmonary edema, pulmonary inflammation, pulmonary hemorrhage, pulmonary infiltration or pulmonary cytokine storm caused by the above diseases, and further for improvement of respiratory system injury. The pharmaceutical composition for improving respiratory system injury according to the present invention alleviates the degree of pulmonary edema, inflammation, hemorrhage, infiltration or cytokine storm, controls the immune response to a non-lethal degree, and does not affect the elimination of pathogens or foreign substances by the immune system, and further maintains the patient's resistance and effectively reduces the mortality rate.

[0012] In one embodiment, the patient refers to an animal for which the combination of active drugs described herein has a therapeutic effect. In one embodiment, the patient is a human.

[0013] In one embodiment, the adsorbent drug may be a carbon material, a molecular sieve, a positively or negatively charged compound, or a combination of one or more of these.

[0014] In one embodiment, the carbon material may be one selected from activated carbon, activated carbon fiber, carbon fiber, carbon sphere, activated carbon sphere, columnar activated carbon, activated carbon powder, carbon powder, fullerene (C60), cellulose-based carbon, bamboo charcoal, soot, carbon aerogel, graphite, expanded graphite, carbon nanotube, nanocarbon ball, coke ball or carbon black, or a combination thereof, but is not limited thereto. In one embodiment, the specific surface area (SSA) of the carbon material (measured by the BET method) is 300 to 3000 m 2 / g, preferably 600 to 2000 m 2 / g, more preferably 900 to 1850 m 2 / g. In one embodiment, the average particle size of this carbon material is 0.1 to 500 microns (μm), preferably 0.5 to 50 microns (μm). In one embodiment, the pore volume of this carbon material is 0.1 to 3.0 ml / g, preferably 0.1 to 1.0 ml / g. In one embodiment, the pore diameter of the carbon material is between 1 and 500 nanometers (nm), preferably 2 to 200 nanometers (nm). In one preferred embodiment, This pharmaceutical composition further contains a water-containing carrier, and this the concentration of the carbon material in the aqueous carrier is 0.001 to 1 wt%.

[0015] In one embodiment, the molecular sieve may be various materials having a single fine pore structure, and the structure may be an A-type molecular sieve (including 3A molecular sieve, 4A molecular sieve, 5A molecular sieve), an X-type molecular sieve (13X molecular sieve, 10X molecular sieve), and the material is adjusted according to the situation. For example, it is aluminosilicate or coal or other biocompatible materials, but is not limited thereto.

[0016] In one embodiment, the positively and negatively charged compound is, for example, a molecular polymer (polyelectrolyte), an ion exchange resin or an ionic surfactant. The above positively and negatively charged compound contains acidic or basic functional groups, so that hydrogen ions (H + ) or hydroxide ions (OH - ) are dissociated in the liquid, so that the compound has a negative charge group (for example, SO 3- 、 R-COO - etc.) to adsorb and bind other cations in the solution, or a positive charge group (e.g., R-NR 3 + etc.) to adsorb and bind other anions in the solution. Pathogens or bacteria, etc., are positively or negatively charged like the negatively charged viral envelope amino acids. Therefore, by adding an adsorbent drug having positively and negatively charged compounds, the virus can be adsorbed to prevent its spread.

[0017] In one embodiment, this pharmaceutical composition The adsorbent drug may be used alone, or a water-containing carrier may be further By containing it, it functions to enable this adsorbent drug to act in a solid suspension state for entering the respiratory tract. Therefore, this pharmaceutical composition may be, but is not limited to, a spray, an inhalant, or a liquid suspension. In one embodiment, This The aqueous carrier may be any buffer solution physiologically compatible with the respiratory system, such as physiological saline or a buffer solution, and may be one of them or a combination thereof. In one embodiment, this pharmaceutical composition containing adsorbent drug is 、 This The aqueous carrier is physiological saline.

[0018] In one embodiment, the adjuvant of this pharmaceutical composition is (a) carbohydrates, such as monosaccharides, such as fructose, galactose, glucose, D-mannose, sorbose and analogs, disaccharides such as sucrose, lactose, trehalose, cellobiose and analogs, cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin, and polysaccharides such as raffinose, maltodextrin, polydextrose, starch, chitin, polydextrose, inulin, etc., (b) amino acids such as alanine, glycine, spermine, asparagine, glutamine, cysteamine, caomine, albumin, isoalbumin, valine and analogs, (c) organic salts prepared from metals and organic acids and bases, such as titanium, zinc, copper, silver, platinum or gold, sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride and analogs, (d) peptides and proteins, such as VEGF polypeptide, PDGF polypeptide, aspartame, trialbumin, human serum albumin, glistine, gelatin and analogs, (e) alditols such as mannitol, xylitol and analogs, (f) synthetic or natural polymers or combinations thereof, such as polylactic acid, poly(lactic-co-glycolic acid), cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, hyaluronic acid, polyethylene glycol, etc., and (g) surfactants including fluorinated and non-fluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof, and (h) nutrients including water-soluble vitamins or fat-soluble vitamins, and (i) antioxidants which are one or a combination of ascorbic acid (vitamin C), glutathione, lipoic acid, coenzyme Q10, ubiquinone (coenzyme Q), α-tocopherol (vitamin E), carotene, and (j) includes dexamethasone, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylhydrocortisone, mometasone, prednisone and triamcinolone, any pharmaceutically acceptable salts, esters, isomers thereof,including, but not limited to, corticosteroids including solvates. When the composition includes a corticosteroid active agent, in a preferred embodiment, dexamethasone may be selected.,

[0019] In one embodiment, the excipients of this pharmaceutical composition include one or more of, but not limited to, triclyceric acid, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, trehalose, lactose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, prolinic acid, water, ethanol, propanol, corn starch, monosyrup, glucose solution, starch solution, gelatin solution, shellac, potassium phosphate, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose (MCC), aldehyde cellulose or hydroxypropyl methylcellulose phthalate, collagen, hyaluronic acid, gelatin or gel, quaternary ammonium salts, sodium lauryl sulfate, and surfactants.

[0020] In one embodiment, the propellant of this pharmaceutical composition refers to a gas that can be liquefied under the pressure at room temperature, is safe for inhalation or topical use, and is suitable for being toxicologically non-toxic. In addition, the selected propellant has no relative reactivity with the adsorbent drug. The propellant includes, but is not limited to, perfluorinated compounds (PFCs), hydrofluoroalkanes (HFAs), fluoroheptane, fluorocycloheptane, fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethylcyclopentane, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroether, fluoropolyether, and fluorotriethylamine (not limited to these). In one embodiment of the present invention, this pharmaceutical composition further contains a therapeutic drug. This therapeutic drug may be, for example, an antibacterial drug, an antiviral drug (which varies depending on the type of virus, and may include Remdesivir, Camostat mesylate, Lopinavir, Ritonavir, Favipiravir, Umifenovir, adenosine nucleotide analogues, protease inhibitor, RNA polymerase inhibitor, fusion inhibitor, cytokine, Entecavir, Imipenem, Interferon, etc., and is not limited thereto), a benzene ring drug, an anticoagulant (such as heparin, warfarin, Clopidogrel, Ethyl salicylate, warfarin, Rivaroxaban, Apixaban, Edoxaban, Enoxaparin sodium, etc.), a thrombolytic drug (such as tissue-type plasogen activator (tPA), recombinant tissue activator (rt-PA), thrombomodulin (TM), thrombolytic enzyme, Fondaparinux, etc.), an α-blocker (such as an α-adrenergic blocker, Terazosin (Hytrin), Doxazosin (Doxaben), Tamsulosin (Harnalidge) or Silodosin (Urief capsule, etc.), a 5α-reductase inhibitor (such as Finasteride (Proscar) or Dutasteride (Avodart capsule), etc.), a nasal decongestant (nasalDecongestants, antitussives, expectorants, mucolytics, tracheal or bronchial dilators (bronchodilators, e.g., beta-2 adrenergic stimulants, anticholinergic drugs, etc.), antibiotics (e.g., aminopenicillins antibiotics, carboxypenicillins antibiotics, sulfonamides and trimethoprim-sulfamethoxazole antibiotics (e.g., TMP-SMX, etc.), beta-lactam antibiotics, unique beta-lactam antibiotics (e.g., monobactams or carbapenems), non-beta-lactam antibiotics (e.g., macrolide or tetracycline), cephalosporins antibiotics, macrolide antibiotics, fluoroquinolones (FQ) antibiotics, vancomycin, rifapentine, chloramphenicol, tigecycline, etc.), antifungal drugs (e.g., amphotericin B antifungal agents, imidazoles antifungal agents, triazoles antifungal agents, griseofulvin antifungal agents, nucleoside analogues antifungal agents, polyenes antifungal agents, triazole antifungal agents (e.g., voriconazole, itraconazole, posaconazole, etc.), echinocandin antifungal agents, voriconazole antifungal agents, azole antifungal agents, isavuconazole, flucytosine, fluconazole, etc.), anti-asthmatic drugsdrugs), anti-inflammatory drugs (e.g., anti-leukotriene preparations, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), etc.), antioxidants (for anti-inflammatory and anti-free radical purposes, e.g., melatonin, anthocyanins, etc.), traditional Chinese medicine extracts (e.g., extract of the decoction of Macot stone (roasted Mao Wu, Ke Shi, Chai Hu, Sheng Jiang, Kakko, Bukuryo, Chorei, Alisma orientale, Hang Ge, Saishin, Chen Pi, Byakujutsu, Purple Moss, Kantouka, Yakan, Ougon, raw gypsum, mandarin orange, almond, yam, roasted licorice root), isoflavone derivatives, flavone compounds, dokudamine benzine, quercetin, quercetin-3-rhamnoside, dokudami (decanoyl acetaldehyde), lauric aldehyde, l-pinene, linalool, camphene, myrcene, limonene, bornyl acetateLeaves containing acetate, caryophellene, afzelin, hyperin, rutin, quercitrin, flowers and fruits containing isoquercitrin, St. John's wort, triterpenoid saponin, momordin, Japanese honeysuckle, kingeranin, hokouei, rosmarinic acid, oleanolic acid, arbutin, rutin, Prunella vulgaris, pseudotaraxasterol palmitate, chlorogenic acid, isochlorogenic acid, caffeic acid, alkaloids, besin, sesame oil, phenylpropanoside, cycloolefin ether terpene, Banlangen injection (4(H quinodimedone, 3 carbonylphenyl)-1(H) quinodimedone, benzoic acid, syringic acid, anthranilic acid, salicylic acid, etc.), antibodies (e.g., Tocilizumab, Sarilumab, Eculizumab, Kevzara, Actemra), vaccines (vaccines capable of binding to the adsorbable drugs in the present invention, e.g., mRNA vaccines, protein vaccines, adenovirus vaccines, attenuated vaccines, molecular vaccines, or nano vaccines), and thus convalescent plasma, but not limited to the above, one of them or a combination thereof, but not limited thereto.

[0021] In one embodiment of the present invention, a coating layer may be formed on the adsorbent drug to adsorb inflammatory substances / harmful substances or to increase the linkage with other adjuvants, excipients, propellants, and aqueous carriers. In one embodiment, the surface of the adsorbent drug may be modified / coated by methods such as oxygen plasma, pickling, plating, or coating, and the surface may be modified or surface-coated to form a coating layer on the surface. In another embodiment, the coating layer may include an oxygen functional group (attached to the surface of the carbon material by plasma treatment to adsorb endotoxins of virus or molecular chain structure), a hydroxyl functional group (attached to the surface of the carbon material by pickling treatment to adsorb virus), a hydroxyl group, a carboxylic acid, an aldehyde group, a carbonate, a metal ion (attached to the surface of the carbon material by high temperature or plating treatment to inactivate the outer membrane of the virus, suppress the virus activity, or kill the virus, which may be silver, platinum, palladium, gold, zinc, or copper, preferably silver ion), a magnetic substance (for reinforcing the adsorption capacity of the carbon material and reducing the residue of harmful substances, preferably iron ion), a cationic compound (for example, a compound containing calcium, magnesium, potassium, or sodium, such as calcium carbonate, calcium phosphate, etc.), an anionic compound (for example, sodium triiodide, etc.), or a halogen ion (for example, an ion such as fluorine, chlorine, bromine, iodine, etc.), or a combination thereof.

[0022] In another embodiment, the adsorbent drug may further bind to metal ions on the surface. The metal ions may be silver, platinum, palladium, gold, zinc or copper. Preferably, it is silver ion-containing activated carbon fiber powder, and secondarily preferably, it is silver ion-containing carbon fiber powder. Note that the silver ion-containing carbon material also has effects such as adsorption of viruses, inactivation of the outer membrane of viruses, and alleviation of cytokine storm disorders, and can reduce the risk of death. In another preferred embodiment, it is zinc ion-containing activated carbon fiber powder or zinc ion-containing carbon fiber powder. In another embodiment of the present invention, the adsorbent drug may be mixed with various nanodelivery systems or carriers, such as liposomes, nanopathogens, nanobacteria or molecular robots. The nanodelivery system can also be combined with various aspects of the coating layer, such as nanospheres, metal ions, cationic drugs, anionic drugs, magnetic substances, etc., to increase the overall stability or increase its usefulness.

[0023] The harmful substances that can be adsorbed by the composition of the present invention may be harmful substances (such as endotoxin), bacteria, viruses, inflammation-promoting hormones, chemokines or cytokines, etc. The present invention further includes a method of using a pharmaceutical composition for improving respiratory system injuries that can be formulated as a spray or inhalant or liquid suspension. When in use, spray by a nebulizer or dry powder inhalation (referring to using the adsorbent drug alone without containing a water-containing carrier) through, or through a device (such as a thoracoscope, endoscope, bronchoscope, infusion tube, infusion bag, infusion pump, or syringe), inject the pharmaceutical composition into the nasal cavity, larynx, specific or unspecified cavities of the lungs (such as pulmonary bronchi or sub-bronchioles) of the patient, and further perform a treatment combined with one-lobe lavage, transpulmonary lavage, or bronchoalveolar lavage, and use physiological saline to remove the pharmaceutical composition and the adsorbed harmful substances.

[0024] The present invention provides a method of using a pharmaceutical composition for improving respiratory system injuries. One embodiment of the method is to deliver a pharmaceutical composition in the form of a spray or inhalant to the lung bronchi or sub-bronchi by means of an aerosol administration method such as nebulizer spraying or dry powder inhalation. , where dry powder inhalation is to use the adsorbent drug alone Furthermore, through the sputum formation of the patient, the pharmaceutical composition is discharged from the lung to complete the treatment course. When a doctor evaluates the patient and cannot remove the sputum with a hair, the pharmaceutical composition can be further treated in combination with lung lavage or bronchoalveolar lavage, and physiological saline is used to remove the pharmaceutical composition and its adsorbed harmful substances to reduce subsequent residual risks. of the lung The manufacturing method and related experiments of the present invention will be described below to explain the effects of the present invention.

[0025] Hereinafter, of the preferred embodiment The manufacturing method of the pharmaceutical composition of the present invention

[0026] 8 mg of the carbon material of the present invention was weighed, and 50 ml of 0.9% physiological saline was added and mixed uniformly. The carbon material system is activated carbon powder, with no modification on the surface, a specific surface area of 1248.8 m / g, an average particle size of 12.08 microns (μm), a median particle size distribution (d50, Median) of 9.453 microns (μm), and a pore volume of 0.4285 ml / g. 2

[0027] Experimental module Referring to FIG. 1, FIG. 1 is a schematic diagram simulating different progressions of COVID-19 using lipopolysaccharide (LPS) at different concentrations of the present invention. To test a compound or treatment method for the prevention of ARDS in the lungs of COVID-19 patients, the present invention uses lipopolysaccharide to induce a pathological model of ARDS. Lipopolysaccharide is a sugar purified from the cell wall of Gram-negative bacteria. When it is delivered to the lungs of rodents by aerosol, it induces a Th1 immune response, causes the invasion of inflammatory cells (mainly neutrophils) into the airways, and causes a substantial increase in cytokines in the lungs, thus causing different degrees of ARDS. The present invention can simulate different progressions of COVID-19 by using lipopolysaccharides at different concentrations. As shown in FIG. 1, as the time of the disease progresses, the time shown on the horizontal axis includes the initial infection (phase I), the lung injury stage (phase II), the cytokine storm stage (phase III), and the recovery stage (phase IV). Here, at half of the progression of the lung injury stage (phase II), a lung inflammatory response is discovered, and the inflammatory response reaches its peak in the cytokine storm stage (phase III).

[0028] Blood oxygen concentration: Generally, the normal value of human blood oxygen saturation is 95% or above. However, in COVID-19 patients, "silent hypoxia" is often observed. Although there may already be hypoxemia, patients do not feel dyspnea, so doctors may be delayed in diagnosing the condition, increasing the risk of sudden death. Mainly, when progressing to the lung injury stage (phase II), patients develop severe pneumonia. According to the WHO's classification of related symptoms of SARS-CoV-2 infection, the clinical symptoms of severe pneumonia are any combination of fever or respiratory tract infection, a respiratory rate of >30 breaths / min, severe respiratory distress, and a blood oxygen saturation of ≤94% on room air (without oxygen device support). In the cytokine storm stage (phase III), patients develop acute respiratory distress syndrome (ARDS). According to the WHO's classification of related clinical manifestations of SARS-CoV-2 infection, patients with acute respiratory distress syndrome (ARDS) clinically exhibit the following situations: (1) Chest imaging (X-ray, computed tomography, lung ultrasound, etc.) reveals bilateral opacities that cannot be explained solely by pleural effusion, lung lobe collapse, or nodules. (2) Origin of pulmonary edema: Objective evidence evaluation is required to rule out respiratory failure that cannot be fully explained by heart failure or fluid overload, and hydrostatic pulmonary edema. (3) Oxygenation (in adults): "Mild ARDS": 200 mmHg < PaO 2 / FiO 2 ≤300 mmHg (combined with PEEP or CPAP ≥ 5 cm H2O or without mechanical ventilation support), "Moderate ARDS": 100 mmHg < PaO 2 / FiO 2 ≤200 mmHg (combined with PEEP ≥ 5 cm H 2 O or without mechanical ventilation support), "Severe ARDS": PaO 2 / FiO 2 ≤100 mmHg (combined with PEEP ≥ 5 cm H 2 O or without mechanical ventilation support). PaO 2In the case where there is no value for SpO 2 / FiO 2 ≤ 315 mmHg may be considered to have ARDS (even if the patient is not receiving mechanical ventilation).

[0029] The severity on the vertical axis can be classified into four grades: mild airway disease (stage 1), pneumonia (stage 2), severe pneumonia (stage 3), and respiratory distress syndrome (stage 4). Here, a low dose of LPS (2 mg / kg) can induce a pathological condition such as pneumonia, a medium dose of LPS (4 mg / kg) can induce a pathological condition such as severe pneumonia, and a high dose of LPS (8 mg / kg) can mimic a pathological condition such as respiratory distress syndrome. Therefore, the present inventors used low-dose LPS as the stage before the lung injury stage (phase II) mimicking COVID-19, medium-dose LPS as the stage after the lung injury stage (phase II) mimicking COVID-19, and high-dose LPS as the cytokine storm stage (phase III) mimicking COVID-19, whereby various progressions / severities of COVID-19 can be mimicked.

[0030] Experimental method After using lipopolysaccharide (LPS) to induce 7- to 9-week-old SD rats into an acute lung injury animal model by intratracheal administration, administer the treatment of the above prescription to Before injury or administer to or after injury administer it was determined whether the occurrence of rat death or near-death phenomena and inflammatory reactions was reduced, and it was examined whether the pharmaceutical composition of the present invention alleviated lung injury and inflammatory reactions histopathologically. The design of the experimental groups in this experiment is as shown in Table 1.

[0031]

Table 1

[0032] Experimental results 1. Mortality rate The mortality rate after treatment was as shown in Table 2. High concentrations of LPS induced acute lung injury and showed a certain mortality rate (treatment group A), while medium and low concentrations of LPS induced acute lung injury (treatment groups B and C), and the mortality rate decreased successfully after treatment.

[0033]

Table 2

[0034] 2. Related tests for lung injury A. Test for improving lung protein accumulation After sterilization, the left lung lobe was washed with PBS to collect bronchoalveolar lavage fluid (BALF), and the total protein amount was measured by enzyme-linked immunosorbent assay (ELISA). Refer to Figure 2 for the experimental results. Figure 2 is a histogram of the total protein amount in each bronchoalveolar lavage fluid group (BALF) after treatment. As shown in Figure 2, in treatment group A (high dose), treatment group B (medium dose), and treatment group C (low dose), by using the pharmaceutical composition of the present invention, the total protein amount in BALF can be significantly reduced, and it was found that it can be reduced by 52%, 51%, and 28% respectively, indicating that the pharmaceutical composition of the present invention has the efficacy of improving lung protein accumulation for lung injuries at each stage.

[0035] B. Test for improving lung inflammation After sterilization, the left lung lobe was washed with PBS to collect BALF, and the concentrations of inflammatory factors such as IL-6 and IL-8 were quantified by ELISA. Referring to Figure 3 and Figure 4, Figure 3 and Figure 4 are histograms of IL-6 (Figure 3) and IL-8 (Figure 4) in each group's bronchoalveolar lavage fluid group (BALF) after treatment respectively. As shown in Figure 3, in treatment group A (high dose) and treatment group B (medium dose), by using the pharmaceutical composition of the present invention, the concentration of the inflammatory factor IL-6 can be significantly reduced. As shown in Figure 4, in treatment group A (high dose), the concentration of IL-8 was significantly It can be reduced, and it has been revealed that the pharmaceutical composition of the present invention has the effect of reducing the lung inflammatory response.

[0036] C. Improvement test of lung infiltration and pulmonary edema The remaining lung lobes (including the right cranial, right caudal, and accessory lobes) were weighed, perfused with 0.8 - 1.0 mL of 10% neutral buffered formalin (NBF), and then stored at room temperature for 72 - 96 hours with 10 times the volume of 10% NBF. After fixation, the lung lobes were cut, embedded in wax, sectioned into 4 - 6 - micron - thick slices with a microtome, and the sections were uniformly stained with hematoxylin and eosin (H&E). 400X magnified photographs of the main cross - sectional area (area of interest: AOI) of the lung lobes were taken to grade polymorphonuclear cell infiltration (PMNL infiltration) and intra - alveolar edema. Each field of view should contain ≧95% of the alveoli. Observation and quantification of lung infiltration and pulmonary edema were performed by 10 random evaluations, and Table 3 shows the scoring system.

[0037]

Table 3

[0038] Referring to Figure 5, Figure 5 is a diagram of alveolar H&E staining of each group after treatment, Figure 6 is a quantitative diagram of polymorphonuclear cell infiltration measured according to the staining diagram of Figure 5, and Figure 7 is a quantitative diagram of pulmonary edema measured according to the staining diagram of Figure 5. As shown in Figures 5, 6, and 7, in treatment group A (high dose), treatment group B (medium dose), and treatment group C (low dose), it was found that the pharmaceutical composition of the present invention can significantly reduce polymorphonuclear cell (PMNL) infiltration and alveolar edema, and it has been revealed that the pharmaceutical composition of the present invention has the effect of improving lung infiltration and pulmonary edema.

[0039] D. Quantitative diagram of lung water weight The right middle lobe of the lung is excised from the lung and weighed to the wet weight standard based on the adjusted body weight. Then, the sample is left in an oven at 60 °C for 24 hours, and the dry weight is obtained from the same calibration scale. Referring to Figure 8, Figure 8 is a quantitative diagram of the lung water weight of each group after treatment. As shown in Figure 8, it was found that in treatment group A (high dose), treatment group B (medium dose), and treatment group C (low dose), the use of the pharmaceutical composition of the present invention can significantly reduce the lung water weight, and it is clear that the pharmaceutical composition of the present invention can significantly reduce the water content of lung tissue and has the effect of improving pulmonary edema.

[0040] As can be seen from the above experiments, the pharmaceutical composition of the present invention can indeed effectively improve various harmful pathological conditions of the lung and also has an improvement effect on COVID-19 with different courses. Referring to Figure 9, Figure 9 is a schematic diagram of the preferred administration timing of the pharmaceutical composition of the present invention. As shown in Figure 9, when combined with the above experiments, the clinically preferred administration timing of the pharmaceutical composition of the present invention is (1) the blood oxygen saturation ≤ 94% under room air without oxygen device support, or (2) It may also be that the radiological evidence shows lung infiltration.

[0041] In short, according to the pharmaceutical composition of the present invention, it has a certain effect on pneumonia with any pathological condition and can achieve the effect of improving respiratory system injury. 。

[0042] The above are only preferred embodiments of the present invention and do not limit the present invention. For those skilled in the art, various changes and modifications are possible for the present invention. Any modifications, substitutions by equivalents, improvements, etc. made without departing from the spirit and principle of the present invention are all included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition for improving respiratory system injuries, which is injected or inhaled into the nasal cavity, pharynx, larynx, trachea, bronchus or lung cavity of a patient's respiratory system, wherein the active ingredient of the pharmaceutical composition includes an adsorptive drug used for adsorbing inflammatory or harmful substances, Here, the adsorbent drug comprises a carbon material, which is selected from activated carbon, activated carbon fiber, activated carbon spheres, columnar activated carbon, or activated carbon powder, and the specific surface area (BET) of the carbon material is 300 to 3000 m. ２ / g.

2. The pharmaceutical composition further comprises a water-containing carrier, and the adsorbable drug is mixed with the water-containing carrier so that the concentration of the suspension is 0.001 to 1 wt %. The pharmaceutical composition of claim 1.

3. The carbon material has an average particle size of 0.1 to 500 microns (μm). The pharmaceutical composition of claim 1.

4. The pore volume of this carbon material is characterized in that it is 0.1 to 3.0 ml / g. The pharmaceutical composition of claim 1.

5. The pharmaceutical composition is characterized in that it is a spray, inhalant, liquid suspension or dry powder inhalation. The pharmaceutical composition of claim 1.

6. The composition further comprises an antibacterial agent, an antiviral agent, a benzene ring drug, an anticoagulant, a thrombolytic drug, an α-blocker, a 5α-reductase inhibitor, a nasal decongestant, an antitussive, an expectorant, a mucolytic drug, a tracheal or bronchodilator, an antibiotic, an antifungal drug, an antiasthmatic drug, an anti-inflammatory drug, an antioxidant, a Chinese herbal medicine extract, an antibody, a vaccine, or plasma of a cured person. The pharmaceutical composition of claim 1.

7. The composition further comprises one or a combination of a metal ion, a magnetic substance, a cationic compound, an anionic compound, or a halogen ion. The pharmaceutical composition of claim 1.

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