WO2015014209A1

WO2015014209A1 - Pyruvate pharmaceutical compositions for osmotic stability and detoxification effect thereof in healthy human beings and lung disease patients

Info

Publication number: WO2015014209A1
Application number: PCT/CN2014/082185
Authority: WO
Inventors: 蒋志君; 马丁⋅阿兰; 莱赫⋅斯坦利
Original assignee: 江苏长泰药业有限公司
Priority date: 2013-08-02
Filing date: 2014-07-15
Publication date: 2015-02-05
Also published as: CN103948578A; CN103720682A; CN103385868A

Abstract

Provided in the present invention is a method for detoxification in healthy human beings and lung disease patients using pyruvate pharmaceutical compositions. Toxins accumulated in mammalian cells because of smoking and air pollution can be eliminated by contact with an effective amount of pyruvate pharmaceutical compositions. Lung disease patients comprise chronic obstructive lung disease (COPD) patients. The pyruvate pharmaceutical compositions are selected from pyruvate, pharmaceutically acceptable salts and precursors thereof or a mixture thereof. The method also comprises the use of other pharmaceutical compositions while using the pyruvate pharmaceutical compositions. The present invention has the following advantages: 1. Directly acting on a lung lesion site with greater targeting and not participating in systemic metabolism. 2. Pyruvate pharmaceutical compositions have lesser toxic side effects and greater security, and the drug is stable. 3. Pyruvate is a natural intracellular substance, has the function of enhancing cellular transport systems and has the effect of promoting lung detoxification, and thereby facilitating respiration, wherein the efficacy thereof is more comprehensive and the effects are better than those of antibiotics or steroids.

Description

Instruction manual

Composition of osmotic acid with stable osmotic pressure and its detoxification effect in healthy people and patients with pulmonary diseases

The present invention provides a method for removing pulmonary toxins, improving lung function, and alleviating cough symptoms by using a stable osmotic pressure pyruvate drug composition. The accumulation of toxins in the lungs caused by smoking and air pollution eventually causes lung diseases such as chronic obstructive pulmonary disease. The invention belongs to the field of medical technology. The invention also encompasses methods of making and using a pyruvate drug composition having a medical effect. Background technique

Air pollution or smoking can cause endotoxin accumulation in cells. These toxins, such as benzene, accumulate in the bronchial wall or lung cells. Most patients with chronic obstructive pulmonary disease are also smokers. Chronic obstructive pulmonary disease (COPD) is a type of lung disease caused by smoking and air pollution leading to accumulation of toxins in the lungs, impaired breathing, decreased lung function, and frequent coughing. Chronic obstructive pulmonary disease mainly includes chronic bronchitis and emphysema. Chronic bronchitis is a chronic, non-specific inflammation of the trachea, bronchial mucosa and surrounding tissues that causes airflow into the lungs to be unsmooth. Emphysema is a persistent expansion of the alveolar tissue at the distal end of the terminal bronchioles due to an increase in residual air volume, which in turn leads to alveolar septal destruction and increased volume, which affects normal breathing. Pulmonary tissue damage caused by chronic obstructive pulmonary disease is irreversible, but symptoms and disease progression can be controlled by using drugs such as antibiotics, expectorants, or bronchodilators. But these drugs do not eliminate lung inflammation. COPD has a range of complications, including respiratory infections, high blood pressure, heart disease such as heart attacks or heart failure, lung cancer and depression. In the last decade, the incidence of COPD has increased significantly due to pollution, smoking and chronic lung infections.

A variety of physiological processes lead to the production of reactive oxygen species, such as cellular aerobic metabolism, drug metabolism, toxins and exogenous substances, ultraviolet light, X-ray radiation, and phagocytic cells (such as white blood cells) through respiratory bursts against foreign substances such as The process of toxins. These toxins include allergens, chemicals in cigarettes, air pollutants, dust particles, fine particles and toxic compounds. The hazards of these substances below 10 μηη are particularly severe as they can penetrate deep into the lungs. Many studies have shown that when the particle size of these particles is close to 2.5 μm or less, these toxins can penetrate into the gas exchange area and may affect other organs through the lungs. For example, hydrogen peroxide can be produced during the breathing of most organisms, especially if the cells are under pressure. These reactive oxygen species can damage cells. Studies have shown that the production of reactive oxygen species can cause many diseases of the skin, tissues and organs, such as atherosclerosis, arthritis, cytotoxicity, skin inflammation, skin photoaging, skin wrinkles, actinic keratosis, Tumor formation, cancer, high blood pressure, Parkinson's disease, lung disease and heart disease.

When cells are damaged by oxides, antioxidants can act to restore cells. Antioxidants prevent the damage of reactive oxygen species to cells and tissues. For example, pyruvate and other alpha-keto acids have the ability to rapidly and chemically neutralize hydrogen peroxide, thereby protecting cells from lysis.

Pyruvic acid is a weakly acidic organic acid having both a carbonyl group and a carboxyl group in the molecule, and has the properties of a carboxylic acid, a ketone and an α-keto acid. Pyruvic acid is a tricotonic acid produced in the body, which is the final product of the glycolytic pathway, or oxidized into acetyl-coenzyme into the mitochondria, enters the tricarboxylic acid cycle, completes the aerobic oxidation of glucose, or is insufficient in oxygen. At the time, it is reduced to lactic acid in the cytoplasm. Pyruvate also achieves the interconversion of sugars, fats and amino acids in the body through the acetyl-coenzyme and tricarboxylic acid cycles. Therefore, pyruvic acid plays an important pivotal role in the metabolic linkage of the three major nutrients.

Pyruvic acid and pyruvate are antioxidants. In macrophages and other cell lines, sodium pyruvate regulates the production and levels of inflammatory mediators such as oxygen free radicals, while increasing the synthesis of nitric oxide. Sodium pyruvate also reduces the excessive synthesis of superoxide anion. Sodium pyruvate can increase the level of glutathione, a major antioxidant in the cell. Pyruvate can enter cells through the transmembrane transport system and can penetrate the blood-brain barrier. All cells have a transmembrane transport system that is capable of concentrating pyruvate in plasma beyond plasma concentrations. After neutralizing the oxygen free radicals, excess sodium pyruvate can enter the bronchial tubes and lung cells.

Now 3⁄43⁄4 surgery (Prior Art)

U.S. Patent No. 5210098 (Nath) prevents and prevents acute nephritis and acute renal failure with pyruvic acid;

U.S. Patent No. 5296370 (Martin et al.) uses pyruvate to prevent and reduce damage to mammalian cells and promote regeneration of damaged cells;

U.S. Patent No. 5,256,697 (Millerer et al.) uses oral pyruvate medicinal precursors to increase insulin resistance, reduce long-term insulin levels, and reduce fat gain;

U.S. Patent Nos. 3920835, 3984556 and 3988470 (Van Scott et al.) use of a compound including pyruvic acid to treat acne, dandruff and palmoplantar disease;

U.S. Patent No. 4105783, 4197316 (Yu et al.) uses a compound including pyruvic acid to treat dry skin;

U.S. Patent No. 4,234,599 (Van Scott et al.) for the treatment of actinic keratosis and non-actinic keratosis with a compound including pyruvic acid;

US Patent No. 4294852 (Wildnauer et al.) uses a compound including pyruvic acid to treat skin diseases; sodium pyruvate can reduce gastric mucosal erosion, ulceration and hemorrhage caused by acetylsalicylic acid in guinea pigs and rats, but not Reduces the analgesic and antipyretic properties of acetylsalicylic acid (Puschmann, Arzneimittelforschung, 1983);

Pyruvate can increase the muscle strength of the myocardium. Stunning myocardium is a short period of coronary occlusion that lasts for hours to days Reversible symptoms of cardiac insufficiency (Mentzer et al., Ann. Surg., 1989);

Pyruvic acid has the effect of stabilizing left ventricular pressure and working parameters and reducing the range of effects of myocardial infarction. Pyruvate also helps restore spontaneous heartbeat and normal heart rate and stress after myocardial infarction (Bunger et al., J. Mol. Cell. Cardiol., 1986; Mochizuki et al., J. Physiol. (Paris), 1980 Regitz et al., Cardiovasc, Res., 1981; Giannelli et al Ann. Thorac. Surg., 1976);

Sodium pyruvate also inhibits the formation of hydrogen peroxide and protects the system from reactive oxygen species (Martin, PhD thesis, 1987-1989).

The above prior art describes a method for inhibiting active oxygen production using pyruvate to treat a range of diseases, but does not mention a method for using pyruvate to exclude pulmonary toxins in patients with chronic obstructive pulmonary disease, in particular.

Summary of the invention

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the deficiencies of the prior art and to provide a method for the exclusion of pulmonary toxins in healthy and chronic obstructive pulmonary disease patients using an optimized pyruvate drug composition. The pyruvate drug composition produces a therapeutic effect by contacting mammalian cells, wherein the optimized pyruvate drug composition can be selected from the group consisting of pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, a pharmaceutically acceptable precursor, or a mixture thereof.

This invention includes the treatment of smokers and patients with chronic obstructive pulmonary disease with a pharmaceutical composition of pyruvic acid and a pharmaceutical carrier. Among them, pyruvic acid decomposes or excretes lung toxins that cause a decrease in lung function by enhancing the function of the pulmonary cell transport system. Wherein the pharmaceutical carrier may be selected from one or more of an osmotic pressure regulating agent, a pH adjusting agent, a nutritional supplement and a fragrance.

The method also includes the use of pyruvic acid while using other drugs such as antibiotics, antivirals, antifungals, antineoplastics, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory drugs, cytokines, and One or more of the steroids. Ideally, the pyruvate drug composition is administered by inhalation through the respiratory tract.

The present invention is a technique for treating diseases in a mammal using a pyruvate drug composition. The use of pyruvic acid to form a lung toxin is a new invention. Toxins such as benzene reduce lung function, and pyruvate drugs can increase the function of the lung cell transport system, thereby eliminating toxins and enhancing the enzyme system, allowing breathing to ventilate and alleviate cough symptoms.

Chronic obstructive pulmonary disease is mainly caused by inflammation of the lungs and bronchus. It is a new technique to improve lung function and reduce cough symptoms by eliminating toxins. Chronic obstructive pulmonary disease mainly includes chronic bronchitis and emphysema. Chronic bronchitis is a chronic, non-specific inflammation of the trachea, bronchial mucosa and surrounding tissues that causes airflow into the lungs to be unsmooth. Emphysema is a persistent expansion of the alveolar tissue at the distal end of the terminal bronchioles due to an increase in residual air volume, which in turn leads to alveolar septal destruction and increased volume, which affects normal breathing.

This type of respiratory inflammation is derived from a physiological process called a respiratory burst. Breathing outbreaks are the normal physiological response of mammalian defense cells such as white blood cells. These defense cells typically release a range of active substances at the site of invasion after the mammal is injured or invaded. These active substances include proteases and reactive oxygen species such as hydrogen peroxide. The purpose of a respiratory burst is to provide a The series can be used by white blood cells to destroy the active substances of foreign cells, viruses, particles and toxins. Breathing outbreaks are a series of coordinated metabolic reactions that occur after white blood cells are exposed to a suitable stimulus. These metabolic reactions are the basis for the white blood cells to use the oxidation reaction to kill foreign matter.

Breathing outbreaks are usually activated within one minute of the leukocyte exposure stimulus. When the respiratory burst is activated, the oxygen consumption of white blood cells increases by more than 100 times normal, resulting in the formation of superoxide compounds, peroxy compounds and hydrogen peroxide. Here, white blood cells include lymphocytes, phagocytic cells, macrophages, and helper cells.

The stimuli that cause respiratory bursts are generally toxins, including allergens, chemicals in cigarettes, air pollutants, dust particles, fine particles and toxic compounds. Specific examples include, but are not limited to, benzene, formaldehyde, ammonia, methanol, nicotine, Tar, Ding, Acetone, Acetic Acid, Arsenic, Cadmium, Carbon Monoxide, Lead, Toluene, Cyanide, Sulfur Oxide, Nitrogen Oxide, Fine Particles (PM), Persistent Free Radicals, Radioactive Contaminants, etc.

Normally, after a respiratory burst, as the stimulus disappears, the white blood cells return to their normal state. If the respiratory burst persists without stopping, the sustained metabolic response of the white blood cells can cause inflammation. White blood cells continue to produce active compounds that eventually attack, damage and kill normal tissue cells and other white blood cells, causing inflammation. The damage and death of peripheral tissues, blood cells and other white blood cells due to the persistent respiratory burst process of white blood cells is the pathological basis of chronic obstructive pulmonary disease. By eliminating these inhaled stimuli and toxins, the present invention provides a method for relieving pulmonary inflammation by osmotic pressure-balanced pyruvate solution.

The pyruvate drug composition used to destroy the toxins acts by contacting the cells of the mammal, especially by contact with the respiratory tract. The pyruvic acid drug composition may be selected from the group consisting of pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, a pharmaceutically acceptable precursor, or a mixture thereof. Pyruvate The drug composition has antioxidant capacity and protects cells from oxides. Our research shows that pyruvate can eliminate toxins from the lungs. Ideally, the pyruvate drug composition will range from 0.1 to 10.0 mM, with a more desirable concentration range of 0.25-5.0 mM, and a more desirable concentration range of 0.5-4.0 mM.

Pyruvate pharmaceutically acceptable salts are pyruvate salts which do not cause toxic side effects in mammalian cells. A typical pyruvate is selected from the group consisting of lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate or a mixture thereof.

Pyruvate is present in a variety of chemical forms known as precursors that release pyruvate by reaction with mammalian cells. Medicinal precursors are those compounds that must be produced by in vivo biochemical reactions. The delay from the entry of a compound into the body to produce a drug is called the drug incubation period. By chemically modifying a biologically active compound to form a novel compound, the novel compound is capable of releasing an otherwise biologically active compound by enzymatic reaction in vivo. The primary purpose of this chemical modification is to enhance the physicochemical properties of the original compound, including absorption, distribution and enzymatic metabolism. The drug incubation period can also include non-enzymatic regeneration of the original compound. The prodrug of pyruvic acid is selected from the group consisting of ethyl pyruvate, pyruvyl glycine, pyruvyl alanine, Pyruvyl leucine, pyruvidoproline, pyruvyl isoleucine, pyruvyl phenylalanine, pyruvic acid amide, pyruvate or a mixture thereof.

The pyruvic acid drug composition also includes a pharmaceutical carrier, including an osmotic pressure regulating agent and an acid-base regulating agent. The osmotic pressure adjusting agent includes and is not limited to one or more of sodium chloride, glucose, sorbitol, glycerin, polyethylene glycol, propylene glycol, and mannitol. One of the ideal osmotic pressure adjusting agents is sodium chloride. The optimized mass concentration of sodium chloride is 0.05%-8%, the more optimized mass concentration is 0.2%-5%, and the more optimized mass concentration is 0.45%-1.8%.

The acid-base regulator includes, but is not limited to, one or more of hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, tartaric acid, sodium tartrate, and potassium hydroxide. In addition, the pharmaceutical carrier is also selected from the group consisting of conventional physiological saline such as bicarbonate solution, Ringer's solution, lactated Ringer's solution, phosphate buffer solution, TRIS buffer solution, HEPES buffer solution, standard citrate Solution (SSC), Hank's Balanced Salt Solution (HBSS), Earl's Balanced Salt Solution (EBSS) or Grignard Balanced Salt Solution (GBSS). The concentration of the osmotic pressure adjusting agent should be within a physiologically acceptable range. Ideally, the final solution has an osmotic pressure in the range of 1-2800 Osm/L, a more desirable osmotic pressure range of 154-1800 Osm/L, and a more desirable osmotic pressure range of 308-1027 Osm/L. Ideally, the pH of the final solution will range from pH 2.5 to 11, with a more desirable pH range of pH 4.0-10, and a more desirable pH range of pH 5.0-9.0.

In addition, the pharmaceutical composition may also include nutritional supplements, fragrances, and mixtures thereof. For example, the nutritional supplement is selected from one or more of leucine, vitamin D, vitamin E, glutamic acid, folic acid, and niacinamide.

The pyruvic acid drug composition can be used both locally in the lesion and systemically in the body. It can also be used locally in the lesion and systemically at the same time.

Ideally, the pyruvate drug composition is administered by inhalation. The pyruvic acid drug composition can be administered in a mist form by a suitable method. The pyruvic acid drug composition can be in a liquid or solid form, and the droplets or solid solid particles must be small enough to be inhaled for administration to the lungs. The organization absorbed smoothly. It is desirable to administer the microparticles between 0.01 and 10 μηη, more preferably between 0.1 and 7 μηη, and more preferably between 0.5 and 5 μηη.

The inhalation course of pyruvic acid may be inhaled one or more times. Typically, each inhalation can last from 1 to 30 minutes, more preferably within 20 minutes, and more preferably within 15 minutes.

A sterile solution of a pyruvic acid drug can be administered in a mist form after treatment using a nebulizer, or can also be administered using a nebulizer. The drug composition can also be administered by inhalation in the form of a dry powder using dry powder inhalation. When administered by dry powder inhalation, it is desirable that the weight per dose ranges from 0.0001 to 10 mg, more preferably from 0.005 to 5 mg per dose, more preferably every time. The weight of the agent ranges from 0.01 to 0.275 mg.

The pyruvate drug composition can also be used with other drugs. The drug may be selected from the group consisting of an antibiotic, an antiviral drug, and One or more of fungal drugs, antineoplastic agents, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory drugs, cytokines, and steroids. The amount of drug used should be a medically effective amount. A medically effective amount refers to a dose that is usually used to treat a particular condition, depending on the condition being treated and other ingredients in the composition of the drug, the primary purpose being to achieve a therapeutic effect. The specific dosage should be determined by an experienced medical practitioner, which is not the scope of interest of the present invention. These drugs can be used before, or after, the use of pyruvic acid.

The antibiotics that can be used can be selected from a variety of water-soluble or water-insoluble drugs, or their acids or salts. The salt may be an organic salt or an inorganic salt. Antibiotics can be in a variety of sustained or extended release forms. Examples of antibiotics include, but are not limited to, guanidine-containing compounds, sulfonamides, nitrofuran, metronidazole, tinidazole, nimozoline, benzoic acid, aminoglycosides, macrolides, penicillins, peptides, Tetracycline, cephalosporin, chloramphenicol, and clindamycin.

The amount of antibiotic used in the present invention depends on the recommended or permissible amount of the particular antibiotic. Ideally, the amount of antibiotic used is about 0.01% to 10% by weight, more preferably 0.1% to 5% by weight, and more desirably 1% to 3% by weight.

Antiviral drugs which can be used can be selected from a variety of water-soluble or water-insoluble drugs, or their acids or salts. The salt may be an organic salt or an inorganic salt. Antiviral drugs can be in a variety of sustained or extended release forms. Examples of antiviral agents include, but are not limited to, RNA synthesis inhibitors, protein synthesis inhibitors, immunostimulating hormones, protease inhibitors, and cytokines. Specific examples include not limited to acyclovir, sodium foscarnet, ribavirin, adenosine, ganciclovir sodium, zidovudine, carbolic acid, adamantyl hydrochloride, interferon alpha-n3.

The amount of antiviral agent used in the present invention depends on the recommended or permissible amount of the specific antiviral agent. Ideally, the antiviral agent is used in an amount of about 0.1% to 20% by weight, more preferably 1% to 10% by weight, more preferably 2% to 7% by weight.

The antifungal agents which can be used can be selected from a variety of water-soluble or water-insoluble drugs, or their acids or salts. The salt may be an organic salt or an inorganic salt. Antifungal agents can be in a variety of sustained or extended release forms. Specific examples of antifungal agents include, but are not limited to, miconazole, clotrimazole, tioconazole, terconazole, povidone iodine, and butoconazole. Other antifungal agents also include lactic acid and sorbic acid. Among them, miconazole and clotrimazole are ideal antifungal drugs.

The amount of antifungal agent used in the present invention depends on the recommended or permissible amount of the particular antifungal agent. Ideally, the amount of the antifungal agent is from about 0.05% to about 10% by weight, more preferably from 0.1% to 5% by weight, more preferably from 0.2% to 4% by weight.

Antineoplastic agents which can be used can be selected from a variety of water-soluble or water-insoluble drugs, or their acids or salts. The salt may be an organic salt or an inorganic salt. Antineoplastic agents can be in a variety of sustained or extended release forms. Examples of antineoplastic agents include those not limited to antimetabolites, antibiotics, plant products, hormones, and various chemotherapeutic drugs. Non-specific The drug includes a sputuming agent and an N-mercapto-N-nitroso compound. Deuteration agents include nitrogen mustard, ethyleneimine, sulfonate and epoxy. Antimetabolites are compounds that interfere with the formation or utilization of normal cellular metabolites, including amino acid antagonists, vitamins and coenzyme antagonists, and antagonists of metabolites involved in nucleic acid synthesis, such as glutamine antagonists, folate antagonists, pyrimidines. Antagonists and guanidine antagonists. Antibiotics are compounds produced by microorganisms that inhibit the growth of other organisms, including actinomycin and related antibiotics, glutarimide antibiotics, sarcomycin, fumagillin, streptavidin, fine-crossed chains. A oxycodone, an actinomycete, a pepsinogen, and an anthracycline antibiotic such as doxorubicin. Plant products include colchicine, podophyllotoxin, and vinca alkaloids. Hormones include steroid hormones for breast and prostate cancer, and corticosteroids for leukemia and lymphoma. Other chemotherapeutic agents include urethane, hydroxyurea and related compounds; thiosemicarbazone and related compounds; phthalimide and related compounds; and triazenes and hydrazines. Antineoplastic agents can also be monoclonal antibodies or X-rays.

The amount of the antitumor agent to be used in the present invention depends on the recommended or allowable amount of the specific antitumor agent. Ideally, the antineoplastic agent is used in an amount of about 1% to 50% by weight, more preferably 10% to 30% by weight, more preferably 20% to 25% by weight.

The present invention provides a method for eliminating lung toxins in healthy people and patients with chronic obstructive pulmonary disease using an optimized pyruvate drug composition. The pyruvate drug composition produces a therapeutic effect by contacting mammalian cells, wherein the optimized pyruvate drug composition is selected from the group consisting of pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, a pharmaceutically acceptable precursor, or a mixture thereof. The invention includes the composition of a drug comprising pyruvic acid and a pharmaceutical carrier for treating a smoker and a patient with chronic obstructive pulmonary disease. Among them, pyruvic acid decomposes or excretes pulmonary toxins that cause a decrease in lung function by enhancing the function of the pulmonary cell transport system. Wherein the pharmaceutical carrier can be selected from one or more of an osmotic pressure regulating agent, a pH adjusting agent, a nutritional supplement, and a fragrance. The method also includes the use of pyruvic acid while using other drugs such as antibiotics, antivirals, antifungals, antineoplastics, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory drugs, cytokines, and One or more of the steroids. Ideally, the pyruvate drug composition is administered by inhalation through the respiratory tract.

The invention has the following advantages:

1. Directly acting on the lung lesions is more targeted and does not participate in systemic metabolism.

2. Pyruvate has less side effects, higher safety and stable drug.

3. Pyruvic acid is a natural substance in cells. It has the function of promoting cell transport system, promoting detoxification of the lungs and facilitating respiration. Its curative effect is more comprehensive than that of antibiotics or sterols, and the effect is better.

DRAWINGS

Figure 1: Percent change in FEV1 after inhalation of saline or 0.5 mM sodium pyruvate in patients with chronic obstructive pulmonary disease; Figure 2: Percent change in FEV1 after inhalation of saline or 1.5 mM sodium pyruvate in patients with chronic obstructive pulmonary disease; Figure 3: Percent change in FEV1 after inhalation of saline or 2.5 mM sodium pyruvate in patients with chronic obstructive pulmonary disease; Figure 4: Percent change in FEV1 after inhalation of saline or 5.0 mM sodium pyruvate in patients with chronic obstructive pulmonary disease; Figure 5: Chronic Percentage change in PEF after inhalation of saline or 0.5 mM sodium pyruvate in patients with obstructive pulmonary disease; Figure 6: Percent change in PEF after inhalation of saline or 1.5 mM sodium pyruvate in patients with chronic obstructive pulmonary disease; Figure 7: Patient with chronic obstructive pulmonary disease Percent change in PEF after inhalation of saline or 2.5 mM sodium pyruvate; Figure 8: Percent change in PEF after inhalation of saline or 5.0 mM sodium pyruvate in patients with chronic obstructive pulmonary disease;

Concrete 3⁄43⁄4"

Example 1 : Toxin study in tissue culture

We used the MatTek EpiDerm test to investigate the ability of pyruvate to stabilize cells, eliminate toxins and increase cell survival. EpiDerm cells are almost identical to lung cells. We treated EpiDerm tissue samples with various concentrations of sodium pyruvate. After one hour of equilibration in sodium pyruvate solution, EpiDerm cells were cultured in a 37 ° C, 5% C02 incubator. The old culture solution was replaced with fresh medium, and the test substance was added to the culture solution at this time. The time of contact between the test substance and the cells was 1 hour, 4 hours and 20 hours, respectively. The main subject is cigarette smoke. The cigarette smoke is condensed on the filter paper and then extracted and added to the cell culture medium. Untreated samples were used as negative controls. After treatment with the test substance, cell culture fluid was used to examine cell viability and cellular stress response (by examining the levels of cytokine IL-1 and IL-8). Repeat this experiment once.

5 ml of 0.5 mM sodium pyruvate contains 0.28 mg of sodium pyruvate; 5 ml of 10 mM sodium pyruvate contains 5.6 mg of sodium pyruvate; 5 ml of 20 mM sodium pyruvate contains 11.2 mg of sodium pyruvate; 5 ml of 40 mM Sodium pyruvate contains 22.4 mg of sodium pyruvate.

Result:

Changes in the levels of IL-1 and IL-8 are the primary test data. Both interleukins have an effect of promoting an inflammatory response. Toxins in cigarettes increase IL-1 and IL-8 levels by more than 200%. Sodium pyruvate solution alone failed to cause an increase in IL-1 and IL-8. However, when sodium pyruvate solution and toxins in cigarettes were present, IL-8 was significantly reduced by at least 200% and IL-1 was significantly reduced by at least 200%. This experiment demonstrates that sodium pyruvate has a role in promoting detoxification of lung cells. Compared with untreated cells, toxins in cigarettes can reduce cell viability by 72%, and after adding pyruvate, cell viability increases by 15%. This data demonstrates that sodium pyruvate can increase cell viability. Example 2: This example is a clinical study data of sodium pyruvate.

Both healthy subjects and patients with chronic obstructive pulmonary disease in this clinical study were or are now smokers and coughed and exposed to air pollution every day. Their symptoms include cough, shortness of breath and decreased lung function. Each patient has a cough diary recorded before and after treatment with sodium pyruvate. Purpose:

1 to check the safety and efficacy of sodium pyruvate inhalation in healthy subjects and patients with mild chronic obstructive pulmonary disease;

2 Determination of sodium pyruvate inhalation can effectively reduce the symptoms of cough in these subjects.

Method:

We used four concentrations of sodium pyruvate solution; 0.5 mM, 1.5 mM, 2.5 mM and 5.0 mM. Eighty subjects consisted of 20 healthy controls and 60 individuals with mild chronic obstructive pulmonary disease. Healthy control individuals were divided into 4 groups of 5 subjects each; each group received four concentrations of sodium pyruvate. Individuals with mild chronic obstructive pulmonary disease were divided into 4 groups of 15 subjects each; each group received four concentrations of sodium pyruvate. Each subject inhaled a single dose of 5.0 mL of different concentrations of sodium pyruvate. Sodium pyruvate is administered by nebulization for about 15-20 minutes each time. A breath test was started on the day of dosing. On the first day, all subjects, including healthy subjects and patients with mild chronic obstructive pulmonary disease, only inhaled saline. In clinical practice, PEF and FEV1 are commonly used as sensitive indicators of chronic obstructive pulmonary disease. PEF is forced expiratory peak flow and FEV1 is forced expiratory volume in one second. These two indicators were tested before saline inhalation and tested again 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after saline inhalation. These test data are baseline data. The next day, the same subjects received treatment with different concentrations of sodium pyruvate solution. The PEF and FEV1 tests were then performed in the same manner. These test data are experimental data.

Result:

1. The percentage change of FEV1 is shown in Table 1. The concentration of 0.5 mM sodium pyruvate is shown in Figure 1. The concentration of 1.5 mM sodium pyruvate is shown in Figure 2. The concentration of 2.5 mM sodium pyruvate is shown in Figure 3. The concentration of 5.0 mM sodium pyruvate is shown in Figure 4. ;

2. The percentage change of PEF is shown in Table 2. The concentration of 0.5 mM sodium pyruvate is shown in Figure 5. The concentration of 1.5 mM sodium pyruvate is shown in Figure 6. The concentration of 2.5 mM sodium pyruvate is shown in Figure 7. The concentration of 5.0 mM sodium pyruvate is shown in Figure 8. . Table 1: Percentage of FEV1 measurements after saline control or sodium pyruvate inhalation

Table 2: Percentage of PEF measurements after saline control or sodium pyruvate inhalation

in conclusion:

A. Safety: All subjects showed good tolerance to inhalation of sodium pyruvate. Serious adverse events and physiological changes that required termination of the study due to sodium pyruvate inhalation were not observed in any of the subjects.

B. Effectiveness: According to changes in measured FEV1 and PEF, sodium pyruvate can help patients with chronic obstructive pulmonary disease to breathe more smoothly. In addition, clinical data indicate that sodium pyruvate solution at a concentration between 0.5 and 1.5 mM is administered by nebulized inhalation to have a significant effect in the prevention and treatment of mild chronic obstructive pulmonary disease. At the same time, the subject's cough diary showed that inhaling sodium pyruvate also reduced the number of coughs per day by 45%. The patient showed a significant reduction in cough symptoms after inhalation of sodium pyruvate Light, but inhaled saline did not change. The results of the measurements showed that normal subjects, whether inhaled saline or sodium pyruvate solution, increased or decreased FEV1 and PEF, but the number of coughs decreased by 50%. Only patients with COPD increased their FEV1 or PEF values, especially This is especially true for smokers. Example 3: Stability study of sodium pyruvate inhaler

See Table 3 for prescriptions

Table 3: Sodium pyruvate inhaler prescription

The sodium pyruvate inhaler prepared in Formulations 1-12 was placed in a 40 ° C stability test chamber for a 6-month accelerated test, and the results are shown in Table 4. The same sodium pyruvate solution still has at least 97% remaining after three years at room temperature.

Table 4: Stability data (percentage is the amount of sodium pyruvate remaining in the solution)

in conclusion:

From Table 4, it was confirmed that sodium pyruvate has good chemical stability at a concentration of 0.5 mM to 6.0 mM. Example 4: Preparation of an inhaler containing 0.5 mM sodium pyruvate

Prescription:

Material Name Usage (g/L) Proportion (%)

Sodium pyruvate 0.0550 0.0055

Sodium chloride 9 0.9

Purified water

Process: Dissolve the prescribed amount of pyruvic acid and sodium chloride in an appropriate amount of purified water, adjust the osmotic pressure of the solution to 308-1027 Osm/L, adjust the pH to 5-9, and prepare a single dose of 0.5 mM sodium pyruvate using BFS technology. Inhalation.

Through clinical research, this product has a good effect on the treatment of mild chronic obstructive pulmonary disease. Example 5: Preparation of 1.5 mM sodium pyruvate inhaler (1000) Prescription: Material name quality ratio Sodium pyruvate 0.0165% 1.059g Sodium chloride 0.85% 54.4g Water 99.2% 6348g Process: Add the prescribed amount of sodium pyruvate and sodium chloride to the 95% balance of purified water and mix well. Add 5% of the remaining amount of purified water and mix well. Aseptically filtered and aseptically filled, a 1.5 mM sodium pyruvate inhaler was dispensed.

Through clinical research, this product has a good effect on the treatment of mild chronic obstructive pulmonary disease. Example 6: Preparation of 2.5 mM sodium pyruvate inhaler (1000) Prescription:

Material name quality ratio Sodium pyruvate 0.0275% 1.765g Sodium chloride 0.85% 54.4g Water 99.1% 6344g Process: Add the prescribed amount of sodium pyruvate and sodium chloride to the 95% balance of purified water and mix well. Add 5% of the remaining amount of purified water and mix well. Sterile filtration followed by aseptic filling and dispensing of 2.5 mM sodium pyruvate inhaler.

Through clinical research, this product has a certain effect on the treatment of mild chronic obstructive pulmonary disease, and is more used for the treatment of severe chronic obstructive pulmonary disease. Example 7: Preparation of 5.0 mM sodium pyruvate inhaler (1000) Prescription:

Material name mass ratio Usage sodium pyruvate 0.055% 3.53g Sodium chloride 0.9% 57.6g Water 99.0% 6339g Process: Add the prescribed amount of sodium pyruvate and sodium chloride to the 95% balance of purified water and mix well. Add 5% of the remaining amount of purified water and mix well. Aseptically filtered and aseptically filled, a 5.0 mM sodium pyruvate inhaler was dispensed.

Through clinical research, this product has a good effect on the treatment of severe chronic obstructive pulmonary disease. Example 8: Preparation of 6.0 mM sodium pyruvate inhaler (1000) Prescription:

Material name mass ratio

Sodium pyruvate 0.066% 4.236g Sodium chloride 0.85% 57.6g Water 99.0% 6338g Process: Add the prescribed amount of sodium pyruvate and sodium chloride to the 95% balance of purified water and mix well, then add 5% The purified water was stirred well. Aseptically filtered and aseptically filled, a 6.0 mMol sodium pyruvate inhaler was dispensed.

Through clinical research, this product has a good effect on the treatment of severe chronic obstructive pulmonary disease.

The inhalant involved in the above embodiment used 5 ml of liquid each time, poured the liquid into the atomizer to generate a water mist, and the natural mist of the lungs was used to inhale the water mist into the lungs for 15 minutes each time. Example 9: Preparation of an inhaler containing 0.5 mM sodium pyruvate (Lactate Ringes' solution)

Prescription:

Material Name Usage (g/L) Proportion (%)

Sodium pyruvate 0.0550 0.0055

Lactate Ringes solution q.s tolL 99.9945

Process: Dissolve the prescribed amount of pyruvic acid in an appropriate amount of lactated Ringers' solution, adjust the osmotic pressure of the solution to 273-1027 Osm/L, adjust the pH to 5-9, and prepare a single dose of 0.5 mM using aseptic technique. Sodium pyruvate spray. Example 10: Preparation of an inhaler containing 1.5 mM sodium pyruvate (HBSS solution)

Prescription:

Material Name Usage (g/L) Proportion (%)

Sodium pyruvate 0.1650 0.01650 HBSS solution qs tolL 99.9835

Process: Dissolve the prescribed amount of pyruvic acid in an appropriate amount of HBSS solution, adjust the osmotic pressure of the solution to 275 (± 50 Osm / L), adjust the pH to 7.1-7.5, this solution can be used by the sprayer to the patient. Example 11: Preparation of a dry powder inhaler containing sodium pyruvate

Prescription:

Material Name Usage (g/L) Proportion (%)

Sodium pyruvate 55.0000 5.5000

Glucose 50 5

Leucine 5 0.5

Sterile water

Process: Mix the prescribed amount of sodium pyruvate, glucose, leucine and dissolve in an appropriate amount of water, and adjust the osmotic pressure to 308-1027 Osm/L with osmotic pressure regulator to adjust the pH to 5-9. After spray drying, it was charged into a powder sprayer with a single delivery dose of 0.275 mg.

Example 12: Preparation of a metered dose inhaler containing potassium pyruvate

Prescription:

Material Name Usage (g/L) Proportion (%)

Potassium pyruvate 165.0000 16.50000

Sorbitol 54.8 5.48

Nicotinamide 5 0.5

Sterile water

Process: Mix the prescribed amount of potassium pyruvate, sorbitol and nicotinamide in a suitable amount of sterile water, and adjust the osmotic pressure to 308-1027 Osm/L with osmotic pressure regulator to adjust the pH to 5-9. After the bacteria were loaded into the metered dose inhaler, a single delivery dose of potassium pyruvate was 0.825 mg.

Example 13: Preparation of 0.1 mM pyruvlylglycine inhaler (1000) Prescription:

Material name quality ratio Pyruvyl glycine 0.03% 1.8g Sodium chloride 0.05% 3g Water 99.92% 5995.2g Process: Add the prescribed amount of pyruvyl glycine and sodium chloride to the 95% balance purified water and mix well, then add 5% The purified water was stirred well. Sterile filtration followed by aseptic filling, dispensing a 0.1 mM pyruvyl glycine inhaler, the osmotic pressure was controlled at 145 ± 50 Osm / L, pH 5-9.

Through clinical research, this product has a good curative effect on the treatment of severe chronic obstructive pulmonary disease. Depending on the severity of the disease, depending on the inhalation time, the dose is between 0.001 and 10 mg, by changing the atomization frequency. The droplet is controlled to be between 0.01 10 μm. Pyruvyl glycine is a precursor of sodium pyruvate. It has the same pharmacological action as pyruvic acid and can be used simultaneously with sodium pyruvate or before or after pyruvate. Example 14: Preparation of O. l mM pyruvlylglycine and antibiotic (azithromycin) compound inhaler (1000) Prescription:

Material name Mass ratio Dosage (1000) Pyruvyl glycine 0.03% 1.8g

Azithromycin 1% 60g

Sodium Chloride 0.45% 27g Water 98.52% 5911.2g Process: Add the prescribed amount of pyruvyl glycine, sodium chloride and azithromycin to the 95% balance purified water, stir well, then add 5% of the remaining amount of purified water and mix well. . Sterile filtration followed by aseptic filling, dispensing 0.1 mM pyruvlylglycine and azithromycin compound inhaler, the osmotic pressure was controlled at 485 ± 50 Osm / L, pH 5-9.

Through clinical research, this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent bacterial infection. According to the severity of the disease, depending on the severity of the inhalation time, the dosage is between 0.001 and 10 mg. The atomization frequency is controlled to be between 0.01 10 μm, pyruvyl glycine is the precursor of sodium pyruvate, has the same pharmacological action as pyruvate, and the azithromycin is stable, so this product can be simultaneously with sodium pyruvate Use, or before or after pyruvate. Example 15: Preparation of 0.5 mM pyruvyl alanine inhaler (1000)

Prescription:

Material Name Mass Ratio Dosage Pyruvyl Alanine 0.17% 1 g

Sodium chloride 1.8% 10.8g Water 98.03% 5988.2g Process: Add the prescribed amount of pyruvyl alanine and sodium chloride to 95% of the remaining amount of purified water, stir well, then add 5% of the remaining amount of purified water to stir. Evenly. Sterile filtration followed by aseptic filling, dispensing 0.5 mMol of acetone alanine inhaler, osmotic pressure controlled at 845 ± 50 Osm / L, pH 5-9.

Through clinical research, this product has a good curative effect on the treatment of chronic obstructive pulmonary disease. Depending on the severity of the disease, depending on the inhalation time, the dose is between 0.001 and 10 mg. By changing the atomization frequency, The droplet is controlled to be between 0.01 10 μm, and the pyruvyl alanine is a precursor of sodium pyruvate. It has the same pharmacological action as pyruvic acid and can be used simultaneously with sodium pyruvate or before or after pyruvate. Example 16: Preparation of 0.5 mM pyruvyl alanine and antiviral (morpholinium) compound inhaler (1000) Prescription:

Material Name Mass Ratio Dosage Pyruvyl Alanine 0.17% lg

Morpholinium 1% 60g Sodium Chloride 1.8% 108g Water 97.03% 5831g Process: Add the prescribed amount of pyruvyl glycine, sodium chloride and morpholinium to 95% of the remaining purified water, stir well and then add 5%. The remaining amount of purified water is stirred evenly. Sterile filtration followed by aseptic filling, dispensing 0.5 mM pyruvlylglycine and morpholinium compound inhaler, the osmotic pressure was controlled at 985 ± 50 Osm / L, pH 5-9.

Through clinical research, this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent viral infection. According to the severity of the disease, depending on the severity of the inhalation time, the dosage is between 0.001 and 10 mg. The frequency is controlled to be between 0.01 10 μηη, pyruvidoglycine is the precursor of sodium pyruvate, and is pyruvic acid. The same pharmacological action, and the morpholinium is stable, so this product can be used simultaneously with sodium pyruvate or before or after pyruvate. Example 17: Preparation of a pyruvate leucine inhaler of 2 (1000)

Prescription:

Material Name Mass Ratio Dosage Pyruvyl leucine 1% 60 g

Sodium chloride 5% 300 water 94% 5640g Process: Add the prescribed amount of pyruvyl leucine and sodium chloride to the 95% balance purified water and mix well. Then add 5% of the purified water and mix well. Aseptically filtered and aseptically filled, 2 mMol of acetone alanine inhaler was dispensed, and the osmotic pressure was controlled at 1344 ± 50 Osm / L, and the pH was adjusted to 5-9.

Through clinical research, this product has a good curative effect on the treatment of chronic obstructive pulmonary disease. Depending on the severity of the disease, depending on the inhalation time, the dose is between 0.001 and 10 mg. By changing the atomization frequency, The droplet is controlled to be between 0.01 10 μm, and pyruvate leucine is a precursor of sodium pyruvate. It has the same pharmacological action as pyruvic acid and can be used simultaneously with sodium pyruvate or before or after pyruvate. Example 18: Preparation of 2 mM pyruvyl leucine and antifungal (terbinafine) compound inhaler (1000) Prescription:

Material name Mass ratio Dosage (1000) Pyruvyl alanine 1% 60g

Terbinafine 1% 60g Sodium chloride 8% 480g Water 90% 5400g Process: Add the prescribed amount of pyruvyl glycine, sodium chloride and terbinafine to the 95% balance of purified water, stir well and then add 5% of the remaining amount of purified water is stirred evenly. Aseptically filtered and aseptically filled, 2 mM pyruvlylglycine and terbinafine combination inhaler were obtained. The osmotic pressure was controlled at 2798±50 Osm/L, and the acid-base regulator was passed. Adjust the pH to 8-11.

Through clinical research, this product has a good effect on the treatment of chronic obstructive pulmonary disease and complicated fungal infection. According to the severity of the disease, depending on the severity of the inhalation time, the dosage is between 0.001 and 10 mg. The frequency is controlled to be between 0.01 10 μm, pyruvyl glycine is the precursor of sodium pyruvate, has the same pharmacological action as pyruvic acid, and terbinafine is stable, so this product can be combined with pyruvic acid. Sodium is used at the same time, or before or after pyruvate. Example 19: Preparation of 4 mM pyruvate proline inhaler (1000)

Prescription:

Material name Mass ratio Dosage Pyruvate proline 3% 180 g

Glucose 0.9 % 54g Vitamin D 0.1% 6g

Water 96% 5760g Process: Add the prescribed amount of pyruvyl valine, glucose and vitamin D to 95% of the remaining amount of purified water and mix well. Then add 5% of the purified water and mix well. Sterile filtration followed by aseptic filling and dispensing of 4 mM pyruvidoproline inhaler with an osmotic pressure of 988 ± 50 Osm/L and an acid-base regulator pH of 8-10.

Through clinical research, this product has a good curative effect on the treatment of chronic obstructive pulmonary disease. Depending on the severity of the disease, depending on the inhalation time, the dose is between 0.001 and 10 mg. By changing the atomization frequency, The droplet is controlled between 0.01 and 10 μm, and the pyruvidoproline is a precursor of sodium pyruvate. It has the same pharmacological action as pyruvic acid and can be used simultaneously with sodium pyruvate or before or after pyruvate.

Example 20: Preparation of 8 mM pyruvidoproline and antineoplastic (paclitaxel) compound inhaler (1000) Prescription

Material name quality ratio (1000) Pyruvate proline 6% 360g paclitaxel 1% 60g sorbitol 1% 60g Grignard equilibrium salt 0.5% 30

Water 94.5% 5490g Process: Add the prescribed amount of pyruvyl valine, sorbitol and paclitaxel to 95% of the remaining purified water and mix well. Then add 5% of the purified water and mix well. Sterile filtration, aseptic filling, dispensing 8 mM pyruvate proline and paclitaxel inhalation, the osmotic pressure is controlled at 1021±50 Osm/L, and the pH is adjusted by acid-base regulator. 10.

Through clinical research, this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent tumors (especially benign tumors). According to the severity of the disease, depending on the severity of the inhalation, the dosage is 0.001~10mg. In the meantime, by changing the atomization frequency, the droplet is controlled to be between 0.01 and 10 μm, pyruvyl valine is the precursor of sodium pyruvate, has the same pharmacological action as pyruvic acid, and paclitaxel is stable, so this product It can be used simultaneously with sodium pyruvate or before or after pyruvate.

Example 21

Pyruvate medicinal precursors increase cell viability

The purpose of this experiment was to measure the effect of prodrugs of pyruvate on increasing cell viability. Fibroblasts were seeded at a density of 1 x 105 cells/ml in 6-well cell culture plates. After 24 hours of incubation, hydrogen peroxide (Η202) solution was added to give a final concentration of hydrogen peroxide between O.OlmM and 0.03 mM. Hydrogen peroxide can cause cellular oxidative stress. Cell viability is measured by the permeability of the test cell membrane.

As an experimental group, pyruvyl leucine was added to the above hydrogen peroxide-treated cells to a concentration of 0.1 to 50 mM. When the concentration of pyruvyl leucine is between 2 and 20 mM, pyruvyl leucine can be significant (PO.05) and effectively increases cell viability by 10-30%. This experiment demonstrates that prodrug prion precursors can increase cell viability.

Claims

Claim

1. The pyruvate drug composition is used for the preparation of a pulmonary toxin drug for patients with healthy and pulmonary diseases, including chronic obstructive pulmonary disease (COPD). The pyruvate drug composition is used to produce a therapeutic effect by contacting the human body, wherein the lung disease includes chronic obstruction. Pulmonary lung disease (COPD) is a type of lung disease caused by smoking and air pollution, which causes lung toxin accumulation, respiratory obstruction, decreased lung function, and frequent cough. Chronic obstructive pulmonary disease mainly includes chronic bronchitis and emphysema. Chronic bronchitis is a chronic non-specific inflammation of the trachea, bronchial mucosa and surrounding tissues, which causes the airflow into the lungs to be unsmooth. Emphysema is the persistent expansion of the alveolar tissue at the distal end of the terminal bronchioles due to the increase in residual air volume, which leads to Alveolar septal destruction, increased volume, affecting normal breathing, lung tissue damage caused by chronic obstructive pulmonary disease is irreversible, but symptoms and disease progression can be controlled by detoxification.

2. A composition having the use according to claim 1, characterized in that the pyruvic acid drug composition in the composition is selected from the group consisting of pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, a pharmaceutically acceptable precursor or a mixture thereof.

3. The composition according to claim 2, characterized in that the pharmaceutically acceptable salt of pyruvic acid is selected from the group consisting of sodium pyruvate, potassium pyruvate, lithium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, acetone. Manganese acid or a mixture thereof.

4. The composition according to claim 2, characterized in that the prodrug of the pyruvic acid is selected from the group consisting of ethyl pyruvate, pyruvyl glycine, pyruvyl alanine, pyruvyl leucine, pyruvazinium. Amino acid, pyruvyl isoleucine, pyruvyl phenylalanine, pyruvic acid amide, pyruvate or a mixture thereof.

The composition according to claim 2, wherein the pyruvic acid, the pharmaceutically acceptable salt of pyruvic acid or the pharmaceutically acceptable precursor has a molar concentration of 0.110 mM.

The composition according to claim 5, wherein the pyruvic acid, the pharmaceutically acceptable salt of pyruvic acid or the pharmaceutically acceptable precursor has a molar concentration of 0.15 to 5 mM.

The composition according to claim 6, wherein the pyruvic acid, the pharmaceutically acceptable salt of pyruvic acid or the pharmaceutically acceptable precursor has a molar concentration of 0.5 to 4.0 mM.

The composition according to claim 2, further comprising a pharmaceutical carrier or a medical auxiliary and purified water, wherein the pharmaceutical carrier or the medical auxiliary may be an osmotic pressure adjusting agent, an acid or a base One or more of a regulator, a nutritional supplement, and a fragrance.

The composition according to claim 8, wherein the osmotic pressure adjusting agent is one or more of sodium chloride, glucose, sorbitol, glycerin, polyethylene glycol, propylene glycol, and mannitol. Kind.

The composition according to claim 9, wherein the osmotic pressure adjusting agent is sodium chloride, and the mass concentration of sodium chloride is 0.05% to 8%.

The composition according to claim 10, wherein the osmotic pressure adjusting agent is sodium chloride, and the mass concentration of sodium chloride is 0.2 to 5%.

The composition according to claim 11, wherein the osmotic pressure adjusting agent is sodium chloride, sodium chloride The mass volume concentration is 0.45 1.8%.

The composition according to claim 8, wherein the acid-base regulator is selected from the group consisting of hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, tartaric acid, sodium tartrate and potassium hydroxide. Or a variety.

The composition according to claim 8, wherein the nutritional supplement is selected from one or more of leucine, vitamin D, vitamin E, glutamic acid, folic acid, and niacinamide.

15. The composition according to claim 8, wherein the pharmaceutical carrier is selected from the group consisting of, but not limited to, bicarbonate solution, Ringer's acetate, lactated Ringer's solution, phosphate buffer solution, TRIS buffer solution, HEPES Buffer solution, standard citrate solution, Hank's balanced salt solution, Earl's balanced salt solution or Grignard equilibrium salt solution.

The composition according to claim 2, wherein the pharmaceutical composition is administered as a carrier by a polar liquid having an osmotic pressure of 1 2800 Osm/L and a pH of 2.5 to 11 .

17. Composition according to claim 16, characterized in that the carrier has a more optimized osmotic pressure of 154 1800 Osm/L and a pH of pH 4.0.

The composition according to claim 17, wherein the carrier has a more optimized osmotic pressure of 308 1027 Osm/L and a pH of 5.0 to 9.0.

19. Composition according to claim 2, characterized in that the contacting method is selected from the group consisting of nebulizers, dry powder inhalers or sprays.

The composition according to claim 19, wherein the pyruvic acid and a pharmaceutically acceptable salt or pharmaceutically acceptable precursor thereof are administered in an amount of 0.0001 to 10 mg.

21. Composition according to claim 20, characterized in that the pyruvic acid and its pharmaceutically acceptable salt or pharmaceutically acceptable precursor are more preferably administered in an amount of 0.0005 5 mg.

22. The composition according to claim 21, wherein the pyruvic acid and its pharmaceutically acceptable salt or pharmaceutically acceptable precursor are more preferably administered in an amount of 0.001 0.825 mg.

23. The composition according to claim 2, wherein pyruvic acid and a pharmaceutically acceptable salt or pharmaceutically acceptable precursor thereof form minute droplets that can penetrate deep into the lungs, said droplet size being 0.01 10 μ m.

24. The composition according to claim 23, wherein the droplet size is 0.17 μιη.

The composition according to claim 24, wherein the droplet size is 0.5 5 μm.

The composition according to claim 2, wherein, when pyruvic acid, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable precursor are used, another drug or drugs are used at the same time, and the drug is selected from the group consisting of antibiotics and antibiotics. One or more of a viral, an antifungal, an antineoplastic, an antihistamine, a protein, an enzyme, a hormone, a nonsteroidal anti-inflammatory drug, a cytokine, and a steroid.

27. The composition according to claim 26, wherein one or more drugs are using pyruvic acid and Medicinal salts and medicinal precursors are used before.

28. The composition according to claim 26, wherein the other drug or drugs are used simultaneously using pyruvic acid and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable precursor.

29. A composition according to claim 26 wherein the other drug or drugs are used after the use of pyruvic acid and its pharmaceutically acceptable salts and pharmaceutically acceptable precursors.