WO2015014209A1 - Compositions pharmaceutiques de pyruvate pour la stabilité osmotique et effet de désintoxication de celles-ci chez des êtres humains en bonne santé et des patients atteints d'affections pulmonaires - Google Patents

Compositions pharmaceutiques de pyruvate pour la stabilité osmotique et effet de désintoxication de celles-ci chez des êtres humains en bonne santé et des patients atteints d'affections pulmonaires Download PDF

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WO2015014209A1
WO2015014209A1 PCT/CN2014/082185 CN2014082185W WO2015014209A1 WO 2015014209 A1 WO2015014209 A1 WO 2015014209A1 CN 2014082185 W CN2014082185 W CN 2014082185W WO 2015014209 A1 WO2015014209 A1 WO 2015014209A1
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pyruvate
composition according
pharmaceutically acceptable
pyruvic acid
acid
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PCT/CN2014/082185
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English (en)
Chinese (zh)
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蒋志君
马丁⋅阿兰
莱赫⋅斯坦利
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江苏长泰药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • 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
  • Chronic obstructive pulmonary disease 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.
  • These toxins include allergens, chemicals in cigarettes, air pollutants, dust particles, fine particles and toxic compounds.
  • the hazards of these substances below 10 ⁇ are particularly severe as they can penetrate deep into the lungs.
  • reactive oxygen species can damage cells.
  • antioxidants can act to restore cells.
  • Antioxidants prevent the damage of reactive oxygen species to cells and tissues.
  • 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 ⁇ -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.
  • 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.
  • 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 uses oral pyruvate medicinal precursors to increase insulin resistance, reduce long-term insulin levels, and reduce fat gain;
  • 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, Arzneiffenbachaba, 1983);
  • 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);
  • 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.
  • 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.
  • pyruvic acid decomposes or excretes lung toxins that cause a decrease in lung function by enhancing the function of the pulmonary cell transport system.
  • 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.
  • drugs such as antibiotics, antivirals, antifungals, antineoplastics, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory drugs, cytokines, and One or more of the steroids.
  • 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.
  • 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.
  • 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.
  • the white blood cells 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.
  • 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.
  • 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).
  • concentration of the osmotic pressure adjusting agent should be within a physiologically acceptable range.
  • 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.
  • 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.
  • the pharmaceutical composition may also include nutritional supplements, fragrances, and mixtures thereof.
  • 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.
  • 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 ⁇ , more preferably between 0.1 and 7 ⁇ , and more preferably between 0.5 and 5 ⁇ .
  • 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.
  • 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.
  • 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.
  • pyruvic acid decomposes or excretes pulmonary toxins that cause a decrease in lung function by enhancing the function of the pulmonary cell transport system.
  • 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.
  • the pyruvate drug composition is administered by inhalation through the respiratory tract.
  • 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.
  • 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 obstruct
  • Example 1 Toxin study in tissue culture
  • EpiDerm cells are almost identical to lung cells.
  • 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.
  • 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. ;
  • sodium pyruvate can help patients with chronic obstructive pulmonary disease to breathe more smoothly.
  • 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.
  • 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 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.
  • 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.
  • Example 7 Preparation of 5.0 mM sodium pyruvate inhaler (1000) Prescription:
  • Example 8 Preparation of 6.0 mM sodium pyruvate inhaler (1000) Prescription:
  • this product has a good effect on the treatment of severe chronic obstructive pulmonary disease.
  • Example 9 Preparation of an inhaler containing 0.5 mM sodium pyruvate (Lactate Ringes' solution)
  • Lactate Ringes solution q.s tolL 99.9945
  • Example 12 Preparation of a metered dose inhaler containing potassium pyruvate
  • Nicotinamide 5 0.5
  • this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent bacterial infection.
  • the dosage is between 0.001 and 10 mg.
  • the atomization frequency is controlled to be between 0.01 10 ⁇ m
  • pyruvyl glycine is the precursor of sodium pyruvate
  • 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)
  • this product has a good curative effect on the treatment of chronic obstructive pulmonary disease.
  • the dose is between 0.001 and 10 mg.
  • the droplet is controlled to be between 0.01 10 ⁇ m, 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:
  • this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent viral infection.
  • the dosage is between 0.001 and 10 mg.
  • the frequency is controlled to be between 0.01 10 ⁇
  • 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)
  • 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.
  • this product has a good curative effect on the treatment of chronic obstructive pulmonary disease.
  • the dose is between 0.001 and 10 mg.
  • the droplet is controlled to be between 0.01 10 ⁇ m, 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:
  • 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.
  • the dosage is between 0.001 and 10 mg.
  • the frequency is controlled to be between 0.01 10 ⁇ m
  • pyruvyl glycine is the precursor of sodium pyruvate
  • 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)
  • 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.
  • this product has a good curative effect on the treatment of chronic obstructive pulmonary disease.
  • the dose is between 0.001 and 10 mg.
  • the droplet is controlled between 0.01 and 10 ⁇ m, 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
  • 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.
  • this product has a good effect on the treatment of chronic obstructive pulmonary disease and concurrent tumors (especially benign tumors).
  • the dosage is 0.001 ⁇ 10mg.
  • the droplet is controlled to be between 0.01 and 10 ⁇ m
  • pyruvyl valine is the precursor of sodium pyruvate
  • paclitaxel is stable, so this product It can be used simultaneously with sodium pyruvate or before or after pyruvate.
  • 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 ( ⁇ 202) 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.
  • pyruvyl leucine was added to the above hydrogen peroxide-treated cells to a concentration of 0.1 to 50 mM.
  • 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%.
  • prodrug prion precursors can increase cell viability.

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Abstract

La présente invention concerne un procédé de désintoxication chez des êtres humains en bonne santé et des patients atteints d'affections pulmonaires au moyen de compositions pharmaceutiques de pyruvate. Des toxines accumulées dans des cellules mammaliennes en raison du tabagisme et de la pollution de l'air peuvent être éliminées par le contact avec une quantité efficace de compositions pharmaceutiques de pyruvate. Les patients atteints d'affections pulmonaires comprennent des patients atteints de bronchopneumopathie chronique obstructive (BPCO). Les compositions pharmaceutiques de pyruvate sont sélectionnées parmi du pyruvate, des sels de qualité pharmaceutique et des précurseurs de ceux-ci ou un mélange de ceux-ci. Le procédé comprend également l'utilisation d'autres compositions pharmaceutiques tout en utilisant les compositions pharmaceutiques de pyruvate. La présente invention présente les avantages suivants: 1. l'action directe sur un site de lésion pulmonaire avec un meilleur ciblage et la non participation à un métabolisme systémique; 2. les compositions pharmaceutiques de pyruvate présentent moins d'effets secondaires toxiques et une meilleure sécurité, et le médicament est stable; 3. le pyruvate est une substance intracellulaire naturelle qui présente une fonction d'amélioration des systèmes de transport cellulaire et un effet favorisant la désintoxication des poumons, ce qui permet de faciliter la respiration, l'efficacité de celui-ci étant plus complète et ses effets étant supérieurs à ceux d'antibiotiques ou de stéroïdes.
PCT/CN2014/082185 2013-08-02 2014-07-15 Compositions pharmaceutiques de pyruvate pour la stabilité osmotique et effet de désintoxication de celles-ci chez des êtres humains en bonne santé et des patients atteints d'affections pulmonaires WO2015014209A1 (fr)

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CN2013103355699A CN103385868A (zh) 2013-08-02 2013-08-02 丙酮酸钠在制备治疗慢性阻塞性肺病药物中的用途
CN201410032871.1A CN103720682A (zh) 2013-08-02 2014-01-23 丙酮酸药物组成及其在制备治疗慢性阻塞性肺病药物中的用途
CN201410032871.1 2014-01-23
CN201410175073.4A CN103948578A (zh) 2013-08-02 2014-04-28 稳定渗透压的丙酮酸药物组成及其在健康人和肺病病人中的排毒作用
CN201410175073.4 2014-04-28

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CN103385868A (zh) * 2013-08-02 2013-11-13 江苏长泰药业有限公司 丙酮酸钠在制备治疗慢性阻塞性肺病药物中的用途
CN106727320A (zh) * 2017-01-13 2017-05-31 江苏长泰药业有限公司 一种用于修复鼻粘膜、降低过敏反应、抗炎作用的组合物
CN109771398B (zh) * 2019-02-25 2019-09-20 广州南鑫药业有限公司 一种帕拉米韦溶液型吸入剂及其制备方法
CN109806224B (zh) * 2019-03-15 2021-05-28 江苏长泰药业有限公司 一种奥洛他定组合物及其制备方法
CN110859307A (zh) * 2019-12-10 2020-03-06 周方强 含有丙酮酸钠的组合物及其用途

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CN102657611A (zh) * 2012-03-02 2012-09-12 江苏长泰药业有限公司 丙酮酸钠鼻喷剂及其制备方法
CN103385868A (zh) * 2013-08-02 2013-11-13 江苏长泰药业有限公司 丙酮酸钠在制备治疗慢性阻塞性肺病药物中的用途
CN103610671A (zh) * 2013-12-10 2014-03-05 江苏长泰药业有限公司 丙酮酸药物组成及其在制备治疗肺癌药物中的用途

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CN103385868A (zh) * 2013-08-02 2013-11-13 江苏长泰药业有限公司 丙酮酸钠在制备治疗慢性阻塞性肺病药物中的用途
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