Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61P11/10—Expectorants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• the present application belongs to the field of medicine, and relates to an inhalation preparation of isoglycyrrhetic acid or a salt thereof, in particular to an inhalation preparation of magnesium isoglycyrrhizate and its use in the preparation of a medicament for treating respiratory diseases.
• Glycyrrhiza is a commonly used medicinal plant whose main active ingredient is glycyrrhizic acid, namely glycyrrhizic acid in the 18- ⁇ configuration and glycyrrhizic acid (also known as isoglycyrrhizic acid) in the 18- ⁇ configuration.
• Chinese patent ZL02111693.8 discloses a new compound magnesium isoglycyrrhizinate (structure shown in formula I, molecular weight 845), which has been proved by a large number of pharmacological and biochemical studies, which are animal models of liver damage caused by different hepatotoxic agents (for example, D-amino group).
• Elevated transaminase reduces hepatocyte degeneration, necrosis and inflammatory cell infiltration, and promotes hepatocyte regeneration.
• Magnesium glycyrrhizinate is superior to natural glycyrrhizin in resisting liver damage.
• licorice The pharmacological effects of licorice are extensive. Traditional Chinese medicine believes that licorice and its extracts have various effects such as cardiotonic, expectorant, antitussive, antiasthmatic, lung protection, broad-spectrum antibacterial and antiviral effects, and pharmacodynamics for its active ingredients. And the research of new dosage forms has been receiving much attention and getting deeper.
• Chinese patent ZL200410041923.8 discloses a magnesium isoglycyrrhizinate gel preparation and its application in preparing medicine for treating psoriasis, chronic eczema dermatitis, contact dermatitis and other allergic skin diseases
• Chinese patent ZL200510106108.X discloses a kind of supply Intravenous magnesium isoglycyrrhizinate preparation and application thereof in preparing medicine for treating liver disease
• Chinese patent ZL200510106109.4 discloses an oral preparation of magnesium isoglycyrrhizinate and its application in preparing medicine for treating liver disease, eczema, dermatitis, psoriasis and urticaria
• Patent ZL200510106110.7 discloses an external preparation of magnesium isoglycyrrhizinate and its application in psoriasis, chronic eczema dermatitis, contact dermatitis and other allergic dermatological drugs
• Viral hepatitis is an infectious disease caused by various liver viruses and mainly caused by liver diseases. Clinical The main manifestations are loss of appetite, nausea, upper abdominal discomfort, liver pain, and fatigue. Some patients may have jaundice fever and liver enlargement with liver damage. Chronic viral hepatitis is the case in which the course of viral hepatitis lasts for more than half a year. Magnesium isoglycyrrhizinate is clinically suitable for chronic viral hepatitis and improves liver function abnormalities, but it is administered intravenously, and patient compliance is poor. Sequential treatment, also known as "conversion therapy,” is a new treatment proposed by American and European scholars in the 1980s.
• Intravenous drip has the purpose of timely treatment for patients who cannot take oral drugs, it will inevitably bring about corresponding adverse reactions, such as infusion reaction, vascular stimulation and phlebitis, causing pain to the patient.
• Sequential therapy can shorten the time of intravenous medication, reduce the incidence of adverse reactions related to infusion, can greatly shorten the hospitalization time of patients, save the expenses of individuals and medical institutions, save limited economic resources, reduce the hospitalization brought by patients Related social labor losses.
• the clinically recommended sequential therapy for chronic hepatitis is relatively simple.
• the commonly used method is intravenous infusion of magnesium isoglycyrrhizinate + oral diammonium glycyrrhizinate capsule. Since liver cells are not the only host cells of hepatitis virus, there is a problem of low bioavailability when using viral preparation of diammonium glycyrrhizinate to treat viral hepatitis, and it is necessary to increase the dose to achieve the desired therapeutic effect, but It also increases the risk of side effects of the drug. Therefore, there is an urgent need to find a better pharmaceutical preparation of magnesium isoglycyrrhizinate and to provide a sequential therapy for chronic viral hepatitis with high bioavailability.
• inhalation formulation a formulation that delivers the drug in the form of a mist to the respiratory tract and/or lungs by a specific device to exert a local or systemic effect.
• the nature of the drug itself also has a greater impact on the absorption process.
• Fine particle dose is an important parameter to evaluate the effectiveness of inhaled preparations. Controlling aerodynamic particle size, changing surface properties, and adjusting the type and size of carriers can increase the microparticle dose and lung deposition rate, thereby increasing bioavailability.
• the drug particles are highly hygroscopic, aggregation, drug particle enlargement and stratification are likely to occur during drug preparation and storage, thereby affecting the amount of lung deposition of the drug particles, and further
• the drug with proper solubility in the respiratory system (such as respiratory secretion or alveolar fluid) is better absorbed; the absorption of the drug in the lung is passive diffusion, and the fat solubility of the drug molecule plays an important role therein.
• COPD chronic obstructive pulmonary disease
• the treatment of stable COPD includes drug treatment and non-medication.
• the main treatments are bronchodilators, glucocorticoids, expectorants (mucilolytic agents), antioxidants, immunomodulators, vaccines, etc., and long-term regular inhaled sugar.
• Corticosteroids are more suitable
• this treatment can reduce the frequency of acute exacerbations and improve quality of life;
• non-pharmacological treatments include education and management, control of occupational or environmental Pollution, oxygen therapy, rehabilitation therapy and surgical treatment, etc., are aimed at relieving symptoms, improving health, enhancing immunity, preventing disease progression, reducing the number of acute attacks, reducing mortality, improving activity endurance, and improving quality of life.
• Cough, expectoration and asthma are the three common symptoms of the respiratory system.
• the three are present and interact with each other, which not only brings pain to the patient, but is even life-threatening.
• Peony is a kind of medicine that can make sputum thinning, reduce viscosity and easy to cough up. It also accelerates mucociliary movement of respiratory mucosa, improves sputum transport function, weakens stimulation of respiratory mucosa, and indirectly acts as an antitussive Asthma is also beneficial for controlling secondary infections.
• One aspect of the invention provides an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• the salt is a magnesium salt, an ammonium salt, a potassium salt, a sodium salt or various amino acid salts, preferably a magnesium salt, an ammonium salt, a potassium salt or a sodium salt. More preferably, it is a magnesium salt.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for nebulizers.
• the inhalation formulation of the invention is an inhalation powder comprising: micronized magnesium isoglycyrrhizinate and one or more pharmaceutically acceptable carriers, wherein the micronized magnesium isoglycyrrhizate particles The diameter is 0.5-10 ⁇ m.
• the micronized magnesium isoglycyrrhizinate has a particle diameter of 0.5 to 5 ⁇ m.
• the "magnesium isoglycyrrhizinate particle size of 0.5-10 ⁇ m" as used in the present invention means that the particle size of most of the isoglycyrrhizic acid raw material drug is in the range of 0.5-10 ⁇ m, and further, the particle size distribution of magnesium isoglycyrrhizinate is limited to X 10 ⁇ 0.5 ⁇ m. X 80 ⁇ 10 ⁇ m.
• the "X 10 " as used in the present invention refers to a particle diameter distribution of 10%, that is, a particle volume content smaller than the particle diameter accounts for 10% of the total particles; "X 50 " means that the particle size distribution is 50%.
• the particle size of % that is, the volume fraction of the particles smaller than the particle diameter accounts for 50% of the total particles
• X 80 refers to the particle size distribution of the particle size distribution of 80%, that is, the volume fraction of the particles smaller than the particle diameter accounts for all the particles. 80%
• X 90 refers to a particle size distribution with a particle size distribution of 90%, that is, a particle volume content smaller than this particle size accounts for 90% of the total particle size.
• the "pharmaceutically acceptable carrier” is selected from the group consisting of lactose, mannitol, trehalose or glycine, preferably lactose, further preferably grinding lactose, sieving lactose or a mixture of sieving lactose and fine lactose, wherein grinding
• lactose ranges from 1 to 350 ⁇ m, preferably has a particle size distribution of X 50 ⁇ 30-110 ⁇ m
• the particle size distribution of sieved lactose ranges from 1 to 200 ⁇ m, preferably has a particle size distribution of X 50 ⁇ 35-115 ⁇ m
• fine lactose The particle size distribution ranges from 1 to 60 ⁇ m, preferably with a particle size distribution of X 90 ⁇ 45 ⁇ m.
• milled lactose refers to lactose which is mechanically ground to a different degree of fineness, and the particle size distribution differs between different grades of ground lactose, specifically, the particle size distribution ranges from 1-350 ⁇ m, with X 50 ⁇ 30-110 ⁇ m particle size distribution;
• Small lactose as used in the present invention means lactose which can be obtained by sieving to obtain a relatively narrow particle size distribution, specifically, a particle size distribution ranging from 1 to 200 ⁇ m, having X 50 ⁇ 35-115 ⁇ m particle size distribution;
• the "fine lactose” according to the present invention specifically includes finely ground lactose and micronized fine lactose having a narrow particle size distribution.
• the fine lactose has a particle size distribution ranging from 1 to 60 ⁇ m. With a particle size distribution of X 90 ⁇ 45 ⁇ m.
• the micronized magnesium isoglycyrrhizate and the carrier are mixed and filled in a capsule or blister.
• each capsule or blister comprises 1-50 mg of micronized magnesium isoglycyrrhizate and 0-50 mg of lactose.
• each capsule/or blister comprises 1-30 mg of micronized magnesium isoglycyrrhizate and 1-40 mg of lactose.
• the inhalation powder of the present invention further comprises: one or more pharmaceutically acceptable additional agents.
• the "pharmaceutically acceptable additive" as used in the present invention includes one or more of a surfactant, a lubricant, and a flavoring agent.
• the pharmaceutically acceptable additive is a surfactant such as a phospholipid, poloxamer.
• the pharmaceutically acceptable additive is a lubricant such as magnesium stearate, micronized silica gel, talc.
• the pharmaceutically acceptable additive is a flavoring agent, including natural flavoring agents and synthetic flavors.
• Natural fragrances such as peppermint oil, orange peel oil, cinnamon oil, spearmint oil, mint water, compound orange peel; synthetic flavors such as banana flavor, pineapple flavor, orange flavor.
• the inhalation preparation of the present invention is a liquid preparation for a nebulizer comprising magnesium isoglycyrrhizinate, an isotonicity adjusting agent, a pH adjuster, and water for injection, having a pH of 6.0 to 8.0, the mist
• the chemist is a continuous atomizer or a quantitative atomizer.
• the magnesium isoglycyrrhizate is present in an amount from 0.1 mg/ml to 5 mg/ml, preferably from 0.1 mg/ml to 2.5 mg/ml. In some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.1 mg/ml to 0.5 mg/ml; in some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.5 mg/ml to 2.5 mg/ml.
• the isotonicity adjusting agent is selected from one or more of the group consisting of glucose, sodium chloride, potassium chloride, mannitol, preferably sodium chloride.
• the pH adjuster is selected from the group consisting of sodium hydroxide, ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium acetate Or a combination of one or more of disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.
• the pH is between 6.5 and 7.0.
• the liquid preparation for nebulizer is provided in the form of a single dose package in a single dose package size of 1 ml, 2 ml or 5 ml. It is preferably 2 ml.
• the inhalation formulation is provided in a multi-dose package in a liquid formulation for nebulizers in a multi-dose package size of 10 ml, 20 ml or 30 ml.
• the liquid formulation for a nebulizer comprises a flavoring agent, including a natural fragrance and a synthetic fragrance.
• Natural fragrances such as peppermint oil, orange peel oil, cinnamon oil, spearmint oil, mint water, compound orange peel; synthetic flavors such as banana flavor, pineapple flavor, orange flavor.
• Another aspect of the invention provides the use of an inhaled formulation of isoglycyrrhizic acid or a salt thereof for the manufacture of a medicament for the treatment of chronic viral hepatitis.
• the isoglycyrrhizic acid or a salt thereof is selected from the group consisting of magnesium isoglycyrrhizinate.
• the present invention provides the use of an inhaled formulation of magnesium isoglycyrrhizinate for the preparation of a medicament for the treatment of chronic viral hepatitis by sequential treatment, wherein the sequential treatment uses magnesium isoglycyrrhizinate injection and magnesium isoglycyrrhizinate inhalation formulation.
• a combination comprising an inhalation formulation of magnesium isoglycyrrhizinate and a magnesium isoglycyrrhizinate injection.
• the invention provides a method of treating chronic viral hepatitis comprising administering to a patient with chronic viral hepatitis a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for nebulizers.
• the invention provides a kit comprising an inhalation formulation, a drug delivery device, instructions, and a suitable package containing one or more single doses of isotonic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for nebulizers.
• the drug delivery device for the liquid formulation for the nebulizer is an atomizer, which is a continuous nebulizer or a metered nebulizer.
• the instructions relate to methods of treating chronic viral hepatitis comprising administering to a patient with chronic viral hepatitis a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• an inhalation preparation of isoglycyrrhizic acid or a salt thereof for use in the preparation of a medicament for treating chronic obstructive pulmonary disease is provided.
• the isoglycyrrhizic acid or a salt thereof is selected from the group consisting of magnesium isoglycyrrhizinate.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the inhalation formulation of the invention is a liquid for nebulizers
• the preparation comprises: magnesium isoglycyrrhizinate, an isotonicity adjusting agent, a pH adjusting agent and water for injection, the pH is 6.0-8.0, and the atomizer is a continuous atomizer or a quantitative atomizer.
• the magnesium isoglycyrrhizate is present in an amount from 0.1 mg/ml to 5 mg/ml, preferably from 0.1 mg/ml to 2.5 mg/ml. In some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.1 mg/ml to 0.5 mg/ml; in some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.5 mg/ml to 2.5 mg/ml.
• the isotonicity adjusting agent is selected from one or more of the group consisting of glucose, sodium chloride, potassium chloride, mannitol, preferably sodium chloride.
• the pH adjuster is selected from the group consisting of sodium hydroxide, ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium acetate Or a combination of one or more of disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.
• the pH is between 6.5 and 7.0.
• the liquid preparation for nebulizer is provided in the form of a single dose package in a single dose package size of 1 ml, 2 ml or 5 ml. It is preferably 2 ml.
• the inhalation formulation is provided in a multi-dose package in a liquid formulation for nebulizers in a multi-dose package size of 10 ml, 20 ml or 30 ml.
• the liquid formulation for a nebulizer comprises a flavoring agent, including a natural fragrance and a synthetic fragrance.
• Natural fragrances such as peppermint oil, orange peel oil, cinnamon oil, spearmint oil, mint water, compound orange peel; synthetic flavors such as banana flavor, pineapple flavor, orange flavor.
• the frequency of administration of the inhaled formulation to the subject is selected from: three times a day, two times a day, once a day, once every other day, preferably one day. Two times a day.
• the pharmacological effects of the magnesium isoglycyrrhizinate inhalation preparation are evaluated by using two methods of administration of the isotonic acid magnesium inhalation preparation, tracheal administration and nebulization administration.
• the isotonic potassium magnesium inhalation preparation is administered by atomization once daily and twice daily. It was divided into three doses of low, medium and high (0.5, 1.5 and 5 mg/ml) to evaluate the pharmacological effects of magnesium isoglycyrrhizinate inhalation preparation.
• LPS lipopolysaccharide
• the invention provides a method of treating chronic obstructive pulmonary disease comprising administering to a patient suffering from chronic obstructive pulmonary disease a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the frequency of administration of the inhaled formulation to a subject is selected from: three times a day, two times a day, once a day, once every other day, preferably two days a day. Times.
• the present invention provides a kit comprising one or more single dose packages Inhalation formulations, administration devices, instructions, and suitable packaging of the form of isoglycyrrhizic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the drug delivery device for the liquid formulation for the nebulizer is an atomizer, which is a continuous nebulizer or a metered nebulizer.
• the instructions relate to a method of treating chronic obstructive pulmonary disease, comprising administering to a patient with chronic obstructive pulmonary disease a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• an inhalation preparation of isoglycyrrhetic acid or a salt thereof for the preparation of a sputum medicine wherein the sputum medicine is a medicine which can make sputum thin, has a reduced viscosity, and is easy to cough up.
• the isoglycyrrhizic acid or a salt thereof is selected from the group consisting of magnesium isoglycyrrhizinate.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the inhalation preparation of the present invention is a liquid preparation for a nebulizer comprising: magnesium isoglycyrrhizinate, an isotonicity adjusting agent, a pH adjuster, and water for injection, having a pH of 6.0 to 8.0, the mist
• the chemist is a continuous atomizer or a quantitative atomizer.
• the magnesium isoglycyrrhizate is present in an amount from 0.1 mg/ml to 5 mg/ml, preferably from 0.2 mg/ml to 2.5 mg/ml. In some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.2 mg/ml to 0.5 mg/ml; in some embodiments, the amount of magnesium isoglycyrrhizinate is from 0.5 mg/ml to 2.5 mg/ml.
• the isotonicity adjusting agent is selected from one or more of the group consisting of glucose, sodium chloride, potassium chloride, mannitol, preferably sodium chloride.
• the pH adjuster is selected from the group consisting of sodium hydroxide, ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium acetate Or a combination of one or more of disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.
• the pH is between 6.5 and 7.0.
• the liquid preparation for nebulizer is provided in the form of a single dose package in a single dose package size of 1 ml, 2 ml or 5 ml. It is preferably 2 ml.
• the inhalation formulation is provided in a multi-dose package in a liquid formulation for nebulizers in a multi-dose package size of 10 ml, 20 ml or 30 ml.
• the liquid formulation for a nebulizer comprises a flavoring agent, including a natural fragrance and a synthetic fragrance.
• Natural fragrances such as peppermint oil, orange peel oil, cinnamon oil, spearmint oil, mint water, compound orange peel; synthetic flavors such as banana flavor, pineapple flavor, orange flavor.
• the effect of magnesium isoglycyrrhizinate inhalation formulation on tracheal secretion in mice is evaluated using a mouse phenol red excretion assay.
• the present invention provides a method of sputum comprising administering to a patient having abnormal sputum secretion and dysfunction of sputum a therapeutically effective amount of an inhaled preparation of isoglycyrrhizic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the invention provides a kit comprising an inhalation formulation, a drug delivery device, instructions, and a suitable package containing one or more single doses of isotonic acid or a salt thereof.
• the inhalation formulation is selected from the group consisting of an inhalation aerosol, an inhalation powder, a liquid formulation for a nebulizer, and a formulation that can be converted to a vapor.
• the inhalation formulation is selected from the group consisting of an inhalation powder or a liquid formulation for a nebulizer; most preferably, the inhalation formulation is selected from liquid formulations for nebulizers.
• the drug delivery device for the liquid formulation for the nebulizer is an atomizer, which is a continuous nebulizer or a metered nebulizer.
• the instructions relate to a method of sputum comprising administering to a patient having abnormal sputum secretion, dysfunction of sputum, a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof.
• isoglycyrrhizic acid (18 ⁇ , 20 ⁇ )-20-carboxy-11-oxo-30-nor-oleicolin-12-ene-3 ⁇ -yl-2-O- ⁇ -D- Pyranoglutonyl- ⁇ -D-glucopyranoside.
• magnesium isoglycyrrhizinate (18 ⁇ , 20 ⁇ )-20-carboxy-11-oxo-30-nor-oleicolin-12-ene-3 ⁇ -yl-2-O- ⁇ -D-pyran Glucuronyl- ⁇ -D-glucopyranoside, which has the structure shown in Formula I.
• the term further includes hydrates thereof, such as tetrahydrate.
• the present inventors have unexpectedly discovered that a medium molecular weight magnesium isoglycyrrhizinate can be prepared into an inhalation preparation, which has a high emptying rate and a high percentage of fine particles, and inhalation can cause magnesium isoglycyrrhizate to rapidly enter the bloodstream in the lungs, thereby entering the bloodstream.
• the cycle plays a full-body role.
• the bioavailability of magnesium isoglycyrrhizinate inhalation preparation is significantly improved, thereby reducing the dosage and reducing the risk of toxic side effects; compared with the injection, the bioavailability of the magnesium isoglycyrrhizinate inhalation preparation is equivalent, but the patient only needs Active or passive inhalation medication greatly reduces the pain caused by injection and improves patient compliance. Therefore, the inhalation preparation of the present invention is extremely suitable for sequential use with an injection solution, and the pain and treatment cost of the injectable medicine are reduced while ensuring the efficacy.
• magnesium isoglycyrrhizinate inhalation can alleviate the clinical symptoms of COPD rats, and inhibit the infiltration of neutrophils-based inflammatory factors in COPD rats.
• Experiments have shown significant effects in the treatment of COPD.
• magnesium isoglycyrrhizinate affects the efficacy, and the nebulized inhalation route (0.4 mg/ml for 30 mg/ml of magnesium glycyrrhizinate for nebulizer) has the most significant effect on reducing inflammation.
• test methods which do not specify the specific conditions in the following examples may be carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art.
• Example 1 Magnesium glycyrrhizinate inhalation powder
• the magnesium isoglycyrrhizinate was treated by micronization to obtain samples of the following different particle size ranges.
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• Example 1a Example 1b
• Example 1c Emptying rate 99% 99% 99% Percentage of fine particles 13% 20% 32%
• the fine particle dose is an important parameter for evaluating the effectiveness of the inhaled preparation.
• the particle size of magnesium isoglycyrrhizinate has a crucial influence on the percentage of fine particles of the key quality index of the inhaled powder. Therefore, the particle size of magnesium isoglycyrrhizinate is controlled within the range of 0.5-10 ⁇ m. The percentage of fine particles is >15%, in line with pharmacopoeia regulations.
• Example 2 Magnesium glycyrrhizinate inhalation powder
• a typical particle size range of lactose D is: X 10 : 1-10 ⁇ m; X 50 : 30-50 ⁇ m; X 90 : 70-150 ⁇ m.
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• each capsule contains 10mg of magnesium isoglycyrrhizinate
• Example 2a Example 2b
• Example 2c Example 2d
• Example 2e Example 2f Emptying rate 99% 97% 97% 90% 97% 98% Percentage of fine particles 35% 40% 46% 48% 43% 45%
• lactose Different types and different particle sizes of lactose have a crucial influence on the key quality indicators of inhaled powder.
• the percentage of fine particles in the sample prepared by sieving lactose alone and the active ingredient is lower, but the sample is prepared by adding a certain amount of fine lactose.
• the percentage of fine particles is significantly improved; the percentage of fine particles of the sample prepared by grinding the lactose and the active ingredient is higher.
• Example 3 Liquid preparation for use in a nebulizer for magnesium isoglycyrrhizinate
• magnesium isoglycyrrhizinate and sodium chloride according to the prescription, add to 1800ml of water for injection, stir until completely dissolved, add ammonia to adjust the pH value of the solution to 6.5-7.0, add the solution to 2000ml of water for injection, filter and sterilize, according to 2ml/ For filling, a liquid preparation for nebulizer containing 10 mg of magnesium isoglycyrrhizinate was obtained.
• Example 4 Liquid preparation for use in a nebulizer for magnesium isoglycyrrhizinate
• magnesium isoglycyrrhizinate and sodium chloride according to the prescription, add to 1800ml of water for injection, stir until completely dissolved, add ammonia to adjust the pH value of the solution to 6.5-7.0, add the solution to 2000ml of water for injection, filter and sterilize, according to 2ml/ For filling, a liquid preparation for nebulizer containing 5 mg of magnesium isoglycyrrhizinate was obtained.
• Example 5 Liquid preparation for use in a nebulizer for magnesium isoglycyrrhizinate
• magnesium isoglycyrrhizinate and sodium chloride according to the prescription, add to 1800ml of water for injection, stir until completely dissolved, add ammonia to adjust the pH value of the solution to 6.5-7.0, add the solution to 2000ml of water for injection, filter and sterilize, according to 2ml/ For filling, a liquid preparation for nebulizer containing 1 mg of magnesium isoglycyrrhizinate was obtained.
• Example 6 Liquid preparation for use in a nebulizer for magnesium isoglycyrrhizinate
• magnesium isoglycyrrhizinate and sodium chloride according to the prescription, add to 1800ml of water for injection, stir until completely dissolved, add ammonia to adjust the pH value of the solution to 6.5-7.0, add the solution to 2000ml of water for injection, filter and sterilize, according to 2ml/ For filling, a liquid preparation for nebulizer containing 0.4 mg of magnesium isoglycyrrhizinate was obtained.
• Example 7 Liquid preparation for use in a nebulizer for magnesium isoglycyrrhizinate
• magnesium isoglycyrrhizinate and sodium chloride according to the prescription, add to 1800ml of water for injection, stir until completely dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 6.5-7.0, add the solution to 2000ml, and filter the bacteria. According to 2 ml/drip, a liquid preparation for nebulizer containing 0.2 mg of magnesium isoglycyrrhizinate was obtained.
• each rat in the inhalation administration group was administered with 200 ⁇ L of magnesium isoglycyrrhizinate for the nebulizer (the actual dose of the rat was 2.24 - 2.49 mg / kg).
• the dose in the gavage group was 10.0 mg/kg; blood was taken from the fundus venous plexus before administration (0h) and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24h after administration.
• the relative bioavailability of magnesium to isoglycyrrhizinate was as high as 68052% after inhalation administration.
• the bioavailability of magnesium to isoglycyrrhizate was 87% after inhalation administration.
• the drug can significantly improve the bioavailability of magnesium isoglycyrrhizinate, and the bioavailability of inhalation administration and intravenous administration is basically the same.
• Example 9 Pharmacodynamic experiment of magnesium isoglycyrrhizinate inhalation preparation for rats with chronic obstructive pulmonary disease
• Male Sprague-Dawley rats were randomly divided into 6 groups according to their body weight, which were randomly divided into 6 groups: high-dose tracheal instillation group (1.67mg/ml magnesium isoglycyrrhizinate, 100 ⁇ l/only). Dosage tracheal instillation group (1.67mg/ml, 25 ⁇ l/only), aerosol inhalation group, model group and blank control group, 10 in each group.
• the other groups were administered with normal saline for 15 days.
• the administration group continued to give smoke stimulation after 30 minutes of administration, and the mental state of the rats was recorded every day.
• Scoring indicators (1) whether there is mucus and cell blockage in the small airway cavity; (2) whether the small airway epithelium has necrotic erosion; (3) small airway epithelial cells goblet cell metaplasia; (4) small airway epithelial cell squamous (5) small airway wall inflammation cell infiltration; (6) small airway wall fibrous connective tissue hyperplasia; (7) small airway wall smooth muscle hyperplasia; (8) small airway wall pigmentation; (9) lung emphysema.
• Lesion score According to the degree of light to heavy lesions, it is quantified as a slight or very small amount of "0.5 points”, mild or small "1 point”, moderate or more "2 points”, or severe "3 points” Very severe or large “4 points", no obvious lesions are 0 points.
• the experimental result data is expressed in the form of mean ⁇ SD.
• One-way ANOVA combined with Post-Hoc (LSD method) was used to analyze the differences between groups.
• Statistical significance was expressed as a P value of less than 0.05.
• the experimental results showed that the rats in the blank control group had normal activities, sensitive reactions, body fat, no symptoms such as cough, sneezing and dyspnea.
• the rats were prone to prone, lack of spirit, stagnation, blinking, and bunching. Unsteady walking, slow weight gain, grayish yellow fur, followed by coughing, sneezing and difficulty breathing.
• high-dose and low-dose tracheal infusion of isoglycyrrhizinate and aerosol inhalation the symptoms of the rats in each group were relieved compared with the model group, and the magnesium isoglycyrrhizinate aerosol inhalation group was more obvious than the other groups.
• the experimental results showed that the lung tissue of the blank control group consisted of alveolar, intrapulmonary bronchial branches and interstitial tissues with clear structure, no emphysema, minimal infiltration of inflammatory cells and goblet cell hyperplasia.
• the main lesions in the lung tissue of the model group were interstitial pneumonia, perivascular tissue edema, inflammatory cell infiltration, increased goblet cells in the bronchial wall of the lung, degeneration and necrosis of bronchial wall cells, and a small amount of exudate in the bronchial cavity. And emphysema and inflammatory cell infiltration were particularly evident (p ⁇ 0.01 or p ⁇ 0.05).
• High-dose, low-dose tracheal infusion group and magnesium isoglycyrrhizinate inhalation group can significantly reduce lung inflammation, improve bronchial wall function, reduce bronchial mucus secretion and improve emphysema.
• magnesium glycyrrhizinate atomization group 0.4 Mg/ml, 30min is the most obvious to reduce inflammation and infiltration.
• Example 10 Pharmacodynamic experiment of magnesium isoglycyrrhizinate inhalation preparation for mice with chronic obstructive pulmonary disease
• ICR male mice, 18-22g, 90 were divided into 9 groups, including blank group, model group, low dose group of magnesium isoglycyrrhizinate inhalation (0.5mg/ml, qd), medium dose group (1.5mg/ml, qd) , high dose group (5.0mg/ml, qd), low dose group (0.5mg/ml, bid), middle dose group (1.5mg/ml, bid), high dose group (5.0mg/ml, bid) and positive Control (A Fordro) group.
• the trachea was instilled into the lipopolysaccharide (LPS) by 30 ⁇ l.
• LPS lipopolysaccharide
• the experimental results showed that a large number of inflammatory cells (white blood cells) were produced in the bronchial airway of the lipopolysaccharide-induced model group, which was up-regulated by 490% compared with the blank group, and the induction of COPD was successful, and the histopathological examination was small.
• the lung tissue structure of the rats showed that the model group showed obvious inflammatory reaction, and the inflammatory cell infiltration was obvious.
• the exuded inflammatory cells were found in the alveolar and connective tissues of the alveolar septum. In particular, the neutrophils around the pulmonary blood vessels and the bronchi of each level are retained and aggregated.
• control group 1 normal saline, NS
• control group 2 normal saline, NS
• positive group ammonium chloride, 1g/kg
• the drug group 1 magnesium isoglycyrrhizinate for nebulizer liquid preparation 0.2 mg/ml, atomization 30 min
• 2 groups diisoglycyrrhizinate for nebulizer liquid preparation 0.2 mg/ml, atomization 15 min).
• the control group 1 and the positive group were intragastrically administered with the corresponding drugs (0.1 ml/10 g), the control group 2 and the group 1 were administered with nebulizer for atomization, atomization for 30 min, and administration of the two groups for 15 min. 1 time a day for 6 consecutive days. Before the sixth administration, the mice were starved for 16-18 hours, only for drinking water. After 30 minutes of administration, ip1% phenol red physiological saline solution 0.2ml/10g, and 30 minutes after phenol red injection, the cervical vertebrae were sacrificed.
• phenol red 1.95 mg was weighed, dissolved by adding 5% NaHCO 3 to 3.9 ml, and the amount of phenol red was 0.5 mg/ml as a stock solution. 0.1 ml of the stock solution and 3.9 ml of 5% NaHCO 3 were added, and 12.5 ⁇ g/ml was sequentially diluted to 10 ⁇ g/ml, 7.5 ⁇ g/ml, 5 ⁇ g/ml, 2.5 ⁇ g/ml, 1.25 ⁇ g/ml, and 0.625 ⁇ g/ml. The phenol red standard curve was prepared by measuring the OD value by a colorimetric instrument at a wavelength of 546 nm.
• the sample OD value was measured by a microplate reader at a wavelength of 546 nm, and the sample phenol red amount was calculated from the phenol red standard curve.

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