JPWO2017177966A5 - - Google Patents

Description

"Cross-reference of related applications"
This application claims the priority of Chinese Patent Application No. 201610237175.3 filed on April 15, 2016, the entire contents of which are incorporated herein by reference.

The present invention belongs to the pharmaceutical field and relates to an inhaled preparation of isoglycyrrhizic acid or a salt thereof. Specifically, it relates to its use in the manufacture of magnesium isoglycyrrhizate inhalation preparations and drugs for treating respiratory diseases.

Licorice (licorice, Glycyrrhiza) is a commonly used medicinal plant whose main active ingredients are glycyrrhizic acids, ie 18-β-arranged glycyrrhizic acid and 18-α-arranged glycyrrhizic acid (also called isoglycyrrhizic acid). Is. The Chinese patent ZL02111693.8 disclosed a novel compound called magnesium isoglycyrrhizinate (having the structure represented by the formula I and having a molecular weight of 845). Many pharmacological and biochemical experiments on the compound have shown that animal models of liver injury due to various hepatotoxic agents (eg, D-galactosamine-induced rat acute liver failure, carbon tetrachloride-induced rat chronic liver failure) , Carbon tetrachloride-induced rat liver cirrhosis and Gal / FCA-induced black mouse immune liver failure), play a role in suppressing increased serum transaminase in animals, reducing hepatocyte degeneration, reducing necrosis and inflammatory cell infiltration, and promoting hepatocyte regeneration. It was definitely recognized. The liver damage reducing effect of magnesium isoglycyrrhizinate is significantly superior to that of natural glycyrrhizic acid.

Licorice has a wide range of pharmacological effects. For example, in traditional Chinese medicine, licorice and its extracts have many effects such as cardiac function enhancement, expectorant, antitussive, asthma relief, lung protection and widespread antibacterial, and antivirus. Research on the pharmacodynamics and novel dosage forms of its active ingredients has received a lot of attention and is becoming more and more sophisticated.

For example, the Chinese patent ZL200410041923.8 disclosed a gel formulation of magnesium isoglycyrrhizinate and its use in the manufacture of drugs for treating psoriasis, chronic eczema dermatitis, contact dermatitis and other allergic skin diseases. The Chinese patent ZL200510106108.X disclosed its use in the manufacture of an intravenous formulation of magnesium isoglycyrrhizinate and a drug for treating liver disease. The Chinese patent ZL200510106109.4 disclosed the oral preparation of magnesium isoglycyrrhizinate and its use in the manufacture of drugs for treating liver diseases, eczema, dermatitis, psoriasis and urticaria. The Chinese patent ZL200510106110.7 disclosed an external preparation of magnesium isoglycyrrhizinate and its use in drugs for treating psoriasis, chronic eczema dermatitis, contact dermatitis and other allergic skin diseases. The Chinese patent ZL200610098077.2 disclosed a freeze-dried powder injection of magnesium isoglycyrrhizinate and a method for producing the same.

Viral hepatitis is one of the main infectious diseases characterized by liver lesions induced by various hepatitis viruses. Its clinical symptoms mainly include loss of appetite, nausea, epigastric discomfort, hepatic pain, and malaise. Some patients have liver enlargement with jaundice fever and liver dysfunction. If viral hepatitis lasts for more than half a year, it is diagnosed as chronic viral hepatitis. Magnesium isoglycyrrhizinate is clinically indicated for chronic viral hepatitis and can improve liver dysfunction, but there is a problem that patients receiving intravenous administration have poor compliance. In response, American and European scholars proposed a new treatment method called sequential therapy in the 1980s. In other words, when treating a disease with a drug, parenteral administration (for example, intravenous injection) is performed for 2 to 3 days at the beginning, and when the clinical symptoms are almost stable and the symptoms improve, the method is switched to oral drug treatment. Is. Intravenous infusion can treat patients who cannot receive oral administration in a timely manner, but adverse events such as infusion reaction, vascular irritation, and phlebitis are unavoidable, causing pain to the patients. Sequential therapy is economical because it can shorten the duration of intravenous administration, reduce the occurrence of infusion-related adverse events, significantly reduce patient hospital stays, and reduce patient and medical institution cost expenditures. At the same time, the situation such as the decrease in related labor resources due to the hospitalization of patients is alleviated. Currently, there are relatively few types of sequential treatment for chronic hepatitis that are clinically recommended, and the most commonly used method is intravenous infusion of magnesium isoglycyrrhizinate and oral administration of diammonium glycyrrhizinate capsules. be. On the other hand, since hepatocytes are not the only host cells for hepatitis virus, there is a problem that bioavailability is low when treating viral hepatitis with a diammonium glycyrrhizinate preparation, and administration is performed in order to achieve the desired therapeutic effect. You need to add the amount. It also poses the problem of increasing the risk that the drug will induce adverse events. Therefore, it is necessary to develop a better drug formulation of magnesium isoglycyrrhizate and provide sequential therapy for chronic viral hepatitis with high bioavailability.

An inhaled preparation is a preparation for delivering a drug in the form of a mist to the respiratory tract and / or the lung using a specific device to exert its effect locally or systemically. The nature of the drug itself also has a great influence on its absorption process. The dose of fine particles is one of the important parameters for evaluating the effectiveness of inhaled preparations, such as controlling the aerodynamic diameter of powder particles, changing their surface properties, and adjusting the type and size of carriers. , The dose of fine particles and the rate of lung deposition can be increased, and the bioavailability can be enhanced. When using a dry powder inhaler, if the drug particles are highly hygroscopic, the drug particles are likely to aggregate, increase in particle size and stratify during the drug manufacturing and storage process, and the amount of drug particles deposited in the lungs and the efficacy of the drug. Is very likely to affect. Drugs with adequate solubility in the respiratory system (eg, airway secretions or alveolar fluid) are effectively absorbed. Since the absorption of a drug in the lung is passive diffusion, the lipophilicity of the drug molecule plays an important role in its diffusion. Most lipophilic drugs are diffused or absorbed through the lipid bilayer membrane of alveolar epithelial cells, so drugs with a higher oil / water partition coefficient are absorbed faster. In addition, the absorption effect of a drug on the lung is also related to its molecular weight, and since most small molecule drugs are absorbed through the membrane pores on the alveolar epithelial cells, generally, the smaller the molecular weight, the faster the drug. Be absorbed. An example of producing magnesium isoglycyrrhizinate as an inhalation preparation and using it for the treatment of a disease has not yet been reported, because the molecular weight of magnesium isoglycyrrhizinate is medium and there is a great difficulty in manufacturing it as an inhalation preparation. It is thought that this is the reason.

Chronic obstructive pulmonary disease (COPD) is a disease that occurs frequently in the respiratory system and is characterized by partial irreversible and persistent airflow obstruction. As airflow obstruction progresses, the chronic inflammatory response of the airways and lungs due to harmful particles or gases increases, causing acute exacerbations and complications, affecting the overall severity of the disease in the patient. According to a related article, COPD has tended to increase in incidence and mortality in recent years and is now the fourth leading cause of death worldwide. Not only does it have a serious impact on people's health, but it also poses a great social and economic burden, so it is treated as a major issue in the field of public health. Symptoms of COPD are divided into a stable phase and an acute exacerbation phase. In the case of stable COPD, the treatment method includes drug treatment and non-drug treatment. Drug treatment mainly includes administration of bronchodilators, glucocorticoids, sputum (mucolytic agents), antioxidants, immunomodulators, vaccines, etc., of which long-term regular inhalation of glucocorticoids is severe COPD ( It is applied to patients with severe (stage III) and most severe (stage IV) (FEV1 <50% predicted value). The treatment can reduce the frequency of acute exacerbations and improve quality of life. Non-drug treatment aims to relieve symptoms, improve health, improve immunity, prevent disease progression, reduce the number of acute attacks, reduce mortality, improve endurance during activity and improve quality of life. Includes related publicity and health care, pollution control of the work or surrounding environment, oxygen therapy, rehabilitation therapy and surgical treatment, etc. However, according to related studies, conventional treatment methods have not been able to alleviate long-term pulmonary dysfunction in COPD patients, and no effective prevention and treatment method has yet been found, especially for progressive pulmonary dysfunction during the stable period. Also, long-term administration of glucocorticoids and β2 receptor agonists inevitably leads to some adverse events, and therefore better drugs and formulations to treat COPD need to be developed.

Cough, sputum and asthma are the three most common symptoms of the respiratory system, which are always comorbid and have the property of strengthening each other, not only causing pain to the patient but also life-threatening. It may even be. Sputum remedies dilute the sputum fluid to reduce its viscosity and promote its excretion, and promote the movement of mucous membranes of the respiratory mucosa to improve the transfer function of sputum and relieve irritation to the respiratory mucosa. As a result, it indirectly fulfills the effects of antitussive and asthma relief, and is a drug that contributes to the suppression of secondary infections.

Spray inhalation therapy is widely used in the field of treatment of common respiratory diseases such as sputum, asthma, and COPD. Along with this, a large demand for inhaled preparations is expected, but the use of glycyrrhizic acid inhaled preparations in the production of sputum drugs and drugs for treating COPD has not been reported at present.

One aspect of the present invention provides an inhalation preparation of isoglycyrrhizic acid or a salt thereof.

In one embodiment of the invention according to this embodiment, the salt is a magnesium salt, an ammonium salt, a potassium salt, a sodium salt, or various amino acid salts, and is a magnesium salt, an ammonium salt, a potassium salt, or a sodium salt. It is preferable, and it is more preferable that it is a magnesium salt.

In one embodiment of the invention according to this aspect, the inhalation formulation is selected from an aerosol inhaler, a dry powder inhaler, a nebulizer liquid formulation, or a vapor convertible formulation, the dry powder inhaler or It is preferably selected from liquid formulations for nebulizers.

In one preferred embodiment of the invention according to this aspect, the inhalation formulation is a dry powder inhaler comprising micronized magnesium isoglycyrrhizinate and one or more pharmaceutically acceptable carriers. The finely divided magnesium isoglycyrrhizinate has a particle size of 0.5 to 10 μm, preferably 0.5 to 5 μm.

As described herein, "the particle size of magnesium isoglycyrrhizinate is 0.5 to 10 μm" means that the particle size of the drug substance of magnesium isoglycyrrhizinate is almost all in the range of 0.5 to 10 μm. Further, it means that the particle size distribution of magnesium isoglycyrrhizinate is limited to X ₁₀ ≧ 0.5 μm and X ₈₀ ≦ 10 μm. As used herein, "X ₁₀ " means a particle size having a particle size distribution of 10%, that is, the volume content of particles smaller than the particle size accounts for 10% of the total particles. " ₅₀ " means a particle size having a particle size distribution of 50%, that is, the volume content of particles smaller than the particle size accounts for 50% of the total particles, and "X ₈₀ " means that the particle size distribution is 50%. The particle size of 80%, that is, the volume content of particles smaller than the particle size occupies 80% of the whole particles, and "X ₉₀ " means the particle size of 90% of the particle size distribution, that is, the particle size. It means that the volume content of particles smaller than the particle size occupies 90% of the total particles.

The "pharmaceutically acceptable carrier" described herein is selected from lactose, mannitol, trehalose, or glycine, preferably lactose, and is finely divided with polished lactose, sieved lactose, or sieved lactose. More preferably, it is a mixture of lactose granules. The particle size distribution range of the polished lactose is 1 to 350 μm, but preferably has a particle size distribution of X ₅₀ <30 to 110 μm, and the particle size distribution range of the sieved lactose is 1 to 200 μm, but X ₅₀ . It is preferable to have a particle size distribution of <35 to 115 μm, and the particle size distribution range of the fine lactose is 1 to 60 μm, but it is preferable to have a particle size distribution of X ₉₀ <45 μm.

As used herein, the term "abrasive lactose" refers to lactose having various finenesses obtained by mechanical polishing and having different particle size distributions in different grades. Specifically, it is a lactose having a particle size distribution range of 1 to 350 μm and a particle size distribution of X ₅₀ <30 to 110 μm. As used herein, the term "sieving lactose" refers to lactose having a relatively narrow particle size distribution obtained by sieving. Specifically, it is a lactose having a particle size distribution range of 1 to 200 μm and a particle size distribution of X ₅₀ <35 to 115 μm. The "fine-grained lactose" described herein includes fine-grained polished lactose having a relatively narrow particle size distribution and finely-divided fine-grained lactose. Specifically, it is a lactose having a particle size distribution range of 1 to 60 μm and a particle size distribution of X ₉₀ <45 μm.

In one embodiment of the invention according to this aspect, the micronized magnesium isoglycyrrhizinate and a carrier are mixed and filled in a capsule or a blister pack. In a further embodiment, 1 to 50 mg of finely powdered magnesium isoglycyrrhizinate and 0 to 50 mg of lactose, 1 to 30 mg of finely powdered magnesium isoglycyrrhizinate and 1 to 40 mg of lactose per capsule or blister pack. It is preferable to include and.

In another preferred embodiment of the invention according to this aspect, the dry powder inhaler further comprises one or more pharmaceutically acceptable additives.

The "pharmaceutically acceptable additives" described herein include one or more of surfactants, lubricants and flavoring agents.

In some embodiments of the invention according to this aspect, the pharmaceutically acceptable additive is a surfactant, such as a phospholipid, poloxamer.

In some embodiments of the invention according to this aspect, the pharmaceutically acceptable additive is a lubricant, such as magnesium stearate, pulverized silica gel, talc powder and the like.

In some embodiments of the invention according to this aspect, the pharmaceutically acceptable additive is a flavoring agent consisting of a natural fragrance and an artificially synthesized fragrance. Examples of the natural fragrance include peppermint oil, orange oil, cinnamon oil, spearmint oil, mint water, and a concentrated ethanol composite solution of orange peel. Examples of the artificially synthesized fragrance include banana flavor, pineapple flavor, and orange flavor.

In another preferred embodiment of the invention according to this embodiment, the inhalation preparation contains magnesium neisoglycyrrhizinate, an isotonic agent, a pH adjuster, and water for injection, and has a pH of 6.0 to 8.0. The nebulizer is a continuous nebulizer or a quantitative nebulizer.

In one preferred embodiment of the invention according to this aspect, the content of the magnesium isoglycyrrhizate is preferably 0.1 to 5 mg / mL and preferably 0.1 to 2.5 mg / mL. In some embodiments, the content of magnesium isoglycyrrhizinate is 0.1-0.5 mg / mL, and in some embodiments, the content is 0.5-2.5 mg / mL. Is.

In one preferred embodiment of the invention according to this aspect, the isotonic agent is selected from one or a combination of one or more of glucose, sodium chloride, potassium chloride and mannitol, preferably sodium chloride.

In one preferred embodiment of the invention according to this embodiment, the pH adjuster is sodium hydroxide, aqueous ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartrate acid, acetic acid. One or a combination of one or more selected from sodium or disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.

In one preferred embodiment of the invention according to this aspect, the pH is 6.5-7.0.

It is preferable that the liquid preparation for a nebulizer is provided in a single dose in a package of 1 mL, 2 mL or 5 mL, and 2 mL thereof is preferable.

In some embodiments of the invention according to this aspect, the inhaled formulation is a liquid formulation for a nebulizer provided in repeated doses in packaging with specifications of 10 mL, 20 mL or 30 mL.

In some embodiments of the invention according to this aspect, the liquid formulation for nebulizer comprises a natural fragrance and a flavoring agent consisting of an artificially synthesized fragrance. Examples of the natural fragrance include peppermint oil, orange oil, cinnamon oil, spearmint oil, mint water, and a concentrated ethanol composite solution of orange peel. Examples of the artificially synthesized fragrance include banana flavor, pineapple flavor, and orange flavor.

Another aspect of the present invention provides an administration form of an inhaled preparation of isoglycyrrhizic acid or a salt thereof. The administration form includes the frequency of administering the inhalation preparation to a subject. The frequency is selected from 3 times a day, 2 times a day, once a day, or once every 2 days, and is preferably twice a day.

Yet another aspect of the present invention provides the use of an inhalation formulation of isoglycyrrhizic acid or a salt thereof in the manufacture of a drug for treating chronic viral hepatitis. The isoglycyrrhizic acid or a salt thereof is preferably magnesium isoglycyrrhizinate.

Yet another aspect of the present invention provides the use of an inhaled magnesium isoglycyrrhizinate formulation in the manufacture of a drug for treating chronic viral hepatitis with sequential therapy. In the sequential therapy, a magnesium isoglycyrrhizate injection solution and a magnesium isoglycyrrhizate inhalation preparation are used.

Yet another aspect of the present invention provides a formulation comprising a magnesium isoglycyrrhizate inhalation preparation and a magnesium isoglycyrrhizate injection.

Yet another aspect of the present invention provides a method of treating chronic viral hepatitis. The method comprises administering to a patient with chronic viral hepatitis an inhalation formulation of a therapeutically effective amount of isoglycyrrhizic acid or a salt thereof. In some embodiments, the inhalation formulation is selected from an aerosol inhaler, a dry powder inhaler, a nebulizer liquid formulation, or a vapor convertible formulation from a dry powder inhaler or nebulizer liquid formulation. It is preferable to be selected.

Yet another aspect of the present invention is an inhalation preparation containing isoglycyrrhizic acid or a salt thereof packaged in one or more single doses, an administration tool, an instruction manual, and an appropriate package. Provide a kit including. In some embodiments, the inhalation formulation is selected from an aerosol inhaler, a dry powder inhaler, a nebulizer liquid formulation, or a vapor convertible formulation from a dry powder inhaler or nebulizer liquid formulation. It is preferable to be selected. In some embodiments, the administration tool for the liquid formulation for a nebulizer is a nebulizer, said nebulizer being a continuous nebulizer or a quantitative nebulizer. In some examples, the instruction manual describes a method of treating chronic viral hepatitis, of which a therapeutically effective amount of an inhalation preparation of isoglycyrrhizinic acid or a salt thereof is administered to a patient with chronic viral hepatitis. include.

Yet another aspect of the present invention provides the use of an inhaled formulation of isoglycyrrhizic acid or a salt thereof in the manufacture of a drug for treating COPD. The isoglycyrrhizic acid or a salt thereof is preferably magnesium isoglycyrrhizinate.

In one embodiment of the invention according to this aspect, the inhalation formulation is selected from an aerosol inhalant, a dry powder inhaler, a nebulizer liquid formulation, or a vapor convertible formulation, the dry powder inhalant or It is preferably selected from the nebulizer liquid preparations, most preferably the nebulizer liquid preparations.

In one preferred embodiment of the invention according to this embodiment, the inhalation preparation comprises magnesium isoglycyrrhizinate, an isotonic agent, a pH adjuster, and water for injection at a pH of 6.0 to 8.0. A liquid formulation for a nebulizer, said nebulizer being a continuous nebulizer or a quantitative nebulizer.

In one preferred embodiment of the invention according to this aspect, the content of the magnesium isoglycyrrhizate is preferably 0.1 to 5 mg / mL and preferably 0.1 to 2.5 mg / mL. In some embodiments, the content of magnesium isoglycyrrhizinate is 0.1-0.5 mg / mL, and in some embodiments, the content is 0.5-2.5 mg / mL. Is.

In one preferred embodiment of the invention according to this aspect, the isotonic agent is selected from one or a combination of one or more of glucose, sodium chloride, potassium chloride and mannitol, preferably sodium chloride.

In one preferred embodiment of the invention according to this embodiment, the pH adjuster is sodium hydroxide, aqueous ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartaric acid, acetic acid. One or a combination of one or more selected from sodium or disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.

In one preferred embodiment of the invention according to this aspect, the pH is 6.5-7.0.

It is preferable that the liquid preparation for a nebulizer is provided in a single dose in a package of 1 mL, 2 mL or 5 mL, and 2 mL thereof is preferable.

In some embodiments of the invention according to this aspect, the inhaled formulation is a liquid formulation for a nebulizer provided in repeated doses in packaging with specifications of 10 mL, 20 mL or 30 mL.

In some embodiments of the invention according to this aspect, the liquid formulation for nebulizer comprises a flavoring agent consisting of a natural fragrance and an artificially synthesized fragrance. Examples of the natural fragrance include peppermint oil, orange oil, cinnamon oil, spearmint oil, mint water, and a concentrated ethanol composite solution of orange peel. Examples of the artificially synthesized fragrance include banana flavor, pineapple flavor, and orange flavor.

In one embodiment of the invention according to this aspect, the administration frequency of administering the inhalation preparation to a subject is selected from 3 times a day, 2 times a day, once a day, or once a day. It is preferably twice.

In one preferred embodiment of the invention according to this embodiment, an inhalation-induced rat COPD animal model of tobacco smoke is used, and isoglycyrrhizinic acid is used by two administration routes of tracheal administration and atomization administration of the magnesium isoglycyrrhizinate inhalation preparation. Evaluate the pharmacological action of magnesium inhalation preparation.

In one preferred embodiment of the invention according to this embodiment, a lipopolysaccharide (LPS) -induced mouse COPD animal model is used, and the administration route of once-daily and twice-daily atomization of the magnesium isoglytyllithinate inhalation preparation is used. The dose is divided into three stages (0.5, 1.5 and 5 mg / mL) of low, medium and high to evaluate the pharmacological action of the magnesium isoglycyrrhizinate inhalation preparation.

Yet another aspect of the invention provides a method of treating COPD. The method comprises administering to a COPD patient a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof. In some embodiments, the inhalation formulation is selected from aerosol inhalers, dry powder inhalers, nebulizer liquid formulations, or vapor convertible formulations, from dry powder inhalers or nebulizer liquid formulations. It is preferably selected, most preferably a nebulizer liquid formulation. In some embodiments, the administration frequency of administering the inhaled product to the subject is selected from 3 times a day, 2 times a day, once a day, or once every 2 days, and is twice a day. Is preferable.

Yet another aspect of the present invention is an inhalation preparation containing isoglycyrrhizic acid or a salt thereof packaged in one or more single doses, an administration tool, an instruction manual, and an appropriate package. Provide a kit including. In some embodiments, the inhalation formulation is selected from aerosol inhalers, dry powder inhalers, nebulizer liquid formulations, or vapor convertible formulations, from dry powder inhalers or nebulizer liquid formulations. It is preferably selected, most preferably a nebulizer liquid formulation. In some embodiments, the administration tool for the liquid formulation for a nebulizer is a nebulizer, said nebulizer being a continuous nebulizer or a quantitative nebulizer. In some examples, the instruction manual describes a method of treating COPD, which comprises providing a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof to a COPD patient.

Yet another aspect of the present invention provides the use of an inhaled formulation of isoglycyrrhizic acid or a salt thereof in the production of expectorant drugs. The expectorant drug refers to a drug that promotes its discharge by diluting the sputum solution to reduce its viscosity. The isoglycyrrhizic acid or a salt thereof contained in the expectorant drug is preferably magnesium isoglycyrrhizate.

In one embodiment of the invention according to this aspect, the inhalation formulation is selected from an aerosol inhalant, a dry powder inhaler, a nebulizer liquid formulation, or a vapor convertible formulation, the dry powder inhalant or It is preferably selected from the nebulizer liquid preparations, most preferably the nebulizer liquid preparations.

In one preferred embodiment of the invention according to this embodiment, the inhalation preparation comprises magnesium isoglycyrrhizinate, an isotonic agent, a pH adjuster, and water for injection at a pH of 6.0 to 8.0. A liquid formulation for a nebulizer, said nebulizer being a continuous nebulizer or a quantitative nebulizer.

In one preferred embodiment of the invention according to this aspect, the content of the magnesium isoglycyrrhizate is preferably 0.1 to 5 mg / mL and preferably 0.2 to 2.5 mg / mL. In some embodiments, the content of magnesium isoglycyrrhizinate is 0.2-0.5 mg / mL, and in some embodiments, the content is 0.5-2.5 mg / mL. Is.

In one preferred embodiment of the invention according to this aspect, the isotonic agent is selected from one or a combination of one or more of glucose, sodium chloride, potassium chloride and mannitol, preferably sodium chloride.

In one preferred embodiment of the invention according to this embodiment, the pH adjuster is sodium hydroxide, aqueous ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartrate acid, acetic acid. One or a combination of one or more selected from sodium or disodium hydrogen phosphate, preferably aqueous ammonia or sodium hydroxide.

In one preferred embodiment of the invention according to this aspect, the pH is 6.5-7.0.

It is preferable that the liquid preparation for a nebulizer is provided in a single dose in a package of 1 mL, 2 mL or 5 mL, and 2 mL thereof is preferable.

In some embodiments of the invention according to this aspect, the inhaled formulation is a liquid formulation for a nebulizer provided in repeated doses in packaging with specifications of 10 mL, 20 mL or 30 mL.

In some embodiments of the invention according to this aspect, the liquid formulation for nebulizer comprises a natural fragrance and a flavoring agent consisting of an artificially synthesized fragrance. Examples of the natural fragrance include peppermint oil, orange oil, cinnamon oil, spearmint oil, mint water, and a concentrated ethanol composite solution of orange peel. Examples of the artificially synthesized fragrance include banana flavor, pineapple flavor, and orange flavor.

In one preferred embodiment of the invention according to this aspect, the effect of the magnesium isoglycyrrhizinate inhalation preparation on tracheal secretion in mice is evaluated using a mouse phenol red excretion experimental method.

Yet another aspect of the present invention provides an expectorant method. The method comprises administering a therapeutically effective amount of an inhaled preparation of isoglycyrrhizic acid or a salt thereof to a patient with abnormal sputum secretion or poor sputum discharge function. In some embodiments, the inhalation formulation is selected from aerosol inhalers, dry powder inhalers, nebulizer liquid formulations, or vapor convertible formulations, from dry powder inhalers or nebulizer liquid formulations. It is preferably selected, most preferably a nebulizer liquid formulation.

Yet another aspect of the present invention is an inhalation preparation containing isoglycyrrhizic acid or a salt thereof packaged in one or more single doses, an administration tool, an instruction manual, and an appropriate package. Provide a kit including. In some embodiments, the inhalation formulation is selected from aerosol inhalers, dry powder inhalers, nebulizer liquid formulations, or vapor convertible formulations, from dry powder inhalers or nebulizer liquid formulations. It is preferably selected, most preferably a nebulizer liquid formulation. In some embodiments, the administration tool for the liquid formulation for a nebulizer is a nebulizer, said nebulizer being a continuous nebulizer or a quantitative nebulizer. In some examples, the instruction manual describes a method of expectoration, which comprises administering a therapeutically effective amount of an inhaled formulation of isoglycyrrhizic acid or a salt thereof to a patient with abnormal sputum secretion or poor sputum discharge function. ..

The chemical name for the term "isoglycyrrhizic acid" described herein is (18α, 20β) -20-carboxyl-11-oxo-30-noroleana-12-en-3β-yl-2-O-β. -D-Glycyrrhizanolunosyl-α-D-Glycyrrinoside Uronic acid.

The chemical name for the term "magnesium isoglycyrrhizinate" is (18α, 20β) -20-carboxyl-11-oxo-30-noroleana-12-en-3β-yl-2-O-β-D-glucopyranulo. It refers to magnesium nosyl-α-D-glucopyranoside uronate, and its structure is as shown in the above formula I. The term also includes its hydrate, eg tetrahydrate.

As a result of diligent research, the inventor of the present application has found that it is possible to produce a medium-molecular-weight magnesium isoglycyrrhizinate as an inhalation preparation, and the discharge rate of the preparation is high and the fine particle ratio is high. We have surprisingly found that magnesium enters the blood rapidly from the lungs and plays a role in the whole body according to the blood circulation. Inhaled magnesium isoglycyrrhizate is significantly more bioavailable than general oral formulations, which can reduce dosages and reduce the risk of toxicity and adverse events. Compared to the injectable preparation, the magnesium isoglycyrrhizate inhalation preparation has almost the same bioavailability, and the drug is administered by voluntary ingestion or passive inhalation, so that the pain associated with the injection is caused. It can be significantly reduced and the compliance at the time of administration is improved. Therefore, the inhaled preparation according to the present invention is particularly suitable for sequential therapy combined with injection administration, and it is possible to reduce the pain associated with the injection administration of the drug and reduce the treatment cost while ensuring the exertion of the medicinal effect. ..

In an inhalation-induced rat COPD animal model of tobacco smoke, an inhalation formulation of magnesium isoglycyrrhizinate relieves clinical symptoms in COPD rats, suppresses infiltration of neutrophil-based inflammatory factors in COPD rats, and reduces lung inflammation. It had the effect of significantly relieving and improving the condition of the bronchial wall, reducing bronchial mucus secretions, and relieving pulmonary emphysema. Related experiments have shown a significant effect on the treatment of COPD. It was also found that the administration route of magnesium isoglycyrrhizinate affects its efficacy. The administration route of atomized inhalation (magnesium isoglycyrrhizate magnesium nebulizer liquid preparation 0.4 mg / mL, 30 min) was most effective in reducing inflammation.

In the LPS-induced mouse COPD animal model, a marked decrease in the white blood cell count in the bronchial respiratory tract of the mouse was observed in the whole dose group of the magnesium isoglycyrrhizate inhalation preparation as compared with the model group. In the low-dose group and the medium-dose group inhaling the nebulizer liquid preparation of magnesium isoglycyrrhizinate twice a day, the same therapeutic effect as the positive control group was observed, and in the high-dose group, the therapeutic effect was low. It was slightly inferior to the dose and medium dose groups. Further, at the same dose, the therapeutic effect of magnesium isoglycyrrhizinate twice a day was superior to that of once a day.

The effect of magnesium isoglycyrrhizate inhaled preparation on mouse tracheal secretion was evaluated by the mouse phenol red excretion experimental method. As a result, the amount of phenol red excreted at 15 min of atomization administration (0.2 mg / mL of liquid preparation for nebulizer of magnesium isoglycyrrhizinate) was significantly higher than that of the control group (p <0.01).

In this section, the invention of the present application will be further described with reference to specific examples. It should be understood that these examples do not limit the scope of claiming protection in the present invention and are used for explanatory purposes.

In the description of the following examples, the test method that does not specify specific conditions may be carried out based on normal conditions or conditions recommended by the manufacturer. Unless otherwise defined, both technical and scientific terms used herein have the same meanings known to those of skill in the art.

[Example 1]
Dry powder inhaler of magnesium isoglycyrrhizinate

Magnesium isoglycyrrhizate was pulverized to obtain samples having different particle size ranges shown in the following table.

[Example 1a]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality indicators of dry powder inhalers in accordance with the relevant description of "Chinese Pharmacopoeia (Chinese Pharmacopoeia)", General Rule 0111.

[Example 1b]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 1c]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

It was found that the dose of fine particles is an important parameter for evaluating the effectiveness of the inhaled preparation, and the particle size of magnesium isoglycyrrhizinate has a great influence on the fine particle ratio, which is the main quality index of the dry powder type inhalant. The fact that the particle size of magnesium isoglycyrrhizinate was controlled in the range of 0.5 to 10 μm to obtain a fine particle ratio of more than 15% is in line with the relevant provisions of the “Chinese Pharmaceutical Code”.

[Example 2]
Dry powder inhaler of magnesium isoglycyrrhizinate

We compared the effects of different types and different particle size ranges of lactose on the primary quality indicators of magnesium isoglycyrrhizate magnesium dry powder inhalers.

[Example 2a]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 2b]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 2c]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 2d]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 2e]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

[Example 2f]

[Manufacturing process]
1) Weigh a predetermined amount of magnesium isoglycyrrhizate and a predetermined amount of lactose.
2) Sift and mix.
3) One capsule contains 10 mg of magnesium isoglycyrrhizinate and is filled in the capsule at 30 mg / grain.
4) Measure the main quality index of dry powder type inhaler in accordance with the related description of "Chinese Pharmaceutical Code", General Rule 0111.

Lactose of different types and particle sizes was found to have a significant impact on the key quality indicators of dry powder inhalers. The fine grain ratio was relatively low in the sample prepared with sieved lactose alone and the active ingredient, but the fine grain ratio was significantly increased in the sample to which a certain amount of fine lactose was added, and it was made with polished lactose and the active ingredient. The sample had a relatively high proportion of fine particles.

[Example 3]
Liquid formulation of magnesium isoglycyrrhizate for nebulizer

[Manufacturing process]
Weigh a predetermined amount of magnesium isoglycyrrhizinate and sodium chloride, add to 1800 mL of water for injection, stir until completely dissolved, and add aqueous ammonia to adjust the pH of the solution to 6.5-7.0. To obtain a solution, water for injection was added to the solution to make 2000 mL, filtration and sterilization were performed, and the solution was filled with 2 mL / bottle to obtain a liquid preparation for nebulizer containing 10 mg of magnesium isoglycyrrhizinate.

[Example 4]
Liquid formulation of magnesium isoglycyrrhizate for nebulizer

[Manufacturing process]
Weigh a predetermined amount of magnesium isoglycyrrhizinate and sodium chloride, add to 1800 mL of water for injection, stir until completely dissolved, and add aqueous ammonia to adjust the pH of the solution to 6.5-7.0. To obtain a solution, water for injection was added to the solution to make 2000 mL, filtration and sterilization were performed, and the solution was filled with 2 mL / bottle to obtain a liquid preparation for nebulizer containing 5 mg of magnesium isoglycyrrhizinate.

[Example 5]
Liquid formulation of magnesium isoglycyrrhizate for nebulizer

[Manufacturing process]
Weigh a predetermined amount of magnesium isoglycyrrhizinate and sodium chloride, add to 1800 mL of water for injection, stir until completely dissolved, and add aqueous ammonia to adjust the pH of the solution to 6.5-7.0. To obtain a solution, water for injection was added to the solution to make 2000 mL, filtration and sterilization were performed, and the solution was filled with 2 mL / bottle to obtain a liquid preparation for nebulizer containing 1 mg of magnesium isoglycyrrhizinate.

[Example 6]
Liquid formulation of magnesium isoglycyrrhizate for nebulizer

[Manufacturing process]
Weigh a predetermined amount of magnesium isoglycyrrhizinate and sodium chloride, add to 1800 mL of water for injection, stir until completely dissolved, and add aqueous ammonia to adjust the pH of the solution to 6.5-7.0. To obtain a solution, water for injection was added to the solution to make 2000 mL, filtration and sterilization were performed, and the solution was filled with 2 mL / bottle to obtain a liquid preparation for nebulizer containing 0.4 mg of magnesium isoglycyrrhizinate.

[Example 7]
Liquid formulation of magnesium isoglycyrrhizate for nebulizer

[Manufacturing process]
Weigh a predetermined amount of magnesium isoglycyrrhizinate and sodium chloride, add to 1800 mL of water for injection, stir until completely dissolved, and add aqueous ammonia to adjust the pH of the solution to 6.5-7.0. To obtain a solution, water for injection was added to the solution to make 2000 mL, filtration and sterilization were performed, and the solution was filled with 2 mL / bottle to obtain a liquid preparation for nebulizer containing 0.2 mg of magnesium isoglycyrrhizinate.

[Example 8]
Pharmacokinetic evaluation after rat inhalation / intragastric administration

Eight healthy SD male rats weighing 223 to 252 g were fed with a standard recipe granular feed for rats on a regular basis every day, fasted for 16 hours before the experiment, and the feeding was restored 4 hours after the administration. No water restriction was applied before, during and after the experiment. The eight SD male rats were randomly divided into four groups, each of which was administered by inhalation of a liquid preparation for nebulizer (2.5 mg / mL) of magnesium isoglycyrrhizinate in a single dose, and magnesium isoglycyrrhizinate. An inhalation preparation (5.0 mg / mL, content based on isoglycyrrhizic acid was 4.486 mg / mL) was intragastrically administered. In the inhalation group, 200 μL of a nebulizer liquid preparation of magnesium isoglycyrrhizinate (actual dose to rats is 2.24 to 2.49 mg / kg) was administered to each rat, and 10.0 mg in the gastric administration group. / Kg was administered. Approximately 0.2-0.3 mL from the rat's orbital venous plexus before administration (0 h) and after 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, respectively. Blood was collected, anticoagulated with EDTA-K2, plasma was centrifuged and weighed exactly 50 μL. After adding 10 μL of the internal standard solution and vortex mixing until uniform, add 200 μL of methanol, uniformly mix at a high speed of 3 min using a vortex mixer, centrifuge for 10 min (4 ° C., 13000 rpm), and separate the supernatant. The same 100 μL was transferred to a 96-well plate, 50 μL of ultrapure water was added, and the mixture was vortex-mixed until uniform. Samples were added and measured by LC-MS / MS, and chromatograms were recorded.

The following table shows the pharmacokinetic results after inhalation of the liquid preparation for nebulizer of magnesium isoglycyrrhizinate and after intragastric administration of the inhalation preparation of magnesium isoglycyrrhizinate.

In addition, the pharmacokinetic parameters of inhalation administration and the average pharmacokinetic parameters of intravenous administration described in the related literature are compared, and the results are shown in the following table.

Compared to intragastric administration, inhalation-administered rats had a higher relative bioavailability to magnesium isoglycyrrhizinate (68052%) and an intravenous bioavailability of 87%. Therefore, inhalation administration was performed intragastrically. It was found that the bioavailability of magnesium isoglycyrrhizinate was significantly higher and had a level almost equivalent to that of intravenous administration.

[Example 9]
Pharmacodynamic experiment of magnesium isoglycyrrhizate inhalation preparation in COPD rat

9.1 Experimental method Using SD male rats, a COPD induction model was constructed by inhaling cigarette smoke. Later, the rats were randomly divided into 6 groups based on their body weight, and 10 rats per group were used. High-dose tracheal infusion group (1.67 mg / mL magnesium isoglycyrrhizate, 100 μL / animal), low-dose tracheal infusion group (1.67 mg / mL, 25 μL / animal), atomized inhalation group, model group and blank, respectively. It was a group. During the experimental period, saline was tracheally administered in the blank group and the model group, and the drug was continuously administered for 15d in each of the remaining groups. During the administration period, smoke stimulation was applied to each administration group 30 minutes after the administration. Rat mental, respiratory, active, hair gloss, and weight gain were recorded daily. After 12 hours from the final dose, whole blood is collected from the orbit of the rat and used for leukocyte count measurement and cell classification comparison. Rats were sacrificed, thoracotomy was performed to expose the trachea and lungs, and the morphology of the lungs and trachea was visually observed. The right lung was ligated in the right main bronchus, and alveolar lavage with 2 mL of physiological saline was performed 3 times in the left lung, and the recovery rate was about 80%. Alveolar lavage fluid (BALF) is obtained and used for leukocyte count measurement and cell classification comparison (white blood cell, neutrophil, lymphocyte and monocyte). Finally, the right lung of the rat was fixed with 10% formalin, HE-stained, the lung injury state was observed under a microscope, and the lesion was pathologically scored. All scores were added up and the mean score for each animal in each group was calculated (mean ± SD).

Evaluation indicators: (1) whether mucous and cell obstruction were found in the small airway cavity, (2) whether necrotizing ulcer was found in the small airway epithelium, (3) cup cell formation of small airway epithelial cells. Raw, (4) Airway epithelial cell squamous epithelialization (5) Airway wall inflammatory cell infiltration, (6) Airway wall fibrous connective tissue hyperplasia, (7) Airway wall smooth muscle hyperplasia, (8) Small airway wall pigmentation, (9) Pulmonary emphysema. Criteria for scoring lesions: In order of severity of lesions, "0.5 points" if slight or very small amount is observed, "1 point" if mild or small amount is observed, moderate or relatively large amount Is "2 points", "3 points" if severe or frequent, "4 points" if very severe or large amount is observed, and "0 points" if no obvious lesion is observed.

9.2 Experimental results Experimental results data are shown in mean ± SD. Differences between groups were analyzed using a one-way ANOVA combined with Post-Hoc (LSD method). If the P value is less than 0.05, it is recognized that there is a statistically significant difference. When the model group and the blank group were compared, they were ^## p <0.05 and ^## p <0.01. In comparison between each administration group of magnesium isoglycyrrhizinate and the model control group, ^* p <0.05 and ^** p <0.01.

9.2.1 Effect of magnesium isoglycyrrhizinate inhalation preparation on body weight of COPD rats According to the experimental results (Table 1), after successful construction of the COPD model, the rats in each administration group weighed compared to the blank group. The increase was slow and there was a significant difference (p <0.01). 16d after administration, the high-dose, low-dose tracheal infusion group and atomized inhalation group of magnesium isoglycyrrhizinate had slower weight gain than the model group. Among them, the weight gain of the atomized inhalation group was relatively high, and there was a significant difference between each group and the blank group (p <0.01).

9.2.2 Effect of inhaled magnesium isoglycyrrhizinate on general symptoms of COPD rats According to the experimental results, the blank control group had normal activity, no abnormal response, thick body, coughing, sneezing and breathing. No symptoms such as difficulty were observed. In the model group, after successful model construction, the rat does not move while maintaining a prone posture, mental stagnation, dull facial expression, sneezing, and tendency to gather, and the pace is not stable. The weight gain was slow, the hair color was dim yellow, and symptoms such as coughing, sneezing and dyspnea were observed. Symptoms were alleviated in each group receiving high-dose and low-dose magnesium isoglycyrrhizinate tracheal infusion and atomization inhalation therapy compared to the model group, of which the magnesium isoglytylritate magnesium atomization inhalation group was less symptomatic than the other groups. It was remarkable.

9.2.3 Effect of inhaled magnesium isoglycyrrhizinate on blood leukocyte count and cell classification comparison in COPD rats

According to the experimental results (Table 2), the number of neutrophils and the proportion of neutrophils in the blood of the model group rats were both increased, and there was a significant difference (p <0.05 or p <0.01). ). This suggests that after successful construction of the COPD rat model, an inflammatory reaction centered on neutrophil infiltration occurred. From a medicinal point of view, neutrophil-based inflammatory factors in the blood of COPD rats were significantly suppressed in the high-dose, low-dose tracheal infusion group and atomized inhalation group of magnesium isoglycyrrhizinate. There was a significant effect (p <0.05 or p <0.01). Among them, the effect of the magnesium isoglycyrrhizate magnesium atomization inhalation group (0.4 mg / mL, 30 min) was the most excellent. The order of effectiveness was magnesium isoglycyrrhizate atomized inhalation group> high dose tracheal infusion group> low dose tracheal infusion group.

9.2.4 Effect of inhaled magnesium isoglycyrrhizinate inhalation preparation on BALF leukocyte count and cell classification comparison in COPD rats According to the experimental results (Table 3), BALF leukocyte count and neutrophil count and proportion in model group rats. All increased, and there was a significant difference (p <0.05 or p <0.01). This suggests that after successful construction of the COPD rat model, an inflammatory reaction mainly due to neutrophil infiltration occurred in the lung. From a medicinal point of view, magnesium isoglycyrrhizate atomized inhalation reduces the number of neutrophils and the proportion of neutrophils.

9.2.5 Pathological effects of inhaled magnesium isoglycyrrhizinate on COPD rats The experimental results (Table 4) show that in the blank group rats, the lung tissue consists of alveolar tissue, intrapulmonary bronchial branches and interstitial tissue. There was no pulmonary emphysema, indicating that very small amounts of inflammatory cell infiltration and cup cell hyperplasia had occurred. The lesions in the lung tissue of the model group rats were mainly interstitial pneumonia, edema of perivascular tissue, complication of inflammatory cell infiltration, increase of cup cells in the intrapulmonary bronchial wall, and degeneration and necrosis of bronchial wall cells. A small amount of exudation was observed in the bronchial cavity, and pulmonary emphysema and inflammatory cell infiltration were particularly significant (p <0.01 or p <0.05). In the high and low dose tracheal infusion group and atomized inhalation group of magnesium isoglycyrrhizinate, effects such as reduction of lung inflammation, improvement of bronchial wall condition, reduction of bronchial mucus secretion, and relief of emphysema are alleviated. Was significantly observed, and among them, the inflammatory infiltration reducing effect of the magnesium isoglycyrrhizinate atomized inhalation group (0.4 mg / mL, 30 min) was the most excellent.

[Example 10]
Pharmacodynamic experiment of magnesium isoglycyrrhizate inhalation preparation in COPD mice

10.1 Experimental method 90 ICR male mice weighing 18 to 22 g were divided into 9 groups. Blank group, model group, magnesium isoglycyrrhizinate inhalation preparation low dose group (0.5 mg / mL, qd.), Medium dose group (1.5 mg / mL, qd.), High dose, respectively. Group (5.0 mg / mL, qd.), Low dose group (0.5 mg / mL, bi.d.), Medium dose group (1.5 mg / mL, b.id.). ), High dose group (5.0 mg / mL, bid) and positive control group (Arformotero). After anesthetizing the mice, 30 μL of LPS was infused into the trachea to construct a model, and after 30 minutes, 10 mL of the drug was administered using an atomizing inhaler, and the atomization time was 30 min. Low dose group (0.5 mg / mL, b.id.), medium dose group (1.5 mg / mL, b.id.), high dose group (5.0 mg / mL, b) In the i.d.) and the positive control group, 10 mL of the drug was administered again using the atomization inhalation device 6 hours after the successful LPS model construction, and the mice were anesthetized and the lung tissue was washed 24 hours later. The alveolar lavage fluid was collected and the number of inflammatory cells was counted. A part of the lung tissue was collected and stained with HE to prepare a pathological slide, and the change status of the inflammatory cells was measured.

10.2 Experimental Results According to the experimental results (Table 5-1), a large amount of inflammatory cells (white blood cells) were generated in the bronchial airways in the LPS-induced model group mice, which increased by 490% compared to the blank group, which led to the construction of a COPD-induced model. Showed success. In addition, histopathological examination of the lung tissue structure of mice showed a marked inflammatory response in the model group animals, and marked inflammatory cell infiltration. Exudative inflammatory cells were found in the alveolar and alveolar septal junctions, with neutrophil retention and aggregation particularly pronounced in the pulmonary blood vessels and at each level of the bronchus.

According to the experimental results (Table 5-2), in the LPS-induced mouse COPD model experiment, there was a significant difference in the leukocyte count comparison between each dose group and the model group of the magnesium isoglycyrrhizinate inhalation preparation. Twice-daily daily low-dose inhalation group (white blood cell 29% reduction) and medium-dose group (white blood cell 33% reduction) have the same therapeutic effect as the positive control group (white blood cell 33% reduction). It was observed that the effect of the high dose group was slightly inferior to that of the low dose group and the medium dose group. At the same dose, administration of magnesium isoglycyrrhizinate twice daily was more effective than once daily. In addition, histopathological examination showed no significant inflammatory reaction in each dose group of the magnesium isoglycyrrhizate inhalation preparation.

[Example 11]
Effect of inhaled magnesium isoglycyrrhizate on airway secretion

11.1 Experimental method Fifty male ICR mice weighing around 21 g were used and randomly divided into five groups. Control group 1 (saline, NS), control group 2 (saline, NS), positive group (ammonium chloride, 1 g / kg), administration group 1 (nebulizer liquid preparation 0.2 mg of magnesium isoglycyrrhizinate) / ML, atomization 30 min), administration group 2 (liquid preparation 0.2 mg / mL for nebulizer of magnesium isoglycyrrhizinate, atomization 15 min). The control group 1 and the positive group were administered the drug intragastrically (0.1 mL / 10 g), the control group 2 and the administration group 1 were administered by atomization for 30 minutes using a nebulizer, and the administration group 2 was administered by atomization for 15 minutes. It was administered once daily for 6 d consecutive times. Immediately before the 6th administration, the mice were fasted for 16 to 18 hours, only water was ingested, and 30 minutes after the administration, 1% phenol red physiological saline solution was added ip (0.2 mL / 10 g), and 30 minutes after the phenol red injection. Later, euthanasia was performed due to cervical spinal dislocation. Wait for a while to avoid significant bleeding when cutting the cervical skin, coagulate the blood in the mouse (to avoid contamination of the lavage fluid with phenol red in the blood), separate the trachea and perform tracheal intubation (needle tip). Inserted into the trachea about 3 mm from the larynx using a pre-polished No. 6 needle, ligated and fixed with a wire), connected a syringe, and gradually inject 5% NaHCO ₃ 0.6 mL into the trachea and gently aspirate. Then, it was repeated 3 times in this way. The cleaning liquids were combined three times and centrifuged at 4000 rpm for 5 minutes to obtain a supernatant liquid.

11.2 Measurement index and its calculation method [Plot of phenol red calibration curve]
1.95 mg of phenol red was weighed and dissolved by adding 5% NaHCO ₃ to make 3.9 mL, and a stock solution containing 0.5 mg / mL of phenol red was prepared. Add ₅ % NaHCO 33.9 mL to 0.1 mL of undiluted solution to make 12.5 μg / mL, in that order 10 μg / mL, 7.5 μg / mL, 5 μg / mL, 2.5 μg / mL, 1.25 μg / mL and 0. It was diluted to 625 μg / mL. The phenol red calibration curve was plotted by colorimetrically measuring at a wavelength of 546 nm using a microplate reader and measuring the OD value.

The OD value of the sample was measured at a wavelength of 546 nm using a microplate reader, and the phenol red content of the sample was calculated based on the phenol red calibration curve.

11.3 Experimental results Experimental results data are shown in mean ± SD. If the P value is less than 0.05, it is recognized that there is a statistically significant difference. Each administration group had ^Δ△ p <0.01 as compared with the control group 2. The experimental results are shown in Table 6. The administration group 2 (a liquid preparation for nebulizer of magnesium isoglycyrrhizinate 0.2 mg / mL, atomization 15 min) significantly increased the amount of phenol red excreted as compared with the control group 2.

Claims (19)

An inhalation formulation for expectoration, characterized in that the active ingredient is magnesium isoglycyrrhizinate. A dry powder inhaler containing finely divided magnesium isoglycyrrhizate and one or more pharmaceutically acceptable carriers, wherein the magnesium isoglycyrrhizate has a particle size of 0.5 to 10 μm. The inhalation preparation according to claim 1, wherein there is. The inhalation preparation according to claim 2, wherein the magnesium isoglycyrrhizate has a particle size of 0.5 to 5 μm. The pharmaceutically acceptable carrier is abrasive lactose, sieved lactose or a mixture of sieved lactose and fine-grained lactose, and the particle size distribution range of the abrasive lactose is 1 to 350 μm, and the particle size of the sieved lactose. The inhalation preparation according to claim 2 or 3, wherein the distribution range is 1 to 200 μm, and the particle size distribution range of the fine lactose is 1 to 60 μm. The abrasive lactose has a particle size distribution of X ₅₀ <30 to 110 μm, the sieved lactose has a particle size distribution of X ₅₀ <35 to 115 μm, and the fine lactose has a particle size distribution of X ₉₀ <45 μm. The inhalation preparation according to claim 4, wherein the inhalation preparation is characterized by. The inhalation preparation according to claim 4 or 5, wherein the micronized magnesium isoglycyrrhizate and the carrier are mixed and filled in a capsule or a blister pack. The inhaled preparation according to claim 6, wherein 1 capsule or blister pack contains 1 to 50 mg of finely divided magnesium isoglycyrrhizate and 0 to 50 mg of lactose. The inhaled preparation according to claim 7, wherein 1 capsule or blister pack contains 1 to 30 mg of finely divided magnesium isoglycyrrhizate and 1 to 40 mg of lactose. The dry powder inhaler further comprises one or more pharmaceutically acceptable additives, which may be one or more selected from surfactants, lubricants, and flavoring agents. The inhaled preparation according to any one of claims 2 to 8, wherein the inhaled preparation is characterized by being present. The inhalation preparation according to claim 9, wherein the surfactant is a phospholipid and / or the lubricant is magnesium stearate. A nebulizer liquid preparation containing magnesium isoglycyrrhizinate, an isotonic agent, a pH adjuster, and water for injection and having a pH of 6.0 to 8.0, wherein the nebulizer is a continuous nebulizer or a quantitative formula. The inhalation preparation according to claim 1, which is a nebulizer. The inhalation preparation according to claim 11, wherein the content of the magnesium isoglycyrrhizate is 0.1 to 5 mg / mL. The inhalation preparation according to claim 12, wherein the content of the magnesium isoglycyrrhizate is 0.1 to 2.5 mg / mL. The inhalation preparation according to claim 11, wherein the isotonic agent is one or a combination of one or more selected from glucose, sodium chloride, potassium chloride, and mannitol. The pH adjuster is one selected from sodium hydroxide, aqueous ammonia, hydrochloric acid, sodium carbonate, sodium hydrogencarbonate, dilute sulfuric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium acetate, or disodium hydrogen phosphate. The inhalation preparation according to claim 11, wherein the inhalation preparation is a combination of a plurality of types. The inhalation preparation according to claim 11, wherein the pH is 6.5 to 7.0. The inhaled formulation according to claim 11, characterized in that it is provided in a single dose in a package of 1 mL, 2 mL or 5 mL specifications. 17. The inhaled formulation according to claim 17, which is provided in a single dose package in a 2 mL specification. Use of magnesium isoglycyrrhizinate in the manufacture of inhaled medicines for expectoration .