阅读说明：本技术 一种用于小儿哮喘的活性药物 (Active medicine for treating infantile asthma ) 是由 刘艳丽 于 2021-08-02 设计创作，主要内容包括：本发明涉及一种包含5-[3-(3-羟基苯氧基)氮杂环丁烷-1-基]-5-甲基-2,2-二苯基己酰胺或其药学上可接受的酸加成盐和2-氨基-2-〔2-(4-辛基苯基)乙基〕丙烷-1,3-二醇或其药学上可接受的酸加成盐药物组合物及其在预防或治疗小儿哮喘中的用途。(The invention relates to a pharmaceutical composition containing 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide or a pharmaceutically acceptable acid addition salt thereof and 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol or a pharmaceutically acceptable acid addition salt thereof and application thereof in preventing or treating infantile asthma.)

1. A pharmaceutical composition comprising (a) a therapeutically effective amount of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide or a pharmaceutically acceptable acid addition salt thereof, (b) a therapeutically effective amount of 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol or a pharmaceutically acceptable acid addition salt thereof, and (c) a pharmaceutically acceptable adjuvant.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable acid addition salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide is the hydrochloride salt.

3. The composition of claim 1 wherein the pharmaceutically acceptable acid addition salt of 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol is the hydrochloride salt.

4. The pharmaceutical composition according to claim 1, wherein the mass ratio of (a) to (b) in the composition is 1 to 2.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients comprise a coating agent, a surfactant, a cellulose derivative, a disintegrant, an excipient, a lubricant, a binder, an antioxidant, a flavorant, a colorant.

6. The pharmaceutical composition of claim 1, wherein the dosage form of the pharmaceutical composition comprises inhalant, tablet, capsule, liquid formulation.

7. The composition of any one of claims 1, 2, 3 for use in treating a respiratory disease in a subject in need thereof.

8. The composition of claim 7, wherein the respiratory disease is pediatric asthma.

9. Use of a pharmaceutical composition according to claim 1 for the manufacture of a medicament for the treatment of a respiratory disease.

10. The use according to claim 9, wherein the respiratory disease is pediatric asthma.

Technical Field

The invention relates to a pharmaceutical composition containing 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide or a pharmaceutically acceptable acid addition salt thereof and 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol or a pharmaceutically acceptable acid addition salt thereof and application thereof in preventing or treating infantile asthma.

Background

Asthma in children is called bronchial asthma, short for asthma, and is the most common chronic respiratory disease in childhood. The traditional Chinese medicine composition is an airway chronic inflammatory disease with multiple cells and cell components participating together, the airway responsiveness is increased due to the chronic inflammation, the wide and variable reversible airflow limitation generally appears, and the symptoms such as recurrent wheezing, shortness of breath, chest distress or cough are caused, the morbidity and mortality of the infantile asthma rise year by year, the current medicine treatment is still the most effective method for preventing and treating the bronchial asthma, and the research on developing the high-efficiency and high-selectivity antiasthma medicine is very important.

For example, international publication No. WO2008/135819 discloses that 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide) is an antagonist of the M3 receptor. 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide) has its particular utility in the treatment of M3-mediated diseases and/or conditions and shows good efficacy for the treatment of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD).

For example, International publication WO94/08943 discloses that 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol or a pharmaceutically acceptable acid addition salt thereof is an immunosuppressant therapeutic drug.

Various therapeutic approaches are known for treating respiratory diseases, for example, corticosteroids, beta 2-adrenoceptor agonists, Phosphodiesterase (PDE)4 inhibitors, PDE3 inhibitors, leukotriene receptor antagonists and the like are known to be all used for treating respiratory diseases, and drugs for treating infantile asthma which are commonly used clinically at present mainly comprise ICS, leukotriene modulators, slow-release theophylline, long-acting beta 2 receptor agonists, mast cell membrane stabilizers, systemic glucocorticoids and anti-IgE antibodies, while for the drugs with poor control of the disease conditions, combination therapy of different drugs is required. However, the prior art has no report on the treatment of respiratory diseases by the combination, and even no report on synergistic interaction.

Disclosure of Invention

In view of the above-mentioned circumstances, the present inventors have made extensive studies to obtain a more effective therapeutic agent for respiratory diseases, particularly asthma in children, and have surprisingly found that 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol (hereinafter referred to as compound B) or a pharmaceutically acceptable acid addition salt thereof enhances the activity of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide) (hereinafter referred to as compound a), and that the compositions synergistically interact to provide improved therapeutic effects.

The present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide or a pharmaceutically acceptable acid addition salt thereof, (b) a therapeutically effective amount of 2-amino-2- [ 2- (4-octylphenyl) ethyl ] propane-1, 3-diol or a pharmaceutically acceptable acid addition salt thereof, and (c) a pharmaceutically acceptable adjuvant.

The invention also provides application of the pharmaceutical composition in preparing a medicament for treating respiratory diseases, wherein the respiratory diseases are infantile asthma.

Further, the pharmaceutically acceptable auxiliary materials comprise a coating agent, a surfactant, a cellulose derivative, a disintegrating agent, an excipient, a lubricant, a binder, an antioxidant, a perfume and a coloring agent.

Further, coating agents, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, shellac, polyvinyl alcohols, polyvinyl pyrrolidone, methyl acrylate;

further, surfactants, for example, sucrose fatty acid esters, polyoxyethylene hardened castor oil, polyoxyethylene fatty acid esters, polyoxyethylene alcohols, polyoxyethylene sorbitan fatty acid esters, alkyl benzene sulfonates, and sodium sulfosuccinate. The amount of the surfactant used is preferably 0.01 to 30 parts by mass, more preferably 0.05 to 20 parts by mass, per 100 parts by mass of the combination of A and B, and when two or more surfactants are used in combination, the total amount of the surfactants is preferably 0.01 to 30 parts by mass, more preferably 0.05 to 20 parts by mass, per 100 parts by mass of the combination of A and B.

Further, cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose. The cellulose derivative is used preferably in an amount of 1 to 2000 parts by mass, more preferably 1 to 1500 parts by mass, based on 100 parts by mass of the combination of A and B. When two or more cellulose derivatives are used in combination, the total amount of the cellulose derivatives is preferably 1 to 4000 parts by mass, more preferably 1 to 3500 parts by mass, per 100 parts by mass of the combination of a and B. When the amount of the cellulose derivative used is less than 1 part by mass relative to the amounts of A and B, the hydrophilicity of the composition cannot be sufficiently improved and a high elution rate cannot be obtained, and when the amount exceeds 15 parts by mass, the hydrophilicity is sufficiently improved in many cases, but the dissolution time of the coated cellulose derivative itself is prolonged and a high elution rate of the composition cannot be obtained.

Further, excipients such as starch, dextrin, carboxymethyl starch, methyl cellulose, hydroxypropyl cellulose, lactose, D-mannitol, glucose, silicic acid, natural aluminum silicate, magnesium silicate, calcium carbonate, magnesium carbonate, sodium hydrogen carbonate, aluminum magnesium hydroxide, synthetic hydrotalcite, polyoxyethylene derivatives, glyceryl monostearate, sorbitan monooleate;

further, lubricants, for example, stearic acid, hardened oil, calcium stearate, magnesium stearate, talc, silicic acid, light anhydrous silicic acid, natural aluminum silicate, titanium oxide, calcium hydrogen phosphate, dried anhydrous alumina gel, polyethylene glycol.

Further, binders such as starch, corn starch, gelatinized starch, dextrin, cellulose, ethyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, gum arabic, gum tragacanth, gelatin, glucose, ethanol, polyvinyl alcohol.

Further, disintegrating agents, such as magnesium stearate, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, sodium carboxymethyl starch, polyvinylpyrrolidone, starch, agar, sodium alginate. The amount of the disintegrant used is preferably 1 to 5000 parts by mass, more preferably 2 to 4000 parts by mass, per 100 parts by mass of the combination of A and B, and when two or more disintegrants are used in combination, the total amount of the disintegrants is preferably 1 to 8000 parts by mass per 100 parts by mass of the combination of A and B.

Further, antioxidants such as sodium sulfite, sodium bisulfite, isoascorbic acid, L-ascorbic acid, cysteine, thioglycerol, butyl hydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbyl palmitate, tocopherol.

Further, flavors such as menthol, vanilla flavor, orange peel oil, peppermint oil, eucalyptus oil, cinnamon oil.

Further, coloring agents such as indigo carmine, caramel, riboflavin, food tar color, iron oxide, alumina, carotene, chlorophyll, and lake.

Further, the dosage form of the pharmaceutical composition comprises inhalant, tablet, capsule and liquid preparation.

The content of the above-mentioned composition A and B in the pharmaceutical composition of the present invention varies depending on the dosage form, and is preferably 0.01 to 99.9% by mass.

The dosage of the pharmaceutical composition of the present invention can be suitably determined depending on the degree of symptoms, administration method, diagnosis result of a doctor, etc., and for example, the dosage of the composition of A and B is preferably 0.1 to 1000mg/kg per body weight per liter kg per day. The pharmaceutical composition of the present invention can be administered in the above-mentioned dose 1 or in divided doses within 1 to 7 days, depending on the severity of the symptoms and the judgment of the physician.

The pharmaceutical compositions of the present invention interact synergistically to provide improved treatment of pediatric asthma.

Detailed Description

The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.

Example 1

Safety experiments on cardiovascular interaction of Compound A and Compound B

The post-administration peak changes in blood pressure and heart rate of male rats after single and combined administration of compound a and compound B were determined. The study design used a random blind approach to select 12 healthy rats with an average body weight of 220g, divided into 3 groups of four and 3 rats per group, with Compound A (4. mu.g/kg), Compound B (8. mu.g/kg), Compound A (4. mu.g/kg) + Compound B (8. mu.g/kg) administered separately. The main pharmacokinetic variables measured were systolic blood pressure, diastolic blood pressure, and heart rate using the calculated mean blood pressure. No major interactions between drugs were found by testing.

Example 2

Synergistic effect of combined administration of compound a and compound B on reduction of airway obstruction

Experiment airway obstruction was induced by intravenous administration of bombesin (4. mu.g/ml) to guinea pigs. Different doses of Compound A (1. mu.g/kg, 2. mu.g/kg, 4. mu.g/kg, 8. mu.g/kg) were administered intravenously alone, and Compound A (1. mu.g/kg, 2. mu.g/kg, 4. mu.g/kg, 8. mu.g/kg) was administered in combination with Compound B (8. mu.g/kg), respectively, and the effect of Compound B on the airway-blocking-reducing effect of Compound A was examined.

This result provides further evidence that compound B significantly enhances the bronchorelaxing activity of compound a.

Example 3

Synergistic Effect of Compounds A + B on the tracheal Ring

The method comprises the following steps: 200-g male Wistar rats were sacrificed, the neck dissected, the trachea excised 1mm above the tracheal bifurcation and 1mm below the thyroid cartilage, and 3mm thick rings were cut in Krebs-Henseleit solution ventilated with 95% oxygen-5% carbon dioxide at room temperature and divided into 6 groups. Krebs-Henseleit solution aerated with 95% oxygen-5% carbon dioxide, pH 7.0. + -. 0.5, washed twice, applied 1g load to each loop and left to stand for 60 minutes.

Selecting 3 groups, adding 150 μmol/L acetylcholine to stimulate trachea, eluting to recover to baseline after trachea is fully contracted, and starting experiment after trachea has a rest of 30 min. 150 μmol/L acetylcholine was re-stimulated, then 3 groups of DMSO-dissolved Compound A (4mg), Compound B (8mg), Compound A (4mg) + Compound B (8mg) were added, and the tracheal ring relaxation values, which caused contraction with different administrations, were measured.

Selecting another 3 groups, adding 100mmol/L KCL to stimulate trachea, eluting to recover to baseline after trachea is fully contracted, and starting experiment after trachea has a rest of 30 min. 100mmol/L KCL was stimulated again, then 3 groups were added DMSO-dissolved Compound A (4mg), Compound B (8mg), Compound A (4mg) + Compound B (8mg), respectively, and the tracheal ring relaxation values that caused contraction upon different administrations were measured.

The conclusion is that in the isolated bronchial rings, the compound A and the compound B synergistically inhibit the contraction induced by acetylcholine and high potassium stimulation, have the synergistic and efficient effect of relaxing the tracheal smooth muscle, and can effectively relieve the symptoms of airway spasm and airway obstruction.

Example 4

Animal experiment of asthma efficacy

Experimental animals: 60 healthy male BN rats with the body weight of 160-230 g are selected and divided into a control group, a compound A group, a compound B group and a compound A + B group, and 15 rats are selected. Each group is administered 1ml of mixed solution of 100mg of aluminum hydroxide gel containing egg protein on the first day, and on the 15 th day, 5L/min of 5% egg protein physiological saline solution is atomized and inhaled for 20 minutes to induce asthma attack, 1 time per day for 7 days, and after the atomization is stopped for 7 days, the groups are continuously excited for 7 days;

animal behavioral observation: after the egg protein is atomized, the rat generates sneezing, coughing, rapid respiration, mouth opening respiration and arch back stagnation, hair color is dry after repeated attacks, and the weight is slowly increased; the inflammation of the large airways is obviously changed, the exudation in the bronchial cavity is increased, and inflammatory cells are obviously increased in the bronchial wall and tissues around the bronchi.

Subsequently, each group of rats was gavaged with the corresponding test substance at the following dose:

control group: equal amount of physiological saline;

compound group a: the compound A0.03mg/Kg;

compound group B: the compound B0.03mg/Kg;

compound group a + B: 0.01mg/Kg of Compound A +0.02mg/Kg of Compound B.

The administration is performed 2 times daily for 7 days. IL-4 and IL-5 detection in serum was performed 7 days later in male BN rats using IL-4 and IL-5 kits to observe changes in IL-4 and IL-5 after drug administration in rats of the experimental group and the control group.

Serum IL-4(pg/ml) and IL-5(pg/ml) of experimental group and control group of BN rat

When the compound A + B is compared with the control group,^***P＜0.01

as can be seen from the pharmacodynamic experiments, the combination of the compounds A and B has good synergistic treatment effect.

Example 5

Determination of the anti-inflammatory Activity of Compounds A + B in egg protein stimulated BN rats

60 clean SD rats, half male and female, with a body mass of 180-. All rats were randomly divided into control group, compound a group, compound B group, compound a + B group, 15 per group. The egg protein challenge method of example 4 was used until the rats developed asthma-like attacks, when the rats developed the symptoms described in example 4, indicating successful replication of the asthma model. Subsequently, each group of rats was administered with the corresponding test substance at the following dose:

control group: an equivalent amount of lactose;

compound group a: the compound A0.03mg/Kg;

compound group B: the compound B0.03mg/Kg;

compound group a + B: 0.01mg/Kg of Compound A +0.02mg/Kg of Compound B.

The drug (well mixed with lactose) and control (lactose) were administered intratracheally as dry powders (i.t.). After 50h, the rats were anesthetized and BAL buffer lavaged each rat bronchoalveolar. The total cell and eosinophil number in BAL buffer, and protein concentration in cell-free buffer were determined.

Compound a administered i.t. at a dose of 0.03mg/Kg showed no significant effect on cell infiltration and protein accumulation. Compound B administered i.t. at a dose of 0.03mg/Kg showed an inhibitory effect on total cell and eosinophil numbers flowing into the alveolar space and protein levels in buffer but did not reach significance, while compound a + B combination showed a significant inhibition of eosinophils and a decrease in protein concentration in BAL fluid. I.e. co-administration of compounds a + B gives a synergistic effect compared to the administration of each compound alone.

Examples 6 to 8

Examples of pharmaceutical preparations

Finely ground compounds a and B, lactose, corn starch, microcrystalline cellulose were mixed with each other in the amounts indicated in the table, the mixture was sieved, then wetted with an aqueous solution of hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, respectively, kneaded, wet granulated, dried, the resulting granules were mixed with magnesium stearate, and the mixture was compressed into the appropriate shape and size.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.