WO2020031148A1

WO2020031148A1 - Pharmaceutical composition, medicinal product and method of treatment of bronchopulmonary obstructive diseases

Info

Publication number: WO2020031148A1
Application number: PCT/IB2019/056801
Authority: WO
Inventors: Nataliya TYKHONIVSKA
Original assignee: Tykhonivska Nataliya
Priority date: 2018-08-10
Filing date: 2019-08-09
Publication date: 2020-02-13
Also published as: WO2020032910A1

Abstract

A pharmaceutical composition comprising a combination of three or more active substances selected from a selective beta-2 adrenergic receptor agonist, anticholinergics, sodium cromoglycate and salts thereof is claimed. Also, the claimed medicinal product, use of the pharmaceutical composition or medicinal product and method of treatment of bronchopulmonary obstructive diseases characterized by the use of a pharmaceutical composition.

Description

PHARMACEUTICAL COMPOSITION, MEDICINAL PRODUCT AND METHOD OF TREATMENT OF BRONCHOPULMONARY OBSTRUCTIVE DISEASES

The invention belongs to medicine: pulmonology, ENT-otolaryngology, pathophysiology. The relevance of the subject of the invention is associated with a significant prevalence in modern conditions of the incidence of asthma. At the same time, there is a lack of effectiveness of existing methods of treating bronchial asthma, especially with moderate to severe and severe course. Therefore, the development of pathogenetically substantiated methods of treating this disease is important for clinical practice.

The invention also relates to a pharmaceutical composition for inhalation. The invention further relates to a method of using such a composition in the treatment of asthma, COPD-chronic obstructive pulmonary diseases, allergies, infectious diseases and diseases of the cardiovascular system.

The pulmonary system includes the upper respiratory tract, in particular the oropharynx and respiratory throat, the lower respiratory tract, which include the trachea with further branching into the bronchi and bronchioles. The upper and lower respiratory tract are called conduction airways. The terminal bronchioles are then divided into respiratory bronchioles, which then pass into the alveolar region, or into the deep parts of the lungs.

Bronchial asthma is one of the common chronic diseases, which is characterized by heterogeneity of clinical forms and variability of the course.

At the present stage, management of bronchial asthma requires an in-depth analysis of the factors responsible for the progression of the disease and the development of exacerbations, as well as the choice of therapy for bronchial asthma based on the clinical and biological phenotypes of the disease.

GINA 2017 emphasizes the heterogeneity of AD with the selection of the most common phenotypes. It is proposed to identify three clinically relevant BA phenotypes: type 1 - eosinophilic allergic asthma, type 2 - eosinophilic non-allergic asthma, and type 3 - non-eosinophilic non-allergic. Analogues of the proposed types are covered in [Wenzel, Bousquet, Hashimoto, Custovic, and Chung]. Type 1 - "early" atopic asthma, "atopic form"; 2 - (severe) to a lesser extent atopic group with later onset of inflammation or severe "internal" asthma; 3 - "more severe", late onset, with obesity, or non-eosinophilic asthma with obesity, or severe asthma with obesity. Both eosinophilic types of AD (allergic and non-allergic) are characterized by Th2-dependent inflammation; non-eosinophilic type of AD is not Th2-dependent inflammation. There is little evidence of the effects of ICS (inhaled corticosteroids) on eosinophil counts and the concentration of cationic protein (ECP) in the blood; such effects can be expected 2 weeks after the start of treatment [Медична газета «Здоров’я України» № 13-14(410-411) 2017 р. «Новий фенотипспецифічний підхід до ведення бронхіальної астми» О.С.Толох, Н.Д.Рудницька, к.м.н. У.Б.Чуловська, к.м.н. Х.І.Вольницька. Львівський національний медичний університет ім. Данила Галицького, КУ ЛОР «Львівський регіональний фтизіо-пульмонологічний клінічний лікувально- діагностичний центр»]. [Health newspaper of Ukraine of Ukraine # 13-14 (410-411) 2017 "A new phenotype-specific approach to managing bronchial asthma": OS Tolokh, ND Rudnitskaya, Ph.D. VB Chulovskaya, Ph.D. HI Volnytska. Lviv National Medical University. Danylo Halytskyi, CU EN “Lviv Regional Phthisiology and Pulmonary Clinical Medical Diagnostic Center”]. Allergy effect of sodium cromoglycate, nedocromil sodium cromoglicic acid linked to their ability to prevent and inhibit the development of early, one that runs on immediate type, phase allergic responses and reduce the signs of allergic inflammation before all through inhibition of the influx of eosinophils in the body and reduce shock activity of eosinophils. [И.И.Балаболкин, О.Ф.Лукина, А.В.Горюков, А.В.Ляпунов -Применение кромонов при аллергических заболеваниях у детей., Педиатрия 2007 Том 8 № 4.] [I.I. Balabolkin, O.F. Lukin, A.V. Goryukov, A.V. Lyapunov -Application of cronons in allergic diseases in children., Pediatrics 2007 Volume 8 No. 4.] The use of cromons is also advisable to achieve and support the control of non-eosinophilic bronchial asthma: bronchial asthma of smokers – cronons reduce respiratory irritation, late menopausal bronchial asthma in obese women who often develop resistance to inhaled corticosteroid therapy.

The goal of treating bronchial asthma is not only the elimination of current symptoms, but also the minimization of inflammation, bronchial hyperreactivity, prevention of exacerbation and the formation of irreversible remodeling of the walls of the respiratory tract and, as a result, a fixed limitation of air flow rate. In this case, it is desirable to minimize pharmacotherapy, given that long-term treatment with corticosteroids is associated with a risk of systemic side effects, as well as limited use of corticosteroids for pulmonary tuberculosis and severe asthma with fungal sensitization (SAFS-Severe Astma with Fundal Sensitization) or allergic bronchopulmonary aspergillosis .

The leading place among the methods of basic therapy for bronchial asthma is occupied by B2 agonists, which are characterized by pronounced bronchodilator activity and a minimal number of undesirable side reactions when used correctly -Cates C.J., Welsh E.J.,Rowe B.H. Holding chambers (spasers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane 15 Database Syst Rev.-2013.

Known is the complex treatment of chronic obstructive pulmonary diseases and bronchial asthma which includes the use of mucolytics and antibiotics as well as a course of ultrasonic inhalations, a suspension of lipin and berodual. The disadvantage of this method is the presence of a mucolytic, which excludes the appointment during exacerbation.

Mucolytics and asthma.

Among the first can be called trypsin, chymotrypsin and their analogues. The mucolytic effect of enzymes is related to the cleavage of peptide (protein) bonds of mucus glycoprotein molecules. In the 50-70's they were used quite widely, but it was soon discovered that proteolytic enzymes contribute to the development of emphysema and pneumosclerosis. Therefore, they cannot be prescribed for chronic lung diseases, the progression of which can lead to emphysema and pneumosclerosis, and these diseases include asthma. In addition, there are other mucolytics - mercaptans - no less effective and absolutely safe.

Unlike proteolytic enzymes, mercaptans, acetylcysteine and mesna, thin the sputum by breaking the disulfide bridges that bind glycoprotein molecules. The mechanism of this reaction is quite simple, but the effectiveness of this effect is extremely high: sputum liquefies almost instantly. Therefore, mercaptans are also used in otolaryngology to cleanse viscous mucus from the upper respiratory tract. By the way, other derivatives of thiols, for example, the domestic preparation unitiol, can also be effectively used as mucolytic agents. Most thiols are used in the form of tattoos or syrups for injection and inhalation. When using thiols inwardly, they are absorbed from the digestive tract into the blood and are secreted through the bronchial wall, which are dilated and exfoliate primarily the parietal layer of mucus. And this significantly increases the effectiveness of the coughing action.

Thus, when thiols are taken orally, as well as when injected, they act extrabronchially falling into the lumen of the bronchus through its wall from the blood. With inhaled use, mercaptans act endobronchially, since they enter directly into the lumen of the respiratory tract, therefore, if there is a lot of mucus in the lungs, the drug does not affect the parietal layer of the secretion, which does not allow to achieve the most effective expectorant effect. In such cases, it is better to combine the use of thiols inside with inhalation.

The scientific literature describes many cases where the use of thiols, in particular acetylcysteine, causes bronchospasm with dyspnea, however, previous inhalation of a bronchodilator prevents it. Contraindications for the use of thiols inside are severe chronic diseases of the digestive system, rarefaction of mucus eliminates its protective function, which can lead, for example, to an exacerbation of peptic ulcer and other ailments. In such cases, these funds are recommended to be used in lower doses and, mainly, in the form of inhalations.

The extrabronchial mechanism of action is inherent in another class of iodine salts, which is used in the form of potions and very rarely in the form of solutions for intravenous administration. Absorbing into the blood, they are then secreted through the wall of the bronchus, in its lumen and by virtue of the laws of osmosis, they increase the water content in the mucus, rehydration of the mucus, improving coughing. An unpleasant feature of these drugs is irritation of the skin and mucous membranes, since it is through them that iodine salts are secreted. This is sometimes manifested by a rash and itching of the skin, exacerbation of chronic inflammatory processes of the mucous membranes in various organs, which naturally limits their use. A positive feature of drugs that contain iodine salts is a fairly pronounced antifungal effect, so one of the additional indications for the use of iodine medicines is the development of candidiasis during treatment with inhaled steroids.

Alkaline solutions also have a property of rehydrating mucus, in particular sodium bicarbonate (sodium bicarbonate), which are used mainly in the form of inhalations. Recommendations of the same type “heavy drinking” declared as expectorant therapy are rather dubious. To this may be added that the solutions of soda, depending on the concentration also cause alkaline hydrolysis of mucus, which increases the efficiency of coughing. Thus, the basis of the expectorant action of saline solutions is the rehydration of bronchial mucus, i.e. the increase in water. This reduces its adhesion (sticking) to the bronchial wall, and according to some reports, and reduces the viscosity.

Another class of pharmacological agents that reduce sputum adhesion, represented by bromhexine and its derivatives – ambroxol.

Bromhexine is a substance of natural origin: it was first isolated from plants. Subsequently, its chemical synthesis was carried out, and it became widely used in pulmonology. Bromhexine and ambroxol are the most effective and safe expectorants today. They are usually used in the form of tablets and potions. The main mechanism of action of bromhexine and its analogues is to stimulate the production in the lungs of special substances - surfactants with high surface activity (like synthetic detergents). Therefore, rising from the alveoli (where they are produced), surfactants "wash" the mucus from the wall of the bronchi. Bromhexine preparations have not only an effective expectorant effect, but also with prolonged intake (more than 3 months) contribute to normalization of secretion, reducing the amount of mucus formed in the respiratory tract. Prolonged treatment with bromhexine at a dose of 48 to 96 mg per day for 3-6 months, especially in autumn and spring, improves not only bronchial drainage, but also gradually normalizes secretion, sometimes to a complete absence of phlegm. At these doses, these agents are absolutely harmless. And according to the available data in the literature, patients who regularly take Lasolvan or bromhexine, tolerance of the disease is twice as rare.

The maximum complete cleansing of the respiratory tract from excess mucus (impairs the patency of the bronchial tubes and reduces the effectiveness of inhalation anti-inflammatory and anti-allergic agents) can be achieved and reducing its amount in the lungs. For this purpose, drugs that affect its production of mucous cells and glands are used. Such preparations include S-carboxymethylcysteine (carboxycysteine or carbocysteine), which is available under various commercial names. It is usually given in capsules or as syrup. An unpleasant side effect of carboxycysteine is its ability to exacerbate chronic diseases of the digestive tract. Therefore, it cannot be applied for a long time.

According to patent UA 100237 C (10.12.2012, bul. No. 23), the use of a formoterol and beclomethasone dipropionate-containing composition for the prevention and / or treatment of asthma exacerbation. More specifically, the present invention is directed to the use of a composition containing a fixed combination of formoterol, its pharmaceutically acceptable salt or solvate or solvate of such salt and beclomethasone dipropionate. The disadvantage of this method is the use of a hormonal drug (see above).

From the patent UA 55763 A (15.04.2003, bul. No. 4) there is a known method of optimizing the treatment of exacerbation of bronchial asthma, which consists in the introduction of patients with breaks with the help of a nebulizer 1 ml of berodual solution in 1:1 dilution with physiological NaCl solution after 30 minutes 2 ml of solution was ambrobene in a 1:1 dilution with saline NaCl, and an hour later - budesonide at a dose of 400-600 mcg in a metered aerosol inhaler. When applying the proposed nebulizer regimen, the asthma attacks stopped on the first day. The disadvantage of this method is that it is quite complex, and in particular precludes the implementation of urgent self-care for patients.

From patent RU2530658 (10.10.2014 bul. No. 28) is known a method of selecting a drug-bronchodilator, which calculates the value of the risk index of cardiohemodynamic disorders (PKP) and if this value is> 0.46 as a drug-bronchodilator for the treatment of asthma in a child in in the period of exacerbation of the disease choose a combined bronchodilator: ipratropium bromide + phenoterol. The disadvantage of this method is the lack of speed, which is a critical factor in reducing exacerbation of asthma.

It is known about the joint use of dietetic drugs (phenoterol hydrobromide 50 μg disodium cromoglycate 1000 μg) and berodual (ipratropium bromide anhydrous 250 μg; phenoterol hydrobromide 500 μg) in the inhalation ratio of 2:1. [Ивашкин В. Т., Яковлев В. Н., Синопальников А. И., Антохин Е. А. Обоснование и тактика ингаляционной терапии с использованием двухкомпонентных аэрозолей при обструктивных бронхиальных заболеваниях. //Терапевти¬ческий архив, 1993, № 8. С. 44-49]. [Ivashkin V. Tv Sinopalnikov AI, Antokhin EA Substantiation and tactics of inhalation therapy using two-component aerosols in obstructive bronchial diseases. // Therapeutic Archive, 1993, № 8. P. 44-49]. At the same time revealed a longer action of drugs. The disadvantage of this method is the fact that it is not detected instantly quick action. which relieves the crisis state of a patient with asthma, especially with two or more active substances, which may have an excellent desired depth of penetration into the respiratory tract, the correction is very difficult through the interaction of excipients with active substances and active substances with one another. With general methods for preparing compositions for inhalation, correction cannot be carried out correctly, since the distribution of the compound of the active ingredients on excipient carriers is rather random.

Berodual contains two active broncholytic ingredients: ipratropium bromide, which has an anticholinergic effect, and phenoterol hydrobromide, which is a beta-adrenergic agent.

Fenoterol hydrobromide is a direct sympathomimetic agent that selectively stimulates beta-2 adrenergic receptor agonist in the therapeutic range.

As there is a growing need for inhalation compositions for use in combination therapy comprising two or more than two active agents, it is imperative to develop new compositions that provide targeted administration of different inhalable drugs to the patient in an accurate and uniform amount.

Thus, the object of the present invention is to provide a pharmaceutical composition for inhalation, which includes more than one active ingredient, where the interaction between different active ingredients is significantly reduced.

The present invention relates to the use of a composition containing a fixed combination of fenoterol, ipratropium bromide and cromoglycate with an additional optional component - dexpanthenol.

Another object of the present invention is to provide a pharmaceutical composition of the above type for inhalation having a more pronounced rapid effect on asthmatic symptoms than the prototype.

Another object of the invention is to provide a composition of a pharmaceutical composition that makes it possible to reduce the amount of active agent per unit dose for a given therapy compared to the prior art compositions.

Another objective is to provide a pharmaceutical composition that allows for the direct introduction of the various active ingredients included in it and to enter the intended scope in the patient's respiratory system and in the required amount.

An additional object of the present invention is to provide a pharmaceutical aerosol composition for use in the treatment of severe acute or chronic symptoms of asthmatic diseases.

These problems are solved by the object of the claims. Advantages of the embodiment are indicated in the dependent claims.

The present invention is based on the use of pharmaceutical compositions for inhalation therapy, comprising at least three components, a selective beta-2 adrenergic receptor agonist, anticholinergic and cromoglycate.

Another limitation for use of commercially available compositions comprising cromoglycate is induction of bronchospasm in case of oral inhalations. This fact restricting use of such composition, especially in patients with predisposition to bronchospasm.

It was unexpectedly revealed that the pharmaceutical composition for inhalation therapy, which consisted of three components, namely, a selective beta-2 adrenergic receptor agonist, anticholinergic and cromoglycate, has an almost instant effect on bronchial asthma attacks, allergic rhinitis, and exercise-induced asthma endogenous bronchial asthma. Gradual therapeutic effect in chronic obstructive pulmonary diseases, allergic lung diseases — allergic alveolitis, chronic obstructive bronchitis with and without emphysema, pulmonary fibrosis, pulmonary emphysema.

In addition, it was found that the introduction of dexpanthenol into the composition provides an additional therapeutic effect in acute conditions, namely. with burns of the respiratory tract.

Panthenol is used for diseases of the upper respiratory tract and bronchi. Use in particular. in the form of aerosols (RU 2472499 Published on January 20, 2013 Bull. No. 2).

An effective amount of dexpanthenol is 0.25-2% panthenol (with dry wheezing and dry cough -2%, with wet 0.25%).

β2-adrenomimetics, expanding small bronchial tubes, promote the admission of bronchodilators (sodium cromoglycate, ipratropium bromide), glucocorticoids (beclamethasone, budesonide), local anesthetics, antibiotics. Siberian Medicine Bulletin 3. 2003].

Thus, according to aspects of this invention, the proposed pharmaceutical composition for inhalation, which includes a fraction of the drug, at least three active pharmaceutical ingredients.

Additionally, the composition contains additional substances, in particular benzalkonium chloride, disodium edetate, polysorbate 80, sodium dihydrophosphate, sodium hydrophosphate, sodium dodecahydrate, sodium chloride, hydrochloric acid, purified water.

Additionally, nasal inhalation route of administration of medicinal product and composition according to the invention removes restriction of use such compositions comprising cromoglycate to patients with predisposition to bronchospasm.

As additional substances, solvents are considered, for example water for injection, anhydrous ethanol, an ethanol-water mixture; propellant 1, 1, 1,2-tetrafluoroethane HFA 134a; preservatives, for example benzalkonium chloride, miramistin, decamethoxin; antioxidants, for example, butyl hydroxyanisole; ph-regulators, freons, propane, butane, isobutane, nitrogen, HFC-227, polyvinylpyrrolidone, polyethylene glycol.

These and other additional substances and their ratios can be selected by a specialist in this industry and introduced into this composition according to his experience and technological feasibility. All such modifications are provided by this invention and are included in it.

Examples

The following examples are intended to illustrate rather than limit the invention.

One of ordinary skill in the art can readily prepare formulations typically takes into account physicochemical properties of the active ingredients of the composition of the invention, such as aqueous solubility, partition coefficient, molecular size, stability of the active ingredients, and binding of the inverse agonist to proteins and other biological macromolecules. This process of preparation also takes into account biological factors, such as absorption, distribution, metabolism, duration of action, the possible existence of side effects, and margin of safety, for the active ingredients. Accordingly, one of ordinary skill in the art could modify the formulations in order to incorporate an active ingredients into a formulation having the desirable properties described above for a particular application.

Example 1. Pharmaceutical Compositions

Example 2. Application

The patient, 49 years old, has been in hospital since 10.04.2012 to 28.04.2012

Complaints when receiving more and more frequent daily attacks of shortness of breath, unproductive cough, stuffy nose all year long.

The result of the analysis:

phlegm sputum - Candida albicans,

alveolar cells - 60 in sight

eosinophils 5 in sight.

General blood test

leukocytes - 4.6 * 10⁹ per liter

eosinophils 5%

NAV 7mm / year

T-helper / T-suppressor - 2.64

Diagnosis: Bronchial asthma persistent moderate. COPD I (chronic obstructive pulmonary disease) moderate course, exacerbation

pulmonary insufficiency II. Persistent allergic rhinitis of moderate severity. Sensitization to household, epidermal allergens in history.

Treatment:

Dexamethasone, lasolvan, re-sorption of / into.

Alkaline inhalation ventolin / flexotide / berodual - via nebulizer.

At discharge, ventolin is recommended for 2 breaths in seizures, serendip 25/125 - 2 breaths - 2 times a day.

A month after the treatment, shortness of breath increased with little exercise, pain in the heart, tachycardia, dryness, sore throat.

Asked for help in a private clinic to the allergist was appointed:

Cetrin 1 tablet once a day for 10 days.

Salbutamol aerosol 2 times a day.

Nasal inhalation of a solution of berodual and sodium cromoglycate.

Dexpanthenol nasal spray, panthenol tablets - 100 mg, once a day

Serrata 1 tablet 3 times a day for 30 days.

The patient's condition has improved since the first day of treatment - pain in the heart area does not notice, the possibility of performing

Example 3. Application

The patient, 28, works at a veterinary clinic

The diagnosis of asthma persistent mild severity uncontrolled COPD II

PI 1.

Allergic rhinitis.

Allergic conjunctivitis persistent, easy flow.

Sensitization to epidermal allergens.

Diffuse goiter 1.

Left adrenal adenoma is non- hormonal.

Uterine adenomatosis.

Immunogram - found secondary immune deficiency of T-helper / T-suppressor 0.71.

Receives berodual aerosol up to 5 times a day, antihistamines periodically.

Recently notes a decrease in the effectiveness of the berodual, refusing to take hormonal inhalation drugs.

A private doctor was offered nebulizer therapy for a mixture of berodual solution - 1%, sodium cromoglycate - 1% and calcium pantothenate - 0.1%.

The patient noted an immediate cessation of allergies - complicated breathing, lacrimation and nasal congestion.

Example 4. Application

Patient, 35 years old, bronchial asthma since childhood, mild course. Smoking for about 15 years, taking salbutamol.

About a year ago, when a dog was presented to his baby, there were asthma attacks, an aerosol, antihistamines, a course of antiparasitic therapy, and restrictions on contact with animals and smoking cessation.

The patient neglected the recommendations. At the time of the ambulance arrival the patient was in a state of fainting sticky cold sweat inhalation berodual did not bring relief.

The ambulance team carried out resuscitation measures - in / in jet dexamethasone 0.12 mg and euphilin. In 20 minutes, the patient's condition improved.

The diagnosis in the hospital - infectious-allergic bronchial asthma, severe course, exacerbation phase.

Asthmatic status, ll., Slowly developing.

Chronic purulent bronchitis.

Antibiotic therapy, hormonal therapy, metabolic therapy were conducted.

In satisfactory condition discharged from hospital.

Recommendations were given: administered inhalation corticosteroids, smoking cessation, and restriction of contact with animals.

After some time, the attack was repeated, before the arrival of the ambulance brigade, the first aid to the neighbor-doctor was given in the form of inhalation through a nebulizer of solutions of chromopharms (sodium cromoglycate) plus a solution of berodual in a ratio of 1:1.

Because the patient was in a serious condition but was conscious of his difficulty in breathing, he was asked to breathe the drug with his nose without wearing any nebulizer mask.

After 10-15 seconds, the patient became much easier (immediately), and after 10 minutes the condition returned to normal and the ambulance was canceled.

UA 100237 C (10.12.2012, bul. No. 23),

UA 55763 A (15.04.2003, bul. No. 4)

RU2530658 (10.10.2014 bul. No. 28)

RU 2472499 Published on January 20, 2013 Bull. No. 2

Медична газета «Здоров’я України» № 13-14(410-411) 2017 р. «Новий фенотипспецифічний підхід до ведення бронхіальної астми» О.С.Толох, Н.Д.Рудницька, к.м.н. У.Б.Чуловська, к.м.н. Х.І.Вольницька. Львівський національний медичний університет ім. Данила Галицького, КУ ЛОР «Львівський регіональний фтизіо-пульмонологічний клінічний лікувально- діагностичний центр»]. [Health newspaper of Ukraine of Ukraine # 13-14 (410-411) 2017 "A new phenotype-specific approach to managing bronchial asthma" : OS Tolokh, ND Rudnitskaya, Ph.D. VB Chulovskaya, Ph.D. HI Volnytska. Lviv National Medical University. Danylo Halytskyi, CU EN "Lviv Regional Phthisiology and Pulmonary Clinical Medical Diagnostic Center"

И.И.Балаболкин, О.Ф.Лукина, А.В.Горюков, А.В.Ляпунов -Применение кромонов при аллергических заболеваниях у детей., Педиатрия 2007 Том 8 № 4.] I.I. Balabolkin, O.F. Lukin, A.V. Goryukov, A.V. Lyapunov -Application of cronons in allergic diseases in children., Pediatrics 2007 Volume 8 No. 4.

Cates C.J., Welsh E.J.,Rowe B.H. Holding chambers (spasers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane 15 Database Syst Rev.-2013.

Ивашкин В. Т., Яковлев В. Н., Синопальников А. И., Антохин Е. А. Обоснование и тактика ингаляционной терапии с использованием двухкомпонентных аэрозолей при обструктивных бронхиальных заболеваниях. //Терапевти¬ческий архив, 1993, № 8. С. 44-49. Ivashkin V. Tv Sinopalnikov AI, Antokhin EA Substantiation and tactics of inhalation therapy using two-component aerosols in obstructive bronchial diseases. // Therapeutic Archive, 1993, № 8. P. 44-49]

Бюллетень сибирской медицины .3 .- 2003 Siberian Medicine Bulletin 3. 2003]

Claims

A pharmaceutical composition comprising a combination of three or more active substances which are selected from selective beta-2 adrenergic receptor agonist, anticholinergic, sodium cromoglycate and their salts, which are characterized in that the active ingredients are in the following ratio:
The pharmaceutical composition according to claims 1, characterized in that the selective beta-2-adrenoceptor agonist is selected from the group comprising salbutamol, terbutaline, fenoterol, rimiterol, hexoprenaline, isoetharine, pirbuterol, tretoquinol, carbuterol, tulobuterol, salmeterol, formoterol, clenbuterol, reproterol, procaterol, bitolterol, indacaterol, olodaterol, an anticholinergic selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide, aclidinium bromide, glycopyrronium bromide, umeclidinium bromide.
The pharmaceutical composition according to claims 1-2, characterized in that it further contains dexpanthenol in the amount of 0.25-2%.
The pharmaceutical composition according to claims 1-3, characterized in that it further contains excipients: benzalkonium chloride, disodium edetate, polysorbate 80, sodium dihydrophosphate, sodium hydrophosphate, sodium dodecahydrate, sodium chloride, hydrochloric acid, purified water.
The medicinal product comprising a pharmaceutical composition according to claims 1-4.
The medicinal product according to claims 1-5 characterized in that it is an inhalant for use in inhalers, in particular nebulizers and aerosols.
The use of the pharmaceutical composition or medicinal product according to claims 1-6, characterized in that the bronchopulmonary disease is asthma, bronchitis or chronic obstructive pulmonary disease, allergic lung diseases, in particular allergic alveolitis, acute conditions, in particular burns respiratory tract, allergic and non-allergic (endogenous) bronchial asthma; exercise-induced asthma and chronic obstructive bronchitis with and without emphysema, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis.
The use according to claims 7, characterized in that the route of administration is nasal inhalation.
A method of treatment characterized by the use of a pharmaceutical composition and (or) a medicine according to one of the preceding paragraphs.