WO2019147154A1 - Pharmaceutical formulation (embodiments) and use of a pharmaceutical formulation (embodiments) - Google Patents

Abstract

The invention relates to medicine, to the pharmaceutical industry, and specifically to pharmaceutical formulations designed to treat bronchopulmonary conditions such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis and pneumonia. The technical result is achieved by creating embodiments of a pharmaceutical formulation based on an M-cholinergic receptor blocker in the form of an iodomethyl of a tropinic ester of d,l-(2-hydroxymethyl-2-phenyl) butyric acid, and a selective β2-agonist in the form of salbutamol hemisuccinate, as well as embodiments of the use of the pharmaceutical formulation for treating bronchopulmonary conditions such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, and pneumonia, said formulation increasing the effectiveness of the preparation by virtue of synergism and by lowering the therapeutic dose compared to monopreparations and minimising side effects. The inventions have undergone practical trials, the pharmaceutical formulations, in each of the proposed embodiments, are industrially applicable and will be widely applicable in the pharmaceutical industry and in medicine.

Description

 PHARMACEUTICAL COMPOSITION

 (OPTIONS)

 APPLICATION OF THE PHARMACEUTICAL COMPOSITION

 (OPTIONS)

APPLICATION AREA

The invention relates to medicine, the pharmaceutical industry, namely, to pharmaceutical compositions intended for the treatment of bronchopulmonary diseases such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia.

 BACKGROUND

 It is known that iodomethyl tropine ester c1,1- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug in a metered dose aerosol dosage form is used in medicine as a bronchodilator for the treatment of various bronchopulmonary diseases [1], [2].

 It has been established that tropine ester iodomethyl b, 1- (2-hydroxymethyl-2-phenyl) butyric acid has antioxidant properties, and to a much lesser extent, unlike other anticholinergics, affects the cholinergic receptors of the heart, stomach, and other organs.

Salbutamol hemisuccinate as a monodrug containing the active ingredient - Salbutamol - alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as sulfate or hemisuccinate - is used in various dosage forms medicine as a bronchodilator for the treatment of various bronchopulmonary diseases and as a tokolitika in obstetrics. Salbutamol hemisuccinate, due to the content in the molecule of succinic acid, has a high biological activity with a minimum of side effects: improves respiration at the cellular level, eliminates the side effects associated with metabolic acidosis, minimizes cardiotoxic effects due to high selectivity (stimulation of ₂ -adrenergic receptors) and metabolism Derivatives of salbutamol, does not lead to the desensitization of p ₂ -adrenergic receptors, does not form, in contrast to salbutamol sulfate, inactive metabolites with effect of p-blockers [3].

 Clinical data suggest safety, efficacy of salbutamol hemisuccinate and its antihypoxic properties [4], [5].

In the invention (Patent RU 2457832) [6], described the composition in the form of an aerosol based on tropine ester iodomethyl with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid, whose content is from 40 to 640 μg, are included in the aerosol also medicinal substances of various pharmacotherapeutic groups - analgesics, anti-allergic, anti-inflammatory, anti-infective, bronchodilator drugs and others. Salbutamol and its derivatives are not included.

 In [6], there is no justification for the use of d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropine ether iodomethylate of medicinal substances from various pharmacotherapeutic groups and data on their chemical and biopharmaceutical compatibility and additional effect.

In the invention (Patent RU 2327450) [7] presented pharmacotherapeutic compositions containing anticholinergics, p ₂ -agonists and corticosteroids. The compositions do not contain iodomethyl tropinate ester b, 1- (2-hydroxymethyl-2-propyl) butyric acid, from p ₂ -agonists use salbutamol base and salbutamol sulfate.

 In [7], the list of medicinal substances in the composition is given, their compatibility with the combined use of the three pharmacotherapeutic groups without substantiating their effectiveness, both with simultaneous and sequential use, however, specific doses of the medicinal substances are not indicated, their compatibility with the combined use.

 In the invention (Patent RU 2356537) [8] describes the use of salbutamol hemisuccinate with various drugs, without tropine ester iodomethyl <1,1- (2-hydroxymethyl-2-phenyl) butyric acid.

Therefore, there is a need to create a pharmaceutical composition that includes two components: tropine ester iodomethyl acetate SC (2-hydroxymethyl-2-phenyl) butyric acid - a blocker of M-cholinergic receptors and salbutamol hemisuccinate - a stimulator of p ₂ -adrenergic receptors for the treatment of such bronchopulmonary diseases as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia.

The technical result, the achievement of which the invention is directed, is the creation of a pharmaceutical composition based on the blocker of M-cholinergic iodomethyl receptor tropine ester b, 1- (2-hydroxymethyl-2-phenyl) butyric acid and selective p ₂ agonist salbutamol hemisuccinate, intended for treatment of bronchopulmonary diseases such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia, which increases the effectiveness of the drug due to blue Gizmo components, reducing the therapeutic dose as compared with monotherapy, minimizing side reactions. DISCLOSURE OF INVENTION

 The technical result is achieved by the fact that:

 - the proposed pharmaceutical composition, including iodomethyl tropinovogo ester SC- (2-hydroxymethyl-2-phenyl) butyric acid in the form of a single agent, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3- benzoldimethanol in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium chloride, succinic acid, water for injection, in the following ratio of ingredients, mass%:

 Tropic ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium chloride 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest

- the proposed pharmaceutical composition, including iodomethyl tropinovogo ester SC- (2-hydroxymethyl-2-phenyl) butyric acid in the form of a single agent, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3- Benzenedimethanol - as a single preparation, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including sodium chloride, 0, L-hydroxyanthic acid, water for injection, with the following ratio of ingredients, mass%:

 iodine methyl tropine ester <1,1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01-1 salbutamol hemisuccinate 0.01-1 sodium chloride 0.01-1

D, L-hydroxyuccinic acid 0.01 - 1 water for injection, the rest

- proposed a pharmaceutical composition comprising iodomethyl tropine ester with 1,1- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate, water for injection, with the following ratio of ingredients, mass%: iodomethyl tropine ester with 1,1- (2-hydroxymethyl-2-phenyl) butyric acid 0.01 - 1 salbutamol hemisuccinate 0.01 - 1

3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate 0.01 - 1 water for injection, the rest

- the proposed pharmaceutical composition comprising tropic ester iodomethyl <3,1- (2-hydroxymethyl-2-phenyl) butyric acid as a single agent, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1 , 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising magnesium sulfate, succinic acid, water for injection, in the following ratio of ingredients, mass%:

 iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 magnesium sulfate 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest

- the proposed pharmaceutical composition comprising iodomethyl tropic ester _< 3,1- (2-hydroxy methyl-2-phenyl) butyric acid as a single agent, alpha 1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1 , 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including zinc sulfate, sodium chloride, water for injection, in the following ratio of ingredients, mass%:

 Tropic ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 zinc sulfate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest

- proposed a pharmaceutical composition comprising tropine ester iodomethyl (1,1- (2-hydroxymethyl-2-phenyl) butyric acid as a single agent, alpha! - [[(1,1- Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as a monodrug, including the active ingredient - salbutamol as hemisuccinate, additionally including sodium benzoate, sodium chloride, water for injection, with the following ratio of ingredients, mass%:

 iodine methyl tropine ester <1,1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium benzoate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest

- proposed a pharmaceutical composition comprising tropic ester iodomethyl b, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1,1-

Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol, in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, with the following ratio of ingredients, mass%:

 Tropic ester iodomethyl <3,1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 lactose monohydrate else

- proposed a pharmaceutical composition comprising tropine ester iodomethyl cT- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1,1-

Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol, in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, further comprising propellant 1,1, 1, 2-tetrafluoroethane (R134A), with the following ratio of ingredients , mass%:

 iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1

1,1,1, 2-tetrafluoroethane (Rl 34A) the rest

- A pharmaceutical composition was proposed, including tropic ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha! [[(1,1- Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising ethanol and propellant 1,1,1,2-tetrafluoroethane (R134A), with the following the ratio of ingredients, mass%:

 iodomethyl tropinovogo ether SC-(2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 ethanol 1-15

1,1,1, 2-tetrafluoroethane (R 134 A) the rest

It has also been proposed to use pharmaceutical compositions for the prevention and treatment of bronchospastic syndrome in bronchial asthma: in case of exacerbation of bronchial asthma for relief of asthma attacks, as part of basic therapy, for the prevention and relief of bronchospasm caused by exercise or exposure to an allergen or other triggering bronchospasm factor; in chronic obstructive pulmonary disease, chronic obstructive bronchitis, pulmonary emphysema, pneumonia, as well as in catarrhal diseases as a bronchodilator as part of basic therapy, namely:

 - proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropic ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium chloro Read, succinic acid, water for injection, with the following ratio of ingredients, mass%:

 Tropic ester iodomethyl <± 1- (2-hydroxymethyl-2-phenyl) oil

acids 0.01-1 salbutamol hemisuccinate 0.01-1 sodium chloride 0.01-1 succinic acid 0.01-1 water for injection the rest - proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1, (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1, 1 -Dimethylethyl) amino] methyl] -4-hydroxy- 1, 3-benzenedimethanol - as a monodrug, including the active ingredient - salbutamol as hemisuccinate, additionally including sodium x Loride, 0, b-hydroxyanthic acid, water for injection, in the following ratio of ingredients, mass%:

 iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01-1 salbutamol hemisuccinate 0.01-1 sodium chloride 0.01-1

0, b-hydroxyanthic acid 0.01 - 1 water for injection the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropic ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate, water for injection, with the following ratio of ingredients, mass%:

 iodine methyl tropine ester (1,1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1

3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate 0.01 - 1 water for injection, the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl <3,1- (2-hydroxymethyl-2-phenyl) butyric acid in monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in as a single preparation, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising magnesium sulfate, succinic acid, water for injection, in the following ratio of ingredients, mass%:

 Tropic ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 magnesium sulfate 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1, (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including zinc sulfate at, sodium chloride, water for injection, in the following ratio of ingredients, mass%:

 tropine ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) oil

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 zinc sulfate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1, (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium benzo Oat, sodium chloride, water for injection, with the following ratio of ingredients, mass%:

iodine tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oily ACIDS 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium benzoate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including lactose monohydrate, with the following m ratio of ingredients, wt%:

 iodine tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oily

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 lactose monohydrate else

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising propellant 1,1,1,2-tetrafluoroethane (R1 34A), with the following ratio of ingredients, mass%:

 iodine tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oily

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 propellant 1,1,1, 2-tetrafluoroethane (Rl 34A) the rest

- proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including c1,1- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, alpha1- [[(1,1-dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as a single agent, including active ingredient - salbutamol in the form of hemisuccinate, additionally comprising ethanol and propellant 134A, with the following ratio of ingredients, mass%: tropic ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oily

 acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 ethanol 1-15 propellant 1,1,1, 2-tetrafluoroethane (Rl 34A) the rest

Also proposed is a pharmaceutical composition comprising tropic ester iodomethyl b, 1- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, with the following ratio of ingredients, mcg:

 iodine methyl tropine ester <1,1- (2-hydroxymethyl-2-phenyl) oil

 acids 40 μg salbutamol hemisuccinate 50 μg lactose monohydrate 24910 μg

And proposed the use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including SC c- (2-hydroxymett-2-phenyl) butyric acid iodomethyl, alpha1- [ [(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, with the following I eat the ratio of ingredients, mcg:

 iodine tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) oily

 acids 40 μg salbutamol hemisuccinate 50 μg lactose monohydrate 24910 μg

The technical result is achieved by the fact that iodomethyl of tropic ester of d, l- (2-hydroxymethyl-2-phenyl) butyric acid and salbutamol hemisuccinate at a joint presence in a single dosage form is not subject to chemical and biopharmaceutical interaction and possible destruction, which is confirmed by special experimental studies.

 Experimental studies were carried out in three directions: photolytic, hydrolytic, and thermal destruction.

 Samples of the main components of the pharmaceutical composition were tested as a homogeneous mixture of dry powders and aqueous solutions in the following ratios:

 - iodomethyl tropine ester with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid: salbutamol hemisuccinate 10 μg: 20 μg;

 - iodomethyl tropine ester with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid: salbutamol hemisuccinate 20 μg: 30 μg;

 - tropic ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) butyric acid: salbutamol hemisuccinate 30 μg: 50 μg.

 The samples were subjected to incandescent lamp illumination in accordance with the Pharmopoeia XI Edition for 120 hours.

 Thermal and hydrolytic degradation was observed by heating the samples to 100 ° C for 3 hours.

 The quality of the prototypes was studied by chromatography in a thin layer of sorbent (TLC) in various solvent systems and high performance liquid chromatography with detection by UV spectrophotometry.

 It was established that only two substances were found in all samples of the pharmaceutical composition: tropine ester iodomethyl with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid and salbutamol hemisuccinate. Consequently, under these harsh conditions, there is no chemical interaction between d, l- (2-hydroxymethyl-2-phenyl) -butyric acid iodomethylate and salbutamol hemisuccinate iodomethyl, molecular degradation does not occur, and no impurities are formed.

Based on the data obtained, it has been proposed to use the pharmaceutical composition in various dosage forms for inhalation used to treat obstructive pulmonary diseases, including bronchial asthma, chronic obstructive pulmonary disease, and pneumonia. EXAMPLES:

 As one of the examples, the claimed pharmaceutical composition is presented in the form of a powder for inhalation from the calculation of the composition of ingredients per dose, where the following ingredients are included as active substances:

 Tropic ester iodomethyl c1,1- (2-hydroxymethyl-2-phenyl) butyric acid 40 µg salbutamol hemisuccinate 50 µg and as an auxiliary substance, the example of the pharmaceutical composition includes:

 lactose monohydrate 24910 µg; the proposed example of the pharmaceutical composition is applicable in the form of capsules, while in one capsule there is a single dose for inhalation presented in the example.

 Dosage form of the combined drug in the form of an inhalation solution for nebulizer therapy contains additional excipients that ensure the stability of the dosage form and its biopharmaceutical properties, as can be seen from the examples below, presented in Tables 1-6.

 Table 1.

Table 2.

 Table 3.

 Table 4.

Table 5.

Table 6.

Dosage inhalation dosage form of the combined preparation in the form of a dry powder is also produced according to standard known technology using a carrier — lactose and using both a multi-dose tank inhaler — a metered-dose powder inhaler, and a single dose — using capsules or blisters, examples are presented in Table 7.

Table 7.

The dosage aerosol dosage form for inhalation based on the pharmaceutical composition is made according to known standard technology in metered dose inhalers using a hydrofluoroalkane propellant, namely, 1,1, 1,2-tetrafluoroethane (R 134A) with an appropriate dose of the combined preparation, as can be seen from Tables 8 and 9.

Table 8.

Table 9.

The above examples clearly illustrate, but do not exhaust all possible uses of the proposed pharmaceutical composition, including tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid and salbutamol hemisuccinate.

 All the proposed variants of the pharmaceutical composition exhibit synergism, thereby enhancing the bronchodilator effect, which is achieved by using variants of the proposed pharmaceutical compositions using significantly smaller doses and, accordingly, fewer side effects.

Thus, the technical result has been achieved by creating variants of the pharmaceutical composition based on the M-cholinergic receptor blocker iodomethyl tropine ester c.1.1- (2-hydroxymethyl-2-phenyl) butyric acid and the selective p ₂ -agonist of salbutamol hemisuccinate, and options for the use of pharmaceutical compositions for treatment of such bronchopulmonary diseases, such as bronchial asthma, bronchitis, pneumonia, providing an increase in the effectiveness of the drug due to synergism, reduction of the therapeutic dose according to eniyu with monotherapy, minimizing side effects.

INDUSTRIAL APPLICABILITY.

 The invention relates to medicine, the pharmaceutical industry, namely, to pharmaceutical compositions intended for the treatment of bronchopulmonary diseases such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia.

 All the proposed variants of the pharmaceutical composition exhibit synergism, thereby enhancing the bronchodilator effect, which is achieved by using variants of the proposed pharmaceutical compositions using significantly smaller doses and, accordingly, fewer side effects.

Variants of the pharmaceutical composition based on the blocker of M-cholinergic receptors of tropine ester c1,1- (2-hydroxymethyl-2-phenyl) butyric acid iodine and selective p ₂ agonist salbutamol hemisuccinate and variants of the use of pharmaceutical compositions for the treatment of bronchopulmonary diseases such as bronchial asthma , chronic obstructive pulmonary disease, bronchitis, pneumonia, provide an increase in the effectiveness of the drug due to synergism, a decrease in therapeutic dose compared to monotherapy Amini, minimizing adverse reactions.

The inventions have been tested, are industrially applicable and will find wide application in the pharmaceutical industry and in medicine. INFORMATION SOURCES:

Money, 2010, ed. 16, p. 251-254 lth care Professional, USPDI, 15 Ed., 1995, p. 537-39, 549.

about the use of medicines. M. 2014, c. XV, p. 230-

Claims

PHARMACEUTICAL COMPOSITIONS (OPTIONS) APPLICATION OF THE PHARMACEUTICAL COMPOSITION (OPTIONS) FORMULA  1.Pharmaceutical composition, including d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, as a single agent, alpha1 - [[(1,1- Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol as a monodrug, including the active ingredient - salbutamol as hemisuccinate, additionally including sodium chloride, succinic acid, water for injection, with the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium chloride 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest 2. Pharmaceutical composition comprising tropic ester iodomethyl d, l- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug, alpha 1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including sodium chloride, DL-hydroxysuccinic acid, water for injection, in the following ratio of ingredients, mass%:  iodomethyl tropinovogo ether d, l- (2-nwpoKCHMeTHH-2 ^ eHKii) oil  acids 0.01-1 salbutamol hemisuccinate 0.01-1 sodium chloride 0.01-1 0, b-hydroxyanthic acid 0.01 - 1 water for injection the rest 3. Pharmaceutical composition comprising tropic ester iodomethyl d, l- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate, water for injection, with the following ratio of ingredients, mass%:  iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate 0.01 - 1 water for injection, the rest 4.Pharmaceutical composition, including d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, as a single agent, alpha 1 - [[(1,1- Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising magnesium sulfate, succinic acid, water for injection, with the following ratio of ingredients, mass%:  tropine ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 magnesium sulfate 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest 5. Pharmaceutical composition comprising tropic ester iodomethyl d, l- (2-hydroxymethyl-2-phenyl) butyric acid as a monodrug, alpha 1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including zinc sulfate, sodium chloride, water for injection, in the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 zinc sulfate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest 6. A pharmaceutical composition comprising d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropine ester iodomethyl, as a single agent, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1, 3-benzenedimethanol - in the form of monodrugs, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including sodium benzoate, sodium chloride, water for injection, in the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium benzoate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest 7.Pharmaceutical composition comprising d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, alpha 1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol , in the form of monopreparation, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including lactose monohydrate, with the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 lactose monohydrate else 8. Pharmaceutical composition comprising d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, alpha 1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzo ldimethanol, in the form of a single preparation, including the active ingredient - salbutamol in the form of hemisuccinate, additionally including propellant 1, 1,1,2 - tetrafluoroethane (R134A), with the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 1,1,1,2-tetrafluoroethane (R134A) the rest 9. Pharmaceutical composition comprising d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of monopreparation, including the active ingredient - salbutamol in the form of hemisuccinate, additionally comprising ethanol and propellant 1,1,1,2-tetrafluoroethane (R134A), in the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil acids 0.01 - 1 salbutamol hemisuccinate 0.01-1 ethanol 1-15 1,1,1, 2-tetrafluoroethane (Rl 34A) the rest Yu.Primenenie pharmaceutical compositions for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropic ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) butyric acid in the form monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium chloride, amber yu acid, water for injection, in the following ratio of ingredients, wt%:  iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium chloride 0.01 - 1 succinic acid 0.01-1 water for injection the rest 11. The use of the pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, emphysema, including tropine ester iodine methyl b, 1- (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1, 1 -Dimethylethyl) amino] methyl] -4-hydroxy- 1, 3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium chloride, 0, b g iroxycytic acid, water for injection, with the following ratio of ingredients, mass%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01-1 salbutamol hemisuccinate 0.01-1 sodium chloride 0.01-1 P, b-hydroxyanthic acid 0.01 - 1 water for injection the rest 12. The use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid as a single preparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in monopreparation in the form of active ingredient - salbutamol in the form of hemisuccinate, additionally including 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate, water for injection, in the following ratio of ingredients, mass%:  Tropic ester iodomethyl <3,1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 3-hydroxy, 2-ethyl, 6-methyl-pyridinium butanedioate 0.01 - 1 water for injection, the rest 13. Use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including c1,1- (2-hydroxymethyl-2-phenyl) butyric acid iodomethyl in the form monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol as hemisuccinate, additionally magnesium sulphate, amber nuy acid, water for injection, in the following ratio of ingredients, wt%:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 magnesium sulfate 0.01 - 1 succinic acid 0.01 - 1 water for injection the rest 14. Application of the pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as a monodrug, including active ingredient - salbutamol in the form of hemisuccinate, additionally including zinc sulfate, sodium lorid, water for injections, with the following ratio of ingredients, wt%:  iodine methyl tropine ester (1,1- (2-hydroxymethyl-2-phenyl) oil acids 0.01 - 1 salbutamol hemisuccinate 0.01-1 zinc sulfate 0.01-1 sodium chloride 0.01-1 water for injection the rest 15. The use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, emphysema, including tropine ester iodine iodine <! D- (2-hydroxymethyl-2-phenyl) butyric acid as monopreparation, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally including sodium benzoate, sodium chloride, water for injection, with the following ratio of ingredients, wt%:  tropine ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 sodium benzoate 0.01 - 1 sodium chloride 0.01 - 1 water for injection the rest 16. The use of the pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodomethyl with!, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1- [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, in the following ratio SRI ingredients, wt%:  iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 lactose monohydrate else 17. The use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, emphysema, including tropine ester iodomethyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1- [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - in the form of a monodrug, including the active substance - salbutamol in the form of hemisuccinate, additionally comprising 1.1, 1, 2-tetrafluoroethane propellant (R134A), with the following ratio of ingredients, mass%:  tropine ester iodomethyl1,1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 propellant 1,1,1, 2-tetrafluoroethane (Rl 34A) the rest 18. Use of a pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodine methyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy- 1, 3-benzene dimethanol - in the form of a monodrug, including the active ingredient - salbutamol as hemisuccinate, further comprising ethanol and propellant 134A, with the following The ratio of ingredients, mass%: iodomethyl tropinovogo ether!, 1- (2-hydroxymethyl-2-phenyl) oil  acids 0.01 - 1 salbutamol hemisuccinate 0.01 - 1 ethanol 1-15 propellant 1,1,1, 2-tetrafluoroethane (Rl 34A) the rest 19.Pharmaceutical composition, including d, l- (2-hydroxymethyl-2-phenyl) butyric acid tropic ester iodomethyl, as a single agent, alpha1 - [[(1,1-Dimethylethyl) amino] methyl] -4-hydroxy- 1, 3-benzene dimethanol in the form of a monodrug, including the active ingredient - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, with the following ratio of ingredients, mcg:  iodine methyl tropic ester b, 1- (2-hydroxymethyl-2-phenyl) oil  acids 40 μg salbutamol hemisuccinate 50 μg lactose monohydrate 24910 μg 20. Application of the pharmaceutical composition for the prevention and treatment of bronchospastic syndrome in bronchial asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, pneumonia, pulmonary emphysema, including tropine ester iodine methyl, 1- (2-hydroxymethyl-2-phenyl) butyric acid, alpha1 - [[(1, 1-Dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol - as a single preparation, containing the active ingredient - salbutamol in the form of hemisuccinate, further comprising lactose monohydrate, with the following ratio of ingredients, mcg:  iodomethyl tropinovogo ether with!, 1- (2-hydroxymethyl-2-phenyl) oil  acids 40 μg salbutamol hemisuccinate 50 μg lactose monohydrate 24910 μg