RU2426531C1 - Liquid water pharmaceutical composition of ambroxol and pharmaceutical preparation based on it, intended for treating diseases of respiratory ways with formation of viscous sputum (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: claimed is novel combination of active substances for creation of pharmaceutical composition, liquid water ambroxol-based medications for treatment of diseases of respiratory ways with formation of viscous sputum, which possess expectorant, mucolytic, anti-inflammatory effect. Preparation contains ambroxol, pharmaceutically suitable water-soluble salt of glycyrrizic acid and extract of thyme. ^ EFFECT: preparation in accordance with invention makes it possible to obtain efficient clinical results (reduction of coughing period duration and quicker recovery of patients with diseases of respiratory ways) and provides multi-directional action on cough pathogenesis in whole. ^ 16 cl, 3 tbl, 10 tbl

Description

FIELD OF THE INVENTION

The invention relates to the field of pharmacology and medicine, specifically to liquid aqueous pharmaceutical compositions of Ambroxol, liquid medicines based on it (for example, syrup, solution or elixir).

The preferred field of use of the invention is the treatment of diseases of the respiratory tract with the formation of viscous sputum (such as acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectatic disease) according to the activities and purposes of the main component of the proposed composition and drug.

The preferred area of use is the treatment of diseases of the respiratory tract with the formation of viscous sputum in children, preferably from 2 years old, persons with swallowing problems, elderly patients.

State of the art

Ambroxol (INN), 4 - [(2-amino-3,5-dibromophenyl) methylamino] cyclohexan-1-ol (and as hydrochloride), odorless white crystalline powder, slightly bitter taste, of the formula:

,

,

as well as bromhexine it belongs to the derivatives of the alkaloid of visicin, but it has a more pronounced effect, because is its active metabolite.

Ambroxol-based drug stimulates mucociliary activity and has an expectorant effect. Ambroxol is widely used in the treatment of cough with acute respiratory viral infections and has established itself as an effective and safe drug / Drug Register, 2009 /.

The high efficiency and good tolerance of ambroxol, as well as a significant degree of patient adherence to treatment, allow some foreign authors to recommend it as the drug of choice for the prevention of chronic bronchitis [Michnar M, Milanowski J. [Clinical evaluation of efficacy and tolerance of oral treatment with ambroxol in patients with chronic bronchitis]. Pneumonol Alergol Pol 1996; 64 (suppl. 1): 90-96]. Russian experts who studied the effectiveness of ambroxol in outpatients with COPD also came to the conclusion that the mucolytic properties of the drug are maximally realized with dys- and hypercrinia, i.e. in patients with chronic bronchitis [Novikov Yu.K., Belevsky A.S. Mucolytics in the complex treatment of COPD. // Therapist. 2001. No. 2].

The effectiveness of ambroxol in respiratory diseases has been proven not only in adults but also in children [Baldini G, Gucci M, Taro D, Memmini C. [A controlled study on the action of a new formulation of ambroxol in asthmatiform bronchitis in children]. Minerva Pediatr 1989; 41: 91-95].

The addition of ambroxol to antibacterial drugs in children with lower respiratory tract infections led to a faster cough and other clinical symptoms, as well as normalization of radiological changes compared to placebo [Spatola J, Poderoso JJ, Wiemeyer JC, et al. Influence of ambroxol on lung tissue penetration of amoxicillin. Arzneimittelforschung 1987; 37: 965-66]. At the same time, excellent tolerability of the drug by children was noted. The safety of ambroxol is confirmed by its widespread use in neonatology and in pregnant women (II and III trimesters) [Kimya Y, Kucukkomurcu S, Ozan H, Uncu G. Antenatal ambroxol usage in the prevention of infant respiratory distress syndrome. Beneficial and adverse effects. Clin Exp Obstet Gynecol 1995; 22: 204-11].

As of July 2008, the following dosage forms of ambroxol were registered in Russia (Drug Circulation. Federal State Institution “Scientific Center for Expertise of Medicinal Products” of the Russian Federal Health Service (2009) (Table 1):

Table 1 Dosage form The amount of active substance Trade marks Solution for oral administration and inhalation 7.5 mg / ml common form Syrup 3 mg / ml, 6 mg / ml common form Pills 30 mg common form Sustained-Release Capsules 75 mg Ambrobene, AmbroGexal Solution for intravenous administration 7.5 mg / ml Ambrobene Effervescent tablets 30 mg, 60 mg Ambroxol-Hemofarm

The following liquid leks are registered in the Russian Federation. preparations containing ambroxol as the only active principle (Circulation of medicines. Federal State Institution “Scientific Center for Expertise of Medicinal Products” of the Russian Federal Health Service, 2009 (table 2):

table 2 Ambroxol Ambrobene (Merkle GmbH) solution for oral administration and inhalation 7.5 mg / ml Ambrobene (Merkle GmbH) syrup 15 mg | 5 ml AmbroGexal (Salutas Pharma GmbH) syrup 6 mg / ml AmbroGexal (Salutas Pharma GmbH) solution for oral administration and inhalation 7.5 mg / ml AmbroGexal (Salutas Pharma GmbH) syrup 3 mg / ml Ambroxol-Vial (Yangzhou No. 3 Pharmaceutical Co. Ltd.) syrup 15 mg | 5 ml Ambroxol-Richter (Gideon Richter Romania A.O.) syrup 30 mg | 5 ml Ambroxol-Hemofarm (Hemofarm A.D.) syrup 15 mg | 5 ml Ambroxol (Rospharm LLC) syrup 15 mg | 5 ml Ambroxol (Rospharm LLC) syrup 3 mg / ml Ambroxol Vramed (Sopharma AO) syrup 15 mg | 5 ml Lazolvan (Beringer Ingelheim Ellas A.E.) syrup 15 mg | 5 ml Lazolvan (Beringer Ingelheim Ellas A.E.) solution for oral administration and inhalation 15 mg | 2 ml Bronchorus (Synthesis AKO OJSC) syrup 3 mg / ml Bronchoxol (Moscow Pharmaceutical Factory CJSC) oral solution 7.5 mg / ml Medox (Zentiva A.S.) syrup 15 mg | 5 ml Flavamed (Berlin-Chemie AG) oral solution 15 mg | 5 ml Halixol (Egis Pharmaceutical Plant OJSC) syrup 30 mg | 10 ml

As a prototype taken the drug Ambrobene (Merkle GmbH), a syrup containing 15 mg of Ambroxol in 5 ml of a liquid aqueous base.

Known multicomponent liquid (syrup) drug "RINIKOLD BRONHO" based on ambroxol, additionally containing chlorphenamine maleate, guaifenesin, phenylephrine hydrochloride / Drug Register, 2009 /. The drug has a spectrum of pharmacological action, which differs somewhat from the spectrum of the pharmacological action of ambroxol, which may be useful for the clinical use of the drug.

Disclosure of invention

An inventive task, therefore, is the creation of a liquid pharmaceutical product based on Ambroxol, which has greater therapeutic efficacy.

An inventive task is also the creation of a pharmaceutical composition for such a drug with a pronounced directed anti-inflammatory effect and synergism in relation to the expectorant effect and general toxicity of the drug (maintaining the toxicity and expectorant effect while reducing the content of ambroxol).

The drug may be especially necessary for the treatment of certain nosological forms of respiratory tract diseases and / or for certain groups of patients (for example, when a cough is combined with tonsillitis and pharyngitis, for patients with immune dysregulation, etc.).

The task is carried out by the fact that a liquid aqueous pharmaceutical composition of Ambroxol is proposed, additionally containing as an active principle a pharmaceutically acceptable water-soluble salt of glycyrrhizic acid and thyme extract (Thymus serpyllum) in an effective amount.

Effective amounts of the active substances in the invention are based on their amounts used in the prior art, at which they provide a pronounced inherent pharmaceutical effect.

In the proposed pharmaceutical composition, in which the main active ingredient is ambroxol, the content of components in 5 ml of the composition is:

Ambroxol - from 5 to 40 mg

salts of glycyrirrhizic acid - from 5 to 250 mg

thyme extract (in terms of dry weight) - from 16 to 160 mg

It is established that the claimed technical result, including a synergistic effect, is provided in the entire range of the above effective amounts of active components.

In a pharmaceutical composition that contains an aqueous base, the content of active substances is from 26 to 450 mg (in terms of dry weight) in 5 ml of the composition.

Any water-soluble, pharmaceutically acceptable salt of glycerrhizic acid may be used in the pharmaceutical composition, preferably the sodium or ammonium salt.

The pharmaceutical composition as an extract of thyme may contain its hydroalcoholic or dry extract.

The pharmaceutical composition may further comprise at least one auxiliary component selected from the group consisting of: preservative, sweetener, thickener, flavoring.

As a preservative, parabens such as methyl and / or propyl paraben (nipagin) / (nipazole), a mixture thereof can be used. Other preservatives may also be used, such as ethyl alcohol, sorbic acid, benzoic acid and their salts.

As a sweetener, the composition may contain sorbitol, maltitol, aspartame, sodium cyclomat, sodium saccharin, xylitol.

As a thickener, gums, cellulose derivatives, polyvinylpyrrolidone, alginates can be used.

As flavoring agents, synthetic aromatic substances and / or natural oils, extracts, and combinations thereof may be used.

The proposed pharmaceutical preparation for the treatment of respiratory diseases with the formation of viscous sputum (including for the treatment of acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectatic disease) based on the described composition can preferably be used in a daily dose of 0.2- 1.5 ml / kg of patient weight and it is preferably a solution, emulsion, syrup or elixir.

The pharmaceutical preparation is especially suitable for patients with swallowing problems, elderly patients or children. As a child’s drug, it is intended for children from two years of age, which is currently explained by the purpose of the comparison for the base drug, but in the future, children’s age for using the drug may be reduced.

A pharmaceutical preparation is also proposed for the treatment of respiratory diseases with the formation of viscous sputum (acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectatic disease) based on the pharmaceutical composition described above, intended for children over 2 years of age and adults, which is an elixir, in the following ratio of active and auxiliary components in 5 ml of the drug:

Ambroxol 5.0 to 40.0 mg Glycyrrhizic acid salt 5.0 to 250.0 mg Liquid thyme extract 100.0 to 1000.0 mg (calculated on dry weight) (16.0 to 160.0 mg) Sorbitol 3000.0 mg Methyl parahydroxybenzoate (nipagin) 3.75 mg Propyl parahydroxybenzoate (nipazole) 1.25 mg Purified water up to 5 ml

and used in a daily dose of 0.2 to 1.5 ml per kg of body weight for oral administration.

As an extract of thyme, it is preferable to use a water-alcohol extract (with a solids content of at least 8%, an average of 16% and an alcohol content of at least 22.0%).

In addition to ambroxol, the active ingredients of the invention are glycyrate and thyme extract. Glycyrate (glycyrrhizic acid and its salts) has an anti-inflammatory and antiviral effect, and liquid thyme extract has a weak expectorant and anti-inflammatory. None of these components, when used in the indicated doses as monotherapy, has a significant expectorant effect.

Thus, only one component of the preparation of the invention (hereinafter “Codelac® broncho with thyme”), Ambroxol, has a pronounced expectorant effect (allowing its use in clinical practice as a single drug).

The presence of an additional anti-inflammatory effect, the preservation of the indicator of general toxicity and expectorant action of the proposed composition with a decrease in the dose of the main component with a similar effect (ambroxol), which allows in practice to reduce the duration of the cough period and accelerate the recovery of patients with respiratory tract disease, suggests synergism in the manifestation of properties and the compliance of the invention with the criterion of "inventive step" as in relation to the pharmaceutical composition uu and medicament, respectively.

The following are specific examples of the implementation and use of the invention, illustrating the invention, but not limiting its scope.

The implementation of the invention

Pharmaceutical compositions (aqueous solution), method for their preparation

Example 1

To prepare the composition, thyme extract was used (Pharmstandard-Tomskkhimfarm OJSC, Russia or another drug registered in Russia) obtained from thyme grass (creeping thyme - THYMUS SERPYLLUM L., family Yasnotkovye-Lamiaceae) by extracting the active ingredient from medicinal raw materials using 30% ethanol obtained from 95% ethanol and purified water. This is a brown liquid with a characteristic smell of thyme. The content of thymol in the extract is not less than 0.01%, and the sum of flavanoid compounds in terms of luteolin is not less than 0.1%

A composition with a ratio of components Ambroxol: glycyrrhizic acid salt: thyme extract = 10: 30: 500 (80 mg in terms of dry substance) is obtained by heating 21.4 g of water to 45-55 ° C, to which 0.2 g of Ambroxol hydrochloride is added , mix until it is completely dissolved and add 0.6 g of the trisodium salt of glycyrrhizic acid, mix until completely dissolved. The solution is filtered through a filter with a mesh size of 50 μm. To the prepared solution at 35-40 ° C add 10 g of liquid thyme extract filtered through a filter with a mesh size of 1 μm. The resulting solution is a light brown to brown liquid. During the storage of the solution, precipitate may form.

The resulting composition composition:

Ambroxol hydrochloride 10 mg / 5 ml Glycyrrhizic acid trisodium salt 30 mg / 5 ml Thyme Extract Liquid 500 mg / 5 ml (with a solids content of at least 8%, an average of 16%) in terms of dry matter 80 mg / 5 ml

Example 2

To prepare a composition with a ratio of components Ambroxol: glycyrrhizic acid salt: thyme extract = 5 (mg): 5 (mg): 100 (mg) (16 mg in terms of dry matter) in 5 ml, the operations of the method according to example 1 are repeated, while take 0.1 g of Ambroxol hydrochloride, 0.1 g of the ammonium salt of glycyrrhizic acid, 2.0 g of thyme liquid extract per 100 ml of solution.

The resulting composition composition:

Ambroxol hydrochloride 5 mg / 5 ml Glycyrrhizic acid trisodium salt 5 mg / 5 ml Thyme Extract Liquid 100 mg / 5 ml (with a solids content of at least 8%, an average of 16%) in terms of dry matter 16 mg / 5 ml

Example 3

To prepare a composition with a ratio of components Ambroxol: glycyrrhizic acid salt: thyme extract = 40 (mg): 250 (mg): 1000 (mg) (160 mg in terms of dry matter) in 5 ml, the operations of the method according to example 1 are repeated, while take 0.8 g of Ambroxol hydrochloride, 5.0 g of the trisodium salt of glycyrrhizic acid, 20.0 g of thyme liquid extract per 100 ml of solution.

The resulting composition composition:

Ambroxol hydrochloride 40 mg / 5 ml Glycyrrhizic acid trisodium salt (glycyrate) 250 mg / 5 ml Thyme Extract Liquid (with a solids content of at least 8%, an average of 16%) 1000 mg / 5 ml in terms of dry matter 160 mg / 5 ml

Elixir, method for preparing it

Example 4

The active substances are taken in the same amount as in Example 1. However, auxiliary substances are used: nipagin, nipazole, sorbitol. The drug is obtained by the following technology.

Stage 1. Preparation of a solution of sorbitol and preservatives

27.7 g of water are heated to 45-55 ° C, 0.075 g of nipagin and 0.025 g of nipazole are added, the mass is heated to 95-105 ° C, held, cooled to 40-55 degrees, 60.0 g of sorbitol is added, heated to 95 -105 ° C, maintained at this temperature and cooled, filtered.

Stage 2. Preparation of Ambroxol Hydrochloride and Glycyrate Solution

21.4 g of water are heated to 45-55 ° C, 0.2 g of Ambroxol hydrochloride are added, stirred until it is completely dissolved and 0.6 g of glycirate is added, stirred until the glycirate is completely dissolved. The solution is filtered through a filter with a mesh size of 50 μm.

Stage 3. Preparation of the Elixir

Two previously prepared solutions are mixed, mixed and 10.0 g of liquid thyme extract are added at a temperature of 35-40 ° C, filtering it through a filter with a mesh size of 1 μm. 120 g (100 ml) of elixir are obtained. The resulting elixir is a viscous liquid from light brown to brown. During the storage of the elixir, a precipitate may form.

The resulting elixir composition:

Ambroxol hydrochloride 10 mg / 5 ml Glycyrrhizic acid trisodium salt (glycyrate) 30 mg / 5 ml Thyme Extract Liquid (with a solids content of at least 8%, an average of 16%) 500 mg / 5 ml in terms of dry matter 80 mg / 5 ml the alcohol content in the elixir is not more than 3.0% Sorbitol 3000 mg / 5 ml Methyl parahydroxybenzoate (nipagin) 3.75 mg / 5 ml Propyl parahydroxybenzoate (nipazole) 1.25 mg / 5 ml Purified water up to 5 ml

Example 5

The operations are repeated as indicated in Example 4, however, the active substances are taken in an amount as indicated in Example 2.

An elixir of the following composition is obtained:

Ambroxol hydrochloride 5 mg / 5 ml Ammonium salt of glycyrrhizic acid 5 mg / 5 ml Thyme Extract Liquid (with a solids content of at least 8%, an average of 16%) 100 mg / 5 ml in terms of dry matter 16 mg / 5 ml the alcohol content in the elixir is not more than 3.0% Sorbitol 3000 mg / 5 ml Methyl parahydroxybenzoate (nipagin) 3.75 mg / 5 ml Propyl parahydroxybenzoate (nipazole) 1.25 mg / 5 ml Purified water up to 5 ml

Example 6

The operations are repeated, as indicated in example 4, however, the active substances are taken in an amount, as indicated in Example 3. An elixir of the following composition is obtained:

Ambroxol hydrochloride 40 mg / 5 ml Glycyrrhizic acid trisodium salt (glycyrate) 250 mg / 5 ml Thyme Extract Liquid (with a solids content of at least 8%, an average of 16%) 1000 mg / 5 ml in terms of dry matter 160 mg / 5 ml the alcohol content in the elixir is not more than 5.0% Sorbitol 3000 mg / 5 ml Methyl parahydroxybenzoate (nipagin) 3.75 mg / 5 ml Propyl parahydroxybenzoate (nipazole) 1.25 mg / 5 ml Purified water up to 5 ml

Syrup, method for producing

Example 7

The operations are repeated as described in Example 4, however, instead of 10.0 g of thyme liquid extract, 1.6 g of dry thyme extract is taken, dissolving it in step 2 together with ambroxol and glycyrrhizic acid salt.

Syrup is obtained by the following technology.

Stage 1. Preparation of a solution of sorbitol and preservatives

27.7 g of water are heated to 45-55 ° C, 0.075 g of nipagin and 0.025 g of nipazole are added, the mass is heated to 95-105 ° C, held, cooled to 40-55 ° C, 60 g of sorbitol are added, heated to 95- 105 ° C, maintained at this temperature and cooled, filtered.

Stage 2. Preparation of a solution of Ambroxol hydrochloride, glycyrate and dry thyme extract

21.4 g of water are heated to 45-55 ° C, 0.2 g of Ambroxol hydrochloride are added, stirred until it is completely dissolved and 0.6 g of Na glycirate is added, stirred until the glycirate is completely dissolved. The solution is filtered through a filter with a mesh size of 50 μm.

Stage 3. Preparation of syrup

Two previously prepared solutions are mixed, mixed, and at a temperature of 35-40 ° C, 10.0 g of liquid thyme extract are added, filtering it through a filter with a mesh size of 1 μm. Bring the syrup volume with water to 100 ml (you need to add about 8.4 ml of water). The resulting syrup is a viscous liquid from light brown to brown in color and has the following composition:

Ambroxol hydrochloride 10 mg / 5 ml Glycyrrhizic acid trisodium salt (glycyrate) 30 mg / 5 ml Dry thyme extract 160 mg / 5 ml Sorbitol 3000 mg / 5 ml Methyl parahydroxybenzoate (nipagin) 3.75 mg / 5 ml Propyl parahydroxybenzoate (nipazole) 1.25 mg / 5 ml Purified water up to 5 ml

Example 8 (Study of acute and chronic toxicity of a composition, synergistic effect with respect to expectorant effect in an experiment on a biological model)

The compositions of examples 1-3 (in the form of a syrup) were studied to study acute and chronic toxicity (general toxic effect), expectorant and anti-inflammatory effects in comparison with Ambrobene syrup manufactured by Merkle GmbH, Germany.

1. The study of the general toxic effect of the drug Codelac broncho with thyme in comparison with the drug Ambrobene.

When studying acute toxicity, white mice were once administered intragastrically with Codelac broncho syrup with thyme and Ambrobene syrup at doses of 16 ml / kg, 18.5 ml / kg, 20 ml / kg, 22.5 ml / kg and 25 ml / kg in the amount maximum permissible for intragastric administration to a given animal species. It was found that the studied preparations Codelac broncho with thyme and the comparison drug Ambrobene at the indicated doses with a single dose did not have a dose-dependent toxic effect and did not cause the death of animals during the first 3 days of observation. It was not possible to calculate the preparations according to the Shtabsky LD50 method due to the achievement of the volume maximum admissible for intragastric administration to this animal species. The state of the animals that survived acute intoxication indicates good tolerance and harmlessness of the preparations in doses exceeding the therapeutic ones by tens of times. Consequently, the results of observations of experimental animals in the post-toxicity period of acute poisoning make it possible to attribute the compared preparations of Codelac broncho with thyme and Ambrobene to class IV low-toxic drugs (N. Hodge et al. Clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV, Baltimor, 1975, 427 p .; KK Sidorov, 1973).

When studying subchronic toxicity for a long time for 2 weeks, sexually mature white laboratory rats were orally administered Codelac Broncho syrup with thyme and Ambrobene syrup comparison drug in twice the maximum allowable therapeutic dose (4.6 ml / kg) and eight times the maximum allowable therapeutic dose (18 4 ml / kg). It was revealed that the studied drug and the comparison drug do not affect the cellular and biochemical composition of the blood. Both drugs do not cause structural disturbances in the remaining internal organs, performing various protective-excretory and regulatory-exchange functions in the body, do not change the relative mass of the internal organs of animals. A comparative study of the preparations showed a coincidence of the toxicity of the Codelac broncho syrup with thyme and Ambrobene syrup; The preservation of toxicity indicators of the proposed multicomponent composition compared with ambroxol monotherapy was identified by the applicant and does not follow from the prior art.

2. The study of expectorant and anti-inflammatory effects of the compositions

An experimental study was conducted that studied the pharmacological expectorant and anti-inflammatory effect of the drug according to the invention ((10 mg of ambroxol + 5 mg of a mixture of sodium glycyrrhizinate and dry extract of creeping thyme) / 5 ml) and Ambrobene (15 mg of ambroxol / 5 ml).

The expectorant effect of drugs was studied when measuring the motor activity of the ciliated epithelium of the frog’s esophagus, anti-inflammatory activity was evaluated on a model of local inflammatory response using Oyvin xylene in rabbits (Gatsura V.V. Methods of the primary pharmacological study of biologically active substances. 1974; I. Oyvin, Monakhova K.N. Pharmacology and Toxicology, 1953).

When studying the expectorant effect of drugs, the studied drugs in the form of 1% aqueous solutions in the amount of 0.1 ml were applied to the mucous membrane of the pharynx. The motor function of the ciliated epithelium of the frog esophagus was judged by the speed of movement of a piece of silk thread (5 mm long) placed on the mucous membrane of the pharynx between the posterior edges of the orbits in the transverse position. Given the significant scatter of the initial velocities of the ciliated epithelium from one animal to another, we used the calculated indicator - acceleration coefficient (Ku), which is the ratio of the time it takes for the thread to pass after the application of the test substances to the time it takes for the thread to pass before the test substances are applied.

As the results showed, both drugs had the same expectorant effect - they equally increased the motor activity of the ciliated epithelium.

The average time of thread movement when applying water and a solution of the test syrup decreased from 86.0 ± 11.6 s to 48.7 ± 8.0 s when using Codelac broncho with thyme and from 86.2 ± 11.5 s to 43.0 ± 7.2 s when using Ambrobene, the acceleration coefficient was 1.83 ± 0.09 and 2.11 ± 0.15, respectively, the differences between the preparations were not significant.

That is, despite the lower content of ambroxol in the Codelac broncho preparation with thyme, the presence of glycyrrhizic acid and thyme extract made it possible to achieve the same severity of expectorant action as when using a higher dose of ambroxol monotherapy.

When studying the anti-inflammatory effect of the drugs, the studied drugs were administered intragastrically using specially made atraumatic metal probes with fused olive at the end and sizes corresponding to the physiological length of the esophagus of the experimental animals, in single and double therapeutic doses an hour before the introduction of the permeability indicator, the role of which was the trypan solution blue. Trypan blue was injected into the marginal vein of the ear in the form of a 1% solution in 0.9% sodium chloride solution at the rate of 2 ml per 1 kg of animal weight. Then, 12 drops of o-xylene were applied to the abdominal skin. An indicator of capillary permeability was the time of appearance of blue-stained spots on the skin and their diameter. The difference in the time of the appearance of spots and their diameter before and after administration of the drug was used to judge its effect on the permeability of capillaries.

The results obtained in the study of the anti-inflammatory effect of the preparations showed that the elixir Codelac broncho with thyme shows a pronounced anti-inflammatory activity, while the comparison drug Ambrobene syrup does not have a statistically significant anti-inflammatory effect (table 3).

Table 3 Anti-inflammatory activity of the drug "Codelac broncho" syrup in comparison with Ambrobene syrup in the study of antiflogistic activity in rabbits Preparations Number of spots The average area of the spots, cm ² The appearance of spots, sec Intact 12 1.76 ± 0.2 249.58 ± 3.26 "Codelac broncho" 0.88 ml / kg (single therapeutic dose) 12 0.96 ± 0.09 * 457.67 ± 4.96 * "Codelac broncho" 1.76 ml / kg 12 0.67 ± 0.08 * 640.92 ± 8.13 * Ambrobene 0.88 ml / kg (single therapeutic dose) 12 1.67 ± 0.11 240.67 ± 1.96 Ambrobene 1.76 ml / kg 12 1.86 ± 0.16 231.75 ± 2.23 • - at p <0.05 with respect to the intact group

Thus, Codelac broncho with thyme has an advantage over the ambroxol monotherapy, as the combination of active ingredients (ambroxol + glycyrate + liquid thyme extract) allows you to maintain a toxicity index, achieve the same severity of expectorant action as when using ambroxol monotherapy in a higher dose, and get an additional anti-inflammatory effect.

Example 9 (Clinical studies, synergistic effect, consisting in obtaining the best therapeutic effect in reducing the dose of the drug, including reducing the duration of the cough period and accelerating recovery, efficacy and safety of the drug)

The use of drugs Codelac Broncho with thyme and Ambrobene in the treatment of patients with unproductive cough in acute respiratory diseases

On the basis of the City Clinical Hospital №23 named. Medsantruda, a clinical study was conducted to study the efficacy and safety of the use of Codelac broncho with thyme and Ambrobene in patients with unproductive cough in acute respiratory diseases.

The study included 40 patients with acute respiratory disease and unproductive cough. Patients were randomly assigned to 2 groups. 20 patients of the first group took the above drug Codelac broncho with thyme inside, 10 ml 4 times a day, for 7 days. 20 patients of the second group received Ambrobene 10 ml orally 3 times a day, in accordance with the instructions for medical use, also for 7 days. The daily doses used of the study drug and the comparison drug were almost the same. After completion of therapy, patients of both groups were monitored for 7 days.

The results obtained during the clinical trial allow us to draw the following conclusions:

- In both groups of patients, there was a decrease in the intensity and severity of coughing, more significant in the Codelac broncho group with thyme, and from the 6th day of treatment the difference between the groups becomes statistically significant. In the Codelac broncho with thyme group, patients taking Codelac broncho with thyme noted only “single cough tremors”, while in the other group “rare cough during the day” is still registered.

- The duration of the cough period in the group of patients Codelac broncho with thyme is much shorter than in the Ambrobene group. By the 6th day of therapy, complete cough disappearance was noted in 30% of patients taking Codelac broncho with thyme, and only in 5% of patients taking Ambrobene (differences are statistically significant).

- In both groups of patients, there was a significant improvement in sputum separation and the absence of pain during its separation. In the group of patients taking Codelac broncho with thyme, the positive dynamics are more pronounced and from the 4th day of treatment the differences between the groups become statistically significant.

- Codelac broncho with thyme and Ambrobene have demonstrated a high level of safety when used in patients with unproductive cough in acute respiratory diseases.

- During the study, in both groups there were no statistically significant changes in the main vital indicators and the results of biochemical, hematological analyzes.

- During the study, in both groups of patients, serious adverse events were not recorded.

- Adverse events recorded in both groups of patients were unexpressed and did not require cancellation or change in the dose of the drug.

Thus, in the course of the study, Codelac broncho with thyme compared with Ambrobene demonstrated a significant advantage in the treatment of patients with unproductive cough in acute respiratory diseases, which is ensured not only by the pronounced expectorant and mucolytic effect of Codelac broncho with thyme (with a lower dose of ambroxol in the composition the drug, compared with the single drug Ambrobene), but, apparently, the presence of an additional anti-inflammatory effect, which can play an important role to improve the rheological properties of sputum and its excretions, which provides multi-directional action of the drug on the pathogenesis of cough in general.

Example 10 (Clinical studies, synergistic effect, consisting in obtaining the best therapeutic effect in reducing the dose of the drug, including reducing the duration of the cough period and accelerating recovery, efficacy and safety of the drug)

The use of drugs Codelac Broncho with thyme and Ambrobene in the treatment of children with unproductive cough in acute respiratory diseases

On the basis of GOU VPO MMA named after THEM. Sechenov conducted a study on a comparative study of the efficacy and safety of Codedelac broncho preparations with thyme and Ambrobene as part of complex therapy in children with unproductive cough in acute respiratory diseases.

The study included sixty patients aged 2 to 12 years with an unproductive cough against an acute respiratory disease. 30 patients are included in the 2-5 year old age group and 30 patients are also included in the 6-12 year old group.

Patients were randomized into 2 groups. 30 patients of the first group took Codelac broncho with thyme inside, 3 times for 7 days a day. 30 patients of the second group received Ambrobene inside 3 times a day in accordance with the instructions for medical use, also for 7 days. The drugs were used in equal doses corresponding to the age of the patient. After completion of therapy, patients of both groups were monitored for 7 days.

The results obtained during the clinical trial allow us to draw the following conclusions:

- During therapy, in both groups there was an increase in the number of patients without night cough. In the group of patients receiving Codelac® broncho with thyme, starting from the 4th day of therapy, the number of patients without night cough significantly exceeds the number of those in the group of patients receiving Ambrobene.

- In both groups of patients, there was a decrease in the intensity and severity of cough, more significant in the Codelac broncho group with thyme, and from the 4th day of treatment the difference between the groups becomes statistically significant.

- The duration of the cough period in the group of patients Codelac broncho with thyme is much shorter than in the Ambrobene group. By the morning of the 7th day, cough disappearance was noted in 44.83% of patients taking Codelac broncho with thyme, and in 13.33% of patients taking Ambrobene.

- In both groups of patients, a significant improvement in sputum separation and the absence of pain during its separation were noted. In the group of patients taking Codelac broncho with thyme, the positive dynamics are more pronounced and from the 6th day of therapy, the differences between the groups become statistically significant.

- Codelac broncho with thyme and Ambrobene demonstrated a high level of safety when used in children with unproductive cough in acute respiratory diseases.

- In the Codelac broncho thyme group, the number of patients whose treatment outcome was rated “Significant Improvement” is statistically significantly greater than among patients treated with Ambrobene.

- During the study, in both groups there were no statistically significant changes in the main vital indicators and the results of biochemical, hematological analyzes.

- During the study, in both groups of patients, serious adverse events were not recorded.

Thus, during the study, the drug Codelac broncho with thyme and thyme compared with Amrobene demonstrated a significant advantage in the treatment of children with unproductive cough in acute respiratory diseases. In a comparative study of the safety of Codelac broncho preparations with thyme and Ambrobene, no significant differences were found between these agents.

Thus, the clinical trials conducted above showed that despite the lower content of ambroxol in the preparation according to the invention compared to the ambroxol Ambrobene monopreparation, the combination of ambroxol with glycyrrhizic acid salt and thyme extract allows to increase the expectorant and mucolytic effect (when using the studied preparation in a lesser dose than the comparison drug), get an additional anti-inflammatory effect and achieve better clinical results.

Claims (16)

1. A liquid aqueous pharmaceutical composition of Ambroxol for the treatment of viscous diseases of the respiratory tract with the formation of viscous sputum, containing in addition as an active principle a pharmaceutically acceptable water-soluble salt of glycyrrhizic acid and thyme extract (Thymus serpyllum) in an effective amount. 2. The pharmaceutical composition according to claim 1, in which the content of ambroxol: salts of glycyrrhizic acid: thyme extract (dry weight) is (5-40 mg) :( 5-250 mg) :( 16-160 mg in terms of dry weight) in 5 ml of the composition. 3. The pharmaceutical composition according to claim 1, in which the content of active substances is 26-450 mg (in terms of dry weight) in 5 ml of the composition. 4. The pharmaceutical composition according to claim 1, which contains a sodium or ammonium salt as a pharmaceutically acceptable salt of glycyrrhizic acid. 5. The pharmaceutical composition according to claim 1, which as an extract of thyme contains water-alcohol or dry extract. 6. The pharmaceutical composition according to claim 1, which further comprises at least one auxiliary component selected from the group including: preservative, sweetener, thickener, flavoring. 7. The pharmaceutical composition according to claim 6, which contains parabens as a preservative, such as methyl and / or propyl paraben (nipagin) / (nipazole), ethyl alcohol, sorbic or benzoic acid, or mixtures thereof. 8. The pharmaceutical composition according to claim 1, which as a sweetener contains sorbitol, maltitol, aspartame, sodium cyclamate, sodium saccharin, xylitol, or mixtures thereof. 9. The pharmaceutical composition according to claims 1-8, which exhibits a mucolytic, expectorant and anti-inflammatory effect. 10. A pharmaceutical preparation for the treatment of respiratory tract diseases with the formation of viscous sputum (acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectatic disease) based on the pharmaceutical composition described in claims 1 to 9, used in a daily dose of 0 2-1.5 ml / kg of patient weight. 11. The pharmaceutical preparation of claim 10, which is a solution, emulsion, syrup or elixir. 12. The pharmaceutical preparation of claim 10, which is intended for patients with swallowing problems, elderly patients or children from two years of age. 13. The pharmaceutical preparation according to item 12, which is intended for children. 14. The pharmaceutical preparation according to claim 12, wherein the content of ambroxol, glycyrrhizic acid salt and thyme extract (dry weight) is (5-40 mg) :( 5-250 mg) :( 16-160 mg) in 5 ml of the preparation. 15. The pharmaceutical preparation according to claims 10-14, which further comprises at least one auxiliary component selected from the group comprising: preservative, sweetener, thickener, flavoring. 16. A pharmaceutical preparation for the treatment of respiratory tract diseases with the formation of viscous sputum (acute and chronic bronchitis, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectatic disease) based on the pharmaceutical composition described in claims 1 to 9, intended for children aged older than 2 years and adults, which is an elixir, with the following ratio of active and auxiliary components in 5 ml of the drug:
Ambroxol 5.0 to 40.0 mg Glycyrrhizic acid salt 5.0 to 250.0 mg Liquid thyme extract 100.0 to 1000.0 mg (based on dry weight 16.0 to 160.0 mg) Sorbitol 3000.0 mg Methyl parahydroxybenzoate (nipagin) 3.75 mg Propyl parahydroxybenzoate (nipazole) 1.25 mg Purified water up to 5 ml
and used in a daily dose of 0.2 to 1.5 ml per kg of body weight for oral administration.