UA47594U - Composition for treating and preventing diseases of respiratory tract - Google Patents

Abstract

A composition for treating and preventing the diseases of the respiratory tract contains Ambroxol hydrochloride, Ketotifen fumarate, Theobromine, the licorice root extract, and the excipients.

Description

Patent of the Russian Federation Mo 2157226 dated 04.07.1996, cl. A61ES 35/78, AbITR 11/14. Publ. officer Bull.

Rospatent "Inventions, useful models", 10.10.2000.

A pharmaceutical composition for the treatment of cold symptoms is known, containing an analgesic, anesthetic, anti-inflammatory, antihistamine and expectorant, as well as a substance having cooling properties (for example, menthone or M-ethyl-p-menthane-3-carboxamide and mixtures thereof). The tool is prescribed in the form of solid and liquid dosage forms for oral and nasal use.

Application of the Russian Federation Me95112502 dated 04.07.1997, cl. A61K47/10. Publ. officer Bull. Rospatent "Inventions, useful models", 27.11.1997.

A pharmaceutical composition for the treatment of respiratory diseases, containing anti-inflammatory, antihistamine, anti-edematous, expectorant, as well as an agent that reduces irritation, is known. The tool is prescribed in the form of tablets, capsules, pills or lozenges.

Application of the Russian Federation Me95121769 dated November 30, 1995, cl. AbIKU/48, 9/28. Publ. officer Bull. Rospatent "Inventions, useful models", 10.02.1998.

A well-known medicine in the form of tablets "Brosal" ("Eiedapi Ipaia", India). 1 tablet contains salbutamol (broncholytic agent) 2 mg, bromhexine hydrochloride (mucolytic agent) Zmg and auxiliary substances: lactose, starch, sodium starch glycolate, talc, magnesium stearate, yellow dye tartrazine. Indications for the use of "Brosal" tablets are bronchial asthma, chronic obstructive bronchitis, emphysema of the lungs, sinusitis.

Compendium 2006 - medicinal product / Ed. V.N. Kovalenko, A.P. Viktorova. - K. Morion, 2006. - vol.1- p.l-230.

The well-known drug "Stoptusyn" in the form of tablets ("mach RPpaptasehisa I5", Czech Republic). 1 tablet contains: dihydrogencitrate butamirate (antitussive agent) 4.0mg, guaifenesin (mucolytic agent) 100.0mg and auxiliary substances: anhydrous silicon dioxide, mannitol, microcrystalline cellulose, glycerine tribehenate, magnesium stearate. "Stoptusyn" is used for coughs and colds.

Compendium 2006 - medicinal preparation! / Ed. V.N. Kovalenko, A.P. Viktorova. - K. Morion, 2006. -

T.2. - b. L-1311. !

A well-known pharmaceutical composition in the form of tablets, containing dry concentrates of raspberry syrup, a decoction of the roots of comfrey, an extract of licorice, an infusion of chamomile flowers, an infusion of mother-and-stepmother leaves (ordinary white), ascorbic acid, starch, calcium stearate and sugar. The tool is used in the complex treatment of diseases of the upper respiratory tract.

Patent of the Russian Federation Me2240812, class Ab1K35/78, Ab1KOU/20, A231I.1/03, Ab1P11/00. Publ. officer Bull. "Inventions. A useful model" dated November 27, 2004.

The well-known syrup "Rensril Expectorant" ("Zepot Vioyesp Rm.la.", India), 5 ml of which contains ambroxol hydrochloride (a mucolytic agent) 15 mg, terbutaline sulfate (a bronchodilator) 1.5 mg, guaifenesic (an expectorant) 5 mg, chlorpheniramine maleate ( antiallergic agent) 2 mg, menthol (distracting agent) 1 mg and auxiliary substances: citric acid, sodium methylparaben, sodium propylparaben, sorbitol, sugar, glucose, propylene glycol, sodium saccharinate, disodium edetate, strawberry essence, dye, purified water.

Indications for use are acute and chronic diseases of the respiratory tract, which are accompanied by the removal of viscous secretions.

Compendium 2006 - medicinal product / Ed. V.N. Kovalenko, A.P. Viktorova. - K. Morion, 2006. -

T.2. - b.L-1191.

A known pharmaceutical composition in the form of tablets containing thermopsis (expectorant) 1.5-595, licorice root extract (expectorant) 0.1-1595, pharmaceutically acceptable granulating agent 1-6095, pharmaceutically acceptable glidant 0.5-1595 . The tool is used for cough.

Patent of the Russian Federation Me2247556, cl. Ab1K9/20, Ab1K35/78, AbIK33/10, AbIR11/14. Publ. officer Bull. "Inventions. Useful models" dated March 10, 2005.

A known antitussive pharmaceutical composition containing theobromine and excipients. The composition is used in the form of an injection solution, syrup, dragee, tablet, lozenge, suppository, capsule, liposomes.

Patent EA Me1971, cl. Ab1K31/522, Ab1R 11/14. Publ. 22.10.2001.

The closest to the claimed are cough tablets "Milistan" ("Mii Neapysage I ityea",

India/UK). 1 tablet contains ambroxol hydrochloride (mucolytic agent) ZOmg, carbocysteine (mucolytic agent) 200mg and auxiliary substances: corn starch, microcrystalline cellulose, sodium methylhydroxybenzoate, sodium propylhydroxybenzoate, magnesium stearate, purified talc, colloidal silicon dioxide, sodium starch glycolate, starch. "Milistan" is used for acute and chronic diseases of the respiratory tract, which are accompanied by the formation of a secret that is difficult to secrete.

Compendium 2006 - medicinal product / Ed. V.N. Kovalenko, A.P. Viktorova. - K. Morion, 2006. -

T.1. - b. L-901.

Among the reasons that prevent the prototype and analogs from obtaining the technical result achieved in the claimed product, one should include the fact that the qualitative and quantitative composition of their components does not allow to sufficiently increase the level and expand the spectrum of their specific activity, reduce or eliminate negative side effects , as a result of which a complex effect on the bronchopulmonary system, minimization of side effects and a favorable ratio of benefit/risk of the product are ensured.

The basis of a useful model is the task of creating a combined remedy for the treatment and prevention of respiratory tract diseases with such a qualitative and quantitative composition of components that would ensure an increase in the level and expansion of the spectrum of specific activity, reduce or eliminate negative side effects, as a result of which a comprehensive effect on the bronchopulmonary system is achieved , minimization of side effects and a favorable benefit/risk ratio of the tool.

The task is solved by the fact that the combined remedy for the treatment and prevention of respiratory tract diseases, containing ambroxol hydrochloride and auxiliary substances, according to the useful model, additionally contains ketotifen fumarate, theobromine and licorice root extract with this ratio of components, g: ambroxol hydrochloride 0 .01-0.03 ketotifen fumarate 0.001 theobromine 0.03-0.05 bare licorice root extract 0.01-0.03 excipients up to 0.5.

The technical result achieved by the implementation of a useful model consists in creating a combined means for the treatment and prevention of respiratory tract diseases with such a qualitative and quantitative composition of components that would ensure an increase in the level and expansion of the spectrum of specific activity, reduce or eliminate negative side effects, as a result of which a complex effect on the bronchopulmonary system, minimization of side effects and a favorable benefit/risk ratio of the product are achieved.

We give specific examples of the development of a useful model.

Example 1

Weighed and sifted components are loaded into the mixer: microcrystalline cellulose, theobromine, ambroxol hydrochloride, licorice root extract, a mixture of ketotifen fumarate with potato starch is added and the mass is thoroughly mixed. The resulting mixture is moistened with a 1095 solution of starch paste, mixed until the components are evenly distributed and subjected to granulation. The mass is dried to a residual moisture of 1.5-2.595. The dried mass is subjected to dry granulation. The obtained granulate is powdered with a mixture of calcium stearate and lactose and is thoroughly mixed again until the components of the granulated mass are evenly distributed, after which it is tableted.

The declared agent has the following ratio of components, g: ambroxol hydrochloride 0.01 ketotifen fumarate 0.001 theobromine 0.05 licorice root extract 0.01 lactose 0.3 microcrystalline cellulose 0.064 calcium stearate 0.005 potato starch 0.06.

Example 2

Weighed and sifted components are loaded into the mixer: microcrystalline cellulose, theobromine, ambroxol hydrochloride, licorice root extract, a mixture of ketotirene fumarate and potato starch is added and the mass is thoroughly mixed. The resulting mixture is moistened with a 1095 solution of starch paste, mixed until the components are evenly distributed and subjected to granulation. The mass is dried to a residual moisture of 1.5-2.595. The dried mass is subjected to dry granulation. The obtained granulate is powdered with a mixture of calcium stearate and croscarmellose sodium and is thoroughly mixed again until the components of the granulated mass are evenly distributed, after which it is tableted.

The declared agent has the following ratio of components, g: ambroxol hydrochloride 0.02 ketotifen fumarate 0.001 theobromine 0.04 licorice root extract 0.02 lactose 0.3 microcrystalline cellulose 0.064 calcium stearate 0.005 potato starch 0.05.

Example C

Weighed and sifted components are loaded into the mixer: microcrystalline cellulose, theobromine, ambroxol hydrochloride, bare licorice root extract, a mixture of ketotirene fumarate and potato starch is added and the mass is thoroughly mixed. The resulting mixture is moistened with a 1095 solution of starch paste, mixed until the components are evenly distributed and subjected to granulation. The mass is dried to a residual moisture of 1.5-2.595. The dried mass is subjected to dry granulation. The obtained granulate is powdered with a mixture of calcium stearate and croscarmellose sodium and is thoroughly mixed again until the components of the granulated mass are evenly distributed, after which it is tableted.

The declared agent has the following ratio of components, g: ambroxol hydrochloride 0.03 ketotifen fumarate 0.001 theobromine 0.03 bare licorice root extract 0.03 croscarmellose sodium 0.3 microcrystalline cellulose 0.064 calcium stearate 0.005 potato starch 0.04.

According to the task set in the useful model, the authors developed a combined remedy for the treatment and prevention of respiratory tract diseases, which contains ambroxol, licorice root extract, ketotifen, theobromine and has a positive effect on all links of the pathological process. Active and auxiliary substances that are part of the claimed product are known in pharmacy, but their quantitative and qualitative combination is new, not known from sources of information.

Ambroxol hydrochloride is a secretolytic and secretomotor agent from the group of enzylamins, stimulates the serous cells of the glands of the mucous membrane of the bronchi, which leads to an increase in mucus secretion and a change in the ratio of serous and mucous components of sputum. This, as well as the activation of hydrolyzing enzymes and increased motor activity of the ciliated epithelium of the bronchi, contributes to the separation of the pathological secretion from the walls of the bronchi and its removal from the respiratory tract. Ambroxol increases the content of surfactant in the lungs, prevents its destruction in pneumocytes, which helps to improve the drainage function of the lungs. The indicated pharmacological properties of ambroxol allow its use in the treatment of respiratory tract diseases accompanied by the formation of viscous secretions: acute and chronic bronchitis, pneumonia, bronchiectasis, sinusitis, rhinitis, etc.

Ambroxol penetrates well through the placental barrier and stimulates the intrauterine synthesis of surfactant in the lungs of the fetus, which allows it to be used for the prevention of respiratory distress syndrome in newborns. When Amkesol tablets are taken orally, ambroxol is quickly and completely absorbed and effectively penetrates into lung tissue. The maximum concentration of ambroxol in blood plasma is observed two hours after oral administration. The half-life is 10-12 hours, it is excreted in the urine.

Ketotifen exhibits anti-allergic activity by inhibiting the action of endogenous mediators of inflammation and the release of mediators of allergy (histamine, leukotrienes), prevents the sensitization of eosinophils by cytokines, which leads to inhibition of the migration of eosinophil granulocytes to the focus of inflammation and the development of bronchial hyperactivity, which is due to the activation of platelets under the influence of the platelet activation factor and stimulation by allergens. These properties ensure the manifestation, first of all, of the anti-asthmatic properties of ketotifen.

Numerous clinical studies have proven the effectiveness of ketotifen in the treatment of lung diseases, mainly in children: bronchial asthma, obstructive bronchitis, etc. Metabolism of ketotifen is carried out in the liver, bioavailability is 5095. In addition, ketotirene does not have side effects that are characteristic of B2-adrenomimetics, in particular salbutamol. The maximum concentration of ketotifen in blood plasma is observed within 2-4 hours, the half-life is biphasic and is 3-5 and 21 hours.

Theobromine is a derivative of xanthine, increases the concentration of CAMP in tissues, which leads to the expansion of the bronchi, increased mucociliary clearance, improvement of pulmonary blood circulation and inhibition of the release of mediators of anaphylactic reactions. Theobromine increases renal blood circulation, reduces reabsorption of water in tubules, exhibits diuretic and antispasmodic properties. In addition, theobromine has an antitussive effect and has no serious side effects.

Licorice root extract contains glycurazide, glycyrrhizic acid, flavonoids, sitosterol, pectins, sugar, starch, mucilage and other bioactive substances. Licorice root extract has pronounced expectorant properties. Glycyrrhizic acid has anti-inflammatory properties. Liquiritoside (flavonoid glycoside) and 2,4,4-trioxychalcone act as antispasmodics.

The combination of several active substances with different pharmacological activities allows at the same time to have a positive effect on all links of the pathological process, to reduce therapeutic doses of active substances, to avoid polypharmacy, which makes it possible to significantly reduce the time required for treatment and improve the patient's quality of life.

The rational selection of active and auxiliary substances of the claimed agent and experimentally found optimal ratios between them within the specified limits provide complex correction of respiratory tract diseases, a high therapeutic effect, which is superior in effect to comparative drugs. During the research, it was unexpectedly found that the claimed combined agent exhibits a mucolytic effect at a much lower dose of ambroxol than monopreparations of ambroxol when used in the clinic.

Next, we present the results of studies that testify to the advantages of the claimed product "Amkesol" in the form of tablets over comparable products. Separate components of the claimed remedy were also studied: ambroxol, licorice root extract, theobromine, in doses calculated according to the method of Y.P. Rybolovlev and co-authors, based on their content in the tablet and the doses in which they are used as monopreparations in the clinic.

The study of the mucolytic action of "Amkesol" tablets was conducted on white, sexually mature rats on the model of tracheobronchitis caused by ammonia alcohol, in comparison with "Brosal" tablets; substances ambroxol, licorice root extract and theobromine. The drugs were administered prophylactically, intragastrically, once a day for 4 days. The last injection was carried out one hour before the reproduction of acute bronchitis. Bronchial secretion was assessed by the difference in the mass of dry and wet cotton swabs, which were placed through an incision in the trachea of experimental animals for 10 seconds. The pharmacological effectiveness of the drugs was determined by:5a ability to increase the mass of bronchial secretion in experimental animals in comparison with indicators of control pathology. The mucolytic activity (A) of "Amkesol" tablets and comparison drugs was calculated according to the formula:

AMd-AMkK

А-- - Е - - --х1«1100955,

AMk, where:

AMd - mass of bronchial secretion in the experiment;

АМКк - the mass of bronchial secretion in the control.

The results of the experiment are shown in Table 1.

Table 1

Study of the mucolytic activity of "Amkesol" tablets (p-b) (Control pathology | 23.0042.48 | 20335145 | 1967417 | 16.0041.32 | - 9mg/kg 14696 10596 10596 809 and licorice, 1.68mg/kg 1896 295 3196 3496 y

339 Bo 1095

Theobromine, bmg/kg 2996 3490 4290 1795 22

(Control pathology | 2517252.74 | 18.8341.08 | 18332085 | 17504121 | - ( 36.8354.707 23.8352.24 21.1752.70 16.33:51.31 o licorice, 84 mg/kg 55 Boron 7496 389 3596 th

ZBMg/kg 8196 9796 4596 1496 and (Control pathology | 24,053.42 | 18,0041.52 | 18831.74 | 433880 | - (' Zb 22 1890 1390 " - differences are significant in relation to control pathology, Р«0.05; p - number of animals in the group;

A, 95 - mucolytic activity.

Analyzing the obtained data, it can be concluded that although the individual components that are included in the composition of my agent did not show high activity, when used in "Amkesol" tablets, synergism and potentiation of their action occurs. In terms of mucolytic activity, "Amkesol" tablets exceed the activity of the comparative drug - "Brosal" tablets.

The study of the antitussive effect of "Amkesol" tablets was conducted on the model of experimental cough, which was caused by irritation of the respiratory tract of sexually mature ants with ammonia vapors in the chamber. The number of coughing fits was counted within 30 minutes after exposure to ammonia. "Brosal" tablets were used as comparison drugs; substances ambroxol, licorice root extract and theobromine. Means were administered in a prophylactic mode for 4 days intragastrically, once a day. The last administration of drugs was carried out during one hour of simulated experimental cough. The antitussive activity of the drug was calculated according to the formula:

AKd-AKk

A---- - - - - I -x10095,

AKk where:

AKd - the number of cough impulses in the experiment;

AKk - the number of cough impulses in the control.

The results of the experiment are shown in Table 2.

Table 2

Study of the antitussive effect of "Amkesol" tablets (p-:b) d)

Tzhvmne | vl | ivvyul | tyuysye vobiz" | yaw pathology "Amkesol", 90 mg/kg 4790 9390 4690 7390 7590 ? 1.83mg/kg 1796 9196 399 7796 5bvo and 1.68mg/kg ZU 4990 279o 559 3195 what | nev |nyuse| nu | via | chav: pathology. 13.85:-1.29 12.1432.27 2.11341.21 5.0051.65 3.1420.78 what a clinic we are not familiar with! : pathology 5.5Mg/kg 5896 369 5496 7396 7395 and 84mg/kg 4890 196 8090 8195 2090 "Brosal", Z5mMg/kg 4695 4295 3795 7395 5395 and plo, | ezhe teyueg|zyunyu | Jewist | ze; pathology

Notes: " - differences are significant with respect to the control pathology, P" 0.05; n - number of animals in the group;

And, to - antitussive activity.

A pronounced antitussive effect of "Amkesol" tablets was established at the level of the comparative drug "Brosal" tablets. Unexpectedly, it turned out that ambroxol (in a much smaller dose than in monopreparations), licorice extract and theobromine, which are included in one pharmaceutical composition, act synergistically, causing an additional increase in antitussive activity.

To evaluate the antiallergic activity of Amkesol tablets, a model of anaphylactic shock was used, the development of which is accompanied by spasms of the smooth muscles of the bronchi of medium and small caliber, asphyxiant convulsions, cyanotic ear and tip of the nose in experimental animals. It was established that "Amkesol" tablets, when used in a prophylactic mode for 21 days, prevented the development of an anaphylactic reaction in houseflies in response to the introduction of an allergen. The anti-shock activity of the drug was at the level of the comparison drug - "Brosal" tablets and amounted to 3895. "Amkesol" tablets also suppress the degranulation of mast cells in sensitized ants, preventing the release of mediators of an allergic reaction of the immediate type and, therefore, exhibit an anti-allergic effect in this model. "Brosal" tablets are inferior to "Amkesol" in terms of the effect of stabilizing mast cells (table 3).

Table C

The influence of "Amkesol" tablets on the development of anaphylactic shock in mice (p-6b)

Severity of anaphylactic shock and before degranulation of obese

Animal groups anti-shock activity, about degranulation! that about cells

Intact control nn 4.0020.93

Anaphylactic shock (AS) 2.8750.37 mon 18.43h2.117

AS "5 tablets "Amkesol"' 1.6720.337 38 4.8620.63 9Omg/kg

AS "5 tablets "Brosal" p' 1,6720,337 38 13,1452,297

Z5Mm/kg

Notes: " - differences are significant in relation to the intact control, P"e0.05; "x - differences are significant in relation to ASH, P"e0.05; yh - differences are significant in relation to "Brosal" tablets, P"0.05; n - number of animals in a group

The results of clinical studies fully confirmed and supplemented the experimental data of preclinical studies. "Amkesol" tablets are a well-tolerated and effective drug for the treatment of acute and chronic diseases of the respiratory tract accompanied by the secretion of viscous sputum: acute and chronic bronchitis, bronchiectasis, tracheitis, laryngitis, pharyngitis, sinusitis, rhinitis, pneumonia, bronchial asthma; the effect of prevention and treatment of pulmonary complications after operations; in the period of preparation for bronchoscopy and after the examination; with cystic fibrosis of the lungs.

Thus, the studies confirmed that the claimed drug has a wide spectrum and a high level of specific pharmacological activity, does not cause side effects, as a result of which a complex effect on the bronchopulmonary system is achieved, which fully confirms the fulfillment of the task set in the useful model - the creation of a highly effective drug for treatment and prevention of respiratory diseases.