RU2540496C1 - Composition for nasal application, based therapeutic agent and method for using same - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: composition for nasal application, containing active and additive ingredients, wherein the active ingredients are presented by sea salt and α-glutamyl-tryptophan in the following ratio of the active ingredients (wt %): sea salt 95.00-98.00; alpha-glutamyl-tryptophan 2.00-5.00. The group of inventions also refers to a therapeutic agent, a method, using and a medical device for preventing or treating upper airway diseases.

EFFECT: group of inventions promotes slime evacuation, reduces infected nasal discharge and relieves swollen mucosa, softens and removes crusts and enhances body defences, as well as normalises the barrier function of nasal mucosa epithelium, improves nasal breathing and causes moistening and anti-inflammatory action.

18 cl, 3 tbl, 1 ex

Description

The group of inventions relates to the creation of a nasal drug and its use in the prevention of diseases of the upper respiratory tract, as part of complex therapy for the initial signs of influenza and the common cold, as an adjuvant for recurrent infections of the tract, in the treatment of allergic diseases.

The deterioration of the environmental situation in the world, an increase in the prevalence of diseases of the upper respiratory tract, including allergic pathology, and epidemics of viral diseases that affect the respiratory system, necessitates the development of measures for the prevention and treatment of these diseases both in the initial stages and in the already far advanced process.

The main reason for their occurrence is a violation in the functioning of the functions of nasal breathing.

These functions include: purification of inhaled air from inorganic (dust) and organic (bacteria, viruses, fungi, protozoa) impurities, its moistening and warming, disinfection, filtering, as well as the nasal cavity performs olfactory, resonant and facial functions. The implementation of the cleansing function occurs due to the presence in the nasal cavity of the corresponding architectonics, which creates a turbulent movement of air on inspiration, hair in anticipation of the nasal cavity and the operation of disinfection mechanisms. An extremely important function of air disinfection is carried out due to the development of mucous membranes of the nasal cavity of factors of non-specific and specific immunological protection and the work of mucociliary clearance. A prolonged exposure to pathological components of atmospheric air also leads to organic disorders.

One of the preventive and therapeutic measures is to cleanse the nasal cavity by rinsing it with various medicines. The prophylactic and therapeutic effect of such agents directly depends on the ability of the agent to remove aggressive organic and inorganic factors of the inhaled air from the nasal cavity and normalize the nonspecific and specific immunological protection and mucociliary clearance.

Therefore, the development of such new effective means and methods of treatment and prevention based on them is an urgent problem of modern pharmacology and clinical medicine, as it will increase the level of social activity and the quality of life of patients and reduce the costs associated with the loss of labor time.

Known nasal drug containing the active and auxiliary substances is made in the form of an isotonic sterile solution having an osmolality of 220 to 350 mmol / kg of water and a pH of 6.0 to 9.5, containing natural minerals and trace elements, in which, as active substances used natural sea salt, as an auxiliary substance - water for injection, in the following ratio wt./vol.%:

sea salt 0.3-3.0

water for injection - the rest,

in addition, the isotonic sterile solution contains ions:

sodium 0.01-1.0;

magnesium 0.001-0.72;

calcium 0.00002-0.00027;

potassium 0.0036-0.0036;

bicarbonates of 0.002-0.003.

(RF patent 2369397 published 10.10.2009)

The patent also describes a method of using the medicinal product, including its administration for therapeutic purposes to children under 1 year of age - 2 times a day, 2 drops in each nasal passage; children from 1 year to 7 years - 3 times a day, 2 drops in each nasal passage; children from 7 to 16 years old - 4 times a day, 2 drops in each nasal passage; adults - 4-6 times a day, 2 drops in each nasal passage. The course of treatment is 2-4 weeks. It is recommended to repeat the course of treatment after a month.

However, this drug, despite the fact that it effectively removes aggressive organic and inorganic factors of the inhaled atmospheric air from the nasal cavity, is not able to normalize the nonspecific and specific immunological protection in the nasal cavity, since it does not contain immunologically active components.

Currently, there are data from placebo-controlled studies that have proven the effectiveness of intranasal use of immunomodulating drugs for the prevention of upper respiratory tract diseases.

A promising direction of such prevention is the use of funds to activate nonspecific resistance of the body. For this purpose, in Russian clinical practice, endogenous interferon inducers are widely used - Tiloron, Arbidol, Cycloferon.

From the literature a dipeptide is known - α-glutamyl-tryptophan in the form of the sodium salt (RF patent 2107691 from 1998). The peptide is used as an immunomodulating agent that affects the reactions of cellular, humoral immunity and nonspecific resistance of the body. It stimulates the regeneration processes in the event of inhibition, improves the course of cellular metabolism. It enhances the processes of differentiation of lymphoid cells, has the ability to stimulate colony forming activity of bone marrow cells, induces the expression of differentiation receptors on lymphocytes, normalizes the number of T-helpers, T-suppressors and their ratio in patients with various immunodeficiency states.

However, our analysis of the prior art showed that this dipeptide was never used as part of a nose wash and was not a part of products containing sea salt.

Thus, the objective of this work was to develop a nasal drug that can remove aggressive organic and inorganic factors of the inhaled air from the nasal cavity and normalize the nonspecific and specific immunological protection and mucociliary clearance.

Given the fact that the peptides are rather unstable in an environment that is sea water, it was also necessary to choose a ratio of the components of the agent that would preserve the stability of the dipeptide in the agent.

The task is achieved by the group of the invention, aimed at solving one problem and achieving one result.

The technical result of the claimed group of inventions is the creation of a composition, drug and medical device based on it, the use of which is able to remove aggressive organic and inorganic factors of the inhaled atmospheric air from the nasal cavity and normalize non-specific and specific immunological protection and mucociliary clearance with the achievement of a synergistic effect from joint use of active ingredients.

In addition, an additional technical result is to obtain a stable composition containing in its composition sea salt and dipeptide.

A composition for nasal use is proposed containing active and auxiliary substances, in which sea salt and α-glutamyl tryptophan are used as active substances in the following ratio of active substances (wt.%):

- sea salt 95.00-98.00;

- alpha-glutamyl-tryptophan 2.00-5.00.

As auxiliary substances, water is used, optionally in combination with preservatives (nipagin, etc.).

The composition may be in the form of drops, or a spray, or an aerosol.

Also proposed is a drug based on the above composition for the prevention and / or treatment of diseases of the upper respiratory tract, in particular acute respiratory viral infections (ARVI) (for example, influenza), and a method for its use.

In addition, a medical device based on the above composition for the prevention and / or treatment of diseases of the upper respiratory tract, in particular acute respiratory viral infections (ARVI) (for example, influenza)

The present group of inventions is illustrated by a detailed description, examples of manufacture and application.

The composition and the agent based on it are prepared as follows.

To prepare a nasal drug in 50 l of water for injection, 1.08 kg of sea salt is dissolved with stirring, using natural sea salt. Then add 25 grams of dipeptide. Then the resulting volume of the solution was adjusted with water for injection to 100 l. After that, the resulting solution is subjected to sterilizing filtration, followed by bottling in containers prepared for therapeutic use.

The ion content per 100 ml of solution:

sodium - not less than 2.5 mg / ml;

magnesium - not less than 0.35 mg / ml;

calcium - not less than 0.008 mg / ml;

potassium - not less than 0.10 mg / ml;

bicarbonates - not less than 0.03 mg / ml.

Also, during the preparation of the drug, you can additionally add a preservative, for this, 1.049 kg of sea salt is dissolved in 50 liters of water for injection, with the use of natural sea salt. Then add 55.25 grams of dipeptide and 40 grams of nipagin. Then the resulting volume of the solution was adjusted with water for injection to 100 l. After that, the resulting solution is subjected to sterilizing filtration, followed by bottling in containers prepared for therapeutic use.

The ion content per 100 ml of solution:

sodium - not less than 2.5 mg / ml;

magnesium - not less than 0.35 mg / ml;

calcium - not less than 0.008 mg / ml;

potassium - not less than 0.10 mg / ml;

bicarbonates - not less than 0.03 mg / ml.

A medical device can be, for example, a spray, which includes a polymer or glass bottle, a spray nozzle, a nozzle cover, a sterile solution of the claimed composition.

The spray can be produced in bottles with a nominal volume of 5, 10, 20, 50, 100 ml.

The pressing force required to trigger the spray should be from 6 to 9 N.

The spray should provide a dispersed composition of the solution aerosol in the range from 5 to 180 microns at a distance of 10 mm from the exit section of the nozzle-sprayer.

The spray should provide a dose of solution output at each working press from 130 to 150 mg.

The spray must be airtight, resistant to climatic factors with a limit of the upper temperature of 25 ° C and disinfection.

A toxicological study of the resulting composition and means based on it showed that:

- in an acute experiment on white outbred mice (males) with the intraperitoneal administration of the drug at a dose of 50 ml / kg of body weight, no death of animals was observed;

- no clinical signs of intoxication were detected in the animals: general condition, behavioral reactions, condition of the coat, eating food in the experimental group did not differ from the control;

- at the autopsy of the tissue at the injection site, regional lymph nodes, internal organs in animals exposed to the drug had no signs of pathology;

- weights of internal organs (liver, kidney, spleen) in experimental mice within the physiological norm and similar control indicators;

- in in vitro experiments with isolated and washed rabbit erythrocytes, the hemolytic effect of extracts was not observed;

- in experiments on rats and rabbits, the absence of the locally irritating effect of the drug on the skin and mucous membranes was shown;

- sterility test of the sample - the result obtained: - the sample is sterilized throughout the expiration date;

- pyrogenicity test of the sample - the result obtained: - the sample is pyrogen-free throughout the expiration date;

- the value of the toxicity index was 70.9% with an acceptable value of the criterion from 70 to 120%;

- the studied samples of the drug meet the requirements for medical devices that have contact with body tissues: in the conditions of the experiment, the materials of the products showed sufficient chemical stability, extracts from them did not adversely affect biological objects.

The group of inventions is further illustrated by the following practical examples showing the effectiveness of the developed drug for the treatment and / or prevention of diseases of the upper respiratory tract.

The following dosage regimens are recommended.

Drop shaped

For therapeutic purposes, a nasal drug is prescribed: for children under 1 year of age - 2 times a day, 2 drops in each nasal passage; children from 1 year to 7 years - 3 times a day, 2 drops in each nasal passage; children from 7 to 16 years old - 4 times a day, 2 drops in each nasal passage; adults - 4-6 times a day, 2 drops in each nasal passage. The course of treatment is 2-4 weeks. It is recommended to repeat the course of treatment after a month.

For preventive purposes

To soften and remove secretions from the nose, drops are instilled into each nasal passage in the required amount, removing the remaining fluid flowing from the nose with a handkerchief or using cotton wool.

The procedure can be repeated many times until the discharge accumulated in the nasal passage is softened and removed.

In children under 1 year of age, it is recommended to carry out a toilet of the mucous membrane of the nasal cavity to preserve its physiological characteristics in the form of instillation of drops 2-3 times a day, 1-2 drops in each nasal passage.

To soften and remove contaminating accumulations and nasal secretions, the drug is used as needed.

In the form of a spray or aerosol

A child from 1 year old to 2 years old is in a supine position, head turned to one side. A nasal drug is injected into the nostril located on top.

Have the baby sit down to clean the nose.

Then similarly repeat the procedure from the other nostril.

Adults and children over 2 years old when using the nasal drug tilt their heads to the side. With the help of others, or independently enter the nasal drug in the form of a spray or aerosol into the nostril located on top. After 2-3 minutes, it is necessary to clean the nose by blowing. Then similarly repeat the procedure from the other nostril.

Recommended single doses of the drug (the number of injections in each nostril) and the frequency of use per day are shown in table 1.

Clinical examples of the use of a nasal drug in diseases of the upper respiratory tract

The drug was prepared in accordance with the approved recipe: 100 ml of the solution contain 1.08 g of sea salt, 25 mg of alpha-glutamyl-tryptophan. The effectiveness of the present composition (K) and placebo (P) was tested on an experimental group of 15 people and a control group of 15 people for 1 year. Both the composition and placebo were administered 4 times a day. The results of the study are presented in table 2.

The total number of colds was 42 cases (i.e., an average of 1.4 diseases per year per person), with a group of volunteers taking a placebo accounting for 76.19%, which is 3.2 times the number of diseases per group of volunteers taking the composition. Here, the “cold” was determined symptomatically (fever, signs of flu, colds, rhinitis, etc.).

Additionally, we investigated cytokines in order to confirm the effect of improving immunity when using the composition. For this, we measured cytokines in the blood, which are responsible for the development of the inflammatory reaction and characterize the immunity in the patient, namely IL-2, INF-γ, IL-4, IL-10 and IL-12. The study was carried out by ELISA. Each of the samples was taken from those who took a placebo and a composition containing sea salt and alpha-glutamyl tryptophan.

Studies have shown that in patients using the agent according to the invention, levels of IL-2, INF-γ, IL-12 increase, with a slight increase in the levels of IL-4, IL-10, in contrast to the control group, which demonstrates the prevention of infection without trends towards its further generalization.

Additionally, the invention is illustrated by the following clinical example.

Example. The patient, 23 years old. He was treated for chronic vasomotor rhinitis, frequent acute respiratory viral infections and acute respiratory infections. Complaints about constant difficulties in nasal breathing, chronic runny nose. He took the composition 4-6 times a day for two weeks. After 2-3 days, an improvement was observed. After treatment, the symptoms of a runny nose disappeared, nasal discharge decreased significantly, and free nasal breathing appeared.

Thus, the proposed new tool is effective and can be widely recommended for therapeutic purposes.

Also, to confirm stability, we conducted a study of the stability of the product during storage.

The stability of the properties of the drug during storage was determined by the method of “accelerated aging”, based on an increase in the rate of chemical processes at elevated temperatures in excess of the maximum allowable when stored under normal conditions.

For this purpose, 3 series of experimental samples in a volume of 300 cm ³ were placed in a thermostat with a temperature of 50 ° C. The quality of the series was evaluated by changing the mass fraction of the ammonium clathrate compound with urea, the density and refractive index in accordance with STO 719544720-0003-2008.

The experiment was carried out for 12 months. Every 2 months, samples were taken and the mass fraction of the active substance was determined by two-phase titration using an anionic standard solution (sodium dodecyl sulfate) in an alkaline medium in the presence of a blue bromophenol indicator, density using a hydrometer, and refractive index using a refractometric method.

The results of the study are presented in table 3. Studies have shown the stability of the drug during storage.

Thus, the proposed nasal drug contains all the active ingredients and minerals of natural sea water and provides active lavage of the nasal cavity: it helps to remove mucus, reduce infected secretions and swelling of the nasal mucosa, soften and remove crusts and increase the body's defenses. The drug normalizes the protective function of the ciliary epithelium of the nasal mucosa and improves nasal breathing. It has a moisturizing and anti-inflammatory effect.

After washing with the agent, the therapeutic effectiveness of drugs applied to the nasal mucosa increases, and the duration of respiratory diseases decreases. The drug reduces the risk of infection spreading in the sinuses of the nose and ear cavity (sinusitis, frontal sinusitis, otitis media, etc.). It reduces the risk of local complications and accelerates the healing processes after surgical interventions (removal of adenoids, polyps, septoplasty, etc.) on the nasal cavity. It relieves irritation of the nasal mucosa in people whose mucous membranes of the upper respiratory tract are constantly exposed to harmful effects (smokers, car drivers, people living and working in rooms with air conditioning and / or central heating, working in hot and dusty workshops, as well as those in regions with severe climatic conditions).

Table 1 Age of patients Medicinal use Hygienic use Children from 1 year to 2 years old 1 injection into each nostril 2 times / day 1 injection into each nostril 1 time / day Children aged 2 years to 7 years 2 injections into each nostril 2 times / day 1-2 injections into each nostril 1-2 times / day Children and adolescents aged 7 to 16 years 2 injections in each nostril 4 times / day 2 injections into each nostril 2 times / day Adults and teenagers over 16 2 injections into each nostril 4-6 times / day 2 injections into each nostril 4-6 times / day

table 2 Patient Card No. age Floor The frequency of colds 0145 TO 24 Husband 0 0146 TO 26 Husband 0 0147 P 19 Wives 0 0148 P 32 Husband 3 0149 TO 33 Wives one 0150 P 21 Wives 2 0151 P 22 Wives 2 0152 TO 45 Husband one 0153 P 41 Wives four 0154 P 26 Wives 3 0155 TO 27 Husband one 0156 TO 43 Wives 2 0157 P 39 Wives 3 0158 TO 38 Wives 0 0159 P 32 Husband 3 0160 TO 25 Wives one 0161 P 22 Husband 2 0162 P 23 Wives 3 0163 P 27 Wives 2 0164 TO 49 Wives one 0165 P 51 Husband one 0166 TO 25 Wives one 0167 P 23 Wives one 0168 TO 45 Wives 0 0169 TO 42 Wives one 0170 TO twenty Wives 0 0171 P 41 Husband one 0172 P 38 Wives 2 0173 TO 37 Husband 2 0174 TO 26 wives one

Table 3 Duration of storage, month Year corresponding to the shelf life Mass fraction of active substance,% Density, g / cm ³ Refractive index ONE HUNDRED Property Stability 2 one 10 1,055 1,353 Acc. Stab. four 2 10 1,055 1,353 Acc. Stab. 6 3 10 1,055 1,353 Acc. Stab. 8 four 10 1,055 1,353 Acc. Stab. 10 5 10 1,055 1,353 Acc. Stab. 12 6 10 1,055 1,353 Acc. Stab.

Claims (18)

1. Composition for nasal use, containing active and auxiliary substances, in which sea salt and α-glutamyl tryptophan are used as active substances in the following ratio of active substances (wt.%):
- sea salt 95.00-98.00
- alpha-glutamyl-tryptophan 2.00-5.00 2. The composition according to claim 1, characterized in that water is used as auxiliary substances, optionally in combination with a preservative. 3. The composition according to claim 2, characterized in that nipagin is used as a preservative. 4. The composition according to claim 1, characterized in that it is made in the form of drops, spray or aerosol. 5. A drug for the prevention or treatment of diseases of the upper respiratory tract, including the composition according to claims 1-4. 6. The drug according to claim 5, characterized in that it is made in the form of drops, spray or aerosol. 7. The drug according to claim 5, characterized in that the diseases of the upper respiratory tract are acute respiratory viral infections (ARVI). 8. The drug according to claim 7, characterized in that SARS is influenza. 9. A method for the prevention or treatment of diseases of the upper respiratory tract, including the introduction into the nasal cavity of the drug according to claim 5 in an effective amount. 10. The use of sea salt and α-glutamyl tryptophan for the manufacture of a nasal drug. 11. The use of claim 10, wherein the drug is in the form of drops, spray or aerosol. 12. The use of claim 10 or 11, characterized in that the drug is intended for the prevention or treatment of diseases of the upper respiratory tract. 13. The use according to claim 12, characterized in that diseases of the upper respiratory tract are acute respiratory viral infections (ARVI). 14. The application of item 13, wherein the SARS is influenza. 15. A medical device for the prevention or treatment of diseases of the upper respiratory tract, including the composition according to claims 1-4. 16. The product according to clause 15, characterized in that it is made in the form of a spray or aerosol. 17. The product according to clause 15, wherein the diseases of the upper respiratory tract are acute respiratory viral infections (ARVI). 18. The product according to 17, characterized in that SARS is influenza.