WO2013129970A2 - Pharmaceutical composition having vasoconstricting, anticongestant and anti-inflammatory activity (embodiments) - Google Patents

Description

 Pharmaceutical composition with vasoconstrictor, anti-congestive, anti-inflammatory effect

 (options)

The technical field to which the invention relates.

 The invention relates to the field of pharmaceutical industry and medicine, can be used to create and use

pharmaceutical compositions with vasoconstrictive, anti-congestive, anti-inflammatory effects in acute rhinitis, inflammatory processes of the maxillary sinus cavities, nosebleeds, conjunctivitis.

The level of technology.

 An important problem of modern medicine is the creation of new effective medicines that can effectively treat various diseases of the nose and eyes, in particular, acute rhinitis, inflammatory processes of the maxillary sinus cavities, allergic conjunctivitis, effectively

stop nosebleeds. For the treatment of these diseases, a drug is used - naphazoline and naphthyzine and sanorin prepared on its basis. The effect of naphazoline is that it excites

adrenoreactive systems, causes constriction of peripheral blood vessels (nafazolin, instructions for use published on the Internet at: http://it-apharm.ru/nafazolin.html).

 Naphthyzine is a 0.05-0, 1% solution of naphazoline, and sanorin is an emulsion containing 10 mg of naphazoline nitrate, 300 mg of boric acid, 0.25 mg of eucalyptus oil and 1,150 mg of liquid paraffin in 10 ml of the drug.

 The advantages of sanorin over naphthyzine are that sanorin is an emulsion that has a milder effect, longer

lingers in the nasopharynx, is washed away from the nasal passages at a slower rate and has a longer effect (RF Patent 2238081, publ. 20.10.2004). In essence, the development of sanorin is an improvement in naphthyzine.

An analogue of the three variants of the invention claimed in the description may be a means for the treatment of sinusitis containing 0.05% naphthyzine solution (RF Patent 2251417, publ. 20.10.2004). In the analogue, it was found that, along with positive qualities, naphthyzine, as a medicine for the treatment of sinusitis, has a delayed anti-inflammatory and antimicrobial effect, which increases the duration of treatment.

 In addition, a disadvantage of the analogue is the low speed of the onset of the therapeutic effect.

 The prototype of the three variants of the invention can be a pharmaceutical composition containing naphazoline (Instructions for the medical use of the drug naphthyzine, published on the Internet at:

http://www.polismed.ru/drug-naftizin-post001.html).

 The prototype refers to alpha 2-adrenergic agonists, has

vasoconstrictor against vascular mucous membranes

(reduces swelling, hyperemia, exudation). It is used for acute rhinitis, sinusitis, eustachitis, laryngitis, to facilitate rhinoscopy, to stop nosebleeds, as an additional tool in the treatment of bacterial conjunctivitis. May also

apply intravenously drip.

 The disadvantages of the prototype are the relatively large time of the onset of the therapeutic effect, low stability during the shelf life and the possibility of increasing the therapeutic effect, only by increasing the concentration

active substance or frequency of use of the drug. And this leads to a quick getting used to the tool and a decrease in the therapeutic effect during the use of the product.

The authors of the invention considered three areas for improving the pharmaceutical composition based on naphazoline: - increase the speed of the onset of the therapeutic effect (decrease the time of the onset of the therapeutic effect);

 - increase the therapeutic effect without increasing the concentration of naphazoline.

- increasing the stability of the pharmaceutical composition with naphazoline during the expiration date.

SUMMARY OF THE INVENTION

 Let us define the terms.

 The inflammatory process of the maxillary sinus cavities is sinusitis, a type of sinusitis characterized by inflammation of the maxillary sinus. Sinusitis is an acute or chronic inflammation

maxillary sinus. The inflammatory process affects one or both maxillary sinuses.

 Sinusitis - inflammation of one or more of the sinuses, occurs as a complication in acute cold, flu, measles, scarlet fever and other infectious diseases.

 Rhinitis is a syndrome of inflammation of the nasal mucosa. Infectious rhinitis is caused by various microbes and viruses; the development of rhinitis contributes to hypothermia, severe dust and gas contamination. Rhinitis is a common symptom of other diseases (for example, flu, diphtheria, measles, etc.).

 Rhinitis is usually caused by viruses and bacteria, but the onset of a runny nose is a sudden severe irritation of the nasal mucosa — for example, dust or chemicals, as well as hypothermia — in the general or in parts of the body, most often of the legs.

 Acute rhinitis is a runny nose due to acute inflammation of the lining of the nasal cavity, accompanied by a disorder of its functions — breathing, smell, tear conduction, etc.

 Conjunctivitis - inflammation of the mucous membrane of the eye (conjunctiva) caused by an allergic reaction or infection (viral, less commonly

bacterial). Shelf life - the period during which the pharmaceutical composition retains its properties in a measure that ensures its use according to

destination.

 Anticongestant (decongestant) agent or anticongestant - decongestant, a means to relieve swelling of the mucosa. Most often, these funds are aimed at stopping a runny nose and nasal congestion.

 Congestion is a rush of blood to a specific part of the body.

 The following are currently well known and applied.

anti-congestive (decongestant) drugs: indanazoline, xylometazoline, naphazoline, oxymetazoline, tetrisoline.

 Anti-inflammatory drugs - drugs that suppress the development of the inflammatory process.

The present invention is the creation of an effective

pharmaceutical composition based on naphazoline, which has a vasoconstrictive, anti-congestive, anti-inflammatory effect.

 The application describes three embodiments of the invention.

 The problem is solved due to the fact that the pharmaceutical composition contains naphazoline and differs from the prototype in that it additionally contains

mineral substances in the following ratio of components in mg / l:

naphazoline - 0. G 10 ³ - 10 10 ³ ;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8,

and the pharmaceutical composition has a vasoconstrictor,

anti-congestive, anti-inflammatory effect.

Also, the problem is solved due to the fact that the pharmaceutical composition contains naphazoline and differs from the prototype in that it is designed in such a way that it contains ¹³ C carbon isotopes, and the ratio:

nC = N ¹³ C / NC,

where pS is the ratio of the amount of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition; N C is the amount of carbon C isotopes in the pharmaceutical

 composition;

 NC - the total number of carbon isotopes in the pharmaceutical composition,

ranges from 0.005 to 0.75,

and the pharmaceutical composition has a vasoconstrictor,

anti-congestive, anti-inflammatory effect.

In other words, the problem is solved due to the fact that the pharmaceutical composition contains naphazoline and differs from the prototype in that it is made in such a way that the ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition is from 0.005 to 0.75.

 Also, the problem is solved due to the fact that the pharmaceutical composition contains naphazoline and differs from the prototype in that it additionally contains

mineral substances in the following ratio of components in mg / l:

naphazoline - 0.1 ^{'10 3} - 10 October ^3,

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8;

 and the pharmaceutical composition contains carbon isotopes C, and the ratio:

nC = N ^, C / NC,

 where pS is the ratio of the number of carbon isotopes C to the total

 the amount of carbon in the pharmaceutical composition;

N ¹³ C is the number of carbon isotopes of ¹³ C in the pharmaceutical composition;

 NC - the total number of carbon isotopes in the pharmaceutical composition,

ranges from 0.005 to 0.75,

and the pharmaceutical composition has a vasoconstrictor,

anti-congestive, anti-inflammatory effect.

Additionally, each of the above pharmaceutical compositions can be made in such a way that the pH is between 4 and 7. In addition, the pharmaceutical composition is performed in such a way that the kinematic viscosity is from 1.016 mm / s to 1.26 mm / s.

 The control of the kinematic viscosity of the composition is carried out using a capillary viscometer.

 The main active ingredient in the pharmaceutical composition is naphazoline: 4,5-dihydro-2- (1-naphthalenylmethyl) -1H-imidazole, made in the form of a hydrochloride or nitrate (naphazoline hydrochloride or naphazorin nitrate).

 The structural formula of the main active substance

 Currently, naphazoline is used in drugs such as naphthyzine, sanorin in the form of a liquid substance or nasal spray.

 In these drugs, the content (concentration) of naphazoline is 0.5 g / l and 1g / l.

 In the application, the authors consider pharmaceutical formulations with naphazoline, the content of which is from 0.1 to 10 g / l in a pharmaceutically acceptable solvent, in particular water. Another solvent may be used.

Technical results for the three variants of the invention are:

 - an increase in the onset of the onset of the therapeutic effect (a decrease in the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of naphazoline in the pharmaceutical composition for acute rhinitis, inflammatory processes of the maxillary sinuses (sinuses) of the nose, nosebleeds, conjunctivitis.

 - increase the therapeutic effect without increasing concentration

pharmaceutical composition and naphazoline in the pharmaceutical composition for acute rhinitis, inflammatory processes of the maxillary sinus cavities, nasal

bleeding, conjunctivitis; - increasing the stability of the pharmaceutical composition with naphazoline during the expiration date.

 An increase in the speed of the onset of the therapeutic effect in acute rhinitis, inflammatory processes of the maxillary sinus cavities, nosebleeds, conjunctivitis can be achieved:

 - dosage of the product, frequency of use and time of exposure;

- the use of liquid-air emulsions, sprays;

 - the use of therapeutic accelerators.

 Medicine knows examples of increasing the onset of the therapeutic effect of a drug.

 So, a solution is known (RF application N 94015245, published December 27, 1995) in which a 5-10% solution of hyaluronic acid is used as a regulator of the rate of exposure.

 A pacemaker drug is also known (RF patent N 2068697, published 10.1 1.1996), in which up to 95% ethyl alcohol is introduced to increase the rate of onset of the pacemaker effect (while maintaining the duration of action). Alcohol due to osmotic phenomena causes pain and local negative reaction, which accelerates the effect of the drug.

 Biologically active additives are also known, which, when introduced together with the active principle, increase the pharmacological activity of therapeutic drugs by optimizing the rate of assimilation of the active principle. So in an antitumor agent (USSR author's certificate N 1683190, published 04/20/1995) is additionally introduced

polyvinylpyrrolidone and sorbic acid. These components increase the antitumor activity of the active principle.

The invention achieves an increase in the rate of onset of the therapeutic effect (as well as other technical results) while maintaining

duration of action and without increasing the concentration of the drug naphazoline in the pharmaceutical composition due to the introduction into the pharmaceutical composition mineral substances, as well as due to the substitution in the pharmaceutical composition of carbon isotopes C for carbon isotopes C.

In studies naphazoline achieved increasing the number of molecules containing at least one carbon isotope ¹³ C.

 The therapeutic effect of naphazoline is to excite the adrenoreactive systems of the human or animal body, which causes a narrowing of peripheral blood vessels.

The introduction of mineral substances into the pharmaceutical composition with naphazoline and the substitution of carbon C isotopes in the pharmaceutical composition with ¹³ C carbon isotopes leads to a more effective, stronger excitation of the adrenoreactive systems of the body. Due to which technical results are achieved.

 A detailed description of the effect of the claimed pharmaceutical formulations will be given below.

 We give general known information about minerals.

 Minerals are subdivided into macro- and microelements.

 Macronutrients include calcium, phosphorus, magnesium, potassium, sodium, chlorine and sulfur.

 Trace elements: iron, copper, manganese, zinc, cobalt, iodine, fluorine, chromium, molybdenum, vanadium, nickel, strontium, silicon, selenium are recognized as essential for human and animal life.

 Macronutrients regulate water-salt metabolism, maintain the osmotic pressure in cells and intercellular fluids, which is necessary for the movement of nutrients and drugs between them. Blood formation processes occur with the participation of iron, copper, manganese, calcium and other mineral substances (elements). Minerals (trace elements) activate the action of enzymes, hormones, participate in all types of metabolism.

 Mineral substances (Fe, Cu, Zn and others) in solution are in the composition of pharmaceutically acceptable salts, for example, succinates, chlorides, nitrates, carbonates or sulfates, as well as in various pharmaceutically

acceptable complex compounds. Minerals, metal salts have an antimicrobial effect, inactivating the enzymes necessary for the life of microorganisms. Enzyme inactivation occurs through the interaction of metal ions with sulfhydryl groups of enzymes.

 Metals have a pronounced local effect on the mucous membranes. At the concentrations of mineral substances considered in the application, the local action of these substances may be astringent or irritating.

 The mechanism of local action of metals is due to their ability to react with tissue proteins. As a result of this interaction, proteins coagulate and form albuminates with metal ions. Moreover, if partial coagulation of proteins occurs only in the most superficial layers of tissues, an astringent or irritating effect is observed, which has a reversible character.

 Studies have shown that the minerals included in the pharmaceutical composition enhance its therapeutic effect without increasing the concentration of the pharmaceutical composition and naphazoline in the pharmaceutical composition for acute rhinitis, inflammatory processes of the maxillary sinus cavities, nosebleeds, conjunctivitis. This is achieved by acting on the enzymatic system of the body.

 When developing the invention it was found that the increase in speed

the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of naphazoline in the pharmaceutical composition, increasing the stability of the pharmaceutical composition with naphazoline during the expiration date

provided by the introduction into the pharmaceutical composition of certain minerals (a certain combination of minerals) in a strictly defined quantity for each mineral. As a result of the studies, a weight range in the pharmaceutical composition was established for each mineral.

The use of less than indicated in the range, the amount of mineral substance does not lead to the achievement of technical results. The use of a larger amount of a mineral substance than indicated in the range not only does not lead to the achievement of technical results, but worsens the therapeutic effect of the action of naphazoline. It was found that with increasing concentration mineral substances in the pharmaceutical composition (above the stated ranges) they suppress the effect of naphazoline, the therapeutic effect of the drug disappears. A strong irritating effect from the action of large concentrations of mineral substances appears.

 An additional increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of the pharmaceutical composition and naphazoline in the pharmaceutical composition, an increase in the stability of the pharmaceutical composition with naphazoline during the shelf life

is ensured by partial replacement in the pharmaceutical composition of carbon isotopes ¹² C with carbon isotopes ¹³ C.

The list of figures drawings.

 Figure 1 presents the chromatogram of the claimed pharmaceutical composition on a column with sorbent C 18. Detection at 220nm.

 Figure 2 presents the chromatogram of the pharmaceutical composition on a column with a sorbent With 18 using a mass selective detector.

 Fig. 3 shows a chromatogram of the pharmaceutical composition on a C 18 sorbent column using a mass selective detector.

 Figure 4 presents the HPLC of the pharmaceutical composition on a column with a chiral sorbent. Detection at 220nm.

 Figure 5 presents the HPLC of the pharmaceutical composition on a chiral column using a mass selective detector.

 Figure 6 presents MS MS molecular ion 237.

 7 presents MS MS molecular ion 21 1.

 On Fig and 9 shows respectively the right and left part of the 1H-NMR spectrum of the pharmaceutical composition.

 Figure 10 shows the 13C-NMR spectrum of the pharmaceutical composition.

 Figure 1 1, 12 and 13 shows two-dimensional NMR spectra of the pharmaceutical composition.

 On Fig presents a diagram of a cavitation reactor for isotopic enrichment of various mixtures.

 On Fig presents a cross section of a cavitation reactor.

Yu On Fig presents a diagram of the installation for isotope enrichment. On Fig presents graphs of the survival of mice for days.

Information confirming the possibility of carrying out the invention.

The invention is illustrated by the following examples.

 Example 1 - a method of introducing minerals into water for injection.

Example 2 - a method of obtaining pharmaceutical compositions.

 Example 3 - tests for general toxicity.

 Examples 4-9 illustrate the effectiveness of the claimed pharmaceutical compositions in comparison with the prototype.

 Example 1. The introduction of minerals into the solution (into water for injection) was carried out according to the methodology / Guidelines on methods for monitoring the quality and safety of biologically active food additives. - M .: Federal Center for State Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004, - 240 s /.

 There are other ways to introduce minerals into the solution. Solutions were prepared from pure metals using pharmaceutically acceptable solvents to ensure storage stability of the solutions.

 At the initial stage of research, the concentration of minerals in pharmaceutical formulations was provided in the following ranges, mg / l: potassium - from 0.01 to 55.0;

 calcium - from 0.01 to 210.0;

 magnesium - from 0.03 to 260.0;

 iron - from 0.005 to 45.0;

 Manganese - from 0.003 to 28.0;

 zinc - from 0.01 to 1 15.0;

 copper - from 0.0001 to 3.0;

 cobalt - from 0.0001 to 12.0;

 chrome - from 0.001 to 12.0;

 molybdenum - from 0.001 to 12.0;

sodium - from 1.0 to 185.0. When developing the application, a set of studies

pharmaceutical compositions, in particular, magnetic resonance studies, chromatographic studies on columns with various sorbents, etc.

 The application presents the results of a study of only one

pharmaceutical composition based on naphazoline and all of the above minerals. The concentration of mineral substances in the composition were as follows, mg / l:

 potassium - 0.3;

 calcium - 5.5;

 magnesium - 2.5;

 iron - 0.03;

 Manganese - 0.009;

 zinc - 0.25;

 copper - 0.009;

 cobalt - 0.009;

 chrome - 0.009;

 molybdenum - 0.009;

 sodium - 13.1.

 The results of studies of the remaining pharmaceutical formulations are similar.

Figure 1 shows the chromatogram of the pharmaceutical composition on a column with sorbent C 18. The absorption of the eluate was measured at a wavelength of 220 nm.

 Figure 2 shows the HPLC of a pharmaceutical formulation with a mass selective detector.

 Peak with a retention time of 3.449 min. corresponds to a molecular ion with the value of the indicator "m / ζ" equal to 237 (t is the mass of the molecule, z is the charge of the molecule).

 FIG. 3 also shows a chromatogram of a pharmaceutical composition with a mass selective detector.

 Peak with a retention time of 6.648 min. corresponds to a molecular ion with the value of the indicator "m / ζ" equal to 21 1.

Figure 4 presents the chromatogram of the pharmaceutical composition on a column with a chiral sorbent. The absorption of the eluate was measured at a wavelength of 220 nm. Figure 5 presents the chromatogram of the pharmaceutical composition on a chiral column with a mass selective detector. Peak with a retention time of 17.07 min. corresponds to a molecular ion with a m / ζ value of 211.

 Figure 6 presents MS MS molecular ion 237. Shown

fragmentation of an ion with a value of "m / ζ" equal to 237.

 Figure 7 presents MS MS molecular ion 21 1. Shown

fragmentation of an ion with a value of "m / ζ" equal to 21 1.

 On Fig and 9 shows the 1H-NMR spectrum of the pharmaceutical composition.

 Ή NMR (600 MHz, DMSO-d6): 7.989 (d, 1 = 8.4 Hz, 1H, 1-H); 7.965 (d, I = 8.4 Hz, 1H, 2-H); 7.95-7.92 (m, W, 3-H); 7.64-7.60 (m, 1H, 4-H); 7.60-7.56 (m, 1H, 5-H); 7.540-7.500 (m, 2H; 6-H, 7-H); 4.335 (s, 2H, 8-H); 3.821 (s, 4H, 9-H).

 Figure 10 shows the 13C-NMR spectrum of the pharmaceutical composition.

¹³ C NMR (600 MHz, DMSO-d6): 169.75 (1-C); 133.64 (2-C); 131.40 (3-C); 129.03 (4-C); 128.86 (5-C); 128.68 (6-C); 128.26 (7-C); 127.18 (8-C); 126.47 (9-C); 125.93 (10-C); 123.23 (1 1-C); 44.57 (12-C); 29.71 (13-C).

 Figure 1 1, 12 and 13 shows two-dimensional NMR spectra of the pharmaceutical composition.

As a result of studies with a wide range of minerals, the authors focused on three: calcium, magnesium and zinc.

 Further, the application presents the results of in-depth studies

pharmaceutical formulations with only these minerals.

 The concentration of metals in solutions was controlled by the atomic absorption method for determining the contents of sodium, potassium, calcium, magnesium, iron, manganese, copper, zinc, lead, cadmium, cobalt, nickel, and chromium. Clause 1.3.2.1 of the source / Guide to quality and safety control methods

dietary supplements. - M.: Federal Center

State Sanitary and Epidemiological Supervision Ministry of Health of Russia, 2004, - 240s /.

Example 2. Obtaining a pharmaceutical composition with calcium, magnesium and zinc. In a reactor with a stirrer, pour 8 l of distilled water. After that, a naphazoline solution (in a 100% naphazoline solution) - South is poured into the reactor, and solutions with mineral substances of the desired concentration are poured with constant stirring. Then adjust the pH of the solution to 4.5.

The resulting solution was adjusted to a volume of 10 l of distilled water (water for injection) and passed through a filter. Thus, the content of naphazoline in solution is 1 g / L.

 The kinematic viscosity of the pharmaceutical composition of 1.016 mm / s (from a range of 1.016 to 1.26 mm / s) is ensured by the concentration of naphazoline and minerals. Determined using a capillary viscometer.

Studies of the stability of pharmaceutical formulations over the shelf life have shown that thus obtained

Pharmaceutical formulations are stable and retain their initial values for 3 to 3.5 years. And after opening the package (bottle) in the air

pharmaceutical formulations, without changing properties, are stored up to 45-50 days.

 UV spectrophotometry and other of the above studies were carried out every six months for 3.5 years. An increase in the stability of the claimed pharmaceutical formulations over 3.5 years has been established compared with naphthyzine and sanorin.

Example 3. Tests for general toxicity was carried out by

intraperitoneal administration of pharmaceutical formulations based on naphazoline and minerals in rats.

 For studies of the concentration of mineral substances in solutions selected, mg / l:

 potassium - 55.0;

 calcium - 210.0;

 magnesium - 260.0;

 iron - 45.0;

 manganese -28.0;

zinc - 1 15.0; copper - 3.0;

 cobalt - 12.0;

 chrome - 12.0;

 molybdenum 12.0;

 sodium - 185.0.

LD ₅ about is a value of from 950 to 1000 mg / kg when administered intraperitoneally.

With intramuscular injection, LD ₅₀ is up to 3000 mg / kg, which allows the claimed compounds to be classified as non-toxic substances.

 With prolonged use of the developed pharmaceutical formulations based on naphazoline and minerals in rats, no changes were found in the organs and tissues of the body.

 Tables 1-12 show the studied pharmaceutical formulations.

The numbering of pharmaceutical formulations in the tables is through.

 The pharmaceutical compositions described in the application have

vasoconstrictive, anti-congestive (decongestant),

anti-inflammatory effect.

 Anti-congestive (decongestant) property described in the application

pharmaceutical formulations, provided by their good vasoconstrictor effect. Anti-inflammatory effect described in the application

pharmaceutical formulations are also provided with their good

vasoconstrictor effect.

 Example 4. Evaluation of the vasoconstrictor effect of pharmaceutical formulations based on naphazoline and minerals was carried out by comparison with the vasoconstrictor effect of the drug naphthyzine.

 Comparative studies were performed on white non-linear mice (males) weighing 26 - 28 g to enhance acute hypoxia according to methodological

recommendations / Guidelines for the experimental study of drugs proposed for clinical study as

antihypoxic drugs. Edited by L.D. Lukyanova. - M., 1990. / and the manual / Manual on the experimental (preclinical) study of new pharmacological substances. Edited by R.U. Khabriev. - M.: Ministry of Health of the Russian Federation, 2005./. Acute hypoxia (normobaric hypoxic hypoxia)

modeled by placing mice in a 250 cm heat chamber.

 In the experiments, the lifespan of animals was recorded after the cessation of air access to the heat chamber. Animals were housed in

heat chamber one by one.

 Naphthyzine was administered once intraperitoneally 30, 60 and 90 minutes before placing the mice in the heat chamber and stopping air from entering the heat chamber.

 The time from the moment of drug administration to the placement of mice in a heat chamber and the termination of air access in the tables is indicated by Tv in minutes.

 Each of the pharmaceutical formulations based on naphazoline and minerals was administered once intraperitoneally also 30, 60, and 90 minutes before placing the mice in the heat chamber and stopping air from entering the heat chamber.

 After placing the mice in a heat chamber, as oxygen was consumed, its concentration in the air and in the body of the mice decreased, and the amount of carbon dioxide increased. As a result, animals developed acute hypoxic hypoxia. The studied pharmaceutical compositions and naphthyzin have a vasoconstrictor effect. Vasoconstriction reduces

the flow of blood (already depleted of oxygen) into the brain, which enhances hypoxia, shortens the life span of mice.

 Life expectancy (until respiratory arrest) was recorded using a stopwatch. To reduce life expectancy, the effectiveness of the tested formulations was judged.

 The increase in hypoxia from the use of naphthyzin is shown in table 13.

The increase in hypoxia from the use of pharmaceutical formulations based on naphazoline and minerals is shown in Tables 14-16. Tables 15 and 16 show data on the effect of ¹³ C isotopes on enhanced hypoxia.

On the model of acute normobaric hypoxic hypoxia (in a heat chamber), it was found that most pharmaceutical formulations based on naphazoline and minerals reduced the life expectancy of mice by an average of 5-15% (and in some experiments, even higher) compared to naphthyzine. This effect was achieved by increasing the vasoconstrictor effect of the developed pharmaceutical compositions. Thus, an increase in the vasoconstrictor effect was established without increasing the concentration of the pharmaceutical composition and naphazoline in

pharmaceutical composition. From tables 14-16 it is seen that mineral substances and isotopes ¹³ With increase the rate of onset of vasoconstrictor action.

 At the same time, the concentration of naphazoline in the pharmaceutical composition did not increase.

 The analysis of tables 13 - 16 shows that the pharmaceutical compositions mm 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, as well as pharmaceutical compositions Ν ° Ν ° 7, 14, 21, 28 , 34, 42, 49, 56, 63, 70, 77, 84 are similar in action to naphthyzine. With an increase in the amount of mineral substances in formulations with naphazoline, their vasoconstrictor effect increases. However, amplification occurs to a certain concentration of minerals.

 At concentrations of minerals, mg / l:

 calcium - 125.50;

 magnesium - 160.0;

 zinc - 72.8,

maximum vasoconstrictor effect of pharmaceutical formulations is achieved.

 The concentration of minerals, mg / l:

 calcium - 125.50 - 150.0;

 magnesium - 160.0 - 200.0;

 zinc - 72.8 - 81.0,

no longer lead to further growth of the vasoconstrictor effect.

At concentrations of minerals, mg / l:

 calcium - 150.0 - 210.0;

 magnesium - 200 - 260.0;

 zinc - 81.0 - 1 15.0,

there is a decrease in the vasoconstrictor effect of pharmaceutical formulations.

When the calcium concentration in the pharmaceutical composition is more than 210.0 mg / l, there is a lack of advantage over the vasoconstrictor effect of naphthyzine. When the concentration of magnesium in the pharmaceutical composition is more than 260.0 mg / l, there is no advantage over the vasoconstrictor effect of naphthyzine.

 When the concentration of zinc in the pharmaceutical composition is more than 1 15.0 mg / l, there is no advantage over the vasoconstrictor effect of naphthyzine.

 The above amounts of minerals in the pharmaceutical composition inhibit the vasoconstrictor effect of naphazoline.

Example 5. In this example, the assessment of vasoconstrictor action

pharmaceutical formulations based on naphazoline and minerals were also carried out by comparison with the vasoconstrictor effect of the drug naphthyzine.

 Studies were conducted on white non-linear mice (males) weighing 35 - 37 g. to enhance brain ischemia. The comparison results are presented in the graphs of FIG. 17.

 Brain ischemia was reproduced by ligation of both common carotid arteries. Animals after surgery were observed for 7 days.

Pharmaceutical formulations based on naphazoline and minerals (as well as formulations with ¹³ C carbon isotopes) and the naphthyzine preparation were administered intraperitoneally during observation days. On the first day, drugs were administered twice: immediately after surgery and 3 hours after surgery. On the second day, the third, etc. - drugs were administered once a day.

 After bilateral ligation of the common carotid arteries (and not using the above drugs, see area 34 in FIG. 17) on day 7, 90% of the mice died during the observed days.

Pharmaceutical formulations based on naphazoline, minerals, and the naphthyzine preparation significantly reduced the survival of mice during the observation period. In addition, a decrease in survival was achieved through the use of C isotopes in pharmaceutical formulations. From the graphs in Fig.17 shows that the survival rate of mice when using most pharmaceutical formulations based on naphazoline and minerals is lower than the survival rate of mice when using the drug naphthyzine.

The vasoconstrictor effects of naphthyzine (2 ml with a concentration of naphazoline 1 g / l), pharmaceutical formulations based on naphazoline with minerals, and pharmaceutical formulations with ¹³ C isotopes on the survival of mice with cerebral ischemia were compared.

 On the graphs (see Fig. 17), the survival curves of mice with naphthyzine and pharmaceutical compositions N ° N ° 1, 8, 14 are plotted over the area indicated by 35.

 With an increase in the amount of mineral substances in formulations with naphazoline, their vasoconstrictor effect increases.

 In the area indicated by 36, the survival curves of mice are obtained using pharmaceutical formulations N2N2 9 - 13.

 In the area indicated by 37, survival curves of mice are obtained using pharmaceutical formulations of Ν ° Ν ° 30 - 34.

 In the area indicated by 38, survival curves of mice are obtained when pharmaceutical formulations Ν2Ν2 51 - 55 are used.

 In the area indicated by position 39, the survival curves of mice are obtained when pharmaceutical formulations состав2Ν2 72 - 76 are used.

In the area indicated by 36, the survival curves of mice also pass with the use of pharmaceutical compositions based only on naphazoline with 0.5%, 1% content of ¹³ C carbon isotopes in the composition.

 Along the upper boundary of the region indicated by 37, there is a survival curve for mice using a pharmaceutical composition based only on naphazoline with 75% carbon C isotopes in the composition.

 From examples 4 and 5 it is seen that in order to increase the vasoconstrictor effect of naphazoline, it is advisable to use mineral substances in the following concentration ranges, mg / l:

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

zinc - 0.065 - 72.8, and it is also advisable to use compositions with 0.5 - 75% content of carbon C isotopes in the composition.

 Strengthening the vasoconstrictor effect of the pharmaceutical composition leads to an increase in anti-congestive and anti-inflammatory effects, and also increases the effectiveness of the composition in acute rhinitis,

inflammatory processes of the maxillary sinuses (sinuses) of the nose, nasal

bleeding, conjunctivitis.

Example 6. The developed pharmaceutical compositions for meringue of naphazoline and mineral substances N ° N ° 8-14 were used in the treatment of inflammatory processes of the maxillary sinus cavities (sinusitis) as prescribed in 42 patients aged 27 to 60 years.

 Additionally, to compare the therapeutic effect, the drug naphthyzin (with a concentration of 1 g / l) was used in the treatment of sinusitis as prescribed in 6 patients of the same age.

Also developed pharmaceutical compositions on meringue of naphazoline, minerals and 0.5%, 1%, 75% of the carbon content of ¹³ C in JSieJNib 29 - 35, 50 - 56, 71 - 77 were used in the treatment

inflammatory processes of the maxillary sinus cavities as prescribed in 126 patients of the same age.

In addition, the developed pharmaceutical compositions on meringue only of naphazoline (with a concentration of 1 g / l) and 0.5%, 1% and 75% of the carbon content of ¹³ C in the composition were used in the treatment of inflammatory processes of the maxillary sinus cavities as prescribed in 18 patients of the same age .

 The developed pharmaceutical formulations were well tolerated by patients. The course of treatment for all patients took 10 days according to the scheme of 5 days of treatment, 3 days break, 5 days of treatment. The method of application of all formulations is in accordance with the instructions for use of the drug naphthyzine.

 The treatment results showed the following.

Pharmaceutical formulations N ° N ° 8, 9, 29, 30 are similar in action to naphthyzine. With an increase in the amount of minerals in formulations with naphazoline (formulations with N2N2 10, 11, 12, 13, 31, 32, 33, 34), their vasoconstrictor the effect is enhanced, which leads to an increase in the treatment of sinusitis. Moreover, the more minerals with the composition, the more pronounced the effect of the treatment. The effect of the treatment was a longer vasoconstrictor and therapeutic effect. On average, the time of action (compared with the time of action of the drug naphthyzin) increased by 5 - 25%. In addition, the time of the onset of the therapeutic effect was reduced (controlled at the time the pupils began to expand) by about 5-10%.

The developed pharmaceutical compositions with 0.5%, 1% and 75% content of carbon isotopes ^{| 3} C in the composition (compositions N ° N ° 29 - 35, 50 - 56, 71 - 77) have a longer duration of action, not only in comparison with the time the effects of naphthyzine (by 5-30%), but also compared with the time of action of pharmaceutical formulations based on naphazoline and minerals (by percent).

Example 7. Comparative studies of the developed pharmaceutical formulations with naphthyzine were also carried out in acute rhinitis and nasal

bleeding. In the treatment of these diseases, an increase in the onset of the therapeutic effect in comparison with naphthyzine was also found. An increase in the therapeutic effect was also found without increasing the concentration of the pharmaceutical composition and naphazoline in the pharmaceutical composition. When using the claimed pharmaceutical compositions, the onset of the therapeutic effect (compared with the onset of the therapeutic effect of the use of naphthyzine) was reduced by 5-15%. The duration of the therapeutic effect (compared with the duration of the therapeutic effect of the use of naphthyzine) increased by 5-25%.

 For nosebleeds, pharmaceutical formulations with a naphazoline concentration up to South / L were used. Found that with increasing

the concentration of naphazoline from 0.1 to 10 g / l significantly - at times - increases the therapeutic effect of pharmaceutical formulations. Additionally, the therapeutic effect was increased by the minerals used in the composition, as well as the substitution of carbon C isotopes for carbon isotopes C. Moreover, it is advisable to apply mineral concentrations close to maximum values

(close to the right border of the intervals of values).

 Comparative studies of the claimed pharmaceutical formulations with naphthyzine for nosebleeds were carried out at a concentration of naphazoline equal to 1 g / L. Pharmaceutical formulations N ° N 9 - 13, 30 - 34, 51 - 56, 72 - 76 have shown their advantage over naphthyzine. The stoppage time of nasal bleeding in patients decreased by 3 - 100%, respectively, with minimum and maximum concentrations of mineral substances.

Additionally, a reduction in stopping time of bleeding by 3-5% was achieved by increasing the concentration of ¹³ C carbon isotopes in the formulations.

Example 8. When developing an application for an invention, comparative studies of developed pharmaceutical compositions based on naphazoline and minerals with naphthyzine in the treatment of conjunctivitis were carried out.

 In studies with eye instillation, formulations with

the concentration of naphazoline is 0.1 - 0.5 g / l and naphthyzine with a concentration of 0.5 g / l.

Comparisons were carried out at concentrations of 0.5 g / L.

 At 0.1 g / L naphazoline concentrations, 5 drops were instilled into each eye three times a day.

 At concentrations of naphazoline and naphthyzine 0.5 g / l, 1 drop was instilled into each eye three times a day.

 The time of onset of the therapeutic effect of the action of the compared drugs was evaluated at the time of removing the redness of the eyes.

 When using the claimed pharmaceutical formulations, time

the onset of the therapeutic effect (compared with the onset of the therapeutic effect of the use of naphthyzine) decreased by 5-10%.

Example 9. The studies evaluated the stability of the claimed

pharmaceutical formulations with naphazoline during the expiration date.

It was found that the mineral substances in the composition increase the stability of the claimed pharmaceutical composition over the expiration date. Minerals in naphazoline molecules slow down the chemical reactions that occur in the molecules.

 It has been experimentally established that if naphthyzin retains its

pharmaceutical properties for 3 years, then pharmaceutical formulations based on mineral substances retain their pharmaceutical properties for 3.5 years. The stability is also enhanced by the substitution of carbon isotopes of 12 C for carbon isotopes of ¹³ C.

 Thus, the application is described and the technical results of pharmaceutical compositions containing are confirmed:

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0; .

 zinc - 0.065 - 72.8.

 The composition of mineral substances in the pharmaceutical compositions described above was limited by the list of mineral substances (macroelements and

trace elements) in the “Guide to the methods of quality control and safety of biologically active food additives. - M.: Federal Center

State Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004, - 240 s. ” The Guide describes a method for introducing mineral substances into a solution, as well as methods for precisely controlling the amount of mineral substances in solutions.

 In the studied variants of pharmaceutical compositions, ranges of weight values (in mg / l) of the components of the compositions are given, which, compared with the prototype, give an effect (according to technical results) of 5% or more.

 For the practical implementation of the invention, in addition to the claimed mineral substances, any may be added or any of the following (with the exception of those already mentioned in the composition of mineral substances) may be added, mg / l:

 potassium - 0.02 - 27.7;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160;

 iron - 0.01 - 24.5;

 Manganese - 0.006 - 7.5;

zinc - 0.065 - 72.8; copper - 0.0003 - 0.5;

 cobalt - 0.0003 - 0.75;

 chrome - 0.0012 - 1.58;

 molybdenum - 0.0013-1.59;

 sodium - 1.3 - 131.4.

 For example, the first composition can be performed as follows:

 the pharmaceutical composition contains naphazoline, and minerals in the following ratio of components in mg / l:

naphazoline - 0.1 10 ³ - 10 10 ³ ;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8;

 cobalt - 0.0003 - 0.75.

 Also, the composition can be performed as follows:

 the pharmaceutical composition contains naphazoline, and minerals in the following ratio of components in mg / l:

naphazoline - 0.1 10 ³ - 10 10 ³ ;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8;

 cobalt - 0.0003 - 0.75;

 molybdenum - 0.0013-1.59.

At present, ¹³ C carbon isotopes in the World are widely used in biochemistry and medicine for diagnostics. The application presents the results of our own research on the effect of ¹³ C carbon isotopes on the stability and effectiveness of the action of drug formulations based on naphazoline.

It was found that increasing the stability of the claimed pharmaceutical composition over the expiration date can be achieved by replacing (from 0.5% to 75%) the carbon isotopes of ¹² C with carbon isotopes of ¹³ C. The carbon isotopes of ¹³ C in naphazoline molecules slow down the chemical reactions in the molecules, form stronger covalent bonds than carbon isotopes ¹² C. Carbon isotopes ¹³ C increase the resistance of molecules to

oxidative effects of radicals.

Carbon isotopes ¹³ C are not toxic. The experiments show that feeding mice and rats with foods enriched with 75% ¹³ C carbon does not lead to side effects and poor health.

In the process of experimental verification of the claimed pharmaceutical composition enriched in ¹³ C isotopes of carbon for stability and toxicity, experiments were conducted on its medicinal properties. It was found that the pharmaceutical composition enriched in 13 C carbon isotopes has an increased vasoconstrictor, anti-congestive, anti-inflammatory effect, compared with a pharmaceutical composition in which there are no C carbon isotopes.

 The studies of the following compositions.

The pharmaceutical composition comprising naphazoline and the pharmaceutical composition are designed to contain 13 C carbon isotopes and a ratio of ¹³ C carbon isotopes to the total amount of carbon in

the pharmaceutical composition is from 0.005 to 0.75.

 A pharmaceutical composition containing naphazoline and minerals in the following ratio of components in mg / l:

naphazoline - 0.1 10 ³ - 10 10 ³ ;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8,

and the pharmaceutical composition is designed in such a way that it contains carbon isotopes ¹³ C and the ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition is from 0.005 to 0.75.

 It was found that the above pharmaceutical compositions have a vasoconstrictor, anti-congestive, anti-inflammatory effect.

 For the practical implementation of the invention, additionally in the above

The claimed pharmaceutical composition with minerals and carbon isotopes ¹³ C may be added to any or added any of the following (with the exception of those already indicated in the composition of mineral substances), mg / l:

 potassium - 0.02 - 27.7;

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160;

 iron - 0.01 - 24.5;

 Manganese - 0.006 - 7.5;

 zinc - 0.065 - 72.8;

 copper - 0.0003 - 0.5;

 cobalt - 0.0003 - 0.75;

 chrome - 0.0012 - 1.58;

 molybdenum - 0.0013 - 1.59;

 sodium - 1.3 - 131.4.

Based on the results of the check, an analysis was made of the effect of the degree of enrichment of pharmaceutical formulations with carbon C isotopes on the vasoconstrictor effect of pharmaceutical formulations based on naphazoline. It was established that the contribution of ¹³ C isotopes to the effect is 5% or more.

 Methods for the production of a stable highly enriched non-radioactive carbon isotope-13 are widely used in the Russian and world

industry. Well-developed methods for producing carbon-13 isotopes by gas diffusion through porous walls, vapor diffusion, thermal diffusion, as well as by distillation, isotope exchange,

centrifugation, electrolysis, genetic engineering, etc. A brief description of these methods is given in the source / Isotope Separation. Physical

Encyclopedia, http://dic.academic.ru/dic.nsf/enc physics / 1071 / ISOTOPES /.

At the Moscow State Academy of Fine Chemical Technology. M.V. Lomonosov practiced modern nanotechnology for the production and incorporation of atoms of stable carbon isotopes ¹³ C into molecules of various structures. At the academy, molecules of isotopically labeled compounds with various levels of isotope enrichment are obtained - from fractions of a percent to one hundred percent of isotopes in a substance. The work is in the interests of medical diagnosis. Source / Nanotechnology and the inclusion of 2H deuterium atoms, 0135 carbon 13C, nitrogen 15N, and oxygen 180 in the molecules of amino acids and proteins. http: //samlib.rii/o/oleg_w_m/cdoc^^

ogijaiwkliuchenieatomowdejterija2hrtf.shtml / provides 165 references to foreign sources of information on the isotopic enrichment of various substances.

In turn, the authors actively participated in the work on the isotopic enrichment of hydrocarbons, as well as reagents for the production of various drugs. The reagent enrichment with carbon isotopes ¹³ C

( ¹² C carbon isotopes were replaced by ¹³ C carbon isotopes) was carried out in a cavitation reactor designed by Professor V. I. Kormilitsyn (Moscow Power Engineering Institute - Technical University).

 The reactor was manufactured according to the methodology given in the source / R.F. Ganiev, V.I. Kormilitsyn, L.I. Ukrainsky. Wave cooking technology

alternative fuels and their efficiency.-M.: Scientific and Publishing Center "Regular and Chaotic Dynamics", 2008.-116 p /.

 The flow rate in the reactor, along the length of the channel, varied from 10 m / s to 50 m / s.

On Fig presents a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular, hydrocarbon reagents to obtain a pharmaceutical composition enriched in carbon isotopes ¹³ C. The reactor is located in the installation, which contains a pump 6NK-6x1,

providing a maximum flow rate of 90 m ³ / h, a pressure of 125 m with an electric motor power of 75 kW, a rotational speed of the electric motor rotor and pump wheel 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

 The installation diagram is presented in Fig.16.

 The cavitation reactor 1 (see Fig. 14) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.

On Fig presents a cross section of a cavitation reactor. The reactor channel in the area of cavitation bodies is divided into several channels. For example, cavitation bodies 5 and 6 divide the channel into smaller channels 13, 14 and 15. Outside, the channel is limited by walls 16 and 17, as well as two covers 1 1 and 12. 13 000135

On Fig arrows 18 shows the direction of movement of the reagent at the inlet to the reactor, arrow 19 shows the direction of movement of the reagent at the outlet of the reactor.

 In the wall 16, channels 24 and 25 are made for supplying carbon dioxide and nitrogen to the cavitation zones.

 Installation works as follows. The hydrocarbon reagent from the tank 28 is pumped through the reactor 27 through the pump 27 and enters the tank 28. The pressure drop in the reactor is controlled by pressure gauges 29 and 30. The temperature of the reactant is monitored by thermometer 31. The reagent is heated in the tank by a heater 32.

 When the reactor is operating, the hydrocarbon reagent moves along the cavitator channel in direction 18. When flowing around cavitation bodies, the flow is divided into several flows. Beyond the cavitation bodies, cavitation areas arise. In particular, behind the bodies (if you look in the direction of movement of the reagent) cavitation 2, 3, and 4 are cavitation zones 20, 21, 22, and 23. Upon entering the cavitation region, the reagent “boils”, cavitation bubbles appear, and cavitation cavities exit the cavitation region the bubbles collapse. At the same time, in the area (in the place) of the collapse of the cavitation bubble, an increase in pressure to several thousand atmospheres and an increase in temperature to a thousand degrees

Celsius. Through channels 24 and 25, carbon dioxide is supplied to the stream so that the gas enters the cavitation zone.

 The gas-vapor mixture obtained in the reactor together with the liquid reagent enters the tank 28. Next, the gas-vapor mixture is passed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with 13 C and 12 C are separated.

In the experiments, the reactor worked from several hours to several days. A direct dependence of the degree of enrichment of the vapor-gas mixture and the reagent with ¹³ C isotopes ^{on the} operating time of the cavitation reactor is established.

The amount of ¹³ C carbon isotopes was controlled by high resolution mass spectroscopy.

As a result of the experiments, the reagent was enriched with carbon isotopes ^{, 3} ° C ^, to 75%. T / RU2013 / 000135

In addition, reagent enrichment was carried out to obtain various pharmaceutical compositions with ^Ι5 Ν nitrogen isotopes.

Substitution of nitrogen isotopes ¹⁴ N with nitrogen isotopes ¹⁵ N was carried out in the above cavitation reactor. When the reactor is operating, the reagent moves along the cavitator channel in direction 18. When flowing around cavitation bodies, the flow is divided into several flows. Beyond the cavitation bodies, cavitation areas arise. At the entrance to the cavitation area, the reagent “boils”, cavitation bubbles appear, when leaving the cavitation area, cavitation bubbles collapse. In the experiment, nitrogen was supplied through the channels 24 and 25 in such a way that the gas fell into the cavitation zones.

The gas-vapor mixture obtained in the reactor together with the reagent enters the tank 28. Next, the gas-vapor mixture is ^passed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with ^Ι4 Ν and ⁵ N are separated.

 As a result of the experiments, reagent enrichment with nitrogen isotopes up to 1.375% was achieved.

Pharmaceutical formulations containing naphazoline were prepared and made in such a way that they contain nitrogen isotopes ¹⁵ N.

 In the experiments received a pharmaceutical composition containing

naphazoline, and configured so that it contains nitrogen isotopes ¹⁵ N and the ratio:

nN = (N ^{, 5} N / ΝΝ) 100%,

where ηΝ is the ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the pharmaceutical composition;

Ν ^{, 5} Ν - the amount of nitrogen isotopes ¹⁵ Ν in the pharmaceutical composition; ΝΝ - the total number of nitrogen isotopes in the pharmaceutical composition,

Took values from the range from 0.01% to 1.375%.

 That is, the values of the ηΝ indicator took values from the range from 0.01% to 1.375%.

It was found that the pharmaceutical composition enriched with nitrogen isotopes ⁵ Ν has an increased vasoconstrictor, anti-congestive, anti-inflammatory effect, compared with the pharmaceutical composition, in which there are no nitrogen isotopes ^Ι5 Ν.

In the framework of the invention confirmed neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic effect

the following pharmaceutical formulations with carbon isotopes ^{, 3} C and nitrogen isotopes ¹⁵ N:

 A. Pharmaceutical composition containing naphazoline, characterized in that it is made in such a way that it contains carbon isotopes C, and the ratio:

nC = N ¹³ C / NC,

 where pS is the ratio of the number of carbon isotopes 13 C to the total

 the amount of carbon in the pharmaceutical composition;

N ¹³ C is the number of carbon isotopes of ¹³ C in the pharmaceutical composition;

 NC - the total number of carbon isotopes in the pharmaceutical composition,

ranges from 0.005 to 0.75;

and, in addition, the pharmaceutical composition contains isotopes of nitrogen ¹⁵ N and

attitude:

nN = (N ¹⁵ N / NN) 100%,

where nN is the ratio of the number of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in the pharmaceutical composition;

N ¹⁵ N - the amount of nitrogen isotopes N in the pharmaceutical composition;

 NN is the total number of nitrogen isotopes in the pharmaceutical composition,

is a value from the range from 0.01% to 1.375%;

and the pharmaceutical composition has a vasoconstrictor,

anti-congestive, anti-inflammatory effect.

 B. Pharmaceutical composition containing naphazoline, characterized in that it further contains mineral substances in the following ratio of components in mg / l:

zo naphazoline - 0.1 ^{'10 3} - 10 October ^3,

 calcium - 0.1 - 125.50;

 magnesium - 0.065 - 160.0;

 zinc - 0.065 - 72.8,

 and the pharmaceutical composition contains carbon isotopes C, and the ratio:

nC = N ¹³ C NC,

 where pS is the ratio of the number of carbon isotopes C to the total

 the amount of carbon in the pharmaceutical composition;

 N C is the amount of carbon C isotopes in the pharmaceutical composition;

 NC - the total number of carbon isotopes in the pharmaceutical composition,

ranges from 0.005 to 0.75;

and, in addition, the pharmaceutical composition comprises a nitrogen isotopes ^Ι5 Ν and

attitude:

nN = (N ¹⁵ N / NN) 100%,

where ηΝ is the ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the pharmaceutical composition;

Ν ¹⁵ Ν - the amount of nitrogen isotopes ¹⁵ Ν in the pharmaceutical composition;

 ΝΝ - the total number of nitrogen isotopes in the pharmaceutical composition,

is a value from the range from 0.01% to 1.375%;

and the pharmaceutical composition has a vasoconstrictor,

anti-congestive, anti-inflammatory effect.

Thus, when implementing the claimed pharmaceutical compositions, all technical results are ensured:

- increase the speed of the onset of the therapeutic effect (decrease in the time of the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of naphazoline in the pharmaceutical composition in acute rhinitis, inflammatory processes of the maxillary sinuses (sinuses) of the nose, nosebleeds, conjunctivitis.

 - increase the therapeutic effect without increasing concentration

 pharmaceutical composition and naphazoline in the pharmaceutical composition for acute rhinitis, inflammatory processes of the maxillary sinus cavities, nasal

 bleeding, conjunctivitis;

 - increasing the stability of the pharmaceutical composition with naphazoline during the expiration date.

 Table 1

Pharmaceutical formulations based on naphazoline and minerals

 *) the numbering of pharmaceutical compositions through tables 1 -

table 2

Pharmaceutical formulations based on naphazoline and minerals

Таблица 3

Table 3

Pharmaceutical formulations based on naphazoline and minerals

Table 4

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² C to carbon isotopes ¹³ C

Таблица 5

Table 5

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

 carbon 12 C to carbon isotopes 13 C

Table 6

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² С for carbon isotopes ^{, 3} С

Таблица 7

Table 7

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ^{| 2} C on carbon isotopes ¹³ C

Table 8

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² C to carbon isotopes ¹³ C

Таблица 9

Table 9

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

 carbon C to isotopes of carbon C

Table 10

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² C to carbon isotopes ¹³ C

Таблица 11

Table 11

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² C to carbon isotopes ¹³ C

Table 12

Pharmaceutical formulations based on naphazoline, minerals when substituted in the pharmaceutical composition of isotopes

carbon ¹² C to carbon isotopes ¹³ C

Таблица 13

Table 13

Increased hypoxia from the use of naphthyzin

dose of the drug per mouse.

Table 14

Increased hypoxia from the use of pharmaceutical formulations based on naphazoline and minerals.

Таблица 15

Table 15

Increased hypoxia from the use of pharmaceutical compounds based on naphazoline, minerals at 0.5% carbon isotopes 13 C.

Таблица 16

Table 16

Enhanced hypoxia from the use of pharmaceutical formulations based on naphazoline, minerals at 75% carbon isotopes C.

Claims

Claim  1. The pharmaceutical composition containing naphazoline, characterized in that it further contains minerals in the following ratio of components in mg / l: naphazoline - 0.1 · 10 ³ - 10 10 ³ ;  calcium - 0.1 - 125.50;  magnesium - 0.065 - 160.0;  zinc - 0.065 - 72.8, and the pharmaceutical composition has a vasoconstrictor, anti-congestive, anti-inflammatory effect. 2. A pharmaceutical composition containing naphazoline, characterized in that it is made in such a way that it contains ¹³ C carbon isotopes, and the ratio: nC = N ¹³ C NC, where pS is the ratio of the number of carbon isotopes ¹³ C to the total  the amount of carbon in the pharmaceutical composition;  N 13 C - the amount of carbon isotopes 13 C in the pharmaceutical composition;  NC - the total number of carbon isotopes in the pharmaceutical composition, ranges from 0.005 to 0.75, and the pharmaceutical composition has a vasoconstrictor, anti-congestive, anti-inflammatory effect.  3. The pharmaceutical composition containing naphazoline, characterized in that it further contains minerals in the following ratio of components in mg / l: naphazoline - 0. G 10 ³ - 10 10 ³ ;  calcium - 0.1 - 125.50;  magnesium - 0.065 - 160.0;  zinc - 0.065 - 72.8, and the pharmaceutical composition contains carbon isotopes ¹³ With, and the ratio: nC = N ¹³ C / NC, where nC is the ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition; N ^I3 C - the amount of carbon isotopes ¹³ C in the pharmaceutical composition;  NC - the total number of carbon isotopes in the pharmaceutical composition, ranges from 0.005 to 0.75, and the pharmaceutical composition has a vasoconstrictor, anti-congestive, anti-inflammatory effect.  4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the pH value is from 4 to 7.