EA021232B1 - Pharmaceutical composition having vasoconstricting, anticongestant, anti-inflammatory activity (embodiments) - Google Patents

Abstract

The invention relates to the field of the pharmaceutical industry and medicine and can be used for the production and application of pharmaceutical compositions having vasoconstricting, anticongestant, anti-inflammatory activity in cases of acute rhinitis, inflammatory processes of the maxillary sinuses, nosebleeds, conjunctivitis. The aim of the invention consists in producing a pharmaceutical composition on the basis of the preparation naphazoline by introducing mineral substances into the pharmaceutical composition, substitutingC carbon isotopes withC carbon isotopes in the pharmaceutical composition.

Description

(57) The invention relates to the field of pharmaceutical industry and medicine, can be used to create and use pharmaceutical formulations with vasoconstrictive, anti-congestive, anti-inflammatory effects in acute rhinitis, inflammatory processes of the maxillary sinus cavities, nosebleeds, conjunctivitis. The objective of the invention is to create a pharmaceutical composition based on the drug naphazoline, by introducing into the pharmaceutical composition of mineral substances, substitution in the pharmaceutical composition of carbon isotopes ¹² C for carbon isotopes ¹³ C.

021232 Β1

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical industry and medicine, can be used to create and use pharmaceutical formulations with vasoconstrictive, anti-congestive, anti-inflammatory effects in acute rhinitis, inflammatory processes of the maxillary sinus cavities, nosebleeds, conjunctivitis.

State of the art

An important problem of modern medicine is the creation of new effective drugs that can effectively treat various diseases of the nose and eyes, in particular acute rhinitis, inflammatory processes of the maxillary sinus cavities, allergic conjunctivitis, and effectively stop nosebleeds. For the treatment of these diseases, the drug naphazoline and naphthyzine and sanorin prepared on its basis are used. The effect of naphazoline is that it excites adrenoreactive systems, causes a narrowing of peripheral blood vessels (naphazoline, instructions for use, published on the Internet at: 1Sp: // Naryatsh. Gi / paGa / οΙίη. Ysh1).

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 1150 mg of petrolatum in 10 ml of the drug.

The advantages of sanorin over naphthyzine are that sanorin is an emulsion that has a milder effect, lingers longer in the nasopharynx, is washed out of the nasal passages with less speed 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 to the two 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 two 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: 1Shr: // \ y \ y \ u.roP5tsb.gi / bgi8-paGP / p1-ro51001.1it1 )

The prototype refers to alpha 2-adrenergic agonists, has a vasoconstrictor effect on the vessels of the 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. It can also be used intravenously drip.

The disadvantages of the prototype are the relatively long time of the onset of the therapeutic effect, low stability during the expiration date and the possibility of increasing the therapeutic effect, only by increasing the concentration of the active substance or the 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:

an increase in the speed of the onset of the therapeutic effect (a decrease in the time of the onset of the therapeutic effect);

an increase in the therapeutic effect without increasing the concentration of naphazoline;

increasing the stability of the pharmaceutical composition with naphazoline over 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. Haymoritis is an acute or chronic inflammation of the 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.).

As a rule, rhinitis is caused by viruses and bacteria, but the beginning of a runny nose is a sudden severe irritation of the nasal mucosa, for example, dust or chemicals, as well as hypothermia - the general or individual parts of the body, most often the legs.

Acute rhinitis is a runny nose due to acute inflammation of the nasal membrane, accompanied by a dysfunction - breathing, smell, tearing, etc.

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Conjunctivitis is an inflammation of the mucous membrane of the eye (conjunctiva) caused by an allergic reaction or infection (viral, rarely bacterial).

Shelf life - the period during which the pharmaceutical composition retains its properties in a measure that ensures its intended use.

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.

Currently, the following anti-congestive (decongestant) drugs are well known and used: indanazoline, xylometazoline, naphazoline, oxymetazoline, tetrisoline.

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

The objective of the present invention is to provide an effective pharmaceutical composition based on naphazoline, which has a vasoconstrictive, anti-congestive, anti-inflammatory effect.

The patent describes two embodiments of the invention.

The problem is solved due to the fact that the pharmaceutical composition is a solution containing naphazoline, differs from the prototype in that it additionally contains mineral substances in the following ratio of components, mg / l:

naphazoline - 0.1 10 ³ - 10'10 ³ ; calcium - 0.1 - 125.50; potassium - 0.02 - 27.7; zinc - 0.065 - 72.8, and the pharmaceutical composition has a vasoconstrictive, anti-congestive, anti-inflammatory effect.

Also, the problem is solved due to the fact that the pharmaceutical composition is a solution containing naphazoline, differs from the prototype in that it additionally contains mineral substances in the following ratio of components, mg / l:

naphazoline - 0.1 10 ³ - 10 10 ³ ; calcium - 0.1 - 125.50; potassium-0.02-27.7; zinc - 0.065 -72.8, while the pharmaceutical composition contains carbon isotopes ¹³ C and the ratio pC \ '^; C / \ C.

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

Ν ¹³ 0 - the amount of carbon isotopes ¹³ C in the pharmaceutical composition;

N0 is the total amount of carbon isotopes in the pharmaceutical composition, ranging from 0.005 to 0.75, and the pharmaceutical composition has a vasoconstrictive, anti-congestive, anti-inflammatory effect.

In other words, in the carbon part, the problem is solved due to the fact that the pharmaceutical composition contains naphazoline, minerals and the ratio of the amount of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition is from 0.005 to 0.75.

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 to 1.26 mm ² / 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-dihydro2- (1-naphthalenylmethyl) -1H-imidazole, made in the form of a hydrochloride or nitrate (naphazoline hydrochloride or naphazoline nitrate).

The structural formula of the main active substance

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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 and 1 g / l.

In the invention, the authors consider pharmaceutical compositions 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.

The technical results for the three variants of the invention are to increase the speed of the onset of the therapeutic effect (decrease 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 for acute rhinitis, inflammatory processes of the maxillary sinuses (sinuses) of the nose, nosebleeds, conjunctivitis;

an increase in the 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;

increasing the stability of the pharmaceutical composition with naphazoline over 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 by the dosage of the drug, the frequency of use and the time of its 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 No. 94015245, published on December 27, 1995), in which a 5-10% solution of hyaluronic acid is used as a regulator of the rate of exposure.

Also known is a pacemaker drug (RF patent No. 2068697, published 10.11.1996), 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, polyvinylpyrrolidone and sorbic acid are additionally introduced into the antitumor agent (USSR author's certificate No. 1683190, published on 04/20/1995). These components increase the antitumor activity of the active principle.

In the invention, an increase in the speed of the onset of the therapeutic effect (as well as other technical results) is achieved while maintaining the duration of action and without increasing the concentration of the drug naphazoline in the pharmaceutical composition by introducing mineral substances into the pharmaceutical composition, as well as by replacing ¹² C carbon isotopes in the pharmaceutical composition with carbon isotopes ¹³ 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 ¹² C carbon 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 include iron, copper, manganese, zinc, cobalt, iodine, fluorine, chromium, molybdenum, vanadium, nickel, strontium, silicon, selenium, which 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, Ζη and others) in solution are contained in pharmaceutically acceptable salts, for example, succinates, chlorides, nitrates, carbonates or sulfates, as well as in various pharmaceutically acceptable complex compounds.

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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 invention, the local action of these substances can 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 surface layers of tissues, an astringent or irritating effect is observed that is reversible.

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 an increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of naphazoline in the pharmaceutical composition, an increase in the stability of the pharmaceutical composition with naphazoline during the shelf life is provided by the introduction of certain minerals (a specific combination of minerals) in the pharmaceutical composition in a strictly defined for each mineral amount. 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 an increase in the concentration of 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 the partial replacement of ¹² C carbon isotopes with ¹³ C carbon isotopes in the pharmaceutical composition.

List of drawings

In FIG. 1 presents a chromatogram of the claimed pharmaceutical composition on a column with a sorbent C18; detection at 220 nm;

in FIG. 2 shows a chromatogram of a pharmaceutical composition on a C18 sorbent column using a mass selective detector;

in FIG. 3 shows a chromatogram of a pharmaceutical composition on a C18 sorbent column using a mass selective detector;

in FIG. 4 shows an HPLC of a pharmaceutical composition on a column with a chiral sorbent; detection at 220 nm;

in FIG. 5 shows a HPLC of a pharmaceutical composition on a chiral column using a mass selective detector;

in FIG. 6 presents Μδ Μδ of molecular ion 237; in FIG. 7 represents Μδ Μδ of molecular ion 211;

in FIG. 8 and 9 show the right and left parts of the '-NMR spectrum of the pharmaceutical composition, respectively;

in FIG. 10 shows the ¹³ C-NMR spectrum of the pharmaceutical composition;

in FIG. 11-13 show two-dimensional NMR spectra of the pharmaceutical composition;

in FIG. 14 is a diagram of a cavitation reactor for isotope enrichment of various mixtures;

in FIG. 15 is a cross-sectional view of a cavitation reactor; in FIG. 16 is a diagram of an isotope enrichment plant; in FIG. Figure 17 shows daily mice survival schedules.

Information confirming the possibility of carrying out the invention

The invention is illustrated by the following examples:

example 1 is a method of introducing minerals into water for injection;

example 2 is a method for producing pharmaceutical compositions;

example 3 - tests for general toxicity;

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

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Example 1

The introduction of mineral substances into the solution (into water for injection) was carried out according to the methodology (see Guidelines for methods for monitoring the quality and safety of biologically active food additives. - M.: Federal Center for Sanitary Inspection of the Ministry of Health of Russia, 2004. - 240 p.).

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 up to 55.0; calcium - from 0.01 up to 210.0; magnesium - from 0.03 up to 260.0; iron - from 0.005 up to 45.0; Manganese - from 0.003 up to 28.0; zinc - from 0.01 up to 115.0; copper - from 0.0001 up to 3.0; cobalt - from 0.0001 up to 12.0; chrome - from 0.001 up to 12.0; molybdenum - from 0.001 up to 12.0; sodium - from 1.0 to 185.0.

When developing the invention, a complex of studies of pharmaceutical compositions was carried out, in particular magnetic resonance studies, chromatographic studies on columns with various sorbents, etc.

In the invention of FIG. Figures 1-13 show the results of a study of only one pharmaceutical composition based on naphazoline and 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 compositions are similar, including those claimed in the invention.

In FIG. 1 shows a chromatogram of a pharmaceutical composition on a column with a sorbent C18. The absorption of the eluate was measured at a wavelength of 220 nm.

In FIG. 2 shows a HPLC pharmaceutical composition with a mass selective detector.

A peak with a retention time of 3.449 min corresponds to a molecular ion with an exponent t / ζ equal to 237 (t is the mass of the molecule, ζ is the charge of the molecule).

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

A peak with a retention time of 6.648 min corresponds to a molecular ion with a t / ζ value of 211.

In FIG. 4 shows a chromatogram of a pharmaceutical composition on a column with a chiral sorbent. The absorption of the eluate was measured at a wavelength of 220 nm.

In FIG. 5 shows a chromatogram of a pharmaceutical composition on a chiral column with a mass-selective detector. A peak with a retention time of 17.07 min corresponds to a molecular ion with a t / ζ value of 211.

In FIG. Figure 6 shows Μδ Μδ of the molecular ion 237. The fragmentation of the ion with the value of t / ζ equal to 237 is shown.

In FIG. Figure 7 shows Μδ Μδ of molecular ion 211. The fragmentation of an ion with the value

- 5 021232 t / ζ equal to 211.

In FIG. 8 and 9 show ¹ H-NMR spectrum of the pharmaceutical composition.

¹ H NMR (600 MHz, ΌΜ δΘ-ά ₆ ): 7.989 (d, 1 = 8.4 Hz, 1H, 1-H); 7.965 (d, 1 = 8.4 Hz, 1H, 2-H); 7.95-7.92 (m, 1H, 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).

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

¹³ C NMR (600 MHz, ΌΜδΘ-ά ₆ ): 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 (11-C); 44.57 (12-C); 29.71 (13C).

In FIG. 11-13 show 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, potassium and zinc.

The invention further presents the results of in-depth studies of pharmaceutical formulations with only these minerals.

The concentration of metals in the solutions was controlled by the atomic absorption method for determining the content of sodium, potassium, calcium, magnesium, iron, manganese, copper, zinc, lead, cadmium, cobalt, nickel, chromium (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 p., See clause 1.3.2.1).

Example 2. Obtaining a pharmaceutical composition with calcium, potassium and zinc.

8 l of distilled water are poured into a stirred reactor. After that, a naphazoline solution (in a 100% naphazoline solution) - 10 g 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 the solution is obtained - 1 g / l.

The kinematic viscosity of the pharmaceutical composition of 1.016 mm ² / s (from a range of 1.016 to 1.26 mm ² / 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 the pharmaceutical formulations thus obtained are stable and retain their initial values for 3-3.5 years. Moreover, after opening the package (bottle) in the air, the pharmaceutical compositions, without changing the 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 were carried out by intraperitoneal administration of pharmaceutical formulations based on naphazoline and minerals in rats.

Lp ₅₀ ranges from 950 to 1000 mg / kg when administered intraperitoneally.

With intramuscular administration, Lp 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.

In the table. 1-12 show the studied pharmaceutical formulations. The numbering of pharmaceutical formulations in the tables is through.

The pharmaceutical compositions described in the invention have a vasoconstrictive, anti-congestive (anti-congestive), anti-inflammatory effect.

The anti-congestive (decongestant) property of the pharmaceutical compositions described in the invention is ensured by their good vasoconstrictor effect. The anti-inflammatory effect of the pharmaceutical compositions described in the invention is also provided by their good vasoconstrictor effect.

Example 4

Assessment 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 (see Guidelines for the experimental study of drugs proposed for clinical study as antihypoxic drugs / Edited by L.D. Lukyanova. - M. , 1990 and the 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) was modeled by placing mice in a 250 cm ³ pressure chamber.

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In the experiments, the lifespan of animals was recorded after the cessation of air access into the pressure chamber. Animals were housed individually in a pressure chamber.

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

The time from the moment of drug administration to the placement of mice in a pressure chamber and cessation of air 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 pressure chamber and stopping air from entering the pressure chamber.

After placing the mice in a pressure 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 in oxygen) to the brain, which increases hypoxia and 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 given in table. thirteen.

The increase in hypoxia from the use of pharmaceutical formulations based on naphazoline and minerals is given in table. 14-16. In the table. Figures 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 pressure 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 the pharmaceutical composition. From the table. Figures 14-16 show that mineral substances and ¹³ C isotopes increase the rate of onset of a vasoconstrictor effect.

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

Table analysis 13-16 shows that the pharmaceutical compositions No. 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, as well as pharmaceutical compositions No. 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; potassium - 27.7; zinc - 72.8, the maximum vasoconstrictor effect of pharmaceutical formulations is achieved.

The concentration of minerals, mg / l:

calcium - 125.50 - 150.0; potassium - 27.7 - 30.0;

zinc - 72.8-81.0, no longer lead to further growth of the vasoconstrictor effect.

At concentrations of minerals, mg / l:

calcium - 210.0; potassium 55.0; zinc - 115.0;

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

When the concentration of calcium 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 potassium in the pharmaceutical composition is more than 55.0 mg / l, there is a lack of advantage over the vasoconstrictor effect of naphthyzine.

When the concentration of zinc in the pharmaceutical composition is more than 115.0 mg / l, there is a lack of advantage over the vasoconstrictor effect of naphthyzine.

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

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Example 5

In this example, the vasoconstrictor effect of pharmaceutical formulations based on naphazoline and minerals was also evaluated by comparison with the vasoconstrictor effect of the naphthyzine drug.

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, 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 ¹³ C isotopes in pharmaceutical formulations.

From the graphs in FIG. Figure 17 shows that the survival rate of mice using the majority of pharmaceutical formulations based on naphazoline and minerals is lower than the survival rate of mice using the naphthyzine preparation.

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.

In the graphs (see Fig. 17), the survival curves of mice with the use of naphthyzine and pharmaceutical formulations Nos. 1, 8, 14 are passed 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 position 36, there are curves of survival of mice when using pharmaceutical compositions No. 9-13.

In the area indicated by position 37, there are curves of the survival of mice with the use of pharmaceutical compositions No. 30-34.

In the area indicated by position 38, there are curves of survival of mice with the use of pharmaceutical compositions No. 51-55.

In the area indicated by position 39, survival curves of mice are passed when using pharmaceutical formulations No. 72-76.

In the area indicated by position 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.

At the upper boundary of the region indicated by 37, the mouse survival curve is obtained when applying a pharmaceutical composition based only on naphazoline with 75% ¹³ C carbon 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; potassium-0.02 -27.7;

zinc - 0.065 - 72.8, and it is also advisable to use compositions with 0.5-75% content of ¹³ C carbon 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, nosebleeds, conjunctivitis.

Example 6

The developed pharmaceutical formulations based on naphazoline and minerals No. 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 of 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 based on naphazoline, minerals and 0.5, 1, 75% of ¹³ C carbon isotopes in compositions No. 29-35, 50-56, 71-77 were used in the treatment of inflammatory processes of the maxillary sinus cavities for 126 patients of the same age.

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In addition, the developed pharmaceutical compositions based only on 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 - 5 days treatment, 3 days break, 5 days treatment. The method of use of all formulations is in accordance with the instructions for the use of the drug naphthyzine.

The treatment results showed the following.

Pharmaceutical formulations No. 8, 9, 29, 30 are similar in action to naphthyzine. With an increase in the amount of minerals in the formulations with naphazoline (formulations No. 10, 11, 12, 13, 31, 32, 33, 34), their vasoconstrictor effect increases, which leads to an increase in the treatment of sinusitis. Moreover, the more minerals in 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 ¹³ C carbon isotopes in the composition (formulations No. 29-35, 50-56, 71-77) have a longer action time not only compared to the naphthyzine action time (by 5- 30%), but also compared with the duration of action of pharmaceutical formulations based on naphazoline and minerals (percent).

Example 7

Comparative studies of the developed pharmaceutical formulations with naphthyzine were also carried out for acute rhinitis and nosebleeds. In the treatment of these diseases, an increase in the onset of the therapeutic effect in comparison with naphthyzine has also been established. 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 of up to 10 g / l were used. It was found that with an increase in the concentration of naphazoline from 0.1 to 10 g / l, the therapeutic effect of pharmaceutical formulations significantly, significantly increases. Additionally, the therapeutic effect was increased by the mineral substances used in the composition, as well as the substitution of carbon isotopes ¹² C for carbon isotopes ¹³ C. Moreover, it is advisable to use the concentration of mineral substances close to the maximum values (close to the right border of the value ranges).

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 No. 9-13, 30-34, 51-56, 72-76 showed their advantage over naphthyzine. The stoppage time of nosebleeds in patients decreased by 3-100%, respectively, with minimum and maximum concentrations of minerals.

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

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

In the studies with eye instillation, formulations with a concentration of naphazoline 0.1-0.5 g / L and naphthyzine with a concentration of 0.5 g / L were used. 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, the onset of the therapeutic effect (compared with the onset of the therapeutic effect of the use of naphthyzine) was reduced by 510%.

Example 9. The studies evaluated the stability of the claimed pharmaceutical formulations with naphazoline over 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 was experimentally established that if naphthyzine retains its pharmaceutical properties for 3 years, then pharmaceutical formulations based on minerals retain their pharmaceutical properties for 3.5 years. The stability is also enhanced by the substitution of carbon isotopes of the genus ¹² C for ¹² C with carbon isotopes ¹³ C.

Thus, the application is described and the technical results of pharmaceutical formulations containing calcium are confirmed - 0.1 - 125.50; potassium - 0.02 - 27.7; zinc-0.065 -72.8.

The composition of minerals in the above pharmaceutical formulations was limited by the list of minerals (macroelements and microelements) (see the Guide to Methods for Monitoring the Quality and Safety of Biologically Active Food Additives. - M.: Federal Center for Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004. - 240 p.) . The manual describes the method of introducing mineral substances into a solution, as well as methods for precise control of 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.

At present, ¹³ C carbon isotopes in the world are widely used in biochemistry and medicine for diagnostics. The invention 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 has been established that increasing the stability of the claimed pharmaceutical composition over the expiration date can be achieved by replacing (from 0.5 to 75%) ¹² C carbon isotopes with ¹³ C carbon isotopes. ¹³ C carbon isotopes in naphazoline molecules slow down the chemical reactions that occur in the molecules and form stronger covalent bonds than carbon isotopes ¹² C.

Carbon isotopes ¹³ C increase the resistance of molecules to the 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 carbon isotopes for stability and toxicity, experiments were also carried out on its medicinal properties. It was found that the pharmaceutical composition enriched in ¹³ C carbon isotopes has increased vasoconstrictive, anti-congestive, anti-inflammatory effects compared to a pharmaceutical composition in which ¹³ C carbon isotopes are absent.

The studies of the following compositions.

The pharmaceutical composition is a solution containing naphazoline and minerals in the following ratio of components, mg / l:

naphazoline - 0.1 10 ³ -10'10 ³ ; calcium - 0.1 - 125.50; potassium - 0.02 - 27.7; zinc - 0.065 - 72.8, while the pharmaceutical composition is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total 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.

Based on the results of the check, an analysis was made of the effect of the degree of enrichment of pharmaceutical formulations with ¹³ C carbon 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 stable highly enriched non-radioactive carbon isotope ¹³ C are widely used in Russian and world industry. Methods for producing ¹³ С carbon isotopes by gas diffusion through porous walls, diffusion in a steam stream, thermal diffusion, as well as by distillation, isotope exchange, centrifugation, electrolysis, genetic engineering, and others are well developed. A brief description of these methods is given (see Isotope separation. Physical Encyclopedia, Lp: //b1.sasabesh1s.gi/b1s.p8$/eps ryu81S8 / 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 percent to 100% of isotopes in a substance. The work is in the interests of medical diagnosis. In the source Nanotechnology and the inclusion of atoms

13 15 18 deuterium H, carbon C, nitrogen N and oxygen O into the molecules of amino acids and proteins. Sp: //8at11b.yy/o/o1ed_n_sh/bosite1818b8e1pd8o1to81pto1bokitep1upap1ebpo1 odua ^ ktsssyetea-10 021232 then \ ubcssp) a211g1G.51it1 enumerated information from 165 different sources provides 165 references to various sources.

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 reagents were enriched with ¹³ C carbon isotopes (replacing ¹² C carbon isotopes with ¹³ C carbon isotopes) in a cavitation reactor designed by Professor V. I. Kormilitsyn. (Moscow Energy Institute Technical University).

The reactor was manufactured according to the methodology (see Ganiev RF, Kormilitsyn VI, Ukrainian LI Wave technology for the preparation of alternative types of fuels and the efficiency of their combustion. - M.: Scientific and Publishing Center Regular and chaotic dynamics, 2008 . - 116 p.).

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

In FIG. 14 is a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular hydrocarbon reagents, for the preparation of a pharmaceutical composition enriched in ¹³ C carbon isotopes. The reactor is located in a plant that contains a 6NK-6x1 pump providing a maximum flow rate of 90 m ³ / h, head 125 m with an electric motor power of 75 kW, a rotational speed of the rotor of the electric motor and pump wheel 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

The installation diagram is shown in FIG. sixteen.

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.

In FIG. 15 is a cross-sectional view 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 13-15. Outside, the channel is limited by walls 16 and 17, as well as two covers 11 and 12.

In FIG. 14, arrows 18 show 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 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 stream is divided into several streams. Beyond the cavitation bodies, cavitation areas arise. In particular, behind the bodies (if you look in the direction of movement of the reagent) cavitation 2-4 are cavitation zones 20-23. Upon entering the cavitation area, the reagent boils, cavitation bubbles appear, and when leaving the cavitation area, cavitation bubbles collapse. Moreover, in the area (in the place) of the collapse of the cavitation bubble, an increase in pressure is observed to several thousand atmospheres and an increase in temperature to 1000 ° C. 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 fed 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 ¹³ C carbon isotopes to 75%.

Thus, the implementation of the claimed pharmaceutical formulations ensures the fulfillment of all technical results:

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;

an increase in the 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;

increasing the stability of the pharmaceutical composition with naphazoline over the expiration date.

- 11 021232

Table 1

Pharmaceutical formulations based on naphazoline and minerals

Mineral substance Serial number of pharmaceutical composition with 0.1 grams naphazoline in a liter of pharmaceutical composition G ¹ 2 3 4 5 6 7 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

*) The numbering of pharmaceutical formulations is through through the table. 1-12.

table 2

Pharmaceutical formulations based on naphazoline and minerals

Mineral substance The serial number of the pharmaceutical composition with I gram naphazoline in a liter of pharmaceutical composition 8 nine 10 eleven 12 thirteen 14 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 3

Pharmaceutical formulations based on naphazoline and minerals

Mineral The serial number of the pharmaceutical composition with 10 substance grams of naphazoline in a liter of pharmaceutical composition fifteen sixteen 17 eighteen nineteen twenty 21 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 4

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 0.1 grams of naphazoline in a liter of pharmaceutical composition at 0.5% ¹³ C carbon isotopes 22 23 24 25 26 27 28 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 5

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 1 gram of naphazoline in a liter of pharmaceutical composition at 0.5% ¹³ C carbon isotopes 29th thirty 31 32 33 34 35 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

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Table 6

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral The serial number of the pharmaceutical composition with 10 substance grams of naphazoline in a liter of pharmaceutical composition when 0.5% carbon isotope ¹³ C 36 37 38 39 40 41 42 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 7

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral Serial number of pharmaceutical composition with 0.1 grams substance naphazoline in a liter of pharmaceutical composition with a carbon isotope content of ³ C one% 43 44 45 46 47 48 49 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 8

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 1 gram of naphazoline in a liter of pharmaceutical composition at 1% carbon isotope ¹³ C fifty 51 52 53 54 55 56 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 9

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 10 grams of naphazoline in a liter of pharmaceutical composition at 1% carbon isotopes ^{| 3} C 57 58 59 60 61 62 63 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

- 13 021232

Table 10

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 0.1 grams of naphazoline in a liter of pharmaceutical composition at 75% carbon isotopes ^{| 3} C 64 65 66 67 68 69 70 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 11

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 1 gram of naphazoline in a liter of pharmaceutical composition at 75% ¹³ C carbon isotopes 71 72 73 74 75 76 77 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 12

Pharmaceutical formulations based on naphazoline and minerals when substituted in the pharmaceutical composition of ¹² C carbon isotopes with ¹³ C carbon isotopes

Mineral substance The serial number of the pharmaceutical composition with 10 grams of naphazoline in a liter of pharmaceutical composition at 75% ¹³ C carbon isotopes 78 79 80 81 82 83 84 Calcium, mg / L 0.01 0.1 0.2 5.0 125.5 150.0 210.0 Potassium, mg / L 0.01 0.02 0.3 6.7 27.7 30.0 55.0 Zinc, mg / L 0.01 0.065 0.1 0.25 72.8 81.0 115.0

Table 13

Increased hypoxia from the use of naphthyzin

Time from the moment drug administration to the premises mice in heat chamber and termination air access (TV), min Life expectancy (average), min Naphthyzin, 2ml ’’ with concentration naphazoline 0.1 g / l Naphthyzin, 2ml with concentration naphazoline 1g / l thirty 22.1 20.0 60 21.3 nineteen. 90 20.8 19.0

*) The dose of the drug per mouse.

- 14 021232

Table 14

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

Serial number pharmaceutical composition Life expectancy (average), min Tv time was 30 min Tv time was 90 min one 22.1 20.8 2 21.5 20.1 3 20.1 19.2 4 19.3 18.8 5 18.0. 17.1 6 18.0 17.0 7 23.0 20.7 8 20.0 19.0 nine 19.7 18.5 10 19.1 17.7 eleven 18.3 17.1 12 17.0 16.1 thirteen 17.0 16.1 14 20.0 19.0 fifteen 18.1 17.6 sixteen 17.7 17.1 17 17.1 16.5 eighteen 16.6 16.1 nineteen 15.6 15.0 twenty 15.6 15.0 21 18.0 17.5

- 15 021232

Table 15

Enhanced hypoxia from the use of pharmaceutical formulations based on naphazoline, minerals at 0.5% ¹³ C carbon isotopes

Serial number pharmaceutical composition Life expectancy (average), min Tv time was 30 min Tv time was 90 min 22 21.9 20.6 23 21.3 19.9 24 19.8 19.6 25 19.0 18.5 26 18.6 16.8 27 18.6 16.8 28 21.8 20.5 29th 19.8 18.8 thirty 19.6 18.3 31 18.9 17.4 32 18.1 16.6 33 16.3 16.1 34 16.3 16.1 35 19.5 18.5 36 17.9 17.4 37 17.5 16.8 38 16.6 16.1 39 16.3 15.8 40 15.4 14.9 41 15.4 14.8 42 17.8 17.3

- 16 021232

Table 16

Enhanced hypoxia from the use of pharmaceutical formulations based on naphazoline, minerals at 75% ¹³ C carbon isotopes

Serial number pharmaceutical composition Life expectancy (average), min Tv time was 30 min Tv time was 90 min 64 20.5 19.3 65 20.1 18.7 66 18.7 18.4 67 18.0 17.2 68 17.6 15.8 69 17.7 15.7 70 20.1 19.4 71 18.7 17.6 72 18.4 17.1 73 17.8 16.2 74 16.3 15.4 75 15.4 15.1 76 15.4 15.1 77 18.7 17.5 78 16.7 16.2 79 16.4 15.5 80 15.5 14.8 81 15.2 14.5 82 14.2 13.2 83 14.5 13.2 84 16.8 16.2

CLAIM

Claims (2)

CLAIM 1. The pharmaceutical composition is a solution containing naphazoline, characterized in that it contains minerals in the following ratio of components, mg / l: naphazoline - 0.1 10 ³ - 10 10 ³ ; calcium - 0.1 - 125.50; potassium - 0.02-27.7; zinc-0.065 -72.8, and the pharmaceutical composition has a vasoconstrictive, anti-congestive, anti-inflammatory effect. 2. The pharmaceutical composition is a solution containing naphazoline, characterized in that it additionally contains mineral substances in the following ratio of components, mg / l: - 17 021232 naphazolin-0.1 '10 ³ - 10 10 ³ ; calcium - 0.1 - 125.50; potassium - 0.02 - 27.7; zinc - 0.065 - 72.8, while the pharmaceutical composition contains ¹³ C carbon isotopes and the ratio pC = A ³ C / HC, where pC is the ratio of ¹³ C carbon isotopes to the total amount of carbon in the pharmaceutical composition; And ³ C is the number of carbon isotopes of ¹³ C in the pharmaceutical composition; NС is the total amount of carbon isotopes in the pharmaceutical composition, ranging from 0.005 to 0.75, and the pharmaceutical composition has a vasoconstrictive, anti-congestive, anti-inflammatory effect. 3. The pharmaceutical composition according to any one of claims 1, 2, characterized in that the pH value is from 4 to 7. TASH. 250020001500 1000'500 0-0 - | I I. | I,, 1 (| [- 2 4 0 8 one ί ΕΗπχ-πηίοΕμβίΓΊ - Μ1 (5) X>. TH7 + y1m5 ΘΙ 1πΙβ> Υ »1 "Ιοη 251 I I 1.51 one one ! one / 1.01 ί / 0.5 V 00 ^ .-- - 2 4 έ 8 16 18 Τιππί | Γηιηί 1g EGV 1 10-5 43 »Μ5 4 4tgy1B1 uh! ² 35? 4 thirteen p1-.----- g .: -— ................. I. ν .......... „......................... 2GS 400 800 UX 1600 1800 zug Molecular non substance - 23 352 - background mass.