EA020402B1 - Pharmaceutical composition comprising sodium, calcium, zinc and having a metabolic, anti-cataract, retina-protecting effect (variants) - Google Patents

Abstract

The invention relates to the art of medicine, specifically ophthalmology. The aim of the present invention is to create an effective pharmaceutical composition having a metabolic, anti-cataract, retina-protecting effect by virtue of said pharmaceutical composition containing taurine and additionally containing mineral substances: sodium, calcium, zinc and also the isotopes carbon-13. Use of the claimed pharmaceutical compositions will result in an enhanced healing effect and a more rapid onset thereof with no increase in the concentration of taurine, and will also result in the increased stability of a taurine-containing pharmaceutical composition during the shelf life thereof.

Description

The invention relates to the field of medicine, namely ophthalmology, and can be used as a means of having a metabolic, anti-cataract, retinoprotective effect.

State of the art

An important problem of modern medicine is the creation of new agents that can effectively protect and also treat eye diseases, which are the most common diseases.

Despite the great work that has been and is ongoing in this area, the creation of new drugs for the treatment of ophthalmic diseases is relevant. One of the areas of scientific research in this area is the search for regulators of biological reactions in the tissues of the eye.

Currently, taufon (with the active substance taurine) in the form of a 4% solution has found widespread use in the pharmacotherapy of ophthalmic diseases.

Taurine - 2-aminoethanesulfonic acid - contributes to the improvement of energy processes, has metabolic, anti-cataract, retinoprotective and other actions.

The invention claimed two variants of the pharmaceutical composition.

An analogue to each version of the pharmaceutical composition is a medicinal substance based on the drug taufon and other medicinal substances (RF patent 2320300, publ. 03/27/2008). An analogue is described in the method of complex treatment of optical neuritis. The method consists in the use of glucocorticosteroids, antioxidants, microcirculants, while medicinal substances: trental, emoxipin, solcoseryl, taufon are fed directly to the optic nerve through an infusion system located in retrobulbar space.

The disadvantage of an analogue is a small therapeutic effect.

Known eye drops (RF patent 2295331, publ. March 20, 2007) of reparative and hypotensive effects based on a biogenic compound, which is one of the end products of the metabolism of sulfur-containing amino acids, containing dextran and benzalkonium chloride, and taurine and additionally cyanocobalamin as a biogenic compound.

The disadvantages of the analogue are the low rate of onset of the therapeutic effect in the treatment of corneal dystrophy, cataracts, corneal injury, damage to the lining of the eye, small therapeutic effect and instability during the expiration date.

Also known patent EAPO 008591, publ. 06/29/2007. The patent proposes the use of derivatives of 3- (3,5-dioxo-4,5-dihydro-3H- (1,2,4) triazin-2-yl) benzamide as P2X ₇ inhibitors for the treatment of various diseases. The patent provides for the use of isotopes ¹³ C, ¹⁵ Ν, etc. for making isotopic labels in a drug. The isotopes determine the dynamics of the distribution of the drug in the tissues of the body.

The disadvantage of the drug is the inability to use for the treatment of eye diseases.

Known food biologically active additive (RF patent 2035880, publ. 05.27.1995) containing sodium, potassium, magnesium, iron, zinc, copper, manganese, nickel, boron, cobalt, molybdenum, vanadium, fluorine, glycerin, glycine, ethylenediaminetetraacetic acid (EDHA), b - (+) - tartaric acid, succinic stone acid, b - (+) - ascorbic acid, distilled water, lithium, citric acid and water. The food supplement has a changing quantitative spectrum of microelements, which makes it possible to adequately increase or decrease their concentration in the formulation to enrich the corresponding group of food products. A nutritional supplement can be used to enrich a variety of foods.

The disadvantage of a dietary supplement is the inability to use for the treatment of eye diseases.

Also known is a taurine-containing food vitamin-mineral supplement (RF patent 2335926, publ. 20.10.2008), including β-acetyl-β-glutamic acid, pyridoxine hydrochloride (vitamin B ₆ ), glycine (aminoacetic acid), zinc acetate dihydrate or zinc citrate , riboxin, nicotinamide (vitamin PP (B3)), taurine and succinic acid (HOOC-CH ₂ -CH ₂ -COOH).

The disadvantage of a dietary supplement is the inability to use for the treatment of eye diseases.

The prototype of the two variants of the invention is the pharmaceutical composition (Un: // teb1.gi/IOS/x0905.Mt), which has a metabolic, anti-cataract, retinoprotective effect and containing taurine.

Signs of a pharmaceutical composition having a metabolic, cataract, retinoprotective effect containing taurine coincide with the signs of two variants of the invention.

Taurine is a sulfur-containing amino acid formed in the body during the conversion of cysteine; stimulates the processes of repair and regeneration in diseases of a dystrophic nature and diseases accompanied by a sharp violation of the metabolism of eye tissues. In the prototype, the content of taurine is 4%. It is used in ophthalmology for dystrophic lesions of the set chatiois of the eye; hereditary tapetoretinal degeneration of the eye; dystrophies and injuries of the cornea; cataracts of various origin.

The pharmaceutical composition contributes to the normalization of the functions of cell membranes, activation of energy and metabolic processes, preservation of the electrolyte composition of the cytoplasm, etc. It has a metabolic effect.

The source (Bunin A.Ya., Ermakova VN, Babizhaev MA The results of the combined use of taufon and timolol in the treatment of patients with open-angle glaucoma / Bulletin of Ophthalmology. - 1990, No. 4, p. 9-11) describes the use of taurine with eye diseases: corneal dystrophy; cataract (senile, diabetic, traumatic, radiation); corneal injury (as a stimulant of reparative processes); lesions of the lining of the eye; glaucoma (to reduce intraocular pressure).

The disadvantages of the prototype are the relatively low speed of the onset of the therapeutic effect in the treatment of corneal dystrophy, cataracts, corneal injuries, damage to the lining of the eye, small therapeutic effect and not stability during the expiration date.

SUMMARY OF THE INVENTION

Definitions of terms.

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

Anti-cataract activity - activity aimed at protecting the lens proteins of the eye (lens protection from clouding, progression of clouding).

Retinoprotective action - an action aimed at protecting the retina.

Metabolic action - an action aimed at metabolic processes in the eye cell.

The metabolic effect includes the optimization of oxygen consumption by cells and tissues; increased resistance to lack of oxygen; normalization of water-salt metabolism; improved metabolism of neurotransmitters;

improvement of microcirculation of fluids in the body; increased visual acuity;

intensification of the processes of regeneration (healing, recovery) and differentiation (maturation) of epithelial tissues and organs.

Metabolic agent - a means of regulating the metabolism in the body.

Electroretinography is a graphic recording of bioelectric potentials that occur in the retina of the eye when exposed to light; carried out using oscilloscopes, electroretinographs.

Retinopathy is not an inflammatory lesion of the retina of the eyeball. The main reason is vascular disorders, which lead to a disorder in the blood supply to the retina. Retinopathy often manifests itself as a complication of hypertension, diabetes mellitus and other systemic diseases.

Progressive retinal atrophy is a term adopted to describe a number of hereditary neuroretinal degenerations: generalized progressive retinal atrophy (GPAS) and central progressive retinal atrophy (CPAS).

The objective of the present invention is to provide an effective pharmaceutical composition having a metabolic, anti-cataract, retinoprotective effect.

The problem is solved due to the fact that the pharmaceutical composition having a metabolic, anti-cataract, retinoprotective effect, contains taurine, a pharmaceutically acceptable solvent, made in the form of eye drops, and differs from the prototype in that it additionally contains mineral substances in the following ratio of components, mg / l :

taurine - 1 10 ³ - 160 10 ³ ; sodium - 0.01 - 395.0; calcium - 0.007 - 135.0; zinc-0.01 -66.9, and water was used as a pharmaceutically acceptable solvent.

The problem is also solved due to the fact that the pharmaceutical composition having a metabolic, anti-cataract, retinoprotective effect contains taurine, a pharmaceutically acceptable solvent made in the form of eye drops, and differs from the prototype in that it additionally contains mineral substances in the following ratio of components, mg / l:

- 2 020402 taurine - 1 10 ³ - 160'10 ³ ; sodium -0.01 -395.0; calcium - 0.007 - 135.0; zinc-0.01 -66.9, while taurine contains ¹³ C isotopes, the ratio of ¹³ C carbon isotopes to the total carbon in taurine ranges from 0.003 to 0.75, and water was used as a pharmaceutically acceptable solvent.

The pharmaceutical composition can be performed with a pH of from 7.0 to 7.9.

In the pharmaceutical composition, the active substance is taurine.

The chemical formula of taurine

ABOUT

II

BUT '£) ^ΝΗ 2

Chemical name: 2-aminoethanesulfonic acid.

Gross formula (or empirical formula) of taurine: ί '.' ₂ Η-ΝΟ ₃ 8.

The taurine molecule contains an acidic sulfo group 8O ₃ H and a basic amino group ΝΗ ₂ .

The kinematic viscosity of the pharmaceutical composition in the form of eye drops is from 1.01 to 1.23 mm ² / s and is determined primarily by the content of the active substance and minerals in the water. The kinematic viscosity of the pharmaceutical composition is determined using a capillary viscometer.

The claimed pharmaceutical formulations are used as a prototype for the following eye diseases: corneal dystrophy; cataract (senile, diabetic, traumatic, radiation); corneal injury (as a stimulant of reparative processes), damage (or damage) to the lining of the eye, etc.

In the pharmaceutical composition, in addition to the active substance and mineral substances, a pharmaceutically acceptable solvent can be used. In addition to the solvent, a pharmaceutically acceptable excipient or pharmaceutically acceptable excipients may be used in the pharmaceutical composition.

In general, a pharmaceutically acceptable excipient may not be used in the pharmaceutical composition.

As a pharmaceutically acceptable solvent can be used water (distilled water, water for injection), as well as another solvent.

As a pharmaceutically acceptable excipient, methyl parahydroxybenzoate (nipagin) or another substance may be used.

A pharmaceutically acceptable excipient is typically a preservative and / or antiseptic. The substance actively inhibits the growth of gram-positive bacteria and gram-negative bacteria.

When used in the pharmaceutical composition of nipagin, its content is selected from the range of 1-10 ³ -300-10 ³ mg / L.

Other substances can be used as preservatives, in particular phenoxyethanol, imidazolidine urea.

In other words, the basis of the pharmaceutical composition is the active substance taurine and mineral substances in a pharmaceutically acceptable solvent, in particular in water.

In the pharmaceutical composition, the active substance taurine and minerals (as well as an auxiliary substance, if applicable) are selected from the above ranges, and the rest (water) is selected.

The technical results of the invention are:

an increase in the speed of the onset of the therapeutic effect (a decrease in the time of the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of taurine in the treatment of corneal dystrophy, cataracts, corneal injury, damage to the lining of the eye;

an increase in the therapeutic effect without increasing the concentration of taurine in the treatment of corneal dystrophy, cataracts, corneal injury, damage to the lining of the eye;

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

Currently, increasing the speed of the onset of the therapeutic effect with the introduction of drugs into the body provides the dosage of the drug and its exposure time;

introducing into the solution an auxiliary ingredient - an accelerator of the speed of exposure (a special case of a regulator of the speed of exposure).

- 3,020,402

Here are some examples.

A known solution (RF application No. 94015245, publ. 12/27/1995), in which a 5-10% solution of hyaluronic acid is used as a regulator of the speed of exposure.

Known pacemaker drug (RF patent No. 2068697, publ. 10.11.1996) containing green toad venom, chlorobutane dihydrate, sodium chloride and water. To increase the onset of the pacemaker effect (while maintaining the duration of action) provided by the specified poison, up to 95% ethyl alcohol is introduced into the drug. Alcohol due to osmotic phenomena causes pain and local negative reaction, which accelerates the effect of the drug.

Biologically active additives are 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 (AS USSR 1683190, publ. 20.04.1995). 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 is achieved while maintaining the duration of action without increasing the concentration of the active substance in the pharmaceutical agent by introducing mineral substances into the pharmaceutical composition.

Below is a summary of 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, etc.) in solution (in particular, in pharmaceutical composition) are contained in pharmaceutically acceptable salts, for example, succinates, chlorides, 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 description, 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 mineral substances that make up the drug enhance their therapeutic effect. This is ensured mainly due to the effect on the enzymatic system of the body.

For all options considered in the invention of pharmaceutical compositions, the rational ranges of the values of the content of mineral substances are as follows, mg / l:

sodium-0.01 -395.0; calcium - 0.007 - 135.0; zinc -0.01-66.9.

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 taurine in the pharmaceutical composition, an increase in the stability of the pharmaceutical composition with taurine during the expiration date are provided by the introduction of certain minerals (a certain combination of minerals) in the pharmaceutical composition 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 greater than specified in the range, the amount of mineral substance not only does not lead to the achievement of technical results, but worsens the therapeutic effect of taurine. It was found that with an increase in the concentration of minerals in the pharmaceutical composition (above the stated ranges), they can suppress the effect of taurine, the therapeutic effect of the drug disappears.

- 4,020,402

An additional increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of taurine in the pharmaceutical composition, and an increase in the stability of the pharmaceutical composition with taurine over the expiration date are ensured by partial replacement of ¹² C carbon isotopes with ¹³ C carbon isotopes in the pharmaceutical composition. isotopic enrichment of various substances that were used to create the claimed pharmaceutical compositions.

List of drawings

In FIG. 1 shows the ¹³ C-NMR spectrum of the pharmaceutical composition.

In FIG. 2 shows the ¹ H-NMR spectrum of the pharmaceutical composition.

In FIG. 3 shows a fragment of ¹ H-NMR spectrum of the pharmaceutical composition.

In FIG. 4 presents a chromatogram of the pharmaceutical composition on a column with a sorbent C18.

In FIG. 5 shows the left side of the chromatogram of the pharmaceutical composition on a column with sorbent C18.

In FIG. 6 shows the right side of the chromatogram of the pharmaceutical composition on a column with sorbent C18.

In FIG. 7 shows a chromatogram of the pharmaceutical composition on a column with a sorbent C18.

In FIG. 8 shows the left side of the chromatogram of the pharmaceutical composition on a column with sorbent C18.

In FIG. 9 shows the right side of the chromatogram of the pharmaceutical composition on a column with sorbent C18.

In FIG. 10 is a graph showing the results of studies of the claimed pharmaceutical formulations.

In FIG. 11 is a diagram of a cavitation reactor for isotopic enrichment of various mixtures.

In FIG. 12 is a cross-sectional view of a cavitation reactor.

In FIG. 13 is a diagram of an isotope enrichment plant.

Information confirming the possibility of carrying out the invention

The invention is illustrated by the examples below.

Example 1 - a method of introducing minerals into water.

Example 2 - a method of obtaining pharmaceutical compositions and verification of stability.

Example 3 - tests for general toxicity.

Example 4 - illustrate the effectiveness of the claimed pharmaceutical compositions having metabolic, anticataract, retinoprotective action.

In the description, for clarity, presents a comparison of the effects of the claimed pharmaceutical compositions with the action of the drug taufon in the treatment of eye diseases in animals. In the experiments used electroretinography.

Example 1

The introduction of minerals into the solution (in water) was carried out according to the method described in the source [Guidelines on 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.

To conduct in-depth studies when developing an application for the invention, the concentration of metals in solutions was provided in the following ranges, mg / l:

sodium - 0.01 - 395.0; calcium - 0.007 - 135.0; zinc-0.01 -66.9.

In addition, studies have been conducted on the extremely high content of minerals in the compositions. These studies will be written below.

The concentration of metals in 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, p.1.3.2.1 of the source [Guide for quality control methods and the safety of dietary supplements. - M.: Federal Center for Sanitary Inspection of the Ministry of Health of Russia, 2004. - 240 p.].

- 5,020,402

Example 2

For example, we describe the receipt of one pharmaceutical composition with the content of taurine and minerals, mg / l:

taurine -40 10 ³ ; sodium - 40.0; calcium - 10.0; magnesium - 1.5; iron - 0.03; zinc-2.5.

8 l of water for injection is poured into the reactor with a stirrer, after which 400 g of taurine is loaded into the reactor, a solution with mineral substances is poured, mg / l:

sodium - 400.0; calcium - 100.0; magnesium - 15.0; iron 0.3; zinc - 25.0 with constant stirring. Then adjust the pH of the solution to 7.4. The resulting solution was adjusted to a volume of 10 l with water for injection and passed through a filter.

The control showed the qualitative performance of the pharmaceutical composition.

In a similar manner, other claimed pharmaceutical formulations with minerals and taurine were obtained and controlled.

Laboratory studies of the claimed pharmaceutical formulations have been performed. In FIG. 1-9 illustrate studies of only one of the above pharmaceutical formulations with taurine and minerals.

In FIG. 1 shows the ¹³ C-NMR spectrum of the pharmaceutical composition: ¹³ C-NMR (360 MHz, Ό ₂ Θ): 46.63; 34.60.

In FIG. 2 shows the ¹ H-NMR spectrum of the pharmaceutical composition.

In FIG. 3 shows a fragment of ¹ H-NMR spectrum of the pharmaceutical composition: ¹ H-NMR (360 MHz, Ό ₂ Θ): 4.75 (s, 23.4H); 3.432 (t, 1 = 7.2 Hz, 2H); 3.262 (t, 1 = 7.2 Hz, 2H).

In FIG. 4 shows a chromatogram of a pharmaceutical composition, on a column with a sorbent C18, with detection at 220 nm.

In FIG. 5 shows the left side of the chromatogram of the pharmaceutical composition, on a column with a sorbent C18, with a mass selective detector. A peak with a retention time of 2.6 minutes was highlighted; 126.7 - signal of the desired ion, 251.8; 376.2; 501.3; 626.2; 626.2; 751.1 - signals of dimer, trimmer, tetramer, etc. the desired ion.

In FIG. 6 shows the right side of this chromatogram of the pharmaceutical composition.

In FIG. 7 shows a chromatogram of a pharmaceutical composition, on a column with a sorbent C18, with detection at 220 nm.

In FIG. Figure 8 shows the left side of the chromatogram of the pharmaceutical composition, on a column with a C18 sorbent, with a mass selective detector. A peak with a retention time of 2.6 minutes was highlighted; 126.7 - signal of the desired ion; 251 - signal of the dimer of the desired ion.

In FIG. 9 shows the right side of this chromatogram of the pharmaceutical composition.

The remaining claimed and described pharmaceutical formulations were also subjected to laboratory studies. Chromatograms of samples of pharmaceutical compositions with a different composition of mineral substances are similar (differences in graphs are small).

In addition, the electrical characteristics of pharmaceutical compositions have been investigated. It has been established that the active substance and mineral substances are present in the pharmaceutical composition in amounts that, at a temperature of 253-773 K, an electric or electromagnetic field frequency of 50-100 Hz, the value of the relative component of the relative dielectric constant from 5 to 80. The dielectric constant of the pharmaceutical composition characterizes its ability to the accumulation of electric charges and can have a significant effect on the activity of the active substance.

It has been established that the value of the real component of the relative dielectric constant (it is also called simply - relative dielectric constant) can be changed by changing the concentration (content) of mineral substances in the pharmaceutical composition. It is advisable to increase the pharmaceutical effect to provide the value of the real component of the relative dielectric constant from 5 to 80. If its values are lower or

- 6,020,402 higher, the effectiveness of the pharmaceutical composition may be reduced. Therefore, in studies, the indicator of the actual component of the relative dielectric constant was a control, a kind of criterion for the applicability of the pharmaceutical composition.

Studies have also shown that the claimed compounds are stable (do not reduce their effectiveness) for 3-3.5 years.

In contrast, studies of Taufon eye drops have shown that they reduce their effectiveness by approximately 20-30% over 3 years.

Example 3

Tests for general toxicity were carried out by administering pharmaceutical compositions based on taurine and minerals to rats.

In addition, tests were conducted on rats, cats and dogs with damage to the retina of the eyeball (retinopathy).

For studies of the concentration of mineral substances in solutions selected, mg / l: sodium - 395.0; calcium - 35.0; magnesium - 23.0; iron - 24.5; zinc - 66.9; potassium 23.0; manganese - 7.5; copper - 0.65; cobalt-0.5; chrome - 0.5; molybdenum - 0.5.

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

With long-term use of pharmaceutical compositions based on taurine and minerals in rats, no changes were found in the organs and tissues of the body (were insignificant).

Tests in rats, cats, and dogs with damage to the retina of the eyeball also confirmed that the claimed pharmaceutical formulations are not toxic. It was found that the compositions do not adversely affect the functional state of the eyeball. In the tests, the morphological composition of the blood was monitored, during which no significant changes in the blood composition were detected.

The authors tested the effect of pharmaceutical formulations with the above mineral content and taurine content of 160 g / l. In the experiments, droppers were used, forming droplets of 25-27 μl. In the tests, visual impairment was not observed (a short-term slight eye irritation was recorded).

Example 4

Evaluation of the effectiveness of the claimed pharmaceutical compositions in animals with progressive retinal atrophy.

Evaluation of the effectiveness of the claimed pharmaceutical compositions was carried out in comparative trials with the drug taufon. The characteristics of α- and β-waves of electroretinograms in animals before and after treatment were used as a comparison criterion.

Electroretinography was carried out according to the method developed by scientists of the Moscow State Academy of Veterinary Medicine and Biotechnology. K.I. Scriabin and on the equipment of the Academy using an electroretinograph.

In the experiments, electroretinograms of healthy animals and patients at different stages of the disease (initial, secondary and last) were recorded.

In particular, the amplitudes of the α and β waves, the change in time to each peak, and the temporal characteristics of the peaks were recorded.

In the table. 10 shows the comparative characteristics of electroretinogram indices in healthy and sick dogs at various stages of the disease. The amplitudes of the αΐ wave, a2 wave, βΐ wave, and b2 wave were used as indicators.

In a similar way (in relative values), electroretinograms in healthy and sick cats and rats at different stages of the disease look.

The studies found that the dynamics of the treatment process is convenient (and visual) to reflect the change in the amplitude of the B2-wave.

- 7 020402

In the table. 11 shows the change in the amplitude of the B2 wave of the electroretinogram during treatment with taufon (taurine) for 50 days. It was established that the amplitude of the b-waves during treatment increases. In FIG. 10 positions 34, 37 and 40 indicate the areas along which the curves of the dependence of the amplitude of the b2-wave from time to time are used when using the taufon preparation. In the graph depicted in FIG. 10, along the ordinate axis - the amplitude of B2 waves in μV, along the abscissa axis - treatment time in days.

For research, animals (dogs, cats, rats) with various types of retinopathy were selected. Animals were divided into three groups with different initial conditions (at different stages of the disease). In the experiments, taufon was used (region 37 in Fig. 10), diluted taufon with water 1:40 with a taurine content of 1 g / l (region 34 in Fig. 10), a composition with taurine content of 160 g / l (region 40 in Fig. 10 )

In FIG. 10 also shows the regions through which the curves of the dependence of the amplitude of the b2-wave on time pass when using pharmaceutical compositions with taurine, minerals and isotopes ¹³ C.

In the experiments, pharmaceutical formulations from No. 1 to No. 45 were investigated (see tab. 1-9). Each composition was tested on 3-7 animals with various types of retinopathy. Also in the experiments used animals that have already passed one or two courses of treatment.

The following is established.

1. Pharmaceutical formulations No. 1, 6, 11, 16, 21, 26, 31, 36 and 41 in their action practically do not exceed the effect of taufon. The graphs depicting the effect of trains No. 1, 6, and 11 run through region 34.

The graphs depicting the effects of trains No. 16, 21, and 26 pass through region 37 closer to the upper boundary.

The graphs depicting the effects of trains No. 31, 36, and 41 pass through region 40 also closer to the upper boundary.

Therefore, it is not practical to use these pharmaceutical formulations in practice.

2. Pharmaceutical composition No. 4 in its effect is equal to the effect of pharmaceutical composition No. 3. The graphs depicting the effect of these compounds pass through region 35.

Pharmaceutical composition No. 9 in its effect is equal to the effect of pharmaceutical composition No. 8. The graphs depicting the effect of these compounds pass through region 35 closer to the lower boundary of the region.

Pharmaceutical composition No. 14 in its effect is equal to the effect of pharmaceutical composition No. 13. The graphs depicting the effect of these compounds pass through region 38.

Pharmaceutical composition No. 19 in its effect is equal to the effect of pharmaceutical composition No. 18. The graphs showing the effect of these compounds pass through region 38 closer to the lower boundary of the region.

Pharmaceutical composition No. 24 in its effect is equal to the effect of pharmaceutical composition No. 23. The graphs showing the effect of these compounds pass through region 38 closer to the upper boundary.

Pharmaceutical composition No. 29 in its effect is equal to the effect of pharmaceutical composition No. 28. The graphs depicting the effect of these compounds pass through region 39.

Pharmaceutical composition No. 34 in its effect is equal to the effect of pharmaceutical composition No. 33. The graphs showing the effect of these compounds pass through region 41 closer to the lower boundary of the region.

Pharmaceutical composition No. 39 in its effect is equal to the effect of pharmaceutical composition No. 38. The graphs showing the effect of these compounds pass through region 41 closer to the upper boundary.

Pharmaceutical composition No. 44 in its effect is equal to the effect of pharmaceutical composition No. 43. The graphs depicting the effect of these compounds pass through region 42.

Thus, pharmaceutical formulations No. 4, 9, 14, 19, 24, 29, 34, 39 and 44 are not practical to use due to the lack of differences in the effectiveness of the action compared with formulations No. 3, 8, 13, 18, 23, respectively , 28, 33, 38, and 44.

3. The studies also found the following.

Pharmaceutical composition No. 5 in its effect is inferior (by about 3-5%) to the effect of pharmaceutical composition No. 3 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 10 in its effect is inferior (by about 3-5%) to the effect of pharmaceutical composition No. 8 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 15 in its effect is inferior (by about 3-5%) to the effect of pharmaceutical composition No. 13 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 20 in its effect is inferior (by about 5-15%) to the effect of pharmaceutical composition No. 18 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 25 is inferior (by about 5-15%) to the effect of pharmaceutical composition No. 20,0402 of the pharmaceutical composition No. 23 and to the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 30 is inferior (by about 5-15%) to the action of pharmaceutical composition No. 28 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 35 is inferior (by about 10-15%) to the action of pharmaceutical composition No. 33 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 40 is inferior (by about 10-15%) to the effect of pharmaceutical composition No. 38 and the action of taurine of the corresponding concentration.

Pharmaceutical composition No. 45 is inferior (by about 10-15%) to the action of pharmaceutical composition No. 43 and the action of taurine of the corresponding concentration.

Thus, pharmaceutical compositions No. 5, 10, 15, 20, 25, 30, 35, 40, 45 in practice, it is impractical to use, since their effect is worse than the action of taufon with the appropriate concentration.

4. It has been established that in practice it is advisable to use pharmaceutical formulations No. 2, 3, 7, 8, 12, 13, 17, 18, 22, 23, 27, 28, 32, 33, 37, 38, 42 and 43.

Table analysis 10, 11 and the graphs shown in FIG. 10 shows that the claimed pharmaceutical compositions provide an increase in the speed of the onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of taurine, as well as an increase in the therapeutic effect without increasing the concentration of taurine.

The obtained results of animal studies can be used in the treatment of corneal dystrophy, cataracts, corneal trauma, damage to the lining of the eye. The mechanisms for treating eye diseases in animals and humans are similar.

The composition of minerals in the pharmaceutical formulations described above was limited by the list of minerals (macronutrients and micronutrients) in the Guide to Methods for Monitoring the Quality and Safety of Dietary Supplements. - M .: Federal Center for State Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004. - 240 p. The Guide 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 above compositions, ranges of weight values (in mg / l) of the components are given, which, in comparison with the prototype (taufon), give an effect (by technical results) of more than 3-5% and higher.

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 studies on the effect of ¹³ C carbon isotopes on the stability and effectiveness of taurine-based medicinal formulations.

It was found that increasing the stability of the claimed pharmaceutical composition over the shelf life can be achieved by replacing (from 0.3 to 75%) ¹² C carbon isotopes with ¹³ C carbon isotopes. It was found that ¹³ C carbon isotopes in taurine molecules slow down the chemical processes occurring in the molecules reactions 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 rats with food and instilling eyes with a taurine composition enriched with 75% carbon ¹³ C does not lead to side effects and poor health.

In the process of experimental verification of the claimed pharmaceutical compositions enriched in ¹³ C carbon isotopes, it was found that these compounds have increased stability, are non-toxic and, in addition, have an increased metabolic, anticataract, retinoprotective effect compared to a pharmaceutical composition in which there are no carbon isotopes ¹³ S.

Methods for the production of a stable highly enriched non-radioactive carbon-13 isotope are widely used in Russian and world industry. Methods for producing the carbon-13 isotope by gas diffusion through porous walls, diffusion in a vapor 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 in the source [Isotope Separation. Physical Encyclopedia. L1p: // FS.asabet1.S.Gi / FS.p8Rb/eps_pLu81C8/1071/IS0T0P0B].

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 100% of isotopes in a substance. The work is in the interests of medical diagnosis. In the source [Nanotechnology and the inclusion of deuterium 2H atoms, carbon ¹³ C, nitrogen ¹⁵ Ν and oxygen ¹⁸ O in the molecules of amino acids and proteins. LR: //8atPb.yi/o/o1ed_no_t/syositep18apY8eysd8o1edto8shto1Yokitep1upapo1ebpo1odg) aotk1) ischea1oto \ uysrep) a211g1G.51it1 | 165 references to foreign sources of information on the isotopic enrichment of various substances are given.

- 9 020402

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 procedure given in the source [R.F. Ganiev, V.I. Kormilitsyn, L.I. Ukrainian. Wave technology for the preparation of alternative 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. 11 is a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular, hydrocarbon reagents for producing taurine 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 an electric motor rotor and a pump wheel of 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

The installation diagram is shown in FIG. thirteen.

The cavitation reactor 1 (see Fig. 11) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.

In FIG. 12 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, 14 and 15. Outside, the channel is limited by walls 16 and 17, as well as two covers 11 and 12.

In FIG. 11, arrow 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 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, 3, and 4 are cavitation zones 20, 21, 22, and 23. Upon entering the cavitation region, the reagent boils, cavitation bubbles appear, and cavitation bubbles collapse when leaving the cavitation region . Moreover, in the area (in 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 are observed. 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 the ¹³ C isotope ^{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 the ¹³ C carbon isotope to 75%.

Thus, pharmaceutical compositions were obtained containing taurine with a carbon isotope content of ¹³ C from 0.3 to 75% of the total carbon in the pharmaceutical composition.

In the graph (see Fig. 10), the curves describing the therapeutic effect of pharmaceutical formulations with a taurine content of 1-10 ³ mg / L pass through regions 34, 35 and 36. Moreover, the curves describing the effect of diluted 1:40 taufon pass through region 34 .

On the graph (see Fig. 10), the curves describing the therapeutic effect of pharmaceutical formulations with a taurine content of 40-10 ³ mg / l (including taufon) pass through regions 37, 38 and 39. Moreover, the curves describing the effect of 4% taufon pass through area 37.

On the graph (see Fig. 10), the curves describing the therapeutic effect of pharmaceutical formulations with a taurine content of 160-10 ³ mg / L pass through regions 40, 41 and 42. Moreover, the curves describing the effect of taurine with a concentration of 160-10 ³ mg / l and without the addition of minerals pass through region 40.

The enrichment of pharmaceutical formulations with ¹³ C isotopes increases their effectiveness by 3-10% and higher compared with the effectiveness of pharmaceutical formulations with only minerals.

- 10,020,402

When implementing the claimed pharmaceutical formulations in practice, the technical results will be ensured:

an increase in the speed of the onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of taurine in the treatment of corneal dystrophy, cataracts, corneal injury, damage to the lining of the eye;

an increase in the therapeutic effect without increasing the concentration of taurine in the treatment of corneal dystrophy, cataracts, corneal injury, damage to the lining of the eye;

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

Table 1

Pharmaceutical formulations based on taurine and minerals

Mineral substance Serial number of pharmaceutical composition with 1 gram taurine per liter 2 3 4 5 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

*) The numbering of pharmaceutical formulations is through.

table 2

Pharmaceutical formulations based on the preparation of taurine, a mineral substance containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.003)

Mineral substance Serial number of pharmaceutical composition with 1 gram taurine per liter 6 7 8 nine 10 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

Table 3

Pharmaceutical formulations based on the preparation of taurine, minerals containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.75)

Mineral substance Serial number of pharmaceutical composition with 1 gram taurine per liter eleven 12 thirteen 14 fifteen Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

- 11 020402

Table 4

Pharmaceutical formulations based on taurine and minerals

Mineral substance Serial number of the pharmaceutical composition with 40 grams taurine per liter sixteen 17 eighteen nineteen twenty Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

Table 5

Pharmaceutical formulations based on the preparation of taurine, a mineral substance containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.003)

Mineral substance Serial number of the pharmaceutical composition with 40 grams taurine per liter 21 22 23 24 25 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

Table 6

Pharmaceutical formulations based on the preparation of taurine, minerals containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.75)

Mineral substance Serial number of the pharmaceutical composition with 40 grams taurine per liter 26 27 28 29th thirty Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

- 12,020,402

Table 7

Pharmaceutical formulations based on taurine and minerals

Mineral substance Serial number of the pharmaceutical composition with 160 grams taurine per liter 31 32 33 34 35 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

Table 8

Pharmaceutical formulations based on the preparation of taurine, a mineral substance containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.003)

Mineral substance Serial number of the pharmaceutical composition with 160 grams taurine per liter 36 37 38 39 40 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

Table 9

Pharmaceutical formulations based on the preparation of taurine, minerals containing ¹³ C carbon isotopes (the ratio of ¹³ C carbon isotopes to the total carbon in the pharmaceutical composition is 0.75)

Mineral substance Serial number of the pharmaceutical composition with 160 grams taurine per liter 41 42 43 44 45 Sodium, mg / L 0.005 0.01 395.0 430.0 510.0 Calcium, mg / L 0.004 0.007 135.0 190.0 230.0 Zinc, mg / L 0.007 0.02 67.0 85.0 95.0

- 13 020402

Table 10

Comparative characteristics of electroretinogram indices in healthy and sick dogs at various stages of the disease

Indicators electroretinograms Dog Health Healthy dog Initial stage diseases Average stage diseases Late stage diseases Amplitude of a 1-wave, μV ST ⁵ 25 “'' 19 ⁴ ' 15> Amplitude of a2-wave, μV 67 53 41 twenty Amplitude of βΐ-wave, μV 198 171 135 thirteen Amplitude of the P2 wave, μV 230 195 150 22

*) The arithmetic average value of an indicator measured in 25 dogs.

**) The arithmetic average of the indicator measured in 16 dogs. ***) The arithmetic average value of the indicator measured in 14 dogs. ****) The arithmetic average of the indicator measured in 11 dogs.

Table 11

Change in the amplitude of the B2 wave of the electroretinogram during treatment with taurine, μV

Initial values amplitudes [12-waves electroreticogram we μV Treatment time, days 10 twenty thirty 40 fifty twenty 32 40 45 49 fifty 22 33 41 46 52 55 71 one hundred 125 145 158 163 155 188 210 230 250 250 170 200 225 240 250 250

CLAIM

Claims (2)

1. A pharmaceutical composition having a metabolic, cataract, retinoprotective effect, containing taurine, a pharmaceutically acceptable solvent, made in the form of eye drops, characterized in that it additionally contains mineral substances in the following ratio of components, mg / l: taurine - 1 10 ³ - 160 10 ³ ; sodium - 0.01 - 395.0; calcium - 0.007 - 135.0; zinc-0.01 -66.9, and water was used as a pharmaceutically acceptable solvent. 2. A pharmaceutical composition having a metabolic, anti-cataract, retinoprotective effect, containing taurine, a pharmaceutically acceptable solvent, made in the form of eye drops, characterized in that it additionally contains mineral substances in the following ratio, mg / l: taurine - 1 10 ³ - 160 10 ³ ; sodium-0.01 -395.0; calcium - 0.007 - 135.0; zinc-0.01 -66.9, while taurine contains ¹³ C isotopes, the ratio of ¹³ C carbon isotopes to the total carbon in taurine ranges from 0.003 to 0.75, and water was used as a pharmaceutically acceptable solvent.