RU2484844C1 - Method for preventing and treating diabetes mellitus complications associated with developing degenerative processes in nerve tissue, pharmaceutical composition for neuroprotective therapy of such complications, and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a method for preventing and treating the diabetes mellitus complications associated with the developing degenerative processes of the nervous tissue, comprising administering a medicine containing a peptide of general formula Pro-Gly-Pro, or a pharmaceutically acceptable salt thereof in effective amounts. There are presented pharmaceutical composition comprising said peptide for the neuroprotective therapy of the complications of diabetes mellitus and the method for preparing it.

EFFECT: group of inventions enables the more effective prevention and treatment of the diabetes mellitus complications associated with the developing degenerative processes of the nervous tissue by the use of the peptide Pro-Gly-Pro, or a pharmaceutically acceptable salt thereof.

9 cl, 2 dwg, 4 tbl, 7 ex

Description

The invention relates to medicine and relates to methods and medicines used for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue.

Diabetes mellitus is accompanied by the development of a number of complications, including those associated with a deterioration in the functioning of the central and peripheral nervous systems. One of the most common complications of diabetes and the main cause of vision loss in middle-aged people is diabetic retinopathy (DR). It is characterized by a specific lesion of the vessels and neuronal layers of the retina. Another complication of diabetes associated with the functioning of the nervous system is diabetic encephalopathy (DE). It manifests itself in the development of impaired memory and learning ability and is especially common in older people. Despite some significant differences in the pathogenetic mechanisms of its occurrence and course, both of these complications are equally characteristic of both insulin-dependent and non-insulin-dependent diabetes. Currently, the main way to prevent DR is to maintain a long-term and most stable compensation for diabetes. Other well-known therapeutic agents to prevent or slow the development of DR in its early stages have been found to be ineffective. In the late stages of DR, the method of laser photocoagulation is recognized as the most effective, but its use is associated with a risk of hemorrhage in the retina and vitreous body. Methods for the prevention and treatment of DE are currently not developed and are not widely used in the treatment of diabetes mellitus.

In the literature there are reports of a positive effect on the course of this type of complication of diabetes mellitus, such as diabetic polyneuropathy (DP), preparations based on vitamins of group B, in particular neuromultivitis (RF patent No. 2262928 for the invention). It is also known to use the antioxidant emoxipin (3-hydroxy-6-methyl-2-ethyl-pyridine hydrochloride) in the treatment of diabetic retinopathy (Kozlov S.A. et al., 2003). However, emoxipin has a number of undesirable side effects inherent in the antioxidant group.

The task set as the basis for the creation of the claimed group of inventions is to develop an effective method and means of preventing and treating complications of diabetes associated with the development of degenerative processes in the nervous tissue, such as, in particular, diabetic retinopathy (DR), diabetic encephalopathy (DE) and diabetic neuropathy (DN). The result achieved in solving the problem lies in the possibility of conducting prophylactic and therapeutic neuroprotective therapy aimed at preventing or slowing down neurodegenerative processes in the retina and brain at all stages of the development of complications of diabetes associated with the development of degenerative processes in the nervous tissue, such as in particular, as diabetic retinopathy (DR), diabetic encephalopathy (DE) and diabetic polyneuropathy (DP).

To achieve the result, a method is proposed for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue, which includes taking a medicament containing a peptide with a neuroprotective effect as an active substance, in which a peptide of the general formula Pro-Gly Pro or a pharmaceutically acceptable salt thereof in effective amounts.

To achieve the result, a pharmaceutical composition for the neuroprotective treatment of complications of diabetes mellitus is proposed, including a peptide with a neuroprotective effect as an active substance and a pharmaceutically acceptable excipient, in which a peptide of the general formula Pro-Gly-Pro or a pharmaceutically acceptable salt thereof is used. The content of the peptide or its pharmaceutically acceptable salt can be selected in the range of 0.01-80 wt.%; the composition can be made suitable for oral administration, for example, in the form of a tablet or capsule or suspension or solution, in the case of a tablet, it is made in the form of a tablet weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt - 10 mg, colloidal silicon dioxide - 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mg. The pharmaceutical composition may also contain a peptide of the general formula Pro-Gly-Pro in the form of an acetate or hydrochloride salt, or as a mixture of the peptide General formula Pro-Gly-Pro and the indicated salts.

To achieve the result, a method for producing a pharmaceutical composition for neuroprotective treatment of complications of diabetes mellitus, comprising mixing the active and auxiliary substances, in which the peptide of the general formula Pro-Gly-Pro or its pharmaceutically acceptable salt is used as an active substance, is also proposed. The content of the peptide or its pharmaceutically acceptable salt can be selected in the range of 0.01-80 wt.%: The composition can be obtained in a form acceptable for oral administration, for example in the form of a tablet weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt - 10 mg, colloidal silicon dioxide - 6 mg, corn starch -54 mg, microcrystalline cellulose - 80 mg.

The invention is illustrated in Fig. 1, which shows the results of the analysis of glial fibrillar acid protein (GFKB) using immunoblotting in soluble and insoluble fractions of protein extracts from the retina of healthy (V) and diabetic rats without treatment (I), and after an 11-week intragastric the introduction of the peptide Pro-Gly-Pro at a dose of 7 mg / kg (III), and Fig. 2 with the results of a selective analysis of the content of various forms of GPCB in the soluble fraction of the extract from the prefrontal cortex of diabetic rats by immunoblottin ha.

The peptide Pro-Gly-Pro (prolyl-glycyl-proline) consists of natural amino acids, has a gross formula C ₁₂ H ₁₉ N ₃ O ₄ and a molecular weight of 269.3. The natural peptide Pro-Gly-Pro is present in trace amounts in the blood and tissues as a product of the degradation of collagen and collagen-like proteins in the digestive tract and body tissues (Samonina et al., 2002). The Pro-Gly-Pro peptide is also formed in the body as one of the degradation products of peptides that are part of the drugs Semax (Met-Glu-His-Phe-Pro-Gly-Pro) and Selank (Thr-Lys-Pro-Arg-Pro -Gly-Pro) (Zolotarev et al., 2006). The data obtained indicate a good absorption of the peptide through the gastrointestinal tract, its high bioavailability, low rate of excretion from the body, and high resistance to the action of proteases.

The Pro-Gly-Pro peptide is known to protect pancreatic cells that produce insulin from the toxic effects of alloxan in a model of experimental insulin-dependent diabetes in animals (Ashmarin et al., 2005; Ashmarin et al., 2008). However, it was not known whether such a peptide exerts a direct antidiabetic effect, i.e., the ability to reduce the concentration of glucose in the blood, against the background of already developed insulin-dependent diabetes. Also, the use of the Pro-Gly-Pro peptide as a means of preventing and treating diabetic retinopathy (DR) and diabetic encephalopathy (DE) is not described.

As used herein, the term “pharmaceutically acceptable salts” means salts that are pharmaceutically acceptable, that is, are safe, non-toxic, and that have pharmacological activity inherent in the parent compound. The pharmaceutically acceptable salts of this invention are prepared by reacting the starting compound of the general formula Pro-Gly-Pro with a pharmaceutically acceptable acid to form an acid addition salt or pharmaceutically acceptable base to form a base addition salt using methods well known in chemistry. Pharmaceutically acceptable acids that form ammonium salts with free amino groups of peptides and functional equivalents include organic acids such as acetic, lactic, malic, ascorbic, succinic, benzoic, citric, methanesulfonic or toluenesulfonic acids, or inorganic acids such as hydrochloric , hydrobromic, hydroiodic, sulfuric or phosphoric acids. Pharmaceutically acceptable bases that form carboxylate salts with free carboxylic acid groups of peptides and functional equivalents include methylamine, ethylamine, dimethylamine, triethylamine, isopropylamine, diisopropylamine and other mono-, di- and trialkylamines, as well as arylamines. It should also be understood that all references to pharmaceutically acceptable salts include pharmaceutically acceptable solvates, complexes or addition compounds, such as hydrates or eturates.

In the framework of the present application, in experiments on sexually mature white rats (190-230), acute and chronic toxicity, as well as the locally irritating effect of the pharmaceutical composition (FC) based on the Pro-Gly-Pro peptide, were studied. In acute experiments, it was shown that with intragastric administration of a dose of FC, causing the death of animals, exceeded the value of 5000 mg / kg In a chronic experiment, daily intragastric administration of FC for 30 days to white rats at doses of 120 mg / kg and 480 mg / kg, exceeding, taking into account scaling over the body surface, 3 and 12 times the dose equivalent to the most preferred daily therapeutic dosage for humans (30 mg ), did not have any undesirable toxic effect. A macroscopic and histopathological study of the tissues of the gastrointestinal tract in animals after a 30-day course of FC administration based on the Pro-Gly-Pro peptide in these doses showed no signs of local irritating effect.

Studies were conducted on mature Wistar rats weighing 250-300g. Animals were kept with free access to food and water, with a 12-hour light regime of lighting. Insulin-dependent diabetes mellitus was caused by a single intraperitoneal injection of a solution of streptozotocin (STZ) in citrate buffer at a dose of 60 mg / kg. Only those animals were selected for the experiment in which six days after STZ administration the blood glucose concentration exceeded the value of 15 mmol / L. The Pro-Gly-Pro peptide in the form of aqueous solutions of a given concentration in drinking low-mineralized water was administered intragastrically by a catheter once a day for 11 weeks.

It is known that chronic hyperglycemia caused by the administration of streptozotocin leads to the development of a number of complications, including DR and DE. The specific neuroprotective effect of the Pro-Gly-Pro peptide was evaluated by its ability to normalize the content of glial fibrillar acid protein (GFKB) in the retina and in the prefrontal region of the cerebral cortex. GFKB is an indicator of glia reactivity and a recognized marker of neurodegeneration (Rungger-Brändle et al., 2000; Zeng et al., 2009). The amount of GPCB in the sample was determined by immunoblotting in soluble (cytosolic) and insoluble (intermediate filaments; extraction with 4M urea) fractions, normalized to the content of the lamin, a nuclear constitutive protein in the sample, and led to the content of the main form of GPCB with a molecular weight of 49 kDa in the soluble fraction of the extract .

All animals taken in the experiment were divided into five groups: I - animals with STZ-induced diabetes, which were drinking water intragastrically for 11 weeks (n = 7); II-IV - animals with STZ-induced diabetes, which for 11 weeks were administered intragastrically solutions of the peptide studied drug Pro-Gli-Pro in doses of 3; 7 and 15 mg / kg / day (n = 5, 4, 7); V - control animals without diabetes, which for 11 weeks were injected intragastrically with drinking water (n = 9). Already 72 h after the introduction of STZ, the blood glucose concentration in most rats exceeded the value of 20 mmol / L and practically did not change during the entire experiment. STZ-induced hyperglycemia also caused a number of other changes in physiological and biochemical parameters characteristic of diabetes mellitus in rats after 12-week hyperglycemia (table 1).

Table 1 Indicator Experimental group V (Norm + H ₂ O) I (Diabetes + H ₂ O) Blood glucose, mmol / l 7.8 ± 0.5 26.0 ± 3.4 *** Glycosylated hemoglobin (HbA1c),% 4.8 ± 0.4 10.2 ± 0.7 *** Mass g 347 ± 19 530 ± 43 *** Daily water intake, ml 160-200 35-50 *** p <0.001 - compared with the group of healthy rats (Student's t-test). All numerical data are presented as mean ± error of the mean.

Prolonged administration of Pro-Gly-Pro (7 mg / kg / day) led to a significant decrease in both soluble and insoluble forms of GFKB in the retina (Fig. 1, Table 2). The study of dose dependence showed that the most effective reduction in GFKB was achieved with Pro-Gly-Pro at doses of 7 and 15 mg / kg / day (table 3). In these doses, the content of both the main (49 kDa) and additional forms (<49 kDa) of GFKB in the retina decreased almost to the levels observed in healthy rats.

Chronic STZ-induced hyperglycemia caused a significant increase in the content of GFKB in the retina (Fig. 1). Quantitative assessment of GFKB in soluble and insoluble retinal fractions by immunoblotting showed that the content of GFKB in diabetic rats increased by 2-3 times (p <0.05) compared with control animals (table 2). At the same time, along with a significant increase in the content of the main form of GPCB with a molecular weight of 49 kDa, an accumulation of additional forms with a lower molecular weight was observed (Fig. 1). Both of these facts indicate intense cytoskeletal rearrangements in astrocytes and Müller cells, characteristic of pathological activation of glia.

table 2 Groups Insoluble fraction Soluble fraction Total fraction (Diabetes + H ₂ O) 1.67 ± 0.25 1.70 ± 0.30 * 3.43 ± 0.42 * (Diabetes + Pro-Gly-Pro; 7 mg / ml) 1.21 ± 0.21 0.68 ± 0.26 1.48 ± 0.26 # (Norm + H ₂ O) 0.88 ± 0.22 0.67 ± 0.13 1.06 ± 0.15 * p <0.05 - compared with the group of healthy rats; # p = 0.07 compared with a group of diabetic rats without treatment (U-test Mann-Whitney). All numerical data are presented as mean ± error of the mean.

Table 3 Groups GKFB (49 kDa) GFKB (<49 kDa) The total content of GKFB (Diabetes + H ₂ O) 3.37 ± 0.51 * 3,50 ± 0,61 *** 6.87 ± 0.99 *** (Diabetes + Pro-Gly-Pro; 3 mg / ml) 2.65 ± 0.41 1.51 ± 0.19 ## 4.16 ± 0.55 (Diabetes + Pro-Gly-Pro; 7 mg / ml) 1.88 ± 0.42 1.08 ± 0.16 ## 2.96 ± 0.56 # (Diabetes + Pro-Gly-Pro; 15 mg / ml) 1.65 ± 0.18 ## 1.15 ± 0.24 ## 2.80 ± 0.30 ### (Norm + H ₂ O) 1.55 ± 0.29 0.56 ± 0.11 2.12 ± 0.31 * p <0.05, *** p <0.001 - compared with the group of healthy rats; # p <0.05, ## p <0.01, ### p <0.001 compared with the group of diabetic rats without treatment (Mann-Whitney U-test). All numerical data are presented as mean ± error of the mean.

As shown by the results of a quantitative analysis using immunoblotting in the prefrontal region of the cerebral cortex, chronic STZ-induced hyperglycemia had practically no effect on the content of GFKB in the insoluble fraction, but caused a significant increase in GFKB in the soluble fraction (Fig. 2). In this case, as in the case of the retina, in addition to the main form of GFKB (49 kDa), the appearance of additional forms of GFKB, characterized by a lower molecular weight, was observed. Quantitative analysis using immunoblotting showed that the total content of GPCB in the soluble fraction from the prefrontal cortex of diabetic rats is approximately 2 times higher than in healthy rats (table 4). With an 11-week intragastric administration of Pro-Gly-Pro peptide to rats, a significant decrease in the content of the main form of GPCB (49 kDa) in the soluble fraction was observed only when a dose of 15 mg / kg / day was used (table 4). Moreover, the content of the main form of GFKB reached the values observed in healthy rats. From each experimental group, a sample with the most characteristic GFKB content was selected.

Table 4 Groups GKFB (49 kDa) (Diabetes + H ₂ O) 1.6 ± 0.07 *** (Diabetes + Pro-Gly-Pro; 3 mg / ml) 1.34 ± 0.21 III. (Diabetes + Pro-Gly-Pro; 7 mg / ml) 1.56 ± 0.24 IV. (Diabetes + Pro-Gly-Pro; 15 mg / ml) 0.75 ± 0.09 ### V. (Norm + H ₂ O) 1.00 ± 0.03 *** p <0.001 compared with the group of healthy rats; ### p <0.001 compared with the group of diabetic rats without treatment (U-test Mann-Whitney). All numerical data are presented as mean ± error of the mean.

Thus, the data obtained in these studies indicate the neuroprotective effect of prolonged systematic administration of the Pro-Gly-Progo peptide on the retina and brain of rats with experimentally induced DR and DE. The protective effect of the peptide was expressed in a decrease in the content of marker protein - GFKB. It was found that to prevent / slow the development of neurodegenerative processes in the retina and brain of rats with STZ-induced diabetes, daily intragastric administration of the peptide at doses of 7 to 15 mg / kg is necessary.

The following examples further illustrate the possibility of using Pro-Gly-Pro as a medicament for the neuroprotective treatment of diabetes complications.

Example 1

A male rat weighing 216 g, which previously caused streptozotocin-induced diabetes, was administered intragastrically for 11 weeks using a probe of 0.9 ml of a solution of Pro-Gly-Pro peptide in drinking water at a dose of 7 mg / kg / day. Then, 3 days after the last administration of the peptide, the rat is euthanized and the method of protein immunoblotting is used to determine the content of the marker protein of neurodegeneration - GFKB - in the retina of the eye and in the prefrontal region of the cerebral cortex of the rat. The measured value of the content of the main form of GFKB (49 kDa) in the retina was 1.65 rel.ed., which is 2.0 times lower than the average for diabetic rats not subjected to peptide treatment (see table 3). In the prefrontal region of the cortex (soluble fraction of the extract), the content of the main form of GFKB (49 kDa) was 1.36 rel.units, which is 1.2 times lower than the average for diabetic rats not subjected to peptide treatment (see table 4 ) The experimental data obtained indicate that prolonged administration of the Pro-Gly-Pro peptide at a dose of 7 mg / kg / day leads to the suppression of neurodegenerative processes caused by chronic hyperglycemia in the retina and, to a lesser extent, in the cerebral cortex.

Example 2

A male rat weighing 215 g, which previously caused streptozotocin-induced diabetes, was administered intragastrically for 11 weeks using a probe of 0.9 ml of a solution of the acetate salt of Pro-Gly-Pro peptide in drinking water at a dose of 7 mg / kg / day. Then, 3 days after the last administration of the peptide, the rat is euthanized and the method of protein immunoblotting is used to determine the content of the marker protein of neurodegeneration - GFKB - in the retina of the eye and in the prefrontal region of the cerebral cortex of the rat. The measured value of the content of the main form of GFKB (49 kDa) in the retina was 1.57 rel.ed., which is 2.1 times lower than the average for diabetic rats not subjected to peptide treatment (see table 3). In the prefrontal region of the cortex (soluble fraction of the extract), the content of the main form of GFKB (49 kDa) was 1.51 rel units, which is 1.1 times lower than the average for diabetic rats not exposed to peptide treatment (see table 4 ) The experimental data obtained indicate that prolonged administration of the Pro-Gly-Pro acetate salt at a dose of 7 mg / kg / day leads to the suppression of neurodegenerative processes caused by chronic hyperglycemia in the retina and, to a lesser extent, in the cerebral cortex.

Example 3

A male rat weighing 233 g, which previously caused streptozotocin-induced diabetes, was administered intragastrically for 11 weeks using a probe of 0.9 ml of a solution of the acetate salt of Pro-Gly-Pro peptide in drinking water at a dose of 15 mg / kg / day. Then, 3 days after the last administration of the peptide, the rat is euthanized and the protein GPCB content is determined in the retina of the eye and in the prefrontal region of the rat cerebral cortex by protein immunoblotting. The measured value of the content of the main form of GFKB (49 kDa) in the retina was 1.50 rel.ed., which is 2.3 times lower than the average for diabetic rats not subjected to peptide treatment (see table 3), and practically differed from that in healthy rats. In the prefrontal region of the cortex (soluble fraction of the extract), the content of the main form of GFKB (49 kDa) was 0.59 rel.units, which is 2.7 times lower than the average for diabetic rats not exposed to peptide treatment (see table 4 ), and 1.7 times lower than in healthy rats. The obtained experimental data indicate that prolonged administration of Pro-Gly-Pro acetate salt at a dose of 15 mg / kg / day leads to a strong suppression of neurodegenerative processes caused by chronic hyperglycemia in the retina and cerebral cortex.

Example 4

In a control experiment, a male rat weighing 240 g, which previously caused streptozotocin-induced diabetes, was administered intragastrically for 11 weeks using a probe of 0.9 ml of drinking water. Then, 3 days after the last administration of the peptide, the rat is euthanized and the protein GPCB content is determined in the retina of the eye and in the prefrontal region of the rat cerebral cortex by protein immunoblotting. The measured value of the total GKFB content was 4.24 rel.ed., which is 2.7 times higher than the average in healthy rats (see table 3). In the prefrontal region of the cortex (soluble fraction of the extract), the content of the main form of HFCB (49 kDa) was 1.48 rel.units, which is 1.5 times higher than the average for healthy rats (see table 4). The obtained experimental data indicate that in the absence of treatment with a peptide of the general formula Pro-Gly-Pro or its pharmaceutically acceptable salt, development of neurodegenerative processes in the retina and cerebral cortex of rats caused by prolonged hyperglycemia is observed.

Example 5

A pharmaceutical composition was prepared for the treatment of complications of diabetes, made in the form of a tablet of the following composition (in milligrams):

- Pro-Gly-Pro peptide - 10 mg;

- colloidal silicon dioxide - 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg.

Pro-Gly-Pro peptide, colloidal silicon dioxide, microcrystalline cellulose and corn starch were successively introduced into the technological capacity of the homogenizer mixer, periodically subjecting the mixture to mixing until a homogeneous mass was obtained. Then, to the resulting mixture, 10% starch paste was gradually added, with constant stirring. The resulting paste was rubbed through a sieve, dried under vacuum and crushed to granules no larger than 1 mm in size. The mass obtained after treatment with magnesium stearate and starch was pressed into tablets weighing 150 mg using a suitable die.

Example 6

A pharmaceutical composition was prepared for the treatment of complications of diabetes, made in the form of a tablet of the following composition (in milligrams):

- acetate salt of the peptide Pro-Gly-Pro - 10 mg;

- colloidal silicon dioxide - 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg.

The acetate salt of the Pro-Gly-Pro peptide, colloidal silicon dioxide, microcrystalline cellulose and corn starch were successively introduced into the technological capacity of the homogenizer mixer, periodically subjecting the mixture to mixing until a homogeneous mass was obtained. Then, to the resulting mixture, 10% starch paste was gradually added, with constant stirring. The resulting paste was rubbed through a sieve, dried under vacuum and crushed to granules no larger than 1 mm in size. The mass obtained after treatment with magnesium stearate and starch was pressed into tablets weighing 150 mg using a suitable die.

Example 7

A pharmaceutical composition was prepared for the treatment of complications of diabetes, made in the form of a tablet of the following composition (in milligrams):

- hydrochloride salt of the peptide Pro-Gly-Pro - 10 mg;

- colloidal silicon dioxide - 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg.

The hydrochloride salt of the Pro-Gly-Pro peptide, colloidal silicon dioxide, microcrystalline cellulose and corn starch were successively introduced into the technological capacity of the homogenizer mixer, periodically subjecting the mixture to mixing until a homogeneous mass was obtained. Then, to the resulting mixture, 10% starch paste was gradually added, with constant stirring. The resulting paste was rubbed through a sieve, dried under vacuum and crushed to granules no larger than 1 mm in size. The mass obtained after treatment with magnesium stearate and starch was pressed into tablets weighing 150 mg using a suitable die.

Claims (9)

1. A method for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue, comprising the use of a medicament containing a peptide with a neuroprotective effect as an active substance, characterized in that a peptide of the general formula Pro-Gly-Pro is used as a peptide or a pharmaceutically acceptable salt thereof in effective amounts. 2. A pharmaceutical composition for the neuroprotective treatment of diabetes complications, comprising a peptide with a neuroprotective effect as an active substance and a pharmaceutically acceptable excipient, characterized in that the peptide of the general formula Pro-Gly-Pro or a pharmaceutically acceptable salt thereof is used. 3. The composition according to claim 2, characterized in that the content of the peptide or its pharmaceutically acceptable salt is 0.01-80 wt.%. 4. The composition according to claim 2 or 3, characterized in that it is made suitable for oral administration, for example in the form of a tablet or capsule, or suspension, or solution. 5. The composition according to claim 4, characterized in that it is made in the form of a tablet weighing 150 mg, the following composition: peptide or its pharmaceutically acceptable salt - 10 mg, colloidal silicon dioxide - 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mg 6. A method of obtaining a pharmaceutical composition for neuroprotective therapy of diabetes complications, comprising mixing the active and auxiliary substances, characterized in that the active substance is a peptide of the general formula Pro-Gly-Pro or a pharmaceutically acceptable salt thereof. 7. The method according to claim 6, characterized in that the content of the peptide or its pharmaceutically acceptable salt is 0.01-80 wt.%. 8. The method according to claim 6 or 7, characterized in that the composition is obtained in a form acceptable for oral administration. 9. The method according to claim 8, characterized in that the composition is obtained in the form of a tablet weighing 150 mg, the following composition: peptide or its pharmaceutically acceptable salt - 10 mg, colloidal silicon dioxide - 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mg

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