RU2768734C1 - Pharmaceutical composition based on turmeric for treating diabetes mellitus, production and use thereof - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry, namely to a turmeric composition for treating diabetes mellitus, a method for preparing and using it. A pharmaceutical composition based on turmeric for treating diabetes mellitus contains an extract of milled rhizomes of the Curcuma longa plant; according to the invention, it is a mechanocomposite of the following composition, wt. %: sodium bicarbonate E500 (ii) 6; air-dry powdered turmeric 94. Disclosed is a method of producing a pharmaceutical composition, according to which air-dry powdered turmeric is mixed with sodium bicarbonate E500 (ii) in ratio of 94:6 by weight, respectively, and the obtained mixture in an air-dry state is subjected to mechanochemical treatment in a flowing roller centrifugal mill-activator, which provides an acceleration of the acting bodies of 80 m/s² and the residence time in the treatment zone is 2.5 minutes, and the cooling system of the activator mills provides the output of the product with a temperature of not higher than 70 °C. Use of the pharmaceutical composition for treating diabetes mellitus.

EFFECT: composition described above is effective for treating diabetes mellitus, has a simplified composition, is obtained by a method with exclusion of liquid-phase stages and drying.

3 cl, 2 tbl, 2 ex

Description

The invention relates to the pharmaceutical industry, namely to the creation of a pharmaceutical composition based on turmeric for the treatment of type 1 and type 2 diabetes mellitus (DM), to a method for producing said pharmaceutical composition and its use.

It is known that diabetes is one of the most serious diseases in the world. Despite the rich history of its study and advances in treatment, DM (both types 1 and 2) remains a widespread pathology and is characterized by a progressive increase in the incidence. A promising approach in the treatment of DM is the use of herbal remedies or their extracts. One such remedy is ground turmeric (crushed rhizomes of the Curcuma longa plant).

The main biologically active substances contained in the rhizome of the Curcuma longa plant have been identified. The chemical components of turmeric extracts contain carbohydrates (4.7-8.2%), essential oils (2.44%), fatty acids (1.7-3.3%), curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin), the content of which is approximately 2%, although it can reach 2.5-5.0% of dry weight, as well as polypeptides such as turmeric (0.1% dry extract) (1. Srinivas L., Shalin VK, Shylaj M. Turmerin: a water soluble antioxidant peptide from turmeric (Curcuma longa) // Arch Biochem Biophys 1992 292(2) 617-623.

It is generally accepted that curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin, the main one in terms of content is curcumin) are the active principle of the Curcuma longa rhizome, however, experiments conducted by some authors of the present invention with ground turmeric and curcumin showed that the use of turmeric causes a hypoglycemic effect in alloxan- induced diabetes mellitus in rats throughout the entire observation period, while the use of curcumin has a short-term effect only on day 1 of the experiment. It is logical to conclude that the observed hypoglycemic effect of turmeric is associated with the content of the plant not only and not so much curcumin as the presence of vitamins, macro- and microelements, as well as biologically active substances with a wide spectrum of action (2. Gaidarova A.P. ., Koroshchenko G.A., Aizman R.I. Effect of turmeric and curcumin on carbohydrate metabolism in alloxan-induced diabetes mellitus in rats // Modern problems of science and education. - 2014. - No. 5.; URL: https:// www.science-education.ru/ru/article/view?id=14779 (date of access: 09/23/2020)).

Known "Tool and method for the complex therapy of patients with diabetes", in which the agent for the complex therapy of patients with type 2 diabetes mellitus contains one component: purified and dried rhizome of the Curcuma Longa plant in the form of a powder with a final particle size of 0.060-0.075 mm (3. Pat. Russian Federation No. 2548731, class A61K 36/9066, class A61R 3/10, published on April 20, 2015).

The disadvantage of this technical solution is the fact that ground turmeric is used, and not its extract, which could enhance the effect of the agent.

The closest technical solution chosen for the prototype is "Pharmaceutical composition for the regulation of sugar and fat in the blood, its preparation and use", in which the composition (rather than a one-component agent), in particular, contains an extract of crushed turmeric rhizomes. The pharmaceutical composition is multicomponent. A method for obtaining a pharmaceutical composition (one of the options in the patent, the closest to the present technical solution and selected as a prototype) includes obtaining an extract of turmeric (by steam distillation). The rhizomes are crushed, water is added tenfold, and extraction is carried out by steam distillation for 8 hours. Essential oil, aqueous solution and residue are collected and stored as a blank, from which a complex is obtained using 8 times beta-cyclodextrin and 80 times water, by stirring at 50°C for 1 hour, cooled for overnight and filtered, then dried at low temperature (40°C) and crushed. A finely divided powder is obtained. It is no less difficult to obtain powders of extracts of other plants included in the composition (in some cases, ethanol is an extractant). The extract powders are then mixed to form granules, tablets or capsules. A pharmaceutical composition is used for the treatment of type 1 and 2 diabetes (4. Pat. RF No. 2409381, class A61K 36/9066, class A61K 36/77, class A61K 36/718, class A61K 36/481, class A61K 36/185, class A61K 36/02, class A61R 3/06, class A61R 3/10, published 01/20/2011).

The main disadvantages of the technical solution chosen for the prototype, from the point of view of the present invention, are the multicomponent nature of the pharmaceutical composition and the complex, multi-stage method for its preparation, including liquid-phase stages and drying.

The problem solved by the claimed technical solution is to simplify the composition of the claimed pharmaceutical composition to two components, to simplify the method of obtaining the claimed pharmaceutical composition by eliminating the liquid-phase stages and drying, to effectively use the claimed pharmaceutical composition for the treatment of type 1 and type 2 diabetes.

The problem solved by the claimed composition is to simplify the composition of the claimed pharmaceutical composition to two components.

The problem solved by the claimed method for obtaining the claimed pharmaceutical composition is to simplify the method by eliminating the liquid-phase stages and drying.

The problem solved by the claimed application is the effective use of the claimed pharmaceutical composition for the treatment of type 1 and type 2 diabetes.

Long-term studies were required to solve the tasks set (in particular, due to the fact that, as indicated above, not only and not so much curcumin is responsible for the overall effect, which did not allow using the content of curcumin as a criterion for optimizing the composition and method for obtaining the claimed pharmaceutical composition ).

The problem is solved thanks to the claimed composition of the pharmaceutical composition based on turmeric. The pharmaceutical composition of the present invention (PCNI) is a mechanocomposite containing 6% of the mass. sodium bicarbonate E500 (ii) and 94% by weight, air-dried ground powdered turmeric (i.e. crushed rhizomes of Curcuma longa).

The meaning of the term mechanocomposite is to emphasize the fundamental differences in the structure and properties of powder materials - mixed systems formed during processing in special activator mills. A distinctive feature of a mechanocomposite is the presence of a developed, with special properties, phase interface of plant raw materials and a reagent and an increased reactivity associated with this effect (5. Mechanocomposites - precursors for creating materials with new properties / [A.I. Ancharov et al.]; O. I. Lomovsky, editor-in-chief, Russian Academy of Sciences, Siberian Branch, Institute of Solid State Chemistry and Mechanochemistry [et al.], Novosibirsk: Publishing House of the Siberian Branch of the Russian Academy of Sciences, 2010. (Integration projects of SO RAS, issue 26), p. 5). In other words, the particles of the components of the mechanocomposite are not simply crushed and mixed, but driven or pressed into each other, as a result of which they easily react with each other.

The mechanocomposite is formed due to the mechanochemical processing of an air-dry mixture of raw materials in an activator mill. In this case, partial hydrolysis of the cell walls of powdered turmeric occurs with the help of a hydrolyzing component - sodium bicarbonate E500 (ii), as a result of which the liquid content of the destroyed cells is extracted into the liquid phase present in the air-dry mechanocomposite (air-dry powders are capillary-porous systems, always containing moisture). During subsequent storage of the resulting mechanocomposite, the process of interaction of the components continues. The solid materials of the mechanocomposite (particles of sodium bicarbonate E500 (ii) and turmeric) serve as a matrix that accumulates the liquid phase - an extract that finally leaves the matrix already when using the FCNI.

This picture corresponds to the modern concept of “mechanochemically assisted extraction” (6. Lomovsky O., Lomovsky I. Mechanochemically Assisted Extraction // in Enhancing Extraction Processes in the Food Industry, ed. by N. Lebovka, E. Vorobiev, F. Chemat, NY - London: CRC Press, 2011, ISBN: 978-1-4398-4593-6); there is no short term in Russian, it is most competent to say: a controlled change in the structure and composition of plant raw materials by mechanochemical methods to intensify the extraction of biologically active compounds (this is the name of the RSF project No. .

Sodium bicarbonate E500 (ii) (another name is baking soda) must comply with the requirements of GOST 32802-2014 (7. GOST 32802-2014. Interstate standard. Food additives. Sodium carbonates E500. General specifications. M .: Standartinform, 2015).

The original air-dried powdered ground turmeric must comply with the requirements of GOST ISO 5562-2017 (8. GOST ISO 5562-2017. Interstate standard. Spices. Whole and ground turmeric (powdered). Specifications. M .: Standartinform, 2017).

This problem is also solved thanks to the claimed method for obtaining FKNI, in which, according to the invention, ground powdered air-dry turmeric is mixed with sodium bicarbonate E500 (ii) in a ratio of 94: 6 by weight, respectively, and the resulting mixture in an air-dry state is subjected to mechanochemical processing in the activator mill, separated into fractions, and the coarse fraction is then returned for re-treatment in the activator mill, and the target fraction is passed through a metal trap.

It is preferable to use a flow roller centrifugal mill-activator (brand RM-10, developed and manufactured by the ICTTM SB RAS, Novosibirsk) as an activator mill, providing an acceleration of the acting bodies of 80 m/s ² and a residence time in the treatment zone of 2.5 min . Setting the cooling system of the activator mill ensures that the product exits at a temperature not higher than 70°C to avoid overdrying, which prevents hydrolysis and extraction inside the matrix. It has been experimentally established that these parameters of mechanochemical treatment make it possible to obtain PCNI with an antidiabetic effect.

When grinding, a certain amount of coarse fraction is always obtained in the target product. At the same time, it is known that the optimal final particle size of turmeric should be 60-75 microns, since when taking the powder, oral cavity receptors should be actively involved, the irritation of which allows you to more effectively activate the neuroendocrine regulatory system; in addition, a large dispersion of grinding allows you to increase the area of absorption of all useful components of the plant in the small intestine (3). Therefore, to remove the coarse fraction, conventional separating devices are used (an air separator or a vibrating sieve enclosed in a sealed casing). The coarse fraction is then returned for re-treatment in the activator mill.

The metal trap is used to remove metal impurities from the finished product, which, in case of exceeding the norms of their content, size and mass of individual particles, can injure the digestive tract of the FKNI consumer.

The totality of the above parameters and circumstances makes it possible to obtain a PCNI with an antidiabetic effect.

The implementation of the claimed invention is shown in the examples.

Example 1. Getting FKNI

Powdered turmeric according to GOST ISO 5562-2017 is mixed with a hydrolyzing component - sodium bicarbonate E500 (ii) according to GOST 32802-2014 until a homogeneous composition in a ratio of 94: 6 by weight. The mixture is processed in a flow roller centrifugal mill-activator RM-10 (IKhTTM SB RAS, Novosibirsk) with an acceleration of the acting bodies of 80 m/s ² and a residence time in the treatment zone of 2.5 min, and the adjustment of the product with a temperature not exceeding 70°C, and then separated in a particle classifier of the KCE type (IKhTTM SB RAS, Novosibirsk) or in a vibrating sieve with mesh No. 0063, enclosed in a sealed casing, into two fractions: coarse, which is returned to processing in an activator mill, and fine, which is then passed through a metal trap and a target product is obtained that satisfies the condition: the residue after dry screening on a sieve with mesh No. 0063 is not more than 10%. The resulting product is a finely ground yellow-pink powder.

Example 2. Experimental study of FCNI in rats with alloxan-induced DM

Purpose: to study the effect of FCNI on carbohydrate and water-salt homeostasis, as well as kidney function in rats with alloxan-induced DM.

Methodology

The experiments were carried out on adult male Wistar rats weighing 250-300 g. Diabetes was modeled in animals, for which rats were injected once into the interscapular region with a 10% solution of alloxan at the rate of 0.1 ml/100 g of body weight (9. Mozheiko L.A. Experimental models for the study of diabetes mellitus, Part I. Alloxan diabetes, Journal of Grodno State Medical University, 2013, 3 (43): 26-29. Alloxan-induced DM is a model of type 1 and 2 DM, since alloxan both affects the pancreatic insular apparatus and changes tissue sensitivity to insulin. All animals were divided into 3 groups: receiving standard food (Group 1) and in addition to it an additive in the form of FCNI powder (Group 2) in the amount of 2% of the food weight. In addition, a control group was isolated, consisting of intact animals on a standard diet. Each group consisted of 10 animals.

All groups of animals were kept under standard vivarium conditions and had free access to water and food during the day.

On the 7th day of the experiment, kidney function was studied by analyzing background urine samples collected in metabolic cells for 3-5 hours of observation, as well as assessing the renal response to oral administration of 5% of the body weight of the water load through the probe. Urine samples after water loading were collected for 3 hours. At the end of the experiment, 5 ml blood samples were taken from the inferior vena cava in animals under ether anesthesia into cooled tubes treated with sodium-free heparin for subsequent physicochemical analysis of the plasma.

The content of the main metabolites in blood plasma, reflecting the state of carbohydrate and water-salt homeostasis, as well as the functional state of the kidneys (creatinine, urea), was determined by the colorimetric method (analyzer "BS-200E", China); glucose - by electrochemical method ("Super GL", Dr. Muller, Germany); the concentration of electrolytes in urine and plasma (Na ⁺ , K ⁺ ) was measured by flame photometry (flame photometer BWB-XPF, UK); the osmolarity of these biological fluids was measured by cryoscopy (milliosmometer Osmomat, Germany).

The calculation of water and ion excretory functions of the kidneys was carried out according to generally accepted formulas (10. Natochin Yu.V. Physiology of the kidney: Formulas and calculations. Leningrad: Nauka Publishing House, 1974). Statistical analysis of the results of the study was performed using standard programs of the Excel 2010 package based on the determination of arithmetic means (M) and their errors (±m). Significance of differences was assessed using the nonparametric Wilcoxon-Mann-Whitney test for independent samples and Student's t-test for dependent values at a significance level of ≤ 0.05.

All experiments were carried out in accordance with the International Guidelines for Biomedical Research Involving Animals adopted by the International Council of Scientific Societies (CIOMS) in 1985, Art. XI of the Helsinki Declaration of the World Medical Association (1964) and the rules of laboratory practice in the Russian Federation (Order of the Ministry of Health of the Russian Federation dated June 19, 2003, No. 267).

results

Biochemical blood parameters were analyzed in rats with DM model at rest in the morning on an empty stomach and after a 7-day intake of FCNI. As can be seen from Table 1, the plasma creatinine concentration significantly increased compared to the control. At the same time, FCNI caused a significant decrease in the concentration of this metabolite in plasma.

Since creatinine is the main indicator of the functional state of the kidneys, it can be concluded that FCNI contributed to the improvement of organ functions in DM. This is also indicated by data on the concentration of urea in animals in different groups. Changes in the blood glucose concentration in animals with alloxan-induced DM indicate, firstly, the development of pathology after the injection of alloxan and, secondly, the hypoglycemic effect of FCNI. Thus, FCNI caused a decrease in the concentration of glucose, creatinine, urea, plasma osmolarity and normalization of the concentration of sodium and potassium. Consequently, the intake of FCNI by rats with DM contributed to the normalization of most indicators characterizing carbohydrate and water-mineral homeostasis and the functional state of the kidneys.

The obtained data on the increase in plasma creatinine concentration in alloxan-induced DM dictated the need to assess the osmo- and ion-regulatory functions of the kidneys in DM. Since the reserve capabilities of the organ are most clearly revealed in the conditions of water-salt stress tests (11. Aizman R.I., Velikanova L.K. Evaluation of water-salt metabolism and kidney function using stress tests. In the book: New methods of scientific research in Clinical and Experimental Medicine, Novosibirsk: NGMI. 1980; 5-13), we analyzed the partial functions of the kidneys of rats not only at rest on an empty stomach, but also after a 5% water load (table 2).

An analysis of the diuretic function of the kidneys under background conditions showed that rats with DM have a significantly higher level of urination than healthy animals due to reduced fluid reabsorption. In parallel with the increase in fluid excretion, the excretion of sodium and potassium increased, which also increased the osmotic clearance. This was due to a decrease in the reabsorption of electrolytes in the renal tubules, as evidenced by a significant increase in the excreted fraction of cations. Taking FCNI contributed to the reduction of the described changes in renal functions. Thus, smaller homeostatic shifts in blood plasma in rats with DM after taking FCNI were undoubtedly due to partial normalization of kidney function.

After the water load, less reserve capabilities of osmo- and ion-regulatory mechanisms were revealed in animals with DM compared with the control. If intact rats developed a pronounced diuretic reaction with the excretion of osmotically free fluid (C ^H2O became positive) and more pronounced inhibition of its reabsorption (% R _H2O reached 88.1%), then in DM a paradoxical reaction was noted - a decrease in diuresis compared to the background and increased fluid reabsorption without significant changes in osmoregulatory processes. In the control, sodium excretion decreased in response to fluid intake, while potassium excretion increased, while in DM, a decrease in the excretion of both cations was noted.

Consequently, FCNI at rest contributed to a decrease in disorders of the osmo- and ion-regulatory functions of the kidneys in DM, however, when the organ was under stress after a water load, these effects were much less pronounced, which may be due to the insufficiency of the reserve mechanisms necessary to normalize the renal response.

Conclusion

Thus, the analysis of the obtained material made it possible to conclude that the FCNI in DM contributed to the normalization of homeostatic plasma parameters characterizing the carbohydrate and water-mineral balance due to the improvement of the functional state of the kidneys. This effect was especially pronounced at rest.

The achieved technical result of the proposed technical solution consists in simplifying the composition of the claimed pharmaceutical composition to two components, in simplifying the method for obtaining the claimed pharmaceutical composition by eliminating the liquid-phase stages and drying, in the effectiveness of the claimed pharmaceutical composition against type 1 and type 2 diabetes.

The use of the invention will allow using a new, technologically simple waste-free method to obtain a useful product - FCNI, which is effective against type 1 and type 2 diabetes.

The social benefit of using the invention lies in the use of FCNI for the treatment of type 1 and type 2 diabetes.

An additional positive effect achieved by the invention is the possibility of using the developed product for food purposes (since the FKNI consists of components used for food purposes).

The invention was created at the expense of a grant from the Russian Science Foundation (project No. 16-13-10200).

Claims (4)

1. Pharmaceutical composition based on turmeric for the treatment of diabetes mellitus, including an extract of crushed rhizomes of the Curcuma longa plant, characterized in that it is a mechanocomposite of the following composition, % wt.: sodium bicarbonate Е500 (ii) 6 air-dry ground turmeric powder 94 2. A method for producing a pharmaceutical composition according to claim 1, characterized in that ground powdered air-dry turmeric is mixed with sodium bicarbonate E500 (ii) in a ratio of 94:6 by weight, respectively, and the resulting mixture in an air-dry state is subjected to mechanochemical processing in a flow roller centrifugal mill-activator, providing an acceleration of the acting bodies of 80 m/s ² and a residence time in the processing zone of 2.5 minutes, and setting the cooling system of the activator mills ensures the product exit with a temperature not higher than 70°C. 3. The use of a pharmaceutical composition according to claim 1 for the treatment of diabetes mellitus.