RU2752781C1 - Encapsulated form food baa - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: inventions group relates to herbal medicine, pharmaceuticals, medicine and food industry. A biologically active additive (BAA) is a complex of biologically active substances (BAS) and contains a dry extract of the following composition: sandy immortelle flowers, columns with corn stigmas, chamomile flowers, dandelion root, peppermint leaves, motherwort herb, angelica roots, marigold flowers, knotweed herb at a ratio of parts 1.5:1.5:1:1:1:1:1:1:1. The BAA is an encapsulated form, which includes the aforementioned complex of BAS and a complex of excipients.

EFFECT: proposed dietary supplement in encapsulated form provides the human body's need for the required number of flavonoids and tannins without pronounced allergic and undesirable reactions and has a cleansing, antioxidant, regenerating, decongestant, cardioprotective, vasodilator, venotonic, anticarcinogenic, anti-inflammatory effect. In particular, the claimed composition of dietary supplements in encapsulated form will have a significant positive effect on the gastrointestinal tract, kidneys and, in particular, the liver.

10 cl, 11 tbl, 5 ex

Description

The group of inventions relates to medicine, pharmaceuticals, herbal medicine and food industry. Mainly the invention relates to a complex of biologically active substances (BAS) containing a dry extract of the following composition: flowers of the immortelle sandy, columns with stigmas of corn, chamomile flowers, dandelion root, peppermint leaves, motherwort herb, angelica roots, marigold flowers, grass knotweed with the following ratio of parts 1.5: 1.5: 1: 1: 1: 1: 1: 1: 1. Also described is the finished form of a biologically active additive (BAA), which is an encapsulated form, which includes the above-mentioned complex of biologically active substances and a complex of excipients. In addition, the technology of obtaining a complex of biologically active substances and a finished form of biologically active additives is described. Additionally, the proposed dosage regimen of dietary supplements in encapsulated form, taking into account the needs of the human body in flavonoids and tannins. The group of inventions makes it possible to obtain a dietary supplement in encapsulated form, which, with the claimed production method, the quantitative and qualitative ratio of the ingredients of the composition, provides the human body's need for the required amount of flavonoids and tannins without pronounced allergic and undesirable reactions, and which has a cleansing, antioxidant, regenerating, decongestant, cardioprotective, vasodilating, venotonic, anticarcinogenic, anti-inflammatory action. In particular, the claimed composition of dietary supplements in encapsulated form will have a significant positive effect on the gastrointestinal tract, kidneys, and, in particular, the liver.

Currently, there is a fairly wide need for nutrient support for the body as a whole, and for certain organs and systems of a person, from outside. Against this background, in recent decades, the close attention of researchers has been attracted by such products that are capable of having a preventive and therapeutic effect on the human body, and at the same time minimizing allergic and unwanted reactions. These, for example, include the product of secondary plant metabolism - flavonoids, due to a wide spectrum of action.

Flavonoids are plant phenolic compounds, the structural basis of which is made up of 2 benzyl rings (A and B) connected to each other by a heterocyclic pyran or pyrone (ring C). Experimental and clinical studies have revealed their antioxidant, cytoprotective, hepatoprotective, antihypoxic and many other effects. No less interest is directed to the study of tannins (DW). DV or tannins represent compounds of the polyphenolic structure, subdivided into hydrolysable and condensed. For condensed, gastroprotective, antioxidant, antimutagenic, antitumor, antibacterial, antiviral activity are characteristic. Hydrolyzed tannins have anti-candidiasis, antifibrotic effects, inhibit the HIV-induced cytopathic effect. DVs are active against methicillin-resistant Staphylococcus aureus and Epstein-Barr virus.

Flavonoids, tannins and their analogs are essential for humans, i.e. requiring constant intake with food or in the form of drugs and food additives.

With uncontrolled or excessive consumption of foods or food additives that are sources of DV and / or flavonoids, undesirable effects may occur, such as allergic reactions, slowing down of intestinal motility, constipation, and impaired absorption of vitamins. In case of violation of the dosage regimen, in most cases, prophylactic and therapeutic effects are not achieved.

Low level of medical compliance is becoming quite common when performing wellness and preventive procedures. First of all, this is facilitated by the shape and delivery of the source of nutrients and health-improving substances. These forms include tinctures, balms, teas, when it comes to nutritional supplements or diets containing a specific list of foods saturated with essential nutrients and / or health-promoting substances.

Some of the ready-made forms, for example, tinctures, are often addictive, especially sedatives - a person without a sedative begins to feel increased anxiety. In addition, tinctures and balms contain alcohol, which means that they are contraindicated for children, pregnant women, breastfeeding and alcoholism. They are also contraindicated for people in those professions where a high concentration of attention is required and when using certain medications. We must not forget about allergic reactions.

The effectiveness of using compositions from collections of dry herbs is not always maximum due to incomplete extraction of extractive substances or the loss of activity of these substances when making teas at home. In addition, such compositions are poorly protected from environmental influences during storage, transportation, and operation. Compositions requiring brewing are often used with a violation of the intake or dosing regimen: they are over-brewed, inappropriate containers and preparation modes are used, etc.

Thus, the object of the invention is to develop a finished form of dietary supplements, which is a source of flavonoids and DV with such a quantitative and qualitative composition that would have the most beneficial effect on these organs and systems of vital activity, in particular, showed high efficiency in relation to the gastrointestinal tract, kidneys and liver, and at the same time practically would not have allergic and undesirable reactions. In addition, another object of the invention is the development of such a finished form that would contribute to an increase in medical compliance when performing health and preventive procedures. An additional object of the invention is a method for obtaining a finished form, which would involve the optimal qualitative and quantitative ratio of the ingredients of biologically active substances and excipients.

The task is solved by creating a dietary supplement of a capsulated form containing a complex of biologically active substances as an active component, including flowers of the immortelle sandy, columns with corn stigmas, chamomile flowers, dandelion root, peppermint leaves, motherwort herb, angelica roots, marigold flowers, mountaineer grass avian in a ratio of 1.5: 1.5: 1: 1: 1: 1: 1: 1: 1 and where the sum of flavonoids in terms of rutin is 2-2.5 mg, and the amount of tannins in terms of tannin is 7, 45-9.15 mg per capsule, and a complex of excipients, including a filler, binder, disintegrant, anti-stick, slip. In addition, the problem is solved by obtaining a dietary supplement of encapsulated form, where in the preferred embodiment of the invention microcrystalline cellulose 101 (MCC) acts as a filler, alpha-polyvinylpyrrolidone (alpha-PVP) K25 acts as a binder, and colloidal silicon dioxide (aerosil ) and / or magnesium stearate. In addition, the task is solved by optimal selection of the dose, which contributes to the achievement of the best effect with almost complete absence of allergic and undesirable phenomena and, with the declared qualitative and quantitative composition of the BAS complex, makes 2 capsules 3 times a day. In addition, the task is solved by the fact that experimentally developed a method for obtaining an encapsulated form that solves the tasks.

The technical result of the claimed group of inventions is to obtain a dietary supplement, which, with the claimed method of production, the quantitative and qualitative ratio of the ingredients of the composition, provides the body with the necessary amount of tannins and flavonoids for preventive and therapeutic effects on the organs and systems of human vital activity, in particular in relation to the gastrointestinal tract, kidneys and liver. ... The claimed composition and method make it possible to obtain such a dietary supplement composition, which has a pronounced synergistic effect, and the claimed form and dosage regimen make it possible to achieve the convenience of taking the food supplement and maintain a high level of medical compliance. Due to the selected composition of biologically active substances, acting as an active component, a complex of excipients and the finished form of biologically active additives, it has improved stability, bioavailability and prolonged action.

There is a composition (RU 2419449, 12/30/2009), which is used to treat patients with medicinal hepatitis, which is a herbal collection that has the following composition: medicinal dandelion, tongueless chamomile (inflorescences), dioecious nettle (leaf), common tansy, inflorescences, medicinal calendula (inflorescences), common juniper (fruit), peppermint (leaf), St. John's wort (grass), linden (flowers), violet tricolor (grass), centaury (grass), flax seed, dill seed, burdock (root), chicory common (grass), highlander bird (grass), common hops (infructescence), blue cornflower (grass), lingonberry (leaf), bearberry (leaf), corn stigmas, immortelle (grass), calamus (roots and rhizomes), three-leaf watch (grass), angelica (root), sweet clover (herb), elecampane (root), field horsetail (grass).

The composition has a large number of components, including quite aggressive herbs, for example, calamus, St. John's wort, watch, linden, which in themselves have pronounced allergic reactions and side effects, and in the complex can unexpectedly enhance not only the positive, but negative qualities of each other ... The multicomponent composition of the composition quite strongly affects the interaction of the ingredients with each other, sometimes weakening and blocking the effect of each other, which can be attributed to the disadvantages of the composition. Based on the description of the patent, the composition is a herbal collection and is represented by a rather complex preparation system, which, as previously mentioned, is a significant drawback. The author of the invention positions the herbal mixture as a remedy for the treatment of patients with medicinal hepatitis, which directly indicates the narrow focus of the composition.

Known dietary supplement for food (RU 2435450, 06/09/2010), containing mint leaves and calendula flowers, characterized in that it additionally contains birch leaves, nettle leaves, chamomile flowers, corn columns with stigmas, grass succession, yarrow grass, St. John's wort, grass knotweed and oat grain.

The disadvantage of this collection is low efficiency when using large doses, as well as a narrow spectrum of activity (vitamin tea) in the presence of effective and diverse plants in its composition. An additional disadvantage is the form of release, since quite often the individual does not comply with the compliance of the drug intake - it leaves the tea unfinished, forgets about it, re-brews it, fills it with water, the temperature of which does not meet the requirements, in addition, tea bags are subject to rapid wear, therefore additional inconvenience.

A dietary supplement (RU 2175869, 08/10/2000) is also known from the prior art, which is an agent for the treatment of chronic cholestatic hepatitis. Collection of medicinal plants, includes flowers of the immortelle sandy, dandelion root, characterized in that it additionally contains tricolor violet grass, corn stigmas, calendula flowers, pine buds, medicinal chamomile flowers, yarrow herb, St. John's wort herb, tansy flowers, flowers lindens, sweet clover, rhizome with calamus roots, common barberry leaves, elecampane root and lingonberry leaves.

The disadvantages include the release form of the drug. Some of the ingredients are severe allergens, for example, linden, sweet clover. In patients with increased secretion of gastric juice, nausea and heartburn sometimes appear due to the relatively high content of tansy.

There is a remedy for the complex therapy of diseases of the liver and biliary tract (RU 2606838, 09/22/2015), containing immortelle flowers, grass of a mountaineer bird, oregano, fruits of milk thistle, rose hips, flax seeds, characterized in that it additionally includes the following plants: birch leaves, lingonberries , chamomile flowers, calendula, St. John's wort, lemon balm, coriander fruits, dandelion roots, licorice.

The disadvantages include the multicomponent composition with a monospecific spectrum of action of several ingredients, which significantly contribute to a limited intake of collection, for example, with calculous cholecystitis due to a pronounced choleretic effect, which can cause hepatic colic. With such a multicomponent composition, an insufficiently high hepatoprotective activity is revealed.

Additionally, there is a remedy for the treatment of gastric ulcer and duodenal ulcer with the eradication of Helicobacter pylori, occurring against the background of chronic liver diseases (RU 2274467, 19.07.2004), which is a collection of medicinal plants, including the herb of centaury, yarrow grass, St. John's wort, dandelion roots, rhizome with calamus roots, burnet root, eucalyptus leaves, tansy flowers, wormwood herb, corn stigmas, sandy immortelle flowers, creeping thyme grass, lingonberry leaves, black elderberry flowers, flax seed, which additionally contains flowers chamomile, sweet clover, erect cinquefoil rhizome, calendula flowers, peppermint leaves, medicinal sage, stinging nettle, linden flowers, bearberry.

The disadvantages include the multicomponent composition, while some of the ingredients can stimulate the secretion of gastric juice, which is far from contributing to the healing of stomach ulcers. The composition is aimed at a narrow field of application, which significantly narrows the range of its use.

From the prior art, a composition of ingredients for a balsam is known (RU 2031107, 16.07.1992), containing the rhizome of calamus marsh, oregano herb, birch leaf or buds, St. John's wort, oak bark, peppermint leaves, motherwort herb, wormwood herb, tansy flowers, yarrow grass, fresh apples, rose hips and black chokeberry, color, citric acid and aqueous-alcoholic liquid, characterized in that it additionally contains buckwheat pericarp, galangal rhizome, dill pods, strawberry leaves, elecampane root, corn stigmas, string herb, nettle leaves, wormwood grass (Chernobyl), knotweed grass, sand immortelle flowers, elderberry flowers, plantain leaves, rowan berries, aniseed or fennel oil and sugar.

The disadvantage is the release form containing alcohol, the complexity of dosing, the danger of addiction, limited consumption due to the composition, the composition itself is multicomponent and has pronounced allergens.

There is a remedy for the treatment of urolithiasis (RU 2281781, 02/14/2005), which is a herbal collection that includes the fruits of an ordinary juniper, cones of ordinary hops, lingonberry leaves, horsetail herb, sweet clover herb, shepherd's purse herb, blue cornflower flowers, flax seeds , characterized in that it additionally contains parsley grass, madder roots, linden flowers, knotweed grass, St. , fennel fruits, corn stigmas, sandy immortelle flowers, calamus roots and rhizomes, licorice root, medicinal dandelion roots, bearberry herb, wormwood herb.

The dietary supplement is declared with a narrow range of applications, which, according to the applicant, is a disadvantage. In addition, the collection can cause side effects in the form of increased choleresis, further leading to attacks of cholecystitis due to the relatively high content of the fruits of anise ordinary. In some patients, this collection can cause the stones to move, leading to pain and sometimes urgent surgery.

Among the patent documents, a remedy for the treatment of chronic viral hepatitis B (RU 2180228, 02.10.2000) is presented, including flowers of tansy, chamomile flowers, elecampane root, characterized in that it additionally contains the roots of Eleutherococcus prickly, lemon balm leaves, celandine herb large, oregano herb, roots of Potentilla erectus, herb of centaury umbellate, common thyme herb, roots of common barberry, calendula flowers, sandy immortelle flowers, corn stigmas, sweet clover, rhizome with calamus roots, dandelion root, lingonberry leaves, bearberry leaves, leaves eucalyptus, juniper fruits, wormwood herb, pink periwinkle herb, pine buds, linden flowers

The disadvantage of this remedy is an insufficiently pronounced therapeutic effect and the liver function does not always improve, which is expressed in the normalization of its biochemical parameters. In addition, the content of common tansy flowers in the collection indicates that the drug has restrictions on consumption - tansy is contraindicated in the treatment of pregnant women and lactating mothers, as this can lead to toxic reactions, and in some cases the collection does not always ensure the normalization of the outflow of bile from hepatic ducts and gallbladder.

A remedy for the treatment of hepatitis of non-infectious etiology (RU 2122418, 04/29/1996) containing immortelle, fennel, mint, characterized in that it additionally contains calendula, corn stigmas, string, yellow sweet clover, chamomile, lingonberry, valerian root, calamus root, tansy ...

Contains unwanted ingredients that can cause severe side effects: tansy, calamus.

The composition described in patent RU 2419449 was selected as the closest analogue.

Thus, there is a need to create such a dietary supplement that will have a wide practical and therapeutic profile, in particular cases, have a beneficial effect on the gastrointestinal tract, kidneys and liver, will be the optimal source of flavonoids and DV, and when taken does not show pronounced allergic and unwanted reactions ...

According to the task at hand, the applicant has proposed a dietary supplement of encapsulated form. When developing the composition of dietary supplements with high quality indicators with a therapeutic effect, the same technological approaches and requirements were used as in the development of drugs.

When developing, the applicant focused on the optimal amounts of flavonoids and tannins for prevention and recovery, which a person can receive when taking dietary supplements, so that at the same time the maximum positive effect is achieved without the manifestation of undesirable reactions.

It was found that the optimal amount of flavonoids in terms of rutin and tannins in terms of tannin for the selected form should be present in amounts of 4-5 mg and 14.9-18.3, respectively. Such a volume would correspond to 1 filter bag weighing 1.5 g. As a result of the development of encapsulated dietary supplements, it was found that the BAS in 1 filter bag weighing 1.5 g corresponds to the amount of BAS in 2 capsules, thus, with the recommended intake of 3 filters, package per day, the optimal mode of taking capsules is 2 capsules 3 times a day. At the same time, for each capsule there are 2-2.5 mg of flavonoids in terms of rutin and 7.45-9.15 mg of tannins in terms of tannin.

To achieve a synergistic effect and to maximize the elimination of undesirable reactions or to bring the latter to the status of the minimum possible, a qualitative and quantitative composition was experimentally selected, including sandy immortelle flowers, columns with corn stigmas, chamomile flowers, dandelion root, peppermint leaves, motherwort herb, roots angelica, marigold flowers, knotweed herb in a ratio of 1.5: 1.5: 1: 1: 1: 1: 1: 1: 1.

All structural and physicochemical characteristics of biologically active substances and excipients (EX) were studied, the information obtained was used to develop the composition and technology of biologically active additives.

Sandy immortelle inflorescences contain flavonoids, glycosides, ascorbic acid, essential oil, resinous and bitter substances, vitamin K, coumarin, scopoletin, dyes, trace elements (iron, aluminum, copper, manganese, chromium).

Helichrysum inflorescences help to improve bile secretion, increase the content of bilirubin and cholates in bile, reduce the concentration of bile acids, have an antispasmodic effect on the smooth muscles of the intestine, gallbladder, biliary tract, and blood vessels.

Corn silk contains tannins, saponins, carotenoids, vitamin K, pantothenic acid, gums, bitter glycosides, vitamin C, fatty and essential oils, sugars, resins, sitosterol and stigmasterol, alkaloids, trace elements.

Corn silk has choleretic, diuretic, hemostatic, hypoglycemic (hypoglycemic) properties. Corn silk stimulates the production of bile, and also improves its outflow, reduces the viscosity of bile, and the amount of bilirubin. Due to this, small stones in the gallbladder and bile ducts gradually dissolve. Vitamin K contained in the stigmas influences the synthesis of prothrombin in the liver and increases the number of platelets. Thus, the hemostatic property of corn silk is determined.

Chamomile flowers are also used for the production of herbal teas (tea drinks) for young children (included in the list of plant materials for use in the production of biologically active food supplements for children from 3 to 14 years old and children's herbal teas (tea drinks) for young children) ).

Pharmacy chamomile contains essential oil (it contains chamazulene and a-basabolol), flavonoids, coumarins, polysaccharides, mineral salts, organic acids, ascorbic acid.

Chamomile (medicinal) exhibits a wide range of therapeutic properties. It has anti-inflammatory, antimicrobial, analgesic, diaphoretic properties. Relieves spasms of the abdominal organs, stimulates the secretory activity of the digestive glands and bile secretion, improves appetite.

Dandelion root contains taraxacin, taraxacerol, flavonoids, insulin, triterpene compounds (traxerol, androsterol, taraxasterol), fatty oil, mucus, rubber, vitamins C, A, B2, E, PP salts of iron, manganese, calcium, phosphorus.

The raw material of medicinal dandelion has choleretic diuretic, antispasmodic, expectorant properties. Dandelion BAS reduce blood cholesterol levels, normalize metabolism and are used to treat anacid gastritis, which are complicated by the pathology of the hepatobiliary system and chronic constipation, and are also used as part of the complex therapy of cholecystitis and hepatocholecystitis.

Mint leaves are also used for the production of herbal teas (tea drinks) for young children (included in the list of plant materials for use in the production of biologically active food supplements for children from 3 to 14 years old and children's herbal teas (tea drinks) for young children) ).

Peppermint leaves contain up to 2.75% essential oil (it contains menthol), tannins, flavonoids, ursolic and oleonic acids, betaine, carotene, hesperidin, trace elements.

Peppermint has antispasmodic, sedative, choleretic, antiseptic, analgesic, weak antihypertensive properties. It improves appetite, enhances the secretion of the digestive glands and bile secretion, reduces the tone of the smooth muscles of the intestine, as well as the biliary and urinary tract.

Motherwort herb (heart) contains the alkaloids leonurin and leonuridine, flavonoids (rutin, quercetin, quinqueloside, etc.), essential oil, saponins, tannins, organic acids (tartaric, malic, P-coumaric, ursolic, vanillic, citric) vitamins A, E, C, bitter substances, mineral salts.

Motherwort raw materials show sedative, hypotensive, antispasmodic, weak diuretic properties, slows down the heart rate, increases the strength of heart contractions.

Angelica contains carbohydrates (umbelliferose); mono- and sesquiterpenoids (alpha-thujene, alpha-thujone, beta-thujone, camphor, alpha-pinene, beta-pinene), steroids (arachinate and beta-sitosterol palmitate, in fruits - beta-sitosterol, stigmasterol; phenol carboxylic acids , chlorogenic, protekhovy).

It has an antispasmodic effect due to the complex content of various groups of biologically active substances.

Calendula flowers are also used for the production of herbal teas (tea drinks) for young children (included in the list of plant materials for use in the production of biologically active food supplements for children from 3 to 14 years old and children's herbal teas (tea drinks) for young children) ).

Marigold flowers (calendula officinalis) contain up to 3% carotenoids (carotene, rubixanthin, flavoxanthin, cytoxanthin, flavochrom, etc.), which give them an orange color. Also contain essential oil, saponins, inulin, tannins, organic acids, resins, mucus and bitter substances.

Calendula officinalis has bactericidal, anti-inflammatory, wound healing, choleretic, antispasmodic, sedative, cardiotonic properties. Its raw material increases the secretory activity of the stomach and liver, enhances bile formation, improves bile secretion, and reduces the content of cholesterol and bilirubin in bile. To improve bile secretion, eliminate stagnation of bile in the gallbladder, usually, calendula is used in combination with yarrow and chamomile.

Knotweed herb contains flavonoids (quercetin, avicularin, isorhamnetin), tannins, coumarins, saponins, vitamin C, silicic acid compounds, pectin, a polysaccharide complex, carotene, iron, organic acids.

Knotweed herb prevents the formation of urinary stones (the action of silicic acid compounds), which are excreted in the urine in significant concentrations. Tannins, which have antimicrobial, anti-inflammatory and astringent properties, have a positive effect on the function of the gastrointestinal tract.

When selecting the optimal composition for the encapsulated form of dietary supplements, which is a full-fledged source of flavonoids and tannins, it was unexpectedly found that all of the above ingredients in a certain quantitative ratio have a synergistic effect. It is especially worth noting motherwort, the addition of which to the composition neutralizes some of the undesirable effects of the remaining parts of the dietary supplement, while at the same time enhancing the practical and therapeutic effect of the food additive as a whole. The rest of the ingredients also directly affect the motherwort, practically negating such negative phenomena as a decrease in heart rate and hypertension, and allowing their possibility only with extremely long-term intake of a food supplement without interruption. Thus, the experimentally selected composition in the given proportions showed that the complex of biologically active substances is of high practical value for the gastrointestinal tract, kidneys and, in particular, the liver.

The specified qualitative and quantitative composition can be considered ready for use if a dry extract is prepared from it for transferring the extract into any of the finished forms known from the prior art. The preferred ready-made form for the claimed composition of the dry extract is considered to be herbal collection in bulk, herbal collection in a filter bag, tincture, balsam, granular, tableted, capsule forms. The most preferred is the capsule form established for the specified composition experimentally.

The indicators of the quality of plant raw materials were evaluated and calculated for compliance with the indicators necessary for solving the task, which are reflected in table No. 1.

Table 1 - Indicators of the quality of plant raw materials Quality indicators Requirements Test results External signs A mixture of inhomogeneous particles of plant materials of dark brown color with light green, grayish-yellow and orange blotches Compliant The taste of water infusion Spicy bitter, slightly astringent Compliant The smell of water infusion Weak, typical of steamed plants Compliant The presence of impurities Not allowed Not found Mass fraction of moisture,% no more 13.00 9.20 Mass fraction of extractive substances extracted by water,% not less 32.50 33.30 Tannins in terms of tannin,%, not less 3.20 3.60 Flavonoids in terms of rutin,%, not less 1.00 1.40 Particles that do not pass through a sieve with holes of 3 mm,%, no more 10,00 2.60 Particles passing through a sieve with holes of 0.2 mm,%, no more 15.00 5.00 Microbiological purity According to the requirements Compliant Package content weight, kg 15.00 ± 5% 15.05

Currently, the most common dosage form for dietary supplements is the tablet form. The technology of tableted dietary supplements is widely used by manufacturers. However, one should take into account its features, which the applicant attributes to disadvantages: multistage, a large amount of technological auxiliary substances in formulations, the impact on biologically active substances of stressful technological conditions, such as humidification, high temperatures, pressing, which can lead to their destruction, which will negatively affect stability and effectiveness of biologically active substances.

In accordance with the task, the applicant has established that it is the capsules that make it possible to ensure high dosing accuracy; during the production of the capsules themselves, the BAS is not exposed to aggressive technological influences, which has a positive effect on the stability and effectiveness of the BAS and allows maintaining the synergistic effect. Additionally, it is worth noting the attractive appearance, masking the unpleasant taste and smell of biologically active substances.

The biopharmaceutical capabilities of modifying the release of biologically active substances from capsules make it possible to vary it in a wide range - from fast to phase and prolonged.

For the claimed capsule form, all types of capsules known from the prior art are valid. Nevertheless, it will be impossible to determine the most preferable for an average specialist without preliminary approbation. The preferred variant of the capsule form in the present invention are capsules made of gelatin, a natural product of hydrolysis of collagen containing raw materials that are waste from food industry.

Gelatin is a polypeptide whose molecule consists of amino acids, including: glycine (about 30%), proline, hydroxyproline, alanine, glutamic and aspartic acids. The amino acids of gelatin have an effect on the body: they improve metabolism, increase mental performance and strengthen the heart muscle, have a beneficial effect on the tissues of the musculoskeletal system, the mucous membrane of the gastrointestinal tract during erosions and peptic ulcer disease and are one of the main sources of energy for the central nervous system, muscles and the brain. The selected type of capsule is easily absorbed and does not give side reactions, in addition, the selected composition of the capsule enhances the synergistic effect of the BAS complex.

Additionally, it should be noted that gelatin, being a natural product, is easily absorbed by the body, quickly dissolves in the acidic environment of the stomach (which is facilitated by the presence of gastric protease pepsin) and releases the contents of the capsules, thereby facilitating the rapid entry of biologically active substances into the body.

Hypromellose capsules are produced by synthetic modification of cellulose and are considered safe for human consumption. It is practically insoluble in hot water, in acetone, in anhydrous ethyl alcohol and in chloroform, but it dissolves in cold water to form a colloidal solution, and exhibits reversible temperature gelation.

Modification of the HPMC molecule with methoxy and hydroxy propoxy groups makes it possible to obtain products with variations in many properties, for example, gelation temperature, viscosity, elasticity, and hydration.

This makes it possible to create products with modified release and with increased resistance to storage conditions and mechanical processing.

HPMC is well compatible with known excipients and has gelatin-like properties. HPMC meets the dietary and cultural needs of all patients. Meets production demands - capsules can be produced and filled with existing equipment. It is characterized by proven safety information and is approved for pharmaceutical use. In addition, it improves the characteristics of capsules, their strength, protection against moisture from microbial contamination, and high compatibility with products.

Hypromellose capsules are more moisture stable than gelatin capsules. The moisture content of the capsules themselves is 6-7%, which is lower than the moisture content of gelatin capsules, which is 12-13%. This is extremely important for hygroscopic biologically active substances and for conditions of filling, transportation, storage as empty capsules.

However, there is a delay in disintegration time of the hypromellose capsule of about 5 minutes in simulated gastric environment and 10 minutes in simulated intestinal fluid. As a result, gelatin capsules remain the leader in the choice of encapsulated form for unlimited and unmodified release of biologically active substances.

Due to the absence of the need to modify the release of dietary supplements, capsules from gelatin were chosen for further pharmaceutical development, due to the physicochemical properties, as well as the expected parameters of the release, dissolution and absorption of the biologically active substances. Nevertheless, based on the types and properties of capsules described by you, various options for the composition of biologically active substances are valid, including options for a modified and / or prolonged action, which can be reproduced by methods known from the prior art for a specialist of average level.

The applicant considered all types of extracts, however, for the task at hand, a dry extract from plant raw materials is the most preferable.

Dry extracts are concentrated extracts from plant raw materials, which are free-flowing masses with a moisture content of no more than 5%. Dry extracts are obtained by drying thick extracts or directly from a purified extract by methods that ensure maximum preservation of biologically active substances: by convection or freeze drying.

The most preferred form of the active substance, placed in hard capsules, is a substance made in the form of granules or powder. In the case of a small dosage of the active substance, fillers (diluents) are introduced into the formulations to ensure the accuracy of dosing by the capsule filling machine: mannitol, lactose, microcrystalline cellulose, corn starch, and other traditional explosives approved for pharmaceutical use.

The choice of excipients is closely related to the technology of preparing the encapsulated mixture for filling; accordingly, the technological properties of the BAS were studied to select and justify the preparation technology.

Example 1. Determination of the flowability of biologically active substances for the subsequent production of the encapsulated form.

The powdery content must first of all have good flowability. Looseness, in turn, depends on many characteristics of the powder: on the fractional composition, amorphousness and moisture content of the substance. Since flowability is a complex characteristic, it is customary to determine it in two ways: by the rate of flow from a standard funnel and by the value of the angle of repose. Angle of repose - the angle between the generatrix of the bulk material cone and the horizontal plane. The slope angle characterizes the effect of friction between particles and the effect of gravity on the powder mass, assesses the effect of particle size, shape and electrostatic interaction between particles during the pouring of powder from the hopper of a capsule filling machine. The value of the angle of repose depends on the shape, size and cohesive properties of the particles; it varies over a wide range: from 25 ° to 30 ° for well-free flowing materials, from 60 ° to 70 ° for poorly free-flowing materials.

Like other characteristics of bulk masses, the bulk density is a complex indicator that depends on many others: particle size distribution, moisture, packing density in the layer. It is important that this is not a constant value, it can change under the influence of vibration and even during storage in a warehouse. Therefore, a distinction is made between the minimum bulk density of a freely poured powder and the maximum - the bulk density after compaction - for a powder freely poured, but compacted by shaking. Bulk density is closely related to the volume of the capsule, the number of which is selected depending on the mass of the contents of the capsule.

The methods are presented in the State Pharmacopoeia of the Russian Federation (GF RF). The qualitative assessment of the flowability of the powder is determined by the values of the Carr and Hausner indices, which are calculated on the scale given in USP 31 (table 2).

Table 2 - Estimation of the Hausner and Carr indices Carr index Compressibility assessment Hausner index 10 very good 1.00-1.11 11-15 good 1.12-1.18 16-20 average 1.19-1.25 21-25 satisfactory 1.26-1.34 26-31 bad 1.35-1.45 32-37 very bad 1.46-1.59 Over 38 very, very bad More than 1.60

Determination of the fractional composition was carried out in accordance with OFS.1.1.0015.15 "Sieve analysis" on any suitable electromagnetic sieve analyzer. An accurate sample of the material was divided into fractions by sieving through a set of sequentially assembled sieves with aperture sizes of 2 mm, 1.25 mm, 710 μm and 315 μm.

The weighed portion was placed on the top largest sieve and the entire set was shaken by hand for 5 minutes. Then the sieves were removed one by one, the material remaining on each sieve was weighed separately. Then the percentage of each fraction of the total weight of the sample was found. Sifting is complete if, with additional shaking, the amount of material passing through the sieve for 1 minute is less than 1% by weight of the material remaining on the sieve.

Determination of bulk density was carried out in accordance with OFS.1.4.2.0016.15 "Degree of flowability of powders" on any suitable tester for determining the bulk density. During the analysis, a sample of the material was weighed with an accuracy of 0.001 g and poured into a glass measuring cylinder with a capacity of 50 ml. The vibration amplitude of 3 mm and the frequency of 150 vibrations per minute were set. After 5 minutes, the device was turned off.

Bulk density was calculated by the formula: ρ = m / v

where ρ is the bulk density before or after tapping (compaction), g / cm ³ ; m is the mass of the material, g; v is the volume of powder in the cylinder before or after shaking (compaction), cm ³ .

Determination of the angle of repose was carried out in accordance with OFS.1.4.2.0016.15 "The degree of flowability of powders" on any suitable flow tester. An exact weighed portion of the powder, about 100 g, was poured into the funnel of the device, the nozzle diameter was 10 mm. The angle of repose is set in the device using a laser sensor.

Hausner and Carr indices

Based on the values of the bulk density, the Hausner index and the Carr index are calculated, according to the values of which the flowability and compressibility are estimated.

Index calculation formulas:

Hausner index (H) H = P _y / r;

Carr index (J) J = 100⋅ (Р _у - р) / Р _у ;

where P _y - bulk density after compaction;

p is the bulk density.

The results obtained after measuring 6 samples are shown in Table 3.

Table 3 Indicator, units rev. The quantity one 2 3 4 five 6 Average Particle size ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm Bulk density before compaction, g / ml 0.40 0.40 0.41 0.39 0.40 0.40 0.40 ± 0.03 Bulk density after compaction, g / ml 0.57 0.58 0.57 0.58 0.57 0.57 0.57 ± 0.02 Angle of repose, degrees 29 28 29 thirty 31 28 30 ± 2 Humidity, % 0.19 0.22 0.22 0.25 0.21 0.19 0.22 ± 0.3 Carr index 11.70 12.20 12.10 13.90 12.10 12.50 12.50 ± 1.3 Hausner index 1.11 1.12 1.10 1.11 1.12 1.13 1.12 ± 0.3

The angle of repose corresponds to 28-31 degrees, the powder was not dusty and spilled out freely from the funnel. The bulk density before compaction is 0.40, and after compaction - 0.57, which confirms the use of the extract in the form of an encapsulated form. On the basis of the calculated values of the Carr and Hausner indices, the flowability of the extract was assessed as "good".

It was unexpectedly found that when adding excipients, taking into account the dosage of biologically active substances, in addition to improving the technological characteristics, the bioavailability of the active ingredient itself increased.

Example 2. Development of the composition of the encapsulated form of a biologically active additive.

Experimentally, the optimal composition of dietary supplements of a capsulated form was selected, containing the previously indicated composition as a BAS, including flowers of the immortelle sandy, columns with corn stigmas, chamomile flowers, dandelion root, peppermint leaves, motherwort herb, angelica roots, marigold flowers, knotweed herb in a ratio of 1.5: 1.5: 1: 1: 1: 1: 1: 1: 1 (table 4).

Table 4 - The name of the most preferred excipients and their purpose. Name of excipients Appointment Microcrystalline Cellulose 101 (MCC) Filler α-polyvinylpyrrolidone (α-PVP)
PVP K25 Binder, disintegrant Colloidal silicon dioxide (aerosil) Anti-stick, slip Magnesium stearate Sliding Gelatin Capsule material Titanium dioxide (E171) dye Triacetin plasticizer Polysorbate 80 plasticizer

Microcrystalline cellulose (MCC), obtained by modification of cotton cellulose, is used as a structuring agent, thickener, emulsifier and stabilizer. They dissolve better and are absorbed faster by the body. At the same time, the use of MCC allows the release of biologically active substances gradually, at a controlled rate, for a long time. Microcrystalline cellulose itself is neither digested nor absorbed by the body.

α-polyvinylpyrrolidone (α-PVP) - is a polymer of N-vinylpyrrolidone, a free-flowing powder with a spherical particle morphology. When used, an optimal balance is achieved between the strength of adhesion and ease of use due to the low viscosity. Have a stable pH value.

Colloidal silicon dioxide (Aerosil) . Used as a glidant to increase particle glide. Its small particle size and large specific surface area provide the necessary properties that improve rheological properties during pressing, prevents caking of powdery materials, and promotes the redistribution of moisture in the capsule.

Colloidal silicon dioxide (Aerosil), which is a light white highly dispersed micronized powder with a large specific surface, which has pronounced adsorption properties. In water, aerosil at a concentration of 1-4% forms jelly-like systems with glycerin, vaseline oil.

Aerosil is widely used as sliding aids to increase the flowability of powder mixture, improve tablet coating processes, ensure disintegration and dissolution rate of tablets and good appearance. Aerosil is used to stabilize suspensions, dry extracts and pills. It provides an even distribution of biologically active substances.

Magnesium stearate is a finely divided white powder that is slightly soapy to the touch. It is a magnesium salt of stearic acid or a mixture of stearic acid salts and synthetic fatty acids. Dissolves in warm alcohol, mixes in oils, practically does not dissolve in water. Magnesium stearate melts at about 88 ° C. Density: 1.02 g / cm³.

Gelatin capsules . Capsules No. 1 were selected as the most suitable in terms of volume for filling with a mass of dry extract that provides dosage of biologically active substances.

To determine and develop the qualitative and quantitative composition of capsules, the results of the quantitative content of biologically active substances in a dry mixture of plant raw materials were used, which are shown in Table 5. The required amount of biologically active substances when used in recommended doses is presented in Table 6.

Table 5 Indicators Content according to ND Content in the sample Flavonoids in terms of rutin,% Not less than 1.0 1.16 ± 0.12 Tannins in terms of tannins,% Not less than 3.2 3.48 ± 0.35

Table 6 Index mg Adequate consumption *
Upper admissible consumption level **, mg %
from an adequate level of consumption per day Flavonoids per rutin 13.35 30 * -100 ** 44.5 Tannins in terms of tannins 49.8 300 * -900 ** 16.6

* ^, ** according to the "Unified Sanitary-Epidemiological and Hygienic Requirements for Goods Subject to Sanitary-Epidemiological Supervision (Control)" Chapter II, Section 1, Appendix No. 5.

As the main biologically active substances, plant raw materials contain various groups of flavonoids in terms of rutin and tannins in terms of tannin.

Flavonoids are a group of biologically active substances with a fixed melting point, bitter taste, colorless or colored yellow, red or blue, depending on the pH of the medium. They are readily soluble in polar solvents, methanol, butanol, and alkali solutions.

Flavonoid glycosides are soluble in water, but aglycones are poorly soluble in water. Most flavonoid aglycones are soluble in acetone, ethyl acetate, chloroform, and other hydrophobic solvents.

The presence of phenolic hydroxyl groups determines the acidic properties of flavonoids and their ability to form phenolates in an alkaline medium. Due to the presence of phenolic hydroxyls, flavonoids are easily oxidized. The easy oxidizability of flavonoids promotes the reduction of other substances in the reaction mixture or prevents their oxidation. This property of flavonoids is called antioxidant or antioxidant. In the process of the experimental selection of excipients, it was found that flavonoid antioxidants are capable of strongly inhibiting oxidation processes even in small quantities, which has a significant effect on the stability of the capsule form.

Rutin, is a bioactive polyphenol of the group of vitamins P, is widely used in medicine due to angioprotective, gastroprotective, diuretic, antispasmodic, anti-sclerotic, anti-inflammatory, antiviral effects.

The extremely low solubility of rutin in aqueous media and body fluids creates certain difficulties in creating drugs and carrying out the extraction process, since it is solubility that is one of the main biopharmaceutical characteristics that largely determines the bioavailability of biologically active substances.

It was experimentally found that the solubility of rutin significantly increases in aqueous solutions of polyvinylpyrrolidone with a molecular weight of 8000 and more, human serum albumin and micellar media of cationic surfactants due to the formation of supramolecular complexes.

Surfactants are widely used in pharmaceutical technology as solubilizers, emulsifiers and stabilizers. Polyvinylpyrrolidone is a cationic surfactant, due to the combination of its surface-active and bactericidal properties, this made it possible to increase the stability and release of biologically active substances in the composition of the capsule form in the process of searching for the optimal composition. To increase the bioavailability of rutin and the stability of dietary supplements, Alpha PVP K25 was chosen as an excipient in the form of a binder, which made it possible to improve the solubility and absorption of flavonoids.

Tannins are high molecular weight, genetically related natural phenolic compounds with tanning properties. They are derivatives of pyrogallol, pyrocatechol, phloroglucinol and have a molecular weight of 1,000 to 20,000.

Tannins amorphous ampholytes; many dissolve well in water and alcohol, have an astringent taste. In solution, give a neutral / slightly acidic reaction of the medium. In the crystalline state, only catechins are known; they are poorly soluble in cold water, preferably in hot water. Most tannins are highly hygroscopic. In medicinal mixtures, they cannot be mixed with salts of heavy metals, protein substances and alkaloids, as precipitates are formed. By causing partial coagulation of proteins, they form a protective film on the mucous membranes and wound surfaces. On contact with air, tannins are easily oxidized, turning into flobaphenes, which cause the extracts to be dark brown in color.

As a result of the experimental selection of the qualitative and quantitative ratio of biologically active substances and excipients for biologically active additives containing the previously indicated complex of biologically active substances, the optimal range and ratio of biologically active substances and excipients was established, taking into account all the stated requirements by the authors when solving the tasks and expressed in wt%: dry extract 40-45%, filler 47-53%, binder, disintegrant 3-5%, anti-stick 0.8-2.2%, sliding 1.2-3.8%.

At the same time, during the installation of the preferred composition, it was recorded that when going beyond the range to the lower side of the dry extract and increasing the range for excipients, a decrease in bioavailability and a decrease in prolongation were observed, as well as a decrease in the quality of the encapsulated form. A similar situation was observed with the reverse overshoot of the ranges. Thus, failure to comply with the appropriate ranges did not allow achieving the stated technical results. The composition shown in Table 7 should be considered the most preferred embodiment of the invention.

Table 7 Recipe Specification Content per capsule, mg % Capsule contents Biologically active substances Dry extract 114,00 42.22 Excipients MCC 101 135.00 50,00 Alpha-PVP K25 10,00 3.70 Aerosil 4,00 1.48 Magnesium stearate 7.00 2.60 Total 270,00 100,00 CAPSUGEL capsules, USA Weight of the filled capsule 340.00-350.00

To select the size of the capsule, the technological characteristics of the mixture for encapsulation containing the extract obtained from plant raw materials were determined, which are presented in table 8.

Table 8 Indicator, units rev. The quantity one 2 3 4 five 6 Average Particle size ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm ≥100 μm Bulk density before compaction, g / ml 0.34 0.32 0.31 0.30 0.30 0.31 0.33 ± 0.02 Bulk density after compaction, g / ml 0.55 0.56 0.57 0.55 0.55 0.55 0.56 ± 0.02 Angle of repose, degrees 28 27 29 28 28 27 29 ± 2 Humidity, % 0.20 0.22 0.25 0.25 0.21 0.19 0.23 ± 0.3 Carr index 10,00 10.20 10.30 10.15 10.10 9.95 10.20 ± 0.3 Hausner index 1.05 1.08 1.09 1.08 1.07 1.10 1.08 ± 0.2

The angle of repose corresponds to 28-29 degrees, the powder was not dusty and spilled out freely from the funnel. The bulk density before compaction is 0.33 and after compaction is 0.55. On the basis of the calculated values of the Carr and Hausner indices, the flowability of the extract was assessed as "very good".

Thus, the obtained quality indicators allow us to conclude that the "flowability" of the mixture for encapsulation increases as a result of mixing the dry extract with the selected auxiliary substances. The most preferred capsule size was chosen size 1.

Example 3. Development of technology for obtaining a dry extract.

To obtain a dry extract, an aqueous extraction of plant raw materials was carried out by obtaining a liquid extract, followed by filtration, evaporation, water-alcohol purification and drying.

Description of the technological process.

1. Obtaining a liquid extract.

On a laboratory balance, 700.0 g of plant material is weighed, placed in an ultrasonic extractor, preferably HO-538, and 7500 ml of extractant is poured in, preferably purified water at 70-80 ° C, the extraction time is about 30 minutes. The temperature of the water circuit is about 60-70 ° C. After the completion of the extraction process, the raw material is squeezed out, the liquid extract is filtered through a sieve with a mesh diameter of preferably 355 µm and then preferably 250 µm. The coefficient of water absorption of plant materials was calculated experimentally and amounted to 3.2. The volume of the obtained liquid extract was approximately 6100 ml.

2. Evaporation of the liquid extract.

A 1000 ml flask is filled with the extract to 2/3 of its volume and evaporated on any rotary evaporator, preferably BUCHI R-300, at a water bath temperature of 60 ° C. The flask rotation speed is 80 rpm. The initial vacuum is 180 mbar, gradually decreasing in 5 mbar steps, down to 30 mbar within 20 minutes, avoiding the boiling point. The total duration of the extractant stripping process is 45 minutes. The obtained volumes of thick extracts are combined. The total volume of the thick extract is 1000 ml.

3. Cleaning

The resulting volume of the thick extract is transferred to a 2000 ml flask. Ethanol 96% in a volume of 200 ml is added to the thick extract and mixed. Then filtered, preferably filtering in a Bunsen flask through a six-layer gauze filter. The volume of the purified thick extract is 1100 ml.

4. Getting dry extract

The purified thick extract is poured into 550 ml drying trays and dried in an oven at 70 ° C for 26 hours. After 26 hours, check the residual moisture content of the dry extract, its value should be less than 5%. At a residual moisture content of more than 5%, the extract is dried for about 4 hours at a temperature of 70 ° C. The resulting dry extract is ground using a dry grinding mill for solid and brittle substances for about 30-40 seconds at a rotation speed of 6000 rpm to a particle size passing through a sieve with a mesh diameter of 250 microns. The dry extract weight is 100.00 g.

Example 4. Encapsulation of dry extract.

To obtain a mixture for encapsulation on an analytical balance, exact weighed portions of the components of the capsule are weighed (Table 7). The mixture is stirred, preferably in a glass beaker with an overhead stirrer for 10 minutes.

Filling of capsules is carried out using any suitable capsule filling machine for this procedure, preferably a manual Optima Aluminum capsule filling machine (Farmalabor Tech, Italy), and the most preferred capsule option is hard gelatin capsules No. 1, manufactured by Capsugel.

Dosing into capsules is carried out using any device known in the art suitable for this operation, however the preferred option is a manual capsule filling machine, more preferably Optima Aluminum. It dispenses in four sequential stages: insertion of empty capsules, separation, filling and reassembly.

The mixture, previously weighed on a balance with an accuracy of 0.0001 g in the amount of 220.00 mg, is dosed into each capsule, then the caps are installed and the locking device is fixed.

Example 5. Determination of quality indicators of a dietary supplement.

Thin layer chromatography. Determination of the authenticity of flavonoids.

Norm: The chromatogram of the test solution should show: the adsorption zone with fluorescence of yellow-orange color approximately at the level of the adsorption zone of CO (standard sample) rutin, the adsorption zone with fluorescence of bright yellow color below the adsorption zone of CO rutin; detection of additional 3-4 adsorption zones is allowed, including the adsorption zone with yellow fluorescence above the CO adsorption zone of rutin.

Qualitative reaction to tannins.

To 1.00 g of the sample, add 10 ml of alcohol (30%) and heat in a water bath under reflux for 30 minutes. Cool and filter. To 1 ml of the filtrate add 2 ml of a 10% solution of vanillin in hydrochloric acid. A red color appears.

Uniformity of capsule mass was determined in accordance with General Pharmacopoeia Monograph 1.4.2.0009.15 "Uniformity of the mass of dosage forms" using an electronic balance. The average weight was determined by weighing 20 dosage units (unopened capsules). Each unit was weighed separately to the nearest 0.001 g and the average weight was calculated.

The capsules were opened and the contents were removed as completely as possible. Weighed the shell. The mass of the contents of each capsule was calculated as the difference between weighings. The determination was repeated on the 19 remaining capsules.

Norm : No more than 2 ^x individual masses may deviate from the average mass of no more than 10.0% - for capsules with contents less than 340 mg.

Disintegration of capsules ... (OFS.1.4.1.0005.15 "Capsules"). The therapeutic effect of dietary supplements depends not only on the dosage of the active substance, but also on the speed and completeness of their release from the capsule. In a liquid medium, the capsules first disintegrate into separate fragments, from which the release of the active substance then begins. In accordance with modern requirements, capsules must combine sufficient mechanical strength required for automatic filling, packaging and transportation, and disintegration in an aqueous medium, which meets the requirements of the State Fund of the Russian Federation.

Determination of disintegration was carried out on a “swinging basket” device ED-2 SAPOx from Electrolab, India. The volume of the medium is 800 ml. Three media were used: 0.1 M hydrochloric acid solution with pH 1.2; acetate buffer pH 4.5; and phosphate buffer pH 6.8. Medium temperature (37 ± 0.5) ° С, volume - 800 ml, the experiment was carried out without using caps.

Dissolution media were prepared in accordance with General Pharmacopoeia Monograph 1.3.0003.15 "Buffer solutions".

To prepare 1 liter of 0.1 M hydrochloric acid solution with pH 1.2, a standard titer was used (ZAO Uralkhiminvest). The content of the fixanal was brought to a volume of 1000 ml with purified water, with stirring on a magnetic stirrer (RO5, IKA, Germany) for an hour while heating to a temperature of 40 ° C.

To prepare 1 liter of acetate buffer with pH 4.5, 63.0 g of anhydrous sodium acetate is dissolved in water, 90 ml of diluted acetic acid (30%) is added, the pH value is adjusted to 4.5 potentiometrically with acetic acid 30%, and the volume is adjusted with purified water to 1000 ml. Then, with stirring on a magnetic stirrer (RO5, IKA, Germany) for an hour while heating to a temperature of 40 ° C.

To prepare 1 l of potassium phosphate buffer with pH 6.8 51.0 ml of 27.2 g / l potassium dihydrogen phosphate solution is mixed with 49.0 ml of 71.6 g / l disodium hydrogen phosphate solution. If necessary, adjust the pH to 6.8 potentiometrically with a stock solution of potassium dihydrogen phosphate or disodium hydrogen phosphate. Then, with stirring on a magnetic stirrer (RO5, IKA, Germany) for an hour while heating to a temperature of 40 ° C.

Norm: unless otherwise indicated in the pharmacopoeial monograph or regulatory documentation, capsules should disintegrate in water in no more than 30 minutes.

Dissolution test ... The "Dissolution" test was carried out according to OFS.1.4.2.0014.15, GF XIV on an apparatus of the "Paddle stirrer" type (EDT-08Lx, Electrolab, India) at a stirrer rotation speed of 50 rpm, directly into each of the six vessels with the dissolution medium one capsule at a time was placed before the stirrer began to rotate.

In accordance with modern requirements, the study of the comparative kinetics of dissolution was carried out in three media: with a pH of 1.2 (0.1 M hydrochloric acid solution); with pH 4.5 (acetate buffer) and with pH 6.8 (phosphate buffer). The volume of the dissolution medium is 500 ml (pH = 1.2) and 800 ml (pH = 4.5 and pH = 6.8), the temperature of the dissolution medium is (37 ± 0.5) ° C. Dissolution media were prepared in accordance with General Pharmacopoeia Monograph 1.3.0003.15 "Buffer solutions", according to the method described above in the section "Disintegration of capsules".

The dissolution profiles should consist of at least three points, excluding the zero point; therefore, samples were taken after 5, 10, 15, 30, and 45 minutes in portions of 10 ml. The same volume of the corresponding buffer solution was added to the dissolution medium to maintain volume. Sampling was carried out from the area of the dissolution vessel located between the surface of the dissolution medium and the upper part of the stirrer blade and at a distance of at least 1 cm from the walls of the dissolution vessel.

Requirements: unless otherwise specified in the regulatory documentation, the amount of active substances released into the dissolution medium within 45 minutes must be at least 75% ( Q ) of the declared content.

Definition of biologically active substances.

Determination of the sum of flavonoids in terms of rutin. The quantitative determination of flavonoids is based on the spectrophotometric method at a wavelength of 415 nm of the products of their interaction with a solution of aluminum chloride and spectrophotometry at a wavelength of 495 nm of the products of their interaction with 2,4-dinitrophenylhydrazine.

The principle of the colorimetric method based on the interaction with aluminum chloride is that the reagent forms acid-stable complexes with the C-4 keto group and with the C-3 or C-5 hydroxyl group of flavones and flavonols, which have absorption maxima in the wavelength range 415 -440 nm.

The principle of interaction with 2,4-dinitrophenylhydrazine is based on its reaction with ketones and aldehydes to form 2,4-dinitrophenylhydrazones. Consequently, flavones, flavonols and isoflavones with C2-C3 double bonds are unable to react with 2,4-dinitrophenylhydrazine, while hydrazones and flavonones form compounds having an absorption maximum at 495 nm. The results of the analysis are presented in Table 9.

Table 9 Sample Content, mg / g Flavonols and their glycosides Flavones and their glycosides Chalcones and their glycosides Flavanones and
their glycosides Flavonoid amount one 8.97 1.66 2.03 6.83 19.49 2 9.90 1.66 2.10 6.80 20.46 3 8.50 1.62 2.00 6.20 18.32 4 8.70 1.58 1.99 6.28 18.55 five 8.65 1.59 1.98 6.34 18.56 6 8.74 1.60 2.01 6.77 19.12

Determination of the amount of tannins in terms of tannin.

The quantitative determination of tannins is based on the method of titration with a permanganate solution until golden yellow coloration. The results of the analysis are presented in Table 10.

Table 10 Sample one 2 3 4 five 6 The content of tanning
substances, mg / g 146.14 145.05 145.12 143.63 144.75 142.99

Microbiological purity ...In terms of microbiological indicators, the dietary supplement must comply with the requirements of clause 10.10 of Chapter II, section 1 "Unified sanitary-epidemiological and hygienic requirements for goods subject to sanitary-epidemiological supervision (control)".

The results of determining indicators for the quality of a biologically active additive are shown in table 11.

Table 11 Indicators results one 2 3 4 five 6 Description acc. acc. acc. acc. acc. acc. Authenticity acc. acc. acc. acc. acc. acc. Quantitative determination, mg 2.55 ± 0.45;
10.60 ± 0.70 2.65 ± 0.45; 10.75 ± 1.70 2.53 ± 0.45;
10.96 ± 0.70 2.54 ± 0.45;
10.50 ± 0.70 2.48 ± 0.45; 11.80 ± 0.70 2.49 ± 0.45;
9.69 ± 0.70 Mass uniformity, mg 342.00 340,00 343,00 342.00 341.00 343,00

As a result, the developed dietary supplement of the encapsulated form meets all of the above indicators. During development, taking into account the dosage of each capsule, it was determined that the recommended dosage regimen is 2 capsules 3 times a day. The capsule form and dosage regimen allows maintaining high medical compliance and receiving the optimal amount of flavonoids and tannins, as well as providing a therapeutic and prophylactic effect on the gastrointestinal tract, kidneys and, in particular, the liver.

Claims (11)

1. Dietary supplement of the encapsulated form, containing a complex of biologically active substances as an active component, which includes sandy immortelle flowers, columns with corn stigmas, chamomile flowers, dandelion root, peppermint leaves, motherwort grass, angelica roots, marigold flowers, grass Knotweed in a ratio of 1.5: 1.5: 1: 1: 1: 1: 1: 1: 1, and a complex of excipients, including a filler, binder, disintegrant, anti-stick, sliding. 2. Biologically active additive of the encapsulated form according to claim 1, characterized in that the complex of biologically active substances is a dry extract. 3. Biologically active additive of the encapsulated form according to claim 1, characterized in that the complex of biologically active substances (BAS) and the complex of excipients are represented by the following composition wt.%: Complex of biologically active substances 40-45%, filler 47-53%, binder , disintegrant 3-5%, anti-stick 0.8-2.2%, sliding 1.2-3.8%. 4. Dietary supplement of the encapsulated form according to PP. 1-3, characterized in that microcrystalline cellulose 101 (MCC 101) is selected as the filler. 5. Dietary supplement of the encapsulated form according to PP. 1-3, characterized in that α-polyvinylpyrrolidone K-25 (α-PVP K25) is selected as a binder, disintegrant. 6. Dietary supplement of the encapsulated form according to PP. 1-3, characterized in that colloidal silicon dioxide - aerosil is selected as the anti-stick. 7. Dietary supplement of the encapsulated form according to PP. 1-3, characterized in that magnesium stearate is selected as the slide. 8. Dietary supplement of the encapsulated form according to PP. 1-7, characterized in that the composition is preferable with the following ratio of components, wt%: complex of biologically active substances 42.22 MCC 101 50,00 α-PVP K25 3.70 aerosil 1.48 magnesium stearate 2.60 9. A method of obtaining a biologically active supplement of the encapsulated form according to PP. 1-8, which includes the following steps: obtaining a liquid extract followed by evaporation, purifying the extract followed by obtaining a dry extract, encapsulating the dry extract. 10. The use of a dietary supplement of the encapsulated form according to PP. 1-9 as a source of flavonoids and tannins.