RU2356546C1 - Sygethin-based pharmaceutical structure for osteoporosis prevention and treatment (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical compositions for oral medical products. The pharmaceutical composition contains Sygethin as an active material and an excipient as one substance or mixed substances, as well as element and vitamin complex containing elements as physiologically acceptable compounds improving bone tissue synthesis with reduced resorption, and vitamins intensifying therapeutic action of Sygethin and ensuring reduced bone tissue resorption with improved synthesis. The pharmaceutical composition represents oral dosage forms, including tablets, capsules, and powders in sachets with colours of each oral dosage form being different.

EFFECT: applied for prevention and treatment of menopausal disorders, particularly for osteoporosis prevention and treatment in menopause women.

6 cl, 6 ex

Description

The invention relates to the pharmaceutical industry and medicine, in particular to solid dosage forms of cigetin-based pharmaceutical compositions for oral medications used in the prevention and treatment of menopausal disorders, in particular in the prevention and treatment of osteoporosis in menopausal women.

Sighetin is a synthetic analogue of Sinestrol (MD Mashkovsky “Medicines”, vol. 2, p. 47. ID “Torgsin”, Kharkov, 1998), which is a synthetic drug with the properties of the female sex hormone estrone (folliculin ) (http://deb.telenet.ru/lmow/Drug929.shtml). Sigetin has a terotonizing effect (“The Register of Russian Medicines”, Encyclopedia of Medicines. Annual digest. Issue 9, 2002, p. 763).

Sighetin is used in obstetric practice, it is used in the treatment of menopause disorders, as well as in post-variectomy syndrome (after surgical removal of the ovaries, radiation therapy), especially in the presence of absolute and relative contraindications to hormone replacement therapy (HRT), as well as in women who refuse to use HRT ( VD Zabelina “Menopause How to Live With It?” CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www, consi1ium - medicum.com/media/ provisor / 03_07 / 29.shtml).

Sigetin is effectively used in the complex treatment of menopausal syndrome of varying severity (92.59% of the positive effects in menopausal syndrome of moderate severity and 86.79% in severe cases) (MV Andreeva et al. “The effectiveness of the drug sagenite in complex treatment of menopausal syndrome of varying severity ”, Medicinal Bulletin No. 8, 2006. www.volgmed.ru/publishing/lv/about/php). Sagenit is the trade name for sigetin in the form of tablets of 0.1 g.

Sighetin is structurally close to sinestrol, but replacing the phenolic rings of hydroxyl radicals with sulfocassium or sodium groups provides very significant changes in the properties of sigetin compared with sinestrol: there is no carcinogenic effect on the myometrium and mammary glands. Taking the drug lowers cholesterol and triglycerides (VD Zabelina “Menopause How to Live With It?” CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www.consilium-medicum.com/media/provisor/03_07/29.shtml) , increases the concentration of beta-lipoprotenins in the blood, improves glucose utilization, sensitivity to the action of insulin, stimulates the processes of tissue metabolism, and has a lipid-lowering effect (Drug Reference. www.recipe.ru).

The use of cigetin leads to a significant weakening of climacteric disorders (sweating, hot flashes, sleep disorders, irritability, depression, weakening of memory, headache, decreased libido, etc.) (V.D. Zabelina “Menopause How to Live With It?” CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www.consilium-medicum.com/media/provisor /03_07/29.shtml). In addition, sigetin significantly reduces trophic changes in the skin, such as dryness, wrinkles, brittle nails, dryness and hair loss, and also reduces urogenital disorders, such as dryness of the mucous membranes of the urogenital system, urethral syndrome, cystalgia, etc., characteristic of menopause syndrome.

The well-known preparation is the dipotassium salt of meso-4,4 '- (1,2-diethylene) dibenzosulfonic acid dihydrate - with the generic name "Sigetin" (trade name "Sagenit"), is available in tablet form containing 0.1 g of active substance (FS 42-1805-88).

The composition of this pharmaceutical composition for tablets based on the well-known oral drug cigetin includes the substance cigetin in the form of a powder of 0.1 g (45.45%); fillers: sugar 0.05 g (22.73%); potato starch 0.05 g (22.73%); the rest is stearic acid and potato starch in an amount sufficient to obtain a tablet weighing 0.22 g. This preparation based on the well-known pharmaceutical composition in the specified solid oral dosage form has the following properties.

Pharmacological action: anti-climacteric, reducing the gonadotropic function of the pituitary gland, stimulating labor, increasing placental blood flow, uterotonizing.

Indications: intrauterine hypoxia, weak labor (primary, secondary, others), postponed pregnancy; hypolipoproteinemia; menopause and menopause in women; menopause disorders and other disorders in the perimenopausal period, manifested by hot flashes, sweating, sleep disturbance, irritability, depression, forgetfulness, degenerative changes in the skin and mucous membranes (brittle nails, thinning of the skin, wrinkles, dry mucous membranes of the genitourinary tract), etc. (www .regmed.ru, Instructions for use of sigetin tablets).

Pharmacodynamics: inhibits the formation of gonadotropic hormones, participates in positive and negative feedback in the hypothalamic-pituitary-ovarian system, affecting the gonadotropic function of the pituitary gland and the hypothalamic center, regulates the function of the adrenal glands. It improves placental circulation, enhances uterine contraction, increases the content of beta-lipoproteins in the blood, sensitivity to the action of insulin, improves glucose utilization, and has a lipid-lowering effect.

Interaction: potentiates the effect of hypocholesterolemic drugs, diuretics, antiarrhythmic antihypertensive drugs, anticoagulants; weakens the effects of drugs of male sex hormones; folic acid, thyroid preparations enhance the action of cigetin (Drug Reference, www.recipe.ru).

Dosage: for menopausal disorders, women are prescribed by mouth 0.05 - 0.1 g (regardless of the time of eating), a daily dose of 0.1 - 0.2 g, the course of treatment is 30 - 40 days (www.regmed.ru, Instructions for use of sigetin tablets).

The well-known drug based on sigetin was not used for the prevention and treatment of osteoporosis in postmenopausal women.

The objective of the invention is the creation of a pharmaceutical composition based on cigetin for oral pharmaceutical preparations used in the prevention and treatment of osteoporosis in women during menopause.

Technical results, including synergistic, which can be obtained using the invention:

the creation of various oral dosage forms based on sigetin for the prevention and treatment of osteoporosis in women during menopause;

- enhancing the therapeutic effect of cigetin while maintaining the therapeutic dose without enhancing the side effect that occurs due to the dose of the drug, due to components that enhance the therapeutic effect of cigetin;

- slowing down the menopause and easing its symptoms due to the estrogen-like action of the components that make up the composition;

- a more effective reduction of menopause due to the use of the components that make up the composition, namely: increasing mental and physical performance, reducing forgetfulness, enhancing mental functions, reducing irritability and depression, restoring the structures of nervous tissue, reducing metabolic metabolic disorders in tissues;

- reducing the risk of developing cardiovascular diseases associated with estrogen deficiency due to the antiatherosclerotic properties of cigetin and the components that make up the composition, reducing the cardiological risk and risk of stroke during their use, as well as reducing the risk of developing high blood pressure;

- reduction of menopausal degenerative changes in the skin, hair, nails and mucous membranes due to the dermatropic properties of the components used;

- reducing the likelihood of diabetes mellitus due to the properties of cigetin and the components used;

- reducing the likelihood of developing breast cancer, colorectal cancer and laryngeal cancer due to the oncoprotective properties of the components used;

- Improving the activity of the gastrointestinal tract (GIT);

- Strengthening the commitment of patients to the use of the drug by combining drugs in one dosage form.

To solve this problem, the present invention provides a pharmaceutical composition for the prevention and treatment of osteoporosis during menopause, containing sigetin as an active substance, an element-vitamin complex including folic acid (vitamin B ₉ ), cyanocobalamin (vitamin B ₁₂ ), pyridoxine (vitamin B ₆ ), ascorbic acid (vitamin C), riboflavin (vitamin B ₂ ), phytonadione (vitamin K), cholecalciferol (vitamin D ₃ ), d-α-tocopherol (vitamin E), calcium pantothenate, zinc, copper, manganese, boron, silicon, fluorine, calcium, magnesium, and filler in the following amount (g) in a daily therapeutic dose

sigetin 0.05 - 0.20 elemental vitamin complex 3,50 - 16,00 filler 0.20 - 20.00

In this case, the filler includes substances that enhance the absorption of elements and vitamins in the body.

The proposed pharmaceutical composition includes the indicated components of the elemental-vitamin complex with the following amount in a daily dose (g):

folic acid 0.0002 - 0.0050 cyanocobalamin 0.00003 - 0.00040 pyridoxine 0.002-0.200 vitamin C 0.06-1.50 riboflavin 0.001-0.010 phytonadione 0.00006-0.00050 cholecalciferol 0.00001-0.00010 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002 - 0.020 Zinc 0.001 - 0.050 Copper 0.0005 - 0.010 manganese 0.0002-0.0100 Boron 0.001 - 0.014 silicon 0.002 - 0.050 Fluorine 0.015-0.020 (as monofluorophosphate) (0.18-0.25) magnesium 0.20-0.80 (as magnesium citrate tetrahydrohydrate) (1.4-5.8) calcium 0.4-1.6 (as calcium citrate tetrahydrohydrate) (1.84 - 7.88)

The proposed pharmaceutical composition is divided into separately accepted time groups of two groups of components, which take into account the mutual positive influence of the components and exclude their negative effect on each other, with the following number of components in a daily dose (g)

in the first group:

sigetin 0.05 - 0.20 folic acid 0.0002 - 0.0050 cyanocobalamin 0.00003 - 0.00040 pyridoxine 0.002 - 0.200 vitamin C 0.03 - 0.75 riboflavin 0.001 - 0.010 Zinc 0.001 - 0.050 manganese 0.0001 - 0.0050 Boron 0.001 - 0.014 filler 0.40 - 3.60

and in the second group:

vitamin C 0.03 - 0.75 phytonadione 0.00006 - 0.0005 cholecalciferol 0.00001 - 0.0001 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002 - 0.020 Copper 0.0005-0.0100 manganese 0.0001 - 0.0050 silicon 0.002-0.050 Fluorine 0.015-0.020 (as monofluorophosphate) (0.18-0.25) magnesium 0.2 - 0.8 (as magnesium citrate tetrahydrate) (1.4-5.8) calcium 0.4-1.6 (as calcium citrate tetrahydrate) (1.80-7.85) filler 0.40-7.20

A filler is proposed containing in the form of a mixture of lactose and lactulose, with a ratio of components in the mixture (wt.%):

lactose 5.0 - 50.0 lactulose powder rest

Lactose and lactulose contribute to the absorption of elements in the gastrointestinal tract, such as calcium.

Single doses of the pharmaceutical composition are in the form of oral forms (tablets, capsules, powders).

In this case, single doses of each of the two groups of components of the pharmaceutical composition differ in color.

In addition, the oral form of the proposed pharmaceutical composition may be in the form of a suspension comprising a mixture of powders homogenized in lactulose syrup. Lactulose can be both the only component of the filler, and one of the components of the filler. Single doses of the pharmaceutical composition are in the form of oral forms (tablets, capsules, powders in sachets).

In this case, single doses of each of the two groups of components of the pharmaceutical composition, made in the form of oral forms (tablets, capsules, powders in sachets) are different in color.

In addition, an oral form of the pharmaceutical composition is provided in the form of a suspension in which the powder mixture is homogenized in lactulose syrup, which is a monofiller or one of the excipient components.

Bones are formed from non-specialized mesenchymal cells - the source of all types of connective tissue. These cells, called osteoblasts, differentiate, actively produce and secrete the organic components of the intercellular substance - carbohydrates, lipids and proteins, including collagen, which makes up almost 90% of the bone's organic mass.

Collagen gives bones rigidity and elasticity. The formed organic mass is calcified, that is, calcium phosphate is deposited. At a later stage, osteoblasts turn into mature bone cells - osteocytes, which are scattered in the dense intercellular substance and occupy only a small part of the total bone volume. Bone tissue resorption is provided by osteoclasts - a special type of bone macrophages that develops from blood monocytes.

Osteoblasts produce enzymes that effectively dissolve and destroy bone material. Over the course of life, bone tissue is gradually renewed, that is, the old tissue is destroyed, absorbed and replaced by a new one. A shift in the balance between the destruction and synthesis of bone substance towards its destruction leads to osteoporosis.

Osteoporosis is a disease characterized by a progressive decrease in bone density, i.e. bone substance per unit volume of the bone. Primary osteoporosis, which occurs mainly after 50 years, and in women is 6 times more likely than in men, is associated with hormonal changes characteristic of the postmenopausal period in women. Secondary osteoporosis is caused by diabetes mellitus, hormonal imbalance, in particular an excess of parathyroid hormone (regulates the content of calcium and phosphorus in the blood, tissue fluid, bone tissue), some surgical operations (for example, removal of the ovary) or chronic immobilization (immobility), some rheumatological, endocrinological, oncological diseases, obstructive pulmonary diseases and bronchial asthma, some diseases of the kidneys, digestive organs, with a length of lnny reception of a number of medicines.

Cyanide (senile) osteoporz occurs in women twice as often as in men, which is explained by sex differences in bone mass. It is known that with age there is a progressive decrease in intestinal absorption of not only calcium, but also vitamin D, as well as the formation of vitamin D in the skin.

Female sex hormones - estrogens - are produced in the ovaries, adrenal glands, in the liver, in adipose tissue, and during pregnancy also in the placenta. Estrogens are mediated with the participation of specific receptors located on the surface of tissue cells and providing for the capture of the hormone molecule and its transfer into the target cell, affect the target cells and bind there to the corresponding receptors - molecular proteins contained in the nuclei of cells. These receptors are located in the cells of tissues of target organs - the uterus, mammary gland, brain, heart, arteries, genitourinary tract, bone tissue, skin, mucous membranes, etc. (A.L. Tikhomirov, Ch.G. Oleinik “Principles of climacteric therapy disorders. ”“ Issues of gynecology, obstetrics and perinatology, ”2005, v. 4, No. 4, pp. 84-89, //medi.ru/doc/181802.htm). Estrogens cause the development of secondary female sexual characteristics, myometrial hypertrophy, endometrial hyperplasia, exerting an anabolic effect on a woman's body, stimulate the macrophage system, antibody production and phagocyte activity, etc.

The direct effect of sex hormones estradiol, progesterone and testosterone on bone tissue is carried out by binding them to specific receptors on osteoblasts. Thus, the spongy substance of bone tissue is a target organ for sex hormones (Menopausal Syndrome, http://www.medinfo.ru/sovety/aku/20_1.phtml).

The effect of estrogen is not limited to target organ tissues. Estrogens retain water, nitrogen in the body, calcium and phosphorus in the bones, increase glucose utilization (increase sensitivity to insulin), increase the level of phosphocreatinin, iron, copper in the blood, and affect the renin-angiotensin system (which is important in the origin of edema and hypertonic reactions). When used together, folic acid potentiates the action of estrogens (Clinical Pharmacology and Pharmacotherapy, chapter 10. www.kuban.su/ medicine / shtm / baza / lek / klfhtm / part 19 / 19-31.htm).

In addition, estrogens are involved in the distribution of subcutaneous tissue, the expansion of peripheral blood vessels, which improves microcirculation and enhances heat transfer, exerts anabolic effects on bones and cartilage, and participates in the formation of a female skeleton. They are the main regulators of the gonadotropic function of the pituitary gland in both the female and male body.

The end of the reproductive period is associated with a significant decrease and then cessation of ovarian function, which leads to a decrease in the secretion of estrogen and progesterone in the ovarian tissue, which is accompanied by an increase (by the feedback principle) in the synthesis of gonadotropins, as well as a decrease in the production of calcitonin, insulin, etc.

A decrease in the production of calcitonin, a hormone of the peptide structure produced by parafollicular cells of the thyroid gland that inhibits bone resorption and the release of calcium and phosphate from it, leads to the development of osteoporosis.

The source for estrogen biosynthesis is cholesterol (cholesterol), which consists mainly of low density lipoproteins. With a decrease in estrogen secretion, the lack of demand for cholesterol as a hormonal substrate for the synthesis of estrogen gradually develops, which significantly increases its concentration in the blood. This contributes to damage to the vascular endothelium, the development of cardiovascular diseases.

Thus, with estrogen deficiency, menopausal disorders can occur, which can be divided into three groups.

Group 1 - early symptoms that occur during the transition to menopause.

Vasomotor: hot flashes, sweating, palpitations, hypertension.

Psycho-emotional: insomnia, depression, irritability, weakening of memory, headaches, decreased libido.

Group 2 - medium-term symptoms that occur 2-4 years after menopause.

Urogenital disorders: dryness, itching and burning in the vagina, pain during sexual intercourse, urethral cider, cystalgia, urinary incontinence.

Trophic skin changes: dryness, wrinkles, brittle nails, dryness and hair loss.

Group 3 - late symptoms occur several years after menopause.

Metabolic disorders: cardiovascular diseases, postmenopausal osteoporosis, diabetes mellitus, obesity, Alzheimer's disease and Alzheimer-like dementia (A.L. Tikhomirov, Ch.G. Oleinik “Principles of treatment of menopausal disorders.” “Issues of gynecology, obstetrics and perinatology, 2005 d, t. 4, No. 4, p. 84-89, //medi.ru/doc /181802.htm).

Sigetin binds in the body to estrogen-sensitive cellular receptors located in the cells of the pituitary, hypothalamus, myometrium and other organs, and blocks (replaces) their connection with natural estrogens. The interaction of cigetin with receptors provides information to the regulatory centers of the hypothalamus, corresponding to a high peripheral level of estrogen. According to the principle of negative feedback, this leads to a decrease in the excess production of follicle-stimulating hormones, a decrease in vasomotor emotional-vegetative and other disorders (V.D. Zabelina “Menopause How to Live With It?” CONSILIUM-PROVISORUM: Tom 03 / N7 / 2003, www.consilium -medicum.com/media/provisor/ 03_07 / 29.shtml).

In this case, positive changes in the hormonal profile occur, in particular, the content of estradiol and progesterone in the blood serum increases significantly (M.V. Andreeva et al. “The effectiveness of the drug sagenite in the complex treatment of menopausal syndrome of varying severity”, Medicinal Bulletin No. 8, 2006 , www.volgmed.ru/publishing / lv / about / php). An increase in the content of estradiol (as well as progesterone) in the blood, in turn, acting on estrogen-sensitive receptors of cells of organs and tissues, reduces menopausal disorders, including reduces bone resorption (http://www.consilium.com.ua/stuff/ doctor / obstetrics-gynaecology-pub / estrogeny-starye-priyateli-i-novye-znakomye /) when estradiol and progesterone bind to specific osteoblast receptors (Menopausal Syndrome, http://www.inedinfo.ru/sovety/aku/20_1 .phtml).

The above medicinal properties of cigetin, namely: a significant weakening of climacteric disorders such as sweating, hot flashes, sleep disorders, irritability, depression, memory loss, headache, decreased libido, trophic skin changes - its dryness, wrinkles, brittle nails, dryness and loss hair, urogenital disorders - dryness of the mucous membranes of the genitourinary system, urethral syndrome, cystalgia, etc., indicate that it interacts directly or indirectly with mish cells, like estrogen different organs and tissues: brain, hypothalamus, pituitary, blood vessels, myometrium, endometrium, mammary glands, urogenital organs, mucous membrane, skin, hair, nails, liver, adrenal glands, thyroid gland, etc. Interaction of cigetin with target cells occurs on a competitive basis with estrogens, that is, with a decrease in the concentration of estrogens in tissues, the proportion of cigetin increases, affecting estrogen-sensitive receptors of target cells.

Sighetin, entering the body, binds to estrogen-sensitive receptors in the body, replacing their connection with natural estrogens and compensating for the low content of estrogens, which together with sigetin also affect estrogen receptors of target organs. However, their combined effect due to negative feedback reduces estrogen-dependent menopause disorders.

The indicated effects of cigetin on organs and tissues provide a pronounced therapeutic effect, significantly reducing the above menopausal disorders associated with estrogen deficiency, including metabolic disorders, which include postmenopausal osteoporosis, cardiovascular disease, diabetes, Alzheimer's disease and alzheimer-like dementia.

The indirect action of cigetin on the thyroid gland stimulates the production of calcitonin and, consequently, a decrease in bone resorption and the release of calcium and phosphate from it, which reduces the likelihood of developing primary and secondary osteoporosis.

Normalization of urogenital disorders under the action of sigetin reduces the excretion of calcium in the urine, which also reduces the likelihood of developing primary and secondary osteoporosis.

Sighetin, like estrogen, increases glucose utilization (increases sensitivity to insulin), thereby reducing the likelihood of diabetes, which is one of the possible causes of secondary osteoporosis. That is, this is another reason why sigetin reduces the likelihood of secondary osteoporosis.

It is also known that sigetin, with a direct effect on some cells of the body, activates the trigger mechanism for introducing calcium ions into the cell through electrically controlled calcium channels. At the same time, sigetin inhibits the calcium pump, which controls the stationary concentration of calcium ions in the cytoplasm. This causes an increase in the concentration of calcium ions in the cells (S. G. Shlykov et al. “Uterotonic action of cigetine and its effect on Mg ²⁺ , ATP-dependent transport and stationary exchange of Ca ²⁺ through myometrium sarcolemma”, Ukrainian Biochemical Journal, 1993 , t. 65, No. 3, p. 57 - 64). Such a direct effect of cigetin provides an additional mechanism for enhancing the transport of calcium ions into the cells of the body and their retention by cells, which contributes to the improvement of metabolic processes associated with calcium ions in menopausal disorders.

The composition of the proposed pharmaceutical composition based on sigetin contains vitamins and nutrients in the form of physiologically acceptable compounds with the following properties.

Folic acid (pteroylglutamic acid; folacin; vitamin B ₉ ) belongs to the B vitamins. It potentiates the action of estrogens (Clinical Pharmacology and Pharmacotherapy, Chapter 19. Estrogens, www.kuban.Su/medicine/shtm/lek/klfhtm /part19/19-31.htm), and when used together with sigetin enhances its therapeutic activity (Instructions for use of sigetin tablets www.regmed.ru). In addition, folic acid has an estrogen-like effect - it can slow down the onset of menopause and alleviate its symptoms (Test - VitaFast®Folic Acid system (Vitamin B ₉ ), www.komprod.com/ru/ products / 65/124/160 / print- ok.html), in this regard, it allows to reduce hormone intake during menopause replacement therapy (//diamedcom.ru/php/content.php?group=2&id ^: = 4663). It is necessary for the body to produce new skin cells, hair cells (www.breath.ru/htms/a94.htm).

Folic acid together with vitamin B ₆ and B ₁₂ provides the basis for the normalization of collagen, which is part of the skin, bones, blood vessels and other body tissues (Description of the drug Osteo Complex, www.dolgolet.ru/bad/bad-kosti-03.html) .

Folic acid takes an active part in the processes of regulation of the functions of the hematopoietic organs, has an antianemic effect in macrocytic anemia. It positively affects the functions of the intestines and liver, increases the content of choline in the liver and prevents its fatty infiltration. It supports the immune system, contributes to the normal formation and functioning of white blood cells. Folic acid reduces a dangerous increase in homocysteine levels (www.medolina.ru. Daily Health News August, 15, 2005), which reduces the risk of cardiovascular disorders (//diamedcom.ru/php/content.php?group=2&id=4663) . Homocysteine is an amino acid that is normally found in small amounts in the blood. High levels of homocysteine in the blood contribute to the formation of plaques on the walls of blood vessels, which can lead to serious cardiovascular problems. In addition, elevated levels of homocysteine can destroy the walls of blood vessels, which can lead to the formation of blood clots, increasing the risk of cardiovascular disease. That is, an increased content of homocysteine damages blood vessels and increases the risk of stroke and heart attack (RU patent No. 2222329). Increased homocysteine levels increase the risk of Alzheimer's disease (www.trimm. M / php / content. Php? Group = 0 & id = 3694).

Folic acid helps maintain mental ability in old age (www.medportal.ru/mednovosti/news/2007/01/19/acid/). The process of DNA replication requires the participation of folic acid, and violation of this process increases the risk of developing cancerous tumors (//itnews.com.ua/28325.html).

Folic acid deficiency in the body may lead to activation of proto-oncogenes, which participate directly in the appearance of cancer cells (www.medportal.ru/mednovosti/news / 2001/12/21 / meat /). Folic acid is used as a means of chemoprophylaxis in the early stages of colon cancer and its predecessors - adenomatous polyps (V. A. Draudin-Krylenko et al. “Suppression of overexpression of proto-oncogen ornithine decarboxylase in adenomatous colon polyps when prescribed to patients with high doses of folic acid ONCOLOGY, Volume 06, No. 3, 2004, www.consilium-medicum.com/media/onkology/04_03/124.shtml).

First of all, bone marrow suffers from a lack of folic acid. Red blood cell precursor cells formed in the bone marrow increase in size when folic acid deficiency occurs, forming megoblasts and leading to megoblastic ahemhh (// itnews.com.ua/28325.html). In addition, folic acid deficiency increases the likelihood of colon cancer, breast cancer, and laryngeal cancer (www.medportal.ru/mednovosti/news / 2006/06/13 / larynx /). Folic acid is involved in the synthesis of amino acids, nucleotides, nucleic acids; necessary for normal erythropoiesis. The folic acid is required by the body to adsorb other B vitamins, that is, a deficiency of folic acid can lead to a deficiency of other vitamins of this complex. Folic acid stimulates the production of hydrochloric acid in the stomach, which is important for most people over 40 with low acidity of gastric juice. It is necessary for the formation and optimal functioning of the nervous system and bone marrow (//vita.x51.ru/publ/3-1-0-5).

Symptoms of folic acid deficiency are anemia, fatigue, weakness, anxiety, depression, a sense of fear, insomnia, distraction, forgetfulness, hostility, paranoia, headache, fainting, indigestion, sore tongue, inflamed mucous membrane of the lips, diarrhea, weight loss, premature graying, etc. Many of these symptoms are also characteristic of menopausal disorders.

The action of folic acid: anti-anemic, preventing fetal abnormalities of the fetus, increasing mental and physical performance, nootropic, antidepressant, restoring the structure of the nervous tissue, anti-atherosclerotic, stimulating the production of hydrochloric acid, strengthening the intestinal wall, antidiarrheal, protecting against intestinal parasites, pathogen and pathogen , dermatotropic, oncoprotective, etc. (Drug Reference, www.recipe.ru).

Estrogen replacement therapy leads to severe folic acid deficiency (www.vitamini.ru/encyclopedia/info.aspx?id=23).

Folic acid is more effective when taken with cyanocobalamin and pyridoxine (www.medolina.ru. Daily Health News August, 15, 2005). Folic acid functions in combination with cyanocobalamin in the formation of new cells, which maintains the necessary level of folic acid in the cells. Without it, cells cannot retain folic acid. In these cells, the division process is disrupted or completely stopped. Folic acid is essential for the absorption of cyanocobalamin and vice versa. Cyanocobalamin together with folic acid is involved in the synthesis of nucleotides, in the formation of red blood cells and cells of the nerve membranes. It is also involved in the metabolism of fats and carbohydrates, and is important for normal growth and the regeneration of folic acid (www.dsm.com/ru_RU/html/dnpru/hnh_maininfovit_index_basics_b 12.htm).

Cyanocobalamin (vitamin B ₁₂ ) is indicated for various types of anemia, myocardial dystrophy, liver diseases, and migraines. It has a pronounced lipotropic effect, prevents fatty liver, increases oxygen consumption by cells in acute and chronic hypoxia. Vitamin B _{12 is} involved in the processes of transmethylation, hydrogen transfer, activates the synthesis of methionine. Enhancing the synthesis and ability to accumulate protein in the body, cyanocobalamin also has an anabolic effect. Increasing the phagocytic activity of leukocytes and activating the activity of the reticuloendothelial systems, vitamin B ₁₂ enhances immunity. Cyanocobalamin plays an important role in regulating the functions of the blood-forming organs: it takes part in the synthesis of purine and pyrimidine bases, nucleic acids necessary for the process of erythropoiesis, and actively affects the accumulation of compounds containing sulfhydryl groups in red blood cells.

A wide range of emotional and cognitive abilities depends on the provision of cyanocobalamin. Maintaining its optimal level in the body helps to prevent depression, senile dementia and confusion of thinking, helps to restrain the breakdown of mental activity as a result of AIDS. Cyanocobalamin helps to normalize low blood pressure. When taken orally, cyanocobalamin is poorly absorbed, its absorption improves while taking folic acid. Vitamin B ₁₂ helps to overcome insomnia, and also helps to adapt to changes in sleep patterns and wakefulness, due to its participation in the synthesis of melatonin. It is advisable to take vitamin B ₁₂ for radiation sickness, diseases of the nervous system (multiple sclerosis, encephalomyelitis, radiculitis, polymyelitis, cerebral palsy, etc.) and allergic diseases such as asthma, urticaria (http://vitamini.solvay-pharma.ru/encyclopedia /info.aspx? id = 24).

Pyridoxine (vitamin B ₆ ) helps to convert folic acid into its active form; contributes to the normalization of estrogen metabolism, plays an important role in metabolism, is necessary for the normal functioning of the central and peripheral nervous system. Pyridoxine as a coenzyme is involved in the metabolism of amino acids and proteins, in the synthesis of neurotransmitters, in the phosphorylated form, it provides decarboxylation, transamination, deamination of amino acids, is involved in the synthesis of protein, enzymes, hemoglobin, prostaglandins, the exchange of serotonin, catecholamines, glutamic acid, histamine, improves unsaturated fatty acids, reduces blood cholesterol and lipids, improves myocardial contractility, stimulates hematopoiesis, improves lipid metabolism in ather sclerosis.

In addition, pyridoxine is indicated for diabetes, as it reduces the content of glycosylated hemoglobin; acts as a diuretic, reducing high blood pressure and thus protecting the cardiovascular system in several ways at once; effective for depression, as it positively affects the production of norepinephrine and serotonin. When taking estrogen-containing drugs, a severe deficiency of vitamin B ₆ occurs (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx? Id = 22).

Riboflavin (vitamin B ₂ ), being a synergist of pyridoxine, is required for the interconversion of various forms of vitamin B ₆ (www.dsm.com/ru - RU / html / dnpru / hnh maininfovit index basics_b6.htm).

Riboflavin acts as an intermediary in the transfer of electrons in various redox reactions. Thus, he participates in many reactions of the metabolism of carbohydrates, fats and proteins, as well as in reactions to produce energy in the respiratory chain. Riboflavin coenzymes play an important role in the conversion of pyridoxine and folic acid into their active coenzyme forms (Basic Vitamins, DSV Nutritional Products, www.dsm.com/ru_RU/html / dnpru / hnh_maininfovit_index_basics_b2.htm).

Riboflavin is necessary for the formation of red blood cells and antibodies, for cell respiration and growth. It facilitates the absorption of oxygen by the cells of the skin, nails and hair, improves the condition of the organs of vision, and plays a large role in preventing cataracts. Riboflavin has a positive effect on the mucous membranes of the digestive tract, minimizing the negative effects of various toxins on the respiratory tract. Riboflavin deficiency affects tissues rich in capillaries and small vessels (brain tissue). With a deficiency, cerebral insufficiency of varying severity can be a frequent manifestation. Riboflavin deficiency can lead to impaired absorption of iron and weaken the thyroid gland (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=16).

Ascorbic acid (vitamin C) is involved in the metabolism of folic acid, in the synthesis of steroid hormones and catecholamines (www.recipe.ru, Cyanocobalamin and folic acid). Ascorbic acid improves the body's ability to absorb calcium and iron, remove toxic copper, lead and mercury; significantly increases the stability of vitamins B ₁ , B ₂ , A, E, pantothenic and folic acids; protects low-density lipoprotein cholesterol from oxidation and, accordingly, vessel walls from deposition of oxidized forms of cholesterol (http://vitamini.solvay-pharma.ru/encyclopedia/ info.aspx? id = 13). It increases the elasticity and strength of blood vessels, blocks toxic substances in the blood, strengthens teeth and gums, is an antioxidant. Ascorbic acid is necessary for the prevention and treatment of cardiovascular diseases, with liver diseases, various infections, colds, with physical and mental stress, and diabetes.

It plays an important role in the regulation of redox processes, participates in the synthesis of collagen and procollagen, which provide the structure of muscles, vascular tissues, bones and cartilage, regulates blood coagulability, normalizes capillary permeability, is necessary for hematopoiesis, has an anti-inflammatory and anti-allergic effect, is a factor, protecting the body from the effects of stress, enhances reparative processes, increases resistance to infections. Ascorbic acid can be used to prevent cancer, such as cancer of the colon, esophagus, bladder and endometrium (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=13). It is advisable to use vitamin C together with vitamin E, since they act synergistically in the body, enhancing the action of each other as antioxidants (patent RU No. 2275192, АКК 31/015, 2006.04.27).

Vitamin E (d-α-tocopherol) is involved in the formation of collagen and elastic fibers of the intercellular substance, slows down aging, and prevents the appearance of senile pigmentation. It improves blood circulation, is necessary for tissue regeneration, is useful in premenstrual syndrome and in the treatment of fibrotic breast diseases. Vitamin E provides normal blood coagulation and healing, reduces the possibility of scar formation from some wounds; lowers blood pressure, helps prevent cataracts, relieves leg cramps, supports healthy nerves and muscles, strengthens the walls of capillaries, and prevents anemia. As an antioxidant, vitamin E protects cells from damage, slowing down the oxidation of lipids (fats) and the formation of free radicals. It protects other fat-soluble vitamins from being destroyed by oxygen, promotes the absorption of vitamin A and protects it from oxygen. Vitamin E prevents increased blood coagulability, favorably affects peripheral blood circulation, participates in the biosynthesis of heme and proteins, cell proliferation, the formation of gonadotropins, and the development of the placenta. Its effectiveness is enhanced in the presence of other antioxidant nutrients. So the anti-cancer protective effect of tocopherol is especially noticeable increases ascorbic acid. Some indications for use: menopausal autonomic disorders, diseases of the ligamentous apparatus and muscles, degenerative and proliferative changes in the joints and ligaments of the spine and large joints, dermatomyositis, some dermatoses, psoriasis, peripheral vascular spasm, as an antioxidant in complex treatment of many diseases, in gerantology (http://vitamini.solvay-pharma.ru / encyclopedia / info.aspx? id = 12).

Phytonadione (vitamin K) plays an important role in the formation and restoration of bones, provides the synthesis of osteocalcin - a bone tissue protein on which calcium crystallizes. It helps to prevent osteoporosis, is involved in redox processes in the body (http://vitamini.solvay-pharma.ru/encyclopedia/ info.aspx? Id = 14).

Cholecalciferol (vitamin D ₃ ) (or its active metabolites, for example, 1-α-25 (OH) ₂ D ₃ - calcitriol or 1-α-OHD ₃ - alpha-calcidol) ensures normal bone growth and development, prevents rickets and osteoporosis . It regulates mineral metabolism and promotes the deposition of calcium in bone tissue and dentin, thus preventing bone osteomalacia (softening). Cholecalciferol affects the general metabolism during the metabolism of calcium and phosphate ions. First of all, it stimulates the absorption of calcium, phosphates and magnesium from the intestines. An important effect of this vitamin in this process is to increase the permeability of the intestinal epithelium for calcium and phosphorus ions.

Cholecalciferol prevents muscle weakness, improves immunity, is necessary for the functioning of the thyroid gland and normal blood coagulation. He is involved in the regulation of blood pressure and heart rate. Cholecalciferol inhibits the growth of cancer cells, which makes it effective in the prevention and treatment of cancer of the breast, ovaries, prostate gland, brain, and leukemia. Cholecalciferol is the only vitamin that acts both as a vitamin and as a hormone. As a vitamin, it maintains the level of inorganic phosphorus and calcium in blood plasma above a threshold value and increases the absorption of calcium in the small intestine.

As a hormone, an active metabolite of the specified vitamin - 1,25-dioxycholecalciferol, which is formed in the kidneys, acts. It affects the cells of the intestines, kidneys and muscles: in the intestines it stimulates the production of a carrier protein, which is necessary for calcium transport, and in the kidneys and muscles it enhances the reabsorption of calcium ions in the body. Since cholecalciferol increases the calcium content in the blood, its excessive intake can lead to an excessive concentration of calcium. In this case, calcium can penetrate the walls of the vessel and provoke the formation of atherosclerotic plaques. This process can be accelerated with a deficiency of magnesium in the body. Phosphorus interferes with the absorption of vitamin D. When treating with large doses of vitamin D _3, it is recommended that vitamin A, as well as B vitamins and ascorbic acid, be taken simultaneously. The normal metabolism of cholecalciferol in the liver is impossible with a lack of vitamin E (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=l 1).

The recommended daily dose of cholecalciferol for people older than 50 is 800 ME (20 mcg) (N.V. Toroptsova, “Prevention of Postmenopausal Osteoporosis: The Role of Calcium and Vitamin D Preparations,” Institute of Rheumatology RAMS, Moscow, Gynecology, vol. 11, v. 5, 2005, www.consilium-medicum.com/media/ gynecology / 05_05 / 287.shtml).

Pantothenic acid (vitamin B ₅ ), as a component of coenzyme A, plays a key role in the metabolism of carbohydrates, proteins and fats and is therefore important for maintaining and restoring all tissue cells. She is involved in reactions that provide energy to the cell, and also take part in the synthesis of vital compounds such as sterols (e.g. cholesterol), hormones (e.g. growth hormones, stress and sex hormones), neurotransmitters (e.g. acetylcholine), phospholipids (components of cell membranes), porphyrin (a component of hemoglobin), antibodies, and also takes part in the metabolism of drugs. Pantothenic acid is used to treat various liver diseases and arthritis, to treat constipation in the elderly, against baldness, to prevent urinary retention after surgery. Calcium pantothenate or panthenol are usually used, which are readily soluble in water and are easily converted into pantothenic acid in the body. Vitamin B ₁₂ promotes the incorporation of free pantothenic acid into coenzyme A. Ascorbic acid reduces the severity of pantothenic acid deficiency. Pyridoxine, folic acid, and biotin are essential for the efficient utilization of pantothenic acid (Essential Vitamins, DSV Nutritional Products, www.dsm.com/en/html/dnpru/hnh-maininfovit-index-basics-panto.htm). Pantothenic acid is necessary for the normal absorption and metabolism of folic acid (http://vitamini.solvay-pharma.ru/encyclopedia/ info.aspx? Id = 20).

Zinc is a component of more than 200 enzymes (www.osteoform.ru/products/calc.htm). It provides carbon dioxide transfer, the stability of biological membranes, and promotes wound healing (http://vitamini.solvay-pharma.ru/elements/article.aspx?id=l816). He takes part in the processes of cell division and differentiation, the formation of T-cell immunity, the functioning of many enzymes, the pancreas insulin, the antioxidant enzyme superoxide dismutase, the sex hormone dihydrocorticosterone, and plays an important role in the regeneration of skin, hair, nails, and secretion of the sebaceous glands. It helps to absorb vitamin E and maintain a normal concentration of this vitamin in the blood. Zinc strengthens the body's immune system, promotes wound healing, as it plays an important role in protein synthesis (www.microelements.ru/Zn).

Zinc affects the activity of the hormones of the pituitary gland, adrenal glands and pancreas. Under the influence of its compounds, the activity of the pituitary gonadotropin hormones is enhanced. It has been established that the hypoglycemic effect of insulin depends on zinc, which is constantly present in insulin. Zinc has lipotropic properties, normalizing fat metabolism, increasing the rate of fat breakdown in the body and preventing liver obesity (//athlete.ru/books/nutrition_pshendin/7_mineralu_makro-i-mikroelementy.htm). Zinc reduces the absorption of copper (patent RU No. 2275192).

An insufficient concentration of zinc in the body leads to serious consequences: schizophrenia and mental disorders, diabetes, prostate adenoma, cataracts, heart diseases, damage to the brain and nervous system, impaired immune system, digestion and food allergies, peptic ulcer. With zinc deficiency, toxic metals accumulate, wounds heal poorly, osteoporosis, skin diseases, excessive fatigue and loss of appetite, hearing impairment, many symptoms of blood sugar imbalance can develop. Malignant tumors develop more easily against the background of lowered zinc levels. Zinc supplements stimulate the production of white blood cells - one of the antitumor components of the immune system, and support the overall activity of T-lymphocytes and natural antitumor cells (natural killers). In addition, zinc is necessary for the production of thymulin - the main hormone of the thymus gland. Calcium supplements can reduce zinc absorption by almost 50% (//mirzdorovia,com.ua/spravka2.php).

Zinc ensures the normal course of metabolic processes, participates in the processes of bone tissue restoration after fractures and in bone loss in people of old age (www.osteoform.ru/products/calc.htm).

Copper is involved in the mechanism of enzymatic catalysis and electron transfer. It is necessary to improve the hormonal background in women; important for osteoporosis and diseases of the osteoarticular apparatus; necessary for people suffering from multiple sclerosis; necessary for disorders of the thyroid gland. She is involved in the synthesis of red blood cells (www.osteoform.ru/products/calc.htm).

Copper is necessary to maintain the ability of the heart to pump blood, to prevent aneurysms and to ensure the growth of strong arterial connective tissue that is resistant to tearing. It is necessary for the production of collagen in the bones, gives excellent results in the treatment of rheumatoid arthritis. Copper is important for maintaining the balance of microflora that inhibits the growth of yeast microorganisms (//mirzdorovia,com.ua/ spravka2.php).

Copper is a vital element that is part of many hormones, enzymes, respiratory pigments, participates in metabolic processes, in tissue respiration, etc. Copper is of great importance for maintaining the normal structure of bones, cartilage of the tendons (collagen), elasticity of the walls of blood vessels, pulmonary alveoli, skin (elastin). Copper is part of the myelin sheaths of nerves, as well as many enzymes. Increased intake of zinc and molybdenum can lead to copper deficiency. Manganese, iron, ascorbic acid can reduce the absorption of copper. Zinc, iron, cobalt (in moderate physiological doses) increase the absorption of copper by the body. In turn, copper can inhibit the body's absorption of iron, cobalt, zinc, vitamin A. Hormonal agents contribute to enhanced excretion of copper from the body (www.microelements.ru/Cu).

Manganese is an essential element for protecting body cells. It is required for the growth, reproduction, healing of wounds, the maximum efficiency of the brain and the proper metabolism of sugars, insulin and cholesterol. Without an optimal amount of manganese, the risk of rheumatoid arthritis, osteoporosis, cataracts, multiple sclerosis and diseases such as epilepsy increases. Calcium and iron supplements can have an antagonistic effect on the absorption of manganese. Zinc and vitamin C contribute to the absorption of manganese. Manganese is necessary for heart diseases and birth defects, for the prevention and treatment of bone and joint diseases, neurological diseases, and asthmatic conditions (//mirzdorovia,com.ua/spravka2.php).

Manganese is involved in the synthesis and metabolism of neurotransmitters in the nervous system; prevents free radical oxidation, ensures the stability of the structure of cell membranes; provides the normal functioning of muscle tissue; participates in the exchange of thyroid hormones; provides the development of connective tissue, cartilage, bones; enhances the hypoglycemic effect of insulin; increases glycolytic activity; increases the rate of fat utilization; reduces lipids in the body; counteracts fatty degeneration of the liver; participates in the regulation of the exchange of vitamins C, E, group B, choline, copper; participates in providing reproductive function; necessary for the normal growth and development of the body.

The main manifestations of manganese deficiency are fatigue, weakness, dizziness; bad mood; deterioration of thinking processes, ability to make quick decisions, memory loss; impaired muscle contractility; degenerative changes in the joints, a tendency to sprains and dislocations, osteoporosis in the menopause; violations of skin pigmentation, the appearance of a small scaly rash, vitiligo; growth retardation of nails and hair; a decrease in the level of “useful” cholesterol in the blood, impaired glucose tolerance, overweight, obesity, infertility, ovarian dysfunction, early menopause, premature aging, immune disorders, allergic reactions, and the risk of cancer. Vitamins B ₁ , E, phosphorus and calcium (in moderation) contribute to the absorption of manganese in the gastrointestinal tract, and the excess intake of phosphorus and calcium is an obstacle (www.microelements.ru/Mn). Manganese promotes the absorption of calcium in the body (www.osteoform.ru/products/calc.htm).

Boron plays a significant role in the metabolism of carbohydrates and fats, a number of vitamins and hormones, and affects the activity of certain enzymes (www.microelements.ru/B). Boron increases the natural levels of estrogen and testosterone in women. It protects against softening of the bone, with an additional intake of boron, the loss of calcium in women is halved. Boron reduces the content of oxalates in the urine and prevents the formation of kidney stones. With boron deficiency, the level of female sex hormones decreases, which causes a number of dangerous diseases, including osteoporosis (www.osteoform.ru/products/calc.htm).

In women during menopause, elimination of boron deficiency is accompanied by an increase in the level of 17 beta-estradiol in blood serum and copper in blood plasma. EEG indicators, memory improve, behavioral reactions normalize. In women aged 48-82 years, post-menopause, a lack of boron causes a decrease in mineral metabolism and bone tissue, which indicates that boron is an essential element in the prevention and treatment of osteoporosis. The lack of vitamin D enhances the effect of boron deficiency on the metabolism of calcium, magnesium, phosphorus. Boron inhibits the body's absorption of ascorbic acid, flavonoids, sulfur-containing amino acids. There is a positive correlation between the metabolism of boron and zinc. Sometimes boron is used to displace copper from the body (www.microelements.ru/B).

Boron increases the sensitivity of cells to estrogen, while, despite a low level of estrogen, the development of osteoporosis stops. In addition, boron enhances cellular protein synthesis and inhibits the action of an enzyme that destroys proteins (collagenase), that is, prevents the destruction of the protein base of cartilage, helping to restore the balance between its synthesis and decay. Boron acts as a catalyst for chemical reactions due to which calcium is absorbed. Boron prevents the leaching of calcium bones and dilution of their structure, helps to maintain hormonal balance in the body, the absorption of calcium by bone tissue. For osteoporosis and joint diseases, the recommended daily intake of boron is from 6 to 12 mg. According to the IPCS international chemical safety program, consumption of up to 28 mg of boron per day is permissible (AMF No. 5, 2007, p.16, article “Foundation for Joint Health”).

Silicon is the main element in the structure of connective tissue - the main protein of muscles, tendons and ligaments. The main role of silicon is to participate in a chemical reaction that bonds individual fibers of collagen and elastin. Silicon is important for cartilage and skeletal growth. It is indicated for connective tissue disorders, diseases of bones, ligaments, cartilage, osteoporosis, paradantosis, arthrosis, poor growth and fragility of nails and hair (www.osteoform.ru/products/calc.htm).

In the highest concentrations, silicon is found in the walls of the aorta, trachea, ligaments, bones, skin (especially in the epidermis), hair, and lymph nodes. With a deficiency of silicon in the body, weakness of the connective tissue is observed (bronchopulmonary system, ligaments, cartilage); bone weakness (osteoporosis); thinning, brittleness, hair loss; tendency to inflammatory diseases of the stomach and intestines; cholesterolemia, the earlier development of atherosclerosis (www.microelements.ru/Si).

Silicon is found in large quantities in connective tissue, since it serves as a binding agent between collagen and hydrolyzed amino acids, present in proteoglycans. Its deficiency in the body leads to multiple bone deformities due to damage and delayed maturation of collagen and glycosaminoglycans, as well as to a decrease in extracellular matrix synthesis. The most biologically active are organosilicon substances, which can be dissolved and absorbed. Moreover, the bioavailability of, for example, methylsilanotriolsilicate is much higher than magnesium aluminosilicate: 80% versus 1% (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.med1ibrary.ru/1 ibrary /).

The magnitude of the applied therapeutic doses, the range of which is from 15 to 20 mg per day, is critical for the nature of the effect of fluorine on bone tissue. Doses of less than 10 mg per day do not have a clinically significant stimulating effect on bone tissue, and doses exceeding 30 mg per day lead to a violation of bone formation. This is expressed in the development of osteomalacia - a violation of the mineralization of the newly formed bone tissue and the accumulation of an organic base that does not contain calcium compounds, and is accompanied by a deterioration in the strength properties of bones. Doses of fluorine in excess of 20 mg per day lengthen the interval between the onset of the formation of an organic matrix of bone tissue and its subsequent mineralization, but these disorders are partially eliminated by the addition of calcium and vitamin D preparations to therapy. Even higher doses of fluorine (more than 60 mg per day ) lead, among other things, to the formation of abnormal fibrous bone tissue, which is not eliminated by calcium and vitamin D (N.V. Bunchuk “Pharmacotherapy of osteoporosis”, Russian Medical Journal, www.kuban.su/medicine/shtm/ baza / rmj / 97 -4 / 4.htm).

Fluorine in the form of sodium fluoride (NaF) or monofluorophosphate in the form of a disodium salt (Na ₂ PO ₄ F) stimulate the activity of osteoblasts, which leads to an increase in the mass of the spongy bone, promotes the formation of tooth enamel. Sodium fluoride replaces the hydroxyl ion in hydroxyapatites with the formation of small crystals, which increases the density of the cancellous bone. To a lesser extent, this affects the increase in the density of the cortical layer of the bone. Sodium fluoride with cyclic administration at a daily dose of 40-50 mg (which corresponds to approximately 16.2-20.3 mg of fluorine) is used to treat the steroid and postmenopausal forms of osteoporosis, as it not only reduces pain, but also reduces the risk of new fractures (C .S. Rodionova "Slow-release sodium fluoride in combination with calcium citrate prevents new vertebral fractures" http://www.mediasphera.ru/mjmp/97/l/rl-97-6.htm).

In the treatment of osteoporosis, sodium fluoride should be combined with calcium, magnesium and vitamin D ₃ . To achieve adequate bone mineralization, calcium intake in the body should be 1-1.5 g per day (//amt.allergist.ru/natrftor_a.html).

Reducing the acidity of gastric juice can lead to a significant (up to 50%) decrease in fluorine absorption when applied in the form of sodium fluoride. The bioavailability of fluorine in sodium fluoride preparations decreases in the presence of calcium or antacids and, if the calcium salts commonly used with fluoride preparations in the treatment of osteoporosis are taken simultaneously, the absorption of fluorine may decrease by 20-50%. Monofluorophosphate is no less effective than sodium fluoride in influencing osteodensitometric indices. At the same time, monofluorophosphate has advantages over sodium fluoride: the bioavailability of fluorine in monofluorophosphate preparations is stable and amounts to 95%; side effects from the gastrointestinal tract are less common (hydrofluoric acid does not form in the stomach); more stable pharmacokinetic indicators. Monofluorophosphate does not interact in the intestine with food and calcium salts, which allows them to be taken simultaneously. 200 mg of monofluorophosphate (Na ₂ PO ₄ F) contains 16.4 mg of fluoride ions (N.V. Bunchuk "Pharmacotherapy of osteoporosis", Russian Medical Journal, www.kuban. Su / medicine / shtm / baza / rmj / 97-4 /4.htm). Therefore, to provide a therapeutic dose of 15 to 20 mg of fluoride per day, it is necessary to take from 183 to 244 mg of monofluorophosphate per day.

Magnesium, an important element for the heart, more than 300 different enzymes depend on magnesium. By preventing platelet adhesion, the likelihood of clots (blood clots) clogging up the arteries is reduced. Magnesium acts simultaneously on all the root causes of hypertension, an excess of insulin in the blood, a low level of potassium and narrowed blood vessels, reducing high blood pressure. Magnesium supplements are recommended for mitral valve prolapse. It is also recommended to take it for asthma - it reduces wheezing and helps to relax the bronchi.

Magnesium helps with muscle and joint pain, fibromyalgia and osteoporosis, headaches and chronic fatigue syndrome. Magnesium is recommended for chemical hypersensitivity, bacterial and viral infections, leg cramps, kidney stone disease, and impaired blood supply to the legs. It is necessary for patients with a diagnosis of diabetes or insulin resistance. Magnesium supplements make it easier for people with type 2 diabetes to regulate their blood calcium. As a result, their need for oral antidiabetic drugs usually decreases and may even completely disappear (// mirzdorovia, com.ua/spravka2.php).

Magnesium is the main anti-stress element. It allows you to effectively reduce psychological and emotional fatigue. Magnesium preparations are an important element in the prevention of osteoporosis and diseases of the musculoskeletal system. Magnesium lowers blood pressure and normalizes heart rate (www.osteoform.ru/products/ calc.htm).

Beryllium is an antagonist of magnesium. The absorption of magnesium can be impaired with excessive intake of manganese, cobalt, lead, nickel, cadmium, calcium. In turn, vitamins B ₁ B ₆ , C, D ₃ , E, calcium, phosphorus, received in optimal amounts, protein, estrogens contribute to an increase in the level of calcium in the body (www.microelements.ru/Mg).

Magnesium (in the form of citrate, lactate, chelate, glycinate, oxide or mixtures thereof) increases the level of calcium, prevents calcification of soft tissues, reduces the risk of kidney stones, activates more than 300 enzymes in the body, serves as a structural element of bones and tooth enamel, lowers cholesterol in blood, together with calcium, provide an optimal balance of excitation and inhibition (Description of the drug Camosten / Camosten ™ www.ortho.ru/agents/BA/Camosten_Stg.htm).

Magnesium deficiency causes chronic fatigue, increased fatigue, irritability, anxiety, increased hair loss, brittle nails, tooth decay, sleep disturbances, night sweats, headaches, dizziness, weakened attention and mental concentration, muscle pain, cramps, tics, heart pain, heart rhythm disturbances, high or low blood pressure, cramps in the stomach and intestines, esophagus, larynx, bronchi, increased reaction to weather changes, low body temperature, cold hands and feet, kidney stones, premenstrual syndrome and painful periods, allergic reactions (Description of the drug Ortho Calcium + Magnesium, www.health-way.ru/index.php4?sID=166&iID=2724).

The ratio of calcium and magnesium 2: 1 provides the best absorption of these minerals by the body and prevents their loss (Description of the preparations, Calcium / Magnesium Chelate www.altura.com.ua/products/camghelat. Html).

Without magnesium, calcium cannot be absorbed. Magnesium balances the intake of calcium and prevents its excretion. 60% of magnesium is found in bone and teeth. A shortage of magnesium entails a deficiency of zinc, copper, calcium, potassium, silicon and their further substitution with toxic heavy metals: lead, cadmium, aluminum. Magnesium affects the entry of calcium into the cell (control of calcium channels). In this regard, magnesium acts as a physiological calcium antagonist and prevents the excessive functional activity of cells. Magnesium supports urine salts in a dissolved state and prevents their deposition, inhibits kidney stone formation, and even in an insignificant concentration inhibits crystallization.

Magnesium, especially in the form of citrate, reduces the absorption of oxalates in the intestine and its urinary excretion. Normalization of acid-base balance is achieved due to the alkalizing effect of both magnesium and citrates, which reinforce each other. Magnesium in the form of citrate has a high bioavailability. Citrates are the best conductor to the cell. They reduce the release of calcium in the urine, promote the absorption of vitamin C and various elements, neutralize toxins, nitrates. Another advantage of citrate is that it is included in the cell’s energy cycle (Krebs cycle), where it forms energy (The role of magnesium in maintaining acid-base balance (pH), http://article.apteka.ru/index.php? go = News & file = print & id = 52).

1 g of magnesium citrate tetrahydrate corresponds to 139.4 mg of elemental magnesium, and dried 1 g of magnesium citrate corresponds to 161.6 mg of elemental magnesium. Therefore, the range of elemental magnesium from 0.2 g to 0.8 g corresponds to the range of magnesium citrate tetrahydrate from 1.43 g to 5.74 g.

Among all the factors ensuring the strength of the skeleton, the ratio of calcium to magnesium is central. Calcium contributes to the improvement of the cardiovascular system, participating in lowering cholesterol and triglycerides. Calcium supplements protect against cancer of the endometrium, pancreas, and colon. Calcium provides stable sleep; it is necessary for osteoporosis and other bone diseases (//mirzdorovia,com.ua/ spravka2.php).

Calcium is involved in the regulation of nerve conduction, muscle contractions and is a component of the blood coagulation system. The use of calcium and vitamin D ₃ prevents the increase in the production of parathyroid hormone (PTH), which is a stimulator of increased bone resorption. Calcium is absorbed in ionized form in the proximal part of the small intestine through an active D-vitamin-dependent transport mechanism (Description of the drug Calcium-D ₃ Nycomed www.voed.ru/ca-d3_ca-d3_forte.htm).

Calcium absorption decreases with age and with increasing duration of menopause. Clinical studies have shown a positive effect of calcium on bone mass in the elderly. A weak antiresorptive effect was established with evidence of prophylaxis of bone loss. The effect is most pronounced in old age, it can take place during the premenopausal period, but is minimal in the early years of postmenopause, when estrogen deficiency leads to a significant loss of bone mass. The recommended rate of calcium intake in women at premenopausal age is 1000 mg per day, and in postmenopausal women over the age of 50 years, 1500 mg per day. There is an inverse relationship between the amount of calcium consumed and the risk of stone formation - high calcium intake prevents the formation of kidney stones. The protective effect of calcium is due to the fact that it binds oxalates and phosphates in the intestine, preventing their excessive excretion in the urine, which promotes the formation of calculi (N.V. Toroptsova, “Prevention of postmenopausal osteoporosis: the role of calcium and vitamin D preparations”, Institute of Rheumatology, Russian Academy of Medical Sciences, Moscow, Gynecology, Volume 11, Volume 5, 2005, www.consilium-medicum. Com / media / gynecologv / 05_05 / 287.shtml).

Calcium ions play an important role in the formation and preservation of bone tissue. Along with special proteins, calcium ions provide bone hardness and elasticity. They take part in the excitation and contraction of muscle fibers, ensuring cell permeability, intercellular interactions, blood coagulation, secretion of hormones, mediators, enzymes. Calcium ions act as a transformer of information that enters the cell, regulate intracellular metabolism, including energy. On the surface of the membranes of cardiomyocytes and blood vessels, calcium ions contain 1000 times more than inside the cells. From the extracellular space, they penetrate into the protoplasm through special calcium channels, affecting various physiological processes of the functions of cells of all organs, vascular tone, systole intensity, diastole. At night, accelerated release of mineral salts from the body occurs (circadian acceleration of resorptive processes in the bone). Therefore, calcium should be taken after dinner and in the evening. A negative dose-dependent effect of the pharmacotherapeutic activity of calcium has been established: its small doses are better absorbed than large doses. In this regard, it is more rational to take a small amount of the drug several times a day. Promote the absorption of calcium, in addition to vitamin D, lactose, hydrochloric acid, citric acid, phosphorus, magnesium (I.S. Chekman "Calcium citrate - clinical and pharmacological activity", wwvv.health-ua.com/articles/ 186.html) or their mixture.

The assimilation of mineral substances occurs in the lumen of the small intestine by transporting cholecalciferol activated transport protein through the intestinal wall. From the intestine, calcium is absorbed in a soluble ionized form. The drug is better soluble in an acidic stomach. Disclosed ionized calcium penetrates well into all tissues. It is excreted mainly with feces in the form of unabsorbed calcium, about 20% is excreted in urine (I. Chekman “Calcium citrate - clinical and pharmacological activity”, www.health-ua.com/ articles / 186.html).

To get calcium into the bones, and not to be deposited, for example, in the vascular wall, we need pyridoxine, ascorbic acid, phytonadione, magnesium, zinc and manganese (Description of the drug Ortho Calcium + Magnesium, www.health-way, ru / index.php4? sID = 166 & iID = 2724). A complex of vitamins, including ascorbic acid, cholecalciferol and tocopherol, contributes to a more complete absorption of calcium and prevents its leaching from bone tissue (Description on the preparation “Calcium C, D, E”, www.svobodny20.ru/content-production-calcium.html) .

The following calcium salts used in medical practice can be used in the proposed composition: glycerophosphate, gluconate, carbonate, lactate, citrate, chloride, phosphate (I. Chekman “Calcium citrate-clinical-pharmacological activity”, www.health-ua.com / articles / 186. html) or a mixture thereof. The lowest digestibility is characteristic of calcium chloride and gluconate, the highest - calcium lactate and calcium citrate. Moreover, the use of calcium citrate does not violate the buffering and biochemical parameters of blood, and does not potentiate stone formation in the kidneys ("Calcium citrate Farmak OJSC for the treatment of osteoporosis", www.apteka.ua/archives/376/18663.html). With any acidity of the gastric juice, calcium citrate is more soluble than, for example, calcium carbonate or calcium phosphate. Moreover, the rate of absorption of calcium from calcium citrate compared with calcium carbonate in the body is 24% higher (Belkhushet Sammy “Preserving bone mass in osteoporosis is an easier task than restoring it”, Polyclinic. No. 2, 2006, pp. 56-57 .poliklin.ru/article200602al 3.php).

Another source indicates that the absorption of calcium from citrate is 61% higher than from carbonate. In addition, it also indicates that citrate provides assimilation of calcium regardless of the acidity of the gastric contents, which is important for patients with decreased secretory function of the stomach and for elderly patients with atrophic gastrointestinal tract changes, as well as calcium preparations based on citrate to a lesser extent cause dyspeptic symptoms than other calcium salts, and calcium citrate more effectively eliminates hyperparathyroidism in elderly patients (N.P. Arlauskas “Evolution of views on the role of combined preparations of Ca and D ₃ in the prevention and treatment of osteoarthritis farrowing ”, 2006, Voronezh, www.voed.ru/ evolution_look_cad3_osterosis.htm).

1 g of calcium citrate contains 211 mg of elemental calcium, and 1 g of calcium lactate contains 130 mg of elemental calcium (N.V. Toroptsova "Prevention of postmenopausal osteoporosis: the role of calcium and vitamin D preparations", Institute of Rheumatology RAMS, Moscow, g “Gynecology”, Volume 11, Volume 5, 2005, www \ v.consiliun-medicum.com/media/gvnecologv/05_05/ 287. shtml).

Calcium deficiency leads to osteoporosis, atherosclerosis, osteochondrosis, spondylosis, dementia and a number of other diseases. Calcium together with other nutrients and vitamins is indicated for the prevention and treatment of osteoporosis, rheumatoid arthritis, caries. It should be taken with stress, depression, nervousness, sleep disturbances, to maintain healthy skin, hair, nails, muscle cramps and tics, numbness of the upper and lower extremities, edema, elevated blood cholesterol, age-related changes in hormonal balance (decrease estrogen levels), pathological processes in the cardiovascular system, to protect the body from heavy metals, with headaches, hypertension, diabetes and metabolic syndrome, inflammation of the bladder (cystitis), malope alcohol consumption, allergic reactions, premenstrual syndrome, painful or heavy periods, back pain, poor posture, thyroid pathologies, weakening of articular joints, habitual dislocation, for the prevention of premature aging (Description of the drug Kalmin, //topaz.e-gloryon.com / 1857865611/1155918656082).

Lactose is absorbed and absorbed by the body in the small intestine (www.solvay-pharma.ru/duphalac/article.aspx?id=741). Lactose promotes the absorption of calcium ions in the upper intestines. Being fermented, lactose maintains low pH values in the intestine, which prevents the formation of insoluble calcium phosphorus salts (www.tiensmed.ru/articles/ correctfeedl 1.html).

Lactulose increases the absorption and retention of calcium, magnesium, zinc, copper and iron in the body (′ ′ Lactusan stimulates the absorption of minerals ”www.lactusan.ru/lactusan/09/), which is especially important with an age-related decrease in absorption during menopause. At the same time, lactulose is more effective than lactose and pectin. The absorption of calcium occurs in the small intestine, due to improved solubility, as well as the large intestine under the action of lactulose. There are two mechanisms of calcium absorption: “active” - transcellular absorption (mainly in the duodenum and highly regulated by vitamin D) and “passive” - paracellular transport through the small and large intestines. Lactulose stimulates “passive” paracellular absorption of calcium. 10 g of lactulose per day increases by 16% the absorption of calcium in postmenopausal women. Since an increase in the absorption of calcium does not increase its excretion in the urine, this indicates an increase in the absorption of calcium in the bones and / or a delay in bone resorption. An increase in urine calcium in menopause is estimated at 20-40 mg / day, which corresponds to bone loss after menopause (40 mg / day is 1% of bone mineral per year). Calcium balance can be increased by higher calcium intake or by increasing the bioavailability of calcium. With the intake of 1000 mg of calcium per day and 10 g of lactulose, the bio-presence of calcium can be increased by 50 mg / day, that is, in an amount sufficient to significantly reduce the negative calcium balance in postmenopausal women and the development of osteoporosis (J. Kh.M., Van Den, Güvel, Theo Muichs, Wim Van Dokkum “Lactulose stimulates calcium absorption in postmenopausal women”, Research Institute of Food and Nutrition, Department of Physiology, Zeist, Netherlands, www.lactusan.ru/lib/?pbid=98).

Lactulose is indicated for hepatic encephalopathy, for the surgical treatment of liver cirrhosis, and also for sub- and decompensation. Lactulose is also prescribed for chronic hepatitis, irritable bowel syndrome associated with intestinal dysbiosis, chronic pancreatitis, constipation of various etiologies, salmonellosis, diabetes mellitus, and obesity. The use of lactulose for the prevention and treatment of calculous cholecystitis in both its stages (physico-chemical and surgical), colorectal cancer, hyperlipidemia (hypercholesterolemia), bronchopulmonary infection, the condition after hemorrhoidectomy, colon diverticulosis, psoriasis, allergic dermatitis is justified.

The expediency of including lactulose in the complex of treatment of patients with obstructive jaundice, chronic renal diseases, including those associated with infection, intestinal and vaginal candidiasis, has been determined. Lactulose is used as a means of detoxification with radiation exposure to the body, burn disease, drug, chemical, alcohol poisoning. Lactulose is much more effective than the widespread irritating laxatives containing hay, bisacodyl, which, with prolonged use, cause a carcinogenic effect (I. Degtyareva et al. “Dufalac (lactulose): classic application and prospects of use in the treatment of chronic liver and intestinal diseases” Ukrainian Military Medical Academy, Kiev, Suchachna Gastroenterologiya, No. 2 (8), 2002, http://www.vitapol.kiev.ua/sgastro/journals/ G_2002_2 / article 16.pdf).

Lactulose prevents the development of colon cancer, lowers blood cholesterol, has antidiabetic activity, anti-endotoxic and laxative effects, improves the absorption of trace elements, is a nutrient medium for the development of protective (beneficial) intestinal microflora: bifidobacteria of the large intestine, which have a pronounced effect on the immune system, lactobacilli and etc. ("Clinical effectiveness" www.solvay-pharma.ru/duphalac/ article.aspx? id = 735). Lactulose is available in powder and syrup form (“Characteristics”, www.solvay-pharma.m / duphalac / article.aspx? Id: = 722).

Until now, combination preparations for oral administration (tablets, capsules, powders, suspensions) used for the prevention and treatment of primary and secondary osteoporosis in women, containing the active substance - cigetine, an excipient that promotes the absorption of calcium by the body’s tissues, were not known as well as an elemental-vitamin complex with physiologically acceptable calcium compounds and components that enhance the therapeutic effect of sigetin.

The proposed complex pharmaceutical composition, on the basis of which combined preparations for oral administration (tablets, capsules, powders, suspensions) are made, contains the active substance sigetin in a daily therapeutic dose of 0.05 to 0.2 g. The therapeutic dose in case of prophylaxis determined by the patient's predisposition to this disease, and in the case of treatment is determined by the severity of the disease.

Sighetin has a number of the above properties, allowing it to be used in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd, and 3rd groups, including for the prevention and treatment of primary and secondary osteoporosis in women.

The proposed complex pharmaceutical composition, on the basis of which combined oral preparations (tablets, capsules, powders, suspensions) are used, used for the prevention and treatment of primary and secondary osteoporosis in women, contains an elemental-vitamin complex with physiologically acceptable calcium compounds and components enhancing the action of sigetin.

Above is one of the possible options for the composition of the elemental-vitamin complex, containing daily doses of vitamins and elements that contribute to the prevention and treatment of osteoporosis, as well as enhancing the therapeutic effect of sigetin.

The composition of this complex includes:

- folic acid, which enhances the therapeutic activity of cigetin, and also has a number of other above-mentioned properties, useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd groups;

- cyanocobalamin (vitamin B ₁₂ ), which increases the effectiveness of folic acid, is necessary when using vitamin D ₃ , and also has a number of other properties mentioned above that are useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd groups

- pyridoxine (vitamin B ₆ ), which promotes the conversion of folic acid into its active form, is necessary when using vitamin D ₃ , and also has a number of other above-mentioned properties, useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd group;

- riboflavin (vitamin B ₂ ), whose coenzymes play an important role in the conversion of pyridoxine and folic acid into their active coenzyme forms, and is also necessary when using vitamin D ₃ ;

- ascorbic acid (vitamin C), which is involved in the metabolism of folic acid, significantly increases the stability of folic acid and other vitamins, is necessary when using vitamin D ₃ , and also has a number of the above properties, useful in the comprehensive prevention and treatment of menopausal disorders 1st , 2nd, and 3rd groups;

- phytonadione (vitamin K), which plays an important role in the formation and restoration of bones, providing synthesis of osteocalcin - a bone tissue protein on which calcium crystallizes;

- cholecalciferol (vitamin D ₃ ) (or its derivatives), which affects the general metabolism during the metabolism of calcium and phosphate ions, stimulates the absorption of calcium, phosphates and magnesium from the intestine, promotes calcium deposition in bone tissue, and also has a number of other properties mentioned above useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd groups. Moreover, when treating with vitamin D _3, it is recommended to simultaneously take vitamins of groups B, ascorbic acid and vitamin E, without which normal metabolism of cholecalciferol in the liver is impossible;

- d-α-tocopherol (vitamin E), which is involved in the formation of collagen fibers, including bones, is necessary for the normal metabolism of cholecalciferol, and also has a number of other properties mentioned above, useful in the comprehensive prevention and comprehensive treatment of menopausal disorders 1st, 2nd and 3rd groups;

- calcium pantothenate, which in the form of pantothenic acid is important for maintaining and restoring all tissue cells, including bone tissue, and also has a number of other properties mentioned above, which are useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd group;

- Zinc, for example, in the form of an amino acid chelate, which facilitates the absorption of calcium, is involved in the processes of bone restoration with loss of bone mass in people in old age, normalizes metabolic processes;

- copper, for example, in the form of an amino acid chelate, which is important for osteoporosis and diseases of the osteoarticular apparatus;

- Manganese, for example, in the form of an amino acid chelate, which affects the absorption of calcium and phosphorus, is necessary for normal bone growth, the formation of cartilage and synovial fluid to lubricate the joints;

- boron, for example, in the form of an amino acid chelate (or fructoborate, Fructes-B, Bora Bora preparations) increases the sensitivity of cells to estrogens and, possibly, to sigetin, acts as a catalyst for chemical reactions due to which calcium is absorbed, prevents the washing out of calcium bones;

- silicon, for example, in the form of methylsilanotriolsilicate, which is necessary for osteoporosis, and also has a number of other properties mentioned above that are useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd, and 3rd groups;

- fluorine, for example, in the form of monofluorophosphate, which increases the population of osteoblasts, which leads to an increase in the mass of the spongy bone and its density;

- magnesium, for example, in the form of citrate, which increases the level of calcium in tissues, prevents calcification of soft tissues, reduces the risk of formation of kidney stones, serves as a structural element of bones, and also has a number of other properties mentioned above that are useful in the comprehensive prevention and treatment of menopausal disorders 1 2nd, 2nd, and 3rd groups;

- calcium, for example, in the form of citrate, which plays an important role in the formation and preservation of bone tissue, reduces the increased activity of parathyroid hormone in elderly patients with osteoporosis, and also has a number of other properties mentioned above, useful in the comprehensive prevention and treatment of menopausal disorders 1st , 2nd, and 3rd groups, and the absorption of calcium is promoted by cholecalciferol, lactose, lactulose, hydrochloric acid, citric acid, magnesium and phosphorus; in order for calcium to get into the bones and not to be deposited in other tissues, pyridoxine, ascorbic acid, phytonadione, magnesium, zinc and manganese are necessary, and cholecalciferol and tocopherol contribute to a more complete absorption of calcium and prevent its leaching from bone tissue.

In the proposed pharmaceutical composition, instead of the specified original elemental-vitamin complex, known vitamin-mineral complexes can be used containing most of the main vitamins and elements listed above - minerals (folic acid, cyanocobalamin, pyridoxine, ascorbic acid, riboflavin, phytonadione, cholecalciferol, tocophenol calcium, magnesium, calcium, zinc, copper, manganese, boron) for example, such as Osteo Complex (Description of the drug. vvww.dolgolet.ru/bad/bad-kosti-0,3html); CentraVita (Description of the drug, www.medimag.com. Ua ) ; Daily Complete Formula (www.rusatlet.com); LaifPak Nano (nuskin.bz/lp-n.html); MULTI-COMPLEX (litovit.chat.ru/vitamin.htm).

The composition of the proposed comprehensive pharmaceutical composition, on the basis of which combined preparations for oral administration (tablets, capsules, powders, suspensions) are used, used for the prevention and treatment of primary and secondary osteoporosis in women, includes an excipient that promotes the absorption of calcium by body tissues.

Such a filler is a mixture of lactose and lactulose at the above ratio of components. Lactose and lactulose contribute to the absorption of calcium in the intestines. In addition, lactulose has a number of other properties mentioned above that are useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd groups.

The ratio of the components of the filler (in wt.% Lactose 5.0 - 50.0; lactulose powder - the rest) provides a flowability of the mixture approximately 10 times higher than that of lactulose powder, while reducing hygroscopicity, which is important in the manufacture of solid oral forms in in the form of tablets, capsules and powders in sachets.

Lactulose is produced in the form of a powder (TU 9223-209-004119785-00) and syrup TU 9229-003-39185375-2003).

In the manufacture of the suspension, lactulose syrup is used as a water-soluble suspension base, and lactose as a dry excipient of the complex pharmaceutical composition.

The combination of components in the proposed pharmaceutical composition provides the following synergistic effect of combined preparations based on this composition.

1. Prevention and treatment of menopausal disorders of the 1st, 2nd and 3rd groups by enhancing the production and potentiation of the action of native estrogens under the action of folic acid, which, in addition, itself has an estrogen-like effect, as well as boron, which increases the sensitivity of cells to estrogens, pantothenic acid and copper, which are involved in the synthesis of estrogens. At the same time, cyanocobalamin in the composition increases the effectiveness of folic acid. Pyridoxine helps to convert folic acid into an active form and normalizes estrogen metabolism. Ascorbic acid is involved in folic acid metabolism and estrogen synthesis, and also enhances the stability of folic acid. Riboflavin coenzymes contribute to the conversion of folic acid into its active coenzyme forms.

2. Prevention and treatment of menopausal disorders of the 1st, 2nd and 3rd groups by increasing the therapeutic activity of cigetin in the presence of folic acid and components that enhance its effectiveness (cyanocobalamin, pyridoxine, ascorbic acid and riboflavin).

3. Prevention and treatment of menopausal disorders of the 1st, 2nd and 3rd groups due to the above therapeutic activity of folic acid itself and components that enhance its effectiveness (cyanocobalamin, pyridoxine, ascorbic acid and riboflavin).

4. Decreased menopausal disorders of the 1st, 2nd and 3rd groups due to the above activity of d-α-tocopherol, which increases in the presence of ascorbic acid.

5. Reduction of menopausal disorders of the 1st, 2nd and 3rd groups due to the above activity of lactulose, magnesium and calcium in the form of salts, for more complete assimilation of which ascorbic acid, cholecalciferol, tocopherol, phytonadione, pyridoxine, zinc and manganese are required , lactose and lactulose.

6. Reducing the risk of osteoporosis due to the above activity of ascorbic acid, phytonadione, zinc, copper, manganese, boron, silicon, fluorine, in the form of monofluorophosphate, cholecalciferol, the metabolism of which is impossible without d-α-tocopherol.

7. Reducing the risk of cancer of the myometrium, endometrium, breast, ovary, colon, colon, larynx, esophagus, bladder, brain, and leukemia due to the absence of carcinogenic effects of cigetine and the oncoprotective properties of folic acid, ascorbic acid, cholecalciferol, tocopherol, zinc, calcium, lactulose.

8. Improving the digestive tract due to the properties of folic acid, pantothenic acid, magnesium and calcium in the form of citrates, lactulose.

9. Strengthening the patient's predisposition to prevention and treatment through the use of complex drugs in one dosage form.

The proposed pharmaceutical composition can be used for the manufacture of oral forms, such as powders, tablets, capsules, as well as suspensions.

The most promising is the use of the proposed pharmaceutical composition in solid oral form in the form of capsules, since in comparison with tablets the manufacture of capsule form is much simpler and cheaper. In addition, capsules in comparison with tablets have a higher bioavailability.

The technological processes for the manufacture of capsules with the proposed pharmaceutical composition are much simpler than the technological processes for the manufacture of tablets, due to the fact that the capsules can be filled with the composition unchanged without exposing it to heat and pressure, as in a complex technological process of pressing in the manufacture of tablets. This reduces the cost of the drug in capsule form compared to the cost of the drug in tablet form.

In addition, encapsulation eliminates the thermal effect on the composition characteristic of tablet compression, which can lead to marriage due to thermal effects on the components of the composition.

The preparation of the drug in capsules without granulation, that is, direct encapsulation of the powder mixture, further reduces the manufacturing cost due to its cost-effectiveness, since additional equipment for granulation is not required, energy costs are reduced, and labor productivity is increased.

In addition, the pharmaceutical composition based on sigetin in the form of capsules has a higher bioavailability in comparison with the proposed pharmaceutical composition based on sigetin in the form of tablets.

Higher bioavailability due to the fact that the capsules swell quickly and dissolve in the gastrointestinal tract. Biopolymer, for example, a gelatin shell, slowly, portion by portion, releases the active substance, ensuring its full absorption. Gelatin capsules are easily and quickly absorbed even in severe disorders of the human gastrointestinal system.

The advantage of the capsules is that they are easily swallowed, permeable to digestive juices, the therapeutic effect of the contents appears 5-10 minutes after administration, the shell of gelatin is impermeable to volatile liquids, gases, air oxygen.

Capsules with the proposed pharmaceutical composition are more promising for use, in particular, in gerontology than tablets.

The possibility of carrying out the invention is illustrated by the following examples, but is not limited to.

Example 1

Dosage powders of a pharmaceutical composition based on cigetin, an elemental-vitamin complex with physiologically acceptable calcium compounds and components that enhance the therapeutic effect of cigetin, as well as an excipient that promotes the absorption of calcium, are made according to the following scheme:

1. Sift the components (powders) through a sieve.

2. Weigh the components (powders).

3. Prepare the mass by mixing the powder of the active substance sigetin with other components, using the trituration technique, with the mandatory control of mass heterogeneity.

4. Dose the prepared mass in sachets.

Components included in one package Component weight g % sigetin 0.05 1.00 folic acid 0,0002 0.0040 cyanocobalamin 0.00003 0,00060 pyridoxine 0.004 0,080 vitamin C 0.05 1.00 phytonadione 0.00006 0.00120 riboflavin 0.002 0.00 cholecalciferol 0.00001 0,00020 d-α-tocopherol 0.02 0.40 calcium pantothenate 0.003 0,060 zinc 0.007 0.140 copper 0,0005 0,0100 manganese 0,0002 0.0040 boron 0.003 0,060 silicon 0.01 0.20 disodium monofluorophosphate 0.06 1.20 magnesium citrate tetrahydrate 0.9 (0.125 elem. Mg) 18.00 calcium citrate tetrahydrate 1.2 (0.25 elem. Ca) 24.00 lactose 0.7 14.00 lactulose 1.99 39.80 weight of bag contents 5,0 100.00

The mass of dosed powders is 5 g ± 3%, which corresponds to HF XI (st. Powders). The daily dose is 2-4 sachets of powder. When taking a dose of the drug, it is recommended to mix in 50 - 100 ml of drinking water.

600 pieces of bags with a mixture of the components indicated in the table were developed using this technology.

Example 2

Two groups of dosed powders of a pharmaceutical composition based on cigetin, an elemental-vitamin complex with physiologically acceptable calcium compounds and components that enhance the therapeutic effect of cigetin, as well as a filler that promotes the absorption of calcium, are made as described in example 1.

However, the prepared mass of each group is dosed in sachets of a different color.

Composition in one package of the first group

The components of the first group, which are part of one bag (red) Component weight g % sigetin 0.05 5,0 folic acid 0,0002 0.02 cyanocobalamin 0.00003 0.003 pyridoxine 0.004 0.4 vitamin C 0.05 5,0 riboflavin 0.002 0.2 zinc 0.007 0.7 boron 0.003 0.3 manganese 0,0002 0.02 lactose 0.3 30,0 lactulose 0.58357 58,357 the mass of the contents of the red bag 1,0 100.0

The mass of dosed powders of the first group is 1 g ± 5%, which corresponds to HF XI (st. Powders). The daily dose is 2-4 sachets. When taking a dose of the drug, it is recommended to mix in 50-100 ml of drinking water.

600 pieces of bags with a mixture of the components of the first group indicated in the table were developed using this technology.

The composition of the second group in one package

The components of the second group, which are part of one bag (yellow) Component weight g % vitamin C 0.05 1.25 phytonadione 0.00006 0.0015 cholecalciferol 0.00001 0,00025 d-α-tocopherol 0.02 0.50 calcium pantothenate 0.003 0,075 copper 0,0005 0.0125 manganese 0,00023 0.00575 silicon 0.01 0.25 disodium monofluorophosphate 0.06 1,50 magnesium citrate tetrahydrate 0.9 (0.125 elem. Mg) 22.5 calcium citrate tetrahydrate 1.2 (0.25 elem. Ca) 30,0 lactose 0.44 1,0 lactulose 1,3162 32,905 the mass of the contents of the yellow bag 4.0 100.0

The mass of dosed powders of the second group is 4 g ± 3%, which corresponds to GF XI (st. Powders). The dose of the drug of the second group must be taken 2-3 hours after taking the dose of the drug of the first group. The daily dose is 2-4 sachets of powder. When taking a dose of the drug of the second group, it is recommended to mix in 50 - 100 ml of drinking water.

600 pieces of bags with a mixture of the components indicated in the table were developed using this technology.

Example 3

A suspension with the proposed pharmaceutical composition based on sigetin is obtained according to the following scheme:

1. Grind the components to particle sizes in the dispersed phase of not more than 0.05 mm

2. Sift the components (powders) through a sieve.

3. Weigh the components (powders).

4. Prepare the mass by mixing the powder of the active substance sigetin with other components, using the trituration technique, with the mandatory control of mass heterogeneity.

5. The prepared mass in the form of a mixture of powders is stirred and homogenized in lactulose syrup. The resulting suspension is poured into 500 g into vials.

Composition of a single dose of suspension and vial.

Components Single dose One bottle Percentage g g % sigetin 0.1 2.5 0.5 folic acid 0,0004 0.01 0.002 cyanocobalamin 0.00006 0.0015 0,0003 pyridoxine 0.001 0,025 0.005 vitamin C 0.54 13.5 2.7 phytonadione 0.00012 0.003 0,0006 riboflavin 0.0012 0,03 0.006 Water-soluble cholecalciferol 0.00002 0,0005 0.0001 d-α-tocopherol 0.016 0.4 0.08 calcium pantothenate 0.0016 0.04 0.008 zinc 0.0016 0.04 0.008 copper 0.0016 0.04 0.008 manganese 0,0004 0.01 0.002 boron 0.006 0.15 0,03 silicon 0.01 0.25 0.05 disodium monofluorophosphate 0.12 3.0 0.6 magnesium citrate tetrahydrate 2.6 (0.375 elem. Mg) 65.0 13.0 calcium citrate tetrahydrate 3.6 (0.75 elem. Ca) 90.0 18.0 lactose 3.0 75.0 15.0 lactulose syrup 10.0 250,0 50,0 suspension mixture weight 20,0 500,0 100.0

The deviation of the cigetine content in 1 g of the suspension is 0.005 g ± 10%, which corresponds to the requirements of GF XI (Art. Suspensions). The daily dose of the suspension 2 times 20 grams. When taking a dose of the drug, it is recommended to stir in at least 100 ml of drinking water.

100 vials of the proposed pharmaceutical composition have been accumulated.

Example 4

Tablets of a pharmaceutical composition based on cigetin, a vitamin-mineral complex with physiologically acceptable calcium compounds and components that enhance the therapeutic effect of cigetin, as well as an excipient that promotes calcium absorption, are made according to the following scheme:

1. Sift the components (powders) through a sieve.

2. Weigh the components (powders).

3. Prepare the mass by mixing the powder of the active substance sigetin with other components, using the trituration technique, with the mandatory control of mass heterogeneity.

4. The prepared mass is tableted using a known direct compression method.

Composition of one tablet

The components that make up one tablet Component weight G % sigetin 0,025 2.5 folic acid 0.0001 0.01 cyanocobalamin 0.000015 0.0015 pyridoxine 0,00025 0,025 vitamin C 0,025 2.5 phytonadione 0.00003 0.003 riboflavin 0,0003 0,03 cholecalciferol 0.000005 0,0005 d-α-tocopherol 0.004 0.4 calcium pantothenate 0,0004 0.04 zinc 0,0004 0.04 copper 0,0004 0.04 manganese 0.0001 0.01 boron 0.0015 0.15 silicon 0.0025 0.25 monofluorophosphate 0,03 3.0 disodium salt magnesium citrate tetrahydrate 0.355 (0.05 elem. Mg) 35.5 calcium citrate tetrahydrate 0.48 (0.1 elem. Ca) 48.0 lactose 0,03 3.0 lactulose 0,045 4,5 tablet mass 1,0 100.0

The disintegration of the obtained tablets is not more than 15 minutes, the weight of the tablets is 1.0 g ± 5%, which corresponds to GF XI (st. Tablets). The daily dose of 8 tablets (4 times 2 tablets).

1000 tablets were prepared using this technology with a mixture of the components indicated in the table.

Example 5

Capsules with the proposed pharmaceutical composition based on sigetin receive according to the following scheme:

1. Sift the components (powders) through a sieve.

2. Weigh the components (powders).

3. Prepare the mass by mixing the powder of the active substance sigetin with other components, using the trituration technique, with the mandatory control of mass heterogeneity.

4. The prepared mass in the form of a mixture of powders is encapsulated in No. 00 hard gelatine capsules with compaction to a mass of 1.0 g ± 10% in each capsule, to obtain oral drug capsules from the proposed pharmaceutical composition of the following composition.

The composition of one capsule.

Components included
in one capsule Component weight g % sigetin 0,025 2.5 folic acid 0.0001 0.01 cyanocobalamin 0.000015 0.0015 pyridoxine 0,00025 0,025 vitamin C 0,025 2.5 phytonadione 0.00003 0.003 riboflavin 0,0003 0,03 cholecalciferol 0.000005 0,0005 d-α-tocopherol 0.004 0.4 calcium pantothenate 0,0004 0.04 zinc 0,0004 0.04 copper 0,0004 0.04 manganese 0.0001 0.01 boron 0.0015 0.15 silicon 0.0025 0.25 disodium monofluorophosphate 0,03 3.0 magnesium citrate tetrahydrate 0.355 (0.05 elem. Mg) 35.5 calcium citrate tetrahydrate 0.48 (0.1 elem. Ca) 48.0 lactose 0,03 3.0 lactulose 0,045 4,5 weight of mixture in capsule 1,0 100.0

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the Global Fund XI (St. Capsules). The daily dose of 4-8 capsules.

1000 units of cigetin capsules with the proposed pharmaceutical composition have been accumulated.

Example 6

Two groups of capsules from a pharmaceutical composition based on cigetin, an elemental-vitamin complex with physiologically acceptable calcium compounds and components that enhance the therapeutic effect of cigetin, as well as a filler that promotes the absorption of calcium, are made according to the following scheme:

1. Sift the components of each group (powders) through a sieve.

2. Weigh the components (powders) of each group.

3. Prepare the mass of each group by mixing the powders of the components of each group, using the trituration technique, with the mandatory control of mass heterogeneity.

4. The prepared mass in the form of a mixture of powders for each group is encapsulated in No. 2 hard gelatine capsules for the first group and No. 00 for the second group with compaction to a mass of 0.25 g ± 10% for the first group in each capsule and compaction to 1.0 g ± 10% for the second group in each capsule, receiving capsules of an oral drug from the proposed pharmaceutical composition of the following composition.

The composition of one capsule of the first group

The components of the first group, which are part of one capsule (green) Component weight g % sigetin 0,025 10.0 folic acid 0.0001 0.04 cyanocobalamin 0.000015 0.006 pyridoxine 0,00025 od vitamin C 0,025 10.0 riboflavin 0,0003 0.12 boron 0.0015 0.6 zinc 0,0004 0.16 manganese 0.0001 0.04 lactose 0.05 20,0 lactulose 0.147335 58,934 weight of mixture in green capsule 0.25 100.0

The disintegration of the obtained capsules with the components of the first group is less than 20 minutes, which meets the requirements of GF XI (st. Capsules).

Capsules of the first group of components must be taken 2 times a day for 2-4 capsules. The daily dose of 4-8 capsules.

1000 capsules with components of the first group of the proposed pharmaceutical composition have been accumulated.

The composition of one capsule of the second group

Components of the second group, which are part of one capsule (yellow) Component weight g % phytonadione 0.00003 0.003 vitamin C 0,025 2.5 cholecalciferol 0.000005 0,0005 d-α-tocopherol 0.004 0.4 calcium pantothenate 0,0004 0.04 copper 0,0004 0.04 manganese 0.000165 0.0165 silicon 0.0025 0.25 disodium monofluorophosphate 0,03 3.0 magnesium citrate tetrahydrate 0.355 (0.05 elem. Mg) 35.5 calcium citrate tetrahydrate 0.48 (0.1 elem. Ca) 48 lactose 0,03 3.0 lactulose 0,0725 7.25 weight of mixture in yellow capsule 1,0 one hundred

The disintegration of the obtained capsules with the components of the second group is less than 20 minutes, which meets the requirements of the Global Fund XI (St. Capsules). Capsules of the second group of components must be taken 2-3 hours after taking the capsules of the first group of components. The daily dose of 4-8 capsules.

1000 pieces of capsules with components of the second group of the proposed pharmaceutical composition have been accumulated.

Thus, a pharmaceutical composition is provided that provides:

- the creation of various oral dosage forms based on sigetin for the prevention and treatment of osteoporosis in women during menopause;

- enhancing the therapeutic effect of cigetin while maintaining the therapeutic dose without enhancing the side effect that occurs due to the dose of the drug, due to components that enhance the therapeutic effect of cigetin;

- slowing down the menopause and easing its symptoms due to the estrogen-like action of the components that make up the composition;

- a more effective reduction of menopausal disorders through the use of the components that make up the composition, namely: increasing mental and physical performance, reducing forgetfulness, enhancing mental functions, reducing irritability and depression, restoring the structures of nervous tissue; decrease in metabolic metabolic disorders in tissues;

- reducing the risk of developing cardiovascular diseases associated with estrogen deficiency due to the antiatherosclerotic properties of cigetin and the components that make up the composition, reducing the cardiological risk and risk of stroke during their use, as well as reducing the risk of developing high blood pressure;

- reduction of menopausal degenerative changes in the skin, hair, nails and mucous membranes due to the dermatropic properties of cigetin and the components used;

- reducing the likelihood of diabetes mellitus due to the properties of cigetin and the components used;

- reducing the likelihood of developing breast cancer, colorectal cancer and laryngeal cancer due to the oncoprotective properties of the components used;

- improvement of the digestive tract;

- Strengthening the commitment of patients to the use of the drug by combining drugs in one dosage form.

Despite the apparent simplicity of the proposed solution to the problem, no similar solution has been proposed so far, although a pharmaceutical composition based on the drug cigetine for oral dosage form in the form of tablets has been known since 1963 (Instructions for the use of cigetin, approved by the Pharmacological Committee of the USSR Ministry of Health on October 12 1963).

Preparations based on the proposed pharmaceutical composition provide comprehensive prevention and treatment of osteoporosis in women due to the presence in the composition of components with different mechanisms of therapeutic effect on the disease.

The proposed pharmaceutical composition based on the sigetin preparation can be recommended for use in serial production in the pharmaceutical industry.

Claims (6)

1. The pharmaceutical composition for the prevention and treatment of osteoporosis during menopause, characterized in that it contains sigetin as an active substance, an elemental-vitamin complex containing folic acid, cyanocobalamin, pyridoxine, ascorbic acid, riboflavin, phytonadione, cholecalciferol, d-α -tocopherol, calcium pantothenate, zinc, copper, manganese, boron, silicon, fluorine, calcium, magnesium and filler in the following amount (g) in a daily therapeutic dose:
sigetin 0.05-0.20 elemental vitamin complex 3,50-16,00 filler 0.20-20.00 2. The pharmaceutical composition according to claim 1, where the elemental-vitamin complex contains the ingredients in the following quantity in a daily dose, g:
folic acid 0.0002-0.0050 cyanocobalamin 0.00003-0.00040 pyridoxine 0.002-0.200 vitamin C 0.06-1.50 riboflavin 0.001-0.010 phytonadione 0.00006-0.00050 cholecalciferol 0.00001-0.00010 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002-0.020 zinc 0.001-0.050 copper 0.0005-0.0100 manganese 0.0002-0.0100 boron 0.001-0.014 silicon 0.002-0.050 fluorine 0.015-0.020 magnesium 0.2-0.8 calcium 0.4-1.6 3. The pharmaceutical composition for the prevention and treatment of osteoporosis during menopause, characterized in that it contains sigetin as an active substance, an element-vitamin complex and an excipient in the form of two groups of components taken separately in time at the following amount in a daily dose, g:
first group:
sigetin 0.05-0.20 folic acid 0.0002-0.0050 cyanocobalamin 0.00003-0.00040 pyridoxine 0.002-0.200 vitamin C 0.03-0.75 riboflavin 0.001-0.010 zinc 0.001-0.050 manganese 0.0001-0.0050 boron 0.001-0.014 filler 0.400-3.600,
second group:
vitamin C 0.03-0.75 phytonadione 0.00006-0.0005 cholecalciferol 0.00001-0.00010 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002-0.02 copper 0.0005-0.0100 manganese 0.0001-0.0050 silicon 0.002-0.050 fluorine 0.015-0.020 magnesium 0.20-0.80 calcium 0.40-1.60 filler 0.40-7.20 4. The pharmaceutical composition according to claim 1 or 3, made in the form of oral form tablets, capsules, powders. 5. The pharmaceutical composition according to claim 3, made in the form of oral forms, where the groups of components differ in color. 6. The pharmaceutical composition according to claim 3, made in the form of a suspension containing a mixture of powders of components homogenized in lactulose syrup.