RU2379043C2 - Pharmaceutical composition for prevention and treatment of menopause osteoporosis in women - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to pharmaceutical compositions for the oral medical products applied in the integrated treatment of menopause osteoporosis in women. There is offered pharmaceutical composition which contains one or more active substances mainly with different therapeutic modalities providing intensified osteogenesis or decreased bone resorption, an element-vitamin complex containing elements in the form of physiologically acceptable compounds, providing intensified bone formations and decreased bone resorption, and the vitamins intensifying therapeutic action of the active substances and ensuring intensified bone formation and decreased resorption, and an excipient in the form of one substance or mixed substances which is monoexcipient or one component of the excipient.

EFFECT: higher effectiveness of the composition.

6 cl, 13 tbl, 8 ex

Description

The invention relates to the pharmaceutical industry and medicine, and in particular to pharmaceutical compositions for oral medications used for the treatment of osteoporosis in menopausal women.

It is known that 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. Osteoclasts, a special type of bone macrophages developing from blood monocytes, provide bone resorption. 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, during effective intake of a number of medications. Prussic (senile) osteoporz occurs in women twice as often as in men, which is explained by gender 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 indirectly with the participation of specific receptors located on the surface of tissue cells and providing the capture of the hormone molecule and its transfer inside the target cell, act on 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 and mammary gland, brain, heart and arteries, the genitourinary tract, bone tissue, skin, mucous membranes, etc. (A.L. Tikhomirov, Ch.G. Oleinik. “Principles of therapy climacteric disorders. ”“ Issues of Gynecology, Obstetrics and Perinatology, ”2005, v. 4, No. 4, pp. 84-89). Estrogens cause the development of secondary female sexual characteristics, myometrial hypertrophy, endometrial hyperplasia, exerting an anabolic effect on the woman's body, stimulate the macrophage system, antibody production and phagocyte activity.

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, 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 estrogen (Clinical Pharmacology and Pharmacotherapy, chapter 10. www.kuban.su/medicine/shtm/baza/lek/klfhtm/part19/19-31.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 occur 2-4 years after menopause.

Urogenital disorders: dryness, itching and burning in the vagina, pain during sexual intercourse, urethral syndrome, 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 disease, postmenopausal osteoporosis, diabetes mellitus, obesity, Alzheimer's disease and Alzheimer-like dementia.

(A.L. Tikhomirov, C.G. Oleinik. “Principles of the treatment of menopausal disorders.” “Issues of gynecology, obstetrics and perinatology,” 2005, v. 4, No. 4, pp. 84-89).

The possibilities of estrogen replacement therapy in preventing bone loss during menopause have been proven by numerous studies. Currently, the most common for the treatment of osteoporosis are estrogen-genic drugs. The introduction of a gestagen component in the pharmaceutical composition can prevent the development of endometrial hyperplasia and reduce the risk of oncological changes. Monopreparations used in hormone replacement therapy (HRT) in the treatment of postmenopausal disorders, including osteoporosis, include estaradiol valerate (2 mg tablets or tablets); 17c-estadiol (dragee or 2 mg tablets); tibalon (livial) (tablets 2.5 mg); the amount of conjugated estrogens from the urine of mares (tablets of 0.625 and 1.25 mg). Two-component preparations of the estrogen-progestogen type include estradiol valerate (2 mg per tablet) with medroxyprogesterone acetate (10 mg or 20 mg per tablet); estradiol valerate (2 mg per tablet) with levonorgestrel (0.15 mg per tablet); estradiol valerate (2 mg per tablet) with norgestrel (0.5 mg per tablet); estradiol (2 mg per tablet) with dydrogesterone (10 mg per tablet); 17c-estradiol (2 mg per tablet) with norethisterone acetate (1 mg per tablet); estradiol valerate (4 mg per tablet) with prasterone entanate (200 mg per tablet).

Conjugated estrogens are prescribed at a dose of 0.625 mg / day continuously with the addition of levonorgesterel on the last 12 days of each treatment cycle. Tibolone 2.5 mg / day and 17B estradiol 2 mg / day + norethisterone acetate 1 mg / day are prescribed continuously (Menopausal Syndrome, www.medinfo.ru/sovety/aku/20_1.phtml).

HRT in postmenopausal osteoporosis is the method of choice for at least the first 5–10 years after menopause. HRT estrogen-progestogen drugs reduces bone loss and improves the well-being of women during menopause, reduces the risk of developing cardiovascular disease.

However, the resumption of menstrual bleeding at the same time makes this treatment unacceptable for many patients (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). In addition, HRT increases the risk of developing breast cancer (N.V. Bunchuk. “Pharmacotherapy of osteoporosis,” Russian Medical Journal, www.kuban.su/medicine/shtm/baza/rmj/97-4/4.htm).

Selective estrogen receptor modulators (SMERs) compete with endogenous estrogens for binding to estrogen receptors and can enhance or inhibit the effects of estrogens. SMER are substances that are estrogen receptor agonists in relation to bone tissue, lipid levels and estrogen receptor antagonists in relation to the uterus and mammary glands. These substances reduce the process of bone resorption and lead to positive changes in the balance of calcium in the body, primarily due to a decrease in calcium loss in urine.

Monopreparations have been developed on the basis of these substances: tamoxifen, raloxifene, keoxifen, droloxifene. Clinical studies on the use of raloxifene in menopausal women in daily doses from 30 to 600 mg showed a decrease in cholesterol and prevention of bone loss.

However, unlike estrogens, raloxifene does not eliminate the vasomotor symptoms of menopause and urogenital disorders (L. Rozhinskaya, “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). Raloxifene slows down bone resorption (while its mechanism of action is similar to that of estrogen), but does not have an anabolic effect.

While there is no data obtained during long-term follow-up, the ability of this drug to reduce the risk of fractures, prevent the development of cardiovascular diseases, breast cancer, ovaries or uterus, as well as its effect on cognitive function. The main side effect of raloxifene is the sensation of “hot flashes” (V. Hovidunkit, D. M. Shobak. “Clinical data on the effect of raloxifene hydrochloride on a woman’s body,” www.mediasphera.ru/mjmp/2000/6/r6-00-12. htm). Raloxifene is not recommended for use in combination with estrogens. Against the background of treatment with SMER, it is recommended to take additional calcium preparations (description of the drug Raloxifene. Www.recipe.ru).

Bisphosphonates are synthetic substances that contain a non-hydrolyzable P-C-P bond and are firmly bonded to bone tissue hydroxyapatite crystals. All bisphosphonates are resistant to enzymatic hydrolysis, have a high affinity for metal ions, forming both soluble and insoluble chelate complexes and aggregates depending on the pH of the solution (E.A. Yuryeva, T.A. Matkovskaya "On bisphosphonates as medicinal compounds (on materials of the international congress) ”, //nature.web.ru/db/msg.html?mid=1170061&s=). As a rule, they have two side chains, one of which is involved in the binding of a substance to a bone mineral, and the other determines the possibilities and biological characteristics of these substances. Bisphosphonates are captured by the skeleton, and many of them suppress bone resorption mediated by osteoclasts.

The main effect of bisphosphonates on the skeleton is to slow down the mineralization of bone and cartilage, as well as inhibiting bone resorption caused by osteoclasts. Slowing mineralization is associated with inhibition of crystal growth. While the effect of bisphosphonates on crystal growth depends in part on the P — C — P structure and their binding of hydroxyapatite, the main structural unit of the mineral matrix, the side chain modifications are decisive regarding the effect of bisphosphonates on bone resorption. In tissue culture, bisphosphonates slow down normal and stimulated bone resorption, prevent osteolysis caused by many factors, including parathyroid hormone, calcitriol, prostaglandins, etc.

Contacting hydroxyapatites, bisphosphonates accumulate in areas of bone resorption under actively resorbing osteoclasts. Within osteoclasts, bisphosphonates cause many changes that reduce their ability to resorb bone tissue (loss of brush border, destruction of the cytoskeleton, inability of osteoclasts to move or bind to bone tissue). Bisphosphonates can also cause osteoclast apoptosis, which contributes to antiresorptive activity (V.V. Povoroznyuk “Bisphosphonates: the role of ibandronic acid in the treatment of postmenopausal osteoporosis”, //

health-ua.com/print_articles.php?aid=1681).

To date, the following bisphosphonates are registered for the treatment of osteoporosis - ethidronate, xidefon (similar to etidronate), alendronate, and ibandronate. The use of clodronate, pamidronate in the treatment of osteoporosis is being investigated.

The daily dosages of bisphosphonates are as follows: ethidronate - 400 mg for 2 weeks, then a break of 10-13 weeks; xidephone - 5-7 mg per 1 kg of body weight in the morning 30 minutes before meals for 1 month, then a 1-2 month break; alendronate - 5 mg 30 minutes before meals for 24 months, and then 10 mg; ibandronate - in a constant mode with an average dose of 2.5 mg; clodronate - 400 mg daily for 1 month, then a 2 month break. In the treatment of alendronate, calcium intake in a dose of at least 500 mg of calcium element is necessary. Bisphosphonates do not combine with each other (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). In the treatment of postmenopausal osteoporosis alendronate (10 mg once a day), estrogens, calcium and vitamin D preparations are prescribed orally (Pharmacological Guide, www.practica.ru/DrugBook/Drugs/dr0018.htm).

The main disadvantage of bisphosphonates is weak, constituting no more than 1-5% of the dose, absorption in the gastrointestinal tract. It can decrease even more if the drugs are taken at the same time as food or calcium. Another disadvantage of bisphosphonates is that if a certain dose is exceeded, bisphosphonates can have a toxic effect on osteoblasts and lead to a violation of bone mineralization (cause osteomalacia).

Due to the long-term preservation of bisphosphonates in bone tissue (their half-life may exceed 1 year), there is a potential danger of impairing the quality of newly formed bone tissue and reducing the strength of the skeleton. This disadvantage is characteristic of first-generation bisphosphonates, in which the gap between the therapeutic and toxic doses is insignificant (ethidronate, clodronate, xidephone, etc.). The bisphosphonates of the second (pamidronate and alendronate) and third (ibandronate and resindronate) generations are characterized by a significant gap between the magnitude of the therapeutic and toxic doses, so the risk of developing osteomalacia is unlikely (N.V. Bunchuk. Pharmacotherapy of osteoporosis, Russian Medical Journal, www.kuban. su / medicine / shtm / baza / rmj / 97-4 / 4.htm).

Calcium supplements, anthocides, and drugs containing polyvalent cations (e.g. aluminum, magnesium, iron) can interfere with the absorption of bisphosphonates (ibandronic acid). Together with a decrease in bone resorption, bisphosphonates slow down bone formation. However, the pace of this slowdown is lagging behind the corresponding indicator for bone resorption (Modern approach to treatment, www.osteoporosu.net/2_12).

Osteoquin (7-isopropoxy-isoflavone) is a derivative of flavonoids - a large class of natural products synthesized in ferns and flowering plants. Some flavonoids have an estrogen-like property that is used in the treatment of postmenopausal osteoporosis. This effect is explained by the spatial relationships between the phenolic hydroxyl group of estradiol and certain flavonoids. The similarity of their configurations ensures their recognition by estrogen receptors. There are three main types of phytoestrogens in plants: flavones, isoflavones, and homesteads.

Ipriflavone - 7-isopropoxy-3-phenyl- (4H) -1-6 benzopyrone is a synthetic derivative of isoflavones of plant origin. This substance causes a growth effect and, although it increases the uterotropic activity of estrogens, it is devoid of estrogenic activity. Animal studies have shown that ipriflavone prevents bone loss in experimental osteoporosis models such as steroid, immobilization, and ovariectomized animals. Ipriflavone has a direct inhibitory effect on bone resorption. It is also known that this substance stimulates collagen synthesis, as well as the growth and differentiation of clonal osteoblastic cells.

Ipriflavone (Osteokhin drug) is available in 200 mg tablets. Daily dose of 600 mg in 3 divided doses after meals. Ipriflavone treatment is combined with calcium and vitamin D salts (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). In addition, ipriflavone in the treatment of postmenopausal osteoporosis is effectively combined with calcitonin and estrogen drugs (Description on the drug Osteokhin, www.recipe.ru).

Testosterone-derived anabolic steroids are used in the treatment of osteoporosis. Their use is based on the following experimental data: human osteoblasts have androgen receptors; anabolic steroids have a direct effect on the proliferation of bone cells and the production of osteocalcin: anabolic steroids inhibit bone resorption; the connection between bone and muscle mass has been established. Anabolic steroids are known to reduce bone resorption and induce a positive calcium balance due to increased absorption of calcium from the intestines and reabsorption of calcium by the kidneys.

Indications for treatment with anabolic steroids are osteoprosis in older people with vertebral fractures, especially in combination with muscle weakness, steroid osteoporosis and osteoporosis in men due to a deficiency of sex hormones. Oral anabolic monopreparations include, for example, oxandrolone, methandienone. The single drug oxandrolone is available in tablet form with 2.5 mg of active substance. The usual daily dose is 2-4 times 2.5 mg. The maximum daily dose of 20 mg. The course of treatment is 2-4 weeks (description of the drug Oxandrolone, www.recipe.ru). The single drug methandienone is available in the form of tablets with 1 mg and 5 mg of the active substance. The usual daily dose is 1-2 mg per day, 5 mg each. The maximum daily dose of 50 mg. The course of treatment is up to 4 weeks. A second course - after 6-8 weeks (description of the drug Metandienone, www.recipe.ru).

Thiazide diuretics have the ability to reduce urinary calcium excretion and increase calcium balance. Their effect on calcium metabolism is complementary to the direct effect of anti-osteoporotic drugs on bone resorption or intestinal absorption of calcium. The short and long extra skeletal effects of thiazide diuretics have been well studied for hypertension, so their use may become preferable in terms of preventing complications of hypertension (stroke and congestive heart failure) in elderly patients.

Thiazide diuretics have a positive effect on bone mass in the vertebrae and peripheral parts of the skeleton, and also reduce the frequency of hip fractures with prolonged use (L. Rozhinskaya, “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). Thiazide diuretics include, for example, the following monopreparations: hydrochlorothiazide, cyclopentiazide. The single drug hydrochlorothiazide is available in the form of tablets with an active substance content of 25 mg, 50 mg and 100 mg. The daily dose is from 12.5 mg to 200 mg, depending on the indication. With arterial hypertension, the daily dose is 12.5-25 mg for a long time. After 3-5 days of treatment, it is recommended to take a break for 3-5 days (description of the drug Hydrochlorothiazide, www.recipe.ru).

Monopreparation cyclopentiazide is available in the form of tablets with an active substance content of 0.5 mg. The daily dose is from 0.5 mg to 2 mg per day, depending on the indications. The drug is prescribed for 3-5-7 days in a row, then take a break for 3-4 days. With prolonged treatment, it is sometimes prescribed 2-3 times a week. The duration of the course and the total duration of treatment depends on the nature and severity of the disease, the effect obtained, tolerance (description of the drug Cyclopentiazide, www.recipe.ru).

For the nature of the effect of fluorine on bone tissue, the value of the therapeutic doses used is critical, the range of which is from 15 to 20 mg per day. 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 bone formation failure. 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 lead to a prolongation of 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.

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) stimulates 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. "Slowly released sodium fluoride in combination with calcium citrate prevents new vertebral fractures", http://www.mediasphera.ru/mjmp/97/1/r1-97-6.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/natrftora.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 mg to 20 mg of fluoride per day, it is necessary to take from 183 mg to 244 mg of monofluorophosphate per day.

Phytin is an organic phosphorus preparation containing a mixture of calcium and magnesium salts of various inositol phosphoric acids, mainly inositol hexaphosphoric acid. Get it from fat-free hemp and other meal. Contains 36% organically bound phosphoric acid. Flavourless white amorphous powder. Slightly soluble in water, soluble in a normal solution of hydrochloric acid (1:10). Stimulates blood formation, enhances the growth and development of bone tissue; improves the functions of the nervous system in diseases associated with a lack of phosphorus in the body. It is used for vascular hypotension, neurasthenia, sexual weakness, hypotrophy, rickets, osteomalacia, diathesis, scrofula, etc. It is produced in the form of tablets of 0.25 g. It is prescribed for 0.25-0.5 g 3 times a day. (www.voronezh.prodenas.ru/go.php?name=bme&mtype=z&type=DRUG&sid=1192).

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/baza/lek/ klftm / part19 / 19-31.htm). In addition, folic acid has an estrogen-like effect - it can slow down the onset of menopause and alleviate its symptoms (VitaFast®Folic Acid Test System (Vitamin B9), www.komprod.com/en/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 (Description of the drug Osteo Complex, www.dolgolet.ru/bad/bad-kosti-03.html), which is part of the skin, bones, blood vessels and other body tissues . 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. A high level of homocysteine in the blood contributes to the formation of plaques on the walls of blood vessels, which can lead to serious cardiovascular problems. In addition, elevated levels of homocestin 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 (Patent RU No. 2222329, 2004.01.27, A61K 31/519). Increased homocysteine levels increase the risk of Alzheimer's disease (www.trimm.ru/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). A lack of folic acid in the body can lead to the activation of proto-oncogenes, which are directly involved 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 / N3 / 2004, www.consiliummedicum.com/media/onkology/04_03/124.shtml). First of all, bone marrow suffers from a lack of folic acid. The erythrocyte precursor cells that are formed in the bone marrow, with folic acid deficiency, increase in size, forming megoblasts and leading to megoblastic anemia (//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 include 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, it is important for normal growth, as well as the regeneration of folic acid

(www.dsm.com/ru_RU/html/dnpru/hnh_maininfovit_index_basics_b12.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.), allergic diseases (asthma, urticaria) (http://vitamini.solvaypharma.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, participates 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.solvaypharma.ru/encyclopedia/info.aspx?id=22). Riboflavin (vitamin B ₂ ), being a synergist of pyridoxine, is required for 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 carbon, fat and protein, as well as in reactions for the production of energy in the respiratory chain. Riboflavin coenzymes play an important role in the conversion of pyridoxine and folic acid to their active coenzyme forms (Basic About 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, vascular 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, providing the structure of muscles, vascular tissues, bones and cartilage; regulates blood coagulation; normalizes capillary permeability; necessary for blood formation; It has anti-inflammatory and anti-allergic effects; It is a factor that protects 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 each other's action as antioxidants (patent RU No. 2275192, A61K 31/015, 2006.04.27).

d-α-tocopherol (vitamin E) 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 diseases of the breast. Vitamin E provides normal blood coagulation and healing; reduces the possibility of scarring from some wounds; lowers blood pressure; helps prevent cataracts; relieves leg cramps; supports the health of nerves and muscles; strengthens the walls of capillaries; 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 anticancer 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 gerontology (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, participates in redox processes in the body (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=14).

Cholecalciferol (vitamin D3) (or its active metabolites, for example, 1-a-25 (OH) 2D3 - calcitriol or 1-a-OHD3 - 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 overall 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 inhibits 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 at the same time. 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=11).

The recommended daily dose of cholecalciferol for people older than 50 years 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, city “Gynecology”, Volume 11, Volume 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 the maintenance and restoration of 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_US/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).

Retinol (Vitamin A) plays an important role in the synthesis of progesterone - the female sex hormone. Retinol is one of the main antioxidants. It is able to suppress the destruction of cells by free radicals, preventing premature aging, reducing the risk of cardiovascular disease, eye cataracts. Vitamin A plays a significant role in the formation of epithelial tissue, which is part of the skin, glands and mucous membranes, respiratory system, digestive and genitourinary tract. It supports local immunity of vital organs. Retinol reduces the risk of a respiratory infection.

Vitamin A is useful in the treatment of certain bowel diseases, such as colitis, Crohn's disease, and duodenal ulcers. It promotes the renewal of skin cells and their normal functioning. Vitamin A is effectively used in the complex treatment of many skin diseases. It enhances the body's immunity, therefore it is especially necessary for older people with weakened immunity. Retinol plays a decisive role in the processes of light and dark adaptation. In addition, it contributes to the hydration of the cornea, and if it is deficient, there is a risk of inflammation of the mucous membrane of the eye and even chronic dry eyes - xerophthalmia. Vitamin A is associated with growth hormone.

The cartilage cells that are most involved in the metabolic process require a large amount of vitamin A. Young bone cells grow, remain active for some time, and then die to give way to new cartilage cells. This requires vitamin A. It protects the body from cancer of the digestive system, bladder, lungs, and skin. Retinol helps to suppress the process of gradual transformation of healthy cells into malignant, has a therapeutic and prophylactic effect in pre-tumor conditions of the shell of the oral cavity, stomach, cervix.

It also reduces the risk of relapse after removal of the tumor. In combination with vitamin C, retinol causes a decrease in lipoid deposits in the walls of the vessel and lowers serum cholesterol. To enhance the effectiveness of retinol, it must be taken simultaneously with tocopherol. In addition, with a low zinc content in the body, vitamin A is poorly absorbed (http // vita.x51.ru / publ / 4-1-0-10). Retinol reduces (mutually) the danger of hypervitaminosis with vitamin D (http // slovari.yandex.ru).

Zinc is a component of more than 200 enzymes (www.osteoform.ru/products/calc.htm). It provides carbon dioxide transfer, stability of biological membranes, and promotes wound healing (http://vitamini.solvay-pharma.ru/elements/article.aspx?id=1816). Zinc takes part in the processes of cell division and differentiation, the formation of T-cell immunity, the functioning of many enzymes, insulin of the pancreas, 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 promotes the absorption of vitamin E and maintains 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 pituitary hormones, adrenal glands and the pancreas. Under the influence of its compounds, the activity of the pituitary gonadotropin hormones increases. 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, A61K 31/015, 2006.04.27). 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 enzyme 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, 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, an increase in overweight, obesity; infertility, ovarian dysfunction, early menopause, premature aging; immunity disorders, allergic reactions, cancer risk.

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 (www.microelements.ru/Mn) is an obstacle. 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, postmenopausal boron deficiency 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 boron and zinc metabolism. Sometimes boron is used to displace copper from the body (www.microelements.ru/B). Boron increases the sensitivity of cells to estrogens, 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 from bones and the discharge of their structure, helps maintain hormonal balance in the body, and 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 (“Foundation for Joint Health.” AMF No. 5, 2007, p.16.).

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, periodontal disease, 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. Organosilicon substances that can be dissolved and absorbed are the most biologically active. 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.medlibrari.ru/library/).

Magnesium is 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 - excess insulin in the blood, low potassium levels and narrowed blood vessels, lowering 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. Vitamins B ₁ , B ₆ , C, D ₃ , E, calcium, phosphorus (supplied in optimal amounts), protein, estrogens, in turn, increase 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 blood cholesterol , 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 disturbance, night sweats; headaches, dizziness; weakening of attention and ability to mental concentration; muscle pain, cramps, tics; heart pain, heart rhythm disturbances; high or low blood pressure; spasms of the stomach and intestines, esophagus, larynx, bronchi; increased reaction to weather changes; low body temperature, cold hands and feet; stones in the kidneys; premenstrual syndrome and painful periods; allergic reactions (Description of the drug Ortho Calcium + Magnesium, www.health-way.ru/index.php4?sID=166&iID=2724). A ratio of calcium and magnesium of 2: 1 ensures the best absorption of these minerals by the body and prevents their loss (Description of drugs, 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 minerals, neutralize toxins, nitrates. Another advantage of citrate is that it is included in the cell’s energy cycle (Krebs cycle), where it forms energy (Does 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 central place is the ratio of calcium and magnesium. 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 (Calcium-D ₃ Nycomed drug description, 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 occur 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”, RAMS Institute of Rheumatology, g . Moscow, Gynecology, Volume 11, Volume 5, 2005, www.consilium-medicum.com/media/gynecology/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 the 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.

They contribute to the absorption of calcium, in addition to vitamin D, lactose, hydrochloric acid, citric acid, phosphorus, magnesium (I. S. Chekman. "Calcium citrate-clinical-pharmacological activity", www.health-ua.com/articles/186.html) or a mixture thereof. The absorption of minerals occurs in the lumen of the small intestine by transporting cholecalciferol activated 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.

Ionized calcium penetrates all tissues well. It is excreted mainly with feces in the form of unabsorbed calcium, about 20% is excreted in the urine (I. S. Chekman. “Calcium citrate-clinical and pharmacological activity”, www.health-ua.com/articles/186.html). In order for calcium to get into the bones and not to be deposited, for example, in the vascular wall, pyridoxine, ascorbic acid, phytonadione, magnesium, zinc and manganese are needed (Description of the drug Orto Calcium + Magnesium, www.health-way.ru/index.php4?sID = 166 & iID = 2724).

A complex of vitamins - 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. S. Chekman. "Calcium citrate-clinical and 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 was 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 (Belhushet Sammy. “Preserving bone mass in osteoporosis is an easier task than restoring it.” Clinic No. 2, 2006, p. 56- 57, www.poliklin.ru/article200602a13.php).

Another source indicates that the absorption of calcium from citrate is 61% higher than from carbonate. In addition, it indicates that citrate provides assimilation of calcium regardless of the acidity of the gastric contents, which is important for patients with reduced secretory function of the stomach and for elderly patients with atrophic changes in the gastrointestinal tract, 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 (NP Arlauskas. “Evolution of views on the role of combined preparations of Ca and D ₃ in the prevention and treatment of osteop Orose, 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.consilium-medicum.com/media/gynecology/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 (in combination with vitamin D), 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 withdrawal, 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: 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). It promotes the absorption of calcium ions in the upper intestine. Being fermented, lactose maintains low pH in the intestine, which prevents the formation of insoluble calcium phosphorus salts (www.tiensmed.ru/articles/correctfeed11.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. 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 urinary 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.” Food and Nutrition Research Institute, 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 (Degtyareva I.I. et al. "Dufalac (lactulose): classic application and prospects for use in the treatment of chronic liver and intestinal diseases." Ukrainian Military Medical Academy, Kiev, “Suchas gastroenterology”, 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 the form of powder and syrup (“Characteristics”, www.solvay-pharma.ru/duphalac/article.aspx?id=722).

Considering the heterogeneity and multifactorial nature of the pathogenesis of osteoporosis, as well as the physiology of bone tissue, in which continuously related processes of bone resorption and bone formation occur throughout life, it seems appropriate to use drugs that affect different aspects of the bone remodeling process. In this case, schemes are applied both for the simultaneous long-term use of two or three drugs that affect bone resorption or bone formation, and their sequential appointment using a constant or intermittent treatment regimen.

Combined therapy of osteoporosis involves a combination of drugs that mutually weaken the negative effects on the body or bone tissue, as well as mutually reinforcing the effect on different parts of the pathogenesis of the disease. Complex therapy (or ADFR therapy) is based on the selective effect of the drugs used on resorbing or bone-forming cell populations. The goal of such therapy is to create a combination of a positive balance at the level of an individual remodeling unit and an increase at a tissue level of remodeling activity. Such a combination should contribute to the rapid increase in bone mass. This can be achieved, for example, by activating bone resorption and bone metabolism.

Below are some well-known variants of single drugs with different therapeutic effects, which are used in the treatment of osteoporosis. A single drug is characterized in that it contains one active substance and the target additive, for example, in the form of a filler.

Phosphate + bisphosphonate. In this case, phosphate and bisphosphonate are two mono-preparations with different therapeutic activity. Phosphate reduces the content of ionized calcium, which leads to the secretion of parathyroid hormone (PTH) and its activation. Phosphate is taken orally at an optimal daily dose of 1.4 g. Bisphosphonate (ethidronate) was used as a depressant. Against the background of this therapy, bone mass increased by 8.4% and the frequency of vertebral fractures decreased in comparison with the control group.

Phosphate + calcitonin. In this case, phosphate and calcitonin are two single drugs with different therapeutic activities. Phosphate reduces the content of ionized calcium, which leads to the secretion of parathyroid hormone (PTH) and its activation. Calcitonin is a hormone that causes a decrease in the content of calcium ions in the blood, which, inhibiting the absorption of calcium ions from bones, provides homeostasis and bone growth. Using this combination, phosphate at a dose of 1.5 g per day and calcitonin at 50 IU for five days every third week were used for 6 months. At the end of the study, an increase in bone mass was 36%. Resorptive and osteoid surfaces in biopsies increased by 60-80%.

Other regimes of complex treatment using monopreparations are also known: calcitriol + calcitonin; fluoride + calcium; calcitriol + fluoride + calcium.

Most often, active vitamin D metabolites are combined with calcitonin, fluoride, and bisphosphonates. Despite the different mechanism of action, fluorides and bisphosphonates used as monotherapy contribute to the development of mineralization defects. In this case, adding small doses of active metabolites of vitamin D to therapy prevents mineralization disorders of the newly formed osteoid (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/).

The combined administration of hormone replacement therapy (HRT) and bisphosphonates (ethidronate and alendronate) showed a significantly greater increase in bone mineral density (BMD) compared with monotherapy with any one drug. That is, the use of HRT and bisphosphonates gave a pronounced additive effect. An additive effect was also observed with the combined use of bisphosphonates (alendronate) and selective modulators of estrogen receptors (raloxifene) (V.V. Povoroznyuk. "Bisphosphonates: the role of ibandronic acid in the treatment of postmenopausal osteoporosis", //health-ua.com/print_articles.php? aid = 1681).

All monopreparations whose action is mainly aimed at inhibiting bone resorption (estrogens and substances of a similar effect, for example flavonoids, selective modulators of estrogen receptors (SMER); calcitonins, bisphosphonates, vitamin D preparations, androgens and anabolic steroids, thiazide diuretics), can support the existing bone mass and protect the architectonics of the cancellous bone, but are not able to significantly increase bone mass (N.V. Bunchuk. “Pharmacotherapy of osteoporosis.” Russian Medical cash, www.kuban.su/medicine/shtm/baza/rmj/97-4/4.htm).

Therefore, it is promising to use, together with these substances, substances that stimulate bone formation, for example, such as parathyroid hormone (PTH), growth hormone (STH, growth hormone), physiologically acceptable compounds of fluorine, silicon, strontium and aluminum, phosphates, ossein-hydroxyapatite complex (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library).

Known pharmaceutical composition for the treatment of osteoporosis, containing elements in the form of physiologically acceptable compounds of fluorine and calcium, for example, as part of the drug Tridine (description of the drug www.recipe.ru). One tablet of this preparation contains 5 mg of fluorine ion (in the form of 134.4 mg of glutamine monofluorophosphate), 150 mg of calcium (in the form of calcium gluconate hydrate and calcium citrate tetrahydrate) and a carrier. This composition accelerates the formation of cancellous bone tissue, and also contributes to the fixation of calcium in bone tissue and stimulates the formation of its mineral component.

However, this well-known pharmaceutical composition does not contain substances that enhance the complex therapeutic effect of the drug, for example, estrogens, SMER or bisphosphonates, which together with the mineral element - calcium - slow down bone resorption.

A known pharmaceutical composition for the treatment of osteoporosis based on the ossein-hydroxyapatite complex, for example, as part of the preparation Osteogenon. One tablet of the drug contains 291 mg of ossein, including non-collagen peptides and proteins - 75 mg and collagen proteins - 216 mg; hydroxyapatite - 444 mg, including 178 mg of calcium element and 82 mg of phosphorus element, the rest is a filler. With systemic osteoporosis, 2-4 tablets are prescribed 2 times a day; to accelerate the healing of fractures - 2 tablets 2-3 times a day, with other indications - 1-2 tablets per day. This composition has a stimulating effect on osteoblasts due to the organic (ossein) component and an inhibitory effect on osteoclasts due to inorganic calcium in the composition of hydroxyapatite (Instructions for the drug Osteogenon. Www.compendium.com.ua_info / -1241 / print / pierre_fabre / osteogenon).

Ossein-hydroxyapatite complex can be combined in the treatment of postmenopausal osteoporosis with other anti-osteoporotic monopreparations (estrogens, calcitonin, fluorine preparations, bisphosphonates). Ossein-hydroxyapatine complex does not reliably prevent bone fractures, therefore it is considered as an additional tool in the treatment and prevention of osteoporosis (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/). In addition, the well-known pharmaceutical composition based on the ossein-hydroxyapatite complex does not contain substances that expand the complex therapeutic effect of the drug, for example, estrogens, SMER or bisphosphonates, which together with the mineral element calcium helps slow down bone resorption, and substances that additionally accelerate bone formation tissues, for example fluorides.

The objective of the invention is the creation of a comprehensive pharmaceutical composition 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 for the prevention and comprehensive treatment of osteoporosis in women during menopause based on active substances that inhibit bone resorption, and active substances that stimulate bone formation, as well as components that enhance the therapeutic effect of active substances;

- slowing down the menopause and weakening 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 the active substances and 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 the active substances 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 proposes a pharmaceutical composition containing one active substance that enhances bone formation or reduces bone resorption, or several similar active substances mainly with different therapeutic effects, an elemental-vitamin complex including biogenic elements in the form of physiologically acceptable compounds that enhance the formation of bone tissue and reduce its resorption, and vitamins that enhance the therapist the natural effect of active substances and contributing to an increase in the formation of bone tissue and a decrease in its resorption, as well as a filler in the form of one substance or mixture of substances.

Biogenic elements - elements involved in the metabolic processes of the body.

The proposed pharmaceutical composition contains these components, for example, with the following amount in a daily therapeutic dose (g):

active substances 0,0005-10,3500 elemental vitamin complex 3.0-16.0 filler 0.2-20.0

The active substance, mainly contributing to the enhancement of bone formation, is the ossein-hydroxyapatite complex, or phytin, or fluorine, for example, in the form of monofluorophosphate, or their physiologically acceptable mixture with the following daily therapeutic dose of each of them (g):

ossein-hydroxyapatite complex 0.5-6.0 (containing calcium elemental 0.121-1.453 elemental phosphorus 0.056-0.656 fitin 0.25-2.00 monofluorophosphate 0.18-0.25 (containing fluorine elemental 0.015-0.020

The active substance that helps to preferentially reduce bone resorption is, for example, one or more synthetic or natural hormones, or a selective estrogen receptor modulator (SMER), or a bisphosphonate, or flavonoid, or an anabolic steroid, or a thiazide diuretic, or a physiologically acceptable mixture thereof with the following daily therapeutic dose of each of them (g):

hormone or mixture thereof 0,0005-0,2500 selective estrogen receptor modulator 0.03-0.60 bisphosphonate 0.002-0.400 flavonoid 0.1-0.6 anabolic steroid 0.001-0.050 thiazide diuretic 0,0005-0,2000

The elemental-vitamin complex includes calcium in the form of a physiologically acceptable compound, while the total calcium content in the daily therapeutic dose of the pharmaceutical composition, taking into account the calcium contained in the ossein-hydroxyapatite complex, is (g):

Calcium 0.1-1.5

In addition to calcium, the elemental-vitamin complex contains other elements that enhance the formation of bone tissue and reduce its resorption, in the form of physiologically acceptable compounds, for example, magnesium, or silicon, or boron, or zinc, or copper, or manganese, or their physiological an acceptable mixture with the following daily therapeutic dose of each of them (g):

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 Magnesium 0.05-0.80

The element-vitamin complex includes vitamins folic acid (vitamin B ₉ ), or cyanocobalamin (vitamin B ₁₂ ), or pyridoxine (vitamin B ₆ ), or ascorbic acid (vitamin C), or calcium pantothenate (vitamin B ₃ ), or riboflavin (vitamin B ₂ ), or cholecalciferol (vitamin D ₃ ), or phytonadione (vitamin K), or d-α-tocopherol (vitamin E), or retinol (vitamin A), or a mixture of them at the next daily therapeutic dose of each them (g):

folic acid 0.0002-0.0050 cyanocobalamin 0.00003-0.00040 pyridoxine 0.002-0.200 vitamin C 0.06-1.50 riboflavin 0.001-0.020 phytonadione 0.00006-0.0005 cholecalciferol 0.00001-0.00010 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002-0.020 retinol acetate 0.001-0.010

The pharmaceutical composition can be divided into two groups that take into account the mutual positive influence of the components and exclude their negative effect on each other, for example, with the following quantity in a daily dose, (g):

first group:

active substance or mixture thereof 0.0005-0.6500 folic acid 0.0002-0.0050 cyanocobalamin 0.00003-0.00040 pyridoxine 0.002-0.200 riboflavin  0.001-0.010 zinc 0.001-0.050

second group:

active substance or mixture thereof 0.0005-0.7000 vitamin C 0.06-1.50 phytonadione 0.00006-0.00050 cholecalciferol 0.00001-0.00010 d-α-tocopherol 0.01-0.20 calcium pantothenate 0.002-0.020 retinol acetate 0.001-0.010 copper 0.0005-0.0100 manganese 0.0002-0.0100 silicon 0.002-0.050 boron 0.001-0.014 magnesium 0.05-0.80 calcium 0.1-1.5

Moreover, as the active substance or mixture of active substances, the first group of components of the pharmaceutical composition contains a hormone or a mixture of hormones, or bisphosphonate, or a physiologically acceptable mixture thereof, and the second group of components of the pharmaceutical composition contains a selective modulator of estrogen receptors, or an anabolic steroid, or thiazide diuretic, or flavonoid, or ossein-hydroxyapatite complex, or phytin, or monofluorophosphate, or a mixture thereof.

The total elemental calcium content in the daily therapeutic dose of the second group of components, taking into account the elemental calcium contained in the ossein-hydroxyapatite complex, is (g) 0.1-1.5.

A filler is proposed that contains one or more substances that enhance the absorption of active substances, nutrients and vitamins in the body. This filler contains in the form of a mixture of lactose and lactulose, which contribute to the absorption of elements in the gastrointestinal tract, such as calcium, magnesium, zinc and copper, with a ratio of components in the mixture (wt.%):

Lactose 5.0-50.0 Lactulose rest

Disposable doses of the pharmaceutical composition are in the form of oral forms - tablets, capsules, sachets 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 distinguished by 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.

Currently, there are no known combination preparations for oral use (tablets, capsules, powders, suspensions) used for the prevention and treatment of primary and secondary osteoporosis in women, based on a pharmaceutical composition containing one active substance that enhances bone formation or reduces bone resorption , or several similar active substances mainly with different mechanisms of therapeutic effect, an elemental-vitamin complex, including components in the form of physical ecologically acceptable compounds that enhance the formation of bone tissue and reduce its resorption, and vitamins that enhance the therapeutic effect of active substances and help enhance the formation of bone tissue and reduce its absorption, as well as a filler in the form of a single substance or mixture of substances that enhance the absorption of active substances, nutrients and vitamins in the body.

The composition of the proposed comprehensive pharmaceutical composition, on the basis of which combined preparations for oral administration (tablets, capsules, powders, suspensions) are made, contains active substances having properties that made it possible to use them in the proposed pharmaceutical composition for the comprehensive prevention and treatment of osteoporosis.

Ossein-hydroxyapatite complex, which has a stimulating effect on osteoblasts due to the organic (ossein) component and an inhibitory effect on osteoclasts due to inorganic calcium in hydroxyapatites. It can be combined with estrogens, fluoride preparations, bisphosphonates, calcitonin.

Monofluorophosphate, increasing the population of osteoblasts, which leads to an increase in the mass of the cancellous bone and its density. The bioavailability of fluorine in monofluorophosphate preparations is stable and is 95%; side effects from the gastrointestinal tract are rarely observed (hydrofluoric acid does not form in the stomach); pharmacokinetic indicators are more stable (than sodium fluoride); does not interact in the intestine with food and calcium salts, which allows you to take them at the same time; in the treatment of osteoporosis, fluoride should be combined with calcium, magnesium and vitamin D.

Fitin, enhancing the growth and development of bone tissue.

Estrogens (together with gestogens), which, like endogenous hormones, reduce bone loss and reduce other menopausal disorders in women during menopause. Folic acid potentiates the action of estrogen. The combination of estrogen-progestogen drugs with bisphosphonates gives an additive effect, increasing the mineral density of bone tissue. They can be combined with the ossein-hydroxyapatite complex; It is recommended to be taken in combination with calcium preparations and it is not recommended to be taken in combination with selective modulators of estrogen receptors.

Selective estrogen receptor modulators that compete with endogenous estrogens for binding to estrogen receptors and can enhance or suppress the influence of estrogens, being agonists of estrogen receptors in relation to bone tissue, lipids and estrogen receptor antagonists in relation to the uterus and mammary glands. They reduce the process of bone resorption and lead to positive changes in the balance of calcium in the body, primarily due to a decrease in calcium loss in urine. They do not eliminate the vasomotor symptoms of menopause and urogenital disorders, do not have an anabolic effect. Their use with bisphosphonates gives an additive effect. When using them, it is recommended to take calcium preparations; they are not recommended to be taken in combination with estrogens.

Bisphosphonates, which inhibit bone resorption due to the affinity for hydroxyapatite, accumulate in the resorption sites and prevent bone destruction. They can be used in the joint therapy of postmenopausal osteoporosis with estrogens, calcium and vitamin D. Their main disadvantage is poor absorption in the digestive tract, which decreases with the simultaneous intake of food, calcium, food additives and other drugs containing polyvalent cations (for example, magnesium, manganese , iron, aluminum, etc.).

Flavonoids (e.g., ipriflavone), which have an estrogen-like property that are used in the treatment of postmenopausal osteoporosis, causing a growth effect. Although they increase the uterotropic activity of estrogens, they are devoid of estrogenic activity, they have a direct inhibitory effect on bone resorption, they stimulate collagen synthesis, as well as the growth and differentiation of clonal osteoblastic cells. In the treatment of postmenopausal osteoporosis, flavonoids are effectively combined with calcitonin and estrogen preparations.

Anabolic steroids, which, being derivatives of testosterone, have a direct effect on the proliferation of bone cells and the production of osteocalcin; reduce bone resorption and induce a positive calcium balance due to increased absorption of calcium from the intestines and calcium reabsorption by the kidneys. Their use is based on the fact that human osteoblasts have androgen receptors.

Thiazide diuretics, which have the ability to reduce urinary calcium excretion and increase calcium balance. Their effect on calcium metabolism is complementary to the direct effect of anti-osteoporotic drugs on bone resorption or intestinal absorption of calcium. They positively affect bone mass in the vertebrae and peripheral parts of the skeleton, and also reduce the frequency of hip fractures with prolonged use.

The therapeutic dose of the above active substances in the case of prevention is determined by the patient's predisposition to the disease, and in the case of treatment is determined by the severity of the disease.

The proposed complex 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, contains an element-vitamin complex, which includes the following elements and vitamins that enhance the formation of bone tissue and reduce its resorption:

- folic acid, which potentiates the action of estrogen, both endogenous and introduced into the body; together with cyanocobolamine and pyridoxine provides the basis for the normalization of collagen, and its effectiveness increases with their combined use; It has an estrogen-like effect, slowing the onset of menopause and easing its symptoms, which allows to reduce hormone intake during menopause replacement therapy; and also has a number of other above-mentioned properties, useful in the comprehensive prevention and complex treatment of menopausal disorders of the 1st, 2nd and 3rd groups, including menopausal osteoporosis; while estrogen replacement therapy leads to a strong deficiency of folic acid in the body;

- 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 comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups ;

- pyridoxine (vitamin B ₆ ), which helps to convert folic acid into its active form; contributes to the normalization of estrogen metabolism; it is necessary when using vitamin D ₃ , and also has a number of other above-mentioned properties that are useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups, including menopausal osteoporosis; while estrogen replacement therapy leads to a severe deficiency of pyridoxine in the body;

- riboflavin (vitamin B ₂ ), which, being a synergist of pyridoxine, is required for the interconversion of various forms of vitamin B ₆ , and its coenzymes play an important role in the conversion of pyridoxine and folic acid into their active coenzyme forms; and also necessary when using vitamin D ₃ ;

- ascorbic acid (vitamin C), which is involved in the metabolism of folic acid and in the synthesis of steroid hormones, catecholamines; improves the body's ability to absorb calcium and iron, removes toxic copper, lead and mercury; significantly increases the stability of vitamins B ₁ , B ₂ , A, E, pantothenic and folic acids; necessary when using vitamin D ₃ ; participates in the synthesis of collagen and procollagen, which provide the structure of muscles, vascular tissues, bones and cartilage, and also has a number of the above properties, useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups; it is advisable to use it together with vitamin E, since in the body they act synergistically, enhancing the effect of each other;

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

- cholecalciferol (vitamin D ₃ ), which affects the general metabolism during the metabolism of calcium and phosphate ions, stimulates the absorption of calcium, phosphates and magnesium from the intestine, contributes to the deposition of calcium in bone tissue, and also has a number of other properties mentioned above that are useful in complex prevention and complex treatment of menopausal disorders of the 1st, 2nd and 3rd groups; moreover, when treating with vitamin D _3, it is recommended to simultaneously take B vitamins, 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 above-mentioned properties, useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 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, takes part in the synthesis of vital compounds, such as hormones (for example, growth hormones, stress hormones and sex hormones), etc .; pantothenic acid is necessary for the normal absorption and metabolism of folic acid; and also has a number of other above-mentioned properties, useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups; while vitamin B ₁₂ promotes the inclusion of free pantothenic acid in coenzyme A, ascorbic acid reduces the severity of pantothenic acid deficiency; for the effective utilization of pantothenic acid, pyridoxine, folic acid and biotin are needed;

- retinol (vitamin A), which plays an important role in the synthesis of progesterone - a female sex hormone, is necessary for the development of cells of cartilage and bone tissue; reduces (mutually) the danger of hypervitaminosis with vitamin D, 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; to enhance its effectiveness, it must be taken simultaneously with tocopherol, in addition, with a low content of zinc in the body, it is poorly absorbed;

- zinc (a non-polyvalent microelement), for example, in the form of an amino acid chelate or citrate, which facilitates the absorption of calcium, is involved in bone tissue restoration during bone loss in people of old age, normalizes metabolic processes; promotes the absorption of vitamin E and maintaining a normal concentration of this vitamin in the blood; affects the activity of the hormones of the pituitary gland, adrenal glands and pancreas; enhances the activity of the pituitary gonadotropic hormones, 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, while it reduces the absorption of copper; calcium supplements can reduce zinc absorption by almost 50%;

- copper (polyvalent microelement), for example, in the form of an amino acid chelate, which is important for osteoporosis and diseases of the osteoarticular apparatus; necessary to improve hormonal levels in women; it is necessary for the production of collagen in the bones, it gives excellent results in the treatment of rheumatoid arthritis, and also has a number of other above-mentioned properties that are useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups; manganese, ascorbic acid are capable of reducing the absorption of copper; zinc (in moderate physiological doses) increases the absorption of copper by the body; while increased intake of zinc can lead to copper deficiency; in turn, copper can inhibit the body's absorption of zinc, vitamin A; hormonal agents contribute to enhanced excretion of copper from the body;

- Manganese (a polyvalent microelement), 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; participates in the exchange of thyroid hormones; provides the development of connective tissue, cartilage, bones; participates in the regulation of the exchange of vitamins C, E, group B, choline, copper; promotes the absorption of calcium in the body; It 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, while vitamins B, E, phosphorus and calcium in moderate amounts, zinc and vitamin A contribute to the absorption of manganese C, and an obstacle to assimilation is the excess intake of phosphorus and calcium ;.

- boron (a non-polyvalent microelement), for example, in the form of an amino acid chelate, which increases the natural level of estrogen and testosterone in women and the sensitivity of cells to estrogen, acts as a catalyst for chemical reactions due to which calcium is absorbed, prevents the leaching of calcium from bones, and 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, while it inhibits the absorption of ascorbino by the body oh acid, flavonoids, sulfur-containing amino acid, and insufficient amount of vitamin D deficiency increases the influence of boron on calcium metabolism, magnesium, phosphorus;

- silicon (a non-polyvalent microelement), for example, in the form of methylsilanotriolsilicate, which is necessary for the prevention and treatment of osteoporosis, as it serves as a binding agent between collagen and hydrolyzed amino acids, present in proteoglycans, and also has a number of other properties mentioned above, useful in complex prevention and complex treatment of menopausal disorders of the 1st, 2nd and 3rd groups;

- magnesium (a non-polyvalent element), 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, useful in complex prevention and complex treatment of menopausal disorders of the 1st, 2nd and 3rd groups;

- calcium (non-polyvalent element), 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 that are useful in the comprehensive prevention and treatment of menopausal violations of the 1st, 2nd and 3rd groups; moreover, cholecalciferol, lactose, lactulose, hydrochloric acid, citric acid, magnesium and phosphorus contribute to the absorption of calcium; 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 needed; ascorbic acid, 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 proposed elemental-vitamin complex, known elemental-vitamin complexes can be used containing most of the major vitamins and minerals listed above (folic acid, cyanocobalamin, pyridoxine, ascorbic acid, riboflavin, phytonadione, cholecalciferol, calcium tocopherol, pantant , calcium, zinc, copper, manganese, boron) for example, such as Osteo Complex (Description of the drug, www.dolgolet.ru/bad/bad-kosti-0,3 html); CentraViga (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 proposed 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, contains a filler that helps to increase the absorption and retention of calcium and magnesium in the body. , zinc and copper.

Such a filler is a mixture of lactose and lactulose with a ratio of components in the mixture (wt.%):

Lactose 5.0-50.0 Lactulose rest

As mentioned above, lactose and lactulose contribute to the absorption of calcium in the intestine. 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 selected ratio of the components of the filler ensures the flowability of the mixture is approximately 10 times higher than that of lactulose powder, while reducing hygroscopicity, which is important in the manufacture of solid oral forms 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 proposed pharmaceutical composition can be used for the manufacture of oral forms, such as powders, tablets, capsules, as well as suspensions. Moreover, the composition of the composition includes active substances having a predominantly different mechanism of therapeutic effect.

The most promising is the use of the proposed pharmaceutical composition in solid oral form in the form of capsules than in the form of tablets, 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, the 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, by direct encapsulation of a mixture of powders, further reduces the manufacturing cost due to its economy, since additional equipment for granulation is not required, energy consumption is reduced, and labor productivity is increased.

In addition, the proposed pharmaceutical composition in capsules has a higher bioavailability in comparison with the bioavailability of the same pharmaceutical composition in tablets.

Higher bioavailability due to the fact that the capsules swell quickly and dissolve in the gastrointestinal tract. Biopolymer, for example 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 gerontology than tablets.

Oral preparations based on the proposed pharmaceutical composition can provide the following.

1. Prevention and comprehensive treatment of osteoporosis in women during menopause due to the therapeutic properties of the active substances that make up the composition.

2. Prevention and treatment of menopausal disorders of the 1st, 2nd and 3rd groups by enhancing the production and potentiation of the action of endogenous 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. In this case, cyanocobalamin in the composition increases the effectiveness of folic acid; pyridoxine promotes the conversion of folic acid into an active form and normalizes estrogen metabolism; ascorbic acid is involved in the metabolism of folic acid and the synthesis of estrogen, and also enhances the stability of folic acid; riboflavin coenzymes contribute to the conversion of folic acid into its active coenzyme forms.

3. Prevention and treatment of menopausal disorders of the 1st, 2nd and 3rd groups by increasing the therapeutic activity of the active substances introduced into the body - estrogens in the presence of folic acid and components that enhance its effectiveness - cyanocobalamin, pyridoxine, ascorbic acid and riboflavin .

4. 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).

5. 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.

6. Reducing 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 absorption of which ascorbic acid, cholecalciferol, tocopherol, phytonadione, pyridoxine, zinc and manganese are required , lactose and lactulose.

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

8. Reducing the risk of cancer of the myometrium, endometrium, breast, ovary, colon, colon, larynx, esophagus, bladder, brain, and leukemia due to the oncoprotective properties of folic acid, ascorbic acid, cholecalciferol, retinol, lactulose.

9. Improving the digestive tract due to the properties of folic acid, pantothenic acid, magnesium, calcium, in the form of citrate, lactulose.

10. Strengthening patients' predisposition to prevention and treatment through the use of complex drugs in one dosage form.

The implementation of the invention is illustrated by the following examples, but is not limited to.

Example 1

Dosage powders of the pharmaceutical composition based on the ossein-hydroxyapatite complex, monofluorophosphate, flavonoid (ipriflavone) and vitamin-mineral complex with physiologically acceptable compounds of elements and vitamins, as well as an excipient, 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 powders of the active substances with other components, using the method of trituration, with the mandatory control of heterogeneity of the mass.

4. Dose the prepared mass in bags (sachets) and seal them, obtaining a preparation of the following composition.

Components included in one package Component weight g % Ipriflavone 0.2 4.0 folic acid 0,0003 0.0060 cyanocobalamin 0.00003 0,00060 pyridoxine 0.004 0,080 vitamin C 0.1 2.0 phytonadione 0.00006 0.00120 riboflavin 0.003 0,060 cholecalciferol 0.00001 0,00020 d-α-tocopherol 0,03 0.60 calcium pantothenate 0.003 0,060 retinol acetate 0.002 0,040 zinc 0.006 0,120 copper 0.002 0,040 manganese 0,0006 0.0120 boron 0.005 0,100 silicon 0.004 0,080 disodium monofluorophosphate 0.08 1,60 ossein-hydroxyapatite complex 1.5 (0.363 elem. Ca and 0.167 elem. P) 30,0 calcium citrate tetrahydrate 0.68 (0.144 elem. Ca) 13.60 magnesium citrate tetrahydrate 0.9 (0.125 elem. Mg) 18.0 lactose 0.35 7.00 lactulose (powder) 1.13 22.6 weight of bag contents 5,0 100.0

According to this technology, 600 pieces of sealed packages of powders have been accumulated.

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

Example 2

Dosage powders of a pharmaceutical composition based on the ossein-hydroxyapatite complex, phytin, a selective modulator of estrogen receptors (raloxifene), flavonoid (ipriflavone) and an elemental-vitamin complex with physiologically acceptable compounds of elements and vitamins, as well as an excipient, are prepared as described in example 1, obtaining drug of the following composition.

Components included in one package Component weight g % raloxifene 0.05 1.00 Ipriflavone 0.1 2.0 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 0,040 cholecalciferol 0.00001 0,00020 d-α-tocopherol 0.02 0.40 calcium pantothenate 0.003 0,060 retinol acetate 0.002 0,040 zinc 0.007 0.140 copper 0,0005 0,0100 manganese 0,0002 0.0040 boron 0.003 0,060 silicon 0.008 0.160 ossein-hydroxyapatite complex 1.0 (0.24 elem. Ca) 20,0 fitin 0.5 10.0 magnesium citrate tetrahydrate 0.86 (0.12 elem. Mg) 17,20 lactose 0.6 12.0 lactulose (powder) 1.79 35.80 weight of bag contents 5,0 100.0

According to this technology, 600 pieces of sealed packages of powders have been accumulated.

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

Example 3

Two groups of metered powders of a pharmaceutical composition based on bisphosphonate (alendronate), flavonoid (ipriflavone), disodium salt monofluorophosphate, an element-vitamin complex, and an excipient are made according to the following scheme: the first two stages of the process are performed as described in Example 1. Then, the mass is prepared each group by mixing the powders of the components of each group, using the method of trituration, with the mandatory control of mass heterogeneity. Dose the prepared mass of each group in bags (sachets) of different colors and seal them.

The components of the first group that are part of one bag (red) Component weight g % alendronate 0.01 2.00 folic acid 0,0008 0.1600 cyanocobalamin 0,0002 0,0400 pyridoxine 0.004 0,800 riboflavin 0.003 0,600 zinc 0.002 0.400 lactose 0.12 24.00 lactulose 0.36 72.00 the mass of the contents of the red bag 0.5 100.00

According to this technology, 600 pieces of sealed powder bags with a mixture of the components of the first group indicated in the table have been accumulated.

The mass of the dosed powders of the first group is 0.5 g ± 5%, which corresponds to HF XI (st. Powders). The daily dose is 1 packet. Take at least 60 minutes before taking the components of the second group, taking other medicines or food. When taking a dose of the drug, it is recommended to mix in 50-100 ml of drinking water.

The components of the second group, which are part of one bag (yellow) Component weight g % Ipriflavone 0.15 3.00 disodium monofluorophosphate 0.06 1.20 vitamin C 0.05 1.00 phytonadione 0.00009 0.00180 cholecalciferol 0.00001 0,00020 d-α-tocopherol 0.02 0.40 calcium pantothenate 0.003 0,060 retinol acetate 0.003 0,060 copper 0,0006 0.0120 manganese 0,0003 0.0060 boron 0.003 0,060 silicon 0.01 0.20 magnesium citrate tetrahydrate 0.9 (0.125 elem. Mg) 18.00 calcium citrate tetrahydrate 1.2 (0.25 elem. Ca) 24.00 lactose 0.65 13.00 lactulose 1.95 39.00 the mass of the contents of the yellow bag 5,0 100.0

600 pieces of sealed bags with a mixture of the components indicated in the table were developed using this technology. The mass of dosed powders of the second group is 5 g ± 3%, which corresponds to GF XI (st. Powders). The dose of the drug of the second group is recommended to be taken no less than 60 minutes after taking the dose of the drug of the first group. The daily dose is 4 packets 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.

Example 4

A suspension with the proposed pharmaceutical composition based on a mixture of the active substances of a selective modulator of estrogen receptors (raloxifene), disodium salt monofluorophosphate, an element-vitamin complex, and also an excipient is made 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. Mix the components (powders), 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.

Components Single dose suspension One bottle Percentage g g % raloxifene 0.1 2.5 0.5 folic acid 0,0004 0,0100 0.002 cyanocobalamin 0.00006 0.00150 0,0003 pyridoxine 0.001 0,025 0.005 vitamin C 0.54 13.50 2.7 phytonadione 0.00012 0.00300 0,0006 riboflavin 0.0012 0,0300 0.006 water soluble cholecalciferol 0.00002 0,00050 0.0001 d-α-tocopherol 0.016 0.400 0.08 calcium pantothenate 0.0016 0,0400 0.008 zinc 0.0016 0,0400 0.008 copper 0.0016 0,0400 0.008 manganese 0,0004 0,0100 0.002 boron 0.006 0.150 0,03 silicon 0.01 0.25 0.05 disodium monofluorophosphate 0.12 3.00 0.6 magnesium citrate tetrahydrate 2.6 (0.375 cells 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

100 vials of the proposed pharmaceutical composition have been accumulated.

The deviation of the content of raloxifsn in 1 g of a suspension of 0.005 g ± 10%, of disodium monofluorophosphate is 0.006 g ± 10%, which corresponds to the requirements of Global Fund XI (Art. Suspensions). The daily dose of the suspension is 2 times 20 grams. When taking a dose of the drug, it is recommended to stir in at least 100 ml of drinking water.

Example 5

Two groups of tablets from a pharmaceutical composition based on estrogen (estradiol valerate), ossein-hydroxyapatite complex, flavonide (ipriflavone), disodium salt monofluorophosphate, an elemental-vitamin complex with components that enhance the therapeutic effect of active substances, and a filler are made as described in Example one.

The components of the first group, which are part of one tablet, yellow-orange Component weight g % estradiol valerate 0.001 0.4 folic acid 0,0008 0.32 cyanocobalamin 0,0002 0.08 pyridoxine 0.004 1,6 riboflavin 0.003 1,2 zinc 0.001 0.4 lactose 0.06 24.0 lactulose 0.18 72.0 weight of one tablet 0.25 100.0

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

The disintegration of the obtained tablets is not more than 15 minutes, the weight of the tablets is 0.25 g ± 7.5%, the drug content is 0.001 g ± 15%, the dosage uniformity is 0.001 g ± 15%, which corresponds to GF XI (st. Tablets).

The daily dose of the first group of tablets is 1-2 tablets per day.

The components of the second group, which are part of one pink tablet Component weight g % Ipriflavone 0.15 15.0 vitamin C 0.1 10.0 phytonadione 0.00009 0.009 cholecalciferol 0.00001 0.001 d-α-tocopherol 0,03 3.0 calcium pantothenate 0.004 0.4 retinol acetate 0.002 0.2 copper 0.002 0.2 manganese 0,0009 0.09 boron 0.003 0.3 silicon 0.008 0.8 disodium monofluorophosphate 0.08 8.0 ossein-hydroxyapatite complex 0.3 (0.072 elem. Ca) 30,0 lactose 0.08 8.0 lactulose (powder) 0.24 24.0 tablet mass 1,0 100.0

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

The disintegration of the obtained tablets is not more than 15 minutes, the weight of the tablets is 1.0 g ± 5%, the deviation of the drug content of ipriflavone 0.15 g ± 5%, disodium monofluorophosphate 0.08 g ± 7.5%, which corresponds to GF XI (Art. . Pills). The daily dose of the second group of tablets is 4 tablets.

Example 6

Two groups of capsules from a pharmaceutical composition based on estrogen (estradiol) and progesterone (dydrogesterone), flavonoid (ipriflavone), a thiazide diuretic (hydrochlorothiazide), disodium salt monofluorophosphate, an element-vitamin complex, as well as an excipient that promotes the absorption of the elements, are made, three stages, as described in Example 1. Then, the prepared mass in the form of a mixture of powders for each group is encapsulated in hard gelatin capsules No. 3 for the first group and No. 00 for the second group with compaction to mass 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, obtaining capsules of the pharmaceutical composition of the following composition.

The components of the first group, which are part of one capsule (green) Component weight g % estradiol 0.001 0.4 dydrogesterone 0.005 2.0 folic acid 0,0004 0.16 cyanocobalamin 0.0001 0.04 pyridoxine 0.002 0.8 vitamin C 0.05 20,0 riboflavin 0.001 0.4 copper 0,0004 0.16 manganese 0.0001 0.04 lactose 0.05 20,0 lactulose 0.14 5,0 weight of mixture in green capsule 0.25 100.0

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

The disintegration of the obtained capsules with the components of the first group is less than 20 min, the content of estradiol medicinal substances is 0.001 g ± 15%, dydrogesterone is 0.005 g ± 10%, the dosage uniformity of estradiol is 0.001 g ± 15%, and dydrogesterone is 0.005 g ± 15%, which meets the requirements of GF XI (v. Capsules).

The daily dose of the first group of capsules is 2 capsules.

The components of the second group, which are part of one capsule (yellow) Component weight g % hydrochlorothiazide 0,025 2.5 Ipriflavone 0,075 7.5 phytonadione 0.000035 0.0035 vitamin C 0,03 3.0 cholecalciferol 0.000005 0,0005 d-α-tocopherol 0.004 0.4 calcium pantothenate 0,0004 0.04 retinol acetate 0.001 0.1 zinc 0,00046 0,046 boron 0.0015 0.15 silicon 0.0026 0.26 disodium monofluorophosphate 0,03 3.0 magnesium citrate tetrahydrate 0.3 30,0 calcium citrate tetrahydrate 0.4 40,0 lactose 0,03 3.0 lactulose 0.1 10.0 weight of mixture in yellow capsule 1,0 100.0

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

The disintegration of the obtained capsules with the components of the second group is less than 20 minutes, the content of medicinal substances is hydrochlorothiazide 0.025 g ± 7.5%, ipriflavone 0.075 g ± 7.5%, disodium monofluorophosphate 0.03 g ± 7.5%, the dosage uniformity of hydrochlorothiazide 0.025 g ± 15%, disodium salt monofluorophosphate 0.03 g ± 15%, which meets the requirements of GF XI (st. Capsules). Capsules of the second group of components are taken no less than 60 minutes after taking the capsules of the first group of components. The daily dose of the second group of capsules is 4-8 capsules.

Example 7

Two groups of capsules from a pharmaceutical composition based on bisphosphonate (alendronate), anabolic steroid (oxandrolone), flavonoid (ipriflavone), disodium salt monofluorophosphate, an element-vitamin complex, as well as an excipient are made by performing the first 3 stages, as described in Example 1. Then the prepared mass in the form of a mixture of powders for each group is encapsulated in No. 1 hard gelatine capsules for the first group and No. 00 for the second group with compaction to a mass of 0.5 g ± 10% for the first group in each capsule and compaction to 1.0 g 10% for the second group in each capsule. In this case, capsules of an oral drug preparation are obtained from the proposed pharmaceutical composition of the following composition.

The components of the first group, which are part of one capsule (green) Component weight g % alendronate 0.01 2.00 folic acid 0,0008 0.1600 cyanocobalamin 0,0002 0,0400 pyridoxine 0.004 0,800 riboflavin 0.003 0,600 zinc 0.002 0.400 lactose 0.12 24.00 lactulose 0.36 72.00 weight of mixture in green capsule 0.5 100.0

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

The disintegration of the obtained capsules with the components of the first group is less than 20 minutes, the content of the drug substance alendronate is 0.01 g ± 7.5%, the dosage uniformity is 0.01 g ± 15%, which meets the requirements of GF XI (Art. Capsules). The daily dose of the first group of capsules is 1 capsule.

Take at least 60 minutes before taking the capsules of the second group, other drugs or food.

The components of the second group, which are part of one capsule (yellow) Component weight g % oxandrolone 0.001 0,100 Ipriflavone 0,075 7.5 phytonadione 0.000035 0.003500 vitamin C 0.05 5.00 cholecalciferol 0.000005 0,000500 riboflavin 0.002 0,200 d-α-tocopherol 0.005 0,500 calcium pantothenate 0.0014 0.1400 retinol acetate 0.001 0,100 copper 0,00046 0,04600 manganese 0.0001 0,0100 boron 0.001 0,100 silicon 0.003 0,300 disodium monofluorophosphate 0,03 3.00 magnesium citrate tetrahydrate 0.3 30,0 calcium citrate tetrahydrate 0.4 40,0 lactose 0,03 3.00 lactulose 0.1 10.0 weight of mixture in yellow capsule 1,0 100.0

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

The disintegration of the obtained capsules with the components of the second group is less than 20 min, the content of the drug substances of oxandrolone is 0.001 g ± 15%, ipriflavone is 0.075 g ± 7.5%, disodium monofluorophosphate is 0.03 g ± 7.5%, the dosage uniformity of oxandrolone is 0.001 g ± 15%, disodium salt monofluorophosphate 0.03 g ± 15%, which meets the requirements of GF XI (st. Capsules). Capsules of the second group of components should be taken no less than 60 minutes after taking the capsules of the first group of components.

The daily dose of the second group of capsules is 4-8 capsules.

Example 8

Two groups of capsules of a pharmaceutical composition based on bisphosphonate (alendronate) are made by performing the first three stages, as described in Example 1. Then, the prepared mass in the form of a mixture of powders for each group is encapsulated in hard gelatin capsules No. 1 for the first group and No. 00 for the second group with compaction to a mass of 0.5 g ± 10% for the first group in each capsule and compaction to 1.0 g ± 10% for the second group in each capsule. Capsules of an oral medicament are prepared from the proposed pharmaceutical composition of the following composition.

The components of the first group, which are part of one capsule (green) Component weight g % alendronate 0.01 2.00 folic acid 0,0008 0.1600 cyanocobalamin 0,0002 0,0400 pyridoxine 0.004 0,800 riboflavin 0.003 0,600 zinc 0.002 0.400 lactose 0.12 24.00 lactulose 0.36 72.00 weight of mixture in green capsule 0.5 100.0

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

The disintegration of the obtained capsules with the components of the first group is less than 20 minutes, the content of alendronate is 0.01 g ± 7.5%, the dosage uniformity is 0.01 g ± 15%, which meets the requirements of GF XI (Art. Capsules). The daily dose of the first group of capsules is 1 capsule. Take at least 60 minutes before taking the capsules of the second group, other drugs or food.

The components of the second group, which are part of one capsule (yellow) Component weight g % raloxifene 0,035 3,500 Ipriflavone 0,075 7,500 phytonadione 0.000035 0.003500 vitamin C 0,045 4,500 cholecalciferol 0.000005 0,000500 riboflavin 0.002 0,200 d-α-tocopherol 0.006 0,600 calcium pantothenate 0.0014 0.1400 retinol acetate 0.001 0,100 copper 0,00046 0,04600 manganese 0.0001 0,0100 boron 0.001 0,100 silicon 0.003 0,300 disodium monofluorophosphate 0,03 3.00 magnesium citrate tetrahydrate 0.2 20,0 calcium citrate tetrahydrate 0.4 40,0 lactose 0.05 5.00 lactulose 0.15 15.0 weight of mixture in yellow capsule 1,0 100.0

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

The disintegration of the obtained capsules with the components of the second group is less than 20 min, the content of the medicinal substance raloxifene 0.035 g ± 7.5%, ipriflavone 0.075 g ± 7.5%, disodium monofluorophosphate 0.03 g ± 7.5%, uniformity of dosage of raloxifene 0.035 g ± 15%, disodium salt monofluorophosphate 0.03 g ± 15%, which meets the requirements of GF XI (st. Capsules). Capsules of the second group of components should be taken no less than 60 minutes after taking the capsules of the first group of components. The daily dose of the second group of capsules is 4-8 capsules.

The combination of components in the proposed pharmaceutical composition ensures the achievement of the technical, including synergistic effect of the combined preparations based on the proposed pharmaceutical composition, which consists in the following:

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

- slowing down the menopause and weakening 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 the active substances and 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 the active substances 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.

Despite the apparent simplicity of the proposed solution to the problem, a similar solution has not yet been proposed,

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 can be recommended for use in serial production in the pharmaceutical production of oral preparations for the prevention and treatment of menopausal osteoporosis in women.

Claims (6)

1. A pharmaceutical composition for the prevention and treatment of osteoporosis in women during menopause, comprising at least one substance selected from the series: an active substance that reduces bone resorption, including bisphosphonate or a hormone, or an active substance that stimulates bone formation, or their mixture, vitamins and a filler, characterized in that it additionally contains at least one active substance that reduces bone resorption, selected from a number of substances, mainly with different mechanisms of action: a selective modulator of estrogen receptors, flavonoid, a thiazide diuretic, estrogen or an anabolic streroid as a hormone, or a physiologically acceptable mixture thereof, and, if necessary, it additionally contains at least one active substance that stimulates bone formation, while substances that stimulate bone formation, selected from the series: ossein-hydroxyapatite complex, phytin, monofluorophosphate or sodium fluoride, or a physiologically acceptable mixture thereof, and it also contains elements forming with itamines, a vitamin-mineral complex, with the following content of components in the daily therapeutic dose of the composition (g):
active substances 0.0005-10.35 vitamin and mineral complex 3.0-16.0 filler 0.2-20.0 2. The pharmaceutical composition according to claim 1, characterized in that in the composition of the vitamin-mineral complex it contains at least one substance selected from the series: calcium, magnesium, silicon, boron, zinc, copper, manganese, folic acid, cyanocobalamin, pyridoxine, ascorbic acid, calcium pantothenate, riboflavin, cholecalciferol, phytonadione, da-tocopherol, retinol acetate or a physiologically acceptable salt thereof. 3. The pharmaceutical composition according to claim 1, characterized in that the oral form is in the form of a suspension in which the mixture of active substances and components of the vitamin-mineral complex is homogenized in lactulose syrup, while the lactulose syrup is a monofiller or one of the excipient components. 4. A pharmaceutical combination for the prevention and treatment of osteoporosis in women during menopause, including at least one substance selected from the series: an active substance that reduces bone resorption, including bisphosphonate or a hormone, or an active substance that stimulates bone formation, or their mixture, vitamins and a filler, characterized in that it additionally contains at least one active substance that reduces bone resorption, selected from a number of substances, mainly with different mechanisms of action: a selective modulator of estrogen receptors, flavonoid, a thiazide diuretic, estrogen or an anabolic streroid as a hormone, or a physiologically acceptable mixture thereof, and, if necessary, it additionally contains at least one active substance that stimulates bone formation, while substances that stimulate bone formation, selected from the series: ossein-hydroxyapatite complex, phytin, monofluorophosphate or sodium fluoride, or a physiologically acceptable mixture thereof, and it also contains elements forming with itamines, a vitamin-mineral complex, with the following content of components in the daily therapeutic dose of the composition (g):
active substances 0.0005-10.35 vitamin and mineral complex 3.0-16.0 filler 0.2-20.0
at the same time, it contains these components in the form of two compositions, which take into account the mutual positive influence of the components and the negative effect on each other that excludes them. 5. The pharmaceutical combination according to claim 4, characterized in that in the composition of the vitamin-mineral complex it contains at least one substance selected from the series: calcium, magnesium, silicon, boron, zinc, copper, manganese, folic acid, cyanocobalamin, pyridoxine, ascorbic acid, calcium pantothenate, riboflavin, cholecalciferol, phytonadione, da-tocopherol, retinol acetate or a physiologically acceptable salt thereof. 6. The pharmaceutical combination according to claim 4, characterized in that the oral form is in the form of a suspension in which the mixture of active substances and components of the vitamin-mineral complex is homogenized in lactulose syrup, while the lactulose syrup is a monofiller or one of the excipient components.