RU2363461C2 - Pharmaceutical preparation for external and local application, based on sygethin - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicinal agents, particularly to pharmaceutical compositions for local and external application during menopausal disorders, containing sygethin, a base, target additive, with the following ratio of components (wt %): sygethin - 0.001-2.0; target additive - 0.000001-42.6; base - the rest. The base is in form of hydrophilic and/or hyperosmolar substances and the target additive is in form of substances chosen from: vitamins, biogenic elements, antioxidants or their physiologically acceptable mixture.

EFFECT: wide area of application of known sygethin preparation, increased bioavilability of the preparation without violating integrity of the skin; intense therapeutic effect of sygethin.

5 cl, 18 ex

Description

The invention relates to the chemical-pharmaceutical industry and medicine and can be used in the prevention and treatment of menopausal disorders, namely, liquid and soft dosage forms of the sigetin preparation.

The end of the reproductive period in women is associated with a significant decrease, and then cessation of ovarian function. As a result, the female body has been functioning for several years in a state of constantly changing endocrine status, ending with a transition to a new hormonal homeostasis, which differs sharply from that at fertile age. This transition is characterized by a deficiency of estrogen and progesterone with a relative predominance of androgens. With a deficiency of sex hormones, menopausal disorders can occur, which are divided into three groups:

Group 1 - early symptoms. Vasomotor: hot flashes, sweating, palpitations, hypertension. Psycho-emotional: insomnia, depression, irritability, weakening of memory, headaches, decreased libido.

Group 2 - medium-term symptoms. Urogenital disorders: dryness, itching and burning in the vagina, pain, urethral syndrome, cystalgia, urinary incontinence. Trophic skin changes: dryness, wrinkles, brittle nails, dryness and hair loss.

Group 3 - late symptoms. Metabolic disorders: cardiovascular disease, postmenopausal osteoporosis, Alzheimer's disease.

The treatment and prevention of menopausal disorders is hormone replacement therapy (HRT). One of the most promising at present is the parenteral administration of hormonal drugs in HRT. For example, Estrozhel hydroalcoholic gel is known, which is used for transdermal administration of 17β-estradiol in HRT in various age periods of women. Estradiol, applied to the skin surface in an alcoholic solution, diffuses into the epidermis, dermis and vascular network for several minutes. It is important that part of estradiol enters the capillary network within a few hours, and part of the hormone is deposited in subcutaneous fat and, gradually getting into the bloodstream, contributes to the stability of estradiol in blood plasma. An advantage when using the drug Ostrozhel is the great variability of the possibilities of applying the drug without compromising bioavailability, which creates the opportunity for women not to fix their attention on the area of application of the drug (//medi.ru/doc/181802.htm).

In some cases, in the treatment of menopausal disorders, there are absolute contraindications to HRT, for example, severe diabetes mellitus, uterine bleeding of unknown origin, acute hepatitis, and others. Relative contraindications for HRT are uterine fibroids, endometriosis, venous thrombosis, and history of embolism, migraine, gall, disease, etc. Side effects of HRT include breast engorgement, decrease or increase in body weight, pastiness, fluid retention, headaches.

In this case, sigetin can be used, which is used in the treatment of menopausal disorders, as well as in post-variectomy syndrome (after surgical removal of the ovaries, radiation therapy), especially in the presence of absolute and relative contraindications to HRT, as well as in case of women refusing to use HRT (V. D .Zabelina “Menopause: how to live with it?” CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www.consilium-medicum.com/media/provisor/03_07/29.shtml).

Sighetin (dipotassium salt of meso-4,4 '- (1,2-diethylene) dibenzosulfonic acid dihydrate) is a synthetic analogue of sinestrol (MD Mashkovsky. "Medicines". T.2, p. 47. Kharkov, "Torgsin" , 1998), which is a synthetic drug with the properties of the female sex hormone estrone (folliculin) (http://deb.telenet.ru/know/Drug929.shtml). Meso-4,4 '- (1,2-diethylene) dibenzosulfonic acid dipotassium salt is slightly soluble in water (1:50), easily soluble in hot water, insoluble in alcohol, has a molecular weight of 510.7 g / mol (FSP 42 -0416279602). Sighetin has a terotonizing effect ("The Register of Medicines of Russia", Encyclopedia of Medicines. Annual collection. Issue 9. 2002, p. 763).

Sigetin is effectively used in the complex treatment of menopausal syndrome of varying severity: 92.59% of cases of positive effects in menopausal syndrome of moderate severity and 86.79% in severe cases (M.V. Andreeva et al. “The effectiveness of the drug sagenite in complex treatment climacteric syndrome of varying severity. ”Medicinal Bulletin No. 8, 2006 www.volgmed.ru/publishing/lv/about/php).

Sighetin is structurally close to sinestrol, but replacing the phenolic rings of hydroxyl radicals with sulfocassium or sodium groups provides very significant changes in the properties of cigetin compared with sinestrol: there is no carcinogenic effect on the myometrium and mammary glands. Taking the drug lowers cholesterol and triglycerides (V.D. Zabelina. “Menopause: how to live with it?” CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www.consilium-medicum.com/media/provisor/03_07/29. shtml), increases the concentration of beta-lipoproteins in the blood, improves glucose utilization, insulin sensitivity, stimulates tissue metabolism, has a lipid-lowering effect (Drug Reference, www.recipe.ru/docs/ls/index.php?action=descr -drug-able & filter = bysearch & filter_param = sigetin & drugid = 11166).

The use of cigetin in oral form leads to a significant weakening of climacteric disorders (sweating, flushing, sleep disorders, irritability, depression, weakening of memory, headache, decreased libido, etc.) (V.D. Zabelina. “Menopause: how to live with it? »CONSILIUM-PROVISORUM: Volume 03 / N7 / 2003, www.consiliuim-medicllm.com/media./provisor/03_07/29.shtml). In addition, sigetin significantly reduces trophic changes in the skin, such as dryness, wrinkles, brittle nails, dryness and hair loss, and also reduces urogenital disorders, such as dryness of the mucous membranes of the urogenital system, urethral syndrome, cystalgia, etc., characteristic of menopause syndrome.

The well-known oral drug with the generic name “Sigetin” (trade name “Sagenit”) is available in the form of tablets with an active substance content of 0.1 g (FS 42-1805-88). This drug has the following properties.

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

Indications: menopause and menopause in women; menopause disorders and other disorders in the perimenopausal period, manifested by hot flashes, sweating, sleep disturbance, irritability, depression, forgetfulness, degenerative changes in the skin and mucous membranes (brittle nails, thinning of the skin, wrinkles, dry mucous membranes of the urogenital tract), etc. (Instructions on the use of sigetin tablets www.regmed.ru/InstrShow2.asp?InstrLinkNx=a16ba19ba15ba10b).

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

The interaction potentiates the action of hypocholesterolemic agents, diuretics, antiarrhythmic antihypertensive drugs, anticoagulants; weakens the effects of male sex hormones; folic acid, thyroid preparations enhance the action of cigetin (Drug Reference. www.recipe.ru/docs/ls/mdex.php?action=descr-drug-able&filter=bysearch&filter_param = sigetin & drugid = 11166).

Dosage: for menopausal disorders, women are prescribed by mouth 0.05-0.1 g (regardless of the time of eating), a daily dose of 0.1-0.2 g, the course of treatment is 30-40 days. (Instructions for use of the sigetin tablets are www.regmed.ru/InstrShow2.asp?InstrLinkNx=a16ba19ba15ba10b).

The drug enhances uterine contractions during childbirth, improves placental circulation. Sigetin is used in the form of a 1% solution to accelerate labor, prevent and treat fetal asphyxiation. In the form of a 1% aqueous solution, sigetin is administered in 1-2 ml intramuscularly or intravenously for 10 days and in the last week of pregnancy 3-4 ml for the prevention of intrauterine threatening fetal asphyxiation. If there are signs of a threatening or intrauterine asphyxiation of the fetus, the woman in labor is injected intravenously with 2-4 ml of a 1% sigetin solution (preferably in 20-40 ml of a 20% glucose solution). Injections can be repeated after 30-60 minutes no more than 5 times (www.medicum.nnov.ru/home/drugs/932.php). Sighetin 1% solution of 4 ml intravenously per 200 ml of 5% glucose solution No. 5 is used in therapeutic measures for immunoconflict pregnancy (//med-stud.narod.ru/nature/akush/rh-cobflict.html). In case of miscarriage in case of hormonal disorders, sigetin with glucose is prescribed together with other drugs //bobych.ru/referat/50/10401/1.html). In case of fetoplacental insufficiency, sigetin is prescribed together with other drugs to improve metabolism in the placenta (www.provisor.com.ua/archive/2005/N3/art_29.htm).

In medical practice, the use of sigetin injection for the treatment and prevention of menopausal disorders is not practiced because of the need for daily intramuscular or intravenous painful injections.

After oral administration, sigetin is absorbed in the gastrointestinal tract, enters the portal bloodstream with a maximum concentration of approximately 16 μg / ml and, after passing through the liver, into the general circulatory system, which is distributed to organs and tissues of the body, including those with target cells with estrogen receptors.

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

In this case, positive changes in the hormonal profile occur, in particular, the content of estradiol and progesterone in the blood serum increases significantly (M.V. Andreeva et al. “The effectiveness of the drug sagenite in the complex treatment of menopausal syndrome of varying severity.” Drug Bulletin No. 8, 2006 .www.volgmed.ru/publishing/lv/about/php). An increase in the content of estradiol, as well as progesterone in the blood, in turn, acting on estrogen-sensitive receptors of cells of organs and tissues, reduces climacteric disorders (http://www.consilium.com.ua/stuff/doctor/obstetrics-gynaecologv-pub/estrogenv -starye-privateli-i-novve-nakomye /).

Since sigetin weakens the effects of male sex hormones, it can be used to reduce the androgenization (virilization) of the female body, including the onset due to an age-related decrease in estrogen levels.

The above medicinal properties of cigetin, namely: an increase in the concentration of beta-lipoproteins in the blood, improved glucose utilization, insulin sensitivity, weakening the effects of male sex hormones, stimulation of tissue metabolism, lipid-lowering effect, a significant weakening of climacteric disorders such as sweating, hot flashes, sleep disorders, irritability, depression, memory loss, headache, decreased libido, trophic changes in the skin - its dryness, wrinkles, brittle nails dryness and hair loss, urogenital disorders - dryness of the mucous membranes of the genitourinary system, urethral syndrome, cystalgia, etc., indicate that sigetin, like estrogen, interacts directly or indirectly with target cells of various organs and tissues: brain, hypothalamus, pituitary gland vessels, myometrium, endometrium, mammary glands, urogenetic organs, mucous membranes, skin, hair, nails, liver, adrenal glands, thyroid gland, etc.

The interaction of cigetin with target cells occurs on a competitive basis with estrogens, that is, with a decrease in the concentration of estrogens in tissues, the proportion of cigetin increases, affecting estrogen-sensitive receptors of target cells. Sighetin, entering the body, binds to estrogen-sensitive receptors in the body, replacing their connection with natural estrogens and compensating for the low content of estrogens, which together with sigetin also affect estrogen receptors of target organs. However, their combined effect due to negative feedback reduces estrogen-dependent menopause disorders. The indicated effects of cigetin on organs and tissues provide a pronounced therapeutic effect, significantly reducing the above menopausal disorders associated with estrogen deficiency.

The bioavailability of low molecular weight drugs with percutaneous administration is higher than with oral administration. In addition, with diseases of the liver and gastrointestinal tract, the absorption and metabolism of the drug are disturbed when administered orally. This affects the effectiveness of its use, leads to an increase in adverse reactions, exacerbation of chronic diseases of the liver and gastrointestinal tract. For local and external use, part of the drug is deposited in the epidermis, subcutaneous fat layer, mucous membrane, directly affecting their target cells containing estrogen-sensitive receptors. Moreover, part of the drug from the epidermos, subcutaneous fat layer and mucous membrane, gradually entering the bloodstream, contributes to the stability of the concentration of the drug in blood plasma.

It is known that in suppositories for rectal administration, the pharmacological effect is manifested much faster than in oral dosage forms. This is due to the rapid absorption of the drug in the large intestine and its entry into the blood, bypassing the liver, through the middle and lower hemorrhoidal veins. By the time of exposure, suppositories approach injection drugs, but their administration does not violate the integrity of the skin.

However, pharmacological preparations in the form of ready-made dosage forms for local and external use containing the active substance sigetin are not currently known.

The objective of the invention is the creation of pharmaceuticals for external and local use based on the active substance - cigetine, used in the prevention and treatment of menopausal disorders in women.

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

- expanding the scope of the well-known drug sigetin;

- increasing the bioavailability of the drug without violating the integrity of the skin;

- enhancing the therapeutic effect of cigetin due to components that enhance its therapeutic effect;

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

- a more effective reduction of menopausal disorders associated with metabolic metabolic disorders in the tissues;

- reducing the risk of developing cardiovascular diseases associated with estrogen deficiency due to the antiatherosclerotic properties of cigetin and the components that make up the composition,

- reduction of cardiological risk and stroke risk during their use, as well as a decrease in the risk of developing high blood pressure;

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

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

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

- reduction in age-related androgenization (virilization) of the female body.

To solve this problem, the present invention proposes a pharmaceutical preparation for external and local use containing sigetin as the active substance, the target additive and base, for example, in the following ratio of components (wt.%):

sigetin - 0.001-2.0; target additive - 0.000001-42.6; the basis - the rest.

As the target additive may be a hypoxidant, for example succinic acid, or vitamins, or biogenic elements in the form of physiologically acceptable compounds, or their physiologically acceptable mixture, for example, with the following amount in the composition of the preparation (wt.%):

hypooxidant - 0.001-2.0: vitamins - 0.001-30.6; nutrients - 0.000001-10.0.

The composition of the proposed drug may include, for example, the following 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 ₅ ), or riboflavin (vitamin B ₂ ), or d-α-tocopherol (vitamin E), or retinol (vitamin A), or vitamin F, or a mixture of them at the following content in the preparation (wt.%):

folic acid - 0.00015-0.5; cyanocobalamin - 0.00001-0.1; pyridoxine - 0.00015-5.0; vitamin C - 0.000018-10.0; riboflavin - 0.000015-2.0; calcium pantothenate - 0.00015-5.0; d-α-tocopherol (in water-soluble form) - 0.000047-4.0; beta-carotene (in water-soluble form) - 0.000025-2.0; Vitamin F (in water-soluble form) - 0.0008-2.0.

The composition of the proposed drug may include the following biogenic elements in the form of physiologically acceptable compounds, for example, zinc, or manganese, or copper, or boron, or silicon, or their physiologically acceptable mixture with the following elements in the preparation (wt.%):

zinc - 0.00002-5.0; manganese - 0.000001-0.5; copper - 0.00001-0.1; boron - 0.00002-1.4; silicon - 0.00003-3.0

In accordance with the invention, the pharmaceutical preparation for external and local use on the basis of cigetin is made in the form of a liquid, for example, a solution, suspension or emulsion, or an ointment-like soft dosage form, for example, an ointment, gel or cream, or a formulated soft dosage form, for example, suppositories or gelatine capsules for rectal or vaginal administration.

Hyperosmolar substances or a physiologically acceptable mixture of hyperosmolar substances, in combination with components providing specified, for example, rheological requirements for the base, depending on the dosage form of the drug, are proposed as a basis in a preparation for external and local use containing sigetin.

It is known that in the intact stratum corneum of the epidermis there are no channels through which particles with sizes above 10 nm could penetrate into the depth of the skin. Moreover, the larger the size of the substance’s molecule, the lower its permeability through the transepidermal barrier. It was found that substances with a molecular weight of 100 kilodaltons do not overcome the transepidermal barrier, that is, this value is the limit of skin permeability. Through microchannels that determine the permeability of the skin characterize the most likely intercellular pathway of the transport of substances through the upper scaly keratin layer of the epidermis.

The most important role in the implementation of barrier-protective functions in the permeability of the skin is played by the state of water molecules present in the microcapillary holes of the horny and shiny skin layers. The water inside the microchannels is largely in a structured state, which significantly slows down the processes of Brownian motion, which are responsible for equalizing the concentration gradient, i.e. permeability. The ordered structural organization of water in the microcapillary holes of the stratum corneum prevents the intensive evaporation of water from the skin surface, creating an additional barrier to the dehydration process. However, water, oxygen, nitrogen and other low molecular weight substances sufficiently easily diffuse through the skin.

In this case, substances capable of reacting (binding) with fragments of the epidermis, including cellular systems, first reach saturation in the epidermis, and then begin to interact with deeper layers of the skin. The intercellular substance of the epidermis and dermis is a gel formed, for example, from hyaluronic acid or from a substance similar to it. Such gel-like structures with a reticular structure are convenient for binding various low- and high-molecular substances (salts, sugars, amino acids, vitamins, peptides, proteins, epidermal cell metabolism products, etc.). Living cells of the epidermis with greater or lesser efficiency retain some of the substances that pass through the horny and shiny layers.

With the regular use of the same type of medicinal and cosmetic products for external use, the fragments of the skin treated with these products are in a state of constant saturation, in which their concentration in the skin remains almost unchanged. Moreover, many low molecular weight components of the drug used can quite easily overcome the transepidermal barrier. 60% of plasma and 45% of plasma proteins daily penetrate from microcapillaries of the circulatory system into tissues, including the epidermis. Returning to the circulatory and lymphatic systems, they carry with them metabolites associated with proteins (cell waste products - toxins) and catabolites (biologically active substances - peptides, proteins, etc., synthesized inside the cell). Substances that have overcome the transepidermal barrier also appear in the blood and, in accordance with this, act on all body tissues (A. N. Decina. "Theory of soft cosmetic effects. Modern cosmetology", Novosibirsk, "Science", 2001, www .golkom.ru / book / 48_1.htm).

Thus, the main requirement for drugs for local and external use with sigetin is the effective transport of the active substance through the transepidermal barrier into the circulatory system, as well as the deposition of part of the active substance into fragments of the epidermis, mucous membrane and subcutaneous fat.

With the transdermal administration of active substances, their effective transport through the transepidermal barrier into the circulatory system is most fully provided by hydrophilic bases with hyperosmolar properties. Osmolar hydrophilic solvents, for example, aqueous solutions of salts, alcohols and their aqueous solutions (for example, ethyl or isopropyl), glycerin, low molecular weight polyethylene oxides (for example PEO-400), propylene glycols (for example, 1,2-propylene glycol), etc., easily penetrate through the tranepidermal barrier, transporting the active substances dissolved in them into the circulatory system. At the same time, due to their osmolar properties, they bind water located in the cellular systems of the styloid and granular layers, which leads to a decrease in the size of cellular systems and, consequently, to an increase in the intercellular space and cross section of microchannels, i.e., an increase in the permeability of the epidermis. In addition, they thin the gel of hyaluronic acid filling the intercellular space, which is an additional factor in increasing the permeability of the epidermis.

If hyperosmotic conditions are created by adding salt systems, the permeability of the epidermis will additionally increase due to a change in the structure of the microcapillary channels of the horn and shiny layers, since when the channel cavities are saturated with positively charged metal ions (Na ⁺ type), the channel structures are transformed into a structure (according to the " flip-flop ") with a tendency to expand the diameter of the channel due to the electrostatic repulsion of positive charges localized on metal atoms (A. N. Decina." Theory of FIR beauty effects. Modern cosmetology ", Novosibirsk," Nauka ", 2001, www.golkom.ru/book/48_1.htm).

Sigetin, being a low molecular weight substance dissolved in a liquid hydrophilic and hyperosmolar base, with local and external use, easily and quickly penetrates the tranepidermal barrier and mucous membranes into the circulatory system. Moreover, with percutaneous administration, the active substance is partially deposited in fragments of the epidermos and subcutaneous fat. The gradual diffusion of active substances from there into the bloodstream ensures their sufficiently stable plasma levels for a long time.

On a liquid low molecular weight hydrophilic and hyperosmolar basis and cigetine, liquid dosage forms of the drug are prepared for external and local use: solutions, liniment, emulsions and suspensions with high penetrating ability.

Adding hydrophilic thickeners to hydrophilic solvents, such as high molecular weight polyethylene oxides (for example, PEO-1500), proxanols (for example, proxanol-268), medical polyvinyl pyrrolidones (for example, with a molecular weight of 12600 ± 2700 or 8000 ± 2000) or others, allows to obtain mild forms of the drug with the active substance sigetin: ointments, creams, gels, suppositories, which provide high permeability of the active substances to the circulatory system.

Gelatin capsules for rectal and vaginal administration are also filled with liquid and soft hydrophilic compositions on a hyperosmolar basis.

Microcirculation is one of the main factors for the effective transportation of the active substance during percutaneous administration or through mucous membranes. It includes not only blood flow through arterioles, capillaries and venules, but also transcapillary exchange, which provides tissue homeostasis necessary for life. Microcyclic disorders are divided into intravascular changes, vascular disorders and extravascular changes. The therapeutic spectrum of drugs used to improve microcirculation in tissues can be largely realized due to their antihistamine, anti-inflammatory and dehydrating effects.

Succinic acid (or its salts, for example succinate) is a hypooxidant, normalizes histamine and serotonin in the body, increases microcirculation in organs and tissues (A.I. Fedin “Oxidative stress and the use of antioxidants in neurology. Www.medmoskva.ru/news/ Out.aspx? Item = 19107). With an increase in the load on any of the body systems, the maintenance of its work is ensured mainly due to the oxidation of succinic acid. The power of an energy production system using succinic acid is hundreds of times greater than all other energy systems in the body. This provides a wide range of non-specific therapeutic effects of succinic acid and its salts. In addition, succinic acid also has such effects as actoprotective and antiviral (S.V. Obolensky “Reamberin - a new tool for infusion therapy in the practice of critical state medicine”, www.critical.ru/consult/pages/reamberin.htm).

In addition, the use of a hyperosmolar base also improves microcirculation in wound tissues due to its dehydrating effect. Folic acid (pteroylglutamic acid; folacin; vitamin B ₉ ) belongs to the B vitamins. Its molecular weight is 441.4 g / mol, slightly soluble in water (1-2) μg / ml, soluble in dilute acid, easily soluble in diluted alkalis (//uniargo.ru/spictures/56.jpg). It potentiates the action of estrogens (Clinical Pharmacology and Pharmacotherapy, chapter 19. “Estrogens,” www.kuban.su/medicine/shtm/baza/lek/klfhtm/part19/19-31.htm), and when used together with sigetin enhances its therapeutic activity (Instructions for the use of sigetin tablets www.regmed.ru). In addition, folic acid has an estrogen-like effect - it can slow down the onset of menopause and alleviate its symptoms (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) . 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).

The 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.consilium-medicum.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/pub1/3-1-0-5). Symptoms of folic acid deficiency are anemia, fatigue, weakness, anxiety, depression, a sense of fear, insomnia, distraction, forgetfulness, hostility, paranoia, headache, fainting, indigestion, sore tongue, inflamed mucous membrane of the lips, diarrhea, weight loss, premature graying, etc. Many of these symptoms are also characteristic of menopausal disorders.

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

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

Folic acid is more effective when taken with cyanocobalamin and pyridoxine (www.medolina.ru. Daily Health News August, 15, 2005). Folic acid functions in combination with cyanocobalamin in the formation of new cells, which maintains the necessary level of folic acid in the cells. Without it, cells cannot retain folic acid. In these cells, the division process is disrupted or completely stopped. Folic acid is essential for the absorption of cyanocobalamin and vice versa. Cyanocobalamin together with folic acid is involved in the synthesis of nucleotides, in the formation of red blood cells and cells of the nerve membranes. It is also involved in the metabolism of fats and carbohydrates, and is important for normal growth and the regeneration of folic acid (www.dsm.com/ru_RU/html/dnpm/hnh_maininfovit_index_basics_b12.htm).

Cyanocobalamin (vitamin B ₁₂ ) is indicated for various types of anemia, myocardial dystrophy, liver diseases, and migraines. It is industrially produced in the form of 0.02% and 0.05% aqueous solution (www.37.com.ua/notes.php?lek=3809). 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 system, 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 use vitamin B ₁₂ in radiation sickness, diseases of the nervous system (multiple sclerosis, encephalomyelitis, radiculitis, polymyelitis, cerebral palsy, etc.), allergic diseases (asthma, urticaria) (http://vitamini.solvay-pharma.ru/encyclopedia /info.aspx?id=24), as well as psoriasis, herpetiform dermatitis, neurodermatitis, photodermatosis, etc. (www.37.com.ua/notes.php?lek=3809).

Pyridoxine (vitamin B ₆ ) is commercially available as a 5% aqueous solution (www.37.com.ua/notes.php?lek=1916). It promotes the conversion of folic acid into its active form; contributes to the normalization of estrogen metabolism; plays an important role in metabolism, is necessary for the normal functioning of the central and peripheral nervous system. Pyridoxine as a coenzyme is involved in the metabolism of amino acids and proteins, in the synthesis of neurotransmitters, in the phosphorylated form, it provides decarboxylation, transamination, deamination of amino acids, is involved in the synthesis of protein, enzymes, hemoglobin, prostaglandins, the exchange of serotonin, catecholamines, glutamic acid, histamine, improves unsaturated fatty acids, reduces blood cholesterol and lipids, improves myocardial contractility, stimulates hematopoiesis, improves lipid metabolism in ather sclerosis. In addition, pyridoxine is indicated for diabetes, as it reduces the content of glycosylated hemoglobin, it acts as a diuretic, reducing high blood pressure and, thus, protecting the cardiovascular system in several ways at once; it is effective for depression, as it positively affects the production of norepinephrine and serotonin. When taking estrogen-containing drugs, a severe deficiency of vitamin B ₆ occurs (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=22).

Riboflavin (vitamin B ₂ ), being a synergist of pyridoxine, is required for interconversion of various forms of vitamin B ₆ (www.dsm.com/ru_RU/html/dnpru/hnh_mainmfovit_index_basics_b6.htm). In addition, it is used for depressions of a non-revolutionary age, acute and chronic hepatitis, seborrheic and non-seborrheic dermatitis, herpes zoster, neurodermatitis, psoriasis, exudative diathesis (www.37.com.ua/notes.php?lek=1916).

Water-soluble pantothenic acid (vitamin B ₅ ) as a component of coenzyme A plays a key role in the metabolism of carbohydrates, proteins and fats, and therefore is important for maintaining and restoring all tissue cells. She is involved in reactions that provide energy to the cell, and also take part in the synthesis of vital compounds such as sterols (e.g. cholesterol), hormones (e.g. growth hormones, stress and sex hormones), neurotransmitters (e.g. acetylcholine), phospholipids (components of cell membranes), porphyrin (a component of hemoglobin), antibodies, and also takes part in the metabolism of drugs.

Pantothenic acid is used to treat various liver diseases and arthritis, to treat constipation in the elderly, against baldness, to prevent urinary retention after surgery. Calcium pantothenate or panthenol are usually used, which are readily soluble in water and are easily converted into pantothenic acid in the body. Vitamin B ₁₂ promotes the incorporation of free pantothenic acid into coenzyme A. Ascorbic acid reduces the severity of pantothenic acid deficiency. Pyridoxine, folic acid, and biotin are essential for the efficient utilization of pantothenic acid (Essential Vitamins, DSV Nutritional Products, www.dsm.com/en_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).

The water-soluble vitamin riboflavin acts as a mediator in electron transfer in various redox reactions. Thus, he participates in many reactions of the metabolism of carbons, fats and proteins, 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). It is available in the form of a 1% solution of riboflavin mononucleotide, which allows it to be dissolved in a hydrophilic base in the manufacture of ointments, creams, emulsion gels.

Water-soluble ascorbic acid (Vitamin C) is involved in the metabolism of folic acid, in the synthesis of steroid hormones and catecholamines (www.recipe.ru/docs/ls/index.php?action=descr-drug-table&filter=bysearch&filter_param = acobbin drug% 20 1261).

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, which provide the structure of muscles, vascular tissues, bones and cartilage, regulates blood coagulability, and normalizes capillary permeability; necessary for hematopoiesis, has anti-inflammatory and anti-allergic effects, 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://vitammi.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, АКК 31/015, 2006.04.27). It is industrially produced in the form of a solution for injection (5% or 10%), which allows it to be dissolved in a hydrophilic base in the production of ointments, creams, emulsion gels.

Vitamin E (d-α-tocopherol) is involved in the formation of collagen and elastic fibers of the intercellular substance, slows down aging, and prevents the appearance of senile pigmentation. It improves blood circulation, is necessary for tissue regeneration, is useful in premenstrual syndrome and in the treatment of fibrotic breast diseases. Vitamin E ensures normal blood coagulation and healing, reduces the possibility of scarring from some wounds, lowers blood pressure, helps prevent cataracts, relieves leg cramps, supports healthy nerves and muscles, strengthens capillary walls, and prevents anemia. As an antioxidant, vitamin E protects cells from damage, slowing down the oxidation of lipids (fats) and the formation of free radicals. It protects other fat-soluble vitamins from being destroyed by oxygen, promotes the absorption of vitamin A and protects it from oxygen.

Vitamin E prevents increased blood coagulability, favorably affects peripheral blood circulation, participates in the biosynthesis of heme and proteins, cell proliferation, the formation of gonadotropins, and the development of the placenta. Its effectiveness is enhanced in the presence of other antioxidant nutrients. So the anti-cancer protective effect of tocopherol is especially noticeable increases ascorbic acid.

Some indications for use: menopausal autonomic disorders, diseases of the ligamentous apparatus and muscles, degenerative and proliferative changes in the joints and ligaments of the spine and large joints, dermatomyositis, some dermatoses, psoriasis, peripheral vascular spasm, as an antioxidant in complex treatment of many diseases, in gerantology (http://vitamini.solvay-pharma.ru/encyclopedia/info.aspx?id=12). At present, a water-soluble form of vitamin E has been obtained (Substances for the cosmetic industry, www.akvion.ru/catalog/skk/), which allows it to be used with a hydrophilic base in the production of ointments, creams, emulsion gels.

Retinol (Vitamin A) is one of the main antioxidants. It is able to suppress cell destruction by free radicals. 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, 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. To enhance the effectiveness of retinol, it must be used 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).

At present, a water-soluble form of vitamin A has been obtained in the form of provitamin A - beta-carotene (substances for the cosmetics industry, www.akvion.ru/catalog/skk/), which allows it to be used with a hydrophilic base in the production of ointments, creams, emulsion gels. The water-soluble form of beta-carotene has a regulatory effect on various parts of cellular and humoral immunity (T and B lymphocytes, immunoglobulins, phagocytic activity). In addition, this drug has both antioxidant and antihypoxic properties. Its administration normalizes lipid peroxidation and increases the activity of protective enzymes of the antioxidant system (EG Bochkarev, Yu.V. Sergeev. “The effect on the immune system of drugs with antioxidant and antihypoxant properties”, www.olifen-corp.ru/3 .html).

Vitamin F is a mixture of unsaturated fatty acids (linoleic and linolenic) or their esters. It is used in the treatment of various skin diseases, moisturizes the skin, and contributes to the thinning of the layer of subcutaneous fat. At present, a water-soluble form of vitamin F has been obtained (www.akvion.ru/catalog/skk/skkvitaminf.php), which allows it to be used with a hydrophilic base in the production of ointments, creams, emulsion gels. Vitamin F has a reparative effect in the treatment of wounds, burns and ulcers (www.icsti.su/base/base2/tec/1.485.shtml).

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 helps to absorb vitamin E and maintain a normal concentration of this vitamin in the blood.

Zinc strengthens the body's immune system, promotes wound healing, as it plays an important role in protein synthesis (www.microelements.ru/Zn). Zinc affects the activity of the hormones of the pituitary gland, adrenal glands and pancreas. Under the influence of its compounds, the activity of the pituitary gonadotropin hormones is enhanced. It has been established that the hypoglycemic effect of insulin depends on zinc, which is constantly present in insulin. Zinc has lipotropic properties, normalizing fat metabolism, increasing the rate of fat breakdown in the body and preventing liver obesity (//athlete.ru/books/nutrition_pshendin/7_mineralu_makro-i-mikroelementy.htm).

Zinc reduces the absorption of copper (patent RU No. 2275192, 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 enzymatic catalysis and electron transfer. It is necessary to improve the hormonal background in women; important for osteoporosis and diseases of the osteoarticular apparatus; necessary for people suffering from multiple sclerosis; necessary for disorders of the thyroid gland. She is involved in the synthesis of red blood cells (www.osteoform.ru/products/calc.htm). Copper is necessary to maintain the ability of the heart to pump blood, to prevent aneurysms and to ensure the growth of strong arterial connective tissue that is resistant to tearing. It is necessary for the production of collagen, gives excellent results in the treatment of rheumatoid arthritis.

Copper is important for maintaining the balance of microflora, inhibiting 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; risk of cancer. Vitamins b), 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.ni/Mn) is an obstacle. Manganese promotes the absorption of calcium in the body (www.osteoform.ru/products/calc.htm). Manganese gluconate stimulates the activity of the natural enzyme contained in the skin - SOD (superoxide dismutase).

Boron plays a significant role in the metabolism of carbohydrates and fats, a number of vitamins and hormones, and affects the activity of certain enzymes (www.microelements.ru/B). Boron increases the natural levels of estrogen and testosterone in women. It protects against softening of the bone, with an additional intake of boron, the loss of calcium in women is halved. Boron reduces the content of oxalates in the urine and prevents the formation of kidney stones. With boron deficiency, the level of female sex hormones decreases, which causes a number of dangerous diseases, including osteoporosis (www.osteoform.ru/products/calc.htm). In women during menopause, elimination of boron deficiency is accompanied by an increase in the level of 17 beta-estradiol in blood serum and copper in blood plasma. EEG indicators, memory improve, behavioral reactions normalize.

In women aged 48-82 years, post-menopause, a lack of boron causes a decrease in mineral metabolism and bone tissue, which indicates that boron is an essential element in the prevention and treatment of osteoporosis. The lack of vitamin D enhances the effect of boron deficiency on the metabolism of calcium, magnesium, phosphorus. Boron inhibits the body's absorption of ascorbic acid, flavonoids, sulfur-containing amino acids. There is a positive correlation between the metabolism of boron and zinc. Sometimes boron is used to displace copper from the body (www.microelements.ru/B).

Boron increases the sensitivity of cells to estrogen, while, despite a low level of estrogen, the development of osteoporosis stops. In addition, boron enhances cellular protein synthesis and inhibits the action of an enzyme that destroys proteins (collagenase), that is, prevents the destruction of the protein base of cartilage, helping to restore the balance between its synthesis and decay. Boron acts as a catalyst for chemical reactions due to which calcium is absorbed. Boron prevents the leaching of calcium 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 (AMF No. 5, 2007, p.16. “Foundation for joint health”).

Silicon is the main element in the structure of connective tissue - the main protein of muscles, tendons and ligaments. The main role of silicon is to participate in a chemical reaction that bonds individual fibers of collagen and elastin. Silicon is important for cartilage and skeletal growth. It is indicated for disorders of connective tissue, bone diseases, ligaments, cartilage, osteoporosis, periodontosis, 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 silicon deficiency in the body, connective tissue weakness (bronchopulmonary system, ligaments, cartilage), bone tissue weakness (osteoporosis), thinning, brittleness, hair loss, tendency to inflammatory diseases of the stomach and intestines, cholesterolemia, earlier development of atherosclerosis (www.microelements) are observed. 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 aluminum silicate: 80% versus 1% (Rozhinskaya L.Ya. “Systemic osteoporosis: a practical guide”, www.medlibrary.ru/library/).

The proposed concentrations of vitamins and nutrients depend on the purpose of the pharmacological preparation for external and local use. Small concentrations are used in compositions to enhance the proliferative activity of cells (A. N. Decina, “Theory of soft cosmetological effects. Modern cosmetology,” Novosibirsk, “Nauka”, 2000, www.golkom.ru/book/48_1.htm). High concentrations of these substances are used when applied topically and locally to the blood at acceptable daily doses equivalent to oral administration.

Hydrophilic bases that can be used with sigetin in the proposed drug are divided into two groups:

- water-soluble bases, which usually contain purified water, hydrophilic non-aqueous solvents: polyethylene oxide, for example, PEO-400, 1,2-propylene glycol, glycerin, ethyl cellosolve, dimexide, and water-soluble polymers: polyethylene oxide, for example PEO-1500, proxanol for example, proxanol-268, polyvinylpyrrolidone, for example, 8000 ± 200 or 12600 ± 2700;

- water-washable bases, which in addition to water-soluble polymers and hydrophilic non-aqueous solvents contain lipophilic substances: higher fatty alcohols, petroleum jelly, liquid paraffin, lanolin, waxes (these bases are usually oil / water emulsions and require the presence of an oil / water emulsifier) .

Substances with high hyperosmolar properties include polyethylene oxides - water-soluble products of the polymerization of ethylene oxide, which are physiologically indifferent compounds. Non-aqueous solvents — PEO-400, 1,2-propylene glycol, glycerin, ethyl cellosolve, dimexide — and polymers (polyethylene oxide, for example PEO-1500, proxanol-268, polyvinylpyrrolidone) possess high hypersomolar properties. They are easily applied to the skin surface and evenly distributed over it while maintaining their homogeneity, low toxicity and do not irritate the tissues, do not violate their physiological functions.

The ability of polyethylene oxides (PEO) to provide the drug with interstitial action fundamentally distinguishes this ointment base from fatty bases.

PEO is an active conductor of drugs across the skin barrier. The important thing is that this penetrating without damage to the cells ability of PEO is enhanced in conditions of inflammation.

Hydrophilic bases on polyethylene oxides are able to dissolve in the secrets of the mucous membranes, completely release medicinal substances, not irritate the mucous membranes, have a long shelf life, high physiological indifference, which contributes to their use in liquid, ointment-like and formable soft dosage forms.

When mixing the PEO-400 solvent with PEO-1500 polymer, the latter acts as a thickener, which, depending on the amount in the total mass, provides the required consistency of the created dosage form.

1,2-propylene glycol, PEO-400, PEO-1500, proxanol-268 can be preservatives in the developed dosage forms ("Theory and practice of local treatment of purulent wounds" under the editorship of Professor B.M. Dotsenko. Kiev, "Health" , 1995, p. 174; 227-235).

On the basis of PEO-1500 polyethylene oxide, the Geko hydrogel is commercially available, which represents a colorless gel-like mass formed by the action of ionizing radiation on a solution of polyethylene oxide in water. The gel is biologically inert, non-toxic. It has a widely varying structural viscosity. It liquefies with the addition of alcohol, glycerol, with vigorous stirring, the pH of a 20% aqueous suspension is 4.0-8.0. Chemical composition: PEO-1500 - 3.5%; distilled water - 96%; preservative (sodium benzoate) - 0.5%. It is used as a basis in the production of ointments, creams, gels, liniments in the pharmaceutical and cosmetic industries (www.medpeterburg.ru/news/Out.aspx?Item=21284). The gel has a stabilizing effect on enzymes (patent RU No. 2089177, A61K 7/48, 1997.09.10).

Polyvinylpyrrolidone is a synthetic polymer inert to the body and not degraded by enzyme systems. It is the basis of detoxification blood substitute fluid that binds toxic substances of various structures and removes them from the body. (Blood-replacing fluids, www.nedug.ru/libraru/doc.aspx?item=38053).

Hyaluronic acid - a polysaccharide from the glucosaminoglycan family, has the ability to bind 1000 times more water than it weighs. Hyaluronic acid has the highest hygroscopicity compared to other moisturizing agents such as glycerin and sorbitol. In this case, the absorbed water is retained inside the gel and does not evaporate even when the relative humidity of the surrounding air decreases. Due to its high hydrophilicity, hyaluronic acid forms highly viscous gels with water that moisturize the skin and mucous membranes. Hyaluronic acid is non-toxic. As part of the gels, hyaluronic acid has an antimicrobial, wound healing and anti-inflammatory effect, promotes the regeneration of the epithelium, prevents the formation of granulation tissues, adhesions, scars, normalizes blood circulation, and does not cause clinical complications.

Hyaluronic acid has a positive effect on the course of local inflammatory processes, binds the microflora, as well as the products of its decay and vital activity, has a pronounced anti-inflammatory effect and a local anesthetic effect. At the same time, hyaluronic acid also provides mechanical protection for wounds, as it forms a thin film that prevents the penetration of environmental factors, pathogenic agents, into the wound. Gels based on hyaluronic acid are used to treat local and general purulent-inflammatory processes, thermal and chemical burns, trophic ulcers in chronic venous insufficiency, radiation injuries of the skin, cracks, abrasions, as well as for the treatment of long-healing wounds of various etiologies (patent RU No. 2195262 , A61K 9/06, 2002.12.27).

Sodium hyaluronate - the sodium salt of hyaluronic acid, is readily soluble in water with the formation of a viscous colorless gel with a pH of 6.0-7.5 (0.1% solution). In its activity, sodium hyaluronate is a complete analogue of hyaluronic acid, promotes tissue regeneration without scarring, and has the ability to stimulate cell migration and proliferation. Used in concentrations from 0.01 to 0.5%.

Organosilicon glycerohydrogel is a new ointment base for external cosmetic and medicinal products, because it combines the beneficial properties inherent in many other ointment bases. This gel conducts various medicines well, has anti-inflammatory, decongestant and antioxidant activity, is able to protect tissues from drying out, saturate them with oxygen, it is non-toxic, economical, and stable during storage. The presence of silicon has a beneficial effect on all types of tissues: epithelial, connective, skin, bone, promotes regenerative processes, enhances blood supply.

Due to the fact that silicon glycerates and glycerohydrogels based on them penetrate well through the skin and conduct drugs, the dose of these substances in pharmaceutical compositions can be reduced (www.uran.ru/gazetanu/2007/04/nu11/wvmnu_p3_11_O42007.htm). Given the high transcutaneous activity of organosilicon glycerohydrogel, it can be used to create drugs for local and external use, transdermal therapeutic systems. This gel can be used as a source of an essential trace element - silicon for the regulation of silicon metabolism in the body (Boyakovskaya TG "Development of organosilicon glycerohydrogels and a comparative assessment of their transcutaneous activity", abstract of the dissertation, www.vita.chel.su/files/docs /diss/boiakovskii.doc).

If necessary, a preservative, for example, nipogin, can be added to the drug.

The type of dosage form of the proposed pharmaceutical preparation depends on the molecular weight of the used hyperosmolar substances, their ratio in the composition of the mixture, the rheological properties of the mixture, as well as the quantitative ratio of the hyperosmolar base with other components of the pharmaceutical preparation. Based on these quantitative ratios and rheological properties of the mixture, the dosage form of the proposed pharmaceutical product for topical and external use may be a liquid, gel, cream, ointment or suppository.

The ointment form is most preferable for external use, since it is well fixed and held on the surface, has longer therapeutic activity, is cheaper to manufacture, convenient to use, which enhances the patient's motivation for treatment.

Using cigetin and hydrophilic bases with hyperosmolar properties, compositions of hydrophilic liquids for external and local use, hydrophilic ointments, hydrophilic creams, hydrophilic gels, which can also be used for the manufacture of suppositories and gelatin or other capsules for rectal and vaginal administration, are proposed.

Hydrophilic liquids, being hyperosmolar (solutions, emulsions, suspensions in the form of liniments), increase the permeability of the skin, effectively transporting the active substance - cigetine, as well as targeted additives to the skin, mucous membranes and through them into the bloodstream.

Hydrophilic ointments are hyperosmolar, as a result of which, when applied, they provide effective transportation of the active substance - cigetin, as well as targeted additives to the skin, mucous membranes and through them into the bloodstream for a long time until the ointment dries.

Hydrophilic creams are prepared on the basis of a water / oil or water / oil / water emulsion stabilized with suitable emulsifiers. These also include colloidal dispersed systems consisting of water-dispersed or mixed water-glycol solvents of higher fatty alcohols or acids, stabilized by hydrophilic surfactants. Creams are two- or multiphase disperse systems, the dispersion medium of which at the set storage temperature, as a rule, has a Newtonian type of flow and low values of rheological parameters. The action of hydrophilic-based creams is similar to the action of hydrophilic-based ointments, but at the same time they have a lower viscosity than ointments, therefore, they more easily penetrate the tranepidermal barrier. According to the rheological properties, they occupy an intermediate position between the liquid and the ointment.

Hydrophilic gels (hydrogels) are prepared on the basis of water, a hydrophilic mixed or non-aqueous solvent (glycerin, 1,2-propylene glycol, PEO-400 polyethylene oxide) and a hydrophilic gelling agent (carbomers, cellulose derivatives, tragacanth, sodium hyaluronate, hyaluronic acid, etc. .). In addition, the new hydrophilic gels mentioned above are currently being developed. Gels are single, double, or multiphase disperse systems with a liquid disperse medium, the rheological properties of which are due to the presence of gelling agents in relatively low concentrations. In this dosage form, the gelling agents can additionally fulfill the role of stabilizers of disperse systems: suspensions or emulsions.

Hydrophilic gels containing bound water in their composition do not have a dehydrating effect, like liquids, creams or ointments on a hydrophilic basis with hyperosmolar properties. They moisturize the focus of inflammation, protecting the wound from drying out. In this case, the heat transfer of the gel-coated part of the surface is reduced, as a result of which it is heated. Under the gel layer, moisture does not evaporate, the upper layers of the skin or mucous membrane macerate (soak), which contributes to the absorption into the skin thickness of various medicinal substances that are present in the gel. In this case, the active substance and the target additives contained in the hydrophilic gel layer on the surface of the skin or mucous membrane diffuse through the transepidermal barrier.

Hydrophilic suppositories, prepared on hydrophilic hyperosmolar bases, are easily dissolved by rectal or vaginal administration, evenly distributing medicinal substances throughout the mucosa, which have both local and resorptive effects on the body.

Gelatin capsules for rectal and vaginal administration are more promising compared to suppositories from a technological, biopharmaceutical and economic point of view. The gelatin shell protects the drug from environmental factors and has advantages over suppositories, since it can encapsulate substances in the form of ointment, liniment, cream, gel, emulsion, suspension, etc.

The release of the drug substance occurs faster and easier than in suppositories, since under the influence of the weakly alkaline environment of the mucous membranes (pH 7.3-7.6) the gelatinous membranes swell, and in this state even a weak effect on them is enough to break it and releasing content. The amount of drug substance in the capsule, which has the necessary therapeutic effect, is a double dose of suppositories.

Thus, the production of rectal and vaginal products in a gelatin shell allows you to save expensive biologically active ingredients and reduce the cost of drugs. Rectal gelatin capsules with the proposed pharmacological preparation meet all the requirements for ideal suppositories and can be used in medicine for rectal administration of the active substance, and vaginal capsules for the treatment of diseases of the urogenital system in women.

In the proposed pharmacological preparation, sigetin, which has a number of the above properties, reduces estrogen-dependent menopausal disorders in women with menopause.

The composition of this drug also includes:

- folic acid, which enhances the therapeutic activity of sigetin, 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, and the concentration of folic acid in the drug can be controlled by pH, as its solubility rises in weak acids and alkalis;

- cyanocobalamin (vitamin B ₁₂ ), which increases the effectiveness of folic acid, 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;

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

- riboflavin (vitamin B ₂ ), whose coenzymes play an important role in the conversion of pyridoxine and folic acid into their active coenzyme forms; maintains healthy skin, nails, hair;

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

- d-α-tocopherol (vitamin E) in a water-soluble form, which is involved in the formation of collagen fibers, supports the skin in a healthy state, and also has a number of other properties mentioned above, which are useful in the comprehensive prevention and treatment of menopausal disorders 1st, 2- Oh, and 3rd group;

- calcium pantothenate, which in the form of pantothenic acid is important for maintaining and restoring all tissue cells, promotes wound healing, 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 her groups;

- Vitamin A in the form of water-soluble beta-carotene, which supports the skin, hair and nails in a healthy state, 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

- Vitamin F (a mixture of unsaturated fatty acids - linoleic and linolenic - or their esters) in a water-soluble form, which ensures a healthy condition of the skin and hair, and also has a number of other properties mentioned above, useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd and 3rd groups;

- zinc, for example, in the form of chloride or gluconate, which plays an important role in the processes of skin regeneration, hair and nail growth, normalizes metabolic processes, and also has a number of other properties mentioned above that are useful in the comprehensive prevention and treatment of menopausal disorders of the first, 2nd and 3rd groups;

- copper, for example, in the form of sulfate or gluconate, which is necessary to improve the hormonal background in women, 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 ;

- Manganese, for example, in the form of acetate or gluconate, which is involved in the exchange of thyroid hormones; provides the development of connective tissue, cartilage, bones; it is necessary for the normal growth of bone tissue, the formation of cartilage and synovial fluid for lubrication of the joints, 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;

- boron, for example, in the form of an amino acid chelate (or fructoborate, Fructes-B, Bora Bora preparations), or tribrate of citrate, aspartate, glycinate), which increases the sensitivity of cells to estrogens, acts as a catalyst for chemical reactions, due to which is absorbed by calcium, and also has a number of other above-mentioned properties that are useful in the comprehensive prevention and treatment of menopausal disorders of the 1st, 2nd, and 3rd groups;

- silicon, for example, in the form of methylsilanotriolsilicate (or 1 chloromethylsilatran or hydrophilic silatran), which is indicated for disorders of connective tissue, bone diseases, ligaments, cartilage, osteoporosis, paradantosis, arthrosis, poor growth and fragility of nails and hair, and also has a number of other the above properties that are useful in the comprehensive prevention and comprehensive treatment of menopausal disorders of the 1st, 2nd, and 3rd groups

The use of a hydrophilic and hyperosmolar base in the proposed pharmacological preparation ensures the fast delivery of the active substance and targeted additives to tissue cells and the bloodstream, bypassing the liver, which reduces the side effects of the proposed drug, in addition, the hyperosmolar base is a preservative for the proposed drug.

The use of a hyperosmolar base further improves microcirculation at the site of application of the drug due to its dehydrating effect, and also has an additional anti-inflammatory effect due to absorption of the liquid and reduction of tissue edema. It is easily applied to the surface of the skin, it is well kept on it, evenly distributed on it, improving the contact of the ointment with tissues, has low toxicity and does not irritate tissues, does not violate their physiological functions.

The dissolution of the active substance and target additives in a polyethylene oxide base increases their dispersion and the ability to more quickly release from the base, which increases the therapeutic activity of the proposed drug. This base is a conductor of active substances through the skin barrier, while such a penetrating without damage to cells is enhanced in conditions of inflammation. The hydrophilic base on polyethylene oxides is able to dissolve in the secrets of the mucous membranes, completely releasing medicinal substances without irritating the mucous membrane, has a long shelf life and high physiological indifference.

The use of vitamins and elements in the proposed preparation together with sigetin enhances its therapeutic effect.

The drug is obtained by mixing the components by known methods.

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

Example 1. The solution for external and local use No. 1.

100 g of a 1.0% solution contains, g:

sigetin - 1.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.2; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; polyvinylpyrrolidone 8000 ± 2000 - 6.0; purified water up to 100 g

Example 2. The solution for external and local use No. 2.

100 g of a 0.5% solution contains, g:

sigetin - 0.5; zinc chloride - 0.006; manganese acetate - 0.002; 1 chloromethylsilatran - 0.01; B vitamins - 0.002; vitamin C - 0.01; succinic acid - 0.1; polyethylene oxide - 400-10.0; purified water up to 100 g

Example 3. The solution for external and local use No. 3.

100 g of a 0.25% solution contains, g:

sigetin - 0.25; B vitamins - 0.002; polyethylene oxide - 400-20.0; purified water up to 100 g

Example 4. Liniment No. 1.

100 g of 2.0% liniment contains, g:

sigetin - 2.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; 1,2-propylene glycol - 60.0; purified water up to 100 g

Example No. 5. Liniment number 2.

100 g of 1.0% liniment contains, g:

sigetin - 1.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; B vitamins - 0.002; 1,2-propylene glycol - 50.0; proxanol - 268 - 5.0; purified water up to 100 g

Example 6

Liniment number 3.

100 g of 0.5% emulsion contains:

sigetin - 0.5; B vitamins - 0.002; PEO-400 - 60.0; purified water up to 100 g

Example 7. Cream No. 1.

100 g of 1.0% cream contains, g:

sigetin - 1.00; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; petroleum jelly - 22.00; glycerol - 17.00; 1,2-propylene glycol - 12.00; emulsifier No. 1 - 10.00; phosphate buffer - 14.00; purified water up to 100 g

Example 8. Cream No. 2.

100 g of 0.5% cream contains, g:

sigetin - 0.5; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; B vitamins - 0.002; petroleum jelly - 22.00; glycerol - 17.00; 1,2-propylene glycol - 12.00; emulsifier No. 1 - 10.00; phosphate buffer - 14.00; purified water up to 100 g

Example 9. Cream No. 3.

100 g of 0.25% cream contains, g:

sigetin - 0.25; B vitamins - 0.002; 1,2-propylene glycol - 35.00; PEO-400 - 25.00; proxanol-268 - 18.00; purified water up to 100 g

Example 10. Ointment No. 1.

100 g of 1.0% ointment contains, g:

sigetin - 1.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; PEO-400 polyethylene oxide - 28.00 proxanol-268 - 20.00; purified water up to 100 g

Example 11. Ointment No. 2.

100 g of 0.5% ointment contains, g:

sigetin - 0.5; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; proxanol-268 - 24.0; 1,2-propylene glycol - 50.0; purified water up to 100 g

Example 12. Ointment No. 3.

100 g of 0.25% ointment contains, g:

sigetin - 0.25; B vitamins - 0.002; PEO-400 - 70.0; proxanol - 268-20.0; purified water up to 100 g

Example 13. Gel No. 1.

100 g of 1.0% gel contains, g:

sigetin - 1.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; sodium hyaluronate - 0.30; purified water up to 100 g

Example 14. Gel No. 2.

100 g of 0.5% gel contains, g:

sigetin - 0.5; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; polyethylene oxide gel 1500 - up to 100 g.

Example 15. Gel No. 3.

100 g of 0.25% gel contains, g:

Example 16. A mixture for the preparation of suppositories No. 1.

100 g of a 1% mixture for the preparation of suppositories contains, g:

sigetin - 1.0; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; water-soluble tocopherol - 0.00005; water soluble beta carotene - 0.001; water soluble vitamin F - 0.01; proxanol-268 - 60.0; polyethylene oxide-400 - 15.0; purified water up to 100 g

300 pieces were made from this mixture. rectal suppositories in the form of a "cigar" with a diameter of 10 mm, weighing 2.5 g with a cigetine content of 0.025 g in one suppository. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example 17. A mixture for the preparation of suppositories No. 2.

100 g of a 0.5% mixture for the preparation of suppositories contains, g:

sigetin - 0.5; zinc chloride - 0.006; manganese acetate - 0.002; copper sulfate - 0.0001; 1 chloromethylsilatran - 0.01; bora aspartate - 0.001; succinic acid - 0.5; B vitamins - 0.002; vitamin C - 0.01; proxanol-268 - 64.0; polyethylene oxide-400 - 16.0; purified water - up to 100 g.

300 pieces were made from this mixture. rectal suppositories in the form of a "cigar" with a diameter of 10 mm, weighing 2.0 g with a cigetine content of 0.01 g in one suppository. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example 18. A mixture for the preparation of suppositories No. 3.

100 g 0.25% of the mixture for the preparation of suppositories contains, g:

sigetin - 0.25; B vitamins - 0.002; proxanol-268 - 66.0 polyethylene oxide-400 - 8.0 purified water  up to 100 g

300 pieces were made from this mixture. rectal suppositories in the form of a "cigar" with a diameter of 10 mm, weighing 2.0 g. with a cigetine content of 0.005 g in one suppository. The solubility of hydrophilic suppositories is no more than 1 hour at a temperature of (37 ± 1) ° С, which corresponds to the requirements of the Global Fund XI (Art. Suppositories, pp. 151-153).

Example 19. Gelatin capsules.

The ointment from example 10 is filled with 500 pieces. gelatin capsules No. 00, a volume of 0.95 ml. The disintegration of the obtained capsules is less than 20 min, which meets the requirements of the Global Fund XI (St. Capsules, p. 143).

On the basis of the proposed solution, a number of new drugs were created in the form of liquid and soft dosage forms containing the active substance cigetine, the target additive and a hydrophilic osmolar base.

The proposed drug based on cigetin, the above target additives and a hydrophilic osmolar base significantly expands the field of application of the known active substance - cigetin, provides bioavailability of the drug without violating the integrity of the skin; increases the therapeutic effect of cigetin due to components that enhance its therapeutic effect; slows down menopause and weakens its symptoms due to the estrogen-like action of the components that make up the drug, more effectively reduces menopausal disorders associated with metabolic metabolic disorders in tissues, reduces the risk of cardiovascular diseases associated with estrogen deficiency due to the antiatherosclerotic properties of cigetine and components included in the composition of the drug reduces the cardiological risk and the risk of stroke when using the drug, as well as reduce the risk of developing high blood counts pressure, reduces the climacteric degenerative changes of the skin, hair, nails and mucous membranes due to the dermatotropic properties of cigetin and the components used, reduces the likelihood of diabetes mellitus due to the properties of cigetin and the components used, reduces the likelihood of breast cancer, colorectal cancer and laryngeal cancer due to the oncoprotective properties of the components used, it reduces the androgenization of the female body with estrogen deficiency.

The search for information did not reveal identical and similar technical solutions.

So far, no similar solution has been proposed, although the sigetin preparation has been known since 1963 (Instructions for the use of sigetin, approved by the Pharmacological Committee of the USSR Ministry of Health on October 12, 1963).

The inventive pharmaceutical preparation can be recommended for the prevention and treatment of menopausal disorders in women, especially urogenital and dermatotropic.

The proposed pharmaceutical product for local and external use on the basis of cigetin can be used for industrial serial production of liquid and soft dosage forms, such as solutions, emulsions, suspensions, liniments, ointments, creams, gels, as well as for industrial production of formed soft dosage forms: suppositories and gelatin capsules for rectal and vaginal administration.

Claims (5)

1. A pharmaceutical composition for local and external use in menopausal disorders, containing sigetin, base, target additive, in the following ratio, wt.%:
sigetin 0.001-2.0 target additive 0.000001-42.6 the basis rest,
at the same time, it contains hydrophilic and / or hyperosmolar substances as a basis, and substances selected from the series: vitamins, nutrients, an antioxidant, or a physiologically acceptable mixture thereof, as a target additive. 2. The pharmaceutical composition according to claim 1, characterized in that as vitamins it contains substances selected from the range: folic acid, cyanocobalamin, pyridoxine, ascorbic acid, calcium pantothenate, riboflavin, d-α-tocopherol, vitamin F retinol or their mixture. 3. The pharmaceutical composition according to claim 1, characterized in that as biogenic elements it contains substances in the form of physiologically acceptable compounds selected from the series: zinc, manganese, copper, boron, silicon, or a physiologically acceptable mixture thereof. 4. The pharmaceutical composition according to claim 1, characterized in that as an antioxidant it contains succinic acid, its salt or a mixture thereof. 5. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a liquid dosage form: solution for external use, suspension, emulsion; or in the form of a soft dosage form: cream, ointment, gel; or in the form of a formulated soft dosage form: suppositories or capsules for rectal or vaginal administration.