RU2360670C1 - Local and external sygethin-based pharmaceutical composition applied in menopausal disorders - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: said composition contains sygethin and as a base, hydrophilic and hyperosmolar substances or their mixture combined with the components ensuring the specified requirements for the base concerning formulation of the composition that can be prepared either as a liquid formulation including solution, suspension, emulsion, liniment, or as a soft formulation including cream, ointment, gel, or as a soft formed formulation including suppositories, or capsulated formulation for peranum or vaginal applications.

EFFECT: invention provides extended application of sygethin and effective decrease in menopausal disorders at its use.

2 cl, 24 ex

Description

The invention relates to the pharmaceutical industry and medicine, in particular to pharmaceutical preparations used in the prophylaxis and treatment of menopausal disorders, in particular, 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:

The first group is early symptoms. Vasomotor: hot flashes, sweating, palpitations, hypertension. Psycho-emotional: insomnia, depression, irritability, weakening of memory, headaches, decreased libido.

The second group is 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.

The third group is 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 for 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 embolism, history, migraine, gall - stone 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, v.2, p. 47. Kharkov: Torgsin, 1998 d.), which is a synthetic drug with the properties of the female sex hormone estrone (folliculin) (http: //deb.telenet.m/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). Sigetin has an anti-tearing effect (“Register of Russian Medicines”, 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 and others. The effectiveness of the drug Sagenit in complex treatment menopausal syndrome of varying severity.Medical 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.m / docs / ls / mdex.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.consilium-medicum.com/media/provisor/03_07/29.shtml). In addition, sigetin significantly reduces trophic changes in the skin, such as dryness, wrinkles, brittle nails, dryness and hair loss, and also reduces urogenital disorders, such as dryness of the mucous membranes of the genitourinary system, urethral syndrome, cystalgia, etc., characteristic of menopausal 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.

Pharmaceutical effect: anti-climacteric, reducing the gonadotropic function of the pituitary gland, stimulating labor, increasing placental blood flow, and uterotone.

Indications: menopause and menopause in women; menopause disorders and other disorders in the periopenopausal 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. (Instruction on the use of sigetin tablets, www.regmed.ru/InstrShow2.asp?InstrLinkNx=a16ba19ba15ba10b).

Pharmacodynamics: Inhibits the formation of gonadotropins. 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, insulin sensitivity, improves glucose utilization, and has a lipid-lowering effect.

Interaction: potentiates the effect of hypocholesterolemic drugs, diuretics, antiarrhythmic antihypertensive drugs, anticoagulants; weakens the effects of male sex hormones; folic acid, thyroid preparations enhance the effect of cigetine (Drug Reference. www.recipe.ru/docs/ls/mdex.php?action=descr-drug-able&filter=bysearch&fllter_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, 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 fetal threatening fetal asphyxiation. If there are signs of threatening or intrauterine asphyxiation of the fetus, the woman in labor is injected intravenously with 2-4 ml of a 1% solution of cigetine (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.m / 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 receptors estrogen.

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 (Ph.D. 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).

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

The above medicinal properties of cigetin, namely an increase in blood concentration of beta-lipoproteins, improved glucose utilization, insulin sensitivity, weakening effects of male sex hormones, stimulation of tissue metabolism, lipid-lowering effect, a significant weakening of climacteric disorders such as sweating; tides; sleep disorders irritability; depression; memory impairment; headache; decreased libido; trophic changes in the skin - its dryness, wrinkles; fragility of 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, blood vessels, myometrium, endometrium, mammary glands, urogenetic organs, mucous membrane, skin, hair, nails , liver, adrenal gland, thyroid gland, etc.

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 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 epidermis, 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, pharmaceutical 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 pharmaceutical preparations for local and external use based on the active substance cigetin, 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 sigetin;

- slowing down menopause and easing its symptoms;

- a more effective reduction of menopause;

- reducing the risk of developing cardiovascular diseases associated with estrogen deficiency, reducing cardiological risk and risk of stroke, as well as reducing the risk of developing high blood pressure;

- reduction of menopausal degenerative changes in the skin, hair, nails and mucous membranes;

- reducing the likelihood of diabetes;

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

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

sigetin 0.001-2,000 the basis rest

In accordance with the invention, the pharmaceutical preparation for local and external 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, such as an ointment, gel or cream, or a formulated soft dosage form, such as suppositories or gelatin capsules, for rectal or vaginal use.

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 topical preparation 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 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, accordingly, act on all tissues of the body (A.N. Decina. Theory of soft cosmetic effects. Modern cosmetology. - Novosibirsk: Nauka. 2000, 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 (e.g., ethyl or isopropyl), glycerin, low molecular weight polyethylene oxides (e.g., PEO-400), propylene glycols (e.g., 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 spike and granular layers, which leads to a decrease in the size of cell 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 (AN Decina. Soft theory of cosmetic effects. Modern cosmetology. - Novosibirsk: Nauka, 2000, www.golkom.ru/book/48_1.htm).

Sighetin, being a low molecular weight substance, dissolved in a liquid hydrophilic and hyperosmolar base, with local and external use easily and quickly penetrates the transepidermal barrier and mucous membranes into the circulatory system. Moreover, with percutaneous administration, the active substance is partially deposited in fragments of the epidermis 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 base and cigetine, liquids for local and external use are made: solutions, liniment, emulsions and suspensions with high penetrating ability.

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

The use of a hyperosmolar base improves microcirculation in wound tissues due to its dehydrating effect.

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-based base, 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 (PEO) - water-soluble products of polymerization of ethylene oxide, which are physiologically indifferent compounds. Hydrophilic 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 hyperosmolar properties. They are easily applied to the skin surface and uniformly are distributed, while maintaining their uniformity, low toxicity and do not irritate tissues, do not violate their physiological functions.

The ability of polyethylene oxides 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 PEO-400 solvent with PEO-15 00 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" edited by prof. 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 is liquefied by adding alcohol, glycerol, with vigorous stirring, the pH of a 20% aqueous suspension of 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, 6 AK 7/48).

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/libram/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, 12/27/2002).

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 ranging from 0.01 to 0.50%.

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 on their basis penetrate well through the skin and conduct medicinal substances, the dose of these substances in pharmaceutical compositions can be reduced (www.uran.m / gazetanu / 2007/04 / nu11 / wvmnu_р3_11_042007.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/flles/docs/diss /bojakovskii.doc).

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

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 can 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 fluids, being hyperosmolar (solutions, emulsions, suspensions in the form of liniments), increase the permeability of the skin, effectively transporting the active substance cigetine 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 transport of the active substance cigetin 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 penetrate more easily through the transepidermal 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 contained in the hydrophilic gel layer on the surface of the skin or mucous membrane diffuses 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 a weakly alkaline medium (pH 7.3-7.6) of the mucous membranes, the gelatinous membranes swell, and in this state even a weak effect on them is enough to break it and release the contents . 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 pharmaceutical product 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 pharmaceutical preparation, sigetin, which has a number of the above properties, reduces estrogen-dependent menopausal disorders in women with menopause.

The use of a hydrophilic and hyperosmolar base in the proposed pharmaceutical preparation ensures fast delivery of the active substance to the cells of the tissue and into 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 in a polyethylene oxide base increases its 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 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 polyvinylpyrrolidone 8000 ± 2000 6.0 purified water up to 100

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

100 g of a 0.5% solution contains, g:

sigetin 0.5 polyethylene oxide 400-10,0 purified water up to 100

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

100 g of a 0.25% solution contains, g:

sigetin 0.25 polyethylene oxide 400-20,00 purified water up to 100

Example 4. Liniment No. 1.

100 g of a 2.0% liniment contains, g:

sigetin 2.0 1,2-propylene glycol 60.0 purified water up to 100

Example No. 5. Liniment No. 2

In 100 g of a 1.0% liniment contains, g:

sigetin 1,0 1,2-propylene glycol 50,0 proxanol-268 5,0 purified water up to 100

Example 6. Liniment No. 3.

In 100 g of a 0.5% emulsion contains, g:

sigetin 0.5 PEO-400 60.0 purified water up to 100

Example 7. Cream No. 1.

In 100 g of a 1.0% cream contains, g:

sigetin 1.00 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

Example 8. Cream No. 2.

In 100 g of a 0.5% cream contains, g:

sigetin 0.5 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

Example 9. Cream No. 3.

100 g of 0.25% cream contains, g:

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

Example 10. Ointment No. 1.

In 100 g of a 1.0% ointment contains, g:

sigetin 1,0 PEO-400 polyethylene oxide 28.00 proxanol-268 20.00 purified water up to 100

Example 11. Ointment No. 2.

100 g of a 0.5% ointment contains, g:

sigetin 0.5 proxanol-268 24.0 1,2-propylene glycol 50,0 purified water up to 100

Example 12. Ointment No. 3.

100 g of a 0.25% ointment contains, g:

sigetin 0.25 PEO-400 70.0 proxanol - 268 - 20,0 purified water up to 100

Example 13. Gel No. 1.

100 g of a 1.0% gel contains, g:

sigetin 1,0 sodium hyaluront 0.30 purified water up to 100

Example 14. Gel No. 2.

100 g of 0.5% gel contains, g:

sigetin 0.5 polyethylene oxide gel 1500 up to 100

Example 15. Gel No. 3.

100 g of a 0.25% gel contains, g:

sigetin 0.25 glycerohydrogel based silicon glycerates 60.0 purified water up to 100

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 proxanol-268 60.0 polyethylene oxide-400 15.0 purified water up to 100

300 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm and a weight of 2.5 g with a cigetine content of 0.025 g in one suppository were made from this mixture. 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 No. 17. Mix for the preparation of suppositories No. 2.

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

sigetin 0.5 proxanol-268 64.0 polyethylene oxide-400 6.0 purified water up to 100

300 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm and a weight of 2.0 g with a sigetin content of 0.01 g in one suppository were made from this mixture. 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 No. 18. Mix for the preparation of suppositories No. 3.

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

sigetin 0.25 proxanol-268 66.0 polyethylene oxide-400 8.0 purified water up to 100

300 pieces of rectal suppositories in the form of a “cigar” with a diameter of 10 mm and a weight of 2.0 g with a sigetin content of 0.005 g in one suppository were made from this mixture. 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 of gelatin capsules No. 00 with 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 pharmaceutical preparations were created in the form of liquid and soft dosage forms containing the active substance sigetin and a hydrophilic osmolar base.

Example 20. Composition for the manufacture of suppositories.

100 g of a 0.5% mixture for the preparation of suppositories contain, g Components g % sigetin 0.5 0.5 gelatin 12.5 12.5 glycerol 61.5 61.5 purified water 25.5 25.5

Example 21

Comparative tests of cigetin were carried out on a model of postvariectomy syndrome after surgical removal of the ovaries in experimental animals (mice).

For rectal administration to mice, a pharmaceutical composition was used containing 1 g of the mixture: 0.005 g of cigetin, the rest was a hydrophilic base (0.125 g gelatin; 0.615 g glycerin, purified water up to 1 g).

A mixture for oral administration containing 1 g was also used: cigetin 0.005 g, glucose 0.2 g, starch - the rest.

With an average mouse weight of 0.025 kg, the rectally administered daily dose of the mixture was 0.04 g, in which sigetin contained 0.0002 g.

In the control group, the animals were orally administered with a mixture containing the same amount of cigetine (in a daily dose of 0.04 g of the mixture, 0.0002 g of cigetine was contained).

After predetermined time periods, the content of follicle-stimulating hormones in the blood plasma of ovariectomized mice was determined by the method of radioimmunological analysis.

In the case of rectal administration of a pharmaceutical composition containing cigetin, there was a more significant decrease in the content of follicle-stimulating hormones (32% more) in comparison with a decrease in the content of follicle-stimulating hormones upon oral administration of a mixture containing cigetin. This proves the more significant therapeutic effect of the pharmaceutical composition in the form of suppositories containing sigetin, in comparison with the oral form of sigetin. After evacuation of experimental animals, a histological analysis of organs was carried out, which did not reveal statistically significant changes in them compared with the control group.

Example 22. The effectiveness of cigetin in rectal form (in old mice with menopausal disorders).

The average life expectancy of mice is 750-810 days (25-27 months). At the beginning of the trials, the mice were 610 days old (about 20 months) and all were healthy.

For testing in mice, a pharmaceutical composition was used containing 1 g of the mixture: 0.01 g of cigetin, the rest was a hydrophilic base (proxanol-268 0.6 g; polyethylene oxide-400 0.15 g; purified water - up to 1 g) (per Example 16 of the description of the invention).

For the control group, a mixture for oral administration was used, containing 1 g: cigetine 0.01 g, glucose 0.2 g, starch - the rest.

With an average mouse weight of 0.025 kg, the rectally administered daily dose of the mixture was 0.04 g, in which sigetin was contained 0.0004 g. In the control group, the animals were orally administered a mixture containing sigetin in the same amount (in a daily dose of 0.04 g of the mixture contained 0.0004 g sigetin).

A daily dose of 0.0004 g sigetin was administered to each animal rectally (experimental group) and orally (control group) for 30 days. Then a break was made for 30 days and the administration cycle was repeated again for 30 days.

At the end of the experiment, in the experimental group of animals, motor activity was significantly higher than in the control group, the weight of the mice in the experimental group was significantly higher than in the control group (on average 5-6%), the degree of baldness in the experimental group was significantly lower. than in the control group.

In addition, the level of estrogen in the blood serum of mice was measured during the experiment. With the same level of estrogen in animals of the experimental and control group at the beginning of the experiment, at the end of the experiment, the level of estrogen in the experimental group of animals was significantly higher (16%) than in animals of the control group.

This proves the higher activity of cigetin in rectal form compared with cigetin in oral form.

Example 23. The effectiveness of cigetine for skin application.

An ointment of the following composition per 100 g was used: sigetin 0.25 g, purified water 25 g, 1,2-polyethylene glycol 28.5 g, polyethylene oxide-400 18.5 g, proxanol-268 - the rest is up to 100 g (according to example 9 descriptions).

In case of cutaneous application, the ointment was applied to mice of the experimental group on areas of the skin exempted from wool in the back. Application on the same skin area was applied 2 times a day for 30 days. The ointment was applied to the skin area in an amount of up to 0.1-0.2 g and rubbed into the skin for 10-15 seconds.

Then a break was made for 30 days and the cycle of ointment applications with sigetin was repeated again for 30 days. The control group of animals ointment was not applied. During the experiment, the skin of animals was monitored at the site of application of the drug — the presence or absence of inflammatory reactions at the site of application of the ointment, itching (scratching), ulceration, pigmentation, allopecia. thickness of the skin fold, dry skin, brittle hair (wool).

As a result of the experiment, reliable data were obtained on the absence of inflammatory and allergic reactions, itching (scratching), ulceration, pigmentation, allopecia in the place of application of the ointment. Moreover, compared with the control group in the experimental group, the degree of age-related alopecia was significantly lower than in the control group, dry skin and brittle hair (wool) were less pronounced.

Example 24. A composition in which there is still significant (p <0.05) a decrease in the content of follicle-stimulating hormones with rectal administration.

100 g of a 0.05% mixture for the preparation of suppositories contains, g Components g % sigetin 0.05 0.05 gelatin 12.5 12.5 glycerol 61.5 61.5 purified water 25.95 25.95

The proposed drug based on cigetin and a hydrophilic osmolar base primarily provides an extension of the field of application of cigetin and a more effective reduction of menopausal disorders, including degenerative changes in the skin, hair, nails, mucous membranes.

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

The above set of features of the proposed pharmaceutical product (composition of the drug, the quantitative ratio of the components and its dosage form) was not previously known, which indicates the novelty of the proposed solution.

The set of essential features of the claimed pharmaceutical product for external use on the basis of sigetin does not follow explicitly from the studied prior art, has significant differences from the considered analogues. 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).

Therefore, the applicant believes that the claimed pharmaceutical product for local and external use on the basis of sigetin has an inventive step. The inventive pharmaceutical preparation can be recommended for the prevention and treatment of menopausal disorders in women, especially urogenital and dermatropic.

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, liniment, ointments, creams, gels, as well as for industrial production of formed soft dosage forms: suppositories and capsules for rectal and vaginal administration.

Claims (2)

1. A pharmaceutical composition for local and external use in menopausal disorders, characterized in that it contains sigetin as the active substance, and hydrophilic and hypersmolar substances or their physiologically acceptable mixture in combination with components that provide the specified requirements for the base in depending on the dosage form of the drug, in the following ratio of components, wt.%:
sigetin 0.05-2,000 specified basis rest 2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a liquid dosage form - a solution, suspension, emulsion, liniment, or in the form of a soft dosage form - cream, ointment, gel, or in the form of a formed soft dosage form - suppositories or capsules for herbal or vaginal use.