RU2295955C1 - Sedative agent - Google Patents

Abstract

FIELD: medicine, chemical-pharmaceutical industry, phytotherapy, pharmacy.

SUBSTANCE: invention relates to designing agents of vegetable origin with sedative effect. Sedative agent is made as a tablet, its core is covered by envelope and tablet contains deviating peony dry extract, lactose, starch, magnesium basic carbonate, polyvinulpyrrolidone and calcium stearate. Envelope contains sugar, magnesium basic carbonate, polyvinylpyrrolidone, titanium dioxide, aerosil, bee wax and vaseline oil taken in the definite ratio. Deviating peony dry extract is prepared from deviating peony rhizomes, roots and herb 40% alcoholic tincture. Invention provides development of agent designated for using in neurotic and neurosis-like states of different genesis that has no toxic effect on morphofunctional state of vital organs and systems of body and doesn't cause impairment of metabolic processes.

EFFECT: valuable medicinal properties of agent.

3 cl

Description

The invention relates to the pharmaceutical industry, namely, to create a sedative of plant origin.

Preparations of the roots of the white-flowered peony are used as a sedative, expectorant, diuretic, antispasmodic, causing a decrease in the uterine myometrium, and also as an antiseptic for infectious diseases of the gastrointestinal tract (Mikhailov and Schröter, 1999).

Experimental studies have established that the main types of pharmacological activity of peony root preparations are sedative, anti-inflammatory, analgesic and antispasmodic. Intragastric administration of a decoction of the roots of the peony potentiates narcotic sleep induced by barbiturates (hexenal) and thiopental, and also has an anticonvulsant effect for seizures caused by camphor and nicotine (Trutneva, 1961), and has an antispasmodic effect on the ileum and uterus of laboratory animals (Hikino, 1985) . A similar effect was noted with the intrauterine administration of a methanol extract of peony roots (Lee, 1982), and ethanol extract stimulated smooth muscle of the uterus in rabbits (Harada et al., 1984). In in vitro experiments, peony root extracts weakened spastic contractions in the muscles of the stomach and uterus (Hikino, 1985).

It has also been shown that peony preparations have a pronounced anticoagulation effect (Pastorova et al., 1999). Thus, intraperitoneal administration of aqueous and ethanol extracts inhibited platelet aggregation induced by ADP, arachidonic acid and collagen, and also limited the spread of intravascular coagulation induced by endocin in laboratory rats (Kim et al., 1990; Kubo et al., 1982; 1984). white mice and rabbits (Wang et al., 1991). In vitro experiments have established that these extracts showed antifibrinogenic activity (Kawashiri et al., 1986).

It has been established that aqueous and ethanol extracts of peony roots have pronounced hepatoprotective activity, normalizing the morphological and functional state of the liver of white rats and mice in acute toxic hepatitis induced by carbon tetrachloride (Yun, Chang, 1980). Repeated intragastric administration of aqueous extracts of peony roots contributed to a decrease in the severity of negative side effects of radiation therapy (Ohta et al., 1993 a; 1993 b).

Tincture of grass and peony roots has a sedative and analgesic effect, increases gastric secretion (Phillipus, 1949).

It has been experimentally established that tincture of peony roots briefly reduces blood pressure and narrows the renal capillaries (Konovalov, 1963; Konovalov et al., 1962), has an antibacterial effect (Vichkanova, Rubinchik, 1961; Kurnakov, 1961; Kalinkina et al., 2000).

It has been established that the pharmacological effects of preparations of peony roots are mainly due to the presence of monoterpene glycoside peoniflorin, which has a wide spectrum of pharmacological activity. Thus, the following types of activity were revealed in pioniflorin: sedative, antipyretic, anti-inflammatory, vasodilator (Sugishita et al., 1984); analgesic (Gibbs, 1974), antispasmodic, hypotensive, antidiuretic, anticonvulsant (Duke, 1985).

For medical purposes, grass, roots and rhizomes of peonies evading plants during flowering are harvested, from which tincture (1:10) is prepared with 40 ° alcohol, and 0.5 g briquettes are formed from dried raw materials

In folk medicine, long ago, root preparations and the aerial parts of the peony were used for a variety of diseases. Alcohol tincture is used for insomnia, hypertension, diseases of the gastrointestinal tract (gastric and duodenal ulcers, gastritis, diarrhea) (Rastit. Resources of the USSR, 1986; Nepokoichitsky, 1996); with liver diseases (Halmatov, 1964); with oncological diseases (Balitsky et al., 1966); with metabolic disorders (Thunder, 1965); as an antipyretic and anti-inflammatory agent for gout, rheumatism, malaria (Balitsky et al., 1966; Lebedev, 2003); in obstetric practice with erosion and uterine cancer (Minaeva, 1991), and also as a tonic for the myometrium (Lebedev, 2003). Tea made from shredded peony and dried petals is an old remedy for epileptic seizures in children (Gindikin, 2002). Infusion of the root is used for stomach cancer, diarrhea, colic of peptic ulcer of the stomach and duodenum, colds, and pain in the uterus (Danikov, 1995). In folk medicine in the regions of the Far East, peony root is part of the formulations recommended for cardiovascular diseases (Dragachev, 1995). In Siberia, peony roots are used as a seasoning for meat dishes, and a decoction is used as a tonic drink (Telyatyev, 1985).

In traditional Chinese medicine, peony roots are part of anticancer drugs (Hammerman, 1976). In Mongolian medicine, preparations of herbs and roots of evading peonies are used for diseases of the kidneys, liver, epilepsy, and also as an antidote (Khaidav, Menshikova, 1978). In Tibetan traditional medicine, peony roots and grass are used to treat nervous diseases, diseases of the gastrointestinal tract and kidneys (Hammerman, 1976; Semenov, Tel'yatiev, 1966), and are also part of multicomponent drugs used in tuberculosis, pneumonia and bronchitis (Blinova Kuvaev, 1965).

In the countries of Southeast Asia, preparations of white-flowered peony are used as analgesic, anti-inflammatory, and antispasmodic agents for amenorrhea and dysmenorrhea, as well as for pain in the chest and abdominal cavity (Pharmacopeia of ... China, 1992). Peony root is also used for dementia, headache, dizziness, spasms of the calf muscles, for the treatment of atonic dermatitis, boils, burns, as well as an antipyretic (Pharmacopeia of ... China, 1992; Bruneton, 1995), liver diseases, allergies and as an anticoagulant (Hikino, 1985).

Drugs for peony evasion are contraindicated during pregnancy, since they contribute to an increase in uterine tone and can provoke abortion (Yordanov, 1972; Woo et al., 1981). In addition, peony preparations are not compatible with the preparations Fritillaria verticillata, Cuscuta japonica, Rheum officinale (Keys, 1976).

A disadvantage of the known funds based on peony evasive as a sedative is that they are an alcohol tincture, and therefore there may be great limitations with appropriate indications.

The objective of the present invention is to provide a sedative in a convenient and dosage form for patients in the period of neurotic and neurosis-like conditions of various origins, based on raw materials - peony plants evading "rhizome, root, grass".

To solve this problem, a tablet form of a sedative is proposed, the active substance of which is a dry extract of evading peony.

A sedative is proposed in the form of a tablet, the core of which is coated, which contains dry extract of evading peony, lactose, starch, basic magnesium carbonate, polyvinylpyrrolidone, calcium stearate in the following ratio of ingredients in g per 1 tablet:

dry peony extract evasion 0.150 lactose 0.114 starch 0.003 magnesium carbonate basic 0,027 polyvinylpyrrolidone 0.003 calcium stearate 0.003

and the shell contains sugar, basic magnesium carbonate, polyvinylpyrrolidone, titanium dioxide, aerosil, beeswax, paraffin oil with the following ingredients in g per tablet:

sugar 0.158 magnesium carbonate basic 0,047 polyvinylpyrrolidone 0.002 titanium dioxide 0.0015 aerosil 0.0010 beeswax 0,00025 Vaseline oil 0,00025

Dry extract of peony evading is obtained from 40% alcohol tincture of rhizomes, roots and herbs of peony evading.

The tool is intended for neurotic and neurosis-like conditions of various genesis, 1 tablet 3 times a day 30 minutes before meals, the course of treatment is 21-30 days.

Evasive peony Paeonia anomala L. (synonyms: irregular peony, pharmacy peony, medicinal peony, marin grass, marin root, heart berries) is a perennial herb from the peony family (Paeoniaceae). Distributed in the European part of Russia, in central Siberia from the Yenisei to Lake Baikal and in the western regions of Transbaikalia, it grows in forest and forest-steppe zones (Telyatyev, 1987). Evading peony - a plant up to 100 cm tall with tuberous roots, furrowed stems; flowers are single, large, pink-red, up to 12 cm in diameter, blooms in late May - June. Belongs to rare, reducing the number of species (Rare and Endangered ..., 1980). For medical purposes, the grass, rhizomes and roots of the peony are harvested.

Chemical composition. The roots of the evading peony contain carbohydrates: glucose, sucrose, starch 7.8-30.9% (Korotaeva, 1953); organic acids: benzoic, salicylic; monoterpenoids: peoniflorin; triterpenoids: α and β amirins (Tomczyk et al., 1979); steroids: β-sitosterol (Golovkin et al., 2001); phenolcardonic acids and their derivatives: salicylic acid (Korotaeva, 1949); phenoglucosides: salicin (Kolovkin et al., 2001); tannins 8.8% (Mikhailova, 1968); flavonoids 1.39% (Shirokov et al., 1980); vitamin C; essential oil (Plant resources ..., 1985); aromatic compounds (Shirokov et al., 1980); traces of alkaloids (Telyatyev, 1987); iridoids 0.9-1.3% (Kolpakova, Popov, 1994); trace elements (chromium, strontium) (Minaeva, 1991).

The invention is illustrated by the following example.

Obtaining a dry extract of peony

A battery of 6 percolators (PR1, PR2, PR3, PR4, PR5, PR6) is loaded with 120 kg of pre-ground raw materials (a mixture of grass and roots with rhizomes of peony evading in a ratio of 1: 1), 20 kg in each percolator. 60 l of ethyl alcohol 40% are added to wet the feed. After 6 hours in PR1 add 20 l of ethyl alcohol 40%, after 2 hours, drain with PR1 in an amount of 20 l is transferred to PR2. Add in PR1 20 l of alcohol 40%. After 2 hours, the extracts are moved according to the scheme: PR1> PR2> PR3. In PR1 add 20 l of pure extractant. Extracts are sequentially moved, repeating step 3 until a prepared (saturated) extract is obtained from PR6. Depleted raw materials are discharged from PR1 and transferred for processing. In PR2 add 20 l of ethyl alcohol 40%, after 2 hours, move according to the scheme: PR2> PR3> PR4> PR5> PR6, drain from PR6 of the saturated extract. Depleted raw materials from PR2 are transferred for processing. Repeat step 6 sequentially with PR3-PR6 percolators, obtaining 220 L of peony extract. The meal is squeezed out, the resulting peony extract in an amount of 40 l is combined with the first, filtered and transferred to the evaporation stage. The combined extract in an amount of 260 l is evaporated under vacuum at t≤80 ° C to a sedimentary moisture content of not more than 5%. The resulting peony extract is crushed, sieved, collected in a labeled container.

The yield of dry extract from raw materials is 8-10%. The content of the amount of iridoids in terms of peoniflorin and absolutely dry matter is at least 8.0%.

Next, tablets are prepared from a coated peony extract of 150 mg.

The raw materials and excipients are pre-screened: dry peony extract, milk sugar, potato starch, polyvinylpyrrolidone (PVP), basic magnesium carbonate, calcium stearate. A humidifier is prepared: a 5% solution of PVP in a 75% solution of ethyl alcohol. Next, get the mass for tableting. Dry components are mixed: dry peony extract, lactose, potato starch, basic magnesium carbonate. Next, the mixture is moistened; carry out wet granulation through a sieve of 4-5 mm; wet granules are dried at a temperature of (45 ± 5) ° С. Then dry granulation is carried out through a 2 mm sieve and dusted with calcium stearate, tabletted, dedusted, and then the tablet core is coated with a coating comprising sugar, magnesium basic carbonate, PVP, titanium dioxide, aerosil, beeswax, paraffin oil.

Experimental studies have been conducted.

The study involved a dry extract obtained from 40% alcohol tincture of rhizomes, roots and herbs of the evading peony (Tinctura Paeoniae).

As a comparison drug used 40% alcohol tincture of peony (Tinctura Paeoniae). Before the experiments, in order to exclude the influence of ethanol, the tincture of peony was dealcoholized by evaporation in a water bath to 1/10 of the initial volume. The resulting residue was adjusted with distilled water to a predetermined volume in accordance with the recommendations set out in the manual (Rules ..., 1992).

The experimental work was performed on white rats of the Wistar line of both sexes weighing 160-200 g, white mice of the CBA line of both sexes weighing 18-20 g. The animals were kept in the standard diet in the vivarium of the institute on a normal diet (Order of the Ministry of Health of the USSR No. 1179 of 10/10/83 g.). The experiments were carried out in accordance with the "Rules for the use of experimental animals" (Appendix to the order of the Ministry of Health of the USSR No. 755 of 08/12/77). Animals were euthanized by instant decapitation under light ether anesthesia.

In addition, model systems were used as objects of study: a suspension of red blood cells, a suspension of mononuclear leukocytes, a suspension of liposomes, cultures of opportunistic microorganisms, preparations of segments of the small intestine of white rats.

In the study of specific pharmacological activity, adequate pharmacological, biochemical, physiological, immunological research methods were used in accordance with the recommendations of the FC MH "Guide to the experimental (preclinical) study of new pharmacological substances" (2000).

The study of the spectrum of specific pharmacological activity of the dry extract evasive included the determination of sedative, anti-inflammatory, analgesic, antihypoxic, antistress, antispasmodic, antibacterial, membrane-stabilizing and antioxidant activity.

The data obtained were statistically processed using the U - criterion of Wilcoxon-Mann-Whitney (Sergienko, Bondareva, 2000). The differences were considered significant at P≤0.5.

The data obtained indicate that a single administration of a dry extract of evading peony (SEPU) in an experimental therapeutic dose of 150 mg / kg has a pronounced sedative effect, as indicated by the potentiation and prolongation of narcotic sleep induced by hexenal, chloral hydrate, and seduxen. Also, the presence of anticonvulsant activity in sepu with seizures caused by convulsants of various mechanisms of action: corazole, strychnine, and thiosemicarbazide was established. Given the mechanisms of action of these hypnotic drugs, it can be assumed that the test agent provides a wide irradiation of inhibitory processes in different parts of the central nervous system, including the cerebral cortex, due to the strengthening of the blocking effects of narcotic drugs on the ascending part of the reticular formation. The presence of anticonvulsant activity indicates that SEPU not only enhances inhibitory processes induced by hypnotic drugs, but also has inhibitory activity itself, providing interruption of the excitation processes caused by the introduction of central nervous system stimulants. Given the most pronounced anticonvulsant activity in convulsions caused by thiosemicarbazide, it can be assumed that the leading mechanism of anticovulsant action of the test drug is the activation of GABA-benzodiazepine chlorine channels. Moreover, it was found that the sedative activity of SEPU in an experimental therapeutic dose of 150 mg / kg corresponds to that of the comparison drug - peony tinctures. The test agent exerts a more pronounced sedative effect with repeated prophylactic administration in the specified dose.

When studying the influence of SEPU on behavioral activity, it was shown that the test tool accelerates the period of adaptation to new unfamiliar conditions, increases orientative research activity, reduces the level of emotionality and anxiety of animals.

The test agent also has a pronounced antihypoxic activity, increasing the lifespan of animals in oxygen-deficient states of various genesis (hypobaric, hemic and tissue hypoxia), increasing the lifespan of animals during low oxygen partial pressure in the air, and in violation of the oxygen-transport function of blood and inhibition of tissue mitochondrial respiration of body cells.

It was found that SEPU has a stress-protective activity, preventing the development of catabolic changes in the internal organs of animals under 24-hour immobilization stress, as evidenced by a less pronounced involution of immunocompetent organs and adrenal hypertrophy in experimental rats. This property of SEPU was most clearly manifested in its ability to delay the development of destructive lesions in the gastric mucosa at the stage of the occurrence of point hemorrhages, preventing the development of larger destruction in the form of erosions and strip-like ulcers. The data obtained indicate the ability of this tool to increase the activity of stress-limiting central systems of the body, in particular the GABA-ergic system.

As a result of a study of non-specific types of toxicity of dry extract of peony evading at doses of 1 and 2 ED ₅₀ , as well as its finished dosage form (tablets), it was found that the test drug belongs to the group of practically non-toxic substances, its long-term (for 3 months) the introduction does not adversely affect the morphological and functional state of the central nervous, cardiovascular and urinary systems, organs of the gastrointestinal tract, metabolic state, and peripheral blood counts.

Based on the foregoing, it can be concluded that dry extract of evading peony and its dosage form with prolonged use do not have a toxic effect on the morphofunctional state of vital organs and systems of the body, does not lead to metabolic disorders in laboratory animals, is a low-cumulative agent; does not have a local irritant effect.

As a result of studies on the assessment of specific types of toxicity, it was found that dry extract of peony evading at a dose of 150 mg / kg (ED ₅₀ ) does not have allergenic, immunotoxic and mutagenic properties, does not have embryotoxic and teratogenic effects, does not adversely affect the postnatal development of offspring laboratory animals.

The indicated properties of the dry extract of peony evasion argue the feasibility of its use in clinical practice as a sedative agent of mild action in neurotic and neurosis-like states of various origins in the proposed tablet form.

The introduction and widespread use of this tool in clinical and preventive medicine will increase the effectiveness of ongoing therapeutic and preventive and recreational activities and limit the import of drugs of this kind.

Claims (3)

1. A sedative containing extract of peony evading, characterized in that it is made in the form of a tablet, the core of which is coated, which contains a dry extract of peony evading, lactose, starch, magnesium carbonate basic, polyvinylpyrrolidone, calcium stearate in the following ratio of ingredients, g for 1 tablet: Dry peony extract evasion 0.150 Lactose 0.114 Starch 0.003 Magnesium carbonate basic 0,027 Polyvinylpyrrolidone 0.003 Calcium stearate 0.003 and the shell contains sugar, basic magnesium carbonate, polyvinylpyrrolidone, titanium dioxide, aerosil, beeswax, paraffin oil with the following ingredients, g per tablet: Sugar 0.158 Magnesium carbonate basic 0,047 Polyvinylpyrrolidone 0.002 Titanium dioxide 0.0015 Aerosil 0.0010 Beeswax 0,00025 Vaseline oil 0,00025 2. The tool according to claim 1, characterized in that the dry extract of peony evading is obtained from 40% alcohol tincture of rhizomes, roots and herbs of the peony evading. 3. The tool according to claim 1, characterized in that it is intended for neurotic and neurosis-like conditions of various genesis, 1 tablet 3 times a day 30 minutes before meals, the course of treatment is 21-30 days.