RU2295968C2 - Combined preparation possessing sedative, spasmolytic and anti-allergic effect - Google Patents

Abstract

FIELD: medicine, pharmaceutical industry.

SUBSTANCE: invention proposes a combined preparation containing valerian tincture, hawthorn tincture, motherwort tincture, peppermint tincture and dimedrol taken in the following ratio of components, wt.-%: valerian tincture, 32-34; hawthorn tincture, 32-34; motherwort tincture, 16-17; peppermint tincture, 16-17, and dimedrol, 0.1-0.2. The combined preparation is used in functional disorders of cardiovascular system, initial symptoms of stenocardia, initial form of arterial hypertension, paroxysmal tachycardia, extrasystolia, insomnia, enhanced irritability and neurosis. The preparation has no toxicity and characterized by minimal risk in development of adverse effects. Invention can be used in treatment of patients with cardiovascular insufficiency, cardiac stenocardia and neurosis.

EFFECT: valuable medicinal properties of preparation.

3 cl, 2 tbl, 3 ex

Description

The invention relates to the pharmaceutical industry and may find application for the treatment of patients with cardiovascular insufficiency, cardiac angina pectoris, neurosis,

Currently, in Russia, the range of complex dosage forms is limited and is represented mainly by herbal preparations with a sedative effect (valoserdin, corvalol, novopassit, valosedan). Often, the composition prescribed by doctors for extemporaneous manufacture includes barbiturates, diphenhydramine, bromides. However, the use of barbiturates as sleeping pills and sedatives should be avoided due to the possibility of their cumulation and development of addiction. The simultaneous use of phenobarbital with other sedative drugs leads to an increase in the sedative-hypnotic effect and may be accompanied by respiratory depression.

Known drugs used in the treatment of cardiovascular insufficiency, containing tincture of valerian and menthol (Zelenin drops, The prescription of a doctor under the editorship of prof. I.S. Chekman, Kiev, Health, 1984, p. 37, rec. 219).

Also known are lily of the valley-valerian drops containing sodium bromide (M.D. Mashkovsky, Medicines - M., Medicine, 1967, part 1, p. 91), used as a sedative for insomnia.

Known drug from the extract of hawthorn fruit, used as a tonic heart muscle, eliminating tachyarrhythmias, enhancing coronary circulation, hypotensive (ed. St. USSR N 2000807, class A 61 K 35/78, published 10/15/93).

Drops containing tincture of valerian, sodium bromide, menthol, and other components used as an anesthetic and sedative are known (Prescription Guide under the editorship of Prof. I.S. Chekman, Kiev, Health, 1984, p. 37, rec. 211 )

Closest to the proposed invention are heart drops (patent RU No. 2169577) containing tincture of valerian, sodium bromide, menthol, tincture of hawthorn in the following ratio, wt.%:

Valerian tincture 42-46 Tincture of hawthorn 42-46 Sodium Bromide 9-10 Menthol 0.5-1.0

The disadvantages of this tool, in our opinion, include the following:

- insufficiency of sedative and antispasmodic action;

- the sodium bromide that is part of the product with prolonged use can cause side effects, such as a runny nose, memory loss, conjunctivitis;

high percentage of tincture of hawthorn (according to literature, tincture of hawthorn may have toxicity to the liver and heart).

An object of the invention is to develop the composition of a combined preparation, characterized by an increase in sedative and antispasmodic action and recommended for the treatment of neurosis, vegetative-vascular dystonia with a tendency to increase blood pressure, heart rate.

This object is achieved in that the combined preparation containing tincture of valerian, tincture of hawthorn, additionally contains tincture of motherwort, tincture of peppermint, diphenhydramine in the following proportions, in wt.%:

Valerian tincture 32-34 Motherwort tincture 32-34 Tincture of hawthorn 16-17 Peppermint tincture 16-17 Diphenhydramine 0.1-0.2

Advantages and distinguishing features of the claimed composition:

An essential distinguishing feature of the claimed composition is the presence in it of alcoholic extracts from medicinal herbs that have a sedative and antispasmodic effect, which allows its use in neurosis as a sedative, in case of vegetative-vascular dystonia.

In addition, the combination drug does not include addictive barbiturates, and the clinical effect is not inferior to drugs such as corvalol, valocordin. The composition is characterized by a pronounced sedative, spasmolytic effect, as well as an anti-allergic effect.

The combined use of tinctures with diphenhydramine causes the effect of potentiating synergism (sedative effect on the central nervous system). In this case, diphenhydramine, which is part of the claimed composition, is completely excreted from the body with urine during the day, mainly in the form of benzhydrol conjugated with glucuronic acid.

The composition is theoretically justified; High pharmacological efficacy is practically shown.

The composition excludes the simultaneous administration of a series of drugs in order to achieve a sedative effect, and also allows to reduce the dosage of other drugs used in the treatment of cardiovascular diseases.

The inventive composition can be used for a long time (for chronic diseases), which is not shown for most complex dosage forms of sedative and antispasmodic (for example, valocormide is not recommended for prolonged use due to the possibility of accumulation of bromine in the body).

The multicomponent nature of the drug, the variety of biologically active substances, and the particular mechanisms of the pharmacological effect provide a high activity of the drug.

The invention allows to expand the range of pharmacological effects and normalize the work of the cardiovascular system due to the selection of components with adaptogenic, sedative, antihypertensive properties.

Thus, the claimed composition is a combined preparation consisting of tincture of hawthorn, tincture of valerian, tincture of peppermint, tincture of motherwort and diphenhydramine. All components that make up the complex composition are approved for use in medical practice:

- The fruits of hawthorn in the form of tincture enhance the contraction of the heart muscle and at the same time reduce its excitability. The presence in the hawthorn of triterpenic acids (ursolic, oleanic, krategovy) and flavonoids enhances blood circulation in the coronary vessels of the heart and in the vessels of the brain. Hawthorn tincture is used for functional disorders of cardiac activity, for angioneurosis, atrial fibrillation and paroxysmal tachycardia.

- Tincture of valerian reduces the central nervous system excitability, enhances the effect of sleeping pills, has antispasmodic properties. It is used as a sedative for nervous agitation, insomnia, neurosis of the cardiovascular system, with gastrointestinal spasms. Often used in combination with other drugs. Sedation appears slowly but stably enough. Valerianic acid and valepotriates have a weak antispasmodic effect.

- Peppermint tincture has a calming and antispasmodic effect. The main active ingredient is menthol and its esters, as well as flavonoids (luteolin-7-glucoside, hesperidin, etc.), organic acids. Irritation of the nerve endings of the oral mucosa leads to reflex expansion of the vessels of the heart and brain.

- Tincture of motherwort contains flavonoids (quercetin, rutin, etc.), saponins, tannins, alkaloids. It has a sedative, hypotensive, negative chronotropic and cardiotonic effect. Assign as a sedative for increased nervous excitability, cardiovascular neurosis, in the early stages of hypertension (antispasmodic effect). Since tincture of motherwort gives an effect rather slowly, it is advisable to combine it with other tinctures of a similar action (with tincture of valerian, etc.)

- Diphenhydramine - benzhydrol beta-dimethylaminoethyl ether hydrochloride is classified as a group of antihistamines. The main action - weakens the effects of histamine in the body. Relieves spasms of smooth muscles, reduces capillary permeability, prevents and facilitates the course of allergic reactions. Along with the antihistamine action, diphenhydramine has a sedative effect, inhibits the nervous excitation in the autonomic ganglia, has a central anticholinergic effect, anti-inflammatory properties, antispasmodic and antiemetic effect. Diphenhydramine is widely used as a sedative and hypnotic, both independently and in combination with other sedatives. The dose of diphenhydramine for adults is 30-50 mg 1-3 times a day.

All drugs that are part of the claimed drug have an antispasmodic effect. Given that in the treatment of diseases, the combined use of drugs with a unidirectional effect is considered most important (the synergism effect is the possibility of using lower doses of the components of the composition, and hence the reduction of possible undesirable side effects), then the inclusion of the above tinctures and diphenhydramine in the complex drug can be considered reasonable.

The drug of the claimed composition has sedative, antispasmodic, antiallergic properties, reduces the processes of excitation in the central nervous system. Facilitates the onset of sleep (provides the onset of light sleep, characterized by mild awakening).

The claimed composition of the combined drug is recommended for use in case of increased nervous excitability, in stressful situations - psychoemotional stresses, various functional diseases of the nervous system (neurosis, neurosis-like conditions, vegetative-vascular dystonia), and sleep disturbance. Children - not assigned.

The combined drug is recommended to be administered orally by 30-40 drops 3-4 times a day 30 minutes before meals. With constant use, it is recommended to take a break for 5-7 days after 7-10 days of admission.

The technology for obtaining the drug includes obtaining tinctures of motherwort, valerian, hawthorn, peppermint using the method of intermittent percolation or the method of accelerated fractional maceration (Drug Technology, Muravyov I.A., v.2, 272 p.).

Tinctures are mixed, and then diphenhydramine is dissolved in them. The resulting solution is defended (at a temperature not exceeding 8 ° C), filtered (using gauze and cotton wool). The resulting preparation is a clear liquid of yellow-brown or greenish color, characteristic odor, contains 63 vol.% Alcohol.

When observing the various series of the claimed composition for 5 years, neither turbidity nor precipitation was observed, which indicates the presence of a small amount of tannins in the preparation and the compatibility of all the ingredients of the recipe.

The combined preparation should contain a dry residue of at least 1.7% (GF XI, issue 2, p. 149).

Heavy metals no more than 0.001% (GF XI, issue 2, p. 149), density no more than 0,902 (GF XI, issue 1, p. 24, method 1).

The resulting combined preparation meets the requirements of the Global Fund XI.

Examples of specific performance:

Example 1

Valerian tincture in an amount of 33.3%, motherwort tincture in an amount of 33.5%, hawthorn tincture in an amount of 16.2%, peppermint tincture in an amount of 16.9% are mixed with each other, then 0.1% of diphenhydramine is added.

Example 2

Valerian tincture in an amount of 33.5%, motherwort tincture in an amount of 33.3%, hawthorn tincture in an amount of 16.5%, peppermint tincture in an amount of 16.6% are mixed with each other, then 0.1% of diphenhydramine is added.

Example 3

Valerian tincture in an amount of 33.8%, motherwort tincture in an amount of 33.0%, hawthorn tincture in an amount of 16.0%, peppermint tincture in an amount of 17% are mixed together, then 0.2% of diphenhydramine is added.

Studies of acute and subacute toxicity of the inventive combined preparation in outbred rats and mice have been conducted. Acute toxicity was determined in the experiments - the death of animals was not observed even when the drug was administered at a dose of 6 ml per 1 kg of animal weight.

With long-term administration of the drug (within 28 days) to rats of both sexes at a dose of 0.1 ml / kg of mass, no significant changes in physiological, hematological and biochemical parameters were recorded in comparison with control groups of animals. Toxic dose - 1.0 ml / kg (also administered within 28 days) - observed the death of animals (mortality 30%), an increase in cytolysis and a change in the histomorphological picture of internal organs, which was not statistically significantly different from those of control animals receiving physiological solution in the same volume throughout the experiment. It can be assumed that the death of animals occurred as a result of cardiovascular failure. The lethal dose could not be established.

When studying subacute toxicity (macroscopic and histological analysis) of the claimed composition (in accordance with the recommendations of the Pharmacological Committee of the Ministry of Health of Russia and the rules of preclinical safety assessment of pharmacological agents), it was found that the drug does not cause degenerative changes in the internal organs of animals (lungs, kidneys, heart, liver). The study of acute toxicity was carried out on white rats males (60 pcs.) And females (60 pcs.) Weighing 200-220 g, as well as on mice of both sexes weighing 20-21 g (120 mice in total), which were administered the drug in doses of 0 5, 1, 2, 3, 4, 6 ml / kg body weight using a probe intraperitoneally. Observation was carried out for 2 weeks after administration of the substance. The death of animals (rats and mice) during the observed period was not recorded. Thus, the combined preparation in accordance with the classification of K.K.Sidorov belongs to the class of practically non-toxic compounds.

A study of the activity of the claimed composition was conducted - sedative activity was studied on a model of non-butal sleep. In total, 10 series of experiments were carried out on 10 animals (white rats - males weighing 180-200 g) in each. In the control group, physiological saline was injected, in the reference series - magnesium sulfate at a dose of 10 ml / kg; in the experimental groups - the claimed composition at a dose of 5 ml / kg of animal body weight 60 minutes before the intraperitoneal administration of nembutal at a dose of 30 mg / kg. Registration of the duration of non-butal sleep was carried out according to the criterion of the lateral position of animals. The results of experimental studies are presented in table 1.

Thus, the claimed composition has a depressing effect on the central nervous system, significantly increases the time of non-numbal sleep in comparison with the control group and reference experiments. A significant increase in the duration of nembutal sleep occurs in various dosages, which indicates a potentiating synergism.

When studying the cardiovascular activity of the claimed composition, outbred white rats were used - males weighing 200-250 g, which were previously implanted with polyethylene catheters under nembutal anesthesia: into the abdominal aorta through the femoral artery to record systemic blood pressure and heart rate; in the left ventricle to record heart indices; into the stomach - for the introduction of the studied substances. The experiments began 24-28 hours after surgery, when the rats were awake. System hemodynamics and heart indices were recorded using disposable SP-01 sensors (USA) and the Bioshell computer program (cardiology research and production complex, Moscow) based on an IBM PC AT 386 personal computer.

In the control group, the claimed composition was administered at a dose of 1 ml / kg into the stomach in the form of an alcohol solution through an implanted polyethylene catheter. The results were statistically processed using the Solo computer program and are presented in table 2.

As shown by the results of studies, the claimed composition does not cause 5 and 60 minutes to significantly reduce the level of systemic blood pressure, heart rate, and cardiac activity, which indicates that the drug does not have a toxic effect on the activity of the cardiovascular system in animals.

Pharmacological studies have shown that when the content of diphenhydramine in the combined preparation in the indicated amount (0.1-0.2%) is observed, the highest activity of the drug. A further increase in the content of diphenhydramine above the claimed amount does not affect the increased activity of the combined drug.

The obtained experimental data showed that the claimed composition has an inhibitory effect on the central nervous system, significantly increases the time of non-mental sleep in comparison with the control and reference experiments. A significant increase in the duration of nembutal sleep indicates potentiating synergism.

Based on the results of pharmacological studies of the claimed composition, the following dosages were proposed for use in medical practice:

30-40 drops 3-4 times a day 30 minutes before meals. In case of constant use of the composition, it is necessary to take a break after 7-10 days of administration (for 5-7 days).

Pharmacological studies in humans have been conducted at the Pyatigorsk City Hospital No. 2. Patients with identified neurosis, vegetative-vascular dystonia with a tendency to increase blood pressure, and palpitations were treated. Under observation were 18 patients aged 45 to 62 years.

All patients were prescribed the claimed composition inside of 30-40 drops 3-4 times a day. If necessary, patients received additional symptomatic therapy. During treatment, clinical, cardiological data, the state of the cardiovascular system, laboratory results, and a survey of patients about their condition were evaluated. The criteria for evaluating the therapeutic effect of the composition was the disappearance of the clinical manifestations of the disease. As the test results showed, the drug was effective in the first days of treatment. It had a pronounced sedative, antispasmodic effect, stopping pain in the heart, as well as normalizing blood pressure. In no case of use was it found side effects, the composition was well tolerated by patients. According to a five-point assessment of the efficiency scale, the composition was evaluated by patients on average 4.8 ± 0.2.

Based on the foregoing, we can conclude that the proposed composition of the combined drug has several advantages in comparison with the prototype.

Thus, from the presented materials it follows that the claimed composition is a practically non-toxic drug with a pronounced sedative, antispasmodic and anti-allergic effect, characterized by a minimal risk of side effects, which will expand the range of domestic complex herbal medicines.

Table 1 The influence of the claimed composition on the duration of non-butal sleep (outbred rats, n = 10). Group Duration of sleep in minutes, M ± m P with control P with reference Control group 62.6 ± 1.2 - - Prototype 77.0 ± 1.5 P <0.05 P <0.05 The inventive composition 111.5 ± 3.0 P <0.05 P <0.05

table 2 The influence of the claimed composition on the parameters of the hemodynamic system in awake rats when introduced into the stomach, M ± m, P <0.05 Options Initial data Change in% after 5 minutes % Change after 60 minutes Blood pressure, mmHg 110 ± 5.4 -7.3 ± 3.6 -2.8 ± 1.2 Heart rate per minute 387 ± 19.7 7.2 ± 3.0 -9.4 ± 4.4 Left ventricular pressure, mmHg 137 ± 12.1 -8.5 ± 4.2 -4.1 ± 2.7 End-diastolic pressure, mmHg 9 ± 0.5 8.5 ± 4.3 9.2 ± 3.9 + dp / dt 12126 ± 245 9.1 ± 5.1 17.2 ± 7.8 -dp / dt -8289 ± 197 13.0 ± 8.2 -12.8 ± 8.3 dp / dt / P 146 ± 15 8.7 ± 4.5 14.2 ± 9.6 dp / dt / pd 176 ± 27 9.1 ± 5.7 12.5 ± 7.1

Note.

+ dp / dt - an indicator characterizing the increase in contractility of the muscles of the left ventricle;

-dp / dt - an indicator characterizing the rate of relaxation of the muscles of the left ventricle;

dp / dt / P - an indicator characterizing the left ventricular myocardial contractility (Veragut index);

dp / dt / Pd - an indicator characterizing the contractility of the left ventricular myocardium, regardless of fluctuations in systemic blood pressure (modified Veragut index).

Claims (3)

1. A combined preparation with sedative, antispasmodic properties, containing tincture of valerian, tincture of hawthorn, characterized in that it additionally contains tincture of motherwort, tincture of peppermint and diphenhydramine in the following ratio, wt.%: Valerian tincture 32-34 Motherwort tincture 32-34 Tincture of hawthorn 16-17 Peppermint tincture 16-17 Diphenhydramine 0.1-0.2 2. The combined preparation according to claim 1, characterized in that it further has an anti-allergic effect. 3. The combined preparation according to claims 1 and 2, characterized in that the composition may be in the form of syrups, elixirs, tablets, capsules, granules and may contain additional excipients.