RU2535020C1 - Pharmaceutical composition possessing sedative and spasmolytic action - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: pharmaceutical composition possessing the sedative and spasmolytic action and containing valerian tea, motherwort tea, hawthorn tea, peppermint tea with a number of biologically active substances in each of the teas, and an antihistamine preparation of diphenhydramine hydrochloride; as ingredients of the biologically active substances, the composition contains flavonoids in a certain amount.

EFFECT: composition possesses the high sedative therapeutic effect, the improved therapeutic effect in treating psychoemotional disorders, including in women suffering from menopausal syndrome.

2 tbl, 3 ex

Description

The invention relates to medicine, more specifically to pharmacy, and can be used for the prevention and treatment of such anxious-suspicious conditions as neurosis, sleep disturbance, asthenia, as well as for psychoemotional disorders in women with menopausal syndrome.

In modern conditions, the load on the central nervous system increases significantly, and therefore such a group of drugs as tranquilizers is widely used. However, with prolonged use of synthetic tranquilizers, a high level of addiction is observed. Therefore, at present, drugs with components of plant origin that have a sedative effect on the nervous system are becoming increasingly relevant.

Among the medicinal plant material with a sedative effect, the most effective and widely used are motherwort grass, hop cones, lemon balm leaves, peppermint grass, rhizomes with valerian roots, and others. Of the dosage forms of this raw material, tinctures are found in medical practice as in combination with each other and with other drugs, since in the treatment of a number of diseases, the combined use of drugs with a single The pressure action, at which manifests a synergistic effect that produces the possibility of using lower doses of the formulation components, and thus decrease undesirable side effects.

From the patent of the Russian Federation No. 2497538, A61K 36/28, publ. 11/10/2013, it is known a product based on the extract of the seeds of the Nelumbo nucifera (Nelumbo nucifera), which has anxiolytic and antidepressant effects.

However, for its production, this tool requires an exotic plant - a lotus.

For the treatment of neurotic conditions associated with asthenia, the manifestation of neurosis, and insomnia, agents based on plants that are widely distributed in central Russia, such as valerian, motherwort, hawthorn, mint, and St. John's wort, are used. In the patent of the Russian Federation 2298413, A61K 36/734, publ. 05/10/2007, a tool for the prevention and treatment of nervous diseases and diseases of the cardiovascular system is described. The product contains a mixture of alcoholic extracts of herbs of melilot, motherwort, St. John's wort, lemon balm, valerian, heather, chicory roots, hops, hawthorn. Similar prescriptions contain applications and patents of the Russian Federation No. 2008128716, A61K 36/8968, publ. 01/27/2010, 2174005, 2185847, 2195951, A61K 35/78, publ., Respectively, 09/27/2001, 07/27/2002, 01/10/2003. Despite the duration of its existence, herbal compositions, collections, decoctions, tinctures are not serious competitors to synthetic drugs, obviously, due to the insufficiently high therapeutic effect.

To enhance their therapeutic effect, phenobarbital preparations are added to tinctures of plants. For example, the finished preparations “Corvalol”, “Valocordin”, “Valosedan”, “Valocormide”. However, these drugs can not be used for long-term therapy of psycho-emotional disorders in connection with the possible development of pathological addiction to barbiturates.

Closest to the claimed invention is a combined preparation with a sedative, antispasmodic and anti-allergic effect according to the patent of the Russian Federation No. 2295968, A61K 36/84, publ. 03/27/2007. This preparation contains, in the following ratio of components, tincture of valerian 32-34 wt.%, Tincture of hawthorn 16-17 wt.%, Tincture of motherwort 32-34 wt.%, Tincture of peppermint 16-17 wt.% And diphenhydramine 0.1 -0.2 wt.%. This drug is taken as a prototype of the claimed invention.

Despite the multicomponent nature of the known agent and the variety of biologically active substances contained in tinctures of herbs, the use of this composition in the treatment of neurosis and psychoemotional disorders associated with menopausal syndrome, showed its lack of therapeutic activity. In addition, according to the patent, the drug is recommended for use within 7-10 days, after which a break for 5-7 days should be taken. Thus, the well-known pharmaceutical composition requires frequent courses of treatment, in which the therapeutic effect of taking herbal components does not have time to gain a foothold.

In accordance with this patent, the drug Valeodicramen was produced in the form of drops for oral administration in dropper bottles of various capacities, in particular 50 ml, containing the same ingredients and their quantitative composition, which are presented in the prototype.

Drops for oral administration 150 ml Valerian tincture 16.6 ml motherwort herb tincture 16.6 ml tincture of hawthorn fruit 8.4 ml peppermint leaf tincture 8.4 ml diphenhydramine 50 mg

As follows from the instructions for use of this drug, it can cause side effects in the form of dyspeptic disorders, in connection with which it is recommended to interrupt treatment and cancel its use.

The technical result of the claimed invention consists in eliminating the side effect of the composition, which is expressed in dyspeptic manifestations, enhancing the sedative therapeutic effect, as well as in a higher therapeutic effect in the treatment of psychoemotional disorders, including in women with menopausal syndrome, due to faster stopping of disorders and achievement more persistent therapeutic result.

This technical result is achieved by the fact that in the known pharmaceutical composition of sedative and antispasmodic action, containing, in the following ratio of components, tincture of valerian 32-34 wt.%, Tincture of motherwort 32-34 wt.%, Tincture of hawthorn 16-17 wt.%, peppermint tincture 16-17 wt.% with a set of biologically active substances in each of the tinctures and antihistamine Dimedrol 0.1-0.2 wt.%, the pharmaceutical composition of the biologically active substances contains flavonoids in an amount equal to 0.0190 ± 0 , 0008 wt.% In terms of routine.

When conducting pharmacological studies of the prototype, it was found that the therapeutic effect of the known composition as a sedative and, especially, as a means of correcting psychoemotional disorders, including in the treatment of menopausal syndrome, depends on the quantitative content of biologically active substances of flavonoids in it. Moreover, prototype studies were carried out on the basis of the information reflected in the dissertation of the candidate of pharmaceutical sciences A. Ayrapetova "Development of quality standards and analysis methods for the multicomponent dosage form" Valeodicramen ", 1999, which indicates the total quantitative content of flavonoids in the preparation" Valeodicramen "equal to 0.0141 ± 0.0005 wt.%. Studies have shown that with an increase in the number of flavonoids in the composition, the therapeutic effect of the pharmaceutical composition increased. In addition, it was found that with an increase in the number of flavonoids, dyspeptic disorders were eliminated with prolonged use of the composition. Thus, according to the results of the study, it was found that with an increase in the number of flavonoids in the composition, the therapeutic effect, in addition to its inherent sedative properties, was expressed in the enhancement of this sedative effect, as well as in a higher therapeutic effect in eliminating psychoemotional disorders, for example, in women with menopause a syndrome.

As follows from the prototype, the well-known pharmaceutical composition consists of shared tinctures of valerian, hawthorn, motherwort, peppermint and diphenhydramine and is used for neurosis, vegetovascular dystonia with a tendency to increase blood pressure and a feeling of heartbeat. This remedy is effective in case of neurosis accompanied by increased nervous excitability, in stressful situations - psychoemotional stresses, as well as various functional diseases of the nervous system. In this case, when preparing the known agent, the amount of flavonoids in the finished form of the agent and their effect on therapeutic activity were not taken into account. Moreover, according to pharmaceutical article FSP 42-0152554704 for tincture of motherwort, it does not provide for the maintenance of any certain amount of flavonoids, and in accordance with pharmaceutical article FSP 42-049057704 for tincture of hawthorn, it contains a sufficient content of a minimum amount of flavonoids - at least 0.003 wt. %

Thus, it does not follow from a known level of knowledge that with psycho-emotional disorders in women, in particular, menopause, caused by hormonal disorders, there will be a higher therapeutic activity of the known composition when it contains the claimed amount of flavonoids.

These conclusions are confirmed by the results of experimental and clinical observations.

The claimed composition is prepared as follows.

Use ready-made alcohol tinctures of valerian, hawthorn, motherwort and mint, prepared by the method of intermittent percolation or the method of accelerated fractional maceration (Technology of medicines, Muravyov I.A., v.2, 272 p.).

To prepare a pharmaceutical composition of different composition, tinctures of motherwort and hawthorn with different flavonoid contents were used. It is known that the number of flavonoids in different representatives of motherwort and hawthorn is significantly different. Therefore, the content of these substances in the corresponding tinctures is different. When preparing a pharmaceutical composition, tinctures of motherwort and hawthorn with a high content of flavonoids in them are used: in the tincture of motherwort on average about 0.040 wt.%, In the tincture of hawthorn - not less than 0.010 wt.%.

To prepare the pharmaceutical composition, the required amount of tinctures is placed in a common glass dish, mixed and a portion of diphenhydramine is added to the solution, after which the solution is thoroughly mixed until diphenhydramine is completely dissolved. Next, the solution was incubated for some time until the insoluble components precipitated. The final product has a complex smell of all tinctures and a color from yellow-brown to green (the density of the finished pharmaceutical composition should be no more than 0.90 g / cm ³ , the dry residue in the preparation should be at least 1.7 wt.%).

The amount of flavonoids in the initial tinctures and pharmaceutical composition is determined by spectrophotometry using a solution of aluminum chloride.

Quantitative determination of flavonoids is as follows.

Prepare aluminum chloride alcohol solution:

3.6 g of aluminum chloride is dissolved by heating in a water bath in 80 ml of alcohol 96% in a 100 ml volumetric flask, cooled, the volume of the solution is adjusted to the mark with the same solvent, stirred and filtered through an ashless filter “Blue Ribbon”.

The shelf life of the solution is 6 months.

Prepare the original test solution:

20 ml of the drug is placed in a volumetric flask with a capacity of 25 ml, the volume of the solution is adjusted with 96% alcohol to the mark, stirred and filtered through a PTFE membrane filter with a pore size of 0.45 μm, discarding the first portions of the filtrate.

5 ml of the original test solution is placed in a 25 ml volumetric flask, 10 ml of alcohol 96%, 0.5 ml of acetic acid, diluted 30%, and 2 ml of aluminum chloride of alcohol solution are added, the volume of the solution is adjusted with 96% alcohol to the mark and mixed thoroughly .

Preparing a comparison solution 1:

5 ml of the original test solution is placed in a volumetric flask with a capacity of 25 ml, add 10 ml of alcohol 96%, 0.5 ml of acetic acid diluted with 30%, bring the volume of the solution with alcohol 96% to the mark and mix thoroughly.

40 minutes after preparation of the test solution, its optical density is measured on a spectrophotometer at a wavelength of 410 ± 2 nm in a cuvette with a layer thickness of 10 mm relative to solution 1.

Prepare a stock solution of CO rutin:

about 0.05 g (accurately weighed) of rutin (FSO HFC, cat. No R0366), previously dried at a temperature of 130 to 135 ° C to constant weight, is placed in a 100 ml volumetric flask and dissolved in 70 ml of alcohol 96% at heated in a boiling water bath, cooled, adjusted to the mark with the same solvent, stirred and filtered through a PTFE membrane filter with a pore size of 0.45 μm, discarding the first portions of the filtrate.

The shelf life of the solution is 1 month, when stored in a dark place in a well-closed container at a temperature of +2 to + 8 ° C.

1 ml of the stock solution of CO rutin is placed in a volumetric flask with a capacity of 25 ml, add 10 ml of alcohol 96%, 0.5 ml of diluted acetic acid 30%, 2 ml of aluminum chloride alcohol solution and bring 96% alcohol to the mark, mix.

Prepare a solution of comparison 2:

1 ml of a stock solution of CO rutin is placed in a 25 ml volumetric flask, 10 ml of alcohol 96%, 0.5 ml of acetic acid diluted 30% are added, 96% alcohol is adjusted to the mark and mixed thoroughly.

40 minutes after the preparation of the CO rutin solution, its optical density was measured on a spectrophotometer at a wavelength of 410 ± 2 nm in a cuvette with a layer thickness of 10 mm relative to comparison solution 2.

The content of the sum of flavonoids in the preparation (X) as a percentage in terms of rutin is calculated by the formula:

X = A ■ a0 •! • 25 • 25 • P-100 = A ■ a0 ■ P = A ■ 20-p-5-100 ■ 25-100 ~ A, - P-400, where

A is the optical density of the test solution;

A is the optical density of a solution of CO rutin;

a0 — weight of CO routine, g;

p is the density of the drug, g / ml;

P is the rutin content in CO,%.

As experimental studies have shown, the best results in increasing therapeutic activity have been established for a pharmaceutical composition with a flavonoid content in terms of rutin equal to 0.0182-0.0198 wt.% Or more.

In the above-described manner, samples of the pharmaceutical composition of several formulations were prepared, which are shown in examples 1-3.

Example No. 1

A composition was prepared containing 33.0 wt.% Tincture of valerian, 33 wt.% Tincture of motherwort, 17 wt.% Tincture of hawthorn, 16.9 wt.% Tincture of mint and 0.1 wt.% Diphenhydramine. The amount of flavonoids in the composition was 0.0182 wt.% In terms of rutin.

Example No. 2

A composition was prepared containing 33.3 wt.% Tincture of valerian, 33.0 wt.% Tincture of motherwort, 16.7 wt.% Tincture of hawthorn, 16.85 wt.% Tincture of mint and 0.15 wt.% Diphenhydramine. The amount of flavonoids in the composition was 0.0190 wt.% In terms of rutin.

Example No. 3

A composition was prepared containing 33.9 wt.% Tincture of valerian, 34.0 wt.% Tincture of motherwort, 16.0 wt.% Tincture of hawthorn, 16.00 wt.% Tincture of mint and 0.1 wt.% Diphenhydramine. The amount of flavonoids in the composition was 0.0198 wt.% In terms of rutin.

The results of measuring the amount of flavonoids in a pharmaceutical preparation prepared according to the prototype and according to the invention are presented in table 1. As follows from the presented results, the number of flavonoids in the composition according to the prototype is on average 0.0140 wt.% In terms of rutin, and according to the claimed invention - 0.0190 wt.% in terms of rutin.

The study of therapeutic activity of the claimed pharmaceutical composition

Elimination of a side effect in the form of dyspepsia, as well as increased therapeutic activity of the claimed drug in the treatment of menopausal syndrome was identified in a series of clinical observations.

For this, 3 groups of women volunteers with manifestations of menopausal syndrome of 10 people in the group were selected.

Women complained of hot flashes, sweating, palpitations during hot flashes, headache both during hot flashes and outside of them, increased body weight, high blood pressure. Almost all women had neurological disorders, which further complicated the course of menopausal syndrome. An examination of the blood in the subjects revealed increased hyperglycemia, increased blood coagulability, and signs of osteoporosis.

All subjects were prescribed pathogenetic treatment, depending on their specific diagnosis. In addition, the 2nd group was prescribed a pharmaceutical composition with a flavonoid content of 0.0138 wt.% In terms of rutin, and the 3rd group was prescribed a pharmaceutical composition according to the invention, i.e. with a high content of flavonoids of 0.0196 wt.% in terms of rutin.

Pharmaceutical compositions in both groups were prescribed at a dose of 40 drops 3 times a day for 14 days. 2 weeks after the start of the study, a break was made in taking pharmaceutical compositions for 1 month, after which a second course of taking sedatives was carried out.

The effectiveness of treatment was judged by the results of a survey of patients, namely: the presence or disappearance of signs of menopausal syndrome, expressed through hot flashes, sweating, headache, tearfulness, irritability, tachycardia, pressure.

Evaluation of the effectiveness of treatment was carried out by comparative analysis of clinical and laboratory data: terms of improving well-being, improving general condition, reducing the duration and frequency of hot flashes, time of disappearance of irritability, disappearance of tachycardia, tearfulness, sleep disturbances, normalization of blood pressure, cessation of pain in the heart before and through 14 days, 1 month and 3 months after treatment.

As the results of the study showed, by the end of the 7th day, subjects of all 3 groups noted a decrease in the frequency of hot flashes, a decrease in sweating, a decrease in tachycardia attacks, and an improvement in sleep and mood. All subjects of the 2nd and 3rd groups had a significant decrease in blood glucose, however, in patients of the 3rd group it was more pronounced.

Psychoemotional improvements in subjects of the 2nd group occurred only on the 10-12th day. Moreover, if women of the 3rd group noted that their improvement in health remains during the entire inter-course break, i.e. within 30 days after the end of taking the drug, then in women of the 2nd group, after 18-25 days, a relapse of a decrease in the emotional background, the appearance of tearfulness, tachycardia and other symptoms were noted. For both groups of patients, the drug was prescribed again. As the polls showed, 3 people from the 2nd group in the second year of taking the pharmaceutical composition with flavonoids equal to 0.0138 wt.% In terms of rutin, dyspeptic disorders in the form of decreased appetite, nausea, and frequent urges to defecate, loose stools, pain in the intestines. They were forced to stop taking the drug. In the 3rd group, which received a pharmaceutical agent with a high content of flavonoids equal to 0.0196 wt.% In terms of rutin, there were no gastrointestinal tract dysfunctions.

In the 1st group, which did not receive sedatives, no improvement in the psychoemotional state or other symptoms of the climacteric state was observed during the entire period of treatment.

Thus, the studies clearly show that an increase in the flavonoid content in a pharmaceutical composition containing tinctures of valerian, mint, motherwort, hawthorn and diphenhydramine, eliminates the side effects of the drug in the form of dyspepsia, as well as enhancing the therapeutic, sedative effect, including treatment menopausal syndrome. The discovered effect on the prevention of dyspeptic disorders does not follow from the known properties of flavonoids. It can be assumed that this is due to their effect on parietal digestion, due to the complex antioxidant and membrane-stabilizing effect of flavonoids.

It should be noted that the claimed composition showed a higher therapeutic activity in the elimination of psychoemotional disorders in patients with post-stress syndrome, as well as in asthenized patients.

The therapeutic activity in the form of enhancing the sedative effect of the claimed drug is shown in an experiment on a series of studies on its effect on the duration of hexenal sleep.

For this, animals (rats weighing 160-170 g) were divided into 3 groups. The animals of the 1st group were injected with physiological saline.

Animals of the 2nd group were injected with the composition according to the prototype, which contained 33.3 wt.% Tinctures of valerian, 33.0 wt.% Tinctures of motherwort, 16.7 wt.% Tinctures of hawthorn, 16.85 wt.% Tinctures of mint and 0.100 wt .% diphenhydramine. The amount of flavonoids in the composition was equal to 0.0138 wt.% In terms of rutin.

The animals of the 3rd group were administered a pharmaceutical agent according to the claimed invention, containing 33.3 wt.% Tinctures of valerian, 33.0 wt.% Tinctures of motherwort, 16.7 wt.% Tinctures of hawthorn, 16.85 wt.% Tinctures of mint and 0.100 wt.% Diphenhydramine. The amount of flavonoids in the composition was equal to 0.0196 wt.% In terms of rutin.

The pharmaceutical composition was injected into the stomach through a probe in an amount of 5 ml / kg in 2 ml of water 1 hour before a single intraperitoneal administration of hexenal at a dose of 60 mg / kg of animal weight. The control group was also administered 2 ml of physiological saline 1 hour before a single injection of hexenal. The research results are presented in table 2. According to these data, the duration of sleep with the introduction of the claimed pharmaceutical composition was significantly longer than with the introduction of physiological saline and pharmaceutical means of the prototype.

Thus, the claimed invention clearly shows a previously unknown therapeutic effect of an increased amount of flavonoids in the pharmaceutical composition on preventing the development of dyspepsia, enhancing sedative activity and increasing the effectiveness of treatment.

Table 1 Valeodikramen The composition according to the invention The number of flavonoids in terms of rutin, wt.% The number of flavonoids in terms of rutin, wt.% 0.0140 0.0198 0.0136 0.0190 0.0138 0.0182 0.0142 0.0198 0.0136 0.0196 Averages Averages 0.0138 ± 0.0002 0.0190 ± 0.0008

table 2 Group of animals The duration of "hexenal sleep" in min 1st group Control (saline) 23.21 ± 1.44 2nd Experimental group (pharmaceutical composition of the prototype, 5 ml / kg) 33.7 ± 2.17 The flavonoid content in the composition is 0.0138 wt.% 3rd Experimental group (pharmaceutical composition according to the invention, 5 ml / kg) 41.2 ± 2.32 The flavonoid content in the composition is 0.0196 wt.%

Claims (1)

A pharmaceutical composition of sedative and antispasmodic action, containing, in the following ratio of components, tincture of valerian 32-34 wt.%, Tincture of motherwort 32-34 wt.%, Tincture of hawthorn 16-17 wt.%, Tincture of peppermint 16-17 wt.% with a set of biologically active substances in each tincture and an antihistamine drug, diphenhydramine 0.1-0.2 wt.%, characterized in that the composition of biologically active substances contains flavonoids in an amount equal to 0.0190 ± 0.0008 wt.% in terms of routine.