RU2635459C1 - Drug with spasmolithic, diuretic and lithiolic action - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: agent containing belladonna alkaloids, tincture of European madder, magnesium salicylate, a mixture of essential oils with a set of active substances, salicylic acid, linoleic and linolenic acids, ethanol and castor oil is proposed, wherein the substance contains the sum of belladonna alkaloids, recalculated for hyoscyamine as belladonna alkaloids, eucalyptus essential oil, anise essential oil and fennel essential oil as essential oils, and 1,8-cineole eucalyptus essential oil as a biologically active substance with a certain content of the ingredients.

EFFECT: pronounced therapeutic effect in pain elimination and excretion of urinary stones, pronounced anti-inflammatory and diuretic effects.

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Description

The invention relates to pharmacy and can be used in the production of drugs with antispasmodic, diuretic and litholytic effects. The agent according to the claimed invention can be used to treat urolithiasis, cholelithiasis, and urinary disorders.

In these diseases, antispasmodics are widely used, both of natural origin and chemically obtained: no-shpu, papaverine, cystenal, spasmocystenal, enatin, rovatin, rovachol.

Means for the treatment and prevention of urolithiasis are described in the patent of the Russian Federation for invention No. 2205655, "Means for the prevention and treatment of urolithiasis", 06/10/2003, and in the patent of the Russian Federation for invention No. 2238735, "Means for litholysis of urinary stones and a method for its preparation" October 10, 2004.

For the treatment and relapses in the formation of stones consisting of calcium and magnesium phosphates, acidification of urine is necessary, which is achieved by using extract from the roots of madder dye (see RF patents for inventions No. 2580282; No. 260,5271; 2281781 and others). However, known herbal remedies are multicomponent, require the use of a large set of different plants that can cause allergic reactions.

From the Big Medical Encyclopedia, the Cystenal pharmacological agent is known, which contains extract / tincture of madder root 0.0093 g, magnesium salicitate 0.14 g, essential oils 5.75 g, ethyl alcohol 0.80 g, olive oil up to 10.0 g (see BME, 1986, v. 27, p. 230). Based on it, the drug "Spazmotsistenal" was created to relieve pain in urolithiasis.

In the book. authors A.T. Burbello, A.V. Shabrov, P.P. Denisenko, “Modern Medicines”, 2003, on page 679, states that spasmocystenal includes Radobellin 250 mcg, Madamen aglycone dyeing 930 mcg, magnesium salicylate 14 mcg, a mixture of essential oils 575 mcg in 1 ml.

The following spasmocystenal composition is described on the website http://dxline.ru/drugs/spasmocvstenal: hyoscyamine 2.5 mg, magnesium salicylate 140 mg, madder tincture 9.3 mg, salicylic acid 20 mg, excipients (anise oil 1.475 g, castor oil, linoleic acid 0.7 g, linolenic acid 0.7 g, dill oil 1.475 g, eucalyptus oil 2.8 g, ethanol 750 mg) - 10 ml.

This technical solution is selected as a prototype.

Belladonna alkaloids (including belladonna vulgaris), which are contained in the spasmocystenal, have an m-anticholinergic effect and lower the tone of smooth muscle organs.

Preparations from madder are capable of gradually loosening and destroying kidney and bladder stones. They also lower tonus and increase peristalsis of muscular contraction of the renal pelvis and ureter, and promote the advancement of stones. The greatest therapeutic effect is manifested in stones consisting of phosphate salts of magnesium and calcium. In addition, madder drugs have diuretic properties, have a bactericidal effect against the coccal group of microbes.

Fennel (dill) oil has pronounced healing properties: anti-inflammatory, bactericidal, wound healing, antioxidant, has a regenerating effect.

Anise oil has a diuretic effect and relieves inflammation of the urinary tract, kidney tissue. Anise oil treats the genitourinary system.

Eucalyptus oil contains compounds such as pinene, eucalyptol (1,8-cineole), myrtenol, which have a bactericidal, antiprotozoal, fungicidal, antiviral effect. With inhalation use, a mucolytic, expectorant, antihypoxic effect develops.

However, when testing the finished product, it was found that this well-known tool is not effective enough to relieve pain in patients with urolithiasis, and also has insufficient anti-inflammatory and diuretic effects.

The technical result of the claimed invention is the creation of a pharmaceutical agent that provides a more pronounced therapeutic effect in eliminating pain and removing urinary tract stones, as well as a more pronounced anti-inflammatory and diuretic effects.

This technical result is achieved by the fact that in the well-known medicament of antispasmodic, diuretic and litholytic action, containing belladonna alkaloids, tincture of madder, magnesium salicylate, a mixture of essential oils with a set of biologically active substances, salicylic acid, linoleic and linolenic acid, ethanol and castor oil , the product contains as belladonna alkaloids the sum of belladonna alkaloids, calculated on hyoscyamine, as essential oils - eucalyptus essential oil, aniseed ether boiled oil and fennel essential oil, and as a biologically active substance - 1,8-cineole of eucalyptus essential oil in the amount of 2.2000-2.6600 g per 10 ml of the product, with the following ingredients in 10 ml of the product:

Sum of belladonna alkaloids in terms of hyoscyamine 0.0020-0.0030 g Tincture of madder root dyeing 0.0093-0.0100 g Magnesium Salicylate 0.1250-0.1550 g Eucalyptus Essential Oil 2.7500-2.8600 g Aniseed essential oil 1.4000-1.5000 g Fennel essential oil 1.4000-1.5000 g Ethanol anhydrous 0.7000-0.8000 g Salicylic acid 0.0180-0.0370 g A mixture of linoleic and linolenic acids 1.3500-1.4500 g Castor oil up to 10 ml

To prepare the claimed product, ready-made belladonna preparations are used, containing alkaloids, for example, dry extract, as well as tincture of madder, magnesium salicylate, aniseed essential oil, eucalyptus essential oil, fennel essential oil, anhydrous ethyl alcohol, salicylic acid, linoleic acid, linolenic acid, Castor oil. The ratios of linoleic and linolenic acids were arbitrarily selected to a total amount of 1.3500-1.4500 g. The effective and auxiliary substances were dissolved and mixed, the resulting solution was defended, and after filtration it was poured into vials. Appearance of the finished product: a clear red liquid with a fragrant odor. Over time (after 6 months), a small shaken precipitate may form that does not affect the quality of the drug. The density of the finished product should be in the range of 0.92-0.94 g / cm ³ .

To prepare the claimed funds, eucalyptus essential oils with different initial contents of 1,8-cineole were used, mainly with a cineol content of 81-91%, which is achieved by repeated rectification of eucalyptus oil.

It is known that the amount of 1,8-cineol in eucalyptus essential oil depends on the variety of plants, age and methods of extracting oil. Accordingly, the indicated indices of 1,8-cineole will also differ from these conditions. Cineol (1,8-cineole, 1,8-epoxy-p-menthane, eucalyptol) molecular weight 154.25; viscous liquid with a camphor smell and a burning taste; melting point 1 ° C, boiling point 176-177 ° C, soluble in some other organic solvents, poorly in water. 1,8-Cineol has a bactericidal, antimicrobial and anti-inflammatory effect.

In accordance with the GF USSR X edition (Art. 278), the essential oil in the leaves of ashen eucalyptus and ball eucalyptus should be at least 2.5%, and the cineol content in this essential oil should be at least 60% (Article 475, GF X). However, this amount of cineole in eucalyptus oil is clearly not enough for the manifestation of high therapeutic activity of the claimed pharmaceutical agent.

Dry belladonna extract with an alkaloids content of 0.7% was used as belladonna extract.

The authors conducted a study of the effect of different amounts of cineole on therapeutic activity. In eucalyptus essential oil, the amount of 1,8-cineole esters was determined by gas-liquid chromatography. The chromatogram shows 3 peaks, where one of the peaks reflects the cineol content. Calculation of the quantitative content of cineole is carried out according to a special formula in which the values of S _A , S _B , S _{c are used} — peak area equal to the product of the peak height and its width at half height; X _A is the percentage of cineol.

Examples of the preparation of the claimed funds

To prepare the product, we used belladonna as a sum of belladonna alkaloids - dry extract, tincture of madder dye, magnesium salicylate, aniseed essential oil, eucalyptus essential oil with a content of cineol 85-95%, fennel essential oil, anhydrous ethyl alcohol, salicylic acid, linoleic acid , linolenic acid, castor oil. The ratios of linoleic and linolenic acids were arbitrarily chosen to a total amount of 1.3500-1.4500 g. Effective and auxiliary substances were dissolved, mixed, the resulting solution was defended, filtered, and after filtration it was poured into containers.

The following are the formulations of the claimed medicinal product prepared in accordance with the claims:

Example 1

Sum of belladonna alkaloids in terms of hyoscyamine 0.0020 g Tincture of madder root dyeing 0.0093 g Magnesium Salicylate 0.1250 g Eucalyptus Essential Oil 2.7500 g Aniseed essential oil 1.4000 g Fennel essential oil 1.4000 g Ethanol anhydrous 0.7000 g Salicylic acid 0.0180 g

A mixture of linoleic and linolenic acids:

Linoleic acid 0.7000 g Linolenic acid 0.6500 g Castor oil up to 10 ml

In 10 ml of the finished product, the amount of 1,8-cineole was 2.3375 g. Eucalyptus oil with a cineol content of 85% was used in the composition.

In 10 ml of the product, the amount of dry belladonna extract containing 0.0020 g of alkaloids in terms of hyoscyamine was 0.2850 g, with the initial content of alkaloids in the dry extract of 0.7%.

Example 2

Sum of belladonna alkaloids in terms of hyoscyamine 0.0025 g Tincture of madder root dyeing 0.0093 g Magnesium Salicylate 0.1400 g Eucalyptus Essential Oil 2.8000 g Aniseed essential oil 1.4750 g Fennel essential oil 1.4750 g Ethanol anhydrous 0.7500 g Salicylic acid 0.0200 g

A mixture of linoleic and linolenic acids:

Linoleic acid 0.7000 g Linolenic acid 0.7000 g Castor oil up to 10 ml

In 10 ml of the finished product, the amount of 1,8-cineole was 2.5200 g. Eucalyptus oil with a cineol content of 90% was used in the composition.

The amount of dry belladonna extract in 10 ml of the product containing 0.0025 g of alkaloids in terms of hyoscyamine was 0.3570 g, with the initial content of alkaloids in the dry extract of 0.7% in terms of hyoscyamine.

Example 3

Sum of belladonna alkaloids in terms of hyoscyamine 0.0030 g Tincture of madder root dyeing 0.0100 g Magnesium Salicylate 0.1550 g Eucalyptus Essential Oil 2.8600 g Aniseed essential oil 1,5000 g Fennel essential oil 1,5000 g Ethanol anhydrous 0.8000 g Salicylic acid 0.0370 g

A mixture of linoleic and linolenic acids:

Linoleic acid 0.6000 g Linolenic acid 0.8500 g Castor oil up to 10 ml

In 10 ml of the finished product, the amount of 1,8-cineole was 2.6600 g. Eucalyptus oil with a cineol content of 93% was used in the composition.

The amount of dry belladonna extract in 10 ml of the product containing 0.0030 g of alkaloids in terms of hyoscyamine was 0.4280 g, with the initial content of alkaloids in the dry extract of 0.7% in terms of hyoscyamine. You can use tincture belladonna.

For a comparative study of the therapeutic activity of the claimed funds was prepared composition containing 1.68 g of cineole per 10 ml, including the following ingredients:

Sum of belladonna alkaloids in terms of hyoscyamine 0.0025 g Tincture of madder root dyeing 0.0093 g Magnesium Salicylate 0.1400 g Eucalyptus Essential Oil 2.8000 g Aniseed essential oil 1.4750 g Fennel essential oil 1.4750 g Ethanol anhydrous 0.7500 g Salicylic acid 0.0200 g

A mixture of linoleic and linolenic acids:

Linoleic acid 0.7000 g Linolenic acid 0.7000 g Castor oil up to 10 ml

Eucalyptus oil containing 60% cineol was used.

The diuretic effect of the claimed drug in addition to clinical observations was studied in rats. Animals were divided into 3 groups: 7 animals in each group. To determine the functional state of the kidneys, diuresis was measured for 18 hours after water loading. Animals of the experimental group 1 received intragastrically 1 drop of the proposed agent (according to Example 2), animals of the 2nd group received the agent of Example 3 in 8 ml of water, and animals of the 3rd group were injected with 1.68 g of cineole per 10 ml (control group). Diuresis in animals in the 1st and 2nd experimental groups increased by 30%, the excretion of sodium ions Na ⁺ increased by 27% compared with the 3rd group, at the same time, a slight decrease in the concentration of potassium K ⁺ ions in the urine was noted.

Therapeutic activity against diuretic, anti-inflammatory and litholytic effects of the proposed funds

In 2 groups (experimental and control for 8 people in the group), 16 patients with urolithiasis were treated using the claimed agent (as in Example 2) and an agent containing 1.68 g of cineole per 10 ml. All patients were on an outpatient basis; all of them noted the presence of pain. The pains were both temporary and constant aching in nature. In 3 patients, stones were located in the kidney (pain radiating to the back), in the rest - in the ureter (pain radiating to the groin, thigh). The course of treatment was 1 month based on 3-4 drops of the proposed composition (according to example 2) or a product with a cineol content of 1.68 g per 10 ml (group 2) on a sugar slice 3 times a day 30 minutes before meals. All patients underwent examination in a urological clinic. Ultrasound data was analyzed in dynamics, if necessary, survey and excretory urography was performed. A radioisotope study was also performed, and in 8 patients, Doppler scanning of the kidneys. There were no complaints of worsening. After taking the drugs, the pain symptom in group 1 disappeared in 3 patients and decreased in 2 of 8 patients, and in group 2 it decreased only in 3 of 8 patients who complained of stitching and aching pains. During the attack, the amount of funds offered was increased to 20 drops. Under normal water load, diuresis increased by an average of 260 ml in group 1 and 200 ml in group 2. Microscopic analysis of urine yielded the following results: prior to treatment, all patients had leukocyturia - up to 500 p / s, erythrocyturia - up to 250 p / p urine pH - from alkaline to acid: up to 5.5. Microbiological analysis of urine revealed Escherichia coli, epidermal staphylococcus, enterobacter, yeast fungi, in the titer from 10 ³ to 10 ⁸ microbial bodies / ml. After treatment, in patients of the 1st group, leukocyturia decreased to 2-4 in the SC, and in the 2nd group - to 8-10. In patients of the 1st group, a decrease in the size of stones was observed on average by 40-50%, and in patients of the 2nd group by 15-20%. At the same time, in 4 patients of the 1st group, the discharge of stones from the ureters was noted.

The claimed tool was also tested in the experiment for the manifestation of antispasmodic activity, responsible for the removal of the pain symptom.

The study of antispasmodic activity was carried out in 2 groups of experiments on isolated sections of the rat small intestine using serotonin at a concentration of 10 ^-4 μg / kg, which causes a reduction in the length of the small intestine of the white rat, equal to an average of 33.4 ± 8.5 mm. Then, in each container, the intestine was washed from serotonin and the agent manufactured in Example 2 was added to the incubation medium of one group. In the finished agent, the amount of cineole was 2.52 g per 10 ml (1 group). A medium with a cineol content of 1.68 g per 10 ml was added to group 2 media. Then, serotonin was added to the incubation media. The bowel contraction in group 1 was 5.0 ± 0.4, and in group 2 10.2 ± 1.6. This experience clearly shows the greater antispasmodic activity of the means according to the invention than the means of the prototype.

Thus, a large therapeutic litholytic, anti-inflammatory and diuretic activity of the proposed drug is shown in comparison with the well-known drug "Spazmotsistenal."

Claims (3)

An antispasmodic, diuretic and litholytic drug containing belladonna alkaloids, tincture of madder, magnesium salicylate, a mixture of essential oils with a set of biologically active substances, salicylic acid, linoleic and linolenic acids, ethanol and castor oil, characterized in that the product contains belladonna alkaloids the sum of belladonna alkaloids, calculated on hyoscyamine, as essential oils - eucalyptus essential oil, aniseed essential oil and fennel essential oil, and as the active substance - 1,8-cineole eucalyptus essential oil in an amount of 2,2000-2,6600 g per 10 ml of the product, with the following contents of ingredients per 10 ml of the product: Sum of belladonna alkaloids in terms of hyoscyamine 0.0020-0.0030 g Tincture of madder root dyeing 0.0093-0.0100 g Magnesium Salicylate 0.1250-0.1550 g Eucalyptus Essential Oil 2.7500-2.8600 g Aniseed essential oil 1.4000-1.5000 g Fennel essential oil 1.4000-1.5000 g Ethanol anhydrous 0.7000-0.8000 g Salicylic acid 0.0180-0.0370 g A mixture of linoleic and linolenic acids 1.3500-1.4500 g Castor oil up to 10 ml