EA033799B1 - Vessel-strengthening product in the form of ointment - Google Patents

Abstract

The invention relates to medicine and pharmacology, and more particularly to development of ointments for treating and preventing pathologic vessel and tissue damages. The preparation can be used for treating diseases associated with venous insufficiency, varicose veins, thrombophlebitis, hemorrhoids, post-traumatic edemas and hematomas, dermatitis and trophic ulcers. The essence of the declared invention is that the developed vessel-strengthening agent, the ointment, contains the base and biologically active substance. The ointment contains spissum hazel extract as a biologically active substance; corn oil, emulsifier No. 1, polyethylene oxide 400, nipagin, nipasol as the base, remainder - purified water, with certain component ratio (g per 100 g). The technical effect of the claimed invention is that the set objective is achieved.

Description

The invention relates to medicine and pharmacology, in particular to the creation of ointments for the treatment and prevention of pathological lesions of blood vessels and tissues. The drug can be used in the treatment of diseases associated with venous insufficiency, varicose veins, thrombophlebitis, hemorrhoids, post-traumatic edema and hematomas, dermatitis and trophic ulcers.

Vascular diseases occupy a significant place in the structure of the morbidity of the population, and every year there is an increase in the number of inflammatory diseases of the veins (phlebitis, thrombophlebitis) and non-inflammatory (atherosclerosis, thrombosis). Diseases associated with chronic venous insufficiency are characterized by such manifestations as edema and trophic lesions, varicose veins, thrombophlebitis, periphlebitis, post-thrombotic syndrome. In cases of impaired venous circulation - congestion, varicose veins, phlebitis and thrombophlebitis, angioprotectors, which are also called capillary aprotectors, are widely used. A large group of phleboactive drugs (troxerutin, detralex, eskusan, cyclo-3-fort, etc.) not only improves venous and lymphatic drainage, but also reduces the permeability of capillaries, increases the tone of the vascular wall, and has a decongestant effect. To solve these problems with diseases of blood vessels and surrounding tissues, some combination drugs are used - a composition of well-known drugs, in particular ointments and gels.

Known [1] is a pharmaceutical composition for the treatment of venous disease, which contains a combination of troxerutin, dexpanthenol, heparin in the form of sodium salt and phenylethyl alcohol and target additives in a certain ratio of components, g / per 100 g of the total weight of the composition. The specified preparation in the form of a soft dosage form, mainly a gel, has a multifunctional effect aimed at different sides of the pathological process due to venous insufficiency. It exhibits an angioprotective effect, eliminates the pathology of microcirculation, has an anticoagulant and anti-inflammatory effect and helps accelerate reparative processes.

As a prototype, the well-known [2] venohepanol preparation was taken for the treatment and prevention of pathological lesions of blood vessels and tissues in the form of a soft dosage form - gel. The preparation contains a gel base and active active ingredients: heparin, dexpanthenol and venorutinol in a certain ratio of components. The drug improves blood circulation and microcirculation in blood vessels and tissues in case of chronic venous insufficiency of thrombophlebitis, hematomas and trophic ulcers of blood vessels and skin, which are accompanied by blockages, inflammations and edema. The objective of the invention is, given the need for effective and safe drugs for the treatment of varicose diseases of the vascular system, in the creation of a new drug of mild form - ointment based on plant materials and expanding the arsenal of domestic drugs.

The essence of the claimed invention lies in the fact that the developed vasoconstrictor in the form of an ointment contains a base and a biologically active substance. As a biologically active substance, the ointment contains a thick extract of hazel; and as a basis - corn oil, emulsifier No. 1, polyethylene oxide-400, nipagin, nipazole and purified water in the following ratio of components (in g / 100 g):

thick hazel extract - 4.9-5.1;

corn oil - 19.0-21.0; emulsifier No. 1: 9.5-10.5; polyethylene oxide-400: 9.5-10.5; nipagin - 0.14-0.16;

nipazole - 0,049-0,051;

purified water - the rest.

A comparative analysis of the claimed invention and the known one showed that the claimed drug differs from the prototype in the composition, its constituent components and the new biologically active component - a thick extract of hazel obtained from a new type of raw material - common hazel leaves.

The main biologically active component of the claimed invention is a thick extract of common hazel - a new substance, the method of preparation of which was developed by the author of the claimed invention and for which Eurasian patent No. 026414 was obtained. A thick extract of common hazel contains tannins, alkaloids, flavonoids, amino acids, organic acids, vitamins, carotenoids and minerals. The extract has an anti-inflammatory effect, reduces stagnation in the venous part of the capillaries and the accumulation of fluid in the tissues, improves lymph flow and venous circulation, reduces the permeability of the vascular walls and has a capillary-strengthening effect. Vitamin C and chlorogenic acid contained in it are powerful natural antioxidants. By stimulating nitrogen metabolism and participating in the construction of protein, chlorogenic acid in combination with dihydroquercetin has a directed capillary and vasodilating effect; reduces the risk of increased thrombosis, improves coronary blood flow and helps reduce vascular spasms. Therapeutic efficacy of a biologically active component

- 1,033,799 is determined in the range of 4.9-5.1 g per 100 g of ointment. As the basis of the ointment, an emulsion base was chosen which, taking into account the properties of the main biologically active component and its solubility in water, has predominant adhesion, uniformity and is evenly distributed on the skin surface. The base contains well-known and widely used in pharmacy components for ointment bases: corn oil, emulsifier No. 1, polyethylene oxide-400, nipagin, nipazole and purified water. To obtain a stable base and ultimately the ointment itself, preliminary studies have found that emulsifier No. 1 has the best performance for the claimed product, and it is rational to use polyethylene oxide-400 and corn oil in the specified limits. Studies have also been conducted on the quantitative content of emulsifier No. 1, the optimal content found for which for this ointment is 9.5-10.2 g per 100 g of ointment.

The ointment is prepared as follows.

To obtain 100 g of ointment, an emulsion base is prepared, for which 20 g of corn oil and 10 g of emulsifier No. 1 are loaded into a reactor with a steam jacket and a stirrer. The mixture is heated with constant stirring to a temperature of 80 ° C. Heating and stirring is carried out until the components are completely dissolved and a homogeneous mass is obtained. 0.15 g of nipagin, 0.5 g of nipazole and a third of the required amount of purified water are loaded into a reactor with a stirrer, heated to 80 ° C and stirred until the components are completely dissolved.

10 g of PEO-400 and 5 g of a thick extract of hazel are loaded into a stirred reactor and mixed for 5-10 minutes until the components are completely dissolved. To the resulting solution add the remaining amount of purified water and an aqueous solution of nipagin with nipazole.

An oil base (phase) is loaded into a homogenizer reactor with a stirrer and a cooling jacket, and then with a continuous stream and with constant stirring an aqueous solution with the active substance is introduced.

Dispersion is carried out for 3-5 minutes, maintaining the temperature within 80 ° C. After that, the reactor is cooled to 30 ° C, supplying cold water to the jacket of the apparatus.

The chilled finished product is a light cream color, practically odorless, of uniform consistency and a density of ± 1 g / cm ^{2 is} supplied for packaging.

The ointment within the claimed values of its constituent components is thermostable, microbiologically pure, pH 5.68, colloid stable and meets the declared properties.

Other examples of the preparation of ointments are presented in table. 1.

Table 1

No. p / p Name of components examples 1 2 3 4 5 1 thick hazel extract 4,5 4.9 5,0 5.1 5.2 2 corn oil 19.0 19.3 20,0 20.5 21.0 3 emulsifier number 1 9.5 9.8 10.0 10,2 10.5 4 polyethylene oxide -400 10.5 10.3 10.0 9.8 9.5 5 nipagin 0.14 0.14 0.15 0.16 0.16 6 ipazol - 0.04 0.04 0.05 0,052 0,052 7 purified water rest

More preferred ranges for the content of ingredients are those in Examples 2-4.

The properties of the ointment were investigated in the Problem laboratory of morphofunctional studies of the National University of Pharmacy of the Ministry of Health of Ukraine. Studies of the effect of the claimed ointment on the development of venous edema and anti-inflammatory activity in various models were carried out on experimental animals: rats and mice by known methods [3, 4].

To study the effect of ointment on the development of tail venous edema in rats (Table 2), which caused venostasis followed by edema by tail vein occlusion for 5 hours after ligature application. The choice of this model is justified by pathomorphological changes in tissues that have many

- 2 033799 in common with the pathology of the vascular wall. Traumatization of the endothelium and the basement membrane, changes in the structure and condition of the main substance of the connective tissue lead to a decrease in capillary resistance. In the course of the study, the initial volume of the tail to the mark on its base was measured. The tail was dried and applied to it (by label, without rubbing) one of the preparations for comparison in the amount of 250 mg. 1 h after application of the preparations, the base of the tail in the region of the label was pressed with ligature with force and the dynamics of the growth of the tail volume was recorded 1, 2, 3, and 6 h after application of the ligature. 1 hour before the removal of the ligature (the ligature was removed 5 hours after application), the drug was applied again. Involution of edema was recorded 1, 3, 6 and 24 hours after the removal of the ligature. The magnitude of the edema was calculated by the difference between the input data and the volume obtained as a result of ligature venostasis in arbitrary units, the activity of the studied drugs was expressed in% by the change in edema in the experimental animals in comparison with the animals of the control pathology group.

As a comparison drug used troxevasin gel 2% (contains troxerutin - 20 mg / g gel). The choice of this drug as a comparison drug is justified by its pharmacological properties, namely the ability to act mainly on capillaries and veins, due to the reduction of pores between endothelial cells as a result of modification of the fibrous matrix located between endothelial cells.

As the research results showed, an ointment based on a thick extract from the leaves of common hazel inhibits the development and accelerates the involution of acute venous stasis. In addition, the results of these studies demonstrate that ointment based on hazel begins to act effectively from the first hours after the ligature is applied, which indicates in favor of its vaso-strengthening properties. The effectiveness in this model of an ointment based on an extract from the leaves of common hazel was at the level of the comparison drug troxevasin gel 2%. Thus, in the course of this experiment, the decongestant and vasoconstrictive effect of the studied agent was proved.

table 2

No. p / p Observation time Control pathology Hazel ointment Troxevasin gel AV, cu / A % The phase of development of acute venous stasis 1 1st hour 6.5 ± 0.43 4.75 ± 0.48 * 4.33 ± 0.21 * 2 2nd hour 7.33 ± 0.42 5.33 ± 0.42 * 6.0 ± 0.36 3 3rd hour 9.16 ± 0.48 7.17 ± 0.52 * 7.0 ± 0.57 * 4 6th hour 12.2 ± 0.60 8.87 ± 0.80 * 8.00 ± 0.78 * No. p / p Observation time Control pathology Hazel ointment Troxevasin gel

AV, c.u./A% Involution phase 1 1st hour 9.33 ± 1.09 7.00 ± 0.58 6.33 ± 0.76 2 3rd hour 8.00 ± 0.97 5.83 ± 0.60 5.00 ± 0.93 3 6th hour 5.33 ± 0.93 4.50 ± 0.43 4.17 ± 0.6 4 24th hour 5.0 ± 0.49 3.83 ± 0.31 3.33 ± 0.49

* The differences are significant in relation to the control (p <0.05);

n is the number of animals in the group (n = 6).

It is known that inflammation plays a leading role in the pathogenesis of venous pathologies, since a decrease in venous outflow causes a violation of capillary blood flow and microcirculation, and the permeability of the vascular walls increases, which leads to secondary inflammatory processes. In this regard, studies have been conducted on the effect of the claimed vasoconstrictor ointment on inflammatory processes. Studies of the anti-inflammatory activity of the ointment were conducted on models

- 3 033799 carrageenan edema. As experimental animals used male rats weighing

200-270 g. As a comparison, ointment eskusan and ointment diclofenac were used. The severity of the inflammatory process was judged by the increase in the volume of the affected limb. Anti-inflammatory activity was calculated by the formula

P - P

PVA = 2 XI00%,

Pk where P _k - the average difference in the volume of the affected and healthy limbs in the control group;

P _about - the average difference in the volume of the affected and healthy limbs in the experimental group.

The experimental results were processed by the method of mathematical statistics using Student's t-test, the results were considered significant p <0.05.

The research results are presented in table. 3.

These studies demonstrate the progression of edema under the influence of phlogogen in animals in the control pathology group up to 3 hours of the experiment and a subsequent decrease in the degree of edema up to 24 hours of observation, however, the paw sizes in rats did not return to the original.

Table 3

No. p / p Observation time Control pathology Hazel ointment Aescusan Ointment Diclofenac ointment R _about , cu / PVA% 1 1 hour 19.20 ± 1.10 10,500 ± 1.23 * 45.3 11.62 ± 2.79 * 39.5 8.00 ± 1.63 * 58.3 2 2 hours 26.50 ± 1.09 13.20 ± 0.95 * / ** 50.1 14.62 ± 2.79 * 44.8 8.43 ± 1.17 * 68.1 3 3 hours 35.67 + 1.17 19.25 ± 2.80 * 46.0 14.83 + 1.19 * 58.4 12.29 ± 1.21 * 65.54 4 4 hours 36.88 + 1.66 21.12 ± 2.63 * / *** 42.7 30.41 ± 2.80 17.54 16.00 ± 1.54 * / *** 56.61 5 24 hours 22.50 ± 1.63 19.13 ± 1.19 14.2 21.20 ± 1.12 5.7 18.14 ± 1.20 18.2

* The differences are significant in relation to the control (p <0.05).

** The differences are significant in relation to diclofenac (p <0.05).

*** The differences are significant in relation to eskusan ointment (p <0.05). n is the number of animals in the group (n = 10).

An ointment based on a thick extract from the leaves of common hazel showed antiexudative properties under conditions of acute carrageenan edema, as evidenced by a significant decrease in animal paw volume throughout the experiment. The anti-inflammatory activity of ointment from common hazel in the model of carrageenan edema averaged 47.1 ± 1.5% during the first 3 hours of the experiment. The maximum activity of the tested ointment for 2 hours of the induced inflammatory process (50.1%), after 24 hours from the start of the observation, a decrease in the PVA of the ointment from hazel was noted to be 14.2%.

The results suggest that the biologically active substances of the ointment based on a thick extract from the leaves of common hazel inhibit the activity of histamine, serotonin and kinins, since the drug has a high activity in the first 3 hours of the experiment. According to the PVA activity during this period, hazel ointment was as close as possible to the values obtained against the background of the use of the ointment with diclofenac, and surpassed the PVA esquusan ointment.

Thus, on the basis of the data presented, it can be concluded that the ointment based on the leaves of common hazel in the model of acute carrageenan edema exhibits pronounced anti-inflammatory properties, significantly affecting the prostaglandin phase of inflammation.

The technical effect of the claimed invention consists in solving the problem.

Literature

1. RF patent No. 2299070. The pharmaceutical composition for the treatment of venous disease and the method for its preparation, from 08.02.2005.

2. RF patent No. 2238737. The drug Venohepanol for the treatment and prevention of pathological

- 4,033,799 lesions of blood vessels and tissues, dated 04/17/2003.

3. Golikov P.P. To the technique of simultaneous study of the anti-inflammatory effect in rats with different types of inflammation // Pharmacology and Toxicology. - 1964. - T. 5, No. 6. - S. 742-743.

4. Guidelines for the experimental preclinical study of non-steroidal anti-inflammatory pharmacological substances. - Moscow: Pharmacological Committee, 1992. - 14 p.

Claims (1)

CLAIM A vasodilator in the form of an ointment contains a base and a biologically active substance, characterized in that the ointment contains a thick extract from hazel leaves as a biologically active substance, and corn oil, emulsifier No. 1, polyethylene oxide-400, nipagin, nipazole and water as a base purified in the following ratio of components (in wt.%): a thick extract of hazel leaves - 4.9-5.1; corn oil - 19.0-21.0; emulsifier No. 1 - 9.5-10.5; polyethylene oxide-400 - 9.510.5; nipagin - 0.14-0.16; nipazole - 0,049-0,051; purified water - the rest.