RU2236844C2 - Anti-inflammatory agent for external application and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: agent comprises 18-20% suspension of liposomes in 0.01 M phosphate buffer, pH = 7.5, prepared of animal and vegetable phospholipids and lipids with laurel and sweet clover chloroform extracts included to their in the weight ratio = 2:2:1, respectively. Herbs chloroform extract contains extracts from laurel and sweet clove in equal amounts in the ratio with chloroform = 1:20. A base comprises ammonium salt of rare-cross-linked copolymer of acrylic acid and pentaerythritol polyallyl esters, triethanolamine, glycerol and para-hydroxybenzoic acid methyl and propyl ester, laurel oil and water taken in the definite ratio of components, wt.-%. Method for preparing an anti-inflammatory agent for external using is carried out by preparing the base aqueous emulsion from ammonium salt of rare-cross-linked copolymer of acrylic acid and pentaerythritol polyallyl esters and triethanolamine, its heating to 60-65^oC and addition of preserving agents solution - para-hydroxybenzoic acid methyl and propyl esters in glycerol followed by emulsification, cooling to 30-35^oC and addition of biological active supplement - 18-20% suspension of liposomes in 0.01 M phosphate buffer, pH = 7.5, prepared of animal and vegetable phospholipids and lipids with laurel and sweet clove extracts included to their in the weight ratio = 2:2;1, respectively. Herbs extract is prepared from a mixture of laurel and sweet clove taken in the equal amounts in the ratio with chloroform = 1:20 followed by repeated emulsification and addition of laurel oil. Invention provides the prolonged effect of the agent.

EFFECT: improved preparing method, valuable medicinal properties of agent.

2 cl, 1 ex

Description

The group of inventions relates to medicine, namely therapeutic and prophylactic agents for external use in diseases of the musculoskeletal system, characterized by the presence of mechanical damage and the inflammatory process, as well as diseases associated with stagnation of venous circulation - thrombophlebitis, hematomas, hemorrhoids, arthritis, etc. .

These diseases are associated with increased capillary permeability, damage and inflammation in the walls of blood vessels, expansion of the cavernous veins of the distal rectum and anus.

Known external medicine - troxevasin gel, which is a derivative of rutin and has anti-inflammatory and decongestant action, and also reduces capillary permeability. / M.D. Mashkovsky. Medicines, M .: Medicine, 1993, v. 1, p. 568 /.

Troxevasin gel is used for chronic venous insufficiency, superficial thrombophlebitis. Used for thrombophlebitis and ointments of non-steroidal anti-inflammatory drugs.

The disadvantages of these funds is that they do not have a complex effect aimed at various parts of the pathogenesis of inflammation, and do not have an effective effect in the treatment and prevention of hemorrhoids, arthritis, and hematomas. Medicines are not transdermal enough.

The closest to the intended application is a tool with antihemorrhoid action. / Pat. RF №2008012, А 61 К 35/78, 02/28/94. Bull. No. 4 /.

The product contains a mixture of medicinal herbs, crushed in a coffee grinder to a pulverized state, aged for 4 hours in melted internal lard. Herbs, turmeric, ivy, clover, St. John's wort, yarrow, gooseberry, goose cinquefoil, clover, chamomile, calendula, tansy, leaves of plantain and sage, oak bark are included in the phyto-collection.

The hemorrhoidal, analgesic, antispasmodic effect of the ointment is due to the synergistic effect of the components of the phyto-collection, which serves as the biologically active principle of the therapeutic agent.

The disadvantage of the ointment is an incomplete complex of biologically active components extracted from the phytobar in the proposed mode in a fat basis.

The resulting dispersion of phyto-collection particles in fat is not stable enough and uniform.

The fat film formed on the surface of the skin reduces the transdermality of the therapeutic agent, its effect is short-lived.

Recently, topical therapeutic agents with a gel or emulsion texture have been recognized as the most effective, since they are more easily absorbed without leaving a greasy film on the skin.

The closest technology to the claimed is a method of obtaining a cream to protect the skin from sunburn / Pat. RF №2020927, A 61 K 7/40, 10/15/94. Bull. No. 19 /.

The method is carried out by preparing an aqueous emulsion of glycerol, triethanolamine, heating it to 75-80 ° C, adding the remaining components of the base, pre-melted and filtered, vegetable oil, isopropyl palmitate, polyethylsiloxane liquid, alcohols of synthetic primary higher fat fractions C ₁₆ -C ₂₀ , stearate polyethylene glycol-400, beeswax, stearin, 2-phenylbenzoxazole 2-hydroxy-4-alkoxybenzophenol, ionol, methyl and propyl esters of paraoxybenzoic acid. Then the mixture is emulsified with constant stirring for 30-40 minutes, cooled to 40-50 ° C and an aqueous solution of black tea concentrates, benzyl alcohol and perfume are introduced. The mass is cooled to 30 ° C and sent to packaging.

The disadvantage of the technology is that the resulting emulsion is not stable enough.

The aim of the invention is to increase the effectiveness and prolongation of the anti-inflammatory and venotonic effects of a medicinal product for external use.

This goal is achieved in that the anti-inflammatory drug for external use contains as a biologically active additive 18-20% suspension of liposomes in 0.01 M phosphate buffer pH 7.5 from phospholipids and lipids of animal and vegetable origin with chloroform extract of laurel included in them and of clover with a weight ratio of 2: 2: 1, while the chloroform extract of herbs contains an extract from a mixture of laurel and clover in equal quantities in a ratio of chloroform equal to 1:20, and the basis is the ammonium salt of a rare cross-linked RA acrylic acid and polyallyl ethers of pentaerythritol, triethanolamine, glycerin, methyl and propyl ethers of paraoxybenzoic acid, laurel oil and water, with the following components, wt.%:

Liposome Suspension 18.0-20.0

Ammonium salt

rare crosslinked copolymer 1.0-1.25

acrylic acid and

polyallyl ethers

pentaerythritol

Triethanolamine 0.7-0.8

Glycerin 2.0-2.5

Methyl ether

paraoxybenzoic acid 0.12-0.15

Propyl ether

paraoxybenzoic acid 0.12-0.15

Laurel oil 0.02-0.03

Water Else

A method of obtaining an anti-inflammatory agent for external use is carried out in that an aqueous emulsion of the base is prepared from the ammonium salt of a rare crosslinked copolymer of acrylic acid and polyallyl esters of pentaerythritol and triethanolamine, heated to 60-65 ° C and a solution of preservatives, which are used as methyl and propyl esters of paraoxybenzoic acids in glycerol, emulsify, cool to 30-35 ° С and a biologically active additive is introduced - an 18-20% suspension of liposomes in 0.01 M phosphate buffer pH 7.5 from phospholipids and l animal and vegetable ipids with the included chloroform extract of laurel and sweet clover with a weight ratio of 2: 2: 1, while the herb extract is prepared from a mixture of laurel and sweet clover herbs in equal amounts in the ratio of chloroform 1:20, the mixture is again emulsified and add laurel oil.

In relation to the prototypes in composition and method, the claimed anti-inflammatory drug for external use has the following distinctive features.

The use as a biologically active additive of a suspension of liposomes from phospholipids and lipids of animal and vegetable origin with the included chloroform extract of laurel and melilot.

Organic plant extract contains components that provide anti-inflammatory and venotonic effects: coumarin, tannins, tocopherols, flavanoids, essential oils, which include cineol, geraniol, eugenol, fat-soluble vitamins (A, E, D, K).

It is known to use in folk medicine an infusion of dry laurel leaves in sunflower oil for external use in arthritis, myositis, and neuralgia. / R.M. Seredin, S.D. Sokolov. Medicinal plants and their use, 1973, p.93 /.

Extraction of medicinal plants with chloroform makes it possible to extract not only the listed medicinal components, but also phospho- and glycolipids. Other known methods for the extraction of biologically active substances (water, salt, alcohol, carbon) do not provide complete extraction of lipid components. / Pat. RF №2020944, A 61 K 35 / 10.15.10.94. Bull. No. 19; Pat. RF №2040265, A 61 K 35/78, 07.27.95. Bull. No. 21 /.

Chloroform extract is involved in the incorporation of plant-derived lipids and other useful components into the liposome membrane from animal lipids in the preparation of liposomes by phase reversal.

The use of lipids of animal origin for producing liposomes is due to the fact that they are similar in composition to the lipid composition of the skin. It is known that a mixture of lipids isolated from white matter in the brain of bulls contains 50% cholesterol, cerebresin, phosphatidylethanolamine, the rest is phosphatidylcholine / lecithin /, phosphatidylinositol, phosphatidylserine, and plant-derived lipids, such as soy, contain almost 87% phosphatidylcholine. / Omelchenko A.M. and other Vestn. Acad. honey. Sciences of the USSR, 1990, No. 8, p. 27-29 /.

The results of studies of the nature of lipids indicate their high biological activity, which determines the possibility of their use in the delivery of drugs to the cells of the body, providing energy to the processes occurring in the cell, and restoring the lipid composition of cell membranes, which changes when metabolic processes are disorganized. Liposomes merge with the cell membrane, while the lipid component of the liposome is embedded in the cell membrane, and the water-soluble drug penetrates the cell cytoplasm. / B.M. Shvets, Yu.M. Krasnopolsky. Vestn. Acad. honey. Sciences, 1990, No. 6, pp. 19-28 /.

It is known that when applying the drug on the skin in bilayer lipid vesicles in the form of ointments or lotions, the penetration of the drug into the skin is 3.5 times higher than with intact agents. / Stozek T. Farm. pol., 1983. V39, No. 1, p. 651-656 /.

Thus, the anti-inflammatory and venotonic effect of the claimed therapeutic agent is provided by liposome membranes in which lipids of animal and plant origin, therapeutic components are balanced, and their rapid exchange with components of the skin cell membranes. The incorporation of liposomes into the cell membrane and the gradual release of drug components ensures the prolonged action of the drug.

The use of a rare-crosslinked copolymer of acrylic acid and pentaerythritol polyallyl esters as a structure-forming component of the ammonium salt, preparing a gel-like mass on their basis, mixing it and emulsifying it with a suspension of liposomes creates the conditions for the formation of a coherent dispersed system due to the polycondensation of the base components with polar lipids of the bilayer membrane and lipids stable distribution of biologically active additives in the mass of the product.

The possibility of practical use of the claimed formulation and method of obtaining a therapeutic agent is illustrated by an example of a specific implementation.

Example 1. Prepare a gel-like solution of a water-soluble polymer. The reactor is filled with purified water 75.87 liters. Download 1.0 kg of carbopol-940 or 1.25 kg of axam. The polymer is carefully poured onto the surface of the water, left to swell for 30-40 minutes. In the case of carbopol-940, 0.8 kg of triethanolamine is charged with a thin stream while the stirrer is on. Steam or hot water is supplied to the mixer jacket, bringing the temperature to 60 ° C, and stirring is carried out until the polymer is completely dissolved. The finished polymer solution is fed via a pump through a filtered unit to the reactor-mixer.

2.0 kg of glycerol is charged into a separate container and, when heated to 60 ° C, propyl and methyl esters of paraoxybenzoic acid are dissolved in 0.15 kg each. The solution is filtered and served in a gel-like polymer solution, stirred, cooled to 35 ° C. Then, 20 l of 18-20% liposome emulsion are fed in portions into the gel-like mass, mixed for 30-40 minutes. To obtain a homogeneous mass, add 0.03 kg of laurel oil and mix for 10 minutes. The finished product is filtered and transferred to the packaging.

The chloroform extract of medicinal herbs is prepared as follows.

The dried leaves of laurel and clover grass are crushed and mixed in equal amounts and kept under a bactericidal lamp for 3 hours. Then the mixture of herbs is poured with chloroform in a ratio of 1:20, the suspension is mixed and insisted in a dark place for 2-3 days. At the end of the extraction, the suspension is stirred and the supernatant is separated. Prepare chloroform extracts of lipid components from the brain of cattle and sunflower seeds.

Liposomes are obtained from a mixture of chloroform extracts of animal and plant origin, the ratio of the volumes of extracts is calculated from the ratio of the obtained lipids equal to 12: 1-20: 1. The weight ratio of chloroform extracts of animal and vegetable origin and a mixture of herbs is 2: 2: 1. Liposomes obtained by the reverse phase method are dispersed in 0.01 M 18-20% phosphate buffer pH 7.5 and adjusted to the desired concentration. Liposome production is carried out according to well-known methodological developments. / Efremenko V.I. Liposomes (preparation, properties, aspects of application in biology and medicine). Deposited scientific papers: monthly bibliographic index. M .: VINITI No. 2, 1999, No. 3733-B98, 12/18/98 /.

The claimed content of all components in the formulation of a therapeutic agent optimally ensures the achievement of the desired effect.

Reducing the amount of liposome suspension below the claimed amount reduces the therapeutic effect of the drug, the increase is impractical, since the achieved effect is almost unchanged.

A decrease in the content of a water-soluble polymer leads to a deterioration of the required consistency and stability of the therapeutic agent, an increase above the stated limits leads to a tough consistency, an increase in the content of acrylic acid in the finished product.

Comparative tests of the claimed anti-inflammatory therapeutic agent and 2% troxevasin gel were carried out at the Pyatigorsk Pharmaceutical Academy by simulating experimental animals with traumatic edema and venostasis followed by edema. A control group was observed in parallel, animals with troxevasin gel applied to the trauma, and a group using the claimed agent.

In traumatic edema, after 1 h, the liposomal agent less effectively suppresses edema, after 3 h - at the level of troxevasin, but after 6 hours it reduces the development of edema by 20.3% and after a day is 34.5% more intense than troxevasin gel.

The development and evolution of edema caused by venous congestion was observed after 1, 3.5, and 24 hours. Troxevasin gel tends to suppress transduction in the acute period of venostasis, as well as transudate resorption 4 hours after the ligature is removed. The liposomal agent in all periods of observation inhibits the development of edema and enhances its involution, and the percentage of suppression of edema at all stages is higher than that of troxevasin.

Thus, the claimed anti-inflammatory agent shows a pronounced anti-inflammatory activity in traumatic edema, effectively inhibits the exudation process and enhances the resorption process in venostasis.

Claims (2)

1. An anti-inflammatory drug for external use, containing a biologically active additive in the form of a suspension of liposomes in phosphate buffer, phospholipids and lipids of vegetable and animal origin with the included chloroform extract of medicinal plants of laurel and melilot, the basis of the ammonium salt of a rare crosslinked copolymer and polyallyl ethers of pentaerythritol, triethylamine triethyl ether , glycerin, methyl and propyl ether of paraoxybenzoic acid and perfume, laurel oil and water, characterized in that it contains 18-20% suspension of liposo in 0.01 M phosphate buffer, pH = 7.5, from phospholipids and lipids of animal and vegetable origin with the included chloroform extract of laurel and sweet clover with a weight ratio of 2: 2: 1, while the chloroform extract of herbs contains an extract from a mixture of laurel and sweet clover in equal amounts in a ratio with chloroform 1:20, in the following ratio of components, wt.%: Liposome Suspension 18.0-20.0 Crosslinked ammonium salt Acrylic Acid Copolymer and polyallyl ethers pentaerythritol 1.0-1.25 Triethanolamine 0.7-0.8 Glycerin 2.0-2.5 Methyl ether paraoxybenzoic acid 0.12-0.15 Propyl ether paraoxybenzoic acid 0.12-0.15 Laurel oil 0.02-0.03 Water Else 2. A method of obtaining an anti-inflammatory agent for external use, comprising preparing an aqueous emulsion of base components with heating, emulsification, cooling and the introduction of a biologically active additive, characterized in that an emulsion is prepared from the ammonium salt of a rare crosslinked copolymer of acrylic acid and polyallyl ethers of pentaerythritol and triethanolamine, and the emulsion is heated to 60-65 ° C and add a solution of preservatives, which are used as methyl and propyl ester of paraoxybenzoic acid in glyc serine, emulsify, cool to 30-35 ° С and biologically active additive 18-20% suspension of liposomes in 0.01 M phosphate buffer pH = 7.5 from phospholipids and animal lipids with chloroform extract of laurel and clover in a weight ratio of 2: 2: 1, while the chloroform extract of herbs is prepared from a mixture of laurel and melilot in equal amounts in a ratio of 1:20 of chloroform, the mixture is emulsified and laurel oil is added.