RU2426525C1 - Preventive ointment for diabetic foot - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to preventive ointment for diabetic foot, which contains antiseptic agents, such as water solution of polyhexanide with polyethylene glycol 4000 and nanostructured powder of bentonite, intercalated with silver ions (Ag⁺). Ointment additionally contains carbamide and nanostructured bentonite powder intercalated with cerium ions (Ce³⁺), and, as carrier, hydrophilic water-soluble polymer based on mixture of polyethylene oxide 1500 and polyethylene oxide 400 and antiseptic agents.

EFFECT: acceleration of process of skin tissues regeneration.

4 cl, 3 ex

Description

The field of technology.

The invention relates to medicine and can be used for the production of ointments for external use with antiseptic properties and intended for the treatment of diseases of the skin of various etiologies in humans.

To treat lesions of the skin of various etiologies, ointments are used, including those with an antiseptic agent based on copper-silver and zinc-containing components, which have a wide range of antimicrobial properties.

The prior art.

In medical practice, the antimicrobial action of these metals is widely known, as well as Au, Pt, Pd (see N.E. Morton, Pseudomonas in Disinfection, Sterilization and Preservation, ed. SSBlock, Lea and Febider 1977 and N. Grier, Silver and Its Compounds in Disinfection, Sterilization and Preservation, ed. SSBlock, Lea and Febiger, 1977).

Known ointments containing silver sulfadiazine and piperacillin sodium / Patent US 4535078, publ. 1985 /, or - wound healing materials based on animal tissues impregnated with silver sulfadiazine salt / Patent US 4599226, publ. 1987 year

Common disadvantages of these drugs, in addition to the adaptation of microorganisms to them, are also:

- the presence of contraindications due to side effects characteristic of sulfa drugs: allergy, dyspeptic disorders;

- the inappropriateness of their use for the treatment of purulent wounds with abundant exudation, characteristic, in particular, for patients with diabetic foot.

The technical solution according to patent RU No. 2331407 proposes a composition with an antiseptic agent based on electrolytic silver, the preparation of which is based on the use of an electrolyzer filled with an electrolyte in the form of a liquid phase of sodium acetate buffer and in which flat silver electrodes with a silver content of 99.99 are placed.

The energy method for producing electrolytic silver, as well as the process for producing a gel in the form of a liposome form of water-soluble substances described in this technical solution, increases the cost of manufacturing the preparation according to the invention.

The technical solution according to patent RU No. 2297840 proposes an ointment containing a carrier in the form of polyethylene glycol and an antiseptic agent based on a mixture of salts of copper acetate Cu (CH ₃ COO) ₂ · N ₂ O and silver acetate AgC ₂ H ₃ O ₂ , which are donors of silver ions and copper in the structure of the ointment.

However, these compounds of soluble salts do not provide long-term protection, because the complexation of silver ions reduces the antiseptic properties of ointments.

In the above technical solutions, the effectiveness of ointments is not shown when using them for the treatment of skin, which is characterized by diabetic foot syndrome.

Diabetic foot syndrome is one of the serious complications of diabetes. The course of the wound process in patients with diabetes has its own characteristics, namely:

low rate of epithelialization of the ulcer surface, including due to the more intense process of lipid peroxidation, which leads to the formation of free radicals (peroxides), significantly slowing down the healing process;

complex pathogenesis of the wound process, accompanied by both anaerobic microflora and hypoxia, causing destructive tissue changes due to impaired selective filtration of biological fluids and metabolic diffusion, which prevents the removal of metabolic products and the provision of tissues with nutrients and oxygen.

These circumstances indicate the need to create ointments that contribute to:

effective suppression of pathogenic microflora, without causing allergic reactions;

optimizing the regeneration process by improving metabolic processes in the skin.

To solve this problem, the technical solution according to patent RU No. 2166950 proposes an ointment containing an enzyme in the form of collagenase, an antiseptic agent based on miramistin, proxanol to delay exudate and pus from the wound, and an ointment base in the form of polyethylene glycol.

The disadvantages of this technical solution include:

individual intolerance of the ointment due to the use of synthesized organic components based on miramistin (benzyldimethyl [3- (myristoylamino) propyl] ammonium chloride) and proxanol, synthesized by the sequential action of 1,2-propylene-glycol propylene oxide and ethylene oxide in the presence of an alkaline catalyst and having the properties of an alkaline catalyst alcohols, which can lead to destructive changes in the skin;

a narrow range of pH values of 7.0-8.0 ointments for the effective action of the enzyme, which can lead to inefficiency of its use in the formulation of ointments intended for the treatment of skin tissues with their characteristic process of increased formation of peroxides.

In the technical solution according to patent RU No. 2348396, an ointment formulation is proposed containing a hydrophilic water-soluble polymer base in the form of polyethylene oxide gels and antiseptic agents, one of which contains an organic ammonium compound.

In this technical solution, as an antiseptic agent containing an ammonium compound, a compound belonging to non-glycoside analogues of pyrimidine nucleosides, in particular xymedon, which, due to the antibacterial, antioxidant, regenerating effects, increases the effectiveness of the treatment of purulent wounds of patients with diabetic foot syndrome, is used.

As the second antiseptic agent, chloramphenicol is used.

However, the presence of chloramphenicol ointment can cause an allergic reaction, and the drug is also weakly active against acid-resistant bacteria.

In addition, the effectiveness of this ointment is due to the significant amount of ammonium compound in it, which increases the cost of manufacturing the ointment. The use of xymedon at a given quantitative content in the ointment formulation can cause skin burning, which is unfavorable for patients with diabetic foot syndrome.

However, an antiseptic agent based on inorganic components is known (see patent RU No. 2330673). This technical solution proposes an antiseptic agent in the form of a nanostructured powder of bentonite intercalated with Ag ⁺ ions, which was obtained by modifying a solution of inorganic salt of silver nitrate bentonite, previously enriched with Na ⁺ cations by treating it with an aqueous solution of inorganic sodium salt with its subsequent purification from chlorine anions. After intercalation, bentonite is purified from sodium salts, followed by nanostructuring of bentonite to a powder particle size of not more than 150 nm.

An antiseptic agent in the form of bentonite powder intercalated with Ag ⁺ ions is obtained from mineral components biologically compatible with tissues of living organisms and can be used as additives in various preparations for antimicrobial treatment of damaged areas of the skin.

However, this technical solution does not solve the problem of the composition of the external ointment for the treatment of non-healing wounds, trophic ulcers, pustular skin diseases of patients with diabetic foot syndrome.

Based on the above analysis of the prior art, the technical solution according to patent RU No. 2348396 is selected as the closest analogue of the present invention.

Disclosure of the invention.

The objective of the present invention was to create an effective prophylactic ointment for the treatment of diabetic foot based on components biologically compatible with tissues of living organisms, providing a technical result to accelerate the process of regeneration of skin tissues.

To solve the technical problem, a prophylactic ointment for the diabetic foot is proposed, containing a carrier in the form of a hydrophilic water-soluble polymer based on a mixture of polyethylene oxide 1500 and polyethylene oxide 400, antiseptic agents, one of which contains an organic ammonium compound, according to the invention, an aqueous solution of polyhexanide with polyethylene glycol 4000 with a ratio of polyhexanide: polyethylene glycol: water, as 1: 0.05: (3-4) weight. h., as another antiseptic agent, nanostructured bentonite powder intercalated by silver ions (Ag ⁺ ) is used, while carbamide and nanostructured bentonite powder intercalated by cerium ions (Ce ⁺³ ) are added to the composition, the ointment has the following content of components, wt. %:

polyhexanide aqueous solution with polyethylene glycol 4000 0.1-0.2 nanostructured bentonite powder, intercalated by silver ions (Ag ⁺ ) 0.1-0.5 nanostructured bentonite powder, intercalated by cerium ions (Ce ³⁺ ) 0.01-0.05 urea 1.5-3.0 carrier rest

According to the invention, a mixture of polyethylene oxide 1500 and polyethylene oxide 400 is used at a ratio of 1: (2.5 ÷ 4) weight. h ..

According to the invention, nanostructured bentonite powders intercalated with Ag ⁺ ions have a particle size of not more than 150 nm.

According to the invention, a nanostructured bentonite powder intercalated with Ce ³⁺ ions is obtained by modification with a 0.3-2.0% aqueous solution of cerium nitrate salt Ce (NO ₃ ) ₃ · 6H ₂ O of a bentonite semi-finished product obtained after its enrichment with sodium (Na ⁺⁾ cations ) when treated with a 3-10% aqueous solution of sodium chloride, followed by purification from chlorine anions, and after intercalation, bentonite is purified from sodium salts with subsequent nanostructuring of bentonite to a particle size of not more than 150 nm.

When implementing the present invention, the process of regeneration of the skin tissue of patients with diabetic foot syndrome is accelerated due to:

use in the formulation of an ointment of antiseptic agents based on an aqueous solution of polyhexanide, a nanostructured bentonite powder intercalated with Ag ⁺ ions, which have a wide spectrum of activity against many types of microorganisms, including aerobic, anaerobic bacteria, yeast and fungi, and providing a complex effect on them as a result of polyhexanide activity in the presence of purulent discharge and prolonged action of silver ions during ion-exchange processes of interaction of bentonite with solutions;

using in the formulation of the ointment a nanostructured powder of bentonite intercalated with Ce ³⁺ ions, which have a high energy potential for interaction with peroxides intensively formed in the skin of patients with diabetic foot syndrome;

the use of carbamide ointment in the formulation, which promotes skin hydration and penetration of active substances into it, which increases the diffusion exchange processes of interaction between skin tissues and ointment components. As a result, tissue hypoxia is reduced, the formation of peroxides in tissues is blocked and their destructive changes are reduced.

When analyzing the prior art, no technical solutions with a combination of features corresponding to the claimed technical solution and providing the result described above were found.

The above analysis of the prior art indicates that the claimed technical solution meets the criteria of "novelty", "inventive step".

The claimed technical solution can be industrially implemented using well-known technological processes, equipment and materials intended for the manufacture of medical ointments.

The implementation of the invention.

The invention is illustrated by the choice of raw materials for the implementation of the invention, examples of its implementation, test results.

For the implementation of the invention using drugs known in the pharmaceutical industry for the manufacture of various ointments.

1. The carrier is in the form of a hydrophilic water-soluble polymer base.

Polyethylene oxide gels with a molecular weight of 1500 (PEO-1500) and 400 (PEO-400) are used as a water-soluble polymer base.

The use of PEO-1500 in the composition of the ointment promotes the active binding of inflammatory exudate in a purulent wound, they are given in a dressing, providing a dehydrating effect.

PEO-400 - is a physiologically indifferent compound, promotes a more uniform distribution of ointment on the wound surface, does not interfere with the gas exchange of tissues, does not violate their physiological functions.

The ratio between PEO-400 and PEO-1500 defined by the present invention is optimal and is recommended when creating ointments for diabetic foot (see, for example, patent RU No. 2348396).

2. An aqueous solution of polyhexanide with polyethylene glycol 4000 with a ratio of polyhexanide: polyethylene glycol: water, as 1: 0.05: (3 ÷ 4) weight. hours

This drug has the trade name "Lavasept", is intended for antiseptic treatment of infected wounds and superficial injuries of soft tissues, including the treatment of skin with diabetic foot syndrome.

The quantitative content of the preparation as defined in the present invention in the composition of the ointment is optimal and meets the recommendations for its use in external antiseptic treatment of infected wounds. A decrease in the quantitative content of the drug in the composition of the ointment worsens its antiseptic properties, and an increase leads to an increase in the costly part and the manifestation of allergic reactions on the skin.

3. Urea (urea).

This product provides skin hydration, retains moisture in the cells of the epidermis, has high permeability, which contributes to an increase in metabolic diffusion processes of interaction between skin tissues and ointment components.

The quantitative urea content specified in the present invention is optimal. A decrease in the amount of urea in the composition of the ointment worsens the diffusion exchange processes, and with an increase in the amount of urea in the composition of the ointment, its organoleptic properties deteriorate.

4. Antiseptic agent based on nanostructured powder of bentonite intercalated with silver ions (Ag ⁺ ).

This antiseptic agent is obtained according to the known technology described in patent RU No. 2330673.

To obtain an antiseptic agent, I use montmorillonite (Na-form bentonite), which is treated with a 3-10% aqueous solution of sodium chloride, followed by washing and filtering the resulting semi-finished product to remove chlorine. The bentonite semi-finished product is then modified with a 10-20% silver nitrate solution, and the modified bentonite is kept in the indicated saline solution. The resulting product after intercalation is purified from sodium salts, nanostructured to obtain bentonite powder. The particle size of the bentonite powder is not more than 150 nm. The inorganic mineral is treated with the said salt solutions at a ratio of weight. hours: bentonite: solution, as 1: (10-40). Depending on the amount of activating and intercalating (modifying) reagents, bentonite powder intercalated with silver ions contains from 2 to 8 wt.% Silver.

The indicated amount of the named metal in bentonite powders is optimal. An increase in the amount of metals leads to an increase in the costly part of obtaining an antimicrobial agent, and with a decrease, the antimicrobial activity decreases.

The quantitative content of the nanostructured powder of bentonite intercalated with silver ions as defined by the present invention is optimal. With a decrease in the content of this antiseptic agent in the composition of the ointment, its antiseptic properties deteriorate. An increase in the quantitative content of this antiseptic agent in the composition of the ointment increases the cost of its manufacture.

5. Nanostructured bentonite powder intercalated by cerium ions (Ce + ³ ).

This product is obtained by modification with a 0.3-2.0% aqueous solution of cerium nitrate salt Се (NO ₃ ) ₃ · 6Н ₂ О of a semi-finished product of bentonite obtained after its enrichment with Na ⁺ cations when treated with a 3-10% aqueous solution of sodium chloride, followed by purification from chlorine anions. After intercalation, bentonite is purified from sodium salts, followed by nanostructuring of bentonite to a particle size of not more than 150 nm. When choosing the Се (NO ₃ ) ₃ · 6Н ₂ О salt, it was assumed that cerium (a metal of variable valency) actively interacts with oxygen to form cerium dioxide (СеО ₂ ), which is an antioxidant that has an inactivating and blocking effect on the formation of peroxide hydroperoxide radicals generated by oxidative processes. This metal belongs to biocompatible materials and is actively used in medicine, for example, in dentistry.

When implementing the present invention in the process of intercalation of the semi-finished bentonite obtained after enrichment with Na ⁺ cations, a 0.5% aqueous solution of cerium nitrate Ce (NO ₃ ) ₃ · 6H ₂ O was used.

The bentonite powder obtained after intercalation, purification and nanostructuring contains cerium in an amount of not more than 0.5 mass%.

The quantitative content of the nanostructured powder of bentonite intercalated with Ce ³⁺ ions as defined by the present invention is optimal under the conditions of blocking peroxides formed during oxidative processes in the skin of patients with diabetic foot syndrome.

With a decrease in the content of this drug in the composition of the ointment, the activity of the ointment by the interaction of cerium ions with peroxides decreases. The increase in the quantitative content of this component in the composition of the ointment increases the costly part for its manufacture.

At the stage of preparation of bentonite semi-finished products enriched in sodium cations, we used a 5% aqueous solution of sodium chloride, and at the stage of nanostructuring of bentonite intercalated with Ag ⁺ ions or Ce ³⁺ ions, we used a Bandelin Sonopuls HD-2070 ultrasonic disperser with a power of 35-75 W / cm ² , frequency - 20-50 kHz.

Nanostructured bentonite powders with a particle size of not more than 150 nm were obtained. To assess the particle size of bentonite used the method of microscopy.

The ointment according to the invention is prepared as follows.

PEO-400 and PEO-1500 polyethylene oxides are fused at a temperature of + 40 ° С, the resulting mixture is cooled with stirring and other ingredients (components) specified by the invention are added to it, mixing of which is carried out, preferably, using an ultrasonic unit that provides effective dispersion of nanostructured powders bentonite.

When implementing the invention, an ointment for treating a diabetic foot was obtained according to the following examples.

Example 1:

polyhexanide aqueous solution with polyethylene glycol 4000 (drug "Lavasept") 0.10 nanostructured bentonite powder, intercalated by ions of Ag ⁺ 0.10

nanostructured bentonite powder,

intercalated by Ce ³⁺ ions 0.01 urea 1,50 polyethylene oxide 1500 28.08 polyethylene oxide 400 70,20

Example 2:

polyhexanide aqueous solution with polyethylene glycol 4000 (drug "Lavasept") 0.20 nanostructured bentonite powder, intercalated by ions of Ag ⁺ 0.50 nanostructured bentonite powder, intercalated by Ce + ³ ions 0.05 urea 3.00 polyethylene oxide 1500 19.25 polyethylene oxide 400 77.00

Example 3 (control):

polyhexanide aqueous solution with polyethylene glycol 4000 (drug "Lavasept") 0.20 nanostructured bentonite powder, intercalated by ions of Ag ⁺ 0.50 polyethylene oxide 1500 19.86 polyethylene oxide 400 79.44

Obtained in examples 1-3 ointment compositions have a uniform plastic structure.

The composition of the ointments in examples 1-3 were evaluated in order to identify their influence on the epithelialization of tissues, characterizing the process of their regeneration.

To conduct evaluation tests, mice were used in the experiment, wounds were applied with a scalpel to the shaved surface of the skin. The depth of the wound is 0.5-0.8 mm, length is 3-4 mm. When conducting tests on skin wounds of mice using gauze swabs, ointments were applied in accordance with their formulation according to examples 1-3. When applying ointments according to examples 1-2, after a day of their application, the formation of scabs began, on the third day the edges of the wound converged and complete epithelialization of the skin took place on the 6th day. When applying the ointment of example 3, epithelialization of the skin took place on the 9th day.

The tests carried out indicate that the ointment made according to the recipe in accordance with the invention actively affects the regeneration of skin tissue, which indicates the effectiveness of the composition of the ointment according to the invention.

Claims (4)

1. A prophylactic ointment for a diabetic foot containing a carrier in the form of a hydrophilic water-soluble polymer based on a mixture of polyethylene oxide 1500 and polyethylene oxide 400, antiseptic agents, one of which contains an organic ammonium compound, characterized in that an aqueous solution of polyhexanide with polyethylene glycol 4000 is used as an ammonium compound when the ratio is polyhexanide: polyethylene glycol: water, as 1: 0.05: (3 ÷ 4) parts by weight, nanostructured powder is used as another antiseptic agent tonita intercalated by ions of silver (Ag ^+), wherein further introduced into the urea and nanostructured powder of bentonite intercalated by ions of cerium (Ce ³⁺⁾ Ointment has the following contents, wt.%:
polyhexanide aqueous solution with polyethylene glycol 4000 0.1-0.2 nanostructured bentonite powder, intercalated by silver ions (Ag ⁺ ) 0.1-0.5 nanostructured bentonite powder, intercalated by cerium ions (Ce ⁺³ ) 0.01-0.05 urea 1.5-3.0 carrier rest 2. Preventive ointment according to claim 1, characterized in that the mixture of polyethylene oxide 1500 and polyethylene oxide 400 is used at a ratio of 1: (2.5 ÷ 4) parts by weight 3. The prophylactic ointment according to claim 1, characterized in that the nanostructured bentonite powders intercalated with Ag ⁺ ions have a particle size of not more than 150 nm. 4. The prophylactic ointment according to claim 1, characterized in that the nanostructured bentonite powder intercalated with Ce ³⁺ ions is obtained by modification with a 0.3-2.0% aqueous solution of the nitric acid salt of cerium Ce (NO ₃ ) ₃ · 6H ₂ O of the semi-finished product of bentonite obtained after its enrichment with Na ⁺ cations during treatment with a 3-10% aqueous solution of sodium chloride, followed by purification from chlorine anions, and after intercalation, bentonite is purified from sodium salts with subsequent nanostructuring of bentonite to a particle size of not more than 150 nm