Technical Field

The invention concerns the area of medicine and can be applied to manufacture ointments for external application, possessing antiseptic properties and intended for treatment of human diseases of integuments, of various etiologies.

Ointments including an antiseptic agent, on the basis of copper, silver and zinc, having a wide spectrum of antimicrobic properties, are used for treatment of diseases of integuments of various etiologies.

State of the art

The antimicrobic action of the named metals and also of Au, Pt, Pd is widely known in medical practice (see H.E. Morton, Pseudomonas in Disinfection, Sterilisation and Preservation, ed. S.S. Block, Lea and Febider 1977 and N. Grier, Silver and Its Compounds in Disinfection, Sterilisation and Preservation, ed. S.S. Block, Lea and Febiger, 1977).

The ointments containing silver sulfadiazine and sodium piperacillin (USP No. 4535078, published in 1985) or wound healing materials on the basis of the animal tissues impregnated with silver salt of sulfadiazine (USP No. 4599226, published in 1987) are known.

Common shortcomings of the given medical products, including tolerance of microorganisms to them, are also the following:

- presence of contraindications due to side effects peculiar to sulpha preparations, in particular to allergy or dyspepsia;

- inexpediency of their application for treatment of purulent wounds with plentiful exudation, peculiar, in particular, for patients with diabetic foot.

The structure with the antiseptic agent on the basis of electrolytic silver is described in the technical specification of the Russian patent RU No. 2331407. Electrolytic silver is obtained by using an electrolyzer filled with an electrolyte which is a liquid phase of the sodium-acetate buffer and in which flat silver electrodes with a content of silver of 99,99% are placed.

The method for obtaining electrolytic silver and also the process for obtaining gel as liposomal forms of water-soluble substances, described in the given technical specification, increase costs for manufacturing the medical preparation according to the above cited patent.

An ointment containing as the carrier polyethylene glycol and an antiseptic agent on the basis of a mix of salts of copper acetate Cu(CH ₃ COO) ₂ H ₂ 0 and silver acetate AgC ₂ H ₃ 0 ₂ , which are donors of ions of silver and copper, when incorporated in the composition of an ointment, is described in the technical specification of the patent RU No. 2297840.

However the specified compounds of soluble salts do not provide long protection, because the formation of complexes of silver ions decreases antiseptic properties of ointments.

Efficiency of ointments when used for treatment of integuments with the syndrome of diabetic foot, is not shown in the above mentioned patents.

The syndrome of diabetic foot is one of heavy complications of diabetes. The clinical course of wound process in patients with diabetes, has the following features, namely:

- low speed of epithelization of the ulcer surface also owing to a more intensive process of peroxide oxidations of lipids, that leads to formation of free radicals (peroxides), considerably slowing down processes of healing;

- complex pathogenesis of the wound process, accompanying both anaerobic microflora and hypoxia, causing destructive changes of tissues, owing to prevention of a selective filtration of biological liquids and exchange diffusion that interferes with removal of products of metabolites and provision of tissues with nutrients and oxygen. The named facts demonstrate the necessity of creating ointments promoting:

- effective suppression of pathogenic microflora while not causing allergic reactions;

- optimization of the process of regeneration, due to improvement of exchange processes in integuments.

In the technical solution according to the patent RU No. 2166950, an ointment is described containing an enzyme as collagenase, an antiseptic agent on the basis of miramistin and proxanols for removal of exudates and pus from the wound and a basis as polyethylene glycol. This patent does not resolve the problems due to the following shortcomings:

- individual intolerance to ointment, owing to the use of the synthesized organic components on the basis of miramistin (benzildimetil [3- (miristilamino) propyl] ammonium chloride) and proxanols, synthesized by consecutive action of propylene oxide and ethylene oxide on 1,2-propylene- glycol in the presence of an alkaline catalyst. It possesses properties of alcohol that can lead to destructive changes of integuments;

- narrow range of values of pH 7,0-8,0 of ointments for effective action of enzyme that can lead to an inefficiency of its use in a composition of ointment intended for treatment of the skin tissues with characteristics deriving from increased formation of peroxides.

A composition of ointment containing a hydrophilic water-soluble polymeric basis, as gels of polyethylene oxide, and antiseptic agents, is described in the technical solution according to the patent RU No. 2348396. One of agents contains an organic ammonium compound.

In particular non-glycoside analogues of pyrimidine nucleoside are used as the antiseptic agent containing ammonium compound, in the given technical specification. More specifically, it can be xymedon which raises efficiency of treatment of purulent wounds of patients with a syndrome of diabetic foot due to antibacterial, antioxidant and recycling effects. Chloramphenicol is used as the second antiseptic agent.

However the presence in the composition of ointment of chloramphenicol can cause allergic reactions; such a preparation is also poorly active to acid-steady bacteria.

Besides, efficiency of action of the given ointment needs the presence of a significant amount of ammonium compounds. What raises costs for manufacturing of the ointment.

Application of xymedon at the specified quantitative contents, in a composition of ointment, can cause burning of the skin. This is a negative effect for patients with the syndrome of diabetic foot.

An antiseptic agent created on the basis of inorganic components is known (see patent RU No. 2330673). The antiseptic agent, as a nanostructured powder of bentonite intercalated by ions of Ag ⁺ , which is obtained by modification of bentonite with a solution of an inorganic salt of silver nitrate, is described in the above identified technical specification. Bentonite is preliminarily enriched with cations of Na ⁺ by processing with a water solution of an inorganic salt of sodium and subsequent cleaning from anions of chlorine. After intercalation, bentonite is cleaned from salts of sodium with subsequent nano structuring up to a size of the particles of bentonite powder of no more than 150 nm.

An antiseptic agent, consisting in a powder of bentonite intercalated by ions of Ag ⁺ , is obtained from the mineral components biologically compatible with tissues of live organisms and can be used as additive in various preparations for antimicrobic treatment of the injured zones of integuments.

However in the given technical solution the problem of a composition of ointment of external application, for treatment of not healing wounds, trophic ulcers and pustular diseases of a skin of patients with a syndrome of diabetic foot is not solved.

In view of the resulted analysis of available art, the technical specification of the patent RU No. 2348396 is chosen as the closest prior art for the present invention.

Disclosure of the invention

The problem of the present invention consisted in the creation of an ointment for treatment of diabetic foot, with preventive efficacy, on the basis of components biologically compatible with tissues of live organisms and providing the technical result of accelerating the process of regeneration of integuments.

For the solution of the put technical problem, an ointment with preventive efficacy for diabetic foot is described. It contains as the carrier a hydrophilic water-soluble polymer on the basis of a mix of polyethylene oxide 1500 and polyethylene oxide 400 and antiseptic agents, one of which contains an organic ammonium compound. According to the invention a water solution of polyhexanide with polyethylene glycol 4000 was used as ammonium compound at the ratio: polyhexanide : polyethylene glycol : water, as 1 : 0,05 : (3÷4) weight by parts. A nanostructured powder of bentonite intercalated by ions of silver (Ag ⁺ ) was used as the other antiseptic agent. Then a carbamide and a nanostructured powder of bentonite intercalated by ions of cerium (Ce ³⁺ ) are additionally injected in the composition and the ointment has the following content of components, in % by weight (% b.w.):

water solution of polyhexanide

with polyethylene glycol 4000 - 0,1 - 0,2 nanostructured powder of bentonite

intercalated by ions of Ag ⁺ - 0,1 - 0,5 nanostructured powder of bentonite

intercalated by ions of Ce ³⁺ 0,01 - 0,05 carbamide 1,5 - 3,0 carrier the rest.

According to the invention a mix of polyethylene oxide 1500 and polyethylene oxide 400 is used at the ratio of 1 : (2,5-4) parts b.w..

According to the invention nanostructured powders of bentonite intercalated by ions of Ag ⁺ have a size of the particles of no more than 150 nm.

According to the invention a nanostructured powder of bentonite intercalated by ions of Ce ³⁺ is obtained by modifying a semifinished product of bentonite with 0,3-2,0% water solution of nitrate salt of cerium Ce(N0 ₃ ) ₃ -6H ₂ 0. Bentonite is obtained after enrichment with cations of sodium (Na ⁺ ), by processing with 3-10% water solution of sodium chloride and subsequent cleaning from anions of chlorine. After intercalation, the bentonite is cleaned from salts of sodium and successively is nanostructured up to a size of the particles of no more than 150 nm.

At realization of the present invention, the process of regeneration of skin tissues of patients with the syndrome of diabetic foot is accelerated due to the following reasons:

- use of antiseptic agents on the basis of a water solution of polyhexanide and a nanostructured powder of bentonite intercalated by ions of Ag ⁺ in a composition of ointment. They have a wide spectrum of activity against many kinds of microorganisms including aerobic and anaerobic bacteria, yeast and funguses and provide a complex influence on them as a result of the activity of polyhexanide in the presence of purulent exudates and of the prolonged action of ions of silver due to ion exchange processes of interaction of bentonite with solutions; - use of a nanostructured powder of bentonite intercalated by ions of Ce ³⁺ in a composition of ointment. Ions possess a high energy potential of interaction with peroxides intensively formed in integuments of patients with a syndrome of diabetic foot;

- use of the carbamide in a composition of ointment. It promotes hydration of the skin and penetration of active substances into it. What increases exchange and diffuses processes of interaction of skin tissues and components of ointment. As a result hypoxia of tissues is decreased, processes of formation of peroxides in the tissues are blocked and their destructive changes are decreased.

Analysis of the available art did not reveal technical solutions with a set of characteristics corresponding to those of the present technical solution and providing the results described above.

The results of the analysis of the available art testifies the conformity of the present technical solution to the criteria of "novelty" and "degree of inventiveness".

The declared technical solution can be industrially realized by using known technological processes, equipments and materials intended for manufacturing ointments for medical purposes.

Detailed description of the invention

The essence of the invention is explained by a choice of raw components for its realization, examples of its realization and results of tests.

Preparations known in the pharmaceutical industry, and intended for manufacturing various ointments, are used for realization of the invention.

1. The carrier is a hydrophilic water-soluble polymeric basis.

Gels of polyethylene oxide with molecular weight 1500 (PEO-1500) and 400 (PEO-400) are used as a water-soluble polymeric basis. Use of PEO-1500 in a composition of ointment promotes active binding of inflammatory exudates in a purulent wound; it transfers them into a bandage providing a dehydration effect.

PEO-400 is a physiologically indifferent compound; it promotes more uniform distribution of ointment on the wound surface; it does not prevent gas exchange of tissues and does not break their physiological functions.

The ratio between PEO-400 and PEO-1500 specified in the present invention is the optimum and it is recommended for creation of ointments for diabetic foot (see, for example, patent RU N. 2348396).

2. A water solution of polyhexanide with polyethylene glycol 4000 at the ratio: polyhexanide : polyethylene glycol : water as 1 : 0,05 : (3÷4) parts by weight.

The given preparation has the trade mark "Lavasept", it is intended for antiseptic treatment of infected wounds and superficial injuries of soft tissues, including for treatment of integuments with the syndrome of diabetic foot.

The quantitative content of said preparation in the composition of ointment specified in the present invention is the optimum and corresponds to recommendations of its use for external antiseptic treatment of infected wounds. Decrease in the quantitative content of the preparation in the composition of ointment, worsens its antiseptic properties while increase leads to increase in costs and to display of allergic reactions on the skin.

3. Carbamide (urea).

The given product provides humidifying the skin, keeps moisture in cells of epidermis and has high permeability, that promotes increase in exchange and diffuse processes of interaction of skin tissues and components of ointment.

The quantitative contents of carbamide specified in the present invention are the optimum. Decrease in amount of carbamide in the composition of ointment worsens exchange diffuse processes while increase in amount of carbamide in the composition of ointment worsen its organoleptic properties.

4. Antiseptic agent on the basis of a nanostructured powder of bentonite intercalated by ions of silver.

The given antiseptic agent is obtained in accordance with the known technology described in the patent RU N. 2330673.

Montmorillonite (bentonite in Na-form) is used for obtaining said antiseptic agent. It is processed with 3-10 % water solution of chloride sodium with subsequent washing and filtering of the obtained semifinished product, for removal of chlorine. Then the semifinished product of bentonite is modified with 10-20 % solution of silver nitrate, with retention intervals of modified bentonite in the specified salt solution. After intercalation, the obtained product is cleaned from salts of sodium and is nanostructured thus obtaining a powder of bentonite. The size of the particles of a powder of bentonite is no more than 150 nm. Processing of an inorganic mineral with the named solutions of salts is carried out at the ratio, in parts by weight, bentonite : solution as 1 : (10-40). The powder of bentonite intercalated by ions of silver contains from 2 up to 8% b.w. of silver, depending on the amount of activating and intercalating (modifying) reagents.

The specified amount of the named metal in bentonite powders is the optimum. The increase in amount of metals leads to increase in costs for obtaining the antimicrobic agent while a decrease worsens its antimicrobic activity.

The quantitative content of a nanostructured powder of bentonite intercalated by ions of silver specified in the present invention, is the optimum. A decrease in the contents of the given antiseptic agent in the composition of ointment, leads to worsen the antiseptic properties. Increase in the quantitative contents of the given antiseptic agent, in a composition of ointment, increases costs for its manufacturing.

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

The given product is obtained by modifying a semifinished product of bentonite with a 0,3-2,0 % water solution of nitrate salt of cerium Ce(N0 ₃ ) ₃ -6H ₂ 0. Bentonite is obtained after its enrichment with cations of Na ⁺ , by processing with a 3-10% water solution of chloride sodium, and subsequent cleaning from anions of chlorine. After intercalation, bentonite is cleaned from salts of sodium with subsequent nanostructuring up to a size of the particles of no more than 150 nm. For the choice of the salt Ce(N0 ₃ ) ₃ -6H ₂ 0, it was taken into account that cerium (metal of variable valency) actively interacts with oxygen with formation of cerium dioxide (Ce0 ₂ ) which is an antioxidant. It is peculiar to it inactivating and blocking influence on formation of peroxide and hydroperoxide radicals, generated in oxidizing processes. This metal pertains to biologically compatible materials and is actively used in medicine, for example, in stomatology.

A 0,5% b.w. water solution of cerium nitrate Ce(N0 ₃ ) ₃ -6H ₂ 0 was used for realization of the present invention, in a process of intercalation of a semifinished product of bentonite obtained after its enrichment with cations of Na ⁺ .

The powder of bentonite obtained after intercalation, cleaning and nanostructuring contains cerium in the amount of no more than 0,5% b.w..

The quantitative contents of a nanostructured powder of bentonite intercalated by ions of Ce ³⁺ specified in the present invention are the optimum for the conditions of blocking peroxides which are formed in the oxidizing processes of integuments of patients with a syndrome of diabetic foot.

Decrease in the contents of the given preparation in a composition of ointment, the activity of ointment, in interaction of ions of cerium with peroxides, is decreased. Increase in the quantitative content of the given component in a composition of ointment, increases costs for its manufacturing.

A 5% b.w. water solution of sodium chloride was used at the stage of obtaining a semifinished products of bentonite enriched with cations of sodium; the ultrasonic dispersant Sonopuls HD-2070, company Bandelin, with power - 35-75, Wt/cm ² and frequency 20-50 kHz, was used at the stage of nanostructuring bentonite intercalated by ions of Ag ⁺ or ions of Ce ³⁺ .

Nanostructured powders of bentonite with a size of the particles of no more than 150 nm were obtained. The method of microscopy was used for estimation of the size of the particles of bentonite.

The ointment according to the invention is obtained as follows:

Polyethylene oxides PEO-400 and PEO-1500 are admixed at a temperature of +40°C; the obtained mix is cooled at randomization and other components specified in the invention are added in it. Mixing is carried out preferably with use of the ultrasonic equipment providing effective dispersion of nanostructured powders of bentonite.

An ointment for treatment of diabetic foot has been obtained with the following examples at realization of the invention. The given amounts are percentages by weight.

Example 1 :

water solution of polyhexanide

with polyethylene glycol 4000

(drug Lavasept) - 0,10 nanostructured powder of bentonite

intercalated by ions of Ag ⁺ 0, 10 nanostructured powder of bentonite

intercalated by ions of Ce ³⁺ 0,01 carbamide 1,50 polyethylene oxide 1500 28,08 polyethylene oxide 400 70,20

Example 2 :

water solution of polyhexanide

with polyethylene glycol 4000

(drug Lavasept) 0,20 nanostructured powder of bentonite

intercalated by ions of Ag ⁺ 0,50 nanostructured powder of bentonite

intercalated by ions of Ce ³⁺ 0,05 carbamide 3,00 polyethylene oxide 1500 19,25 polyethylene oxide 400 77,00

Example 3 (control) :

water solution of polyhexanide

with polyethylene glycol 4000

(drug Lavasept) 0,20 nanostructured powder of bentonite

intercalated by ions of Ag ⁺ 0,50 polyethylene oxide 1500 19,86 polyethylene oxide 400 79,44

Ointment compositions obtained according to examples 1-! homogeneous plastic structure. Compositions of ointments from examples 1-3 were evaluated with the purpose of revealing their influence on epithelization of tissues, describing the process of their regeneration.

Mice were used for carrying out evaluation tests in the experiment, i.e. wounds were inflicted on shaved surface of their skin by the scalpel. Depth of a wound was 0,5-0,8 mm and length was 3-4 mm. When carrying out the tests, ointments were rendered on skin wounds of mice, with use of gauze tampons, according to their compounding by examples 1-3. Formation of scabs has begun at application of ointments by examples 1-2 within 24 hours from their application. Lips of a wound were met on the third day and full epithelization of the skin took place on the 6th day. Epithelization of the skin took place on the 9th day at application of the ointment according to example 3.

The tests carried out testify that the ointment made according to the invention actively influences the regeneration of tissues of integuments, what testifies the efficiency of the composite structure of the ointment according to the invention.