RU2636530C2 - Pharmaceutical compositions for treatment of wounds and burns - Google Patents

Abstract

FIELD: pharmacology.SUBSTANCE: pharmaceutical composition for the treatment of burns and wounds includes the following components, wt %: colloidal silver - 0.0001-0.1, colloidal zinc oxide - 5-15, glycerol - 5-15, methylcellulose - 0.05-5, distilled water is the rest. The invention provides an acceleration of tissue regeneration processes in burn wounds. The invention can be used in therapy and surgery for wound healing as a reparative, antiinflammatory and microcirculation-improving agent for the treatment of thermal, solar and chemical burns.EFFECT: composition has no local irritation or allergic effect, it can be easily removed from the skin surface and is easy to use.4 dwg, 3 ex

Description

FIELD OF THE INVENTION

The invention relates to veterinary medicine and pharmacology, in particular to a pharmaceutical composition for treating wounds and burns, in particular to soft external medicines in the form of hydrophilic ointment, gel, emulsion, liniment, and can be used in therapy and surgery for healing burn wounds, as a reparative, anti-inflammatory and microcirculation enhancing agent for the treatment of thermal, sun and chemical burns.

State of the art

Known drug for the treatment of infected wounds and burns containing an ionic form of silver, represented by a limited number of expensive soft dosage forms for external use of foreign production: "Argosulfan" (see Pharmaceutical plant Elfa A.O., Poland: cream 2%), "Dermazin ”(See Lek, Slovenia: 1% cream), Ebermin (see Center for Genetic Engineering and Biotechnology, Cuba: ointment) (see the State Register of Medicines. Website of the Federal Service for the Supervision of Health Care and social development [elek throne resource]. - Access mode: http://www.regmed.ru).

The disadvantage of these drugs is the low viscosity liquid consistency, which is mainly suitable for debridement (rinsing, washing) and does not provide a prolonged action, while a lot of dressing is used up, and silver solutions are expensive and have a short shelf life.

The known preparation of silver salts of sulfanilamides, which is an antibacterial drug for topical application, helps protect wounds from infection, which relieves pain and burning in the wound, reduces treatment time and preparation time of the wound for skin transplantation, which in many cases leads to an improvement that eliminates the need for transplantation (see. "The Register of Medicinal Products of Russia - Encyclopedia of Medicines." Edition, seventh, revised and supplemented, 2000; Mashkovsky MD "Medicines". In dv x parts h 11 -. 12th edition, revised and enlarged -. M .: Medicine, 1994. - 688 s)..

The disadvantage of this drug is also a low viscosity liquid consistency, suitable mainly for debridement (rinsing, rinsing) and not providing a prolonged action.

Known tool for the treatment of infected wounds containing zeolite Kholinsky deposits, while it is a powder of zeolite modified with silver in an amount of 0.1-0.4 weight. % with particle sizes of 17-20 Å (see US Pat. RU No. 2245151, IPC A61K 33/00, A61K 33/38, A61P 17/02, publ. January 27, 2005).

The disadvantage of this tool is that when working with it, in particular, it is difficult and painful to wash (remove) it from wounds during repeated dressings, since it is a fine powder of natural silver-modified aluminosilicate, in addition, with pathogenic microflora located in In the wound, only finely dispersed Ag of the surface layer of aluminosilicate interacts, while most of Ag is in the pore space of the zeolite, a low therapeutic effect.

The closest in technical essence and the achieved positive effect and adopted by the authors for the prototype is a tool for the treatment of wounds and burns, which use the use of ultrafine silver-containing systems, which are nanocomposites of zero-valent metallic silver with a particle size of 10-25 nm, stabilized with arabinogalactan or its sulfated derivative, as anti-inflammatory, antiexudative and wound healing agents.

A means for treating wounds and burns, having anti-inflammatory, antiexudative, antimicrobial and wound healing activities, made in a soft dosage form for external use in the form of a hydrophilic gel, containing silver nanocomposites as an active pharmacologically active substance and additionally containing carbomer as a hydrophilic base, as well as triethanolamine, glycerin or 1,2-propylene glycol and purified water in the following ratio of components to mass. %:

silver and arabinogalactan nanocomposite or its sulfated derivative (AG + Ag ⁰ ) (AGSO ₃ H + Ag ⁰ ) 0.1-1.0 carbomer 0.2-1.5 triethanolamine 0.1-1.0 glycerol or 1,2-propylene glycol 5.0-50.0 purified water up to 100.0

The use of agents for treating wounds and burns in a needy subject (see Pat. RU No. 2513186, IPC A61K 33/38, A61K 31/737, A61K 47/10, A61K 47/30, A61P 17/02, B82B 1/00, B82Y 5/00 publ. 04/20/2014).

The disadvantage of this tool is that the pathogenesis of burns of varying severity is accompanied by impaired protein synthesis, acid-base balance, a combination of enzymatic decomposition reactions of complex high molecular weight and bioorganic compounds, which leads to tissue necrosis, exudative reactions, the formation of granulation tissue, bacterial contamination of the burn surface.

Disclosure of invention

The objective of the invention is to develop a pharmaceutical composition for the treatment of wounds and burns, with a highly effective regenerating, wound healing effect, as well as improving microcirculation funds for the treatment of burn wounds, made in the form of a pharmaceutical hydrophilic ointment composition.

The technical result, which can be achieved using the present invention, is to accelerate the regeneration of tissues of burn wounds.

The technical result is achieved using a pharmaceutical composition for the treatment of wounds and burns, including colloidal silver, glycerin and distilled water, while it additionally contains colloidal zinc oxide and methyl cellulose in the following ratio of components in wt. %:

colloidal silver 0.0001-0.1 colloidal zinc oxide 5-15 glycerol 5-15 cellulose 0.05-5 distilled water rest

Thus, the technical result is achieved due to the pharmaceutical hydrophilic ointment composition, which includes methyl cellulose as a structurant and the hydrophilic base of the entire ointment composition, colloidal particles of silver and zinc oxide as the main active components, glycerin as a water-retaining component and distilled water, while colloidal silver in the composition of a pharmaceutical hydrophilic ointment composition due to its high bactericidal, fungicidal and counter Rusnė properties, the use of colloidal particles of zinc oxide as a main active hydrophilic ointment pharmaceutical composition component is associated with their anti-inflammatory, a drying adsorbing, astringent and antiseptic action (bactericidal and fungicidal properties). And, as you know, zinc oxide is a source of zinc ions, which, saturating the tissue of the wound surface, additionally stimulate the regeneration processes. It is also known that the morphology of an aseptic wound process goes through 3 stages:

1 - inflammation,

2 - proliferation of connective tissue,

3 - scar formation, epithelization (see Kochetygov NI Burn disease. - L., 1973.) Depending on the nature of the wound, the depth and size of the damage, the reactivity of the organism, and the microbial primary pollution, the healing processes can proceed with different options: primary healing, secondary - through suppuration and healing under the scab.

Primary healing is a process in which incised or postoperative wounds with minimal tissue trauma are sutured in layers, that is, the edges of the damage stick together, a thin fibrin film between them sprouts with blood vessels and fibroblasts and undergoes organization with scar formation, passing through all stages: edema, inflammation, germination blood vessels, the formation of connective tissue, the formation of collagen and elastic fibers and epithelization, almost simultaneously. Secondary healing occurs through suppuration (this may be due to primary infection, the formation and infection of a hematoma): swelling and inflammation of the tissues begins with the formation of purulent-necrotic masses, rejection, and only then does the vascular proliferation phase begin with the formation of granulation connective tissue with collagen germination and scar formation. Each wound serves as a “gateway” for the penetration of bacterial microflora, which is saprophytic, but under certain conditions becomes pathogenic. O. Jepsen (1972) conducted an analysis of bacterial contamination of wounds during frequent operations at 3 stages: immediately after the incision, microbial contamination of the wound is observed in 4.8% of cases, before healing of the wound - 18% of cases and during the first ligation - 47 , 4% of cases.

The basis of bacterial microflora is staphylococcus, however, in the future, with the development of the inflammatory process, gram-negative flora and other microbial associations (aerobic and anaerobic) are added: hemolytic streptococcus, Escherichia coli and Pseudomonas aeruginosa, enterobacteria and others. If more effective antibacterial agents are not applied on time, infected wounds are difficult to treat, can lead to the formation of abscesses, fistulas, or long-term non-healing ulcers.

In medicine, in addition to silver, one of the components of anti-burn therapy with anti-inflammatory, drying, adsorbing, astringent and antiseptic effects are zinc compounds, which are used externally in the form of powder, ointment, paste, liniment.

Zinc is one of the vital trace elements. It is necessary for the normal functioning of any cell in the body. Most of it is found in the skin, liver, kidneys, in the retina, in the prostate gland.

The ability of zinc to take part in the processes of ligand formation with organic molecules explains the extremely wide spectrum of its participation in various biological systems and processes. Zinc is indispensable for gene expression and nucleic acid metabolism, and, accordingly, for all processes of cell growth and differentiation. Zinc is a structural component of biological membranes, cellular receptors, proteins, and is part of more than 200 enzymatic systems. Vital hormones such as insulin, corticotropin, growth hormone and gonadotropins are zinc-dependent. In addition, it is necessary for the formation of red blood cells and other formed elements of the blood. It is believed that zinc has antioxidant properties and also improves the action of other antioxidants.

Zinc is part of enzymes and complexes that provide the most important physiological functions of the body, in particular:

- the formation, growth and metabolism of cells, protein synthesis, wound healing;

- activation of immune responses directed against bacteria, viruses, tumor cells;

- the absorption of carbohydrates and fats;

- maintaining and improving memory;

- maintaining taste and olfactory sensitivity;

- ensuring the stability of the retina and transparency of the lens of the eye;

- normal development and functioning of the genital organs.

Zinc derivatives, such as sulfate, acetate, gluconate and zinc oxide, are some of the components of various complex dermatological and cosmetic formulations (for example, “Zinc ointment”, “Lassar paste”, etc.), which can be used both in monotherapy and and in combination with antibiotics (for example, Zenerit lotion containing zinc acetate and erythromycin, used in the treatment of acne). Their pharmacological action is the formation of albuminates and protein denaturation. When applied to the affected surface, exudation, inflammation and tissue irritation are reduced.

The widespread use of zinc oxide as an essential component of dermatological preparations is due to its anti-inflammatory, drying, adsorbing, astringent and antiseptic properties; in this case, ZnO, in contrast to its soluble compounds, has an important advantage - it is practically insoluble in water, therefore, has a less irritating effect.

An analysis of the biomedical properties of ZnO shows the feasibility of introducing zinc oxide in a highly dispersed (colloidal) state into the composition of the pharmaceutical hydrophilic ointment composition. Currently, colloidal ZnO is used as antiseptics in toothpaste and cosmetics, paints, plastics and textiles. Due to photocatalytic activity and light absorption in the UV range, zinc oxide is widely used in sunscreens. A comparative analysis of sunscreens showed that 228 out of 1200 creams contain zinc oxide. Moreover, in 30% of creams containing zinc oxide, this substance was in the form of colloidal or nanoparticles (see http://www.tga.gov.au/npmeds/sunscreen-zotd.htm#pdf).

The essence of obtaining a pharmaceutical hydrophilic ointment composition for the treatment of burns is as follows. The required amount of methylcellulose grade MC-100 is mixed with distilled water and left to swell for 30-60 minutes. Then, the required amount of colloidal zinc oxide (ZnO), glycerol and colloidal silver is added to the formed methyl cellulose gel with constant stirring, followed by physicochemical action to prevent the processes of destabilization and aggregation of ZnO and Ag colloidal particles with the following ratio of components in wt. %:

colloidal silver 0,000-0,1 colloidal zinc oxide 5-15 glycerol 5-15 cellulose 0.05-5 distilled water rest

The developed ointment composition is an odorless white or yellow ointment, uniform in consistency (no mechanical impurities) and having a neutral reaction of the medium (pH≈7).

Brief description of drawings and other materials

In FIG. 1 gives a pharmaceutical composition for the treatment of wounds and burns, the area of burn wounds on the background of the use of various drugs, table.

In FIG. 2 - the same, the diagram of the area of burn wounds for the entire experimental period on the background of the use of ointment "Argosulfan"; zinc ointment; ointments made in accordance with example 2, and the control group, chart.

In FIG. 3 - the same, experimental burn wounds on the 5th day against the background of application: a) ointment "Argosulfan", b) zinc ointment, c) ointment made in accordance with example 2, d) control group, photo.

In FIG. 4 - the same, experimental burn wounds on the 10th day against the background of application: a) ointment "Argosulfan", b) zinc ointment, c) ointment made in accordance with example 2, d) control group, photo.

The implementation of the invention

Examples of specific performance of obtaining a pharmaceutical composition for the treatment of wounds and burns.

Example 1. A pharmaceutical hydrophilic ointment composition for treating burns is prepared as follows. The required amount of methylcellulose grade MC-100 is mixed with distilled water and left to swell for 30-60 minutes. Then, the necessary amount of colloidal zinc oxide (ZnO), glycerol and colloidal silver is added to the formed gel of methyl cellulose with constant stirring, followed by physicochemical action to prevent the processes of destabilization and aggregation of colloidal particles of ZnO and Ag. The developed ointment composition is an odorless white or yellow ointment, uniform in consistency (no mechanical impurities) and having a neutral environment (pH≈7). The result is a hydrophilic pharmaceutical ointment composition with the following ratio of components in wt. %:

colloidal silver <0.0001 colloidal zinc oxide 1-5 glycerol 0.1-5 cellulose 0.01-0.04 distilled water rest

Example 2. Carried out analogously to example 1, but take the following ratio of components in wt. %:

colloidal silver 0.0001-0.1 colloidal zinc oxide 5-15 glycerol 5-15 cellulose 0.05-5 distilled water rest

Example 3. Carried out analogously to examples 1 and 2, but take the following ratio of components in wt. %:

colloidal silver 0.2-1 colloidal zinc oxide 15-25 glycerol 15-20 cellulose 5.1-10 water rest

Examples of specific trials of a pharmaceutical composition for treating wounds and burns on outbred white rats.

An experiment to study the influence of the developed pharmaceutical hydrophilic ointment compositions on the healing process of burn wounds is carried out on outbred white rats, from the age of 6 months, weighing up to 250 g. All animals are kept in the same vivarium conditions on a standard food regimen. For research, 6 groups of 10 animals each were formed:

1 group, on the wound surface of which the ointment composition according to example 1 is applied;

Group 2 - ointment composition according to example 2;

3 group - ointment composition according to example 3;

4 group - zinc ointment;

5 group - argosulfan;

6th group - control.

The duration of the experiment is 21 days, of which 7 days the animals were kept in quarantine. A day before modeling a thermal burn on the lateral surface of the rat’s body, 4 × 4 cm of skin is shaved with a razor. 5-10 ml of a 0.9% NaCl solution are previously injected under the skin for convenient shaving - the skin is stretched and there is no damage when shaving arises.

Thermal burn modeling is carried out according to the generally accepted methodology (see: Security chamber for experimental research of a burn wound in a laboratory animal: Pat. 7926, Republic of Belarus, A.V. Glutkin, T.V. Kovalchuk, V.I. Kovalchuk; applicant, Grodno State Medical University - No. u 20110577; Declared July 15, 11; Publ. 02/28/12. Afitsyinybul. National Center for Intellectual Studies. - 2012. - No. 1. - P. 256-257; Comparative study of the healing process of burn wounds, immunity indicators and pathomorphology of lymphoid organs in rats with a burn disease during transplantation of cultured of allofibroblasts, Sh.Kh. Mamadaliev and other Bulletin, emergency medical. - 2009. - No. 2. - S. 61-65).

When applying burns, an empty glass tube with an internal diameter of 22 mm (cross-sectional area 4 cm ² ) and a length of 15 cm is filled with hot water, placed vertically in boiling water at 2/3 of the height, heated for 1 min, filled over the edge by 2 / 3 heights and in an upright position are brought into tight contact with the exposed area of the skin of the animal for 10 s. Its area is about 8-9% of the entire surface of the body. To calculate its rat rats, use the formula proposed by Micah link:

S = k × 2 / 3W,

where S is the surface of the body, cm ² , W is the body weight of the animal, kg, k is the constant of Micah (9.46).

The resulting burns of grade III B have a round shape, the bottom of the wounds was bright red, sometimes with a brown tint. The edges are slightly overhanging pieces of soft tissue of red-brown color. Around the wound there is a zone of hyperemia with a width of 0.5-0.8 cm. Every day, twice a day, examination of experimental animals is carried out, treatment of the wound surface and the healing indicators are recorded. During the experimental period, the burn surface was monitored on days 1, 3, 5, 10, 14. Test substances were used at a dose of 10 mg / cm ² . Saline was used as a control substance.

On the next day after modeling the burn, objects are monitored.

On the third day in animals of all experimental groups along the edges of the wound surface the scab began to be rejected with different intensities, weak epithelization of the wound edges was observed. The demarcation lines around the wounds in group No. 1-3 were within 2-3 mm. The weakest regeneration processes are observed in 4, 5 and 6 groups. The demarcation line was within 4-6 mm, and in the 4th group reached 8 mm.

By the 5th day in most animals of the experimental groups there is a positive dynamics of regeneration processes. A decrease in the area of burn wounds and gradual rejection of the scab is noted, marked edge epithelization of the burn wound is noted. In groups 1, 3, 4, 5, and 6, deep wounds formed on the site of the scab crusts in all animals, along the edges of which epithelization slowly proceeded; an increasing zone of hyperemia was noted around the wound. In the 4th group, where the animals were applied with zinc ointment, extensive areas of edema were observed around the wounds, reaching 25 mm in diameter, of irregular shape and fuzzy edges.

By the 6th day in groups 1-3, burn scab rejection occurred. The scab in the experimental groups was dry, thin. Regenerative processes were actively going under it. Enhanced marginal epithelization was noted without the development of concentric contraction of wounds.

On the 10th day of the experiment, the scab is removed from the burn surfaces (two individuals from each group). A clean and pink bottom, located at the level of the edges of healthy skin, is observed only in animals of groups 1-3, positive reparative processes are noted, including the restoration of microcirculation in burn wounds. In the remaining groups, the bottom was deep, uneven, the scab was removed with difficulty, the repair processes under it were slow with the risk of developing concentric contraction and scarring. In the 4th group, an extensive zone of hyperemia is noted around the wound.

On the 14th day of the experiment, the area of burn wounds in all groups decreased (relative to the first day):

Group 1 - hydrophilic pharmaceutical ointment composition according to example 1 - by 90.5%;

Group 2 — hydrophilic pharmaceutical ointment composition according to example 2 — by 92.8%;

3 group — hydrophilic pharmaceutical ointment composition according to example 3 — by 86.6%;

4 group - zinc ointment - by 69.7%;

Group 5 - argosulfan - by 71.8%;

6 group - control - by 60.7%;

The final and complete healing of burn wounds in rats of experimental groups No. 1-3 occurs on days 16-18, in groups No. 4 and 5 on the 22nd and 19th day of the experiment, respectively, in the control group on day 29.

Created hydrophilic pharmaceutical ointment composition according to this invention, meets all the biomedical requirements for the creation of modern medicines for the treatment of burn wounds:

- contains active ingredients with reparative, anti-inflammatory and microcirculatory enhancing properties;

- flexible, which makes it possible to use it for surfaces with complex relief;

- creates an optimal microenvironment for wound healing;

- has a high adsorption capacity against wound exudate;

- prevents the penetration and multiplication of pathogenic microorganisms into the wound;

- has sufficient permeability to gases (oxygen, carbon dioxide), necessary for active reparative processes;

- has no local irritant and allergic effects;

- easily removed from the surface of the skin; convenient to use for medical personnel and the patient.

Thus, the hydrophilic pharmaceutical ointment composition according to this invention can be used as a highly effective regenerative, wound healing, microcirculation improving agent for treating burn wounds and other injuries of the skin and mucous membranes.

The invention in comparison with the prototype and other known technical solutions has the following advantages:

- has a highly effective regenerative, wound healing effect;

- is a microcirculation enhancing agent for the treatment of burn wounds.

Claims (2)

A pharmaceutical composition for treating wounds and burns, including colloidal silver, glycerin and distilled water, characterized in that it further comprises colloidal zinc oxide and methyl cellulose in the following ratio of components in wt. %: colloidal silver 0.0001-0.1 colloidal zinc oxide 5-15 glycerol 5-15 cellulose 0.05-5 distilled water rest

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