RU2751048C1 - Medicinal film containing melatonin for the treatment of thermal injury - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: present invention relates to the field of medicine, namely to a method for producing a drug for local treatment of wounds with thermal injury in the form of a drug film with melatonin, comprising preparing a film mass containing: an aqueous solution of sodium carboxymethylcellulose (Na CMC) 4% - 100 g; glycerin - 5.0 g; ethyl alcohol 96% - 10.0 g; melatonin - 0.5 g, followed by mixing and drying under aseptic conditions.EFFECT: present invention provides potentiation of the therapeutic effect, reduction of microbial contamination, accurate dosage of the drug, which eliminates possibility of overdose and the development of undesirable side effects, the film is firmly fixed on the surface of the wound, absorbs exudate, creating a moist environment in the wound, thereby promoting early granulation, plasticity provides an atraumatic effect.1 cl, 4 dwg, 5 ex

Description

The invention relates to medicine, in particular to pharmacy, and consists in a method for producing a drug for the local treatment of wounds in thermal injury in the form of a drug film with melatonin. When implementing the method prepare a film mass (in terms of 100 g of irrigation solution), containing: an aqueous solution of sodium carboxymethylcellulose (Na CMC) 4% - 100.0; glycerin 5.0 g; ethyl alcohol 96% 10.0 g; melatonin 0.5 g. The film mass is stirred, poured into a mold and left to dry for 72 hours at room temperature under aseptic conditions. EFFECT: potentiation of the therapeutic effect, reduction of microbial contamination, precise dosage of the drug, which excludes the possibility of overdose and the development of undesirable side effects. The film is firmly fixed on the surface of the wound, absorbs exudate, creating a moist environment in the wound, thereby promoting early granulation. Plasticity provides an atraumatic effect.

To obtain the proposed films, known substances are taken:

Sodium salt of carboxymethyl cellulose (NaCMC): an amorphous colorless substance; molar mass (30-25). 103; softening temperature 170 ° С; density 1.59 g / cm3 (25 ° С, 50% relative humidity); bulk density 0.3-0.8 g / cm3; darkening temperature 227 ° С, carbonization temperature 252 ° С. Soluble in water, aqueous solutions of alkalis, NH3, NaCl and solvents for cellulose, insoluble in organic solvents, mineral oils. When dissolved in water, NaKMC forms viscous transparent solutions. [one]

Glycerin trihydric alcohol: clear, colorless or almost colorless, odorless syrupy liquid. The melting point of glycerin is 18 ° C, the boiling point is 260 ° C. Density - 1.26 g / s m ³ , viscosity 1.49 Pa * s (deductions 8.94 * 10-4 Pa * s, for propylene glycol 0.056 Pa * s). Hygroscopic. Miscible with water and alcohol 96%, slightly soluble in acetone, practically insoluble in fatty oils. [2]

Ethyl alcohol 96% Transparent colorless mobile liquid with a characteristic alcoholic odor. Miscible with water, chloroform, acetone and glycerin in all respects. [3]

Melatonin substance-powder crystalline powder from white with a creamy shade to light cream color. Let's dissolve in methanol, in ethyl acetate, very little, we will slowly dissolve in water (when heated to 30 ° С). [four]

The invention relates to medicine, in particular to pharmacy, for the development of medicinal films containing melatonin, and can be used for local treatment of wounds in thermal injury.

Analogs of the presented invention are hydrocolloid dressings used in medicine, imported: Algoplaque (URGO Lab., France) [5] - a sterile adhesive dressing consisting of carboxymethylcellulose particles distributed over an elastomeric network on a polyurethane semipermeable base, and Hydrocoll (Paul Hartmann, Germany) [6] is a self-fixing absorbent hydrocolloid dressing with a semi-permeable covering layer that does not allow bacteria and water to pass through; these dressings do not contain an active ingredient in their composition and mainly play the role of a protective barrier on the surface of the wound. Described is the use of a new generation hydrocolloid dressing - Askin Hydro (BBraun, Germany) [7], which is a polyisobutylene matrix containing a natural highly absorbent polymer from plantain and carboxymethylcellulose, which gives the dressing reliable adhesion, absorbs wound bacteria, eliminates the odor in the wound, enhances macrophage activity on the damaged area.

Also proposed is a dermatological film of protective action, which is a cosmeceutical wound-healing film containing: aloe extract liquid 1.0 wt.h. and Actovegin 0.4 parts by weight. (as active ingredients); hydroxypropyl methylcellulose (HPMC) 1.08 parts by weight (as a basis); miramistin 0.5 parts by weight, glycerin 0.6 parts by weight, Plasdon K29 / 32 0.05 parts by weight, Kollidon F90 0.05 parts by weight. (as auxiliary substances) and purified water 10.0 wt.h. To obtain the specified film HPMC, Kollidon F90, Plasdon K29 / 32 and Actovegin are dissolved in purified water heated to 70 ° C and containing liquid aloe extract, glycerin and miramistin, at a constant temperature and stirring speed, followed by cooling the mass until a transparent gel is formed and by vacuum, then the film mass is applied to a substrate and dried at room temperature [Application No. 2693051 RU, IPC A61R 17/02 A61K 9/00 A61K 8/02 A61K 47/38 A61K 47/32 A61K 47/186 A61K 47/18 A61K 47 / 10 A61K 35/14].

Described is a method of obtaining a coating for wounds containing, by weight. %: polysaccharide of plant origin 2-95, drug up to 0.5, rubber latex - the rest. The coating can be made in the form of a monolayer film. The invention makes it possible to prolong the action of drugs and thereby increase the atraumaticity of treatment, especially for burns and extensive trophic skin lesions. 9 p.p. f-ly [Application No. 2193896 RU, IPC A61L 15/44, A61L 15/30, A61L 15/28].

Various compounds can be used as active substances in the composition of transdermal films for local therapy: antioxidants, antibiotics, immunomodulators, antihistamines and vitamins, hormonal preparations.

One of the endogenous regulators of homeostasis with pleiotropic action is melatonin (N-acetyl-5-methoxypyramine). Currently, data have been accumulated on the presence of specific receptors for melatonin on various cells in the human body, which determines its effects on cell metabolism and function [8]. The antioxidant effect of melatonin has a fairly serious evidence base [9]. Revealed a direct, due to the chemical nature of the interaction of melatonin with reactive oxygen and nitrogen species, as well as its ability to activate the antioxidant enzyme glutathione peroxidase [10]. Not only melatonin itself, but also a wide range of its derivatives and metabolites that can neutralize, suppress or actively bind free radicals and their derivatives [11]. The data on the immunomodulatory effects of melatonin are presented. Melatonin increases the masses of immune organs under conditions of immunosuppression and has an antiproliferative effect on activated lymphocytes [12]. Melatonin modulates the innate immune response, increases the number and activates NK cells and monocytes, and increases phagocytosis [13]. Melatonin regulates the proliferative response of T-lymphocytes and their polyclonal stimulation, the activity of the THY subpopulation and the intensity of cell apoptosis [14]. The data on the ability of melatonin to stimulate the synthesis of some cytokines, interferons, including IL-17, suppress LPS-stimulated production of TNF-α, IL-1, IL-6, IL-8 and IL-10 [15]. The literature contains numerous data on changes in the immune status in TT of varying severity and area of damage, the development of complications, including changes in the number and activity of immunocompetent cells in the focus of damage and peripheral blood. The role of oxidative stress in the pathogenesis of TT was demonstrated. An important role in the pathogenesis of TT is played by cytokines and other endogenous mediators, the multifunctionality of which allows us to make an assumption about the possibility of their use for the correction of disorders of homeostasis in TT. One of these substances can be melatonin, the receptors for which are present in the skin, and the pleiotropic effects of which have recently been actively studied and demonstrated in arterial hypertension, diabetes mellitus, and malignant tumors in experimental and clinical conditions. The presence of pronounced immunotropic and redox-status regulatory effects of melatonin both in physiological conditions and in pathology suggests its effectiveness in TT of a limited area under conditions of local application.

So, for the treatment of atopic dermatitis, detoxification therapy, local glucocorticoid-containing ointments and an immunomodulatory drug, the pineal gland hormone melatonin, are prescribed at a dose of 3 mg at 21.00 with a course of 21 days. This method provides the effectiveness of treatment by reducing the level of IgE [Application No. 2268737 RU, IPC A61P 17, A61K 35/30].

The basis of the invention is the problem of developing a transdermal drug film with melatonin, which has an antioxidant, regenerating effect, characterized by simplicity of technology, prolonged action and ease of use.

The closest analogue of the invention is a method for producing a drug with topical erythropoietin in the form of a film for treating wounds. When implementing the method prepare a film mass containing: an aqueous solution of Na CMC 3% 20.0 g; glycerin 1.5 g; PEG 400 0.5 g; sorbic acid 0.006 g; EPO 1000 ME. The film mass is stirred, poured into a mold and left to dry for 72 hours at room temperature. [Application No. 2611401 RU, IPC: A61K 47/38 A61K 47/30 A61K 47/12 A61K 47/10 A61K 38/18

This problem is solved by the fact that a transdermal film with melatonin for the treatment of thermal injury, containing melatonin as an active substance, and sodium carboxymethyl cellulose as a shaper, additionally contains ethyl alcohol 96% and glycerin, with the following ratio of the components of the film mass, g, to obtain after drying for 72 hours at room temperature, a film with an area of 56 cm2:

NaKMTS aqueous solution, 4% - 100.0

Glycerin - 5.0

Ethyl alcohol 96% - 10.0

Melatonin - 0.5

The claimed composition of a transdermal medicinal film with melatonin for treating wounds in TT allows stabilizing the melatonin molecule and contributes to its maximum prolonged release.

The proposed method eliminates the possibility of inaccurate dosing, microbial contamination and wound damage during dressing. The use of a medicinal film containing melatonin is used for the first time.

To solve the above problem, the technological characteristics of the dosage form were investigated: adhesive capacity, tensile strength, adsorption activity, swelling kinetics, biopharmaceutical availability, microbiological purity, study of the antioxidant activity of melatonin in vitro.

The technology is carried out under aseptic conditions as follows: using the method of pouring the film mass onto the substrate (mold) Homogenization of the film mass is carried out mechanically. Drying is carried out at room temperature to a residual moisture content of 10%. Packing is carried out in polyethylene or blister packaging.

The proposed method differs from the existing ones in that, in addition to the biopolymer, which has a reparative and barrier function, an antioxidant and reparative drug is included. As a result, potentiation of the therapeutic effect, reduction of microbial contamination is achieved. In addition, the proposed dosage form allows you to accurately dose the drug, which excludes the possibility of overdose and the development of unwanted side effects. Due to the properties of adhesion, the film is firmly fixed on the surface of the wound. It absorbs exudate on itself, creating a moist environment in the wound, thereby contributing to early granulation. Plasticity provides an atraumatic effect.

An example of a specific implementation.

Example 1.

The composition of the film mass: sodium carboxymethyl cellulose (Na CMC) 4% aqueous solution - 100.0 g; glycerin 5.0 g; ethyl alcohol 95% -10.0, melatonin - 0.5 g.

A 4% aqueous solution of the former is prepared. In a beaker, 4.0 Na CMC is pre-soaked in the entire volume of water, left for 3 hours for swelling, and then placed in a water bath and heated with constant stirring until complete dissolution. A weighed amount of melatonin is dissolved in a measured amount of ethyl alcohol and introduced into a sodium-CMC solution, mixed, glycerin is added, deaerated, leaving for 1 hour at room temperature to remove air. The mold is wiped with ethyl alcohol 96% and poured with the resulting mass, evenly distributed over the mold and left for 72 hours at room temperature. The quality of the films is evaluated in terms of appearance, adhesiveness, tensile strength, adsorption activity, and biopharmaceutical availability.

The resulting films are thin, with an average thickness of 0.3 microns, plastic, without foreign inclusions, microcracks are absent. Tear-resistant with good adhesive properties.

Example 2.

The composition of the film mass for the preparation of 1 film: an aqueous solution of sodium carboxymethyl cellulose 4% - 100.0 g; PEG 400 - 5.0 g; ethyl alcohol 96% -10.0; melatonin 0.5.

Manufacturing technology is similar to example 1.

The resulting films are dense, low-plastic, brittle, without foreign inclusions, microcracks are absent. Tensile strength, have good adhesive ability.

Example 3.

The composition of the film mass: Polyvinyl alcohol aqueous solution 4% -100.0 g; glycerin 5.0 g; ethyl alcohol 95% - 10.0, melatonin - 0.5 g

Manufacturing technology is similar to example 1.

The resulting films are thin, sticky, poorly removable from the substrate, without foreign inclusions, there are no microcracks.

Example 4.

The composition of the film mass: Aqueous solution of hydroxypropyl methylcellulose (HPMC) 3% - 100.0 g; glycerin 5.0 g; ethyl alcohol 95% - 10.0, melatonin - 0.5 g

Manufacturing technology is similar to example 1.

The resulting films are thin, sticky, non-plastic, brittle, without foreign inclusions, there are no microcracks. Not tear-resistant, have poor adhesion.

Example 5.

The composition of the film mass: an aqueous solution of Na CMC 3% - 100.0 g; glycerin 1.0 g; polyvinylpyrolidone (PVP) 1.0 g; ethyl alcohol 95% - 10.0, melatonin - 0.5 g.

Manufacturing technology is similar to example 1. A solution of the film former is prepared by weighing No. CMC and PVP in one glass. The resulting films are thin, with an average thickness of 0.3 microns, plastic, without foreign inclusions, microcracks are absent. Tear-resistant with good adhesive properties.

The resulting dosage forms were assessed visually, according to the assessment of microbiological purity, as well as for compliance with biopharmaceutical indicators.

The determination of the adsorption activity of the films was carried out according to the method.

About 0.3 g of the preparation (accurately weighed) was placed in a flask with a ground stopper with a capacity of 200-250 ml. Was added with a cylinder 100 ml of methylene blue solution with a concentration of 0.01% and stirred on a shaker with an orbital type of rotation at a number of vibrations of at least 120 per minute for an hour. The contents of the flask were then filtered through an ashless filter, discarding the first portions of the filtrate. 5 ml of the obtained solutions of the test and control methylene blue solutions were placed in volumetric flasks with a capacity of 100 ml, the volume was brought to the mark with purified water, and the optical density was measured on a spectrophotometer at a wavelength of 667 nm in a cuvette with a working layer thickness of 10 mm. Purified water was used as a reference solution.

The results are shown in Figure 1.

The release of melatonin from the films was carried out by dialysis through a semipermeable membrane, followed by determination of the melatonin content by UV spectrophotometry. The results are shown in Figure 2.

The determination of the kinetics of swelling was carried out according to the method: about 0.10 g of PL (accurately weighed) is placed in a glass bottle with purified water in a volume of 3 ml. After 5 minute time intervals, the PL is removed, dried with filter paper and weighed on an analytical balance. The results are shown in Figure 3.

The determination of catalase activity in NP was carried out by the reaction with ammonium molybdate. For this, 2 ml of a freshly prepared 0.03% hydrogen peroxide solution, 100 μl of the isolated NF suspension and 100 μl of a solution of the investigated compounds were measured into a test tube (0.1 g of the film was dissolved in 1 ml of water, filtered). Purified water in the same volume was added to the comparison tube instead of the drug solution. In the control solution, 2.1 ml of purified water and 100 μl of the NF suspension were measured. A solution consisting of 2 ml of 0.03% hydrogen peroxide solution and 0.2 ml of purified water was used as a blank sample. The solutions prepared in this way were incubated at 370C for 10 minutes, and then 1 ml of 4% ammonium molybdate solution was added to each tube. The color intensity was measured at 410 nm against the control sample. Figure 4 shows the minimum concentrations of compounds at which 50% inhibition of antioxidant activity (ED50) is observed.

It can be seen from the examples given that films of composition 1 have optimal properties, maximum adsorption and osmotic activity.

The composition of the film mass: sodium carboxymethyl cellulose (Na CMC) 4% aqueous solution - 100.0 g; glycerin 5.0 g; ethyl alcohol 95% - 10.0, melatonin - 0.5 g.

Bibliography:

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Claims (1)

A method of obtaining a drug for local treatment of wounds in thermal injury in the form of a drug film with melatonin, comprising preparing a film mass containing: an aqueous solution of sodium carboxymethylcellulose (Na CMC) 4% - 100 g; glycerin - 5.0 g; ethyl alcohol 96% - 10.0 g; melatonin - 0.5 g, followed by mixing and drying under aseptic conditions.

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