RU2177314C2 - Composition eliciting antiseptic, reparative and analgetic properties - Google Patents

Abstract

FIELD: medicine, veterinary science, pharmacy. SUBSTANCE: invention proposes the composition with antiseptic, reparative and analgetic properties based on hydrophilic base and containing trimecain, antiseptic myramistin and calcium pantothenate (D-panthenol). Invention provides the possibility of proposed composition for treatment and prophylaxis of suppurative complication, burn, traumatic, postoperative wounds, bedsores and trophic ulcers. EFFECT: enhanced effectiveness of composition, valuable medicinal properties. 2 cl, 8 tbl

Description

The invention relates to the field of medicine, veterinary medicine and can be used for the prevention and treatment of wounds of various origins and localization, trophic ulcers and pressure sores. Among the well-known dosage forms that are used in medicine as drugs for local treatment of wounds during the 1st and 2nd phases of the wound healing process, multicomponent ointments on a hydrophilic basis are most common. These drugs include Levomekol ointment, composition (wt.%): Chloramphenicol - 0.75; methyluracil - 4.0; polyethylene oxide 1500 - 19.05; polyethylene oxide 400 - 76.2 (In the book: Theory and practice of local treatment of purulent wounds (edited by B. M. Datsenko) // Kiev "3dorovya" 1995, p. 238), ointment "Levosin", composition (wt. .%): chloramphenicol - 1.0; sulfadimethoxine - 4.0; methyluracil - 4.0; trimecaine - 3.0; polyethylene oxide 1500 - 17.6; polyethylene oxide 400 - 70.4 (ibid., p. 240), Dioxol ointment, composition (wt.%): dioxidine - 1.0; trimecaine - 4.0; methyluracil - 4.0; polyethylene oxide 1500 - 18.2; polyethylene oxide 400 - 72.8 (ibid., p. 241), ointment "Iodmetrixide", composition (wt.%): iodopyrone - 15.0; trimecaine - 5.0; methyluracil - 5.0; polyethylene oxide 1500 - 15.0; polyethylene oxide 400 - 60.0 (ibid., p. 243), Sulfamekol ointment, composition (wt.%): mafenide acetate - 10.0; methyluracil - 4.0; trimecaine - 5.0; polyethylene oxide 1500 - 16.2; polyethylene oxide 400 - 64.8 (ibid., p. 245), Metrocain ointment, composition (wt.%): metronidazole - 2.0; chloramphenicol - 1.0; trimecaine - 4.0; polyethylene oxide 1500 - 18.6; polyethylene oxide 400 - 74.4 (ibid., p. 247), Streptonitol ointment, composition (wt.%): nitazole - 2.0; streptocide - 5.0; Vaseline oil - 20.0; propylene glycol - 30.0; alcohols of fatty fractions C ₁₆ - C ₂₁ - 6.8; preparation 0C ₂₀ - 1.2; distilled water - 35.0 (ibid., p. 248), ointment "Nitatsid", composition (wt.%): nitazole - 2.5; streptocide - 5.0; proxanol 268 - 20.0; polyethylene oxide 400 - 29.0; 1,2-propylene glycol - 43.5 (ibid., P. 250) and others.

 Their components provide them with a comprehensive therapeutic effect on the wound: antimicrobial, dehydrating, anti-inflammatory, analgesic.

However, the listed drugs, when used for local treatment of wounds, exhibit a number of disadvantages, which include:
1) the occurrence of allergic reactions (skin rashes) in the case of individual hypersensitivity to chloramphenicol (Levomekol, Levosin);
2) the occurrence of toxic reactions in the case of individual intolerance to dioxidine and sulfonamide drugs and nitazole ("Dioxol", "Streptonitol", "Nitatsid");
3) wound reinfection due to a narrow (directed) spectrum of antibacterial action (Levomekol, Levosin, Metrokain, Sulfamekol);
4) dehydration and violation of granulation tissue due to the high osmotic effect of the polyethylene oxide base (Levomekol, Levosin, Dioxol), as a result of which the use of ointments with a pure polyethylene oxide base in the 2nd phase of the wound healing process is not practical, although they contain they are composed of a substance (methyluracil) that stimulates the reparative tissue regeneration;
5) the listed ointments are ineffective in the treatment of wounds infected with pathogenic fungi.

 Closest to the claimed solution for the component composition is the ointment "Levosin", which we took as a comparison drug (PS).

 The basis of the invention is the task: to search for a combined composition that does not cause side effects when used and has associated antibacterial, fungicidal, reparative and anesthetic activity.

This goal is achieved by the fact that in a hydrophilic-based composition containing trimecaine and an antiseptic, miramistin is introduced as an antiseptic and D-panthenol and / or calcium pantothenate are additionally introduced in the following ratio of components (wt.%):
Miramistin - 0.3 - 0.7
D-panthenol and / or calcium pantothenate - 4.0 - 5.0
Trimecaine - 4.0 - 10.0
Hydrophilic base - Up to 100
As a hydrophilic base, aqueous mixtures of various polyethylene oxides, propylene glycol and other gelling agents are used, for example, proxanol-268 and / or modified cellulose.

The inventive composition (AP) is an emulsifier with a slight specific odor. Receive emulsifier by mixing at a temperature of 40-60 ^o C industrial and approved for use in health care components.

 Miramistin (VFS 42-2098-91) is known and used as a means of preventing sexually transmitted diseases (AS USSR N 1832496). Its use in this technical solution led to an unexpected result, expressed in the synergism of the action of the main components in the wound healing and analgesic effect, as well as in the appearance of hypoallergenic properties.

 The basis for the choice of regenerative processes in the tissues of D-panthenol (OAB 1991, band III) or calcium pantothenate (FS 42-2530-88) as the stimulant was the literature data on the fact that pantothenate-containing compounds (derivatives of pantothenic acid, a precursor and a fragment of universal acylation coenzyme - Co-A) are involved in the regulation of intracellular metabolic processes.

The locally irritating properties of ZS were studied by applying it once at a dose of 500 mg / kg body weight (the density of the applied ZS is 200-250 mg / cm ² ) on pre-depilated, thin-needle-scarified areas of rabbit skin. The condition of the skin was evaluated after 20 minutes, 24, 72, and 120 hours after the application of AP. In this case, the general condition of the animals, the presence and degree of erythema, and swelling were recorded.

 The research results showed that the claimed ointment not only does not show a local irritant effect, but also has a pronounced anti-inflammatory effect.

 When studying the allergenic effect of ZS, it was found that no statistically significant differences between the parameters of active skin anaphylaxis in guinea pigs were sensitized and intact, which indicates the absence of allergenic properties of ZS.

 The allergenic properties of ZS were studied in experiments on guinea pigs. Animals were sensitized with the drug by daily application of AP on pre-depilated skin areas with an area of up to 10% of the total body surface of animals. Sensitization was carried out in doses of 5 mg / kg body weight for 14 days. At 21 days from the start of sensitization, a permissible dose of AP was introduced, which was 50 mg / kg body weight. Simultaneously with the application of the resolving dose of the ointment, the animals were intravenously injected with 1.0 ml of a 1% Evans blue solution.

 As a result of the studies, it was found that there were no differences between the color of the skin of sensitized and intact animals. The skin of the sensitized animals was even, smooth, no swelling of the skin and mucous membranes was observed, there were no rashes, desquamation, and other signs of allergy.

 Thus, it can be concluded that AP does not have allergenic properties.

 The specific activity of AP was evaluated by its ability to have a wound healing effect with a different method of reproducing wounds.

 1. With the chemical method of reproducing wounds. The experiments were carried out on white rats weighing 200 ± 10 g. Wounds were caused by intraperitoneal administration of 6% dextran solution to animals and subcutaneous administration of 9% acetic acid. During the appearance of necrotic ulcers at the injection site of acetic acid, CS was applied.

 AP and PS were applied to the affected area at a dose of 300 mg / kg of animal body weight.

 The criterion for the specific wound healing action of CS was the moment of the appearance of the dividing strip between healthy skin and the necrotic area, the onset and complete rejection of the scab, the general condition of the animals and the condition of the skin at the wound site after rejection of the scab. The results are presented in table. 1.

 As can be seen from the data table. 1, statistically significant differences between treated and untreated animals are noted already after 7 days from the start of treatment, and complete rejection of the scab is observed by 22-27 days. In untreated animals, a similar effect is observed only by 40-49 days.

 Significant differences were observed between animals treated with ES and PS. At the same time, a more rapid appearance of the demarcation line, the beginning and rejection of the scab at the site of the wound, and more rapid (5-7 days) wound healing were noted.

 Thus, the obtained results testify to the pronounced wound healing effect of GL in wounds reproduced with the help of chemicals, and its advantage over PS.

 2. In acute local thermal damage to the skin and underlying tissues. The wound healing and anesthetic properties of GL were studied on the model of local thermal damage to the skin of animals. For the study, we used a model of contact thermal burn, which was applied under ether rush anesthesia to mice on the depilated dorsal surface of the back using a standard device (Device for applying a metered burn to small animals. // V.V. Minukhin, V.G. Shamrai, T. N. Gubina et al. // Med. Journal, 1985. Section 3, N 12. Publ. N 3621, p. 66).

 Treatment of animals was started 24 hours after the burn. The burn surface area and pain reactions in animals were taken into account when manipulating the wound and surrounding tissues.

 There were 18 animals in each group.

 The results of experiments on the planimetry of the burn surface in animals of the experimental and control groups are presented in table. 2.

 An analysis of the data shows that in mice treated with AP, a decrease in the area of burn wounds occurs reliably earlier and at a faster pace than in animals treated with PS.

 During manipulations in the field of skin burn injuries in animals untreated and treated with PS, increased pain sensitivity was observed, which was manifested in an increase in motor reactions. At the same time, in the group of animals in which ZS was used to treat burns, pain sensitivity was not noted.

 In the control group, 6 animals died, in the group where AP was used, 2 mice died, and among animals treated with PS, 4 mice died.

 Thus, compared with PS, PS has more pronounced wound healing properties, and also causes an anesthetic effect.

 3. With experimental purulent wounds. Experimental wounds were modeled in rats, guinea pigs and rabbits according to the generally accepted method and contaminated with 0.2 ml of a daily culture of S. aureus 209 P at a concentration of 9.0 CFU / ml with a dose sufficient for the development of a purulent-inflammatory process (G.E. Afinogenov , N. P. Elinov, Antiseptics in Surgery, 1987). Wounds were inflicted in the back and limbs under conditions of limb ischemia. Purulent wounds formed 3 days after the operation period, in animals with experimental ischemia, limb wounds formed by the end of 2 days.

 Treatment of animals in all groups began on day 3 after modeling the wound process and was carried out by applying gauze dressings with AP once a day.

 To control the dynamics of the wound process, planimetry of the wound surface, the state of microbial contamination were carried out, wound healing was recorded.

 The results of observations of the dynamics of the wound process in experimental animals are presented in table. 3.

 The data given in table. 3, indicate that the most effective way to treat experimental purulent wounds was with the use of AP. The terms of wound healing, as well as other indicators of the favorable course of the wound healing process in the 1st group of animals occurred 2-4 days earlier than in other groups.

 In animals with wounds in conditions of limb ischemia, the difference in the positive indicators of the course of the wound process in the group where the AP was used was 5-6 days.

 The determination of microbial contamination of the wound showed that this indicator was most pronounced in the group of animals with limb wounds subjected to ischemia (P <0.05), which indicates the greatest microbial invasion in conditions of impaired peripheral blood supply to the wound.

The decrease in the degree of bacterial contamination of wounds to a critical level (5.0 CFU / ml _(log) ) was most likely to occur (4 days) in groups of animals treated with AF, while in animals treated with PS, this indicator reached 7 days after treatment, and in animals where treatment was carried out according to the traditional regimen, for 14 days (P <0.01).

 4. In the treatment of post-amputation wounds in patients with obliterating diseases of the extremities.

 The test took into account the general condition of the patient, the dynamics of local changes in the wound, bacteriological control of wound contents.

 Treatment of post-amputation wounds was performed with dressings with AP once a day against the background of conventional therapy.

 The results of clinical trials are presented in table. 4.

 The analysis of the presented data shows that the most effective treatment results were noted in the group of patients with the use of AP. So, the average treatment time in this group of patients was 12.1 ± 1.3 days. While in the group of patients receiving PS, this indicator was 17.3 ± 1.3 (P <0.05), and in the group with traditional treatment - 29.1 ± 1.2 (P <0.01) .

 In patients treated with AF, cleansing of purulent wounds occurred 1-2 days faster than in other groups. A more rapid appearance of pink juicy granulations, epithelialization islands, activation of reparative processes in the edges of wounds was also noted.

 In patients with post-amputation wounds who received AF, a decrease in pain symptoms in the wound surface area was noted.

 Thus, on the basis of the studies and analysis of the obtained data array, it can be concluded that the ZS has pronounced wound healing and anesthetic properties.

 The study of the effect of ZS on the intact skin of animals and humans showed its complete harmlessness, since no adverse reactions were detected (see tab. 5-8).

Claims (1)

1. Composition with antiseptic, reparative and analgesic properties, containing trimecaine and a hydrophilic antiseptic, characterized in that it contains miramistin as an antiseptic and additionally contains D-panthenol and / or calcium pantothenate in the following ratio of components, wt.%:
Miramistin - 0.3 - 0.7
D-panthenol and / or calcium pantothenate - 4.0 - 5.0
Trimecaine - 4.0 - 10.0
Hydrophilic base - Up to 100
2. The composition according to claim 1, characterized in that as a hydrophilic base contains a mixture of the following components, wt.%:
Proxanol-268 - 6.5 - 20
1,2-Propylene glycol - 13 - 44
Polyethylene oxide-400 - 13 - 29
Purified water - Up to 100s

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