RU2722127C1 - Wound healing product in the form of an ointment containing rubidium chloride - Google Patents

Abstract

FIELD: medicine; pharmaceutics.SUBSTANCE: invention refers to medicine and pharmacology, namely to medicines formulated in the form of an ointment for topical application, and can be used for treating skin and mucosal injuries, trophic ulcers, wounds and burns. Wound healing agent is presented in the form of an ointment which consists of rubidium chloride, chlorhexidine bigluconate, methyluracil, as well as an ointment base consisting of a mixture of Vaseline and lanolin, with the following components content, WT%: lanolin 65–75, Vaseline 10–20, chlorhexidine bigluconate 0.5–1, methyluracil 5–10, rubidium chloride 5.EFFECT: invention provides manifested wound healing action and stabilization of inflammatory processes elimination, acceleration of reparative processes, epithelisation and scar formation.1 cl, 2 ex

Description

The invention relates to medicine and pharmacology, in particular to medicines made in the form of an ointment for topical application - treatment of injuries of the skin and mucous membrane, trophic ulcers, wounds, burns, damage to the skin, including those complicated by purulent-inflammatory processes. The developed drug can be used in surgery for healing wounds, including those that are resistant to traditional influences.

Currently, purulent diseases of the soft tissues are widespread, require an integrated approach to treatment and significant economic costs. Infections of the skin and soft tissues, burns are one of the most common reasons for seeking medical help to the hospital. The treatment of burn disease, as a rule, is complex and includes the treatment of burn toxemia and local effects aimed at accelerating the healing of a burn wound and preventing infection (Kantemirova B.F., Shekhter A.B. Application of collagen coatings in the treatment of deep burn wounds of the skin. Vestnik Akad Medical Sciences, 1975, N7, s82-85). Antiseptics, antibiotics, sulfa drugs are used to fight infection of burn wounds; to accelerate healing - methyluracil, solcoseryl, enzyme preparations (Mashkovsky MD Medicines. M. Medicine, 1988). The disadvantage of these funds is a weak wound healing activity, the need for frequent change of dressings with a medicinal product, leading to additional trauma to the wound, deep rough scarring, causing a violation of the fixation of the organ. In Russia, 24% of nosocomial infections are soft tissue infections (Kozlov RS, Krechikova OI, Ivanchik NV etal. Etiology of Nosocomial Bacterial Infections in Russia. Rosnet Study Group. Proceedings of the 48th Inter-science Conference on Antimicrobial Agents and Chemotherapy; 2008 Oct 25 -28; Washington, DC, USA; p. 572, abst. K-4108). Damage to soft tissues due to trauma of any etiology can be accompanied by infection, which significantly lengthens the time of wound healing, the patient’s hospital stay and increases costs. Local treatment of wounds and burns is a necessary component of comprehensive measures used in the treatment of wound healing (Savelyev V.S. Surgical infections of the skin and soft tissues. Russian national recommendations. 2009, p. 89). In the art there is a need for economically competitive agents with wound healing and antiseptic properties, and which are an alternative to expensive agents for local treatment of wounds.

Previously, we developed wound healing agents containing rubidium chloride in the form of a solution (RF patent No. 2681531, 03/07/2019) and powder (RF patent No. 2636523, 11/23/2017).

Thus, a wound healing agent is known, which is benzylpenicillin sodium salt dissolved in a solution of 1.86% rubidium chloride in a ratio of 50,000 units of benzylpenicillin sodium salt per 1 ml of rubidium chloride solution (RF patent No. 2681531, 03/07/2019). The disadvantage of this tool is the difficulty of dosing, the need to use a gauze cloth to hold a liquid product on the surface of the wound, which adheres to the wound as it dries.

Known wound healing agent, which is a powder of crystalline rubidium chloride (RF patent No. 2636523, 11/23/2017 - prototype).

However, the drug in the form of a powder has several disadvantages: a slower onset of the pharmacological effect, a change in the properties of the drug during storage under the influence of environmental factors (loss of crystallization water, absorption of water vapor, carbon dioxide, oxidation and other chemical processes when the powders are wetted), irritating effect on the mucous membranes.

The technical problem to be solved in the present invention is the creation of a highly effective wound healing agent that has a pronounced clinical effect, is convenient to use and dosing, is well retained and distributed on the surface of wounds, burns, damaged skin and mucous membranes, trophic ulcers, including those complicated by purulent-inflammatory processes.

The essence of the invention lies in the fact that the wound healing agent is an ointment of rubidium chloride, chlorhexidine bigluconate, methyluracil, as well as an ointment base consisting of a mixture of petrolatum and lanolin, which has anti-inflammatory activity and hemostatic effect.

Rubidium chloride has anti-inflammatory activity and hemostatic effect, stimulates blood circulation, increases the activity of leukocytes and lysozyme.

Chlorhexidine is an antiseptic that is active against gram-positive and gram-negative microorganisms, yeast, dermatophytes present on the skin or on the skin as a result of contamination of the wound.

Methyluracil is a well-known anti-inflammatory, immunostimulating, accelerating wound healing. It is used topically to treat sluggishly healing wounds, burns, trophic ulcers, pressure sores and deep wounds.

A medicine in the form of an ointment has several advantages: firstly, the consistency, which makes it easy to distribute it on the surface; secondly, due to the content of lanolin, which has high hygroscopicity, the ointment has the ability to be retained for a long time on the surface of the wound, regardless of the amount of exudate formed, which contributes to a longer action at the application site.

Rubidium chloride is used as one of the active components. In a series of preliminary experiments to select the optimal quantitative content of the active substance, we found that the content of rubidium chloride in the amount of 5 g per 100 g of ointment (i.e. 5%) provides a positive therapeutic effect. With a lower content of rubidium chloride, the wound healing effect is less pronounced, and an increase in the content of rubidium chloride does not lead to an increase in the effect.

Vaseline and lanolin were used as an ointment base.

Vaseline does not have irritating properties, moisturizes the skin and stimulates regeneration processes, which leads to the speedy restoration of the integrity of the epithelium. Vaseline is used in dermatology in the treatment of skin diseases of traumatic and inflammatory origin.

Lanolin is highly hygroscopic, which contributes to the absorption of exudate and the long-term retention of the ointment on the surface of weeping wounds.

The components of the proposed ointment, taken in a quantitative ratio in wt. %:

Lanolin 65-75

Vaseline 10-20

Chlorhexidine 0.5-1

Methyluracil 5-10

Rubidium chloride 5.

The ointment is prepared as follows: in a mortar, petroleum jelly and anhydrous lanolin are first ground in the indicated amounts, gradually adding small amounts of chlorhexidine bigluconate, methyluracil and rubidium chloride until a homogeneous state is achieved. The resulting mass is stirred for 15-20 minutes, until an elastic-elastin consistency is obtained.

The agent is applied to the wound daily in the form of an ointment after the preliminary toilet of the wound alone or as part of a sterile dressing.

Technical results achieved are: a pronounced wound healing effect in the 1st, 2nd and 3rd phases of the wound healing process, acceleration of the elimination of inflammatory processes. Due to the convenience of application and the duration of stay on the surface of the wound (which is achieved due to the form of the product - ointment), the ability to adsorb the exudate of weeping wounds, there is a decrease in edema by 2-3 days of its use, improvement of the condition of the affected tissues, reparative processes are accelerated, the time of repair is much faster epithelization and scar formation.

When developing the tool, experimental tests of the wound healing agent were carried out

Example 1. In order to simulate an uninfected burn wound, nonlinear white laboratory male rats weighing 140 ± 5.6 (control group), 138 ± 6.3 (reference group) and 132 ± 6.1 (experimental group) were used. A day before modeling the burn in the region of the upper third of the thigh, depilation of skin areas (3.5 cm × 3.5 cm) was carried out by shaving.

On the day of surgery, the rats were in the regime of food and drinking deprivation. The animals were divided into three groups of 20 rats - control, reference and experimental. Before the start of the experiment, everyone underwent anesthesia: Zoletil at a dose of 0.3 mg IM, Xylanite at a dose of 0.8 mg IM. Effective action was determined by the suppression of consciousness, general behavioral activity and pain sensitivity (it was evaluated by the pin-prick method - the level of skin analgesia was determined by needle injections). The onset of action corresponded to 1-7 minutes, the maximum effect was 20-30 minutes, the duration was 1-4 hours from the time of administration. For burns, an empty glass tube with a cross-sectional area of 4 cm2 was filled with hot water, placed vertically in boiling (100 ° C) water at 2/3 of the height, heated for 1 min, and brought into close contact with the exposed skin in the vertical position animal for 15 sec. As a result of the contact, burns of the III degree are rounded in shape, with a bright red bottom of the wound. Around the wound there was a zone of hyperemia up to 0.7 cm wide.

The control group included: toilet wounds, irrigation with sterile isotonic sodium chloride solution, application of an ointment base (lanolin and petrolatum) that did not contain rubidium chloride, chlorhexidine and methyluracil.

The reference group included: toilet wounds, irrigation with sterile isotonic sodium chloride solution, an ointment containing chlorhexidine and methyluracil but not containing rubidium chloride.

In the experimental group were carried out: toilet wounds, irrigation with sterile isotonic sodium chloride solution, an ointment containing chlorhexidine, methyluracil, and rubidium chloride.

The wound healing process was observed for 21 days.

The following indicators were evaluated: exudation, perifocal inflammation, granulation and epithelization. The severity of these indicators was evaluated in points. A planimetric measurement of the area of the wound was carried out. The average area of the wounds was evaluated on the 3rd, 5th, 7th, 10th, 12th, 15th, 17th, 19th and 21st days of the experiment.

On the 5th day of the experiment, the average wound area in the reference group decreased by 19%, while in the experimental group by 21% compared with the initial wound area. In the control group, the wound area decreased by only 15%. The edges of the wound in all groups were covered with epithelium, but only in the experimental group the epithelization was completely completed and the edges were completely soldered to the bottom of the wound, while in the control group there were only traces of epithelization. In the reference group, in places there were no signs of the formation of tight contacts of the edges of the wound with its bottom.

On the 10th day of observation, the scab was absent in all groups, however, the height and condition of the bottom of the wound were significantly different. In the experimental group, 17 out of 20 animals had a clean bottom at the level of the edges of the skin without scab remnants and areas of bright hyperemia. In the reference group, high purity of the bottom of the wound was observed in 14 animals. While in the control group there were only 6 such animals. The rest had scab remnants with areas of hyperemia. The average wound area in the experimental group decreased by 46%, in the reference group by 41%, and in the control group by 26%.

On the 15th day of observation, the average area of the wound in the experimental group decreased by almost 75% of the initial value. In the reference group, the average area was 68%, and 52% in the control. The final healing time in the control group was 17 days, in the reference group 18-19 days, and 23-24 days in the control group.

Example 2. In order to simulate an infected wound against diabetes mellitus in rats, non-linear white laboratory male rats weighing 142 ± 5.8 were used. An alloxan model was chosen to model diabetes mellitus. The administration of alloxan causes damage to the β-cells of rat pancreas, which in the first day is manifested by an increase in blood glucose. Pronounced hyperglycemia (more than 10 mmol / l) is formed by the 10th day of observation, and persists during the entire observation period.

The formation of an infected wound was started on the 10th day after the administration of alloxan. On the day of surgery, the rats were in the regime of food and drinking deprivation. The animals were divided into three groups of 12 rats - control, reference and experimental. Before the experiment, everyone underwent anesthesia: Zoletil at a dose of 0.3 mg / m, Xylanite at a dose of 0.8 mg / m. The infected wound was modeled as follows: a skin flap was stenciled in the scapular region 2 × 2 cm (400 mm ² ) to the muscle layer, the bottom of the resulting wound and its edges were crushed with a Kocher clamp. Then S. aureus in an amount of 5 × 10 6 CFU / ml and C. albicans in an amount of 5 × 10 6 CFU / ml were injected into each wound. The formation of a purulent wound with visible signs of exudation was observed on the 3rd day. Purulent focus in experimental animals occurred after 4-5 days. The signs of the formation of a purulent foci were considered the appearance of pronounced hyperemia, edema and mobility. The formed lesion was subjected to surgical treatment under local infiltration anesthesia caused by 0.25% procaine solution. Surgical treatment consisted in the removal of necrotic tissue and wound discharge to “clean” tissues.

Wound treatment was started the day after the first surgical treatment of the wound. Dressings were performed once a day. All groups included: toilet wounds, removal of necrotic masses, irrigation with sterile isotonic sodium chloride solution. In the control group, an ointment base (lanolin and petrolatum), which did not contain rubidium chloride, chlorhexidine bigluconate and methyluracil, was then applied. In the reference group, after the toilet of the wound and irrigation with sterile isotonic sodium chloride solution, an ointment containing chlorhexidine bigluconate and methyluracil but not containing rubidium chloride was applied to the wound surface. In the experimental group were carried out: toilet wounds, irrigation with sterile isotonic sodium chloride solution, an ointment containing chlorhexidine bigluconate, methyluracil, and rubidium chloride. The following criteria were used to evaluate the effectiveness of the proposed drug: the terms for cleansing the wound from purulent necrotic tissues, the timing of the appearance of granulations, the timing of wound epithelization, and the area of the wound. The wound area was evaluated planimetrically at 3, 7, 10, 14 and 21 days from the start of treatment.

Results. On the third day of observation, hyperemia of the edges and bottom of the wound was observed in all groups, edema and purulent tissue infiltration were visualized. However, the volume of purulent discharge was significantly less in the experimental group, compared with the control and reference. The formation of granulation tissue, a decrease in the severity of hyperemia and edema occurred in the experimental group by the 6th day, and on the 7th day purulent discharge was not observed in 10 rats from 12 animals of the experimental group. At the same time, a decrease in the phenomena of purulent tissue infiltration, cleansing of the wound from necrotic masses was noted in the control and reference groups by 9 and 8 days, respectively.

The change in the area of the wound surface in experimental animals was evaluated in dynamics. On day 7, the wound area in the control group was 55% of the original, in the reference group 34%, and 26% in the experimental group. On day 10, the wound area in the control group was 38.7% of the original, in the reference group 24.2%, and 6% in the experimental group. Complete closure of the wound defect in the experimental group occurred by the 15th day of observation. At the same time, the percentage of complete wound healing in the control group was 67%, and in the reference group 83%.

The terms of complete wound healing in the reference group were 17 days, in the control group 20 days.

An ointment containing chlorhexidine, methyluracil and rubidium chloride has a pronounced wound healing effect in the treatment of various injuries of the skin and mucous membrane - wounds, cracks, pressure sores, trophic ulcers of various origins, superficial burns of 1-3 degrees, purulent wounds.

Claims (2)

A wound healing agent containing rubidium chloride, characterized in that it is made in the form of an ointment, which consists of rubidium chloride, chlorhexidine bigluconate, methyluracil, and also an ointment base consisting of a mixture of petrolatum and lanolin, with the following components, wt. %: Lanolin  65-75 Petroleum jelly  10-20 Chlorhexidine bigluconate  0.5-1 Methyluracil  5-10 Rubidium chloride  5