RU2417089C2 - Iodinated magnesium chloride - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical preparations, and can be used in medical and veterinary practice. An antimicrobial, antimycotic, antiviral and anti-inflammatory agent, contains the natural mineral bischofite in the form of a standardised bittern of density 1.268 g/cm with magnesium chloride content 95-96%, and iodine in the following proportions, %: natural mineral bischofite bittern 98, iodine 2.

EFFECT: higher pharmacological efficacy.

4 tbl

Description

The invention relates to antifungal, antimicrobial, antiviral, anti-inflammatory drugs and can be used in medical and veterinary practice.

Magnesium chloride is one of the main components of the natural mineral bischofite, having a certain pharmacological interest, the deposits of which are discovered in the Lower Volga region.

Currently, a technology has been developed to produce a native balneological bischofite from bischofite technical brine by removing technogenic and toxic impurities (TU 9318004-01896777-2001) and a bischofite drug (VFS 42-2950-97). In clinical practice, the pasty bischofite "BISHOLIN" (TU 461-4721933-07-90) has been used for a long time. As a pasty base, substances such as carboxymethyl cellulose, aerosil, polyethylene glycol are used. Since 2002, the Volgograd pharmaceutical factory has been producing a balneological product, POLICATAN ointment, based on the natural mineral bischofite and local anesthetic (TU 9318-001-01896477-2001). There is information about the development of a bischofite patch (Mashkovsky MF 1997; Spasov A.A 1992), which is a dried paper impregnated with bischofite brine or cotton fabric.

POLY SERVICE-M (Moscow) produces the Tiger Eye gel containing bischofite, clay and extracts of silicon-containing herbs (TU 64-19-162-92).

An analogue of the proposed substance is the drug "POLICATAN", patent No. 2053774, which contains, g:

- brine of magnesium chloride mineral bischofite, standardized for a specific gravity of 1.27-0.01 g / cm - 100;

- Slastilin - 0.01;

- Menthol - 0.005;

- Thymol - 0.005;

- Stabilizer - 0.0002-0.005.

The disadvantages of the prototype are weak pharmacological properties in relation to antimicrobial and antifungal actions.

The aim of the invention is to expand the arsenal of drugs used in medical and veterinary practice, which has bioavailability, stability of the dosage form during storage and allows you to show pronounced antimicrobial, antifungal, antiviral and anti-inflammatory effects.

The technical result is achieved by the fact that the proposed iodized magnesium chloride (IHM) is a composition in the form of a liquid substance of a uniform consistency of yellow-brown color, when mixed with optimally selected concentrations of the following components,%:

- An active brine of bischofite chloromagnesium mineral with a specific density of 1.268 g / cm, with a magnesium chloride content of 95-96% - up to 98%;

- Iodine - up to 2%.

a highly effective antiseptic agent is formed that has a pronounced antimicrobial, antifungal, antiviral and anti-inflammatory effect.

Comparative analysis with the prototype allows us to conclude that the claimed tool has both matching features with the known prototype in terms of the content of the natural bischofite mineral, and distinctive in content and optimally selected iodine concentration - up to 2%, as a result of which it has the most pronounced antimicrobial, antifungal, antiviral and anti-inflammatory effect.

Antimicrobial and antifungal action.

As a definition of the effectiveness of the claimed funds, experimental studies were carried out in vitro of the antimicrobial and antifungal properties of IHM in a comparative aspect with polycatan. Antimicrobial activity was determined against gram-negative (E. coli, K.pneumoniae, P.vulgaris, S.enteritidis, S.faecalis, S.viridans) microorganisms. Used 3 seed doses of microbes, while their final concentration in the samples was 10 ² , 10 ⁴ and 10 ⁶ CFU / ml Table 1 shows the data on the study of the antimicrobial activity of IHM and polycatan.

Table 1 Antimicrobial activity No. n / a Test strain Minimum inhibitory concentration (%) (IPC): The concentration of bacteria in the sample (CFU / ml) 10 ² 10 ⁴ 10 ⁶ IHM Poly Katan IHM Polycatan IHM Polycatan one. E.coli 6 / ++ ++ 6 / ++ ++ 12 / ++ + 2. K.pneumoniae 6 / ++ ++ 12 / ++ ++ 25 / ++ + 3. S.enteritidis 12 / ++ + 25 / ++ - 50 / ++ - four. P.vulgaris 6 / ++ ++ 6 / ++ ++ 25 / ++ + 5. S.sonnet 12 / ++ + 25 / ++ - 50 / ++ - 6. P.aeruginosa 50 / ++ - 100 / + - 100 / + - 7. S.epidermidis 6 / ++ ++ 6 / ++ ++ 25 / ++ + 8. S.aureus 12 / ++ ++ 12 / ++ + 25 / ++ + 9. S.faecalis 6 / ++ ++ 6 / ++ ++ 12 / ++ + 10. S.viridans 12 / ++ ++ 25 / ++ + 25 / ++ +

The degree of greater or lesser zone of growth inhibition was determined by the effectiveness of drugs:

/ ++ / - complete growth retardation; / + / - weak growth retardation;

/ - / - lack of growth retardation.

As can be seen from the data in table No. 1, ICM at 6% concentration inhibits the growth of half of the tested test strains with a small microbial load (10 ² CFU / ml) and 40% of the strains with an average concentration of bacteria (10 ⁴ CFU / ml). The causative agents of acute intestinal infections (S.sonnei and S.enteritidis), as well as pathogenic staphylococci and streptococci (S.aureus and S.viridonis) at a minimum concentration are suppressed by a 12% concentration of ICM. The pathogen of Pseudomonas aeruginosa (P.aeruginosa) was found to be the most resistant to the action of ICM. .

The antifungal activity of ICM was studied using Saburo's liquid nutrient medium. Representatives of yeast-like and mold fungi that are often found in clinical and veterinary practice have been studied as test strains. The results of the study of the antifungal activity of the ICM are presented in table 2.

table 2 Antifungal activity No. p / p Minimum inhibitory concentration (%) (IPC) The concentration of mushrooms in the sample (CFU / ml) 10 ² 10 ⁴ 10 ⁶ IHM Polycatan IHM Polycatan IHM Polycatan one. Candida albicans 12 / ++ + 50 / + - 100 / + - 2. Penicillum citreoviridae 12 / ++ ++ 25 / ++ ++ 50 / ++ + 3. Mucor racemosus 6 / ++ ++ 12 / ++ ++ 50 / ++ + four. Aspergillus niger 25 / ++ + 50 / + - 100 / + -

As can be seen from the data in table No. 2, 6-12% solutions of ICM inhibit the growth of 10 ² CFU / ml of yeast-like fungi of the genus Candida and mold fungi Mucor racemosus and Penicillum. Aspergillus was more resistant to the action of drugs. To inhibit the growth of higher concentrations of fungi, 25-100% solutions of IHM are necessary. Thus, the results of the experiments indicate the presence of marked antimicrobial and antifungal activity in the ICM, in a comparative aspect, with polycatan.

Anti-inflammatory effect.

As a result of the study, it was found that IHM has a depressing effect on the exudative phase of the inflammatory process.

An experimental study of the anti-inflammatory, locally-irritating and wound healing effects of drugs was carried out using the model of open planar skin wounds.

Full-layer skin wounds were reproduced in animals anesthetized with hexenal (120 mg / kg, intraperitoneally). For this, the hairline was removed on the back of rats and a skin area of approximately 20 * 20 mm ^{2 was} excised. On the wound surface was applied ICM in a volume of 0.4 ml. Applications were performed daily 2 times a day for 21 days. In control animals, the wound surface was left untreated.

To calculate the area of the wound, its surface contour was fixed on a transparent film. The film was cut along the contour and weighed. The size of the wound area (S, mm ² ) was calculated by the formula:

S = 100 * Mr / M _pl , where Mr is the mass of a transparent film cut along the contour of the wound, mg; M _PL - the mass of the square of a transparent film with an area of 100 mm ² , mg. Wound areas were recorded on days 1, 3, 5, 10, and 15 after surgery. The initial wound area in experimental animals averaged 352.8 ± 44.1 mm ² and did not statistically differ from that in control rats - 350.0 ± 35.4 mm ² .

The wound healing effect of the drug was evaluated statistically by the dynamics of changes in swelling and wound area (% of the initial) in the rats of the experimental group in relation to the same indicators in the control, as well as by the rate of decrease in wound area. The rate of reduction of the area of wounds (V) is calculated by the formula:

V = (S-St) / t, where S is the initial wound area, mm ² ; S _t is the area of the wound after t days; t is the number of days of observation.

The results of the study. During the first 2-3 days after surgery, all rats showed a decrease in motor activity and appetite, and the appearance of thirst. In this case, changes in the nature of the secretions were not observed. Animals treated with IHM recovered and gained weight faster. So, on the 14th day, the body weight in the experimental rats was 109.4 ± 16.0% of the initial value, and in the control - 99.5 ± 16.2%.

Table 3 Change in the size of a wound defect in white rats when applying drugs Groups The size of the wound defect in% of the initial value in days. Wound Area Reduction Rate 3 5 10 fifteen The control
naya (polika
tan) 89.1 ± 3.49 62.4 ± 7.61 39.1 ± 5.66 20.9 ± 2.51 21.5 ± 2.73 Experienced (IHM) 70.8 ± 5.88 48.6 ± 6.69 20.7 ± 2.96 8.7 ± 1.03 18.5 ± 2.26

From the data of a planimetric study shown in Table 3, it can be seen that under the influence of the ICM, the inflammatory reaction decreased, the healing of skin wounds was significantly accelerated, all phases of the wound process proceeded faster in time. The size of the wound defect at all stages of observation was also significantly smaller than in the control. The wound healing acceleration index (V) compared with the control was: V = (V _experiment * 100%) / V _control = 116.19%.

As a result of the study, it was found that ICM is able to relieve inflammation, stimulate reparative processes, causing early and intensive proliferation of fibroblasts, earlier formation of granulation tissue, synthesis and fibrillogenesis of collagen fibers, relatively rapid maturation of scar tissue and epithelization of the wound surface, and also does not show local annoying effect.

Antiviral effect.

The experiments were carried out on 30 male guinea pigs weighing 250-300 g, which were infected with herpes simplex virus of the second type in the form of a virus-containing suspension with an infectious titer of 5-6 Lg CPD ₅₀ / ml on the scarified surface of the penis according to the method of S. S. Marennikova. The studies were carried out in 3 groups of ten animals: the first (control) - without treatment, the second (experimental) - treatment with the prototype, the third (experimental) - treatment with the claimed agent. The treatment was carried out 48 hours after infection by the use of drugs, rubbing them into the affected surface three times a day for 8 days.

In animals of the control group, after 24-48 hours, redness, swelling and vesicle vesicles appeared at the site of infection. 72 hours after infection, the clinical picture of genital herpetic infection was pronounced: fusion of individual pustules, the appearance of painful ulcers, bleeding surfaces and orchitis were noted. In some animals, the infection assumed a generalized character, expressed in the form of paresis and paralysis of the hind limbs and subsequent death on day 9-10.

The dynamics of the development of the infectious process was evaluated by the severity of the main signs of the disease. The severity was determined on a conventional four-point scale, taking into account four main signs: hyperemia of the mucous membrane, edema, specific virus-induced elements (vesicles, pustules, ulcers), orchitis and assigning each of them a score from 0 to 4. Lack of hyperemia was rated at 0 points, weak redness - 1 point, pronounced redness on a small area of skin - 2 points, pronounced redness on a significant area of skin - 3 points, pronounced redness on a large area of skin - 4 points. Such an assessment for all of the above features was carried out for 15 days for all groups of animals and calculated the average score in each group based on one animal. The calculation results are presented in table 4.

As can be seen from the data shown in table 4, reflecting the dynamics of the severity of the infectious process, the peak incidence in all groups of animals occurs 3-5 days after infection. The average score, characterizing the most pronounced development of clinical symptoms in the control group, was 14.9 (the maximum possible value of 16 points - all 4 signs of the disease are pronounced and evaluated at 4 points; the minimum possible value of 0 points - all 4 signs of the disease are absent). The severity of the manifestations of infection in the control group of guinea pigs not receiving treatment was higher throughout the observation period compared with the animals of the experimental groups. The therapeutic effect of the claimed drug and prototype was observed starting from the 2nd day of treatment, and on day 3-4 of the course of treatment it exceeded the prototype by visual assessment of the clinical picture. The effectiveness of the therapeutic effect of the claimed drug in comparison with the prototype was determined by the number of completely healthy animals on the 6th day of treatment and the number of dead animals on the 10th day after infection as a result of generalization of the process. The results are presented in table 4.

Table 4 The dynamics of the antiviral process. Observation days Average points per animal The number of recovered / dead animals IHM Polycatan The control IHM Polycatan The control one 2 3 2 10 10 10 2 6 5 5 10 10 10 3 10 9 10 10 10 10 four eleven 12 12 10 10 10 5 eleven 12 13 10 10 10 6 10 12 fourteen 10 10 10 7 10 13 fourteen 10 10 10 8 8 12 13 10 10 10/1 9 7 12 13 10 10 9/2 10 6 eleven 13 10 10/2 7/2 eleven 5 10 10 10 8 5 12 four 9 10 10 8 5 13 3 7 8 10 8 5 fourteen 2 5 6 10 8 5 fifteen one 3 6 10 8 5 Average value 9.6 13.5 14.9

As can be seen from the data presented in table 4, the claimed drug exceeded the prototype in maximum therapeutic effect by 14%, and also 100% prevented the generalization of herpetic infection, which is due to a more pronounced anti-inflammatory and antiviral effect compared to the prototype.

In experiments on white mice and guinea pigs, the toxic effect of IHM was studied. The LD ₅₀ values were determined, which for white mice are 0.13 ml of the initial concentrated preparation (for oral use) and 0.048 ml (for subcutaneous use); for guinea pigs - 1.2 ml, (oral administration) and 0.52 ml (parenteral administration). When conducting a comparative analysis of the blood, it was shown that the LD ₅₀ values for mice and guinea pigs significantly exceed the daily dose (in terms of unit weight). In experiments on the study of chronic toxicity in white mice and guinea pigs, doses corresponding to daily doses for farm animals were used. The experimental results showed the complete harmlessness of the tested doses of IHM with prolonged use.

As a result of experimental studies, it was found that the claimed tool "iodized magnesium chloride" has a more pronounced antimicrobial, antifungal, antiviral and anti-inflammatory effect in relation to the prototype and will find wider application in medical and veterinary practice.

Claims (1)

Antimicrobial, antifungal, antiviral and anti-inflammatory agent containing the natural bischofite mineral in the form of a standardized brine with a density of 1.268 g / cm and a magnesium chloride content of 95-96%, characterized in that it additionally contains iodine in the following ratio of components,%:
Bischofite Chrommagnesium Mineral Brine 98 iodine 2