UA143211U - PHARMACEUTICAL COMPOSITION IN GEL FOR TREATMENT OF ALLERGIC SKIN REACTIONS TO IRRITANTS - Google Patents

Abstract

The pharmaceutical composition in the form of a gel for the treatment of allergic skin reactions to irritants contains the active substances - dimethindene maleate, dexpanthenol and excipients: disodium edetate, carbomer, trometamol, propylene glycol, phenoxyethanol.

Description

The utility model is in the field of pharmacy and medicine, namely pharmaceutical compositions in the form of gels for the treatment of allergic skin reactions to irritants, in particular skin itching, such as from insect bites, mild solar erythema, uncomplicated minor skin burns and allergic irritation of small areas of skin .

External therapy of allergic skin diseases is an integral part of treatment and often takes a leading role. Acute allergic reactions are treated symptomatically. The main drugs are adrenaline, corticosteroids, antihistamines.

Treatment of local reactions to the poison of Hymenoptera insects. Cold, external therapy with topical antipruritic drugs (Fenistil gel, Psilo-balm) are used for allergic local reactions. The patient is prescribed an antihistamine drug of the second generation (loratadine, cetirizine, etc.;), in case of a strong local reaction, topical glucocorticosteroids (GCs) of the non-fluorinated series (methylprednisolone aceponate, mometasone furoate, etc.). In the most severe cases of a local reaction, the appointment of a two- to three-day course of prednisolone at a dose of 30-40 mg/day is justified.

The number of cases of hypersensitivity to various representatives of insects is increasing every year. This determines the expediency of developing new topical agents for the local therapy of manifestations of allergic reactions to insect bites or stings. The issue of treating the consequences of insect bites in children is particularly acute, as constant combing of bite sites is a threat of wound infection and delayed healing.

One of the ways of medical treatment of insect allergy, taking into account the expressiveness of the reaction, is the use of systemic and local antihistamine drugs. On the pharmaceutical market of Ukraine, the group of antihistamine drugs is quite numerous - more than 60 names of drugs in the form of tablets, capsules, effervescent tablets, syrups, drops. The group of means for local therapy includes only 4 drugs: Psilobalsam (Germany), Fenistil-gel (Switzerland), Fenistil Penzivir (Germany), Dermadrin (Austria).

In view of the economic aspects of the cost of imported medicines, which have developed in Ukraine at present, as well as the powerful development of domestic industrial pharmacy, the development of a gel with a combination of antihistamine and reparative substances is relevant. The advantage of gels, as carriers of medicinal substances, in this case additionally provides cooling and soothing

From the effect on the affected areas of the skin.

The well-known homeopathic ointment on a fat basis Irykar (per://sotrepaisht.sot.tsa/ipto/6472/ihikag), which contains matrix tincture of grapes and has anti-inflammatory, anti-itching, anti-allergic activity.

The disadvantage of this ointment should be considered the impossibility of absorption by the fatty ointment base of secretions, which may be accompanied by allergic dermatoses.

A well-known pharmaceutical composition in the form of an ointment for the treatment of allergic skin diseases (pat.OA Mo 33380, AbIK 9/06, AbIK 36/00, 25.06.2008, Bull. Mo 12) contains an active ingredient of plant origin. It is made on an emulsion basis, and contains a complex of black currant polysaccharides as an active substance. The emulsion base contains corn oil, emulsifier Me1, polyethylene oxide 400, glycerin, nipagin, nipazol and water.

The well-known sinaflan ointment (Compendium 2000/2001 - Medicinal preparation / Edited by V.N.

Kovalenko, A.P. Viktorova - K.: MORION, 2000.- P.429,428,413,831,295), which contains fluocinolone acetonide 0.025 g and auxiliary substances - propylene glycol, medical petroleum jelly, anhydrous lanolin, ceresin. The drug has an anti-inflammatory, anti-allergic, anti-pruritic effect.

However, the indicated remedy has a side effect caused by the presence of a steroid hormone in its composition. With long-term use, degenerative changes of the skin are possible (thinning of the epithelium, vacuolization of the cytoplasm of cells, disintegration of their nuclei, premature keratinization of cells, parakeratosis of the stratum corneum). In addition, local infectious complications are possible. The fatty ointment base contributes to the formation of a "greenhouse effect" and the appearance of a feeling of oiliness of the skin.

Hormonal ointments, such as prednisone ointment, Fluorocort, Elocom (pEr:/Lymly.IKag.iptoLekKagvima) are known to be used for the treatment of allergic dermatoses. These drugs have a similar antiallergic effect, which is due to the presence of corticosteroids. Disadvantages inherent to the specified means are common to all hormonal means.

There is "Psilobalsam" (STADA Artsnaimittel AG, 0-61118 Bad Filbel, Stadashstrasse, 2-18, Germany), which contains diphenhydramine hydrochloride and auxiliary substances: cetylpyridinium chloride, polyethylene glycol glyceryl caprolaparate, carbomer, tromethamine, purified water.

The well-known antihistamine gel "Fenistil" (GSK Konsumer Helsoker S.A., Switzerland), containing dimethindene maleate and auxiliary substances: benzalkonium chloride, disodium edetate, 60 carbomer 974P, sodium hydroxide, propylene glycol, purified water.

These drugs have a pronounced antiallergic effect, but their use is limited for children. After application of Fenistil, dryness and burning sensation may occur at the application site.

The basis of the useful model is the task of improving the pharmaceutical composition for the treatment of allergic skin reactions to irritants by using a complex of active substances to obtain a tool effective in the treatment of allergic skin manifestations to irritants, which has practically no side effects, is non-toxic, and is suitable for long-term use.

The task is solved by the fact that in the pharmaceutical composition in the form of a gel for the treatment of allergic reactions of the skin to irritants, containing the active active substances dimethindene maleate and dexpanthenol, and auxiliary substances: disodium edetate, carbomer, trometamol, propylene glycol, phenoxyenol, with the following ratio of components, mass 9o: dimethindene maleate 0.05-0.15 dexpanthenol 1.0-5.0 disodium edetate 0.01-0.2 carbomer 0.5-1.5 trometamol 0.5-2.0 propylene glycol 10-20 phenoxyethanol 0.75-1.0 purified water, the rest.

The quantitative ratio of the remaining components of the base, optimal for the claimed composition, was determined experimentally.

The active and auxiliary substances that make up the stated gel are known in pharmacy, but their quantitative and qualitative combination is new, not known from sources of information.

Dimethindene maleate is a derivative of phenindene. It is an antagonist of histamine at the level of NI1 receptors.

It has an anti-allergic and anti-pruritic effect. Thanks to the active substance - dimethindene maleate, which is part of Fenistil gel, when the drug is applied to the skin, itching and irritation accompanying skin allergic reactions are reduced. The drug also has local anesthetic properties and cools the skin when applied.

When applying the gel topically, thanks to its specially developed base, the active substance quickly penetrates the skin and begins to act within a few minutes. The maximum effect is achieved after 1-4 hours. The systemic bioavailability of the active substance is 10 95.

Dexpanthenol is a pantothenic acid derivative. Pantothenic acid - a water-soluble vitamin of group B - is a component of coenzyme A. It stimulates skin regeneration, normalizes cell metabolism, and increases the strength of collagen fibers. An increase in the need for

Pantothenic acid is observed when the skin or tissues are damaged, and its deficiency can be compensated by local application of dexpanthenol. Optimal molecular weight, hydrophilicity and low polarity enable its penetration into all layers of the skin. It has a regenerating, weak anti-inflammatory effect.

The composition of the gel base was selected experimentally. Due to the optimal ratio of components, this base is the most appropriate, because it promotes the maximum release of the active substance, is chemically indifferent, washes off with water, helps to moisturize the skin, is able to absorb exudate and is technologically convenient when preparing the gel.

Disodium edetate and its salts are used in pharmaceuticals, cosmetics and food products as stabilizers, antioxidants, antimicrobial preservatives and water softeners.

Carbomer is used as a basis for soft dosage forms

Trometamol is a carbomer neutralizing agent.

Propylene glycol is a solvent that exhibits stabilizing and osmotic properties; has an antioxidant, preservative effect, prevents mold.

Phenoxyethanol is used in pharmacy and cosmetics as an antimicrobial preservative.

The claimed pharmaceutical composition in the form of a gel for the treatment of allergic skin diseases can be prepared using standard equipment as follows.

Preparation of raw materials. Dimethindene maleate is dissolved in propylene glycol at a temperature of (4543)0C. Dexpanthenol is separately mixed with purified water in a ratio of 1:1.

Phenoxyethanol is separately mixed with purified water in a ratio of 1:11. Disodium edetate is separately dissolved in water in a ratio of 1:10-1:20. Trometamol is separately dissolved in purified water.

Preparation of the gel base. Disperse the carbomer with the remaining amount of water for 30 minutes. Trometamol solution is added to the carbomer dispersion until the pH of the dispersion system is pH 6-7. Then add disodium edetate solution and mix.

A solution of dimethindene maleate, a solution of dexpanthenol, and a solution of phenoxyethanol are added alternately to the gel base with an interval of 10-15 minutes. with constant stirring.

Homogeneous colorless gel, transparent or slightly opalescent

This composition of the gel is optimal from the point of view of pharmacological action and production technology.

Example 1. All animal procedures in the experiment were reviewed and approved

by the Bioethics Commission of the National Academy of Sciences for compliance with regulatory requirements (Protocol of Ministry of Health dated March 20, 2019).

Before the experiment, the animals were acclimatized for 7 days in the test room. During the acclimatization period, each animal was examined daily (behavior and general physiological state were evaluated).

Healthy animals that met the criteria for inclusion in the study were selected for the experimental group. The groups were formed by the randomization method of random selection using body weight as the main feature of the distribution (the deviation in initial weight between groups did not exceed 10 9b).

The animals were kept in a separate room with controlled microclimate parameters: air temperature 20-24 "C, humidity 45-65 95, light mode "12 hours day/night". Rats were kept in plastic cages with 3 heads in each, ants - three heads each in a plastic cage. The room was ventilated and the air sterilized using a quartz lamp was carried out daily. The animals had free access to water. For drinking, they used settled tap water from drinking troughs. For feeding the animals, they used granulated balanced feed (TU.U15.7-2123600159-001: 2007).Animal care was carried out in accordance with the standard operating procedures of the Center for Disease Control and Prevention of the NFAU.

Three test samples (T3) of the gel were provided for the study, the composition of the test samples of the antiallergic gel (composition per 100 g) is shown in Table 1.

Table 1

Coo)

Example 2. Determination of the optimal composition of the gel on the model of thermal burn of the paw in mice.

To determine the optimal composition of the gel, a convenient and easily reproducible model of acute thermal damage to the paw in mice was used. Experiments were conducted on male mice, weighing 18-22 g. Acute thermal inflammation was caused by immersing the animal's paw in hot water (temperature 64 "C) for 4 seconds.

Taking into account that the research drug contains dexpanthenol and dimetinden maleate as standard drugs of comparison (PP), the cream "Bepanten", produced by GP, was used

Grenzach, Produktions GmoH, Germany, which contains dexpanthenol 50 mg/g and "Fenistil" gel (Novartis Consumer Health S.A., Switzerland), the active ingredient of which is dimetindene maleate, 1 mg/g.

The investigated TK was applied to the damaged paw immediately after the burn in an amount sufficient to cover the entire surface of the damaged paw. The necessary amount of TK - 0.2 g/animal, was selected empirically. After 3 hours, the application of TK was repeated. On the second day, the animals were taken out of the experiment with an overdose of inhalation anesthesia. At the level of the ankle joint, both paws were cut off, and they were weighed on electronic scales. For each animal, the difference between the weights of the damaged and undamaged paws (0) was calculated separately.

Table 2

The design of the study of the anti-inflammatory effect of TK

Positive control.////Ї7777777711111111111111111111111111111111Ї1111117с1С

0.2 g/animal

Immediately after modeling: 7 SS inflammation and after 3 hours in a row

Example 2. Study of the antiallergic effect of the new gel on the model of allergic contact dermatitis of ants.

Anti-inflammatory: the effectiveness of the studied agents was calculated according to the formula (1):

Kk where

Od - the difference between the masses of the damaged and undamaged paws in the experimental group;

Ok is the difference between the masses of the damaged and undamaged paws in the control group.

On the basis of the obtained results, the most effective anti-inflammatory drug Me2 was selected for further research (Table 2).

Among known experimental allergic skin lesions, the model of contact allergic dermatitis induced by 2,4-dinitrochlorobenzene is one of the severe but well-reproducible ones. Dinitrochlorobenzene (2,4-DNHB) is a strong allergen, has a high penetrating ability when applied to the skin and provokes the development of a pronounced inflammatory reaction of an allergic nature. According to clinical signs, this model is the most adequate for the main manifestations of allergic dermatitis in humans.

In connection with this, the study of the antiallergic properties of the Mo 2 gel was conducted on a model of allergic contact dermatitis caused by 2,4-DNHB.

Experiments were carried out on 24 ants weighing 400-700 g. On a carefully cut area of the skin of the right side measuring 2 x 2 cm, 5 drops of 96% alcohol-acetone solution of DNHCB were applied for 6 days in a row.

On the 14th day after the start of sensitization, the ants were treated with a dissolving application with 5 drops of 95 drops of DNAHB solution on identical intact areas of the left half of the body. After 24 hours, a pronounced inflammatory reaction developed at the site of the skin test. Experimental animals were divided into 4 groups. The design of the study of antiallergic action is presented in Table 3.

Table C

Time control////// |. 111111111111111111111111111Ї11111115СС

Positive control./////Ї-77777777771111111111111111111111111Ї11111115ССС

0.5 g/animal

ZO The comparison drug "Fenistil" gel, 0.195 was chosen taking into account its pharmacological effect. Yes, "Fenistil" gel, 0.1 95, belongs to antihistamines and contains in its composition dimetindene maleate - a derivative of phenindene, a histamine antagonist at the level of

NI1 receptors. The drug has an anti-allergic, anti-pruritic and anti-inflammatory effect and is used in the treatment of allergic dermatitis.

Cream "Bepanten", 5 95, a product containing the active substance dexpanthenol, which exhibits anti-inflammatory and wound-healing effects.

Treatment with the studied means was continued daily for 11 days. The intensity of inflammation was assessed visually by the severity of the inflammatory reaction of the skin according to a 5-point system.

The expressiveness of the inflammatory reaction of the skin is given in table. 4.

Table 4

The thickness of the skin fold as an indicator of the expressiveness of inflammation, infiltration changes of skin tissues (as a result of conjugation of antigen with skin proteins and activation of effector cells, leukocytes, phagocytes) was determined before the application of the dissolving application of DNHB, on the 3rd, 5th, 8th and 11th day of treatment ( after application of DNHCB solvent application). The number of leukocytes in peripheral blood was determined on day 0 (initial data), after application of the allergen solution (1 day of treatment) and on day 11 of treatment). The immunological status of the animals was assessed at the maximum development of the allergic reaction - 5 days, by the content of immunoglobulins in the blood.

The content of serum immunoglobulins ID, M, (b) was determined using test systems manufactured by "NVL Granum" (Ukraine) according to the principle of competitive enzyme immunoassay.

The content of total Id E was determined by the sandwich method (two-site enzyme immunoassay), also using test systems manufactured by "NVL Granum" (Ukraine).

Statistical data processing. The obtained data were processed by methods of variation statistics (mean value, its standard error (M), maximum (tah) and minimum (tip) value of the sample) using non-parametric methods of analysis (Kruskal's test

Wallis, Mann-Whitney test). Differences were considered statistically significant at p<0.05. To obtain statistical conclusions, we used the standard Ziaibiis software package (version 6.0).

Example 3. Study of the pharmacological activity of a gel with anti-allergic effect.

Determination of the most effective gel sample with anti-allergic effect by anti-inflammatory activity on the model of acute thermal inflammation in mice.

The conducted study showed that of the three gel samples, only the Me2 sample statistically significantly reduced the severity of inflammation, which was evidenced by a statistically significant decrease in the difference between damaged and undamaged paws (Table 1). According to the obtained data, the anti-inflammatory activity of TK Mo1 was 17 95, TK Mo2 - 23 95, TK Mo3 - 6 95, and PP "Bepanten" and "Fenistil" - 12 95 and 13 95, respectively (Table 5).

Therefore, the combination of two effective active substances in the gel increases the activity of the product twice as compared to the individual components (Table 5).

Thus, the most optimal composition of the new gel with anti-allergic properties was determined on the model of thermal burn of the paw of mice - TZ Me2 with the content of 3 g of dexpanthenol and 0.1 g of dimentindene maleate per 100 g of gel. The Me2 test sample was selected for further investigation of the antiallergic effect.

Table 5

Effectiveness of TZ gel with antiallergic effect in conditions of acute thermal inflammation in mice, p--7 (M (tip; tah)

Positive control.//////77777777111111111 11111111 87(67122) I and Mm3 71111118 1116

Notes: 1.7 - the differences are statistically significant in relation to the indicators of the positive control group (criterion

Mann-Whitney);

2. n - number of animals in each group.

Study of the pharmacological activity of a gel with antiallergic effect (Me2 gel) on a model of allergic contact dermatitis caused by 2,4-dinitrochlorobenzene

According to the obtained data, the clinical manifestations of allergic contact dermatitis developed gradually, reaching the maximum intensity on the 5th day. Allergic inflammation of the skin was characterized by swelling of tissues and pronounced infiltration (2-fold increase in skin folds per 5 days (Table 6), hyperemia with hemorrhagic phenomena, the presence of hemorrhagic crusts with ulcers (the severity of the lesion was estimated at 3.7 points according to the median, Table 6).

Observation of animals showed that the development of an allergic reaction was accompanied by deterioration of the general condition of animals: deterioration of appetite, impaired activity, piloerection.

Against the background of allergic inflammation, pronounced leukocytosis was observed - an increase in the content of leukocytes in the blood in response to the solvent application of the allergen by 1.3-1.5 times compared to the initial data (Table 7).

Table 6

Antiallergic effect of Me2 gel on a model of allergic contact dermatitis caused by 2,4-

DNHB

Severity of allergic reaction

Terms | Thickness of the skin fold, mm Intensity of the lesion, research points) Control! Gel Gel Gel | Control) Gel Gel Gel pathology |"Fenistil"| "Bepanten")| Mo 2 | pathology |"Fenistil"| "YBepanten") Mo 2 g. 2.5

Output , 2.67 (24;| 2.6(22; in. data 2.6 (2.4; 2.9) 28) 29) (2.2; 2.7 zi (2.7; 2 22 (2 ; 1-day IZ,5(2,554,6) m 13,2(353,5)1(28;1 2,0(153) | 23(2:3) | 2,3(1:5) |" ' 3.5) C) 3.)6 to (34: 40(3A: | 38 2.8 (2:

Z-day 4.5(4,055.5) " shchi ' 13.05 32(3545) I125(253,. 1 23(23 1 4.5) 4.5) 45 Z) d9(35: | BO(4Й : | I 2.5 (1;

B-day 5.1(4,155,9) " because ' 1040; 3,7(354) | 3,5(254) | 53,3(2:54) | in 5,5) 5,3) | 50 4) 3.0 0.8 (0; 3.4 (2.9; 3.4 (3.1; ' ' ' and 4.3 (3.6; 5.0) : g re8; 32(2 :4) |22(11:3) ) 221;3) | 2) 8th day 4.2) 3,8) 35 "/f/b . 129 11th day 5 (32:39) 37: | ZY ( ov 28(1:3) |12(0:12u | 10(0:2u 3.9) 3.5) 3 9 same 2)

Note. 7 - the deviation is statistically significant in relation to the control pathology, p-0.05.

In the following days, in the control group of animals, a slow attenuation of the inflammatory process was noted, but the thickness of the skin fold and the level of leukocytes remained almost at the same level (tables 6, 7).

Table 7

The effect of Mo 2 gel on the content of leukocytes in the blood of ants with allergic contact dermatitis caused by 2,4-DNHB (p-6b) X-och

Experiment conditions h. and 1 day 11.88:20.95 15.7150.57 14.08:50.91 11.2950.97 16.71х0.75 10.8750.617 12.08:х0.81 16, 25:x0.76 11.33x0.907 11.29x0.91 15.5451.06 10.1750.967

Notes: 1.7 - the differences are statistically significant in relation to the indicators of the positive control group (criterion

Mann-Whitney); 2. n - number of animals in each group.

Against the background of treatment with Mo 2 gel, experimental animals, starting from the 8th day, observed a pronounced therapeutic effect, confirmed by a statistically significant decrease in the thickness of the skin fold and clinical signs in comparison with similar indicators of animals from the control group. Disappearance of hemorrhages, swelling, hyperemia and normalization of the content of leukocytes was noted (Table 6-7).

The effectiveness of the comparison drugs - "Fenistil" and "Bepanten" gels was also manifested on the 8th day of the experiment, but the antiallergic effect of these agents was somewhat lower than that of the Mo 2 gel (Table 6-7).

All animals had persistent alopecia in the area of the allergic lesion, which remained for 2 weeks after the end of the treatment.

Confirmation of the development of an allergic reaction in response to allergen sensitization is an increase in the content of total IDE by 1.7 times compared to the indicator in intact animals (Table 8). Determination of the spectrum of immunoglobulins in the blood serum of ants showed that hyperimmunoglobulinemia occurs against the background of allergic contact dermatitis - the content of Id M and Id c in groups of animals with experimental dermatitis increased by 1.3 and 1.1 times compared to intact values (Table 8) . The obtained dynamics of the studied indicators confirm the literature data on the mechanism of development of allergic inflammation. It is shown that in the pathogenesis of allergic dermatitis, an imbalance of cellular and humoral reactions plays a key role - hyperactivity of T-helpers of the second type (humoral reactions) and suppression of the activity of T-helpers of the first type (cellular link of immunity). Activation of T-helpers of the second type leads to hyperproduction of IDE antibodies, which is confirmed in our study (Table 8).

Table 8

The effect of Mo 2 gel on the immunoglobulin profile of ants with allergic contact dermatitis caused by 2,4-dinitrochlorobenzene, (p-6) Met control pathology

Notes: " - statistically significant deviation in relation to the intact control, p-0.05; "x- statistically significant deviation in relation to the control pathology, p-0.05;

F - deviation is statistically significant in relation to the comparison drug, "Fenistil" gel, p-0.05;

B - the deviation is statistically significant in relation to the comparison drug, "Bepanten" gel, p-0.05.

With the use of the studied means, the content of immunoglobulin E decreased to physiological values. The dynamics of this indicator in all groups of animals that were injected with Mo 2 gel and comparison drugs was unidirectional and the same in expression (Table 8). The content of Id M and b also decreased in all experimental groups. However, the most obvious normalization of indicators was observed when using the Mo 2 gel. In contrast to the PP gels "Bepanten" and Fenistil, in the group of animals to which the Mo 2 gel was applied, the content of Id M and C was equal to the values of intact animals (Table 8). When using PP the content of Id c remained at the level of the control pathology. Analyzing the obtained data, it can be assumed that the combination of two active substances in the Mo 2 gel leads to an increase in the anti-allergic effect of the investigated agent.

In this way, the study of the pharmacological activity of three samples of the gel with anti-allergic effect made it possible to choose the optimal ratio of active substances.

According to the results of determining the anti-inflammatory effect, the Mo 2 gel, which includes dimethindene maleate - 0.1 g and dexpanthenol - 3 g, showed the greatest effectiveness.

On the model of contact allergic inflammation, the Mo 2 gel showed effectiveness, which, according to a number of indicators, is superior to the effectiveness of the comparative drugs "Bepanten" and "Fenistil" gels.

The analysis of the obtained data allows us to assume that the combination of two active substances in the Mo 2 gel leads to an increase in the antiallergic effect of the investigated agent.

Claims (1)

FORMULA OF THE USEFUL MODEL Pharmaceutical composition in the form of a gel for the treatment of allergic skin reactions to irritants, containing active active substances - dimethindene maleate, dexpanthenol and auxiliary substances: disodium edetate, carbomer, trometamol, propylene glycol, phenoxyethanol, with the following ratio of components, wt. 9: dimethindene maleate 0.05-0.15 dexpanthenol 1.0-5.0 disodium edetate 0.01-0.2 carbomer 0.5-1.5 trometamol 0.5-2.0 propylene glycol 10-20 phenoxyethanol 0.75 -1.0 purified water, the rest.