RU2292879C2 - Medicament for treatment of hyperkeratosis, ingrown nail and for hygienic treatment of nails deformed after trauma and/or aging change - Google Patents

Abstract

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a medicament as an ointment formulation used in treatment of hyperkeratosis, ingrown nail and in hygienic treatment of nails deformed as result of trauma and/or aging changes. Proposed agent contains urea, its stabilizing agents, namely a mixture of glycine and aliphatic (C₁-C₃)-alcohol, and vaseline oil and glycerol as a lipid base and emulsion wax as an emulsifying agent.

EFFECT: valuable medicinal properties of agent.

7 tbl, 1 dwg, 18 ex

Description

The invention relates to the pharmaceutical industry and medicine and relates to an urea ointment intended for the treatment of hyperkeratosis in case of ichthyosis, xerosis, ichthyosiform dermatoses, psoriasis, eczema, and ingrown nails, as well as for the hygienic treatment of nails deformed as a result of trauma and / or age-related changes .

Preparations for the treatment and hygienic procedures of this purpose contain moisturizing and emollient ingredients as active substances. Among them, those substances that are contained in significant quantities in corneocytes of healthy skin and whose content is reduced in tired, thinned, or ontogenetically modified skin, are particularly interesting, namely urea, which not only performs the function of retaining moisture, but also exhibits keratolytic activity due to its property deploy proteins, solubilize and / or denature them [1]. The most effective drugs with urea are emulsion soft dosage forms. This is because the lipid phase of the drug helps to preserve the natural surface epidermal barrier layer, as a result of which transepidermal moisture loss is reduced.

However, dosage forms of preparations containing urea have a fundamental limitation arising from the ability of urea to hydrolyze. In the presence of water, ammonia and carbon dioxide are formed, which leads to a decrease in the amount of active substance, an undesirable increase in the pH of the aqueous phase, and aggregative instability of the emulsion ointment base.

To stabilize urea in ointments, carboxylic acids are used: succinic, malic, lactic [2, 3], or their esters, for example, triglycerides — esters of glycerol and acetic or propionic acids [4, 5]. But these measures do not allow to achieve the desired goal - to stabilize urea; thus, only pH can be adjusted. In addition, compositions containing acids have a very low pH (about 2 or less), repeated local application of such compositions causes skin irritation.

The closest analogue of the proposed tool is a drug for the treatment of hyperkeratosis, ingrown toenails, as well as for the hygienic treatment of nails deformed as a result of trauma and / or age-related changes, which is an oil-in-water emulsion composition containing urea, its stabilizer, lipid base, emulsifier, water [6].

The urea content reaches 30 wt.%, As a stabilizer of urea, natural hydroxy acid is used - lactic acid, which at a concentration of 0.5-8 wt.% Is able to exhibit coordination types of chemical interaction with urea. The composition of the product may also include amino acids, such as arginine, series, citrulline, ornithine, as well as other additives, including polyhydric alcohols, the contents of which are not indicated.

The main disadvantages of this tool include a rather high content of lactic acid (from 0.5 to 8%) and, therefore, low pH values. High concentrations of hydrogen ions, as mentioned above, catalyze the decomposition of urea and adversely affect the condition of the skin.

As emulsifiers, the well-known, the above tool contains either the products of the addition of fatty acid esters with sorbitan to ethylene oxide (Tween-80), or a complex of diethanolamine and cetyl phosphate. The use of these emulsifiers is, firstly, uneconomical, and secondly, the chemical structure of these substances is far from natural compounds, and therefore they do not have a beneficial effect on the skin or the human body as a whole.

The objective of the present invention is to provide a highly effective, low toxic, stable urea-based drug with the best range of consumer properties.

In accordance with the present invention, there is described a medicament for the treatment of hyperkeratoses, ingrown nails, as well as for the hygienic treatment of nails deformed due to trauma and / or age-related changes, which is an ointment containing urea, its stabilizers, a lipid base, emulsifier and water, with this, as stabilizers, the ointment contains a mixture of glycine and aliphatic alcohol C ₁ -C ₃ , as a lipid base - paraffin oil and glycerin, as an emulsifier - emulsion wax in the following ratio of components (wt.%):

Urea 27-33 Glycine 0.1-0.5 Vaseline oil 6-10 Emulsion Wax 6-12 Glycerol 8-12 Aliphatic alcohol C ₁ -C ₃ 8-12 Purified water up to 100.

For the first time, the fact of chemical stabilization of urea with aliphatic alcohol and glycine was established, and their joint use (in a certain concentration ratio) gives a synergistic effect.

The use of emulsion wax as an emulsifier in the declared concentrations makes it possible to obtain a highly dispersed emulsion for this complex composition (with a droplet size of the lipid phase of 10 μm to 75%), stable during long-term storage.

The combined use of the proposed stabilizers and emulsifier leads to a stable drug (tables 1, 2, 3).

The described product due to the content of emulsion wax has a more beneficial effect on the skin than dosage forms that include other emulsifiers (Tween-80 or a complex of diethanolamine and cetyl phosphate). Emulsion wax is obtained by fusion of dispersed synthetic primary alcohols C ₁₇ -C ₁₈ or synthetic primary fatty alcohols with potassium salts of phosphate esters of these alcohols. Due to the presence of phosphorus groups in the molecules of potassium salts of esters of higher fatty alcohols, the structure of the latter is similar to the skin fat phospholipids — lecithin and cephalin. Due to this, emulsion wax has an effective emollient effect on the skin, without leaving a feeling of greasy, prevents the loss of moisture in the skin.

The invention is illustrated by the following examples.

Example 1 (composition No. 1)

8 g of liquid paraffin and 10 g of emulsion wax are melted at a temperature of 75 ° C, mix thoroughly. 30 g of urea are dissolved in 42 ml of purified water at a temperature (40-50 ° C), the resulting solution is heated to 75 ° C. The melt of lipophilic components is slowly added to an aqueous urea solution and emulsified for 5 min at a temperature of 75 ° C using a homogenizer. Add 10 g of glycerol, the resulting ointment is quickly cooled with running water with slow stirring.

Example 2 (composition No. 2)

Carried out analogously to example 1. In 32 ml of purified water at a temperature of (40-50 ° C) 30 g of urea are dissolved. After emulsification is completed, 10 ml of ethyl alcohol is added to the mixture.

Example 3 (composition No. 3)

Carried out analogously to example 1. 0.05 g of glycine is added to an aqueous urea solution.

Examples 4-6 (composition No. 4-6)

Carried out analogously to example 2. In an aqueous solution of urea add 0.1 g of glycine, 0.2 g of glycine and 0.5 g of glycine, respectively. Water for the preparation of an aqueous solution of urea is taken accordingly less.

Example 7 (composition No. 7)

8 g of liquid paraffin and 10 g of emulsion wax are melted at a temperature of 75 ° C, mix thoroughly. 30 g of urea are dissolved in 32 ml of purified water at a temperature (40-50 ° C), the resulting solution is heated to 75 ° C, 0.05 g of glycine is added. The melt of lipophilic components is slowly added to an aqueous urea solution containing glycine and emulsified for 5 min at a temperature of 75 ° C using a homogenizer. 10 ml of alcohol and 10 g of glycerol are added, the resulting ointment is quickly cooled with running water with slow stirring.

Examples 9-11 (compositions No. 8-10) Carried out analogously to example 7. The components of the urea stabilizer mixture are added in the amounts shown in table 1.

Table 1.
Compositions of ointment compositions comprising urea, ethyl alcohol and glycine Composition number Urea,% Ethanol, % Glycine,% one 30,0 - - 2 30,0 10.0 - 3 30,0 - 0.05 four 30,0 - 0.1 5 30,0 - 0.2 6 30,0 - 0.5 7 30,0 10.0 0.05 8 30,0 10.0 0.1 9 30,0 10.0 0.2 10 30,0 10.0 0.5

The amount of ointment base up to 100%

Examples 12, 13 (compositions No. 11 and 12)

Compositions with urea content of 27% and 33%, glycine 0.3% and 0.4%, liquid paraffin 6% and 10%, emulsion wax 6% and 12%, glycerol 8% and 12% and aliphatic alcohol C ₁ are similarly prepared -C _3, respectively.

The obtained samples of ointments are packaged in aluminum tubes with an internal adhesive coating. Assess the quality of the ointment after storage under various conditions for different times. The stability of ointments is evaluated by measuring the amount of ammonia.

The results are shown in tables 2 and 3.

Table 2.
Storage in tubes at a temperature of 40 ° C for 63 days Composition number Ethanol, % Glycine,% Ammonia,% one - - 0,065 2 10.0 - 0,037 3 - 0.05 0.059 four - 0.1 0,068 5 - 0.2 0,047 6 - 0.5 0,057 7 10.0 0.05 0,040 8 10.0 0.1 0,029 9 10.0 0.2 0,029 10 10.0 0.5 0,031

The data in table 2 indicate that the ointment is satisfactorily preserved only if they simultaneously contain ethyl alcohol (8-10%) and glycine (0.1-0.5%) (examples 8-10). In these cases, the amount of ammonia in the ointments is minimal, which indicates a slight decomposition of urea.

Table 3.
Storage in tubes at temperatures of 0 ° C, 10 ° C and 20 ° C for 22 months. Composition number Storage temperature, ° С pH Ammonia,% Urea,% 8 0 7.19 0.018 27.0 9 0 6.85 0.018 27.3 10 0 6.70 0,020 27.0 8 10 6.76 0.018 29.3 9 10 6.25 0.018 28.7 10 10 6.60 0.017 28.3 8 twenty 8.39 0,060 28.8 9 twenty 8.36 0,063 28.8 10 twenty 8.02 0,067 27,2

The data in table 3 indicate that the presence of two stabilizers (alcohol and glycine) in selected quantities can slow down the hydrolysis of urea and get a stable drug. The use of only alcohol or only glycine as a stabilizer, although it leads to a decrease in the rate of hydrolysis of the substance, however, this decrease is not enough to obtain a stable preparation.

Table 4.
Storage in tubes at a temperature of 40 ° C for 12 months. (accelerated storage methodology) Composition number Urea Content% ^* Ammonia odor Ammonia content,% one 26.10 ++ 2,52 2 - ++ 3 28.21 ++ 1.55 four 28.33 ± 1,56 5 27.97 ± 1.55 6 29.67 + 1.30 7 30.57 ± 0.88 8 27.27 ± 0.86 9 29.53 ± 0.72 10 28.60 - 0.75 Note: ^* - arithmetic mean of two or three definitions. ++ - expressed; + - weak; ± - hardly perceptible; - - absence.

The data in table 4 indicate the presence of a synergistic effect from the use of selected stabilizers in selected quantities.

Example 14. The determination of the degree of loosening of the stratum corneum of the epidermis and the degree of softening of the claws in animal experiments.

1. The determination of the degree of loosening of the stratum corneum of the epidermis was evaluated using histological and morphometric methods. The experiments were performed on male guinea pigs (albinos) with a body weight of 250-300 g. Ointments in the amount of 0.5 g were applied to the pads of the hind limbs twice (morning and evening) 5 times a week for 2 weeks. Animals of intact and receiving ointment base applications were used as a control. A total of 4 groups of guinea pigs, 5 animals each, were examined:

- intact animals - control;

- ointment base - control;

- comparison drug (salicylic ointment 10%);

- study drug.

At the end of the experiment, guinea pigs were killed by chloroform vapors. Fragments of the skin of the pads of the hind limbs were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin and examined using an Axioscop - 2 light microscope (Zeiss). Using the DiaMorf hardware and software complex (Russia), the area of the stratum corneum and the area of slits (voids) in it were determined with an increase in the lens of 40 × in each field of view of the skin section of the pads of the back legs of each animal group. Based on the data obtained, the area of the horny substance in the field of view and the "coefficient of loosening" of the stratum corneum of the epidermis were determined by the formulas:

1. S _p. = S _r.s. -ΣS _u. where

S _p. - the area of the horny substance of the epidermis (without gaps) in the field of view of the microscope,

S _p.sl - the area of the stratum corneum of the epidermis in the field of view (together with cracks in it),

ΣS _u. - the total area of the cracks in the stratum corneum of the epidermis in the field of view of the microscope,

2.

To _bit. - "coefficient of loosening" of the stratum corneum of the epidermis.

Statistical processing of the results was carried out using t-student test. Differences in means were considered significant with a probability level of at least 95% (marked with asterisks in the table).

It was established that the application of the studied drug leads to a decrease in the height of the epidermis, a decrease in the thickness and degree of monolithicity of its stratum corneum, loosening of the latter and often to its detachment from the underlying layers. Structural manifestations of the specific dermatotropic activity of the comparison drug were less consistent and significant variability (see drawing).

Morphometric studies confirmed visual observations (table 5).

Table 5.
Indicators characterizing the degree of loosening of the stratum corneum of the epidermis of the skin of the pads of the hind legs of guinea pigs after 2 weeks of daily double applications of the studied drug Groups of animals The area of the horny substance (without gaps) of the epidermis of the skin of the fingerpads in the field of view of the microscope (μm ² ) Loosening coefficient To _bit Intact 16646 ± 812 0.123 ± 0.020 Ointment base 14222 ± 833 0.186 ± 0.020 ^* Study drug 13872 ± 917 0.279 ± 0.030 ^** Comparison drug 13646 ± 950 0.142 ± 0.020 ^* - significant deviation in relation to the intact group at P <0.05
^** - significant deviation with respect to the intact group at P <0.001

The values given in table 5 demonstrate that the area of the horny substance in the epidermis (without the area occupied by the voids) falling on the microscope field of view shows a tendency to decrease under the influence of both keratolytic agents (the studied drug and the reference drug), and the emulsion base of the studied the drug. However, the degree of loosening, and consequently, swelling and softening of the stratum corneum, after the application of the studied drug - turned out to be two times higher than when applying the comparison drug.

Thus, the studied drug loosens the stratum corneum of the skin epithelium, i.e. has a keratolytic effect against soft keratin; while this indicator has significant advantages over the known keratolytic agent used in this experiment as a comparison drug.

2. The degree of softening of the claws was evaluated by determining the dynamic shear force. The object of study was the trimmed claws of the forelimbs of guinea pigs with a body weight of 250-300 g. Manipulations were performed under hexenal anesthesia (80 mg / kg, ip). The clipped claws were immersed in the test ointment for a period of 14 days (in vitro test). The assessment was carried out in comparison with the claws of guinea pigs of the control groups and groups of animals treated with the comparison drug. In total, 4 groups were studied, each of which included 6 individuals of both sexes:

- intact animals - control;

- emulsion base;

- comparison drug (salicylic ointment 10%);

- study drug.

On the 15th day of the experiment, the claws were thoroughly wiped from the ointment, after which the scissors made a dynamic effort to cut the claw. The force applied to the slice was determined using a measuring device, the scale of which was 0.1-1 kg (unit of division 100 g). Statistical processing of the results was carried out using t-student test. Differences in means were considered significant with a probability level of at least 95% (marked with an asterisk in the table). The results are presented in table.6.

The results indicate that the ointment base and the comparison drug do not have a pronounced softening effect on the claw plate in comparison with intact animals. A statistically significant decrease in the force of impact on the claw section was observed only in the main group in animals of both sexes after exposure to the studied drug. Sexual differences were noted in this group of animals: in females, the degree of softening of the claws was higher than in males. Apparently, the differences obtained are due to the sexual characteristics of organisms (in particular, the size of the claw matters, in females it is smaller than in males).

Table 6.
Dynamic shear force (in gs) of guinea pig claw plates Intact control Study drug Comparison drug Ointment base ♀ ♂ ♀ ♂ ♀ ♂ ♀ ♂ 565.0 ± 40.3 600.2 ± 42.3 177.8 ± 8.5 ^* 253.0 ± 19.2 ^* 522.5 ± 32.4 666.7 ± 47.1 598.6 ± 27.4 600.0 ± 27.5 n = 12 n = 12 n = 9 n = 9 n = 9 n = 9 n = 14 n = 13 ^* - significant deviation with respect to the intact control at P <0.001

Thus, the studied drug causes softening of the claw plates in guinea pigs of both sexes, i.e. has a keratolytic effect against solid keratin.

Example 15. The treatment of hyperkeratosis of various origins.

Under observation were 34 patients with various diseases with increased keratinization (19 patients with psoriasis, 5 - ichthyosis, 2 - ichthyosiform erythroderma, 4 - Devergey's disease, 4 - follicular keratosis). Among the patients there were 23 men and 11 women aged 6 to 55 years. 19 patients previously received treatment with various skin softening agents, including 5% salicylic ointment. All patients had multiple rashes located on the chest, back, and limbs. Ointment with urea 30% as a monotherapy was prescribed 2 times a day. The treatment was carried out on an outpatient basis. The effectiveness of therapy was evaluated by the dynamics of changes in clinical signs recorded once a week. Before and after treatment, clinical and biochemical blood tests were performed.

Improvement came at the end of the first week of treatment - hyperkeratosis decreased, the elements of the rash became flatter, and the surrounding skin was softer. After 2 weeks of treatment, a significant improvement was observed, which allowed switching to external funds of other groups. The results of treatment after a 2-week course are shown in table 7.

Table 7.
Treatment of diseases with increased keratinization Recovery Significant improvement Improvement Lack of improvement Worsening men 6 fifteen 2 0 0 women 2 8 one 0 0 Total: 8 23 3 0 0 23.5% 67.7% 8.8%

As can be seen from table 7, a positive effect was achieved in all patients, the result was significantly better with exacerbation of chronic acquired diseases compared with genetically determined ones. None of the patients had side effects or deviations in laboratory parameters, which indicates the safety of therapy.

Thus, the urea ointment causes a decrease in hyperkeratoses regardless of their origin, which is associated with the keratolytic effect of the ointment. The effect occurs in the first week of treatment and increases by the end of the second week. The keratolytic effect is not accompanied by inflammation or other undesirable effects.

Example 16. Hyperkeratotic growths on skin lesions to be removed.

We observed 2 children and 10 adults with hyperkeratotic layers at the age of 5 to 40 years, of which three were male. Nine patients had warts on the fingers and toes, the rest had calluses. Urea ointment was prescribed to all patients for a short time - 3-7 days. The results were taken into account at the end of this period, and for people with callosities after another 3 weeks. All patients achieved a favorable result - keratinization of warts was reduced, which made it possible to remove them with liquid nitrogen, pain when walking in patients with localization of warts on the feet stopped, callosities became flatter. In patients with callosity, treatment was continued for up to 1 month, which caused complete (in 1) and incomplete (in 2) regression of rashes.

Thus, the softening and removal of the excess stratum corneum on warts makes it possible to remove them in the most gentle way. It is important that a decrease in keratinization reduces pain during walking and wearing shoes.

Example 17. Hygienic treatment of deformed nails.

Under our supervision, there were 5 patients with an ingrown nail, 1 man and 3 women and a child of 12 years old. The age of patients is from 12 to 60 years. All patients had an isolated unilateral lesion of the big toe in the form of excessive growth of the lateral nail roller and a deformed nail plate, deeply cutting under the fabric of the roller. All patients experienced constant pain while walking, the lesions periodically suppurated, which in 2 patients in the past required surgical treatment, but the problem remained after nail regrowth. After 2 weeks of applying the ointment with urea 30%, applied 2 times a day to the nail plate and under the nail roll, the pain decreased, processing (cutting) of the nail plate was facilitated. In the period of the subsequent 4-6-month observation of purulent inflammation, not a single patient was noted.

Thus, the use of urea ointment with ingrown nails reduces pain, facilitates cutting of nail plates, and can be effective symptomatic therapy, which is especially important, given the lack of pathogenetic.

Example 18. Hygienic treatment of nails with other pathologies.

The group consisted of 10 patients with fungal infections of the nails (onychomycosis), 28 patients with thickening (onychodystrophy), deformation (as a result of trauma and / or age-related changes), and constitutional hardness of the nail plates.

After a 1-month application of an ointment with urea 30% in the form of applications on affected nails 2 times a day, patients could effortlessly remove the overgrown part of the nail plates with forceps or scissors and file the nails from above. At the same time, a decrease in the thickness of the nail plates made it possible to feel more comfortable in shoes.

Thus, the regular use of urea ointment leads to softening of the nails, which makes it easier to trim and treat them with thickening, deformation or excessive hardness of various origins. This reduces the subjective sensations associated with the pressure of the shoe on thickened nails.

Literature:

1. Ashton H. et al. // Br. J. Dermatol. - 1971. - V.84. - P.194-196.

2. German patent No. 2608221.

3. German patent No. 2725525.

4. German patent No. 2913040.

5. US patent No. 3666863.

6. French patent No. 20033312 is a prototype.

7. French patent No. 2342059.

Claims (1)

A medicine for the treatment of hyperkeratoses, ingrown nails, as well as for the hygienic treatment of nails deformed as a result of trauma and / or age-related changes, which is an ointment containing urea, its stabilizers, lipid base, emulsifier and water, while the ointment contains as stabilizers a mixture of glycine and aliphatic alcohol C ₁ -C ₃ , vaseline oil and glycerin as a lipid base, emulsion wax as an emulsifier in the following ratio of components, wt.%: Urea 27-33 Glycine 0.1-0.5 Vaseline oil 6-10 Emulsion Wax 6-12 Glycerol 8-12 Aliphatic alcohol C ₁ -C ₃ 8-12 Purified water up to 100

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