RU2397770C1 - Multivitamin ointment for skin softening, nutrition and healing and method of obtaining it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to field of pharmaceutics and deals with multivitamin ointment for skin softening, nutrition and healing, which contains fat-soluble vitamins A, E, D₃, antioxidants, emulsion wax, vaseline oil, glycerol, ethyl alcohol and water, and method of obtaining it.

EFFECT: there is claimed multivitamin ointment for skin softening, nutrition and healing.

3 cl, 2 dwg, 2 tbl, 3 ex

Description

The invention relates to medicine and relates to the creation of an ointment composition containing a complex of fat-soluble vitamins intended for the treatment of skin atrophy, dryness, damage (burns, abrasions, cracks, erosion, abrasion, diaper rash), to prevent and reduce signs of skin aging, for use in in the complex therapy of skin diseases (ichthyosis, psoriasis, atopic dermatitis, eczema, etc.), to protect the skin from the effects of damaging factors, improve its appearance, as well as the method for its preparation.

It is known that retinoids (synthetic analogues of vitamin A) enhance the regeneration of the epidermis, both physiological and reparative, inhibit the process of terminal differentiation of keratinocytes, promote the production of glycosaminoglycans by the cellular elements of the dermis, and enhance immune responses [1, 2]. Vitamin E prevents lipid peroxidation, protects cell membranes from the damaging effects of peroxides [3], slows down the aging process of the structural components of the skin. Vitamin D in the form of cholecalciferol (vitamin D ₃ ) is a natural component of the skin, as synthesized in it under the influence of sunlight. Skin cells have receptors for its active metabolite - calcitriol, which has anti-proliferative and anti-inflammatory properties in relation to the skin, affects the differentiation of keratinocytes and can be largely considered as an analogue of steroid hormones [4]. The intensity of insolation, its duration, as well as the surface area exposed to ultraviolet rays, vary significantly. So, the period when solar radiation is able to provide the formation of vitamin D ₃ in the skin for residents of an area around 55 ° north latitude (Moscow, Nizhny Novgorod, Novosibirsk, Tomsk, Yekaterinburg) is only 4 months a year: from mid-April to mid-August, in zone 60 ° and to the north (St. Petersburg, Arkhangelsk, Syktyvkar) - about 3 months or less: from May to July. Vitamin D deficiency occurs in the elderly; It is shown that in people aged 65 years and older, there is a 4-fold decrease in the ability to form vitamin D in the skin.

Known oil-based preparation containing vitamins A, E, D, which helps restore skin cells that are damaged mechanically or by high temperatures, and also improves hair growth [5].

The disadvantage of this drug is the unreasonably high content of vitamins E and D. Excess vitamin E can adversely affect the state of the developing and dying germinal system in children and the elderly. In addition, its excess may undesirably affect the stability of vitamin A. High doses of vitamin D are even more dangerous. Vitamin D can disrupt calcium metabolism, enhance the process of stone formation in the kidneys and liver.

Closest to the medical indications and technical nature of the claimed composition (prototype) is a drug, which is an ointment with vitamins A, E, D, containing antioxidants, emulsifier, paraffin oil, glycerin, ethyl alcohol and water [6]. At the same time, vitamin D is part of the preparation in the form of ergocalciferol (vitamin D ₂ ).

The specified ointment is prepared as follows: vitamins A, E, D and antioxidants are mixed with a part of paraffin oil and introduced into the melt of emulsifier and paraffin oil. When the mixture is heated to 60 ° and stirring, water heated to 60 ° is gradually added in portions. After cooling to room temperature, ethyl alcohol and glycerin are added.

In accordance with modern concepts, vitamin D ₂ (ergocalciferol) and vitamin D ₃ (cholecalciferol), regardless of the pathway of formation or entry into the body, undergo similar biochemical transformations, the result of which is the formation of active metabolites. The most effective metabolite is calcitriol, which is often called the D-hormone. This product has numerous regulatory functions characteristic of vitamin D, including a number of immunomodulating and dermatotropic effects, which are manifested in local inhibition of proliferation of T and B lymphocytes, keratinocytes, differentiation of plasma cells, secretion of immunoglobulin G, in ensuring homing of T lymphocytes and et al. Vitamin D ₂ enters the human body only with food and its conversion to the active metabolite in vivo occurs by enzymatic cascade, first in the liver and of the kidney [4]. The advantage of vitamin D ₃ is that its synthesis in the skin is a natural physiological process, and the subsequent formation of the active metabolite of calcitriol (l, 25 (OH) ₂ D ₃ ) occurs not only in the liver and kidneys, but also locally in the skin, where it concentrates and exerts local regulatory effects. It was shown that the enzymes necessary for this process (25- and 1-hydroxylases) are synthesized by dermal T-lymphocytes and dendritic cells. A similar effect with respect to vitamin D ₂ is less pronounced, which the authors attribute to the selectivity of enzymes that convert an inactive vitamin into an active metabolite, specifically in relation to vitamin D ₃ as a natural component of the skin [7].

In addition, vitamin D ₂ contains in its structure a double bond in the radical and additionally a CH ₃ group [8]. The presence of a double bond leads to a greater susceptibility to oxidation of D ₂ , and the presence of the CH ₃ group increases toxicity and leads to a greater burden on the body.

Taking into account that the skin is the site of the formation of vitamin D ₃ (cholecalciferol) in the body in vivo, studies have been carried out to develop a dermatotropic preparation containing as the active substance a more physiological form for the skin and a form of vitamin D more widely used in the modern pharmaceutical industry namely, cholecalciferol (vitamin D ₃ ).

In accordance with the invention, a multivitamin ointment is described that stimulates the regeneration of the epidermis, softens and nourishes the skin, containing fat-soluble vitamins - retinol palmitate (vitamin A), tocopherol acetate (vitamin E), cholecalciferol (vitamin D ₃ ), and as a fat phase of the ointment base - vaseline oil, as an emulsifier - emulsion wax, as well as ethyl alcohol, glycerin, water and antioxidants in the following ratio of components, wt.%:

Retinol palmitate 0.1-1.5 Tocopherol acetate 0.05-0.7 Cholecalciferol 0.0005-0.007 Antioxidants 0.1-0.3 Emulsion wax 5.0-15.0 Vaseline oil 5.0-15.0 Glycerol 5.0-15.0 Ethyl alcohol 95% 5.0-15.0 Distilled water up to 100.0

Also described is a two-stage method for producing a multivitamin ointment that stimulates the regeneration of the epidermis, softens and nourishes the skin, while at the first stage, cholecalciferol is dissolved in liquid paraffin while heating, followed by mixing the obtained oil solution of cholecalciferol with retinol palmitate and tocopherol acetate to obtain multivitamin the second stage is mixed with a melt of liquid paraffin, emulsion wax and antioxidants at 70-80 ° C, followed by the introduction of floor the learned mixture into water heated to 70-80 ° C, adding ethanol and glycerol to the resulting emulsion and homogenizing.

The manufacture of a multivitamin ointment consists of two stages - the manufacture of a multivitamin preparation and the manufacture of an ointment composition. At the first stage, a multivitamin preparation is made from a mixture of three vitamins - vitamin A, vitamin E and vitamin D ₃ .

The production technology of a multivitamin preform consists, in turn, of two stages: 1) the manufacture of a 2.5% solution of cholecalciferol in oil; 2) mixing vitamin A, vitamin E and manufactured 2.5% cholecalciferol solution.

In the first stage, a weighed amount of cholecalciferol is dissolved in oil by heating the mixture to 60 ° C and stirring. In the second stage, the obtained amount of the prepared 2.5% cholecalciferol solution is mixed with the calculated amounts of vitamin A and vitamin E. The mixture is stirred in a reactor with a stirring device for three hours, after which it is discharged into aluminum containers. The containers with the workpiece are purged with nitrogen and sealed. The multivitamin preform is stored in a refrigerator at a temperature of +3 to + 8 ° C.

At the second stage, the actual manufacture of a multivitamin ointment composition is performed. Its essence is that the calculated amount of multivitamin preform is first introduced into a mixture (melt) of liquid paraffin, emulsion wax and antioxidants, heated to a temperature of 70-80 ° C. The resulting mixture is gradually introduced into purified water heated to a temperature of 70-80 ° C, after which ethyl alcohol 95% and glycerin are gradually added to the resulting emulsion in the form of an alcohol-glycerin mixture. The ointment is homogenized for a certain time and cooled to room temperature.

Introduction to the multivitamin ointment production technology of the multivitamin preparation stage allows:

1. Significantly reduce the cost of working time spent on weighing each vitamin separately, and in general - for the duration of the entire process.

2. To extend the shelf life of vitamins in the form of this preform, because Vitamin E is a natural antioxidant that stabilizes vitamins A and D.

3. To simplify the calculations carried out before the start of the production process when forming a series of finished products of optimal volume.

The high effectiveness of the claimed drug in the treatment of the above conditions and increase the protective properties of the skin takes place due to the joint dermatotropic effect of three fat-soluble vitamins. The use of cholecalciferol (vitamin D ₃ ), which is natural for the skin, as a part of the ointment, results in a preparation that is more physiological for the skin and has a high pharmacological dermatotropic effect.

Example 1

200 g of cholecalciferol is dissolved by heating the mixture to 60 ° C in 7.8 kg of oil. The resulting solution of cholecalciferol is stirred for three hours in a reactor with 40 kg of vitamin A and 20 kg of vitamin E. The resulting multivitamin preform is poured into containers, purged with nitrogen, sealed and transferred to storage in a refrigerator (from +3 to + 8 ° С). 3.4 kg of a multivitamin preform, 15 kg of liquid paraffin, 15 kg of emulsion wax, 200 g of butylhydroxyanisole (BOA) and 200 g of butylhydroxytoluene (BOT) are heated in a reactor to a temperature of 70-80 ° C. After heating, the resulting mixture is introduced into 126.2 kg of purified water, heated to a temperature of 70-80 ° C. After that, 20 kg of 95% ethyl alcohol and 20 kg of glycerol in the form of an alcohol-glycerin mixture are gradually added to the emulsion obtained. The ointment is homogenized and cooled to room temperature.

Example 2

100 g of cholecalciferol is dissolved by heating the mixture to 60 ° C in 3.9 kg of oil. The resulting cholecalciferol solution is stirred for three hours in a reactor with 20 kg of vitamin A and 10 kg of vitamin E. The resulting multivitamin preform is poured into containers, purged with nitrogen, sealed and transferred to storage in a refrigerator (from +3 to + 8 ° С).

6.8 kg of a multivitamin preform, 32 kg of liquid paraffin, 32 kg of emulsion wax, 400 g of BOA and 400 g of BOT are heated in a reactor to a temperature of 70-80 ° C. After heating, the resulting mixture is introduced into 248.4 kg of purified water, heated to a temperature of 70-80 ° C. After that, 40 kg of 95% ethyl alcohol and 40 kg of glycerol in the form of an alcohol-glycerin mixture are gradually added to the emulsion obtained. The ointment is homogenized and cooled to room temperature.

Similarly obtained ointments, the composition of which is shown in table 1.

Table 1 The composition of the multivitamin ointment Name of components The number of components,% one 2 3 four Retinol palmitate 0.1 0.5 one 1,5 Tocopherol acetate 0.05 0.25 0.5 0.7 Cholecalciferol 0,0005 0.0025 0.005 0.007 Antioxidants 0.1 0.1 0.2 0.3 Emulsion wax 5,0 8 8 15.0 Vaseline oil 5,0 8 8 15.0 Glycerol 5,0 10 10 15.0 Ethyl alcohol 95% 5,0 10 10 15.0 Distilled water up to 100.0 up to 100.0 up to 100.0 up to 100.0

Preclinical Studies

The study showed that the claimed drug has a specific pharmacological dermatotropic activity. The morphological manifestations of the effects of the ointment of the claimed composition on the intact skin of males and females of randomly bred rats of 1.5-2 months of age were studied in comparison with the effects arising from the effects of the prototype drug. Keeping, caring for animals and removing them from the experiment was carried out in accordance with the requirements of the "Rules for the Use of Experimental Animals" (Appendix to the order of the Ministry of Health of the USSR dated 12.08.1977, No. 755).

Experimental animals were divided into 4 groups:

1) intact control;

2) ointment base;

3) prototype drug;

4) the claimed drug.

Applications of the ointment base, the prototype drug and the inventive preparation were carried out daily for 14 days on the skin of the interscapular region of the back, devoid of hair, in an amount of 0.5 g / live / day; animals of the intact control group, as well as experimental rats, had their hair cut on their backs. Material was taken for morphological and morphometric studies in all groups one day and one month after the end of the applications; at both stages of the experiment, each group consisted of 6 females and 6 males. Histological skin preparations from the application area were prepared in accordance with standard methods (fixation in 10% formalin, paraffin embedding, section staining with hematoxylin and eosin) and examined using an Axi-oskop 2 light microscope (Zeiss, Germany). Morphometric studies (measuring the thickness of the cellular epidermis, i.e., to the stratum corneum) were performed using computer technology on the hardware-software complex Diamorph (Russia) using CITO video analysis software. The results are processed by methods of variation statistics. It was established that daily skin applications of ointments containing various forms of vitamin D (D ₂ - ergocalciferol and D ₃ - cholecalciferol) daily for 14 days cause a statistically significant increase in the thickness of the cellular epidermis in animals of both sexes, leading to a change in the shape of the cells of the basal layer (from flat and cubic to prismatic) and an increase in the number of mitosis figures in it, increase the representation of cells of the granular layer, which together can be considered as morphological signs of stimulation of proliferative ciency keratinocytes and influence their differentiation (Table 2, Figure 1, 2). The detected effects almost disappear 1 month after the cancellation of the applications while maintaining the morphological signs of a decrease in keratinization.

table 2 The thickness of the cellular epidermis of the interscapular region of the back of rats one day and a month after the end of the application of multivitamin ointments (n = 6) Groups The thickness of the cellular epidermis (to the stratum corneum) in microns Males Females 1 day 30 days 1 day 30 days Intact control 23.0 ± 0.4 26.8 ± 0.6 19.3 ± 1.0 17.4 ± 0.7 Ointment base 24.9 ± 0.4 26.8 ± 0.5 22.0 ± 0.7 18.2 ± 1.0 Prototype drug 47.5 ± 1.7 * 24.1 ± 0.9 42.7 ± 1.3 * 16.4 ± 0.6 The inventive drug 45.6 ± 1.3 * 22.4 ± 0.7 * 39.6 ± 1.4 * 16.6 ± 0.6 * significant deviation in relation to the indices of the control groups at p <0.001.

Thus, the results of a comparative experimental study using histological and morphometric methods for assessing the skin of experimental animals under the influence of multivitamin ointments containing a complex of fat-soluble vitamins indicate a high pharmacological manifestation of the dermatotropic effect of the described drug. Clinical researches

The studies were carried out in the Scientific dermatological center "Retinoids", Moscow, license series MDKZ No. 17970/9429.

The multivitamin ointment of the described composition is intended for the treatment of skin diseases and for the care of healthy skin. The drug has a reparative, anti-inflammatory and antipruritic effect, normalizes keratinization processes, enhances the protective function of the skin. It is used in complex therapy in adults and children with ichthyosis and ichthyosiform dermatoses, in the treatment of seborrheic dermatitis, cracks, erosion and skin burns, uninfected wounds and ulcers, eczema, atopic dermatitis, neurodermatitis, allergic contact dermatitis (outside the acute stage), psoriasis, dry skin. It is used to prevent relapse of chronic inflammatory and allergic skin diseases, after cessation of treatment with glucocorticosteroids (in the subacute period), with easily irritated skin, including with increased sensitivity to cosmetics.

Case Studies

1. Bnoy B.Ya., 39 years old, doctor: eczema, subacute stage. Sick from childhood, rashes in the form of small nodules, peeling, crusts on the background of erythema on the legs, trunk, hands, moderate itching. High allergic sensitivity to any external agents. Systemic treatment with antihistamines, outwardly prescribed PM with D ₃ . The ointment is well tolerated, does not cause irritation, after a week of application, the skin became softer, itching and peeling decreased.

2. B-naya P.G., 14 years old, patient: seborrheic dermatitis. Sick for 3 years, constantly on the skin of the face erythematous-squamous rashes of a bright pink color, summer improvement. Used PM with D ₃ for 3 months. It notes a significant improvement - peeling has stopped, redness has decreased, the skin has become softer, the foci are barely noticeable. Despite prolonged use, the effectiveness of the external agent has not decreased.

3. B-noy O.A., 8 years old, patient: regular ichthyosis. Sick from the first months of life, worried about constant dryness and peeling of the skin, moderate itching. Rashes disappear in the summer. On the skin of the whole body, with the exception of skin folds, palms and soles, fine plate peeling. Larger scales on legs. Previously used emollient cosmetic creams with little effect. Used PM with D ₃ for 1.5 years. During the first month _{, a} significant improvement was achieved - the skin became soft, peeling remained only on the legs, the itching stopped. In the following months, the ointment was applied as needed with increased dryness and the appearance of peeling. No addiction was noted. Systemic treatment was not required.

Thus, a multivitamin ointment with D ₃ can be used in dermatological practice. In patients with easily irritable skin or hypersensitivity to cosmetics, as well as personal hygiene products and household chemicals, the use of an ointment containing vitamin D ₃ is preferable, since the cholecalciferol contained in it is an exact analogue of cholecalciferol, which is formed in the skin under natural conditions .

The greater effectiveness of the claimed drug is based on local immunomodulating effects of vitamin D ₃ metabolites in the skin, i.e. directly in the place of its formation.

Information sources

1. Afanasyev Yu.I., Nozdrin V.I., Volkov Yu.T. and others. Vitamin A - a regulatory factor in the processes of histogenesis // Usp. modern biol. - 1990. - T. 110, No. 3 (6). - S. 410-418.

2. Afanasyev Yu.I., Nozdrin V.I., Mikhailov O.I. and other functions of vitamin A // Successes sovr. biol. - 1986.- T. 101, issue 2. - S. 215-227.

3. Pletsy KD, Vasipa S. B., Davydova T. V., Fomina V. G. Vitamin E: immunocorrective effect in patients with bronchial asthma // Vopr. honey. chemistry. - 1995. - T. 41, No. 4. - S.33-35.

4. Schwartz G.Ya. Vitamin D and D-hormone. - M .: Publishing house Anaharsis, 2005 .-- 150 p.

5. DE 3800 972, A1 Off, A61K 31/59, 07.27.1989.

6. RU 2004234, C1, A61K 9/06, 12/15/1993.

7. Sigmundsdottir H, Junliang P., Gudrun F.D. et al. DCs metabolize sunlight-induced vitamin D3 to "program" T cell attraction to the epidermal chemo-kine CCL27 // Nature immunology. - 2007. - Vol.8, N 3. - P. 285-293.

8. Mashkovsky M.D. Medicines - M.: Medicine, 1967. - T.1. - S. 473-474.

Claims (3)

1. A multivitamin ointment that stimulates the regeneration of the epidermis, softens and nourishes the skin, containing vitamins A, E and D, antioxidants, emulsion wax, liquid paraffin, glycerin, ethyl alcohol and water, characterized in that it contains cholecalciferol as vitamin D in the following the ratio of components, wt.%:
Retinol palmitate (Vitamin A) 0.1-1.5 Tocopherol Acetate (Vitamin E) 0.05-0.7 Cholecalciferol (Vitamin D ₃ ) 0.0005-0.007 Antioxidants 0.1-0.3 Emulsion wax 5.0-15.0 Vaseline oil 5.0-15.0 Glycerol 5.0-15.0 Ethyl alcohol 95% 5.0-15.0 Distilled water up to 100.0 2. The method of producing a multivitamin ointment according to claim 1, characterized in that the process is carried out in two stages - at the first stage, cholecalciferol is dissolved in paraffin oil when heated, followed by mixing the obtained oil solution of cholecalciferol with retinol palmitate and tocopherol acetate to obtain a multivitamin preform, which at the second stage is mixed with a melt of liquid paraffin, emulsion wax and antioxidants at 70-80 ° C, followed by the introduction of the mixture into water heated to 70-80 ° C, adding Niemi to the resulting emulsion of ethyl alcohol and glycerol and homogenization. 3. The method according to claim 2, where the dissolution of cholecalciferol in paraffin oil is carried out at 60 ° C and the multivitamin preform obtained in the first stage is stored at a temperature of from 3 to 8 ° C.

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