EP3439616A1

EP3439616A1 - Epidermal lipid barrier restoring cream for facial skin, neck and decollete area for metabolic syndrome patients

Info

Publication number: EP3439616A1
Application number: EP15902371.2A
Authority: EP
Inventors: Julija Voicehovska; Jana JANOVSKA; Irena Daberte; Vladimirs VOICEHOVSKIS; Andrejs Skesters; Alise SILOVA; Sergejs BABIKOVS; Olga ZUBOVA; Dagmara SPRUDZA; Janis KISIS; Ludmila Ivanova
Original assignee: Rigas Stradina Universitate
Current assignee: Rigas Stradina Universitate
Priority date: 2015-08-24
Filing date: 2015-08-25
Publication date: 2019-02-13
Also published as: WO2017034384A1; EP3439616A4; LV15082A; LV15082B

Abstract

The invention relates to the field of medicine, namely family medicine (general practitioners), therapy, endocrinology, gerontology, dermatology and cosmetology and solves the problem of restoration of epidermal lipid barrier in facial skin, decollete and the neck in metabolic syndrome patients. The goal of the invention is to develop a cream composition that restores epidermal lipid barrier and lipid layer of facial skin, neck and decollete for use in patients with metabolic syndrome. Set goals are achieved through the design of a specific ē cream composition, which contains seleno-L-methionine, Vitamin E alpha-tocopherol, squalane, methyl-4- hydroxybenzoate, glycerol monostearate 60, cetylalchol, middle chain triglyceride, white petrolatum, macrogol-20-glycerolmonostearate, 1,2-propanediol and distilled water in the certain ratios mass relationships.

Description

EPIDERMAL LIPID BARRIER RESTORING CREAM FOR FACIAL SKIN,

NECK AND DECOLLETE AREA FOR METABOLIC SYNDROME PATIENTS

The invention relates to the field of medicine, namely family medicine (general practitioners), therapy, endocrinology, gerontology, dermatology and cosmetology and solves the problem of restoration of epidermal lipid barrier in facial skin, decollete and the neck in metabolic syndrome patients.

LEVEL OF SOPHISTICATION

Background of the invention

Metabolic syndrome is a combination of changes linked to disruption of metabolism, in which the lack of sensitivity to insulin develops and cell glucose uptake is diminished. Metabolic syndrome features hypertony, obesity, ischaemic heart disease, diabetes mellitus type 2. Development of metabolic syndrome includes, but not limited to increase in waist circumference (more than 102 cm in men, more than 88 cm in women); arterial blood pressure of at least 135/85 raraHg. These patiens' blood features increased lipid peroxidation markers. Oxidants activate cell responses with protein, lipid and DNA destruction. Under such conditions, skin barrier function gets suppressed and moist is evaporated more intensively, which leads to skin dryness, which then leads to excessive exfoliation, thickening of corneum layer, greyish discoloration and various skin diseases (seborrhea, atrophic dermatitis, psoriasis, eczema etc.) [1].

Human skin represents an intricate tissue system that is based on epidermis, derma and subcutaneous fat outline. Inside basal epidermal layer melanocytes and Langerhans cells reside. Principal epidermal layer consists of fibers of protoplasm and granulous layer is comprised of cells rich in keratohyalin complexes. Derma is the connective part of the skin and makes up for the majority of volume. Derma is separated from epidermis with the basal membrane [2].

Outer part of the epidermis is covered with corneum layer, which in turn is covered in water-lipid mantle with acidity of 4.5 - 5.5 pH. This level of acidity provides bactericidal protection and enhanced lipid synthesis. Acidic properties of the skin are defined by sweat and sebum. Many microbes that appear on the skin die within 20-30 minutes [3]. Water-lipid mantle forms and epidermal barrier that is made up of corneal scale-like cells which are called corncocytcs. Among them lie intercellular lipids - ceramides. Ceramides glue corneocytes together and form an impenetrable, uniform epidermal barrier. Ceramid molecules posess polar structure - they feature hydrophilic heads (attract water) and lipophilic tails (attract fats). Epidermal lipid barrier blocks harmful substances from entering the skin and takes part in humoral homeostasis in derma. Lipid barrier consists of cholesterol, ceramides and unsaturated fatty acids (Omega-3, Omega-6). These fatty acids posess antiinflammatory properties, stimulate Langerhans cells and strengthen epidermal lipid layer [4]. Free fatty acids are located around ceramides inside the lipid layer and provide water repellency, form water-in-oil emulsion. Under the disruptive conditions, microorganisms chemicals and other exogenous, aggressive factors enter the skin through a damaged lipid layer.

Skin features its own system of immune cells, starring Langerhans cells (2-5% of cellular epidermis). Langerhans cells take part in destruction of bacteria and initiate immune response, under which dermal dendritic cells, epidermal macrophages and other cells take part. Skin ageing is related to the state of immune system [5]. Past 25 years, natural ageing sets in motion: skin macrophage amount reduces, oxidants activate cell reactions that disrupt protein, lipid and DNA structures. Such processes are most active and prominent in patients eith metabolic syndrome (MS). We know that metabolic syndrome also features a latent inframmation that activates peroxidation. Accumulation of lipid peroxidation and oxidative lipoprotein and lipid layer damage lead to morphologic changes of skin structural components [6]. Antioxidative defense system is weakened and/or ineffective in patients with metabolic syndrome due to oxidative stress. Under such stress, keratinocyte synthesis is reduced, transepidermal water evaporation intensifies, skin becomes markedly dry with cracks and erosions present. These changes lead to microbiota imbalance, fungal skin infections and papilloma development. Restoration of epidermal lipid layer of the skin is a particularly urgent task in patients with metabolic syndrome [7].

In Table 1 we provide the spectrum of epidermal lipid layer disorders and respective clinical features. Table 1

Detection of epidermal lipid barrier damage is performed via dermatoscopy (dampness/dryness, oiliness, pH) and sciasopy (dispigmentation ratio and microrelief studies). Transepidermal water loss is measured with Tewameter® TM 300 probe, Courage + Khazaka electronic GmbH, Germany. Sciascopy is performed with MoleView SIAscope V Handset, Astron, United Kingdom, and for dermatoscopy is done with HEINE alpha+, Heine Optotechnic, Germany. In testing, data on multiple characteristics is analysed and reflect the state of epidermal lipid layer [8-1 1]:

^• coriicometry (skin dampness, stratum corneum water content), performed with a dermatoscope. Corneometry is based on capacitance measurement in a dialectric medium. Any change of dielectric constant under water amount fluctuations in superficial skin layers leads to capacitance change. Dampness is measured on a scale, a base for which is dielectric capacitance of water - 81. Usually, skin dampness is classified in 4-6 grades (very high 45-99.0, high-normal 35.1-40.0, reduced-low 20.1-29.9, dehydrated - lower than 20.0);

^• transepidermal fluid loss - water evaporation measurement at the skin surface, based on open-chamber diffusion. Method is based measurement of partial water pressure in a closed chamber with a single humidity probe. An increase in partial water pressure in the chamber in a certain amount of time;

^• acid-base balance, pH meter - pH meter is equipped with high precision glass electrode;

• sebumetry - skin oiliness measurement in various areas. This method is based on photometry. A polymer film is used, that becomes a selective lipid absorbent. This film is then placed in a photometer before and after applying a probe to the skin surface. Measurements are carried out in mkg/cm2. Sebumetry is not dependent on skin dampness. The probe consists of three components, one of which is matte paper, sensitive to fatty components that reacts only to sebum and absorbs it. The microprocessor interprets acquired change of colour and detects type of skin (dry, normal, oily or combined)

• mexametry (evaluation of various pigments in the skin)- enables measurement of melanin in the skin and erythema amount. Method is based on different waavelength absorption of light spectrum by the skin. Mexametry is especially useful in quantitative allergy and inflammation evaluation under UV-induced damage.

• microrelicf studies via microphotography - equipping digital tools for relief and microstructure evaluation allows for further data reevaluation and comparison through treatment.

As of now, we know of cosmetic compositions for treatment and prophylaxis of UV-induced skin dryness. Known compositions are mixtures of plants and various oils [12-14]. UV-related prooxidative influence may be corrected with vitamins- antioxidants [15-21]. Retinoids are widely used in UV-induced damage prophylaxis [22]. Local use of selenomethionine cream under sun exposure is known for skin cancer prevention [23]. Ceramides-rich moistening cream is frequently used in children with atopic dermatitis [24].

Moistening creams are widely known in managing dry skin [25-26]. Tocopherol is also used in creams used specifically for UV protection [27].

All of moistening solutions known to us indeed help with dry skin and alleviate most of symptoms through water volume increase, but do not restore, or solve the problem of epidermal lipid barrier in patients with metabolic syndrome.

As a temporary mean of restoring of said barrier, petroleum jelly may be used [28]. Petrolatum and derivatives are used after medical or cosmetic procedures that feature removal of corneal stratum (laser grinding, dermabrasion, mechanical epidermis removal, peeling). A disadvantage of petrolatum is a very low absorbability, due to which it covers the skin with a greasy layer that reduces its usage, and strong occlusive effect (blocks evaporation), which leads to reduction of skin permeability and other complications. Use of petrolatum is recommended only in severe damage to epidermal layer, when an overwhelming skin cell reaction is expected due to loss of external protection, and in cases when the skin itself is not able to sustain full barrier. In other cases blocking evaporation through horny layer is strongly discouraged.

Fatty emulsion, that provides simultaneous moistening and nutrition to the skin is well researched [29]. Said emulsion does not protect from ageing that is related to free radicals induced damage of the skin in patients with metabolic syndrome.

Selenium and vitamin E cream [30], being wax stabilised, highly dispersed mink oil and water emulsion, does not prevent damage to the lipid layer in patients with MS. Also worth noting that prolonged use of this composition with a higher water amount may slow down stratum corneum restoration, which works unfavourably for patients with metabolic sydrome [31]. Compositions based on plant extracts and oils are not known for restoring lipid layer in patients with MS [32-36].

Finally, the solution that restores epidermal lipid layer in patients with metabolic syndrome is not yet known.

Disclosure

Goal and the technical result of the invention is:

development of a cream that restores epidermal lipid barrier and lipid layer of facial skin, neck and decollete for use in patients with metabolic syndrome, that also prevents free-radical induced damage to lipid layer under latent inflammation under metabolic syndrome.

Milestones:

• Search for components of a novelty composition and their ratios

• Design of cream preparation technology

• Optimal cream form development

Set goals are achieved through the design of a specific cream composition, which contains seleno-L-methionine, Vitamin E alpha-tocopherol, squalane, methyl hydroxybenzoate, glycerol monostearate 60, cetyl alcohol, middle chain triglyceride, white petrolatum, macrogol-20-glycerol monostearate, 1 ,2-propanediol and distilled water. Correspondingly, the cream contains seleno-L-methionine, Vitamin E alpha- tocopherol, squalane, methyl hydroxybenzoate, glycerol monostearate 60, cetyl alcohol, middle chain triglyceride, white petrolatum, macrogol-20-glycerol monostearate, 1,2-propanediol and distilled water in the ratio of components, mass g (%):

seleno-L-methionine 0,0005 - 0,0015;

Vitamin E alpha-tocopherol 0,50 - 1 ,50;

squalane 1 1 ,25 - 18,75; methyl hydroxybenzoate 0,05 - 0,15;

glycerol monostearate 60 2,52 - 4,20;

cetyl alcohol 3,78 - 6,29 middle chain triglyceride 4,72 - 7,87;

white petrolatum 16,05 - 26,74; macrogol-20-glycerol monostearate 4,40 - 7,34;

1 ,2 -propanediol 6,29 - 10,49; distilled water up to 100 %.

Cream is composed as a white or yellow tinted homogenous mass with pleasant odor, according to its fatts used in composition. All cream components are permitted for use as pharmaceuticals.

Cream is designed for restoration of epidermal lipid barrier of facial skin, neck and decollete area in patients with metabolic syndrome.

Detailed description of cream composing ingredients

Seleno-L methionine (Selenomethionine, Se-Met (SEM)— selenomethionine L-enantiomere, naturally-occurring selenium containing amino acid, notable source of selenium. Selenomethionine functions as a bioantioxidant, interacts with vitamins, enzymes, biological membranes in biosystems and an organism as a whole. Interacting with glutationperoxidase, it neutralises oxides and peroxides, protects cell membranes from destruction, works as an antihistamine, stimulates collagen and keratin biosynthesis. Not only it makes skin more elastic and resilient, it also lowers seborrheic events, activates skin regeneration and restores epidermal structure. Inorganic selenium, selenium disulfide, is used in scalp seborrhea [37]. As accepted in the US, selenium recommended daily allowance for an adult is 50-220 mkg, and in China no toxicity was noted when intake reached 750 mkg, with intoxication symptoms apearing when daily selenium intake was around 5000 mkg [38].

Selenomethionine is a hydrophilic substance, and its optimal amount in the cream is 0,0005-0,0015 g. With its amount lower than 0,0005 g, antioxidant action was also lowered and with amount higher than 0,0015 g it was difficult to produce the cream due to change in consistency and excessive lamination, with cream becoming less homogenous.

Squalane - naturally-occurring hydrocarbon of carotinoid group that resembles transparent oil with no colour or odor. Squalane does not have double bonds, thus being chemically stable and may be stored for over 2 years, does not oxidize and rancidify. Squalane is synthesized in sebaceous glands, is a major component of sebum and water-lipid mantle of the skin. According to demiatocosmetology, squalane is a high-grade emollient. In contrast to triglicerydes and sebum fatty acids, squalane is non-comedogenic [39-40]. On application, squalane spreads easily, forms a protective film that prevents moisture loss and enhances skin breathing. Bearing natural similarity to the skin itself, squalane easily transfers through epidermis, does not leave trace of oiliness, all while giving the skin a softer and silky feel. Squalane is hydrophobic, takes active role in metabolism and bological steroid synthesis, possesses antibacterial properties and helps prevent ageing spots.

Optimal squalane content in the cream is 11,25 - 18,75 g. If squalane is less than 1 1 ,25 g, its smoothing and skin restoring properties were markedly reduced, and more than 18,75 g of squalane introduced difficulties in cream synthesis as decrease in compositional stability and lamination.

Vitamin E alpha-tocopherol - light-yellow, transparent, viscous fluid with low odor. On exposure to sunlight it oxidizes and darkens. Tocopherol is a hydrophobic agent, is found in green parts of plants, vegetable oils and is a natural antioxidant. It takes part in inactivation of free radical goups, protects cell membranes from destruction, especially under UV radiation, has an active role in protein biosynthesis, makes skin elastic and firm, prevents irritation, lowers chance of seborreic events, activates skin regeneration [41]. Introduction of Vitamin E into the composition allowed for a faster epidermal lipid layer regeneration in patients with metabolic sndrome. Optimal alpha-tocopherol (Vitamin E) content in the composition is 0,50 - 1,50 g. When Vitamin E is less than 0,5 g, its effects were markedly reduced and when it was more than 1,5 g, consistency of the cream changed, it becoming less viscous.

Methyl hydroxybenzoate, (methyl paraben) CH3(C₆H₄(OH)COO - white or cream-coloured crystalline powder, poorly soluble in cold water, soluble in wark water, ethanol and propylenglycole. Possesses wide spectrum of antibacterial and antifungal properties, naturally occurs in several plants, i.e in blueberries. It is used to counter Gram-positive bacterias, molds and Gram-negative bacterias [42]. In human body, methyl parabens is absorbed easily and fully through skin or gastrointestinal tract and breaks down into simple substances and is rapidly excreted with urine without accumulation in the organism. In composition, methyl paraben is used as a stabilizer and/or prolonger and effective in very low concentrations, pure form and as a 0,25%-5% alcohol solution. Optimal amount of methyl paraben is noted at 0,05 - 0,15 g. When its amount was lower than 0,05 g, stabilizing effect was reduced dramatically and when it was more than 0,15 g, consistency of the cream changed with insoluble inclusions being present and visible.

Glycery monostearate 60 - white powder, obtained from naturally occurring stearic acid and glycerol. It is a pearlescent (light reflecting), waxlike emollient, emulsifier and thickener, which was added during stabilization phase to form a homogenous emulsion. Glyceryl monostearate 60 is used as a stabilizer and structuring component to prevent separation of hydrophobic and hydrophilic phases of the composition [43]. With it being less than 2,52 g, thickening effect was markedly reduces and if there was more than - 4,20 g, the composition turned excessively thick, which introduced difficulties in application.

Cetyl alcohol, 1-hexadecanol, ΰΗ₃(Ο¼)₁₄Ο¾0Η - long chain, fatty alcohol, a solid white substance that is used as fatty base emulsifier and/or opacifier. It enhances consistency, increases water-in-oil stability [44]. Recommended amounts are 3,78 - 6,29 g. When the amount of cetyl alcohol is less than 3,78 g, emulsifying properties were reduced and cream laminated. When its amount was more than 6,29 g, composition became fluent.

Medium chain triglycerydes - oily fluid, obtained from coconut oil, water- insoluble, can be mixed with other oils [45]. It enhances cream spreadability, dissolves lipophilic components. Recommended amounts to use are 4,72 - 7,87 g. If the composition had less than 4,72 g of medium chain triglycerides, the cream laminated markedly and in there was more than 7,87 g of said triglycerides, the cream became more fluent.

White petrolatum - a semi-solid hydrocarbon mixture obtained through mixing white ceresine and paraffin with fragrance oils [46]. Soft paraffin is used as a thickener in skin cream and ointment design. External use of petrolatum restores water-lipid protective mantle of the skin, prevents loss of fluid by the cells, reduces scaling and cracking of the skin. Petrolatum is used to soften facial and hand skin, especially in environment-induced damage (sun, wind, temperature fluctuations). With its amount in the composition less than 16,05 g, its thickening effects were less pronounced and over 26,74 g cream consistency changed for markedly thicker.

Macrogol-20-glycerol monostearate (HO-(CH2^~CH2^~0)„-H) - white powder that forms hydrogen bonds with water molecules. It is used in medicine and cosmetics as a bonding, structuring and stabilizing component that introduces smoothness to the composition [47]. High degree of hydrophyly allows for an effective homogenization of the composition in amount 4,40 - 7,34 g when emulsifying cream hydrophobic components. With it being less than 4,40 g, thickening effect was markedly diminished and when macrogol was more than 7,34 g, cream consistency turned excessively thick, which made the cream difficult to apply.

1,2-propanediol fCH3CH(OH)CH20H) - organic substance, colorless hygroscopic, odorless fluid that keeps moist, softens and disperses, and is a good solvent [48]. Most of low-molecular organic compounds mix with 1,2 propanedion easily, especially those containing oxygen and nitrogen. With its amounts less than 6,29 g, thickening effect was markedly reduced and when its amount was over 10,49 g cream became excessively thick.

Aqua - basic component of water-in-oil emulsion. Recommended use is 33,0- 34,6 g. When it was less than 33,0 g, thickening effect was markedly reduced. When the amount of aqua was more than 34,6 g, cream became excessively thick, which made it difficult to use and apply.

Novelty cream composition was successfully used to obtain dosage forms into the tin tubes of 65,0 g and/or 30,0 g.

All components of the novelty cream are permitted for use as separate pharmaceuticals in dermatology in ranges stated in current disclosure.

Composition of the novelty cream and production technology corresponds to standards of REGULATION (EC) No 1223/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 30 November 2009 on cosmetic products, Article 11.

Composition example I-II

Composition includes:

seleno-L-methionine 0,0005-0,0015; Vitamin E alpha-tocopherol 0,50 - 1 ,50; squalane 1.1 (,25 1 Hg'ZSg methyl hydroxybenzoate 0,05 - 0,15;

glycerol monostearate 60 2,52 - 4,20;

cetyl alcohol 3,78 - 6,29;

middle chain triglyceride 4,72 - 7,87;

white petrolatum 16,05 - 26,74; macrogol-20-glycerol monostearate 4,40 - 7,34;

1,2-propanediol 6,29 - 10,49; distilled water up to 100 %.

Cream development method

Difficulty in manufacturing a novelty composition was in squalane, glycerol, triglycerides, petrolatum and alpha-tocopherol being hydrophobic agents and selenomethionine, macrogol and propanediol being hydrophilic agents.

Method of manufacturing of a cream 1^st composition

1. Cream hydrophobic part manufacturing: hydrophobic part of the cream was produced by melting 2,52 g of glycerol monostearate 60 and 3,78 cetyl alcohol under 65-70°C, then adding melting 16,05 g of petrolatum, then adding 11,25 g of squalane and 4,72 g of medium-chain triglycerides, then stirring until homogenous. Composition must be 60°C.

2. Production of hydrophilic part of the cream is the following: dissolve 6,29- 10,49 g of 1,2 propanediol and 0,05-0,15 g of methyl paraben at 45-50°C in heat-resistant glassware, add remaining distilled water (aqua), stir, add 4,40-7,34 g of macrogol-20-glycerol monostearate, dissolve through heating to 60°C.

3. Add hydrophobic part to hydrophilic in cream production container, stir with specialized equipment for 15-20 min until the substance cools down to 30-35°C.

4. Then, add 0,50-1,50 g of alpha-tocopherol acetate and 0,0005-0,0015 g of selenium-L-mcthionine (dissolved in residual distilled water) to obtained mass. Stir the cream with specializes stirring equipment for 10 minutes until homogenous. Production of second cream composition is equal to the first composition. Cream is composed as a white or yellow tinted homogenous mass with pleasant odor, according to its fatts used in composition. Obtained cream is packed in opaque containers (tin tubes) in 65,0 and 30,0. Cream is intended for use in patients with metabolic syndrome with the aim of restoring epidermal lipid layer of facial skin, neck and decollete area. Cream possesses good component biocompatibility, is easily absorbed by the skin, cover the skin in thin elastic layer, has pH of 4,0-5,0. It also exhibits soothing effects, reduces irrtation and in prolonged use does not cause adverse reactions.

To evaluate cream efficacy in epidermal lipid layer damage prophylaxis and/or treatment in patients with metabolic syndrome, we performed a prospective clinical trial based in dermatology and esthetic medicine clinic "LIPEX" (Riga, Latvia). On the basis of informed consent, volunteers were invited to take part in the trial. We invited male and female metabolic syndrome patients aged from 39 to 55 years of age, non-smokers, who do not visit tanning salons, with moderate sun exposure (spend whole summer season under Central and Northern Europe conditions). We then selected 2 homogenous groups (group 1, n=12; group 2, n=15) of patients with diagnosed metabolic syndrome. Metabolic syndrome diagnosis was based on the US National Institute of Health criteria [1] and presence of three or more symptoms:

• abdominal obesity with waist circumference over 88 cm for female patients and over 102 cm for male patients

• fasting blood glucose level over 6.1 mmol/L

• blood triglyceride level over 1.69 mmol/L

• high density lipoprotein level lower than 1.29 mmol/L in female patients lower than 1.04 mmol/L

• arterial blood pressure over 135/85 mmHg

Trial protocol, informed written consent form and participation questionnaire were in concordance with Helsinki Declaration on humanity principles in medicine and were approved by Riga Stradins University Ethics Committee, Latvia. We report no conflict of interest. After preliminary clinical evaluation, we prescribed Group 1 (n=12) patients the cream for prolonged use (2 months, for the period of most active sun exposure, May- June). Cream was applied in thin layer 2 times per day (in the morning and in the evening) on clean facial skin, neck and decollete areas. We did not prescribe any cream to Group 2 patients. Clinical evaluation was repeated in both groups in 14, 30 and 60 days from the start of cream use.

Clinical trial included anthropometric data (BMI, waist circumference, arterial blood pressure), blood sample tests (glucose, lipoproteins). To evaluate epidermal lipid layer of the skin sciascopy and dermatoscopy was performed utilizing MoleView SIAscope V Handset, Astron, United Kingdom, and HEINE alphas, Heine Optotechnic, Germany, respectively.

State of skin relief and morphology (turgor, microrelief, papillomas) were evaluated through dermatoscopy. Pigmentation and exfoliation was detected with sciascopy. Measurements of skin pH were performed with a pH meter. Transepidermal fluid loss, tevametry, was evaluated with Tewameter® TM 300, Courage + Khazaka electronic GmbH, Germany. We perfomed data evaluation and quantification in database and statistics software SPSS 20.0, IBM, USA. Results were registered as numerical values. Range of normal values for comeometry was starting with 40 to highest, for tevametry it was less than 12, pH measurement interval was 5,5-5,8 pH. Each sign was evaluated on a scale from 0 to 3 with 0 indiacating absence of the sign, 1 - low expression, 2 - moderate expression and 3 for prominent expression.

We also evaluated structural changes and skin immunity through performing histologic research with 400x magnification light microscopy and immunohistochemistry of punch-bioptates. Immunohistochemistry included CD la, CD31, CD34, CD3, CD8.

Table 2 represents both groups results:

Group 1, n=12 Group 2, n=15

With cream No cream

Skin turgor (0-1-2-3 scale) Medium, high Medium, low

Hydration 27,2±1,1 19,1 +1,2

transepidermal loss of water

Co neometry

Exfoliation (0-1-2-3 scale) Average index 1,8 Average index 2,6

Large cells N=34,4% Large cells N=<¾ 7±5%

Lentigo, uneven Average index 1 ,2 Average index 2,8 pigmentation(0- 1 -2-3

scale)

pH 5,5-5,8 5,4-5,6

Skin morphology and Average index 1 ,6 Average index 2,8 relief (0-1-2-3 scale)

During clinical examination in the beginning of the trial majority of patients from both groups complained about dryness and exfoliation. Then, after 2 months of the new cream use the following data were obtained (group 1 , n=12): 1) hydration was 27, 2 ± 1, so, higher compared with patients from group 2 (n=15): 19,1 ± 1,2; 2) exfoliation - 1.8 for patients of Group 1 and 2.6 - for patients of group 2, ie peeling more pronounced in patients in group 2; 3) pigmentation - 1.2 for patients of Group 1 and 2.8 - for the second group; indeed, pigmentation is more pronounced in patients of group 2; 4) skin relief - 1.6 for the first group and 2.8 for patients in group 2; the presence of papillomas and skin elastosis was more pronounced in patients in group 2. Thus in patients of Group 1 , who applied a new cream for 2 months, improvement of the barrier function of the skin, its relief and elasticity was ascertained. According to data obtained in the study of skin immunity by means of immunochistochemistry, activity of Langerhans cells (the cells of skin immunity) in patients of the 2^nd group was reduced. In addition, marked lymphocytic infiltration and accumulation of Birbeck granules (evidence of inflammation) was revealed in the skin of 2^nd patients group (no cream applied). But 1^st group patients (cream was applied) demonstrated increase of immune competent Langerhans cells, number of Birbeck granules reduced by half, indicating improvement of the local skin immunity.

Studies have confirmed that the cream of the new formulation has a cosmetic and medical - preventive properties, restores epidermal lipid barrier of the skin and skin barrier function in patients with the metabolic syndrome: improves turgor and hydration of the skin, restores elasticity and smooth skin relief, reduces the phenomenon of pigmentation, inflammatory papilloma.

Difficulty in inventing the cream was due to lack of knowledge on parts and proportions of the composition, with which an effective epidermal lipid layer restorative action could be achieved. Additional difficulties were due to some parts of novelty composition being hydrophilic (selenomethionine) and some being hydrophobic (Vitamin E, squalane). We lacked knowledge on conditions, under which hydropholic and hydrophobic components may be combined into a cream with high greasiness. Experimentally discovered components, their relations and technologic conditions of the novelty solution allowed to produce a homogenous cream that retains its efficacy and spable consistency for 6 to 8 months in room temperature.

Novelty cream composition represents a mixture of water and fats, fat-like and other compounds. High percentual fat and fat-like substance content is crucial in achieving epidermal bilipid layer restoration and its water-lipid mantle. Technologically it is difficult to combine such amounts of fats without the risk of lamination of end-product. For creams of this type, it is important to use specialized emulsifiers, which, when introduced in stated amounts, provide smoothness and cream-like consistency of the novelty composition. Stability under storage and good extrusion of a finished medicinal form from a container (tin tube) is crucial for patient use.

The stand-out feature of our composition is the use of several structure defining emulsifiers. Simultaneous use of these emulsifiers and their strictly sequential introduction in a technique described in the disclosure, provide a prominent and stable effect of complex cream composition preservation. Presence of specific hydrophilic components (aqua, selenomethionine, glycerol) and specific ratios of solvents (cetyl alcohol, glycerol), allows to retain the activity of hydrophilic (selenomethionine) and hydrophobic (tocopherol, squalane, triglicerides) active substances that form the cream.

We did not find mention of the composition of described novelty cream in scientific, technical and patent information sources. Performed experimental and clinical trials provide an insight on presence of "inventional level" criteria. INDUSTRIAL APPLICABILITY

We developed 2 industrial packaging forms of the cream in 65,0 g and 30,0 gue tin tubes. Stability and technological qualities of novelty cream is retainedonths at room temperature.

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Claims

>ERMAL LIPID BARRIER RESTORING CREAM FOR FACIAL SKIN,NECK AND DECOLLETE AREA FOR METABOLIC SYNDROME PATIENTS CLAIMS

1. Epidermal lipid barrier restoring cream for facial skin, neck and decollete area for metabolic syndrome patients, characterized in that it contains seleno-L- methionine, a-tocopherol, squalane, methyl hydroxybenzoate, glycerol monostearate 60, cetyl alcohol, middle chain triglyceride, white petrolatum, macrogol-20-glycerol monostearate, 1 ,2-propanediol and distilled water. Correspondingly, the cream contains seleno-L-methionine, Vitamin E alpha- tocopherol, squalane, methyl hydroxybenzoate, glycerol monostearate 60, cetyl alchol, middle chain triglyceride, white petrolatum, macrogol 20 glycerol monostearate, 1 ,2-propanediol and distilled water.

2. Epidermal lipid barrier restoring cream for facial skin, neck and decollete area for metabolic syndrome patients, according the first claim, characterized in that it contains the seleno-L-methionine, Vitamin E alpha-tocopherol, squalane, methyl hydroxybenzoate, glycerol monostearate 60, cetyl alcohol, middle chain triglyceride, white petrolatum, macrogol-20-glycerol monostearate, 1 ,2-propanediol and distilled water in the following ratio of components, mass g (%):

seleno-L-methionine 0,0005-0,0015 ;

vitamin E alpha-tocopherol 0,50-1 ,50;

squalane 1 1 ,25-18,75;

methyl hydroxybenzoate 0,05-0, 15 ;

glycerol monostearate 60 2,52-4,20

cetyl alcohol 3,78-6,29

middle chain triglyceride 4,72-7,87;

white petrolatum 16,05-26,74;

macrogol-20-glycerol monostearate 4,40-7,34;

1 ,2-propanediol 6,29-10,49;

distilled water up to 100 %.