Preparation and its application in atopic dermatitis in children

Abstract

A preparation consisting of active components made up of fish oil (as a source of omega-3 fatty acids, i.e. EPA and DHA), blackcurrant seed oil (as a source of omega-6 fatty acids, i.e. GLA) and vitamin D3, which has synergy action on skin disorders in children, such as skin inflammation, itching, eczema, atopic dermatitis because it allows the use of lower individual doses of each active ingredient that target different points in the skin inflammation process.

Description

[0001] PREPARATION AND ITS APPLICATION IN ATOPIC DERMATITIS IN CHILDREN

[0002] FIELD OF INVENTION

[0003] The subject invention relates to the field of pharmacy and cosmetics, in particular, it relates to a preparation consisting of active components made up of fish oil (as a source of omega-3 fatty acids), blackcurrant seed oil (as a source of omega-6 fatty acids) and vitamin D3, and to the pharmaceutical application thereof in the treatment and / or prevention of skin disorders in children, such as skin inflammation, itching, eczema, atopic dermatitis. According to the International Patent Classification (IPC, 2022), the subject invention holds designation A61K 9 / 00, A61 K 9 / 51 , A61K 31 / 12, A61 K 36 / 15, A61 K 47 / 24 (2006.01) A61 K 47 / 44.

[0004] TECHNICAL ISSUE

[0005] The subject invention solves the technical issues of the method of obtaining a preparation with distinct properties in improving the function and appearance of the skin using an appropriate amount of omega-3 fatty acids, omega-6 fatty acids and vitamin D3 for the treatment and / or prevention of skin disorders in children, such as atopic dermatitis.

[0006] STATE OF THE ART

[0007] Atopic dermatitis is a very common skin disease that has been increasing in the population over the years. It occurs equally in adults and children. Although atopic dermatitis may occur at any age, it most often occurs in infants and children. As children with atopic dermatitis grow up, in some children their skin condition improves or the disease goes away, although their skin often remains dry and easily irritated, while in others, atopic dermatitis continues to be a significant issue reflected in certain limitations in quality of life. Atopic dermatitis is characterized by disruption of the skin barrier and transepidermal water loss, which allows the penetration of allergens, irritants and pathogens that lead to inflammation.

[0008] The symptoms of atopic dermatitis include: skin inflammation, red or brownish skin patches, itchy skin especially at night, and dry, cracked or scaly skin. Although each person with atopic dermatitis experiences a unique combination of symptoms, which may vary in severity over time, the most common ones are dry, itchy skin and rashes on the face, inside the elbows and behind the knees, hands, and feet. Itching is the main symptom of atopic dermatitis. Scratching and rubbing in response to itching irritate the skin, increase inflammation and actually make the itching worse. Itching is particularly troublesome during sleep when conscious control of scratching is lost. The appearance of skin affected by atopic dermatitis depends on the intensity of scratching and the presence of secondary skin infections. The skin may be red and scaly or thick and leathery, contain small bumps or ooze fluid and become crusted and infected. Other skin features that may occur in some people with atopic dermatitis include the following:

[0009] - atopic fold (a Dennie-Morgan fold): an extra fold of skin that develops under the eye

[0010] - cheilitis: inflammation of the skin on and around the lips

[0011] - hyperlinear palms: increased number of skin folds on the palms

[0012] - hyperpigmented eyelids: eyelids that have become darker in color due to inflammation or hay fever

[0013] - ichthyosis: dry, rectangular scales on the skin

[0014] - keratosis pilaris: small, rough bumps, mostly on the face, upper arms and thighs

[0015] - lichenification: thick, leathery skin resulting from constant scratching and rubbing

[0016] - papules: small raised bumps that may break open when scratched and become crusted and infected

[0017] - urticaria: hives (red, raised bumps) that may occur after exposure to an allergen, at the onset of a seizure, or following exercise or a warm bath.

[0018] The skin of people with atopic dermatitis is more prone to irritation and infections. The outer layer of the skin, called the epidermis, is divided into two parts: the inner part, which contains moist living cells, and the outer one, known as the stratum corneum, which contains dry, flattened, dead cells. Under normal conditions, the stratum corneum acts as a barrier, preventing the rest of the skin from drying out and protecting other layers of the skin from damage caused by irritants and infections. When this barrier is damaged, irritants act more intensively on the skin and a person's skin is more likely to become infected with bacteria or viruses.

[0019] In most cases, there are times when the disease worsens (recurrence) and then ones when the skin improves or cleans completely (remissions). Atopic dermatitis is a grave and often chronic impairment of the quality of life of sufferers. A baby with atopic dermatitis may be restless and irritable due to itching and discomfort.

[0020] Atopic dermatitis also involves high treatment costs and currently there is no known preparation that will completely cure atopic dermatitis. Although treatments may reduce the severity and frequency of seizures, a variety of medications are used to treat atopic dermatitis. Namely, topical corticosteroids and ointments have been used for many years to treat atopic dermatitis. However, due to their side effects, these medications are used only in resistant cases and administered only for a short period of time. Certain drowsy antihistamines may reduce nighttime scratching and allow for more restful sleep when taken at bedtime, but they are not as potent as other agents and may only be used as adjunctive therapy. Topical calcineurin inhibitors are also used because they reduce inflammation in the skin and help prevent seizures. However, these compounds have side effects. Other treatment options include barrier repair moisturizers to reduce water loss and work to repair the skin, as well as phototherapy, but these options may only be effective for mild to moderate dermatitis. Because of the shortcomings of known atopic dermatitis treatments, researchers are trying to find new therapies.

[0021] In view of the above, it can be seen that there is still a need for the treatment of atopic dermatitis, especially for a treatment that is safe, effective, easy to use and incurs lower costs.

[0022] Multiple studies show the positive effects of using omega-3 and omega-6 fatty acids in the treatment of various diseases, including atopic dermatitis. The omega-3 fatty acid itself has a strong anti-inflammatory effect that reduces symptoms and works effectively in atopic dermatitis by suppressing the activity of immune cells that cause atopic dermatitis. Whereas omega-6 fatty acid works on the skin itself by improving firmness and elasticity. Namely, as the skin consists of several protective layers structured to retain moisture and prevent the penetration of harmful cells, it is very important to reduce transepidermal water loss (TEWL), i.e. to prevent drying of the skin, which is one of the main side effects when it comes to atopic dermatitis. Precisely by using omega-6 fatty acid, this water loss is reduced by strengthening the protective barrier of the skin.

[0023] In GB 2 453 157 A1 , eicosapentaenoic acid is combined with other substances to form a composition for the treatment of skin diseases, including atopic dermatitis and eczema, which is applied topically, while the present invention is applied orally.

[0024] Patent applications EP2046309, WO 2008 / 012645 and WO 2015 / 042442 describe preparations containing DHA, EPA and / or GLA where fatty acids and vitamin D3 are isolated individually, while in the present invention there is a combination of DHA, EPA and GLA with synergy action on atopic dermatitis, which makes a clear difference in relation to the aforementioned documents. This synergy enables greater effectiveness of the subject combined preparation, as well as fewer potential side effects because it allows the use of lower individual doses of each active ingredient targeting different points in the process of developing atopic dermatitis than it would be the case in a preparation containing a single, individual active ingredient, such as in the mentioned documents.

[0025] A recent research shows that vitamin D can regulate the adaptive and innate immune response in various inflammatory and autoimmune diseases, and that it has the ability to express more than 200 genes, including those in the gut microbiome, where vitamin D receptors are abundant, showing that vitamin D has an effect on both the immune system and the function of the skin barrier. Namely, the active metabolite of vitamin D has an antiinflammatory effect on human monocytes and macrophages by down-regulating the expression and production of several pro-inflammatory cytokines including TNF-a, IL-1 b, IL-6 and IL-8. It plays a role in maintaining immune tolerance through the mediation of other cytokines by reducing the release of pro-inflammatory cytokines from Th1 cells and inhibiting the release of IgE by reducing B cell function. Adaptive and innate immune responses include mucosal macrophages and dendritic cells capable of synthesizing biologically active vitamin D, modulating host-microbe interactions, cell differentiation and proliferation, and susceptibility to pathogenic infections. This is very important in maintaining a healthy microbiome, indicating that the immune system and the microbiome are interconnected, and that vitamin D is a critical mediator in this sequence.

[0026] Based on all of the above, it can be seen that omega-3 and omega-6 fatty acids as well as vitamin D3 are crucial for the function and appearance of the skin, and therefore dietary supplements containing them may have positive effects in patients with atopic dermatitis. As a result, the addition of various oils rich in omega acids and the addition of vitamin D3 may modulate the inflammatory response in the dermal and epidermal layers of the skin.

[0027] SUMMARY OF THE INVENTION

[0028] It was surprisingly found that a preparation containing the active components of fish oil, blackcurrant seed oil and vitamin D3 shows a synergistic effect in inhibiting inflammatory skin conditions, especially atopic dermatitis. Due to this synergy, the amount of active components needed to achieve the desired pharmacological effect is such that it reduces any possible side effect, makes it easy to use and / or reduces the cost of treatment. The preparation containing the active components of fish oil, blackcurrant seed oil and vitamin D3 affects the formation of a lipid layer on the surface of the skin that reduces water loss, and thus improves skin hydration, by acting as a barrier preventing the entry of bacteria and allergens and strengthens the immune system. The preparation with active components according to the present invention is packaged in a bottle as oil with a dosing cup or spoon. DETAILED DESCRIPTION OF THE INVENTION

[0029] The subject invention provides a preparation that contains omega-3 fatty acids (EPA and DHA), omega-6 fatty acid (GLA) and vitamin D3 as active components. The preparation itself is in the form of oil with added natural lemon flavor for a more covenient application in children aged 6 months to 3 years.

[0030] Omega-3 and omega-6 fatty acids in the body are precursors of biologically active substances known as eicosanoids. Eicosanoids are powerful mediators of multiple biochemical processes and play an important role in coordinating physiological interactions between cells, but eicosanoids derived from omega-3 and omega-6 fatty acids differ in intensity and sometimes in the type of effectiveness. Eicosanoids formed from omega-3 fatty acids, i.e. from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have a milder and more favorable effect on the body. They are generally less inflammatory, inactive or even anti-inflammatory. Eicosanoids derived from omega-6 fatty acids, i.e. from arachidonic acid (AA), generally promote inflammatory processes, while eicosanoids derived from omega-6 fatty acids, i.e. from gamma-linoleic acid (GLA), suppress inflammatory processes. Taking the foregoing into account, the balance between pro-inflammatory and anti-inflammatory eicosanoids is crucial, and therefore the application of appropriate dietary supplementation, containing omega-3 fatty acid and GLA, may stimulate the production of anti-inflammatory eicosanoids and reduce the inflammatory effects of eicosanoids from AA by three mechanisms: displacement, competitive inhibition and counteraction.

[0031] Omega-3 fatty acids are important for the human body because they reduce inflammation and can help prevent chronic diseases. They may also be important for brain health and development, as well as for normal growth and development. Omega-3 fatty acids that are important from the point of view of nutrition are a-linoleic acid (ALA), eicosapentaenoic acid (EPA) and decosahexaenoic acid (DHA), whereby a-linoleic acid (ALA) is mainly found in foods of plant origin, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in fish and fish oils. a-Linoleic acid (ALA) is a very significant nutrient because it cannot be produced by the human body, but when taken into the body, it can be used to form eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the efficiency of converting ALA into EPA and DHA is very poor, and therefore EPA and DHA must be taken additionally.

[0032] In the subject invention, purified fish oil is used as a source of omega-3 fatty acids, i.e. EPA and DHA, and such fish oil is obtained from wild fish from the South Pacific due to its extremely low level of heavy metals. Compared to the levels of heavy metals set by GOED (Global Organization for EPA & DHA omega), the amount of heavy metals of the subject invention is the following: less than 0.001 mg / kg of Pb, less than 0.001 mg / kg of Cd, less than 0.001 mg / kg of Hg and less than 0.01 mg / kg of As, while according to GOED the amount of Pb is less than 0.05 mg / kg, the amount of Cd is less than 0.1 mg / kg, the amount of Hg is less than 0.1 mg / kg and the amount of As is less than 0.1 mg / kg. The reason for using fish oil as one of the active ingredients of the preparation is that fish oil is the only oil in which it is possible to achieve an optimal ratio of EPA and DHA of 3:2 (so that in 2 g of oil there is 1 g of EPA and DHA in a 3:2 ratio). The use of omega-3 fatty acids, i.e. EPA and DHA, according to the present invention, is reflected in the reduction of inflammatory processes on the skin, such as atopic dermatitis, and the maintenance of an appropriate level of hydration that protects the skin from drying out, which is essential for skin health.

[0033] The amount of EPA and DHA in the present invention ranges from 550 mg to 650 mg and from 350 mg to 450 mg, for EPA and DHA, respectively.

[0034] According to the present invention, the active component is gamma-linolenic acid (GLA), which is structurally an omega-6 fatty acid. GLA is a precursor to prostaglandins, which are eicosanoids (biologically active compounds) that regulate various physiological processes, including inflammation and immune responses. Prostaglandins that are formed from GLA usually have anti-inflammatory properties and can help suppress inflammation. For example, in skin diseases, GLA can help maintain skin hydration and thus reduce itching and redness on the skin. Since GLA is an essential fatty acid, meaning the body cannot produce it on its own, it must be taken through diet or dietary supplements.

[0035] According to the present invention, the source of gamma-linolenic acid (GLA) is blackcurrant seed oil (Ribes nigrum) because it contains a very high amount of GLA compared to other oils. Blackcurrant seed oil contains 13-17% gamma linolenic acid, while evening primrose oil contains 8-10% GLA. Blackcurrant itself has a high concentration of anthocyanins, polyphenolic substances, antioxidants, vitamin C and vitamins A, B5, B6, B1 , E. Therefore, blackcurrant seed oil, in addition to being used to support skin health and relieve the symptoms of atopic dermatitis, has a moderate immune-enhancing effect that may be attributed to its ability to reduce prostaglandin E2 production.

[0036] The amount of GLA in the present invention ranges from 5 mg to 15 mg.

[0037] Vitamin D3, also known as cholecalciferol, is a form of vitamin D. It is an essential vitamin substance that plays a key role in various biological processes and is important for maintaining health and preventing various health issues. It plays an important role in the regulation of the immune system and inflammatory processes by helping the body defend itself against infections and inflammation and can support the function of immune cells such as T-lymphocytes. In this way, the inflammatory and vascular response of the skin is improved, and secondary skin infection is reduced. The amount of vitamin D3 in the present invention ranges from 2.5 pg to 5.5 pg.

[0038] According to the subject invention, the ratio of EPA:GLA in the composition is 60:1 (EPA:GLA), while the ratio of EPA:DHA = 3:2. The advantage is that there is no composition on the market with this structure and in these concentrations, which, due to its synergism, targets multiple points of the cause of atopic dermatitis.

[0039] The subject preparation is in the form of an oil, which is administered orally, and not a capsule, both because of its volume and because it is more convenient for use in children aged 6+ months. The daily dose of the subject preparation is once a day, preferably in the evening after dinner, 1.25 ml of oil for children aged 6 months to 1 year. For children aged 1 to 3 years, as well as for children older than 3 years and adults, the daily dose is once a day, preferably after dinner, 2.5 ml of oil.

[0040] The preparation according to the present invention is used for the treatment of diseases and / or disorders of the skin, such as inflammation of the skin, itching, eczema, psoriasis, atopic dermatitis, especially atopic dermatitis.

[0041] EXAMPLE

[0042] Below example shows beneficial therapeutic effects on atopic dermatitis using the composition according to the present invention. This example is intended to illustrate the invention in more detail without in any way limiting the scope of claims.

[0043] The effect of the composition in the treatment of atopic dermatitis in children

[0044] In this example, the effectiveness of the subject preparation was tested on children suffering from atopic dermatitis. Children aged 1 to 7 years had been receiving subject preparation for 4 months. Children were divided into two groups. Group A represented the group of children who had been treated with the active preparation, i.e. the preparation of the subject invention, which is an oil containing the active components of purified fish oil, as a source of EPA and DHA, blackcurrant seed oil, as a source of GLA, vitamin D3, and the inactive components of MCT oil (medium-chain fatty acids) and natural lemon flavor. Group B represented the group of children who had been treated with oil without active ingredients - MCT and natural lemon flavor (placebo). This investigated the effect of omega-3 fatty acids (DHA and EPA), omega-6 fatty acids (GLA) and vitamin D3 on the clinical picture of atopic dermatitis. The following parameters were monitored: SCORAD (Severity SCORing Atopic Dermatitis) - a clinical tool used to determine (evaluate) the extent and severity of atopic dermatitis (0-70; >25-50 - moderately severe AD, >50-70 - severe form of AD), PO-SCORAD (Patient -Oriented SCORAD) - a tool for the self-assessment of the severity of the eczema or pediatric eczema by their parent (0- 70; >25-50 - moderately severe AD, >50-70 - severe form of AD), FLDQI (Family Dermatology Life Quality Index) - the most frequently used questionnaire for assessing the impact of the disease on family quality of life (0-30; >13 severe atopic dermatitis). Additionally, data on the level of itching (0-10), the severity of sleep disturbances (0-10) and the amount of topical corticosteroid use (g / month) were collected.

[0045] The Table shows findings that clearly indicate that there is a statistically significant difference between group A and group B in all the mentioned examined parameters. In group A, there was a significant clinical improvement of atopic dermatitis: a significant decrease in SCORAD and POSCORAD, and a significant increase in the quality of life assessment (FLDQI). Likewise, the level of itching decreased in children, and the level of sleep disturbances also decreased. There was also a significant reduction in the use of corticosteroids (by as much as 70%).

[0046] Table: Effectiveness of the subject preparation on the treatment of atopic dermatitis in children

[0047] Based on the presented findings, it is clear that the use of the subject preparation significantly improves the condition of children suffering from atopic dermatitis;

Claims

Patent claims1 . A preparation containing active components, characterized in that it contains omega-3 fatty acids from fish oil, omega-6 fatty acids from blackcurrant seed oil and vitamin D3.

2. The preparation according to claim 1 , characterized in that omega-3 fatty acids consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the ratio of 3:2, in the amount of 550 mg to 650 mg and 350 mg to 450 mg for EPA and DHA, respectively.

3. The preparation according to claim 1 , characterized in that the omega-6 fatty acid is gamma-linolenic acid (GLA) in the amount of 5 mg to 15 mg.

4. The preparation according to one of claims 1 to 3, characterized in that the ratio of EPA and GLA is 60:1.

5. The preparation according to claim 1 , characterized in that the amount of vitamin D3 ranges from 2.5 pg to 5.5 pg.

6. Use of the preparation containing fish oil, blackcurrant seed oil and vitamin D3 for the treatment and / or prevention of skin disorders in children.

7. Use according to claim 6, characterized in that the skin disorder is atopic dermatitis.

8. Use according to one of claims 6 to 7, characterized in that that said preparation is administered orally to children aged 6 months to 3 years.

Images