WO2008046606A2 - Topical composition for the treatment of eczema - Google Patents

Abstract

The invention relates to oil-free, topical compositions in a formulation based on water for use on the skin, comprising hyaluronic acid and/or the salts thereof and at least one electrolyte salt as a component and if applicable, chondroitin sulfate in a composition imitating the natural amniotic fluid. It is particularly suited for the treatment and prevention of eczema and especially of neurodermitis, of atopic eczema and of eczema of infants.

Description

 Topical composition for the treatment of eczema

The present invention relates to a topical composition in a water-based formulation suitable for application to the skin. This composition is particularly suitable for the treatment of eczema, and especially eczema, atopic dermatitis and infant eczema.

In Germany alone, around 6 million people suffer from atopic dermatitis and atopic eczema, especially in children and infants. The cause of this skin disease is still in the dark today; the treatment recommendations are therefore very broad and divergent. Atopic dermatitis, neurodermatitis, atopic dermatitis and infant eczema are at the heart of this disease.

Treatments to date have been multimodal, including external skin treatment, which may include sebostasis compensation, anti-porginous treatment of severe itching, anti-microbial treatment for superinfection, and anti-inflammatory treatment of chronic dermatitis (see review) by H. Ott and P. Höger, Treatment of Atopic Eczema in Children, Pediatric Practice 65, 445-458 (2004).

EP 0 715 852 A discloses the use of hyaluronic acid or its salt as an agent for the treatment of a skin disease selected from contact dermatitis, xerosis senilis, asteatosis, housekeeping eczema, keratosis, chronic eczema such as neurodermatitis, miliaria and diaper dermatitis. impact. As formulations mainly fat-based or fat / water or oil / water mixtures are described as the basis for the application of hyaluronate. In one example, an aqueous solution of sodium hyaluronate in purified water is described as an anti-miliaria or nappy rash.

Other hyaluronic acid and / or salt-containing compositions for skin application are known from US 5,631,242.

DE 102 38 161 A1 describes a mineral ampoule for the mucosal and topical application of active substance as an alternative to oral administration in order to create a possibility of mineral substance substitution. To improve the water binding capacity, the agent may contain hyaluronic acid and / or a salt thereof.

DE 10 2004 002 001 A1 describes the use of hyaluronic acid for the treatment of inflammatory diseases, in particular skin or mucous membrane diseases. Mention may also be made of additives such as e.g. 2- or 3-valent metal ions, which can cross-link and stabilize by chelation, on the other hand, can accelerate the degradation of the active hyaluronic acid.

US 2001/0036924 A1 discloses a chemical complex and a pharmaceutical composition containing this complex, wherein the treatment application mentioned is, inter alia, topical eczema. The chemical complex contains a special pyridinecarboxy derivative and a glycosaminoglycan such as hyluronic acid. Other constituents of the pharmaceutical carrier system include fats or fat-like substances and, as buffering agents, salts of sodium, potassium, aluminum, magnesium or calcium.

Sodium hyaluronate was also used in eye drops of BIO-Fi ^® brand.

The treatment applications used earlier and today have not been able to cure the symptoms of atopic dermatitis or atopic dermatitis satisfactorily.

The invention is therefore based on the object to improve the treatment of atopic dermatitis or atopic dermatitis.

The object is achieved by a fat-free, topical compositions in a water-based formulation suitable for application to the skin and having hyaluronic acid and / or its salt and at least one electrolyte salt as constituents and in a composition modeled on the natural amniotic fluid. It is particularly suitable for the treatment and prevention of eczema, and especially eczema, atopic dermatitis and infant eczema.

Surprisingly, it has been found that a combination of hyaluronic acid and / or its salt with at least one electrolyte salt as effective components achieves a marked improvement in affected skin areas of patients with atopic dermatitis. A surprisingly clear improvement already sets in after days of treatment.

It is believed that the reduction of active ingredients to the combination of hyaluronic acid and / or its salt and electrolyte salt in complete absence of fat, as well as a limited selection of optional further ingredients such as chon- droitinsulfat and optionally preservative in the treated patient an artificial amniotic fluid environment due to the similarity of the composition according to the invention with natural amniotic fluid contributes to the surprisingly good effect. In contrast, fat supplements, at least in amounts customary for skin formulations, can in addition irritate the skin and can also cause the skin to reduce or lose its own ability to produce fat. Instead, the combination of hyaluronic acid / hyaluronate and electrolyte salt achieves a combination effect which is believed to provide a water-retention effect in the skin and a water-repellent effect due to the application of electrolyte salt to the skin Inside the body, especially the underlying tissue in skin layers are pulled, which together strongly counteract the dryness in atopic dermatitis.

According to the invention, any known per se hyaluronic acid and / or its salt can be used. It may be of artificial and / or natural origin, due to a desired approximation and simulation to an amniotic fluid environment, the hyaluronic acid and / or its salt is preferably of natural origin. Particular preference is given to the selection of sodium hyaluronate. The molecular weight of the hyaluronic acid or the salt thereof can be chosen arbitrarily. Particularly good results were obtained with hyaluronic acid and / or its salt having an average molecular weight in the range of 2 × IU ⁶ to 3 × IU ⁶ . In order to avoid the risk of skin irritation as much as possible, the hyaluronic acid and / or its salt is preferably essentially protein-free and free of nucleic acids. For this purpose, the constituents mentioned are at most in an amount of 0.2%, preferably at most 0.1% and more preferably at most 0.05 wt .-%, based on the amount of in the Containing hyaluronic acid and / or its salt contained. Suitable amounts of hyaluronic acid and / or its salt can be suitably adjusted as needed, for example in an amount effective against eczema and in particular atopic dermatitis, but optionally also in a purely caring and, in particular, prophylactic use. The amount may also depend on whether a still to be diluted for the final use concentrate or an already dilute aqueous solution is provided. Suitable amounts are for example in the range of 0.0001 to 50 wt .-%, preferably in the range of 0.001 to 5.0 wt .-%, more preferably in the range of 0.01 to 3.0 wt .-% and in particular in the range of 0.05 to 1.0% by weight of the total composition.

For example, if the composition is in the form of a liquid or fluid, the amount of hyaluronic acid and / or its salt may be at least 0.001 mg / ml, preferably at least 0.1 mg / ml and especially at least 1 mg / ml.

By the term electrolyte salt is meant a compound which is capable of dissociating into ions, especially when dissolved in water. Suitable electrolytes are organic and in particular inorganic salts. Examples of organic salts are salts of organic acids, especially of naturally occurring skin acids, such as sodium, potassium and / or ammonium salts of citrate, lactate, bicarbonate, carbonate, citrate, acetate, propionate and the like. Examples of possible inorganic salts include, but are not limited to, sodium, potassium, calcium, magnesium, iron and / or ammonium salts of halide such as chloride, bromide and iodide, sulfate, sulfite, carbonate, hydrogen carbonate , Phosphate, hydrogen phosphate and / or silica. The electrolyte salt preferably contains at least one from the group consisting of sodium, potassium, calcium, magnesium, manganese, chloride, phosphate, hydrogen phosphate, carbonate and hydrogen carbonate. Suitably, the electrolyte salt is used in a mixture of different salts. Sea salt, for example salt from the Dead Sea, is particularly preferred in this sense.

The amount of electrolyte salt employed in the topical composition of the present invention can be varied as needed.

Suitable amounts of the electrolyte salt alone or in a mixture of different salts are for example in the range of 0.1 to 50 wt .-%, and preferably in the range of 1 to 30 wt .-% of the total composition. The amount can also be selected depending on the desired formulation depending on the application. For example, a concentrate formulated as a bath additive may contain higher levels of salt, for example, in the range of 10 to 50 and especially 20 to 30% by weight of the total composition, while in the case of a gel formulated for application to the skin, a lower Range of salt is selected, for example in the range of 0.1 to 10 wt .-% and in particular from 1 to 5 wt .-% of the total composition.

The composition is preferably and advantageously adjusted to have an overall hyperosmolarity. As a result, the composition is hyperosmolar to the tissue to be applied; the osmolarity of the composition is higher than that in the tissue affected by the application, and especially greater than the osmolarity prevailing in the skin. Preferably, the osmolarity is significantly higher, eg more than 20% higher, more than 50% higher or even more than 100% higher. If necessary, the osmolarity of the Composition even more than 5 times, possibly even more than 10 times de osmolarity of the affected tissue amount. This can be achieved particularly effectively that water from lower tissue regions or lower skin layers is drawn by osmosis to or under the skin surface. Thus, a beneficial effect on the water balance in the affected skin regions or the underlying tissue is exercised in an efficient manner. Combined with the hyaluronic acid or its salt, this effectively counteracts the dehydration of atopic dermatitis. Depending on your wishes, however, hyperosmolarity does not necessarily need to be respected.

A liquid component of the composition of the invention consists of a water base. Preferably, no further liquid components or solvents are used in addition to water. The water base is preferably pure water. The composition of the invention may also be lyophilized or dry and dissolved for application in the water base.

In addition to the constituents of the composition according to the invention already described, chondroitin sulfate can also be included in the composition according to the invention, since this substance is also suitable for a desired amniotic fluid simulation. As another optional additive which is advantageous for certain applications, the composition according to the invention may further be added with a preservative in a suitable amount, for example in a range from 0.0001 to 5% by weight, preferably from 0.001 to 1% by weight of the total composition become. Conventional preservatives can be used. A preferred preservative is benzalkonium chloride. In addition to the desired constituents of the composition according to the invention already mentioned, preferably no further components are used in the composition in order to come as close as possible to an artificial fruit water simulation and to avoid possible skin irritations and / or other unwanted side effects. Thus, it is preferred that the composition according to the invention does not contain any of the following components: fats, oils, waxes, silicones and silicone derivatives, cortisone, hydrocortisone or other cortisone derivatives, perfumes, antibiotics, dyes, pigments, thickeners, surface-active substances, emulsifiers, emollients Substances, osmolytes, alcohols, glycols, polyols, polymers, foam stabilizers and organic solvents.

A particularly suitable composition for the treatment of atopic dermatitis is defined as consisting exclusively of water, hyaluronic acid and / or its salt, the at least one electrolyte salt and optionally chondroitin sulfate and a substance selected from the group of preservatives. With regard to the appropriate quantities, reference is made to the respective description above.

With regard to a condition that is modeled on the amniotic fluid, the pH of the formulation of the composition according to the invention is preferably set in a range from 6.0 to 8.0 and more preferably in a range from 6.5 to 7.5.

The composition according to the invention can be used for cosmetic, nourishing, dermatological, therapeutic and / or prophylactic purposes.

Due to the effectiveness of the combination of hyaluronic acid and / or its salt and an electrolyte according to the invention salt in a fat-free composition, the composition according to the invention as described above is particularly suitable for the treatment of eczema, especially atopic dermatitis. Particularly good results have been obtained in the treatment of infant eczema in childhood patients, eg, up to the age of 16 years or less, including infants up to and including 3 years of age. An artificial simulation effect is most effective in toddlers of up to 1 year, especially at the age of 3 to 12 months.

The type of formulation is suitably adapted to the ingredients described above. Particular embodiments include, but are in no way limited to, a concentrate as a bath additive for bathing, or a water-based gel for application to the skin.

In another aspect, the composition of the present invention described above is included in a metering device for metering the composition into portions suitable for the desired application. The metering device suitably constitutes a container with an internal volume from which the material enclosed in the internal volume of the composition according to the invention can be at least partially removed. Suitable articles are, for example, a package (one or several common or separate packages of original packaging and possible refill packs), a tube, a can or other suitable container. The metering device according to the invention is preferably designed in the form of a dispenser, corresponding to known soap dispensers, for dispensing the composition in the form of a fluid. Further possible embodiments and modifications of the metering device described are readily possible. The following examples describe possible embodiments and in principle substantiate the effect of the composition according to the invention, without, however, limiting the invention to:

Example 1:

For a bath additive in the form of a concentrate, the following ingredients are mixed into a formulation:

sodium hyaluronate

(average molecular weight: 2,600,000, protein content: 0.01%, nucleic acid content 0.010 Abs. 260nm) 0.3g

Salt from the Dead Sea 80.0 g

Aqua purificata ad. 250.0 ml

Example 2:

For a gel for application to the skin, the following ingredients were mixed:

sodium hyaluronate

(average molecular weight:

2,600,000; Protein content: 0.01%; Nucleic acid content 0.010 Abs. 260nm) 332 mg

Salt from the Dead Sea 2.0 g

benzalkonium chloride,

50% aqueous solution 100 mg

Aqua purificata ad. 50.0 ml Example 3:

Formulations given in Example 1 and Example 2 were used to treat patients, with the results described below:

Patient # 1: male, age at diagnosis Eczema: 7 months; affected skin: face, trunk and arms and legs.

Severity of eczema at the beginning of treatment: score

4th

Severity after treatment after 10 days: Score 1. None

Side effects.

Patient # 2: female, age at diagnosis Eczema: 4 months; affected skin: face, neck, trunk, arms and legs.

Severity at the beginning of treatment: Score 3.

Severity after treatment after 9 days: Score 1.

Patient # 3: male, age at diagnosis Eczema: 5 months; affected skin: face, neck, trunk, arms and legs.

Severity at the beginning of treatment: score 5.

Severity after treatment after 10 days: Score 1.

To determine the effectiveness as stated above, the Investigators' Global Assessment (IGA) was used by default. The IGA is a six-step statistical index that serves to assess the overall severity of the inflammatory process (erythema, infiltration / papule formation). The IGA score ranges from 0 to 5 as follows: Sσore definition

0 = Healed No signs of inflammation

1 = Almost straight visible: healed • Erythema

• Papule formation / infiltration

2 = Mild mild:

Expression • weak erythema

• slight papule formation / infiltration

3 = Moderate Moderate: severity • moderate erythema

• medium paperboard formation / infiltration

4 = Heavy Heavy:

Expression • severe erythema

• strong papule formation / infiltration

5 = Very severe Very severe: severity • severe erythema

• severe papule formation / infiltration with oozing / crusting

Claims

claims 1. Fat-free topical composition in a water-based formulation suitable for application to the skin Hyaluronic acid and / or its salt and at least one electrolyte salt as constituents, wherein the composition is hyperosmolar. 2. Composition according to claim 1, characterized in that the electrolyte salt contains at least one constituent of the group consisting of sodium, potassium, calcium, magnesium, manganese, chloride, phosphate, hydrogen phosphate, carbonate, bicarbonate and sulfate. 3. Composition according to one of the preceding claims, characterized in that the electrolyte salt contains sea salt. 4. Composition according to one of the preceding claims, characterized in that the water base consists of pure water. 5. Composition according to one of the preceding claims, characterized in that it additionally contains chondroitin sulfate. 6. Composition according to one of the preceding claims, characterized in that the pH of the formulation is adjusted in the range of 6.0 to 8.0. Composition according to any one of the preceding claims, characterized in that it contains one, several or all the following ingredients are not included: fats, oils, urea, urea derivatives, glucose, waxes, silicones and silicone derivatives, cortisone, hydrocortisone or other cortisol derivatives, perfumes, antibiotics, dyes, pigments, thickeners, surfactants, emulsifiers, emollients, osmolytes, alcohols , Polyols, polymers, foam stabilizers and organic solvents. Composition according to any one of the preceding claims, characterized in that it consists exclusively of water, hyaluronic acid and / or its salt, the at least one electrolyte salt and optionally a substance selected from the group of preservatives. 9. Composition according to one of the preceding claims, characterized in that it contains benzalkonium chloride as a preservative. Composition according to any one of the preceding claims, characterized in that hyaluronic acid and / or its salt is selected from sodium hyaluronate. 11. Composition according to one of the preceding claims, characterized in that the hyaluronic acid and / or its salt is substantially protein-free and nucleic acid-free. 12. Composition according to one of the preceding claims, characterized in that it has a fluid state and the amount of hyaluronic acid and / or its salt is at least 1 mg / ml. 13. Using a combination of Hyaluronic acid and / or hyaluronate salt and an electrolyte salt in a non-fatty, hyperosmolar composition for the treatment of eczema. 14. Use according to claim 13 for the treatment of atopic dermatitis or other eczematous skin diseases.