DE102013211039A1 - Galenic formulation in colloidal form containing ceramide oligomers and their use - Google Patents

Abstract

The present invention relates to a formulation in colloidal form for topical application on and / or in the skin and / or appendages and / or mucous membranes, containing a lipophilic phase in an amount of 0.1-50 wt .-%, the one Hybrid molecule consisting of two lipids or lipid-analogous compounds from the group consisting of ceramides, sphingosines, phospholipids, glycolipids, fatty acids, sterols and their combinations, a mixture of surfactant and co-surfactant in an amount of 5-65% by weight and a hydrophilic phase, which contains suitable mixtures of cosolvents and water, in an amount of 20-95% by weight.

Description

The present invention relates to a formulation in colloidal form for topical application to and / or in the skin and / or skin appendages and / or mucous membranes, containing a lipophilic phase in an amount of 0.1-50 wt .-%, the Hybrid molecule of two lipids or lipid-analogous compounds from the group consisting of ceramides, sphingosines, phospholipids, glycolipids, fatty acids, sterols and combinations thereof, containing a mixture of surfactant and cosurfactant in an amount of 5-65% by weight and a hydrophilic phase containing suitable mixtures of cosolvents and water in an amount of 20-95% by weight.

Basically, all biological membranes, in particular cell membranes, contain as essential constituents so-called lipids and lipid-analogous substances which have structurally different structures, but which are similar in their basic construction. The basic similarity of the structure is that they are composed of a lipophilic (hydrophobic) and a hydrophilic (lipophobic) part of the molecule that they thus have a so-called amphiphilic structure, which is sometimes very pronounced.

The amphiphilic structure of the lipids and lipid-analogous substances, d. H. the simultaneous presence of a (strongly) hydrophobic and a hydrophilic, polar portion of the molecular structure, causes the lipids and lipid-analogous substances in an aqueous phase (usually together with other lipids) spontaneously to a lipid bilayer, a so-called Arrange "lipid bilayer", the u. a. represents the basis of the structure of biological membranes. The construction principle of this bilayer is the same for all lipids and lipid-analogous substances. They arrange themselves in two parallel, close together layers, whereby in each case the hydrophobic remainders of the concerning molecules lie directly opposite in the inside of the membrane and come into contact. They thus form the hydrophobic inner region of the membrane bilayer, while the hydrophilic radicals on both sides of the lipid bilayer are in contact with the aqueous phase of the extra and the intracellular space. The tendency to form this lipid bilayer exists both inside and outside an organism, e.g. In an aqueous system in which the properties of the lipid bilayers can be studied in dedicated experimental arrangements.

The group of lipids and lipid-analogous substances consists essentially of different ceramides with different structure (ceramide 1-9), free fatty acids (especially palmitic acid), cholesterol and various cholesterol esters, such as. B. cholesterol sulfate together.

In the case of ceramides, the lipophilic region consists of the alkane radical of the sphingosine basic structure and the fatty acid radical (acyl radical) coupled to the NH group of sphingosine, while the hydrophilic region is defined by the two OH groups and by the -NH-CO structure of the Sphingosine body is formed.

In the case of the phospholipids, the lipophilic region consists of the two alkane radicals of the fatty acids bonded in the 2- and 3-positions of glycerol via an ester bond, while the hydrophilic region consists of the glycerol and the phosphate group bonded in the 1-position of the glycerol and of the phosphate group bound further components serine, ethanolamine, choline and inositol is formed.

In the case of glycolipids (cerebrosides), the lipophilic region consists of the alkane radical of the sphingosine basic structure and the alkane or alkene radical of the fatty acid bound to the NH ₂ group, while the hydrophilic region is formed by the two OH groups and by the NH-CO structure of the sphingosine main body and by the attached to the hydroxymethylene monosaccharide unit is formed.

In the case of straight-chain, unbranched saturated and unsaturated fatty acids such. As the palmitic acid and linoleic acid, the hydrophobic molecular region consists of the alkane or alkene residue of the fatty acid, while the hydrophilic portion is a carboxyl group.

In the case of cholesterol and its esters as well as lanosterol and sitosterol, the lipophilic part of the molecules consists of the cyclopentanoperhydrophenanthrene skeleton with the branched aliphatic side chain attached in position 17, while the hydrophilic structure is the OH group in position 3 of the ring system, which may also be esterified with the highly hydrophilic sulfate.

The structure of the lipid bilayer in an organism is spontaneously formed. Although it has a considerable stability, z. For example, in the presence of a lipid metabolic disorder, the possibility that a biological membrane loses some of its lipid components because these molecules are either too slow and / or inadequately formed or metabolized too rapidly. As a result, the respective membranes impoverish the respective components, which u. a. leads to a disruption of the membrane structure and function.

However, the physiological composition of the membrane lipids of the stratum corneum of the human skin is still of vital importance for the normal structure and function of the skin for a second reason.

The presence of sufficient levels of these lipids assures the unrestricted ability of the skin to bind a physiological amount of water. The loss of part of the stratum corneum lipids therefore leads to a restriction of the water-binding capacity, which can be determined clinically by the so-called corneometry. Furthermore, in the course of lipid loss, the so-called trans epidermal water loss (TEWL) of the skin increases. This manifests itself in the appearance of a "dry" and wrinkled skin, which occurs esp. Frequently, but not exclusively, in older age.

A well-known example of such changes is the depletion of the stratum corneum lipid bilayers of human skin on ceramides. For example, in the case of atopic dermatitis in the skin of the patients, low levels of, inter alia, ceramide 3, ceramide 4, ω-hydroxyceramides ( Macheleidt O, Kaiser HW and Sandhoff K (2002): J Invest Dermatol 119 (1): 166-173 ) and sphingosine.

• • Atopische Dermatitis
• • ”trockene” Haut-Xerose, Xerodermie
• • dyshidrotisches Ekzem
• • chronisches kumulativ-toxisches Kontaktekzem
• • alternde Haut
• • durch UV-Licht stark beanspruchte Haut
• • Sebostase
• • Verhornungsstörungen
• • Diabetes-bedingte Hautschäden

As numerous other scientific publications of recent years show, various skin lesions and skin diseases are based on changes not only in the ceramide but in the entire lipid composition of the stratum corneum layer of the human skin. These changes lead to a more or less reduced water-binding capacity and to a limited barrier function of the affected skin areas for water, ie to an increase in the TEWL value ( McIntosh TJ, Stewart ME, Downing DT (1996): Biochemistry 35 (12): 3,649-3,653 ; Coderch L, de Pera M, Perez-Cullell N, Estelrich J, de la Maza A, Parra JL (1999): Skin Pharmacol Appl Skin Physiol 12 (5): 235-246 ). Skin changes and skin diseases of this kind are, for example:

• • Atopic dermatitis
• • "dry" skin xerosis, xerodermia
• • dyshidrotic eczema
• • Chronic cumulative toxic contact dermatitis
• • aging skin
• • skin exposed to UV light
• • Sebostasis
• • Cornification disorders
• • Diabetes-related skin damage

Especially in the field of clinical medicine, it is desirable in the mentioned cases of diseases, the structure of the present in the organism biological membrane, i. e. the lipid bilayers to suitably alter and / or stabilize.

According to recent findings on the pathomechanism of atopic dermatitis ( Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G (2002): J Invest Dermatol 119 (2): 433-439 ) and related diseases, the cause of the susceptibility of the skin in the case of such a disease, among other things, an altered lipid metabolism or reduced lipid content of the stratum corneum. In addition to ceramide metabolism, these changes include fatty acid metabolism. Low levels of free fatty acids were found in atopic dermatitis, but also in other skin diseases such as psoriasis, (lamellar) ichthyosis and contact dermatitis in the skin of patients ( Pilgram GS, Vissers DC, van der Meulen H, Pavel S, Lavrijsen SP, Bouwstra JA, Koerten HK (2001): J Invest Dermatol 117 (3): 710-717 ); Man MQM, Feingold KR, Thornfeldt CR, Elias PM (1996): J Invest Dermatol 106 (5): 1096-1101 ; Mao-Qiang M, Elias PM, Feingold KR (1993): J Clin Invest 92: 791-798 ; Mao-Qiang M, Jain M. Feingold KR, Elias PM (1996): J Invest Dermatol 106 (1): 57-63 ; Velkova V, Lafleur M (2002): Chem Phys Lipids 117 (1-2): 63-74 ,

Today's possibilities to alleviate the symptoms and consequences of the above-mentioned skin diseases, esp. Of atopic dermatitis (a cure is currently out of the question) are still very limited. The topical use of special glucocorticoids and immunosuppressive agents is associated with considerable risks due to the toxicity of these substances. Certain corticoids even cause a downright counterproductive effect, leading to a loss of lipids, esp. Of ceramides, cholesterol and free fatty acids.

In view of the current state of knowledge about the importance of a physiological lipid composition of the stratum corneum membranes, it is logical that attempts are made to compensate for the deficiencies of membrane lipids present in the stratum corneum by exogenous delivery. In practice, therefore, trying with the help of ointments, creams and the like, the missing lipids, z. As ceramides and free fatty acids, the changed or diseased skin supply. This is done, for example, by specifically formulated lipid preparations, u. a. using liposomes as a vehicle to transport the lipids into the skin. Numerous products are now on the market for cosmetic purposes and for the treatment of these skin diseases.

• • Das Ausmaß des Heilerfolgs ist nicht so groß, dass von einer vollständigen Gesundung der erkrankten Haut gesprochen werden kann.
• • Um einen einigermaßen akzeptablen Heilerfolg an der Haut über einen längeren Zeitraum zu gewährleisten, müssen die genannten Lipide und Lipid-analogen Substanzen in kurzen Zeitabständen permanent der Haut zugeführt werden, d. h. die eingesetzten Wirksubstanzen zeigen keine nachhaltige Wirksamkeit.

The therapeutic measures described here can certainly be regarded as fundamentally correct, since they logically attempt to compensate for the existing deficits of the stratum corneum on lipids and lipid-analogous substances. However, the experience gained during the last few years with these therapeutic measures shows that, despite the fact that the therapeutic approach is in principle correct, the results of these cosmetic and medical treatments are by no means convincing. In part, the success of the measures carried out is uncertain or unsustainable. Even if an approximately acceptable success of the curative treatment arises, such a treatment has at least two serious disadvantages:

• • The extent of the healing success is not so great that one can speak of a complete recovery of the diseased skin.
• • To ensure a reasonably acceptable healing success on the skin over a longer period of time, the said lipids and lipid-analogous substances must be permanently supplied to the skin at short intervals, ie the active substances used show no lasting effectiveness.

Both disadvantages are due to a common cause. These lipids are not static components of the skin, but they are intermediates of a reaction sequence in which the lipids required by the skin z. B. be provided by syntheses of the organism or from the diet and incorporated into the biological membrane. After performing their function as a membrane component of the stratum corneum they are then introduced into specific degradation reactions of the organism.

This reaction sequence represents a flow equilibrium in which a certain amount of said components is synthesized by the action of certain enzymes and released from the membrane after a certain residence time in the membrane, in order then to be eliminated via enzyme-controlled metabolic degradation processes. There is thus a certain throughput of substance. The exogenously supplied as Hauttherapeutica lipids are introduced into this reaction sequence. If there is a priori disturbance of this reaction sequence, which then leads to a pathologically reduced lipid composition of the stratum corneum, it can be expected that the exogenous supply of lipids in the form of a therapeutic agent can fundamentally change nothing or not at this pathological condition, since the exogenously added lipid portion is metabolized by the organism in the same way as is the case with the endogenously present lipid portion.

Healing success therefore, with the currently available therapeutic options, depends to a great extent on the fact that the therapeutic substitutes in question are able to penetrate the skin more quickly than they are introduced into the existing physiological degradation steps and that they last for a longer period of time, in extreme cases lifelong , fed continuously.

The present problem is not easily solved. The rate of uptake of lipids and lipid-analogous substances into the stratum corneum is subject to certain physiological and physical-chemical or biochemical limits, e.g. B. with regard to the rate of diffusion of the cosmetic and therapeutic active substances. This speed can not be increased arbitrarily. On the other hand, the lipid-synthesizing and lipid-degrading enzymes involved in the aforementioned reaction sequences are not or not without serious problems in the sense of an increase (synthesizing enzymes) or a reduction in their activity (metabolizing enzymes) to influence by exogenous measures.

The first-mentioned therapeutic approach, ie the activation of lipid-synthesizing enzymes by exogenous active substances (eg nicotinamide), is only possible to a limited extent and has hitherto been achieved only in vitro ( Tanno O, Ota Y, Kitamura N, Katsub T, Inoue S (2000): British J Dermatol 143 (3): 524-531 ). The second therapeutic approach, ie, the inhibition of lipid-metabolizing enzymes by exogenous drugs has apparently not yet been successful, since apparently inhibitors of lipid-metabolizing enzymes with sufficiently high specificity do not exist.

Since lipids or lipid-analogous compounds are often very difficult to incorporate into cosmetic and dermatopharmaceutical formulations, there is an urgent need for suitable formulations which allow sufficient penetration into the human stratum corneum. This problem is particularly acute in hybrid molecules consisting of two lipids or lipid-analogous compounds, since these are rigid as extremely lipophilic lipids and therefore both difficult to incorporate into galenic formulations and do not penetrate from classic semi-solid formulations into the stratum corneum.

It was therefore an object of the present invention to provide a galenic formulation for lipid or lipid-analogous compounds which has good penetrating properties in the stratum corneum.

This object is achieved by the galenic formulation having the features of claim 1. The further dependent claims show advantageous embodiments. Claims 16 and 17 indicate uses according to the invention.

• a) ein Hybridmolekül aus zwei Lipiden oder Lipid-analogen Verbindungen aus der Gruppe bestehend aus Ceramiden, Sphingosinen, Phospholipiden, Glykolipiden, Fettsäuren, Sterolen und deren Kombinationen, wobei die Lipide oder Lipid-analogen Verbindungen über ihr lipophiles Ende miteinander verknüpft sind, in einer Konzentration von 0,001–5 Gew.-%,
• b) eine Mischung aus Tensid und Cotensid in einer Menge von 5–65 Gew.-%,
• c) eine lipophile Phase in einer Menge von 0,1–50 Gew.-% und
• d) eine hydrophile Phase in einer Menge von 20–95 Gew.-%.

The invention relates to a galenic formulation in colloidal form for topical application to the skin and / or mucous membrane, which contains the following components:

• a) a hybrid molecule of two lipids or lipid-analogous compounds from the group consisting of ceramides, sphingosines, phospholipids, glycolipids, fatty acids, sterols and combinations thereof, wherein the lipids or lipid-analogous compounds are linked together via their lipophilic end, in one Concentration of 0.001-5% by weight,
• b) a mixture of surfactant and cosurfactant in an amount of 5-65% by weight,
• c) a lipophilic phase in an amount of 0.1-50 wt .-% and
• d) a hydrophilic phase in an amount of 20-95 wt .-%.

According to the invention, it is thus proposed that the topical formulation in colloidal form consists of four essential constituents. It thus contains a ceramide or a ceramide mixture, a lipophilic, a mixture of surfactant and cosurfactant and a hydrophilic phase.

The proposed colloidal carrier systems showed a greatly improved bioavailability of incorporated ceramides in the galenic target compartment lower stratum corneum (stratum compactum) with unusually good skin compatibility compared to previously known vehicle systems. The ceramide-containing systems formed spontaneously at unexpectedly low surfactant / cosurfactant levels.

The hybrid molecules of two lipids or lipid-analogous compounds are preferably selected from the group consisting of ceramides, sphingosines, phospholipids, glycolipids, fatty acids, sterols and combinations thereof, wherein the lipids or lipid-analogous compounds are linked together via their lipophilic end.

• • Die grundsätzliche Struktur der eingesetzten Lipide oder Lipid-analogen Substanzen, welche die Ausbildung der Lipid-Doppelmembran ermöglicht, bleibt nicht nur erhalten, sondern die Fähigkeit zur Ausbildung der Doppelmembran wird verstärkt, weil die durch die genannten Erkrankungen geschädigte Haut ohnehin nur eine eingeschränkte Fähigkeit zum Aufbau und zum Erhalt der physiologischen Lipid-Doppelmembran besitzt.
• • Die Struktur der eingesetzten Lipide oder Lipid-analogen Substanzen wird bei erhaltener Grundstruktur so verändert, dass sie nur noch in geringerem Umfang als Substrate der in der Haut, speziell im Stratum corneum, vorhandenen metabolisierenden Enzyme fungieren können. Dies bedeutet, dass sie in deutlich geringerem Umfang als die originären Lipide oder Lipid-analogen Substanzen in die jeweiligen enzymatischen Reaktionsfolgen eingeschleust werden und somit als wesentliche strukturelle Bestandteile des Stratum corneum über einen längeren Zeitraum als die originären Lipide bzw. Lipid-analogen Substanzen erhalten bleiben.
• • Die Abänderung der Molekülstruktur erfolgt jedoch andererseits nur in einem so geringen Umfang, dass durch den geringen stoffwechselbedingten Um- oder Abbau der zugeführten Lipid-Hybridmoleküle solche Substanzen entstehen, die den körpereigenen Lipiden oder Lipid-analogen Substanzen möglichst ähnlich sind. Auf diese Weise wird die Gefahr erheblich verringert, dass Stoffwechselprodukte mit toxischer Wirkung entstehen.
• • Eine vergleichsweise geringe, steuerbare Abbaubarkeit der Lipid-Hybridmoleküle wird dadurch erreicht, dass die kovalente Bindung zwischen den beiden originären Lipidmolekülen über ein Sauerstoffatom erfolgt. Dieses Sauerstoffatom wirkt als metabolische Sollbruchstelle, da z. B. Cytochrom-P₄₅₀-abhängige mischfunktionelle Monooxygenasen die in unmittelbarer Nachbarschaft zum Sauerstoffatom stehenden Kohlenstoffatome oxidativ angreifen, was zu einem Auseinanderbrechen des Hybridmoleküls unter Bildung der ω-hydroxylierten originären Lipide führt.

The contained hybrid molecules according to the invention have the following properties:

• • The basic structure of the lipids or lipid-analogues used, which allows the formation of the lipid double membrane, not only remains, but the ability to form the double membrane is enhanced because the damaged skin by the aforementioned diseases anyway only a limited ability for building and maintaining the physiological lipid double membrane possesses.
• • The structure of the lipids or lipid-analogous substances used is modified so that they can function only to a lesser extent as substrates of existing in the skin, especially in the stratum corneum, existing metabolizing enzymes. This means that they are introduced to a much lesser extent than the original lipids or lipid-analogous substances in the respective enzymatic reaction sequences and thus remain as essential structural components of the stratum corneum over a longer period of time than the original lipids or lipid-analogous substances ,
• On the other hand, the modification of the molecular structure only takes place to such a small extent that, owing to the low metabolic change or degradation of the lipid hybrid molecules supplied, substances which are as similar as possible to the body's own lipids or lipid-analogous substances are formed. In this way the risk of metabolic toxicity is significantly reduced.
• • A comparably low, controllable degradability of the lipid hybrid molecules is achieved by covalent bonding between the two original lipid molecules via an oxygen atom. This oxygen atom acts as a metabolic predetermined breaking point because z. For example, cytochrome P ₄₅₀ -dependent mixed-function monooxygenases oxidatively attack the carbon atoms in the immediate vicinity of the oxygen atom, which leads to a breakup of the hybrid molecule to form the ω-hydroxylated original lipids.

These properties are realized according to the invention as follows. The coupling of two lipid molecules to lipid hybrid molecules ensures that such a molecule is degraded or rebuilt by the enzymes of the lipid metabolism present in the organism much more slowly than is the case for the original lipids. The molecular enlargement associated with the covalent bond between two lipid molecules leads to a strong reduction of the enzymatically controlled metabolization, because with the well-known substrate specificity of most enzymes, the (approximate) doubling of the size of the lipid molecule significantly decreases the rate of lipid turnover or lipid degradation.

On the other hand, the resulting degradation products are so similar in their general structure to the naturally occurring secondary products of the lipid metabolism that a Infiltration into the corresponding reaction sequences after a slow-running degradation of the active substances according to the invention is possible without problems. In addition, it is not to be expected in any way that the lipid hybrid molecules have a relevant toxicity because of the great similarity with the original lipid molecules.

A certain degree of the enzymatic metabolization of the lipid hybrid molecules, which, however, is to be regarded as significantly lower than that of the monomeric lipid molecules, is thus a property of the molecule which is desirable for pharmacokinetic and pharmacodynamic reasons, because this ensures better the controllability of the therapy than if no metabolic degradation would be possible.

Some controlled rate of metabolism of the lipid hybrid molecules can be achieved by having an oxygen atom between the two lipid molecules coupled to each other. The carbon atoms adjacent to this oxygen atom may be enzymatically hydroxylated, such as by the cytochrome P ₄₅₀ -dependent mixed-function monooxygenases. Such hydroxylation occurring in the immediate vicinity of the oxygen atom leads to the formation of unstable compounds having a hemiacetal structure which decompose into the corresponding reaction products. The one reaction product is a lipid molecule with ω-standing OH group, the other reaction product is a lipid molecule with ω-standing aldehyde function, which is further oxidized to the carboxylic acid group. It thus becomes apparent that oxidative biochemical degradation of the described lipid hybrid molecules gives rise to reaction products which are very similar to the starting compounds of the original lipid molecules.

Another essential aspect of the pathogenesis of the abovementioned skin changes or skin diseases is the reduced water-binding capacity of the skin tissue, in particular in the region of the stratum corneum. Physiologically, the water is not incorporated within, but because there are several parallel lipid layers in the space between the individual lipid bilayers. This is due to the fact that the interior of the lipid bilayer is composed of the highly hydrophobic fatty acid residues, while the medium outside the lipid bilayer is hydrophilic in nature. Storage of water in the hydrophobic inner regions of the lipid double membrane is practically impossible.

The skin changes and diseases mentioned above are due, on the one hand, to the loss of part of the lipids from the parallel lipid bilayers and, on the other, to the partial loss of water from the hydrophilic interlayers located between these bilayers. The aim of the therapeutic measures in these diseases is thus not only the reconstruction and stabilization of the lipid bilayers themselves, as is done with the aid of the above-described lipid hybrid molecules, but also the structure and stabilization of a pronounced hydrosphere on the surface of the lipid -Doppelschicht, which are crucial for the water binding capacity of the skin.

The lipids from the group of ceramides preferably consist of the compounds hitherto described in the scientific literature: ceramide-1 (ceramide EOS), ceramide-2 (ceramide NS), ceramide-3 (ceramide NP), ceramide-4 (ceramide EOH) , Ceramide-5 (ceramide AS), ceramide-6 (ceramide AP), ceramide-7 (ceramide AH), ceramide-8 (ceramide NH) and ceramide-9 (ceramide EOP) and the corresponding ω-hydroxyceramides. The said ceramides, however, do not constitute uniform substances with a precisely defined relative molar mass, but each ceramide represents a family of compounds with different lengths of the amide-like fatty acid present in the molecule and / or of the alkyl radical present in the sphingosine fraction.

The lipids from the group of sphingosine derivatives are preferably the sphingosine itself and the sphingomyelin, which have structural similarity with the ceramides.

The lipids from the group of phospholipids are preferably the phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol.

The lipids from the group of glycolipids are preferably the cerebrosides with the sphinosine skeleton and a sugar residue (glucose or galactose) and the complex glycolipids with up to seven sugar residues, which are called gangliosides.

The lipid-analogous substances from the group of fatty acids preferably consist of palmitic acid, stearic acid or oleic acid or of other saturated or unsaturated monocarboxylic acids having a chain length between 10 and 40 carbon atoms. The fatty acids are preferably selected from the group consisting of n-hexadecanoic acid (palmitic acid, C ₁₅ H ₃₁ -COOH), n-dodecanoic acid (lauric acid, C ₁₁ H ₂₃ -COOH), n-tetradecanoic acid (myristicin, C ₁₃ H ₂₇ -COOH ), n-octadecanoic acid (stearic acid, C ₁₇ H ₃₅ -COOH), n-Eico-sansäure (arachic acid, C ₁₉ H ₃₉ -COOH), n-tetracosanoic acid (lignoceric acid, C ₂₃ H ₄₇ -COOH), 9- Hexadecenoic acid (palmitoleic acid, C ₁₅ H ₂₉ -COOH), 9-octadecenoic acid (oleic acid, oleic acid, C ₁₇ H ₃₃ -COOH), 9,11-octadecadienoic acid (C ₁₇ H ₃₁ -COOH), 9,12-octadecadienoic acid (linoleic acid, C ₁₇ H ₃₁ -COOH), 9,12,15-octadecatrienoic acid (linolenic acid, C ₁₇ H ₂₉ -COOH), 5,8,11,14,17-eicosapentaenoic acid ("EPA", C ₁₉ H ₂₉ -COOH), 4,7,10,13,16,19-docosahexaenoic acid ("DHA", C ₂₁ H ₃₁ -COOH), decanoic acid (C ₁₀ H ₂₁ -COOH), octacosanoic acid (C ₂₈ H ₅₇ -COOH) and 9-octacosenoic acid ( C ₂₈ H ₅₅ -COOH).

The lipid-analogous substances from the group of sterols are preferably the cholesterol, cholesterol sulfate and various cholesterol esters as well as other sterols such as lanosterol and sitosterol.

Biological membranes are structurally lipid double membranes in which the lipophilic areas of the membrane-forming lipids, including the ceramides, are arranged in the interior of the membrane, resulting in a general structure in which the hydrophilic areas of the molecules on the membrane surface are the extra or the Intracellular space facing. in the general structure of the membrane lipids HO-MemLipid-CH ₃ the OH group indicates the hydrophilic region of the respective lipid, e.g. For example, the OH groups contained in the sphingosine structure of the ceramides or the OH group in the 3-position of the cholesterol molecule or the OH group in the carboxyl function of the fatty acids (such as, for example, palmitic acid). The indicated CH ₃ group denotes the hydrophobic region of the membrane lipid concerned, z. Example, the alkane or alkene radical of the amide-like bound fatty acid in the ceramides, the branched alkyl side chain of the cholesterol molecule or the alkane or alkene radical of a fatty acid.

Between the lipophilic areas of the lipid molecules act relatively weak molecular forces of attraction, so-called van der Waals forces. The forces are large enough to give the membrane a certain stability, which u. a. It can be seen that the structure of the membrane is formed spontaneously. On the other hand, the forces on the other hand are not so great that they could counteract a (in particular disease-related) partial loss of lipids from the membrane.

However, the loss of lipid from the membrane can be effectively reduced or prevented if not only van der Waals forces act between the lipophilic regions of certain lipid molecules, but if they are linked by a covalent bond, as indicated in the next scheme is. This scheme describes a lipid double membrane in which membrane lipids ("MemLipid") are incorporated, each having a covalent bond between the two lipophilic ends of the lipid molecules. From the schematic representation of such a link HO-MemLipid-CH ₂ -CH ₂ -MemLipid-OH shows that the linkage of two identical lipid molecules to the dimer or two different lipid molecules to the so-called. Lipid hybrid molecule via the two terminal CH ₃ groups of the respective lipid monomers takes place. The two OH groups of the resulting compound characterize the two hydrophilic regions at the ends of the dimer or lipid hybrid molecule.

Because of the (low) metabolism desired under point 4 of the above requirements, it is advisable to insert an oxygen atom between the two lipid molecules to be joined. This results in the following structure: HO-MemLipid-CH ₂ -O-CH ₂ -MemLipid-OH

Due to the covalent bond within the lipid hybrid molecules now present, the stability of this membrane structure to the normal biological membrane structure increases considerably.

In aging skin and various skin diseases, however, not only is a partial lipid loss of the lipid layers present in the skin occurring, but there is also a reduced water-binding capacity or an increased transepidermal water loss (TEWL) of different skin layers.

The advantage of the colloidal system of the invention lies in particular in the composition of exclusively dermatologically very well-tolerated ingredients, in relatively low emulsifier concentrations and in the small particle size of the dispersed lipophilic phase.

There are different connection variants for the formation of the hybrid molecules depending on the respective lipids.

In the case of ceramides and glycolipids (cerebrosides), covalent bonding takes place either via the alkyl chain of the sphingosine basic structure or via the fatty acid radical or via the combination of the two points of attack, in the case of the fatty acids via the alkyl group on the alkyl chain, in the case of sterols and their derivatives (esters) via one of the two terminal methyl groups of the branched in position 17 of the sterol structure Alkyl chain and in the case of phospholipids on the respective terminal methyl group of one of the two standing in the 2-position or 3-position of glycerol fatty acid residues or the combination of both points of attack.

Another preferred variant provides that the lipids or lipid-analogous compounds are connected via a spacer. The spacer preferably consists of at least one atom selected from the group consisting of carbon, nitrogen or oxygen or combinations thereof. Particularly preferably, the spacer consists of an oxygen atom or an -O- (CH ₂ ) _n -O group with n = 1 to 20.

Essential for the formation of colloidal carrier systems is the surfactant-cosurfactant mixture, which is used at 5-65 wt .-%, preferably 15-30 wt .-%. From a material point of view, combinations of different skin-compatible surfactants, in particular selected from the group consisting of fatty alcohols, glycerol fatty acid esters, polyglycerol fatty acid esters, Polyoxyethylenfettsäureester, Polyoxyethylenfettsäureglyceride, Zuckerfettsäureester, especially sucrose fatty acid esters and alkylpolyglycosides, sorbitan fatty acid esters, Polyoxyethylenfettalkoholether, poloxamers, cholesterol preferred. The mixing ratio of surfactant to cosurfactant is preferably 0.5-3.5 for surfactant and 1.5-4.5 for the cosurfactant, more preferably preferably 1: 4 to 1: 2 and especially 1: 3.

Also included is a hydrophilic phase, e.g. B. composed of alcohols, glycols, polyols or liquid macrogols and water or buffer, individually or in combination, preferably from a mixture of 1,2-pentanediol and water in a mass ratio of 20: 1 to 2: 1, preferably 15: 1 to 5: 1, more preferably 10: 1. The proportion of 1,2-pentanediol is 10-70 wt .-%, preferably 50 wt .-% and that of the water is 1-50 wt .-%, preferably 5-15 wt .-%.

The preparation of the colloidal carrier systems takes place in which the lipid or the lipid mixture is dissolved in either the lipophilic phase or in the cosolvents (glycols or polyols). Thereafter, surfactant and cosurfactant are dissolved in the mixture of lipophilic phase and cosolvents. The water content is mixed with the water-soluble cosolvents (glycols or polyols) and, by vigorous shaking, the lipophilic phase containing the surfactant mixture is incorporated into the hydrophilic phase.

The lipophilic phase consists in this system of a skin-friendly oil, especially from medium-chain triglycerides, fatty oils, especially native vegetable oils such. As olive oil or avocado oil. The lipophilic and at the same time colloidal phase is present at 0.1-50% by weight, with 5% by weight being preferred.

Preferably, the lipophilic phase is a liquid synthetic wax, in particular isopropyl palmitate, isopropyl myristate, oleyl oleate, decyl oleate, ethyl oleate and an unsaturated fatty acid, in particular linoleic acid or oleic acid in a mass ratio of 20: 1 to 1:20, preferably from 10: 1 to 1: 1 and more preferably 5: 1.

According to the invention, the above-described galenic formulation can be used as a medicament, in particular for the treatment of diseases in which there is a disturbance of the lipid composition of the cell membranes of an organism with regard to their content of lipids or lipid-analogous substances.

Also, the galenical composition of the present invention can be used for the treatment of diseases in which there is a disturbance in the composition of the lipid bilayers of the stratum corneum of the skin in terms of its content of lipids or lipid-analogous substances.

Another use of the galenical composition according to the invention relates to the preparation of cosmetic preparations, in particular as a microemulsion.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited non-patent literature

• Macheleidt O, Kaiser HW and Sandhoff K (2002): J Invest Dermatol 119 (1): 166-173 [0013]
• McIntosh TJ, Stewart ME, Downing DT (1996): Biochemistry 35 (12): 3,649-3,653 [0014]
• Coderch L, de Pera M, Perez-Cullell N, Estelrich J, de la Maza A, Parra JL (1999): Skin Pharmacol Appl Skin Physiol 12 (5): 235-246 [0014]
• Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G (2002): J Invest Dermatol 119 (2): 433-439 [0016]
• Pilgram GS, Vissers DC, van der Meulen H, Pavel S, Lavrijsen SP, Bouwstra JA, Koerten HK (2001): J Invest Dermatol 117 (3): 710-717 [0016]
• Man MQM, Feingold KR, Thornfeldt CR, Elias PM (1996): J Invest Dermatol 106 (5): 1096-1101 [0016]
• Mao-Qiang M, Elias PM, Feingold KR (1993): J Clin Invest 92: 791-798 [0016]
• Mao-Qiang M, Jain M. Feingold KR, Elias PM (1996): J Invest Dermatol 106 (1): 57-63 [0016]
• Velkova V, Lafleur M (2002): Chem Phys Lipids 117 (1-2): 63-74 [0016]
• Tanno O, Ota Y, Kitamura N, Katsube T, Inoue S (2000): British J Dermatol 143 (3): 524-531 [0024]

Claims (17)

Galenic formulation in colloidal form containing: a) a hybrid molecule of two lipids or lipid-analogous compounds from the group consisting of ceramides, sphingosines, phospholipids, glycolipids, fatty acids, sterols and combinations thereof, wherein the lipids or lipid-analogous compounds are linked together via their lipophilic end, in one Concentration of 0.001-5% by weight, b) a mixture of surfactant and cosurfactant in an amount of 5-65% by weight, c) a lipophilic phase in an amount of 0.1-50 wt .-% and d) a hydrophilic phase in an amount of 20-95 wt .-%. Galenic formulation according to claim 1, characterized in that the ceramide molecules are selected from the group consisting of ceramide-1, ceramide-2, ceramide-3, ceramide-4, ceramide-5, ceramide-6, ceramide-7, ceramide -8, ceramide-9 and their ω-hydroxyceramides. Galenic formulation according to one of the preceding claims, characterized in that the lipids or lipid-analogous compounds are covalently linked to each other via their lipophilic end. Galenic formulation according to one of the preceding claims, characterized in that the covalent bonding of the lipids or lipid-analogous compounds via their lipophilic end in the case of ceramides and glycolipids (cerebrosides) either via the alkyl chain of the sphingosine skeleton or via the fatty acid residue or the combination of the two points of attack, in the case of the fatty acids via the methyl group on the alkyl chain, in the case of sterols and their derivatives (esters) via one of the two terminal methyl groups of the branched alkyl chain in position 17 of the sterol structure and in the case of the phospholipids on the respective terminal methyl group of one of the two standing in the 2-position or 3-position of glycerol fatty acid residues or via the combination of both points of attack takes place. Galenic formulation according to one of the preceding claims, characterized in that the lipids or lipid-analogous compounds are connected via a spacer. Galenic formulation according to the preceding claims, characterized in that the spacer consists of at least one atom selected from the group consisting of carbon, nitrogen or oxygen or combinations thereof or contains. Galenic formulation according to the preceding claims, characterized in that the spacer preferably consists of an oxygen atom or an -O- (CH ₂ ) _n -O-group with n = 1 to 20. Galenic formulation according to one of the preceding claims, characterized in that the surfactant and / or cosurfactant is selected from the group consisting of fatty alcohols, glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid glycerides, sugar fatty acid esters, especially sucrose fatty acid esters and alkylpolyglycosides, sorbitan fatty acid esters, polyoxyethylene fatty alcohol ethers, poloxamers, Cholesterol and lecithin. Galenic formulation according to one of the preceding claims, characterized in that the surfactant-cosurfactant mixture in a mass ratio of 0.5-3.5 for surfactant and 1.5-4.5 for the cosurfactant, is used. Galenic formulation according to one of the preceding claims, characterized in that the surfactant-cosurfactant mixture consists of polyglycerol fatty acid esters in a mass ratio of 1: 1. Galenic formulation according to one of the preceding claims, characterized in that the hydrophilic phase is selected from alcohols, glycols, polyols or liquid macrogols and water or buffer. Galenic formulation according to claim 11, characterized in that the hydrophilic phase consists of a mixture of 1,2-pentanediol and water in a mass ratio of 20: 1 to 2: 1, preferably 15: 1 to 5: 1 and particularly preferably 10: 1, consists. Galenic formulation according to one of the preceding claims, characterized in that the lipophilic phase medium-chain triglycerides, fatty oils, especially native vegetable oils such. B. olive oil or avocado oil are included. Galenic formulation according to one of the preceding claims, characterized in that the lipophilic phase is a liquid synthetic wax, in particular isopropyl palmitate, isopropyl myristate, oleyl oleate, decyl oleate, ethyl oleate and an unsaturated fatty acid, in particular linoleic acid or oleic acid, in a mass ratio of 20: 1 to 1:20 , preferably from 10: 1 to 1: 1 and more preferably 5: 1 is included. Galenic formulation according to one of the preceding claims as a medicament, in particular for the treatment of diseases in which a disorder of the lipid composition of the cell membranes of an organism in terms of their content of lipids or lipid-analogous substances, or of diseases in which there is a disturbance of the composition of the lipid bilayers of the stratum corneum of the skin in terms of their content of lipids or lipid-analogous substances , Use of the galenic formulation according to claims 1 to 14 for topical application to the skin and / or nail and / or hair and / or mucous membrane. Use of the galenic formulation according to claims 1 to 14 for the preparation of cosmetic preparations, in particular in the form of a microemulsion.